Embed Size (px)
Citation preview
UNIVERSITY OF OULU P .O. Box 8000 F I -90014 UNIVERSITY OF OULU FINLAND
A C T A U N I V E R S I T A T I S O U L U E N S I S
University Lecturer Tuomo Glumoff
University Lecturer Santeri Palviainen
Postdoctoral research fellow Sanna Taskila
Professor Olli Vuolteenaho
University Lecturer Veli-Matti Ulvinen
Planning Director Pertti Tikkanen
Professor Jari Juga
University Lecturer Anu Soikkeli
Professor Olli Vuolteenaho
Publications Editor Kirsti Nurkkala
ISBN 978-952-62-1682-9 (Paperback)ISBN 978-952-62-1683-6 (PDF)ISSN 0355-3221 (Print)ISSN 1796-2234 (Online)
U N I V E R S I TAT I S O U L U E N S I S
MEDICA
ACTAD
D 1434
AC
TAA
nja Hulkko
OULU 2017
D 1434
Anja Hulkko
THE ASSOCIATION OF LIFETIME ANTIPSYCHOTIC AND OTHER PSYCHIATRIC MEDICATIONS WITH COGNITION IN SCHIZOPHRENIA
THE NORTHERN FINLAND BIRTH COHORT1966 STUDY
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU,FACULTY OF MEDICINE;MEDICAL RESEARCH CENTER OULU;OULU UNIVERSITY HOSPITAL
ACTA UNIVERS ITAT I S OULUENS I SD M e d i c a 1 4 3 4
ANJA HULKKO
THE ASSOCIATION OF LIFETIME ANTIPSYCHOTIC AND OTHER PSYCHIATRIC MEDICATIONS WITH COGNITION IN SCHIZOPHRENIAThe Northern Finland Birth Cohort 1966 Study
Academic dissertation to be presented with the assentof the Doctoral Training Committee of Health andBiosciences of the University of Oulu for public defencein Auditorium 1, Building PT1 of the Department ofPsychiatry (Peltolantie 17), on 10 November 2017, at12 noon
UNIVERSITY OF OULU, OULU 2017
Copyright © 2017Acta Univ. Oul. D 1434, 2017
Supervised byDocent Erika JääskeläinenProfessor Jouko MiettunenProfessor Matti Isohanni
Reviewed byProfessor Annamari Tuulio-HenrikssonDoctor Jan-Henry Stenberg
ISBN 978-952-62-1682-9 (Paperback)ISBN 978-952-62-1683-6 (PDF)
ISSN 0355-3221 (Printed)ISSN 1796-2234 (Online)
Cover DesignRaimo Ahonen
JUVENES PRINTTAMPERE 2017
OpponentAssistant Professor Olli Kampman
Hulkko, Anja, The association of lifetime antipsychotic and other psychiatricmedications with cognition in schizophrenia. The Northern Finland Birth Cohort1966 StudyUniversity of Oulu Graduate School; University of Oulu, Faculty of Medicine; MedicalResearch Center Oulu; Oulu University HospitalActa Univ. Oul. D 1434, 2017University of Oulu, P.O. Box 8000, FI-90014 University of Oulu, Finland
Abstract
Antipsychotic medication forms the basis of the long-term, even lifelong treatment ofschizophrenia. Antipsychotic polypharmacy and adjunctive psychiatric medications are alsocommon treatment strategies. The long-term effects of psychiatric medication, especially oncognition in schizophrenia, are largely unknown. Cognitive impairment is a central, persistingsymptomatic feature during the lifespan course of schizophrenia and a key predictor of functionaloutcome. This naturalistic study aimed to analyse how the lifetime exposure to antipsychotic,benzodiazepine and antidepressant medications, and lifetime trends in antipsychotic use, wereassociated with cognition in early midlife in schizophrenia. Non-psychotic controls were includedas a reference group of normative cognitive performance.
The study samples consisted of 40–60 subjects with schizophrenia and 73–191 non-psychoticcontrols from the Northern Finland Birth Cohort 1966. Data on the lifetime use of medicationswere collected from medical records, registers and interviews and connected with informationfrom extensive psychiatric and neurocognitive assessments at the ages of 34 and 43 years.
Higher cumulative lifetime exposure to antipsychotics was associated with poorer verballearning and memory at 34 years of age, a decline in verbal learning and memory between the agesof 34 and 43 years and poorer global cognition at the age of 43 years in schizophrenia. A relativelylong antipsychotic-free period before the cognitive assessment was associated with better globalcognition at 43 years of age. Other lifetime trends in antipsychotic use, antipsychoticpolypharmacy or cumulative benzodiazepine or antidepressant exposures were not associated withglobal cognition.
This naturalistic study was the first to report an association between higher cumulative lifetimeantipsychotic exposure and poorer cognition in early midlife in schizophrenia, which was notlikely confounded by the use of other psychiatric medications or illness-related factors. Thoughresidual confounding is still possible, these results suggest that high-dose long-term antipsychotictreatment may have some influence on the clinical course of schizophrenia, possibly byattenuating cognitive recovery. More research on the long-term effects of psychiatric medicationsis needed to develop the safe and effective treatment of schizophrenia.
Keywords: antidepressants, antipsychotics, benzodiazepines, cognitive decline,cognitive performance, schizophrenia
Hulkko, Anja, Elinaikaisen psykoosilääkityksen ja muun psyykenlääkityksenyhteys kognitioon skitsofreniassa. Pohjois-Suomen vuoden 1966 syntymä-kohorttitutkimusOulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta; Medical ResearchCenter Oulu; Oulun yliopistollinen sairaalaActa Univ. Oul. D 1434, 2017Oulun yliopisto, PL 8000, 90014 Oulun yliopisto
Tiivistelmä
Psykoosilääkitys on skitsofrenian pitkäaikaisen, jopa elinikäisen hoidon perusta. Useiden psy-koosilääkkeiden yhtäaikaiskäyttö ja muiden psyykenlääkkeiden oheiskäyttö ovat yleisiä hoito-strategioita. Psyykenlääkkeiden pitkäaikaisvaikutuksia etenkin kognitioon skitsofreniassa tunne-taan huonosti. Kognitiiviset puutokset ovat keskeinen, elinaikaisesti pysyvä skitsofrenian oire-piirre ja merkittävimpiä ennustetekijöitä. Tämän naturalistisen tutkimuksen tavoite oli analysoi-da elinaikaisen psykoosi-, bentsodiatsepiini- ja masennuslääkealtistuksen sekä elinaikaisten psy-koosilääkkeiden käytön trendien yhteyttä kognitioon varhaisessa keski-iässä skitsofreniassa. Ei-psykoottiset verrokit toimivat normatiivisen kognitiivisen suorituskyvyn vertailuryhmänä.
Tutkimusaineisto koostui Pohjois-Suomen vuoden 1966 syntymäkohorttiin kuuluvista 40 ja60 henkilöstä, joilla oli skitsofrenia, sekä 73 ja 191 ei-psykoottisesta verrokista. Tiedot psyyken-lääkkeiden elinaikaiskäytöstä kerättiin sairauskertomuksista, rekistereistä ja haastatteluista, ja neyhdistettiin 34 ja 43 vuoden iässä tehtyihin laajoihin psykiatrisiin ja neuropsykologisiin tutki-muksiin.
Korkeampi kumulatiivinen elinaikainen psykoosilääkealtistus oli yhteydessä heikompaankielelliseen muisti- ja oppimissuoriutumiseen 34-vuotiaana ja sen suurempaan laskuun 34 ja 43ikävuoden välillä sekä heikompaan kognitioon 43-vuotiaana skitsofreniassa. Suhteellisen pitkäpsykoosilääketauko ennen neuropsykologista tutkimusta oli yhteydessä parempaan kognitioon43-vuotiaana. Muut elinaikaisen psykoosilääkityksen käytön trendit, psykoosilääkkeiden yhtäai-kaiskäyttö tai elinaikainen kumulatiivinen bentsodiatsepiini- tai masennuslääkealtistus eivätolleet yhteydessä kognitioon.
Tämä naturalistinen tutkimus kuvasi ensimmäisenä yhteyden suuremman kumulatiivisenelinaikaisen psykoosilääkealtistuksen ja heikomman kognition välillä varhaisessa keski-iässäskitsofreniassa. Muiden psyykenlääkkeiden käyttö tai sairauteen liittyvät tekijät eivät näyttäneetsekoittavan tätä yhteyttä. Vaikka on mahdollista, että kaikkia sekoittavia tekijöitä ei pystyttyhuomioimaan, tulosten perusteella korkea-annoksinen, pitkäaikainen psykoosilääkitys saattaavaikuttaa skitsofrenian taudinkulkuun heikentämällä kognitiivista toipumista. Lisätutkimustapsyykenlääkityksen pitkäaikaisvaikutuksista tarvitaan skitsofrenian turvallisen ja tehokkaan hoi-don kehittämiseksi.
Asiasanat: bentsodiatsepiinit, kognitiivinen suoriutuminen, kognitiivisen suoriutumisenmuutos, masennuslääkkeet, psykoosilääkkeet, skitsofrenia
To my loving parents
8
9
Acknowledgements
For as long as I can remember I have been concerned about what is real and true.
To me, existence has always seemed to be filled with mystery and wonder, as have
human beings and their interactions with so much more than meets the eye. My
childhood dreams of being an explorer of the universe or nature turned into an even
greater fascination for human beings and their minds as I grew older. In medical
school I naturally drifted towards psychology and psychiatry. Ever since I started
specialising in psychiatry, I knew I had found my professional passion and identity.
My search into myself, as well as the external reality, has taken me to many
uncomfortable places and revealed more uncertainty and complexity than clarity. It
has made me hold to the scientific method as the most reliable source of knowledge
in many questions, but also made me value many aspects of human experience and
reality that cannot rightfully be described or contained by it. Simultaneously, in
taking my first steps as a researcher I have pursued becoming a psychiatrist and an
integrative cognitive analytic psychotherapist. It is hard to tell, which path I will
focus on in the future, but I hope to continue somehow being a clinician-scientist.
This doctoral study started from a presentation in the specialising doctors’
meeting organised by the Department of Psychiatry of Oulu University Hospital
and University of Oulu. While digging deeper into how antipsychotic medications
affect the brain under the guidance of Professor (now emeritus) Matti Isohanni, he
invited me to join his research project in the Department of Psychiatry, University
of Oulu, in 2012. The possibility to study an interesting topic in a highly
accomplished, international research group with financial support inspired and
enabled me to start and carry out this work. Above all, the warm, personal support
and friendship of my supervisors, Adjunct Professor Erika Jääskeläinen, Professor
Jouko Miettunen and Professor (emeritus) Isohanni have motivated and kept me
going. I am deeply grateful to each of you for your hard work, personal investment
and for being able to benefit and learn from your expertise, experience and wisdom.
This doctoral research was carried out at the Research Unit of Clinical
Neuroscience, University of Oulu. Most of the work was done at the Department
of Psychiatry, Oulu University Hospital. I warmly think of many people in that
place, where my career in psychiatry started. I owe my deepest gratitude to
Professor Juha Veijola and Adjunct Professor Outi Saarento for the excellent
research facilities. I am also very thankful to Jani Moisala, Niina Keränen and other
staff at the department for their help, I often could not have managed without.
10
I highly appreciate the mentoring and discussions as a medical student with the
supervisor of my advanced studies thesis, Professor (emeritus) Karl-Erik Wahlberg,
on schizophrenia, adoptive family study and family therapy traditions of Oulu, not
to forget our roots in the Torne Valley. I have had the priviledge to learn from and
enjoy the company of so many skilled professionals, superiors and specialists,
fellow psychiatric residents and many excellent nurses and personnel. I wish to
especially thank my senior Tuula de Bruijn for her guidance in treating psychosis
patients and my mentor Piia Sankelo for her counsel and trust in me. However, the
most unforgettable lessons I have learned from my patients, to whom I wish to
express my highest regard.
I wish to express my gratitude to late Professor Paula Rantakallio (1930–2012)
and Professor Marjo-Riitta Järvelin for their fundamental work with the Northern
Finland Birth Cohort 1966, which has enabled me to use this extensive database as
a study material. I also wish to acknowledge the work of all the professionals who
have been involved with collecting and managing the data of the NFBC1966.
I am grateful to the co-authors of the original publications for their valuable
contribution and expertise. My warmest gratitude goes to Professor Peter Jones for
the original idea of this research design and to Graham Murray, M.D., PhD and
Jennifer Barnett, PhD, at the University of Cambridge, who kindly guided me and
arranged time to meet me in the beginning of this project in the UK. All of your
high expertise and native language skills advanced every article. I owe my gratitude
to Jani Moilanen, M.D., PhD for his important work with antipsychotic medication
data and Irina Rannikko, PhD for her neuropsychological expertise and patient
consultation and help. I wish to thank my statistical experts, Marianne Haapea, PhD
and Riikka Marttila, M.Sc. for your highly important part in making sure our results
were reliable, and how much fun it has been working with you. I wish to express
my thanks to Professor Anne Remes for her neurological expertise and Sanna
Huhtaniska, M.D. for her understanding of neuroimaging. I owe my deepest
gratitude to Professor Hannu Koponen for his psychopharmacological knowledge
and his practical help, Piia Frondelius and Kirsi Varmo in arranging research
facilities for the last year of this work at the Clinical Research Institute HUCH Ltd
in Helsinki.
I wish to thank the members of our research group for being such a friendly
and supportive community, and excellent company on many conference trips and
social gatherings. Sharing our doubts and triumphs, and seeing many of you defend
your work has encouraged me tremendously. I would especially like to thank Teija
Juola for your help and warmness, and Tanja Nordström and Heli Lehtiniemi for
11
your important work with the data. I am also grateful for the opportunity to use the
facilities at the Center for Life Course Health Research, University of Oulu.
I owe my deepest gratitude to my follow-up group, Professor Pirkko Riipinen,
Helinä Hakko, PhD and Kristiina Moilanen, M.D., PhD, who gave me warm and
professional feedback and guidance in the different phases of my doctoral studies.
I wish to express my high regard and gratitude for the pre-examiners, Professor
Annamari Tuulio-Henriksson and Jan-Henry Stenberg, PhD, for your constructive
and encouraging feedback and expertise, which have improved and ensured the
quality of this study. I am deeply thankful to Louise Morgan for her excellent work
in correcting the language of this thesis. Finally, I owe my deepest gratitude to
Assistant Professor Olli Kampman, who has agreed to be my honorable opponent.
I wish to acknowledge the following foundations and institutions, who have
financially supported my doctoral research: Medical Research Center Oulu at Oulu
University Hospital and University of Oulu, The Faculty of Medicine at the
University of Oulu, H. Lundbeck A/S, The Foundation of Emil Aaltonen, The
Finnish Psychiatric Association, The Finnish Cultural Foundation Lapland
Regional Fund, The Foundation of Jalmari and Rauha Ahokas, The Memorial
Foundation of Maud Kuistila, The Academy of Finland and The Sigrid Juselius
Foundation, as well as The Oulu Duodecim Society and University of Oulu
Graduate School for supporting my conference presentations.
I warmly remember the people and friends I met, when in the beginning of this
project I spent the autumn semester 2012 at the Newbold College of Higher
Education in England. I am especially grateful to Helen and Mike Pearson for your
personal, philosophical and spiritual support and wisdom.
My beloved parents, I thank you from the bottom of my heart for your endless
love, care, appreciation and presence in my life. Since I was a little girl I have been
inspired by your desire and commitment to educate yourselves, even though your
path was not as smooth as mine, and how you have continued learning and
following your time until old age. You are my examples in how to lead this life, get
things done, be responsible, trustworthy and persistent. You have always believed
my dreams were possible, supported me in every decision and most constantly
loved me. I am incredibly grateful for being allowed to have you by my side so far
and share the biggest moments of my life with you.
My dear siblings, despite living mostly quite separate lives, I would like you
to know that my heart has always been filled with a little sister’s love and adoration
for who you are. I hope to get to know you even better and I cherish having you
and all of my wonderful nieces, nephews and all of your families in my life.
12
My dear friends from the north, I cannot begin to express all of what you mean
to me. My brother Esa, and my dearest Tanja, Maria, Heidi, Mari and Kristina, in
different phases of life you have been my companions and soulmates. You are the
ones I have grown up to be my adult self with. You and your spouses and children
have been and are my family. I am deeply indebted to you for your kindness and
support during the doctoral studies, especially for those countless times you have
welcomed me to stay in your homes, accommodated and fed me. I also highly
appreciate my old and new friends in Helsinki, and the heartfelt CAT community,
who give me so much joy and a sense of belonging.
My dear mother- and father-in-law, sisters- and brothers-in-law and your lovely
children, in the relatively short time we have known each other I have come to
highly respect and love each and every one of you. I am very grateful that you have
welcomed and accepted me so well, and I am most happy to belong to your family.
My most beloved husband, when I started this project, I had no idea of you.
You have transformed my life in so many ways, including my family name. It was
quite a start for our marriage to have your wife spend all the days and evenings
writing her compilation thesis out of nothing. It was the best part of the day to be
back with you, as it always is. You are the best company, support and motivation
for everything. It is the greatest blessing and happiness to have found you and to
share my life with you, my kind, loving, sophisticated linguist-theologian soulmate.
Finally and above all, I would like to thank and praise my Lord and Saviour
Jesus, to whom I am forever indebted for everything.
Helsinki, September 2017 Anja Hulkko
13
Abbreviations
AIM Abstraction, Inhibition and Working Memory
APA American Psychiatric Association
ATC Anatomical Therapeutic Chemical classification
CGI Clinical Global Impression
CPZ chlorpromazine
CRCH Care Register for Health Care
CVLT California Verbal Learning Test
DDD defined daily dose
DSM Diagnostic and Statistical Manual of Mental Disorders
D2 dopamine 2 receptor
ECT electroconvulsive treatment
ICD International Classification of Diseases
IQ intelligence quotient
NFBC1966 Northern Finland Birth Cohort 1966
NICE National Institute for Health and Care Excellence
PANSS Positive and Negative Syndrome Scale
RCT randomised controlled trial
SCID The Structured Clinical Interview for DSM disorders
SMR Standardised Mortality Ratio
SOFAS Social and Occupational Functioning Assessment Scale
VOLT Visual Object Learning Test
WHO World Health Organization
14
15
Main definitions
Adherence The extent to which a medication is used
according to prescription.
Antidepressants A class of medications used to treat
depressive disorders according to their
main indication.
Antipsychotic polypharmacy The simultaneous use of two or more
antipsychotic agents.
Antipsychotics A class of medications used to treat
psychotic symptoms and disorders.
Atypical antipsychotics Antipsychotic medications with serotonin
dopamine antagonism and a
pharmacological profile including effects
for positive psychotic symptoms, low
extrapyramidal symptoms and less
hyperprolactinemia than with typical
agents.
Benzodiazepines A class of medications with sedative,
sleep-inducing, anxiolytic, anticonvulsant
and muscle relaxant effects.
Chlorpromazine equivalent Dose equal to 100 mg of chlorpromazine.
Chlorpromazine equivalent dose-year A measure of cumulative exposure to
antipsychotic medication equivalent of
using 100 mg of chlorpromazine per day
for a year.
Cognitive functions Separable, interrelated mental processes
related to acquisition, processing, storing
and acting on information, such as
attention, memory, verbal skills,
visuospatial functions, processing speed
and executive functions.
Cognitive impairment/deficit Difficulty or reduction in global
cognitive performance or specific
cognitive ability.
Defined daily dose An average daily dose of a medication
used for its main indication in adults
16
based on global health statistics
evaluated by the WHO.
Defined daily dose year A measure of cumulative exposure to
medication equivalent of using one
defined daily dose per day for a year.
Effect size A quantitative measure of the strength of
an association between two variables or
groups.
Global cognition A concept which contains general
cognitive performance combining
performances on several, local cognitive
functions.
Intelligence quotient A total score derived from several
standardised neuropsychological tests
designed to assess human intelligence.
Maintenance treatment Continuous long-term treatment with
antipsychotics.
Neuropsychological assessment Tasks designed to assess specified
cognitive functions administered in a
standardised manner defined in a test
manual.
Practice effect Improvement observed in repeated
cognitive test performance due to
practice and learning instead of actual
cognitive improvement.
Typical antipsychotics Antipsychotic medications with the
primary pharmacological property of
dopamine 2 receptor antagonism
resulting in alleviation of positive
psychotic symptoms but also with many
side-effects.
17
List of original publications
This thesis is based on the following publications, which are referred to throughout
the text by their Roman numerals:
I Husa, A. P., Rannikko, I., Moilanen, J., Haapea, M., Murray, G. K., Barnett, J., Jones, P. B., Isohanni, M., Koponen, H., Miettunen, J., & Jääskeläinen, E. (2014). Lifetime use of antipsychotic medication and its relation to change of verbal learning and memory in midlife schizophrenia – An observational 9-year follow-up study. Schizophrenia Research 158(1–3):134–141. doi: 10.1016/j.schres.2014.06.035
II Husa, A. P., Moilanen, J., Murray, G. K., Marttila, R., Haapea, M., Rannikko, I., Barnett, J. H., Jones, P. B., Isohanni, M., Remes, A. M., Koponen, H., Miettunen, J., & Jääskeläinen, E. (2017). Lifetime antipsychotic medication and cognitive performance in schizophrenia at age 43 years in a general population birth cohort. Psychiatry Research 247:130–138. doi: 10.1016/j.psychres.2016.10.085
III Hulkko, A. P., Murray, G. K., Moilanen, J., Haapea, M., Rannikko, I., Jones, P. B., Barnett, J. H., Huhtaniska, S., Isohanni, M. K., Koponen, H., Jääskeläinen, E. & Miettunen, J. (2017). Lifetime use of psychiatric medications and cognition at 43 years of age in schizophrenia in the Northern Finland Birth Cohort 1966. European Psychiatry 45: 50–58. doi: 10.1016/j.eurpsy.2017.06.004
Reprinted with permission from Elsevier (I, II, III). Original publications are not
included in the electronic version of the dissertation.
18
19
Contents
Abstract
Tiivistelmä
Acknowledgements 9 Abbreviations 13 Main definitions 15 List of original publications 17 Contents 19 1 Introduction 23 2 Schizophrenia 25
2.1 Diagnosis of schizophrenia ..................................................................... 25 2.1.1 Schizophrenia spectrum disorders ................................................ 26
2.2 Symptoms of schizophrenia .................................................................... 27 2.3 Epidemiology of schizophrenia ............................................................... 31
2.3.1 Incidence and prevalence ............................................................. 31 2.3.2 Outcome and mortality ................................................................. 31
2.4 Aetiology of schizophrenia ..................................................................... 32 2.4.1 The genetic basis of schizophrenia ............................................... 33 2.4.2 Environmental risk factors ........................................................... 33 2.4.3 Aetiological hypotheses and models ............................................ 34
2.5 Neurobiological models of schizophrenia ............................................... 35 2.6 Structural and functional neuroimaging findings in schizophrenia ......... 37 2.7 Neurocognition in schizophrenia ............................................................ 37
2.7.1 Longitudinal course of cognition in schizophrenia during
the lifespan ................................................................................... 38 2.8 Treatment of schizophrenia ..................................................................... 41
2.8.1 Psychosocial treatment ................................................................. 41 2.8.2 Pharmacological treatment ........................................................... 42
2.9 Research on schizophrenia, antipsychotics and cognition in the
Northern Finland Birth Cohort 1966 ....................................................... 47 3 Psychiatric medications and cognition in schizophrenia 49
3.1 Antipsychotic medication and cognition in schizophrenia ...................... 49 3.1.1 Cognition in drug-naïve and medicated persons .......................... 50 3.1.2 Clinical trials on antipsychotics and cognition ............................. 50 3.1.3 Longitudinal studies on antipsychotics and change of
cognition ....................................................................................... 52
20
3.1.4 Antipsychotic dose and cognition ................................................. 58 3.1.5 Antipsychotic polypharmacy and cognition ................................. 59 3.1.6 Methodological challenges in studying the cognitive
effects of antipsychotic medications in schizophrenia ................. 59 3.2 Benzodiazepines and cognition in schizophrenia .................................... 61 3.3 Antidepressants and cognition in schizophrenia ..................................... 62 3.4 Cognitive effects of other medications in schizophrenia ......................... 64 3.5 Summary of previous studies on psychiatric medications and
cognition in schizophrenia ...................................................................... 65 4 Aims and hypotheses of the study 69
4.1 Aims of the study .................................................................................... 69 4.2 Hypotheses of the study .......................................................................... 69
5 Material and methods 71 5.1 The Northern Finland Birth Cohort 1966 ................................................ 71 5.2 Participant identification ......................................................................... 71
5.2.1 Psychiatric baseline study at the age of 34 years (Study I) ........... 71 5.2.2 Psychiatric follow-up study at the age of 43 years (Studies
I–III) ............................................................................................. 72 5.2.3 Study samples ............................................................................... 73
5.3 Data on psychiatric medications ............................................................. 76 5.3.1 Collection of medication data ....................................................... 76 5.3.2 Classification of medications ........................................................ 77 5.3.3 Definitions of the dose of medication ........................................... 77 5.3.4 Descriptions of psychiatric medication variables (Studies
I–III) ............................................................................................. 80 5.4 Neuropsychological assessment .............................................................. 82
5.4.1 California Verbal Learning Test .................................................... 82 5.4.2 Other cognitive measures ............................................................. 84 5.4.3 Global cognitive performance ...................................................... 86
5.5 Background variables and covariates ...................................................... 88 5.6 Statistical methods .................................................................................. 89
6 Ethical considerations and personal involvement 91 6.1 Ethical considerations ............................................................................. 91 6.2 Personal involvement .............................................................................. 91
7 Results 93 7.1 Characteristics of the samples (I–III) ...................................................... 93 7.2 The current and lifetime use of psychiatric medications (I-III) ............... 95
21
7.3 Cognitive performance at the baseline and follow-up (I–III) .................. 98 7.4 Cumulative exposure to antipsychotics and verbal learning and
memory at the baseline (I)....................................................................... 99 7.5 Cumulative exposure to antipsychotics and change in verbal
learning and memory between the baseline and follow-up (I) .............. 101 7.6 The current use of psychiatric medications and global cognition
at the 43-year study (III) ....................................................................... 104 7.7 Lifetime cumulative exposure to antipsychotics and global
cognitive performance at the 43-year study (II, III) .............................. 104 7.8 Lifetime trends in use of antipsychotics and global cognition at
the 43-year study (III) ........................................................................... 108 7.9 Lifetime cumulative exposure to benzodiazepines and
antidepressants and global cognition (III) ............................................. 109 8 Discussion 111
8.1 Main findings ........................................................................................ 111 8.1.1 Cumulative exposure to antipsychotics and baseline
performance and change in verbal learning and memory ........... 111 8.1.2 Cumulative lifetime antipsychotic exposure and global
cognition ..................................................................................... 112 8.1.3 Lifetime trends and timing of antipsychotic use,
antipsychotic polypharmacy and global cognition ..................... 112 8.1.4 Cumulative exposure to benzodiazepines and
antidepressants and global cognition .......................................... 113 8.2 Comparison with earlier research .......................................................... 113
8.2.1 Cognitive impairment and course of cognition in
schizophrenia and controls ......................................................... 113 8.2.2 Antipsychotic medication and cognition in schizophrenia ......... 114 8.2.3 Benzodiazepines and antidepressants and cognition in
schizophrenia .............................................................................. 117 8.3 Mechanisms of the cognitive effects of medications ............................ 119 8.4 Antipsychotic medication, cognition and brain changes ....................... 121 8.5 Antipsychotic medication, cognition and outcome ............................... 122 8.6 Strengths and limitations ....................................................................... 123
8.6.1 Strengths ..................................................................................... 123 8.6.2 Limitations.................................................................................. 125
9 Conclusions 127 9.1 Main conclusions .................................................................................. 127
22
9.2 Clinical implications ............................................................................. 127 9.3 Future research ...................................................................................... 128
References 131 Original publications 153
23
1 Introduction
Schizophrenia is one of the most serious and challenging illnesses facing humanity.
It is among the leading causes of disability (Vos et al., 2015) and associated with
marked personal suffering and stigma (Mestdagh & Hansen, 2014), increased
morbidity and mortality (Saha, Chant, & McGrath, 2007), impaired social and
occupational functioning, and reduced quality of life (Harvey, 2014). The personal
and societal economic burden due to schizophrenia is enormous (Chong et al.,
2016).
The treatment of schizophrenia has been transformed in many ways since the
discovery of antipsychotic medications in the 1950s. Due to antipsychotics, many
more people with schizophrenia achieve remission (Green, 2016). However, the
recovery rate in schizophrenia has not improved over the past decades
(Jääskeläinen et al., 2013).
Since the first scientific formulations, impaired cognition has been in the focus
when determining schizophrenia (Green & Harvey, 2014). Cognition refers to
functions of the mind related to information processing. Cognitive functions, such
as the ability to make perceptions, focus attention, think, understand and express
oneself with language, learn and remember, are essential to humanity. Cognitive
abilities have been advantageous in adaptation to present circumstances, likely
playing a role in the success of the human species, Homo sapiens (wise or knowing
human). Cognitive functions, such as attention, memory and executive functioning,
are essential for independent everyday functioning and surviving the demands of
working life. In the information society, cognitive abilities have a higher role than
ever in enabling an involved and meaningful life.
Cognitive impairment is the most stable and constant feature of schizophrenia
during the lifespan (Keefe, 2014). Mild developmental deviations (Howes &
Murray, 2014) and cognitive deficits often emerge during the childhood of persons
who will later develop schizophrenia, and during the most intense adolescent years
of growth and acquisition of cognitive skills development lags further behind
(Reichenberg et al., 2010). Cognitive deficits go through further decline before or
during the onset of illness (Bora & Murray, 2014; de Paula, Hallak, Maia-de-
Oliveira, Bressan, & Machado-de-Sousa, 2015; Mollon & Reichenberg, in press).
However, neurocognitive deficits established by the first psychosis seem to mostly
follow a relatively stable trajectory during adulthood (Szöke et al., 2008) and old
age (Irani, Kalkstein, Moberg, & Moberg, 2011). Varying courses are also observed
(Bozikas & Andreou, 2011), though, reflecting the heterogeneous
24
neurodevelopmental and neurodegenerative processes involved in schizophrenia
(Pino et al., 2014; Rund, 2014).
The goal in the treatment of schizophrenia has shifted from remission to
recovery (www.psychiatry.org/psychiatrists/practice/professional-interests/
recovery-oriented-care). Neurocognitive impairment has re-emerged as the focus
of extensive research in schizophrenia during recent decades, because impairments
in neurocognition and social cognition seem, to a great extent, to account for the
poor outcome still associated with schizophrenia (Green, 2016).
Despite optimism of neuroprotective or neurogenesis promoting qualities of
atypical antipsychotics and antidepressants, possibilities of neurocognitive
enhancers and cognitive remediation associated with quantifiable changes in the
brain (Thorsen, Johansson, & Løberg, 2014), cognitive impairments have proven
to be particularly resistant, especially to drug treatment. Besides inefficacy,
concerns have been raised about the adverse effects of psychopharmacological
treatment, particularly due to associations of antipsychotics with structural brain
changes, and adverse cognitive effects with anticholinergic treatment of
neurological side-effects of typical antipsychotics and the long-term use of
benzodiazepines.
An additional, essential, angle in the treatment of schizophrenia is its long
duration, often starting early in the course of life and continuing until old age. The
effects of various illness processes, treatments and lack of appropriate treatments,
as well as associated adversities during the long-term, often lifelong course of
schizophrenia, are highly complex. Clinical treatment trials, mostly lasting from
weeks to some months, can poorly elucidate the long-term effects of psychiatric
medications, which remain largely unknown in schizophrenia (Leucht et al., 2012;
Vernon et al., 2014).
This naturalistic study aims to find further understanding of the associations
between long-term psychopharmacological treatment and cognitive impairment in
schizophrenia, focusing especially on the mainstay treatment, antipsychotic
medication.
25
2 Schizophrenia
Schizophrenia is a serious, psychotic syndrome with multiple causes, presentations,
courses and outcomes. Rather than one distinct illness, schizophrenia may perhaps
be more accurately conceptualised as several disorders, which have various clinical
manifestations (Tandon, Keshavan, & Nasrallah, 2008). The interplay of multiple
genetic and environmental factors underlies the etiopathological process leading to
heterogeneous phenotypes, in which the thoughts, affects and behaviour of an
individual with schizophrenia are often markedly affected (Kahn et al., 2015).
Schizophrenia can present itself as one psychotic episode, but most often it has a
chronic course with various phases and trajectories (American Psychiatric
Association [APA], 2010). Despite the development of treatments, schizophrenia
is associated with substantial morbidity and mortality (Saha et al., 2007), as well
as personal and societal costs (Chong et al., 2016).
2.1 Diagnosis of schizophrenia
Accounts of mental illness and psychoses can be found throughout recorded history.
In the late nineteenth and early twentieth centuries psychiatrists, such as Emil
Kraepelin and Eugen Bleuler, started characterising psychiatric disorders. The first
coordinated diagnostic manual for exclusively psychiatric disorders, the Diagnostic
and Statistical Manual of Mental Disorders (DSM), was presented in 1952 and
integrated with the International Classification of Diseases (ICD) published by the
World Health Organization (WHO). Since then, the classifications and diagnostic
criteria of psychiatric disorders, including schizophrenia, have gone through
several major revisions with extensive empirical work on the constructions and
validation of the diagnostic criteria and development of semi-structured diagnostic
interviews, such as the SCID-I (Spitzer, Williams, Gibbon, & First, 1989).
The historical development of diagnostic systems is also an integral part of this
study due to its longitudinal nature. The psychiatric diagnoses of this study were
based on the third revised version (DSM-III-R; American Psychiatric Association
[APA], 1987) and fourth version (DSM-IV; American Psychiatric Association
[APA], 1994) of DSM. Additionally, the tenth revision of ICD (ICD-10; World
Health Organization [WHO], 1992) was utilised in the identification of participants
from the information in the Care Register for Health Care (CRCH, formerly Finnish
Hospital Discharge Register). The diagnostic criteria of schizophrenia according to
DSM-III-R, ICD-10 and DSM-IV are presented in Table 1.
26
The main differences between ICD-10 and DSM-III-R, DSM-IV and the most
recently updated version DSM criteria, DSM-5 (American Psychiatric Association
[APA], 2013), include the requirement of functional impairments in the DSM
criteria and duration criteria of the symptoms. The characteristic symptoms are
required to be present most of the time at least for a month in ICD-10. In DSM, the
duration of any symptoms is 6 months with characteristic symptoms for at least a
week in DSM-III-R or a month in DSM-IV and DSM-5.
DSM-5 and ICD-10 are currently the most widely-used diagnostic criteria in
clinical practice. ICD-10 is the current diagnostic system in Finland, though an
update to ICD-11 is soon to be published. In DSM-5 the traditional clinical subtypes
of schizophrenia have been removed due to the lack of relevance to therapy and
prognosis (Gaebel & Zielasek, 2015; Linscott, Allardyce, & Os, 2010). First rank
symptoms, i.e. specific types of delusions and hallucinations, are also less
emphasised, because their specificity for schizophrenia has been questioned (Bhati,
2013). At least two characteristic symptoms, with at least one of them being
delusions, hallucinations or disorganised speech, are required for a schizophrenia
diagnosis in DSM-5, whereas DSM-IV or ICD-10 require only one first rank
symptom or two other characteristic symptoms. DSM-5 has also approached a more
dimensional assessment of schizophrenia with providing severity ratings for
symptoms and related clinical phenomena in psychosis (hallucinations, delusions,
abnormal psychomotor behaviour, negative symptoms, impaired cognition,
depression, mania) (Barch et al., 2013; Gaebel & Zielasek, 2015).
2.1.1 Schizophrenia spectrum disorders
Schizophrenia, along with some other closely-related psychotic disorders, forms a
group identified as schizophrenia spectrum disorders (APA, 2013). Schizophrenia
spectrum disorders other than schizophrenia share some of the same characteristic
symptoms, but their duration is shorter and no decline in functioning is required
(Bhati, 2013). Schizophrenia spectrum disorders are often studied together. In this
study, the whole schizophrenia spectrum was studied, including, in addition to
schizophrenia, schizophreniform disorder, delusional disorder and schizoaffective
disorder.
In DSM-III-R, DSM-IV, ICD-10 and DSM-5, schizophreniform disorder is
defined as sub-syndromal schizophrenia with multiple psychotic symptoms, the
duration of which is longer than 1 month but less than 6 months. Essential in the
definition of delusional disorder is the presence of one or more delusions for at
27
least 1 month without other psychotic symptoms in DSM classifications or at least
3 months without persistent schizophrenic psychotic or mood symptoms in ICD-
10. In DSM-III-R, DSM-IV and ICD-10, the delusions are required to be non-
bizarre, but this requirement has been removed from DSM-5. In schizoaffective
disorder the symptoms of a mood episode and schizophrenia occur together. In the
DSM criteria there also has to be a period of at least 2 weeks during which psychotic
symptoms are present without prominent mood symptoms. In ICD-10, only the
existence of schizophrenic psychotic symptoms for at least 2 weeks is required.
2.2 Symptoms of schizophrenia
The symptoms of schizophrenia have traditionally been divided into positive
psychotic symptoms, such as hallucinations and delusions, and negative symptoms,
including, for example, paucity of speech, affective flattening, anhedonia and
avolition. Additionally, disorganisation symptoms, such as disorganised speech or
behaviour and poor attention, are often distinguished as a separate symptom
dimension (APA, 2010). The diagnostic characterisations of schizophrenia have
emphasised the disorder as a psychosis, which essentially means loss of the sense
of reality (Kahn et al., 2015). Cognitive impairments are also acknowledged as a
core aspect of psychopathology in schizophrenia, but they have not been included
in the characteristic diagnostic symptoms of DSM-5. However, the dimensional
assessment of clinical symptoms in DSM-5 includes cognitive impairment as well
as affective symptoms (Barch et al., 2013).
The clinical manifestations of schizophrenia are heterogenous. No specific
symptom is characteristic of the disorder, but the symptoms vary between
individuals and during different phases in the same person during their lifespan.
Subtle cognitive, social and motor impairments are often observed in childhood,
unspecific mood and anxiety symptoms and social withdrawal later in adolescence
and youth, before a prodromal phase with subclinical psychotic symptoms that
often precedes the onset of first psychosis (Howes & Murray, 2014).
The symptomatic course of schizophrenia is individual, the symptoms can be
continuously present or episodic with symptomatic relapses and remissions. The
symptoms can also be progressive, stable or lead to recovery (Jääskeläinen et al.,
2013).
28
Tabl
e 1.
The
dia
gnos
tic c
rite
ria
of s
chiz
ophr
enia
acc
ordi
ng to
DS
M-II
I-R, I
CD
-10
and
DS
M-IV
.
Des
crip
tion
DS
M-II
I-R (A
PA
, 198
7)1
ICD
-10
(WH
O, 1
992)
2 D
SM
-IV (A
PA
, 199
4)3
Dia
gnos
is c
ode
295
(exc
ept 2
95.4
and
295
.7)4
F20
295
(exc
ept 2
95.4
and
295
.7)4
Sym
ptom
dura
tion
≥ 1
wee
k ≥
1 m
onth
≥1
mon
th
Cha
ract
eris
tic
sym
ptom
s an
d
sign
s
Crit
erio
n A
At l
east
two
of th
e fo
llow
ing:
1. B
izar
re d
elus
ions
(e.g
. bei
ng c
ontro
lled,
thou
ght b
road
cast
ing,
thou
ght i
nser
tion
or
with
draw
al).
2. S
omat
ic, g
rand
iose
, rel
igio
us, n
ihili
stic
or
othe
r del
usio
ns w
ithou
t per
secu
tory
or
jeal
ous
cont
ent.
3. D
elus
ions
with
per
secu
tory
or j
ealo
us
cont
ent i
f acc
ompa
nied
with
hal
luci
natio
ns o
f
any
type
.
4. A
udito
ry h
allu
cina
tions
(com
men
ting
voic
es
or v
oice
s co
nver
sing
).
5. A
udito
ry h
allu
cina
tions
on
seve
ral
occa
sion
s w
ith c
onte
nt o
f mor
e th
an o
ne o
r
two
wor
ds, h
avin
g no
app
aren
t rel
atio
n to
depr
essi
on o
r ela
tion.
Eith
er a
t lea
st o
ne o
f the
follo
win
g:
a) T
houg
ht e
cho,
thou
ght i
nser
tion
or w
ithdr
awal
,
or th
ough
t bro
adca
stin
g.
b) D
elus
ions
of c
ontro
l, in
fluen
ce o
r pas
sivi
ty,
clea
rly re
ferr
ed to
bod
y or
lim
b m
ovem
ents
or
spec
ific
thou
ghts
, act
ions
, or s
ensa
tions
;
delu
sion
al p
erce
ptio
n.
c) H
allu
cina
tory
voi
ces
givi
ng a
runn
ing
com
men
tary
on
the
patie
nt's
beh
avio
ur, o
r
disc
ussi
ng h
im b
etw
een
them
selv
es, o
r oth
er
type
s of
hal
luci
nato
ry v
oice
s co
min
g fro
m s
ome
part
of th
e bo
dy.
d) P
ersi
sten
t del
usio
ns o
f oth
er k
inds
that
are
cultu
rally
inap
prop
riate
and
com
plet
ely
impo
ssib
le.
Or a
t lea
st tw
o of
the
follo
win
g:
e) P
ersi
sten
t hal
luci
natio
ns in
any
mod
ality
, whe
n C
riter
ion
A
At l
east
two
of th
e fo
llow
ing:
1. D
elus
ions
.
2. H
allu
cina
tions
.
3. D
isor
gani
sed
spee
ch.
4. G
ross
ly d
isor
gani
sed
or c
atat
onic
beha
viou
r.
5. N
egat
ive
sym
ptom
s i.e
. affe
ctiv
e
flatte
ning
, alo
gia
or a
volit
ion.
Not
e: O
nly
one
Crit
erio
n A
sym
ptom
is
requ
ired
if th
e de
lusi
ons
are
biza
rre
or
hallu
cina
tions
con
sist
of a
voi
ce k
eepi
ng u
p
a ru
nnin
g co
mm
enta
ry o
n th
e pe
rson
’s
beha
viou
r or t
houg
hts,
or t
wo
or m
ore
voic
es
conv
ersi
ng w
ith e
ach
othe
r.
29
Des
crip
tion
DS
M-II
I-R (A
PA
, 198
7)1
ICD
-10
(WH
O, 1
992)
2 D
SM
-IV (A
PA
, 199
4)3
6. In
cohe
renc
e, m
arke
d lo
osen
ing
of
asso
ciat
ions
, mar
kedl
y ill
ogic
al th
inki
ng, o
r
mar
ked
pove
rty o
f con
tent
of s
peec
h if
asso
ciat
ed w
ith b
lunt
ed, f
lat o
r ina
ppro
pria
te
affe
ct/d
elus
ions
or h
allu
cina
tions
/cat
aton
ic o
r
othe
r gro
ssly
dis
orga
nise
d be
havi
our.
occu
rrin
g ev
ery
day
for a
t lea
st 1
mon
th, w
hen
acco
mpa
nied
by
delu
sion
s (w
hich
may
be
fleet
ing
or h
alf-f
orm
ed) w
ithou
t cle
ar a
ffect
ive
cont
ent,
or w
hen
acco
mpa
nied
by
pers
iste
nt
over
-val
ued
idea
s.
f) N
eolo
gism
s, b
reak
s or
inte
rpol
atio
ns in
the
train
of t
houg
ht, r
esul
ting
in in
cohe
renc
e or
irrel
evan
t spe
ech.
g) C
atat
onic
beh
avio
ur, s
uch
as e
xcite
men
t,
post
urin
g or
wax
y fle
xibi
lity,
neg
ativ
ism
, mut
ism
and
stup
or.
h) "N
egat
ive"
sym
ptom
s, e
.g. m
arke
d ap
athy
,
pauc
ity o
f spe
ech,
blu
ntin
g or
inco
ngru
ity o
f
emot
iona
l res
pons
es (n
ot d
ue to
dep
ress
ion
or to
neur
olep
tic m
edic
atio
n).
C
riter
ion
B
Det
erio
ratio
n fro
m a
pre
viou
s le
vel o
f
func
tioni
ng in
suc
h ar
eas
as w
ork,
soc
ial
rela
tions
and
sel
f-car
e.
C
riter
ion
B
Soc
ial/o
ccup
atio
nal d
ysfu
nctio
n: F
or a
sign
ifica
nt p
ropo
rtion
of t
ime
sinc
e th
e on
set
of th
e di
stur
banc
e in
one
or m
ore
maj
or
area
s of
func
tioni
ng s
uch
as w
ork,
inte
r-
pers
onal
rela
tions
or s
elf-c
are
are
mar
kedl
y
belo
w th
e le
vel a
chie
ved
prio
r to
the
onse
t.
30
Des
crip
tion
DS
M-II
I-R (A
PA
, 198
7)1
ICD
-10
(WH
O, 1
992)
2 D
SM
-IV (A
PA
, 199
4)3
Crit
erio
n C
Con
tinuo
us s
igns
of t
he d
istu
rban
ce p
ersi
st
for a
t lea
st 6
mon
ths,
incl
udin
g ac
tive
phas
es
of c
riter
ion
A s
ympt
oms
for a
t lea
st 1
wee
k,
with
or w
ithou
t pro
drom
al o
r res
idua
l
sym
ptom
s.
Crit
erio
n C
Con
tinuo
us s
igns
of t
he d
istu
rban
ce p
ersi
st
for a
t lea
st 6
mon
ths,
incl
udin
g at
leas
t 1
mon
th o
f Crit
erio
n A
sym
ptom
s (o
r les
s if
succ
essf
ully
trea
ted)
and
per
iods
of
prod
rom
al o
r res
idua
l sym
ptom
s.
Exc
lusi
on
crite
ria o
r oth
er
spec
ific
crite
ria
Crit
erio
n D
The
full
depr
essi
ve o
r man
ic s
yndr
ome,
if
pres
ent,
deve
lope
d af
ter a
ny p
sych
otic
sym
ptom
s or
was
brie
f in
dura
tion
rela
tive
to
the
dura
tion
of th
e ps
ycho
tic s
ympt
oms
in A
.
Crit
erio
n E
Ons
et o
f the
pro
drom
al o
r act
ive
phas
e of
the
illne
ss b
efor
e ag
e 45
.
Crit
erio
n F
Org
anic
men
tal d
isor
der o
r men
tal
reta
rdat
ion.
If th
e cr
iteria
for m
anic
or d
epre
ssiv
e ep
isod
e ar
e
also
met
, the
abo
ve c
riter
ia m
ust h
ave
been
met
befo
re th
e di
stur
banc
e.
Org
anic
bra
in d
isea
se.
Alc
ohol
/dru
g in
toxi
catio
n, d
epen
denc
e or
with
draw
al.
Crit
erio
n D
Sch
izoa
ffect
ive
diso
rder
, moo
d di
sord
er w
ith
psyc
hotic
feat
ures
.
Crit
erio
n E
No
dire
ct p
hysi
olog
ical
effe
cts
of a
subs
tanc
e or
gen
eral
med
ical
con
ditio
n.
Crit
erio
n F
With
a h
isto
ry o
f Aut
istic
Dis
orde
r or a
noth
er
Per
vasi
ve D
evel
opm
enta
l Dis
orde
r, th
e
addi
tiona
l dia
gnos
is o
f Sch
izop
hren
ia is
mad
e on
ly if
pro
min
ent d
elus
ions
or
hallu
cina
tions
are
als
o pr
esen
t for
at l
east
1
mon
th (o
r les
s if
succ
essf
ully
trea
ted)
. 1 D
iagn
ostic
and
Sta
tistic
al M
anua
l of M
enta
l Dis
orde
rs, T
hird
Edi
tion,
Rev
ised
. 2 I
nter
natio
nal C
lass
ifica
tion
of D
isea
ses,
Rev
isio
n 10
. 3 D
iagn
ostic
and
Sta
tistic
al M
anua
l of M
enta
l Dis
orde
rs, F
ourth
Edi
tion
(DS
M-IV
). 4 2
95.4
= S
chiz
ophr
enifo
rm d
isor
der,
295.
7 =
Sch
izoa
ffect
ive
diso
rder
.
31
2.3 Epidemiology of schizophrenia
2.3.1 Incidence and prevalence
Schizophrenia affects every society and culture in the world, but there is
considerable variation in the frequency estimates between different populations
(McGrath, Saha, Chant, & Welham, 2008). The annual median incidence of
schizophrenia was 15.2 per 100,000 people in a review of 158 studies from 33
countries with a 5.6-fold difference between regions (McGrath et al., 2004). The
incidence of schizophrenia has been described as being highest in early adulthood,
earlier in men (between 20 and 24 years) than in women (25–29 years), but with a
higher incidence of schizophrenia in women than men after the age of 40 years
(Kirkbride et al., 2006).
Globally, the incidence rates of schizophrenia have been significantly higher
in males versus females (ratio 1.4:1), in migrant versus native-born populations
(4.6:1) and in urban versus mixed rural and urban settings (19:13.3 per 100,000)
(McGrath et al., 2004). Urban birth and upbringing have been associated with a
higher risk for schizophrenia (Harrison et al., 2003; Pedersen & Mortensen, 2001).
In Finland, the risk of any psychotic disorder was lower in urban areas and the
highest risk of schizophrenia was found for those born in Northern (OR 7.72) or
Eastern (OR 3.99) Finland (Perälä et al., 2008).
The global median lifetime prevalence for schizophrenia is 0.4% (10–90%
quantile 0.2–1.2%) (Saha, Chant, Welham, & McGrath, 2005). In the Finnish
population, the lifetime prevalence of schizophrenia was 1.0% and it was
significantly highest (1.84%) in Northern Finland (Perälä et al., 2007). Globally,
the median lifetime prevalence of schizophrenia has been significantly higher in
migrant versus native-born populations (ratio 1.8:1) and lower in the least
developed countries in comparison with emerging or developed countries (Saha et
al., 2005).
2.3.2 Outcome and mortality
The course and outcomes of schizophrenia are various, ranging from full
psychopathological remission and recovery to severe, chronic illness states (Lang,
Kösters, Lang, Becker, & Jäger, 2013). The proportion of patients with a good
32
outcome is around 40% (Hegarty, Baldessarini, Tohen, Waternaux, & Oepen, 1994)
and the proportion with a chronic course has varied between 34% and 57% (Lang
et al., 2013), though outcome definitions and duration criteria have been various.
Factors associated with poor long-term outcome include, for example, younger
onset age (Immonen, Jääskeläinen, Korpela, & Miettunen, in press), marked
negative symptoms, male gender, cognitive impairment, low educational level,
social isolation, repeated hospitalisations and longer duration of untreated
psychosis (Lang et al., 2013). The median recovery rate in schizophrenia is 13.5%,
including achieving both clinical remission and improved level of social
functioning with either enduring for at least 2 years (Jääskeläinen et al., 2013).
Despite advances in treatment, good outcomes or recovery rates have not improved
during the past decades (Hegarty et al., 1994; Jääskeläinen et al., 2013).
Mortality of persons with schizophrenia (median standardised mortality ratio
(SMR)) is globally 2.6 times higher compared with the general population for all
causes (10–90% quantile 1.2–5.8) and elevated in most causes of death categories,
including the highest 12.9-fold risk of death for suicide and 2.4-fold risk of death
for natural causes (Saha et al., 2007). In Finland, all-cause mortality is 4.5-fold
higher in first-episode schizophrenia than in the general population (Kiviniemi et
al., 2010). There is no significant difference in SMR between high-income
countries and emerging economies (Saha et al., 2007). Globally, life expectancy in
schizophrenia is 20 years lower in schizophrenia due to high mortality in all age
groups and the mortality gap between schizophrenia and the general population has
increased during the recent decades (Laursen, Nordentoft, & Mortensen, 2014).
However, in the Nordic countries the development has been different and the gap
has slightly decreased (Wahlbeck, Westman, Nordentoft, Gissler, & Laursen, 2011).
2.4 Aetiology of schizophrenia
The etiopathology of schizophrenia remains unknown. Multiple genetic and
environmental factors and interactions between and within them have been
associated with the etiopathogenesis leading to the diverse clinical manifestations
of schizophrenia (Gaebel & Zielasek, 2015; Matheson, Shepherd, Laurens, & Carr,
2011). Identified risk factors, whether genetic or non-genetic, are neither sufficient
nor necessary for the development of schizophrenia (Clarke, Kelleher, Clancy, &
Cannon, 2012; Tandon et al., 2008).
33
2.4.1 The genetic basis of schizophrenia
Heritability of schizophrenia is high, contributing to about 80% of the liability for
the illness (Cannon, Kaprio, Lönnqvist, Huttunen, & Koskenvuo, 1998).
Schizophrenia is familial and the risk of schizophrenia is higher the closer-related
an affected family member is (Kendler et al., 1993). For example, the risk of
schizophrenia for a twin with an affected monozygotic twin is 46% and dizygotic
twin 9% (Cannon et al., 1998).
There is a large number of candidate susceptibility genes, ranging from major
copy number variations to single gene polymorphisms, which account for liability for
schizophrenia (Tandon et al., 2008). Genes associated with schizophrenia are
involved in the regulation of synaptic activities (for example dopamine 2 receptors
(DRD2), glutamatergic synaptic or calcium channel function), neurodevelopment
and immune functions (Ripke et al., 2014). Schizophrenia has partly separate and
partly shared genetic liability with other psychiatric disorders, especially with
bipolar disorder, but also with major depressive disorder, autism spectrum disorder
and other developmental disorders (Smoller et al., 2013).
2.4.2 Environmental risk factors
Environmental factors implicated in the aetiology of schizophrenia have included
biological and psychosocial risk factors spanning the development from prenatal
period to early adulthood (Tandon et al., 2008). Risk factors during pregnancy and
birth include high paternal age (Matheson et al., 2011), maternal prenatal stress
(Negrón-Oyarzo, Lara-Vásquez, Palacios-García, Fuentealba, & Aboitiz, 2016)
and nutritional deficiencies (McGrath, Brown, & St Clair, 2011), complications in
pregnancy (for example, maternal diabetes, pre-eclampsia, rhesus incompatibility),
abnormal foetal growth and development and complications in delivery (for
example, hypoxia) and birth during winter or spring (Cannon, Jones, & Murray,
2002; Matheson et al., 2011).
Risk factors during infancy and childhood are urbanicity, immigrant status,
childhood adversities (for example, low socioeconomic status and physical, sexual
and psychological abuse) and cognitive and motor deficits (Brown, 2011; Dickson,
Laurens, Cullen, & Hodgins, 2012; Matheson et al., 2011). Risk factors during
adolescence and adulthood comprise use of cannabis (Wilkinson, Radhakrishnan,
& D'Souza, 2014) or tobacco (Gurillo, Jauhar, Murray, & MacCabe, 2015), poor
school performance (MacCabe, 2008) and stressful life events (Beards et al., 2013).
34
2.4.3 Aetiological hypotheses and models
Several etiological models have been developed to integrate the findings of genetic
and environmental exposures in the etiopathological process leading to
schizophrenia. The vulnerability-stress model assumes that genetic factors create a
vulnerability to psychosis and the interaction of this vulnerability with
environmental protective and risk factors results in normal development or
emergence of psychopathology when an individual threshold of stress is exceeded
(Zubin & Spring, 1977). The gene-environment interaction model postulates that
the effects of environmental risk factors depend on a person’s genetic liability or
that the expression of a person’s genetic predispositions varies in different
environments (Maynard, Sikich, Lieberman, & LaMantia, 2001). The two-hit
hypothesis presumes a “first hit”, an early predisposing genetic or environmental
disruption in the brain development, which requires a “second hit” for the disorder
to develop (Maynard et al., 2001). The hybrid model stresses the reversibility of
the pathophysiological process and the possibility of moving back and forth
between asymptomatic and symptomatic states along the psychosis continuum
(Yung & McGorry, 1996).
The neurodevelopmental hypothesis (Weinberger, 1987) of schizophrenia is
based on evidence from epidemiological, genetic and neuroimaging studies of
genetic, pre- and perinatal hazards, childhood developmental deviances and
structural brain defects, which are all associated with schizophrenia (Pino et al.,
2014; Rapoport, Giedd, & Gogtay, 2012). According to the neurodevelopmental
hypothesis, schizophrenia is the result of disturbed development and maturation of
the brain starting in the foetal period, being elaborated during adolescence and early
adulthood (Rapoport et al., 2012) and continuing throughout life (Andreasen, 2010).
In the development of the cortex of the brain, reviewed by Insel (2010), the
prenatal period is the time of most active neuronal proliferation and cell migration,
while the formation of neuronal circuits and myelination dominate the first two
decades after birth. Disturbances at any stage of this development may be
influential. Especially during the last stage of maturation of the prefrontal cortex,
reduced proliferation of the inhibitory pathways and excessive pruning of
excitatory pathways have been hypothesised to lead to an excitatory-inhibitory
imbalance. Deficient myelination has also been hypothesised to alter the
connectivity of the brain (Insel, 2010). Additionally, neuroimmunologic, infectious
or autoimmune processes have been proposed to be involved in the
neurodevelopmental pathogenesis of schizophrenia (Altamura, Pozzoli, Fiorentini,
35
& Dell'Osso, 2013). These mechanisms, regulated by interacting genetic and
environmental factors, offer some insight into possible neurodevelopmental
pathways to schizophrenia, but none of them have been proven causal (Insel, 2010).
An integrated sociodevelopmental-cognitive model has been proposed to
combine the neurodevelopmental and sociodevelopmental hypotheses with the
dopamine hypothesis and cognitive theories (Howes & Murray, 2014).
Sociodevelopmental adversities not only interact with genetic and early hazards,
resulting in anomalous neurodevelopment, but they also sensitise the dopamine
system and bias cognitive schemas towards interpretations resembling psychotic
reasoning. Stress increases dopaminergic dysregulation, which increases stress,
leading to a vicious circle and hardwiring of psychotic interpretations. Even though
acute stress is relieved, dopaminergic dysfunction is not completely normalised and
fluctuations in it can predispose to psychotic relapses.
The neurodegenerative hypothesis identifies schizophrenia as a chronic and
progressive neurodegenerative disorder, resulting in biochemical and structural
changes in the brain that lead to loss of neurological and behavioural functions
(Pino et al., 2014). Some persons with schizophrenia have a chronic course of
illness with a deteriorating trajectory, but, neuroimaging and neuropathological
findings do not support an atrophic process and continuous brain tissue loss over
time (Andreasen, 2010).
The progressive neurodevelopmental model integrates the neurodevelopmental
and neurodegenerative hypotheses in its view of schizophrenia as a complex and
heterogeneous disorder which cannot be explained by a single developmental or
degenerative process, but rather has components of various dynamic processes
(Pino et al., 2014). A review analysing neurotoxic effects found studies in which
the duration of untreated psychosis was associated with changes in neurocognitive
functioning and brain structures, and studies in which it was not (Rund, 2014). The
conclusion was that neurotoxicity hypothesis of psychosis has only limited
empirical evidence, and rather than a linear relationship, there may be a threshold
after which neurotoxic effects of active psychosis can be detected, which can shed
additional light on the role of neurodegeneration in schizophrenia.
2.5 Neurobiological models of schizophrenia
The dopamine hypothesis of schizophrenia has long dominated the neurochemical
view of schizophrenia. It is based on psychosis-inducing effects of drugs (for
example, amphetamine) that release dopamine and antipsychotic effects of drugs
36
blocking the dopamine 2 (D2) receptor (Carlsson, 1988). Molecular imaging
studies have found increased synthesis, release and synaptic concentrations of
dopamine, suggesting a presynaptic dysregulation of dopamine in schizophrenia
(Howes et al., 2012). Additionally, the sensitisation of the dopaminergic system
can enhance this dysregulation (Howes & Murray, 2014). The dopaminergic
dysfunction or hyperactivity in the mesolimbic dopaminergic pathway or
subcortical disinhibition have been hypothesised to lead to the emergence of
positive psychotic symptoms (Stahl, 2008; Weinberger, 1987). Additionally, the
hypodopaminergic state of mesocortical pathways projecting to ventromedial
prefrontal cortex has been postulated to lead to the negative and affective symptoms,
and hypoactive mesocortical projections to dorsolateral prefrontal cortex have been
connected with the cognitive deficits in schizophrenia (Stahl, 2008).
The glutamate hypothesis has emerged more recently based on findings of the
N-methyl-D-aspartate (NMDA) receptor hypofunction as a potential molecular
mechanism underlying the cognitive deficits in schizophrenia (Thomas, Bozaoglu,
Rossell, & Gurvich, 2017). Glutamate is the primary excitatory neurotransmitter,
controlled by the NMDA receptors. NMDA receptor antagonists (for example,
ketamine) have induced positive, negative and cognitive symptoms in healthy
volunteers (Insel, 2010; Thomas et al., 2017). Additionally, agents activating the
glycine modulatory site on the NMDA receptor have been associated with
reductions in negative, cognitive and positive symptoms in schizophrenia (Coyle,
2006). Glutamatergic pathways regulate other neural pathways, tonically inhibiting
the mesolimbic dopamine pathway through GABAergic interneurons and exciting
the mesocortical pathway. Thus, glutamatergic hypoactivation has been thought to
result in mesolimbic hyperactivation, leading to positive symptoms and
mesocortical hypoactivation linked to negative and cognitive symptoms (Stahl,
2008). An anti-NMDA-receptor encephalitis has been associated with psychotic
symptoms mimicking schizophrenia (Weickert & Weickert, 2016).
Additionally, abnormal cholinergic, GABAergic, and histaminergic
functioning have been implicated as being behind the neurocognitive impairments
in schizophrenia (Foster, Jones, & Conn, 2012; Nakazawa et al., 2012; Vohora &
Bhowmik, 2012).
37
2.6 Structural and functional neuroimaging findings in schizophrenia
Structural brain abnormalities have been quantified in persons with schizophrenia
in comparison with unaffected people, including decreases in total brain volume
and grey and white matter volumes and enlargement of the lateral and third
ventricles (Haijma et al., 2013). The grey matter deficits especially affect frontal,
temporal and parietal lobes, medial temporal structures (amygdala, hippocampus
and parahippocampal gyrus), and thalamus (Shenton, Whitford, & Kubicki, 2010).
There is evidence of progression of the cortical changes during the illness course
(Crossley et al., 2009; Vita, De Peri, Deste, & Sacchetti, 2012), which is associated
with poorer outcome (Dietsche, Kircher, & Falkenberg, 2017; Hulshoff Pol & Kahn,
2008; van Haren et al., 2011). Volume increases in putamen spreading during
illness course to the whole dorsal striatum have also been found (van Haren et al.,
2011). Structural white matter abnormalities especially affect the connectivity of
the frontal and temporal lobes (Fitzsimmons, Kubicki, & Shenton, 2013).
Functional neuroimaging studies have detected functional changes in cortical
and subcortical structures, some of which were connected to structural changes
(Radua et al., 2012). Increased striatal dopamine uptake was related to positive
symptoms, reduced ventral striatal reward responses and reduced interaction
between medial prefrontal cortex and amygdala to negative symptoms, and reduced
dorsolateral prefrontal cortex activation to cognitive symptoms (Kahn et al., 2015).
The regional alterations in structure and functioning seem to reflect larger scale
abnormalities in neuronal circuits and connectivity between brain regions, which is
also thought to underlie the cognitive deficits in schizophrenia (Fitzsimmons et al.,
2013; Kahn et al., 2015).
2.7 Neurocognition in schizophrenia
The neurodevelopmental and neurobiological changes, which translate to
functional and structural abnormalities of the brain, are also associated with
cognitive functioning in schizophrenia (Woodward, 2016). Meta-analyses of
neurocognitive performance in persons with schizophrenia consistently report a
generalised mean cognitive impairment of 0.92–1.03 standard deviations in
comparison with general population controls (Dickinson, Ramsey, & Gold, 2007;
Fioravanti, Bianchi, & Cinti, 2012; Heinrichs & Zakzanis, 1998; Mesholam-Gately,
38
Giuliano, Goff, Faraone, & Seidman, 2009; Schaefer, Giangrande, Weinberger, &
Dickinson, 2013).
Cognitive impairments have been quantified across a wide range of
neuropsychological measures extending to all cognitive functions measured by
standard clinical tests, mean effect sizes varying between 0.42 and 1.55 in different
measures (Mesholam-Gately et al., 2009, Schaefer et al., 2013). Particularly large
deficits have been found in verbal memory (Heinrichs & Zakzanis, 1998;
Mesholam-Gately et al., 2009; Reichenberg & Harvey, 2007; Schaefer et al., 2013),
executive functions (Reichenberg & Harvey, 2007) and processing speed
(Dickinson et al., 2007; Mesholam-Gately et al., 2009; Schaefer et al., 2013).
The cognitive impairments in schizophrenia are more severe than in bipolar
disorder or depression, with both similarities and differences in cognitive profiles
(Barch, 2009; Tuulio-Henriksson et al., 2011). Milder neurocognitive impairments
have also been observed in non-affected relatives of persons with schizophrenia,
suggesting neurocognitive deficits are endophenotypes of schizophrenia (Gur et al.,
2007).
The heterogeneity in schizophrenia also extends to cognitive performance, and
according to some reports 27–55% of persons with schizophrenia have a normal
cognitive capacity (Bryson, Silverstein, Nathan, & Stephen, 1993; Palmer et al.,
1997). However, inside this neurocognitively normal, high-functioning
schizophrenia group, 64% showed impairment in at least one cognitive domain
(Palmer et al., 1997). Moreover, in some estimations cognitive performance of 98.1%
of persons with schizophrenia was below an expected level, which was based on
premorbid intelligence and parental education (Keefe, Eesley, & Poe, 2005).
2.7.1 Longitudinal course of cognition in schizophrenia during the
lifespan
Premorbid cognition
Premorbid neurocognitive development is individual and heterogenous, and it can
also be normal. On a group level, a generalised, mild cognitive deficit affecting
most or all cognitive functions has already been observed in the childhood in
persons who will later develop schizophrenia (MacCabe, 2008; Mollon &
Reichenberg, in press). Further decline in this cognitive deficit has been described
39
to happen during the premorbid period, for example, in school years from 1st to
12th grades (Bilder et al., 2006).
The premorbid cognitive decline has been hypothesised to result from the
deterioration of cognitive functions during childhood development, but in a birth
cohort study two other developmental hypotheses were supported instead
(Reichenberg et al., 2010). Static developmental cognitive impairments, i.e. early
emerging and stable deficits, were found in verbal and visual knowledge
acquisition, reasoning and conceptualisation. Developmental lags, i.e. initially
normative performance with a slower growth than in healthy controls, were
detected in processing speed, attention, visual-spatial problem solving and working
memory between ages 7–13. Based on these findings, the origins of schizophrenia
could include two interrelated developmental processes with early static deficits
and lagging further behind in different cognitive functions (Reichenberg et al.,
2010).
Cognition at the onset and early course
The findings of the course of cognitive impairments during transition from the
premorbid phase through prodromal stages to the first psychotic episode differ from
each other. The neurocognitive deficits may further increase before the onset of
first psychosis (Mollon & Reichenberg, in press) and exacerbate with illness onset
(Heaton et al., 2001). A systematic review reported smaller cognitive deficits in the
prodromal phase than in first-episode schizophrenia, suggesting further cognitive
decline in transitioning to psychosis (de Paula et al., 2015). In addition, one meta-
analysis found that IQ impairments became larger between premorbid period and
first-episode schizophrenia (Mesholam-Gately et al., 2009). However, a meta-
analysis of longitudinal studies found cognitive improvement in persons with ultra-
high risk, first-episode schizophrenia and healthy controls (Bora & Murray, 2014).
This contrasts the mostly cross-sectional findings of cognitive decline during the
prodromal phase and suggests that the cognitive deficits in schizophrenia are
already established before the prodrome during abnormal neurodevelopment (Bora
& Murray, 2014).
A meta-analysis of longitudinal studies suggested that the cognitive
impairments may slightly improve during the first episode (Bora & Murray, 2014).
The literature is most consistent about the finding that the early longitudinal course
of cognitive impairments after the first psychotic episode on a group level is
relatively stable. In a meta-analysis the degree of cognitive impairment in first-
40
episode schizophrenia was similar with impairments observed in a 9-years-older
and more chronic sample (Mesholam-Gately et al., 2009).
In a systematic review of longitudinal studies (Bozikas & Andreou, 2011), the
neurocognitive deficits present at first-episode schizophrenia remained mostly
stable for up to ten years. However, compared with other cognitive domains, there
was more variation in the longitudinal course of verbal memory deficits with short
follow-ups of up to three years reporting similar changes or improvement of
patients and longer follow-ups reporting less improvement or deterioration in
patients compared with controls. Improvement in psychopathology (positive,
negative or overall symptoms) positively influenced the cognitive trajectory
(Bozikas & Andreou, 2011).
Cognition in midlife and old age
Global neurocognitive impairment in persons with schizophrenia seems to persist
and remain relatively stable during midlife (Szöke et al., 2008) and old age until
the age of 65 years in schizophrenia (Irani et al., 2011; Rajji & Mulsant, 2008;
Zipursky, Reilly, & Murray, 2013). It has been speculated that a faster cognitive
deterioration in comparison with normative aging might occur, but it is unclear if
this finding is related to schizophrenia or other risk factors (Shah, Qureshi, Jawaid,
& Schulz, 2012). On the lifetime perspective, severe cognitive deficits have been
associated with youth-onset schizophrenia and some relatively preserved cognitive
functions with late-onset schizophrenia (Rajji, Ismail, & Mulsant, 2009).
Additionally, community dwellers have been described with a more stable
cognitive trajectory than institutionalised patients (Kurtz, 2005; Rajji & Mulsant,
2008).
Conclusions on the course of neurocognition
The most consistent finding of the longitudinal course of cognition in schizophrenia
is global cognitive impairment, which persists in every clinical state through the
lifespan (Schaefer et al., 2013). Cognition is impaired since childhood, declines
further before or during the prodrome and at the onset the cognitive deficits are
pronounced. The cognitive deficits may slightly improve early in the course of
illness, after which they remain relatively stable and cognition declines at mostly
the same rate as in normative aging with a possible faster decline in old age, at least
in some persons with schizophrenia. The cognitive course of individuals with
41
schizophrenia and specific neurocognitive domains can be variable, reflecting the
heterogeneous neurodevelopmental and neurodegenerative processes behind the
etiopathology of schizophrenia (Flashman & Green, 2004).
2.8 Treatment of schizophrenia
Comprehensive, multidisciplinary assessment, including psychiatric, somatic,
psychosocial, developmental, educational and occupational evaluation, is a key
element in confirming the right diagnosis and, ideally in agreement with an
informed patient, developing an individualised treatment plan which is regularly
updated (National Institute for Health and Care Excellence [NICE], 2014). A
supportive therapeutic alliance and co-operation with the social and therapeutic
network are other key elements that form the basis of the treatment of a person with
schizophrenia.
The general goals in the treatment of schizophrenia are to reduce or remove
symptoms, prevent relapses, maximise quality of life and functional adaptation and
advance and sustain remission and recovery (APA, 2010). The focus has transferred
from hospital treatment and institutionalisation to increased outpatient treatment
and intention to integrate a person with schizophrenia into society (Harvey,
Loewenstein, & Czaja, 2013).
There are many guidelines for the treatment of schizophrenia in which the most
essential forms of treatment are antipsychotic medication in combination with
individually tailored psychosocial interventions (Gaebel, Riesbeck, & Wobrock,
2011).
2.8.1 Psychosocial treatment
Psychosocial interventions recommended by most guidelines of schizophrenia
treatment include cognitive behaviourally-oriented psychotherapy, family
interventions with psychoeducation, community based treatment (adapted to the
mental health system) and vocational rehabilitation or supported employment
(Gaebel et al., 2011). Art therapy is recommended by NICE (2014) for negative
symptoms. The Finnish guidelines from 2015 (www.kaypahoito.fi) present music
therapy, different types of group therapies, physiotherapy, psychophysical therapies
and wellness training as having some evidence in alleviating some aspects of the
illness, functioning or risk factors of somatic illnesses. The APA guidelines (2010)
and Finnish guidelines both endorse social skills training and cognitive remediation.
42
In the Finnish guidelines cognitive rehabilitation is presented as the only treatment
with a strong evidence base in improving cognitive functions, but due to their
developmental phase, cognitive rehabilitation programmes are not recommended
as routine treatment.
Cognitive remediation has been reported to improve both global cognition
(Hedge’s g 0.41) and most studied cognitive domains (Hedge’s g range 0.39–0.54)
in schizophrenia (McGurk, Twamley, Sitzer, McHugo, & Mueser, 2007), with
quantifiable neurobiological chances most consistently found in prefrontal areas
(Thorsen et al., 2014). Cognitive remediation is most efficient in a clinically stable
phase also in chronic schizophrenia and it improves psychosocial functioning the
most when combined with other psychiatric rehabilitation (McGurk et al., 2007;
Wykes, Huddy, Cellard, McGurk, & Czobor, 2011).
2.8.2 Pharmacological treatment
Antipsychotic medication has been shown to reduce positive psychotic symptoms
and the risk of relapse in schizophrenia (Leucht et al., 2012). The use of
antipsychotics has also been associated with lower overall mortality (Tiihonen,
Mittendorfer-Rutz, Torniainen, Alexanderson, & Tanskanen, 2016; Vermeulen et
al., in press). Antipsychotics distinctively have the main role in the
pharmacological treatment of schizophrenia. Other pharmacological agents are not
even mentioned by all treatment algorithms (NICE, 2014).
In a review of five selected, high quality treatment practice guidelines for
schizophrenia (Gaebel et al., 2011), the guidelines generally give similar
recommendations for the administration of antipsychotic treatment. The choice of
the medication should be made, if possible, in a shared decision with an informed
patient considering effect-side-effect profiles and prior experience of use. Newer
guidelines do not prefer atypical over typical antipsychotics. Recommended
dosages of typical agents are 300–1000 CPZ equivalents during acute treatment.
Lower doses are often recommended in the first episode and maintenance treatment.
Preferable route of administration is oral and long-acting injectable antipsychotics
are recommended if preferred by the patient or in case of poor adherence.
Maintenance antipsychotic treatment is recommended in all guidelines, but its
duration is most vaguely presented due to lacking evidence (Gaebel et al., 2011).
Intermittent treatment strategies with stepwise discontinuation and early
intervention plan are not recommended by any guideline. An intermittent strategy
is presented as an alternative with some first-episode patients (APA, 2010) or with
43
non-acceptance or contraindicated maintenance treatment (NICE, 2014). Some
guidelines make no statement of the duration and others guide to continue
maintenance treatment for at least 6 months after acute phase or 1 year in first
episode, or 2 years to indefinite in multi-episode patients. In the case of treatment
resistance all guidelines advice clozapine treatment after at least two trials of 4–8
weeks on effective dose of different antipsychotics (including at least one atypical
agent). Some recommend clozapine augmentation, if response to clozapine is not
optimal (NICE, 2014).
Table 2 summarises recommendations for the pharmacological and other
biological interventions of schizophrenia according to the guidelines of the
American Psychiatric Association (APA, 2010), the National Institute for Health
and Clinical Excellence (NICE, 2014) and the current evidence-based Finnish
guidelines for the treatment of schizophrenia (www.kaypahoito.fi). The earlier
versions of the APA (2004) and NICE (2009) guidelines were included in the
review by Gaebel et al. (2011).
The use of other psychiatric medications, such as benzodiazepines and
antidepressants, is common in schizophrenia, particularly with incomplete
treatment response or adverse-effects of antipsychotics, or with specific
presentations of psychosis such as catatonia, or comorbid psychiatric symptoms.
However, the indications and efficacy of other psychopharmaca in the treatment of
schizophrenia are less clear. There is no evidence of the efficacy of benzodiazepines
for psychotic symptoms (Dold, Li, Gillies, & Leucht, 2013) and concerns have been
raised about the safety of especially long-term use of benzodiazepines, which has
been associated with higher mortality in schizophrenia (Fontanella et al., 2016;
Tiihonen et al., 2016). Antidepressants may have some efficacy in decreasing
depressive (Whitehead, Moss, Cardno, & Lewis, 2003) and negative (Singh, Singh,
Kar, & Chan 2010) symptoms, and moderate to high exposure to antidepressants
has been connected with lower mortality in schizophrenia (Tiihonen et al., 2016).
Other pharmacological treatments of schizophrenia besides antipsychotics are
not mentioned at all in the NICE guidelines (2014). In the APA 2010 guidelines
benzodiazepines are presented as an option for the treatment of catatonia, anxiety,
agitation and insomnia. The Finnish guidelines (2015) advise short-term use of
benzodiazepines for sedation and anxiety in acute psychosis and lorazepam in the
treatment of catatonia. Antidepressants are recommended for the treatment of
major depression and obsessive-compulsive disorder in the APA (2010) guidelines
and for clinical depression, negative symptoms and selective serotonin reuptake
inhibitors (SSRIs) for aggression in the Finnish guidelines.
44
Additional biological treatments for schizophrenia mentioned in the APA 2010
or Finnish guidelines (2015) are mood stabilisers for mood lability and aggression,
beta-blockers for aggression and electroconvulsive treatment (ECT) for catatonia.
Options other than clozapine or its antipsychotic augmentation in treatment
resistance are ECT, repetitive transcranial magnetic stimulation (rTMS) and
augmentation of clozapine with lamotrigine. The Finnish guidelines also mention
that anticholinergics with high doses of typical antipsychotics may impair cognitive
recovery.
45
Tabl
e 2.
Pha
rmac
olog
ical
and
oth
er b
iolo
gica
l tre
atm
ents
of s
chiz
ophr
enia
acc
ordi
ng to
sel
ecte
d tr
eatm
ent g
uide
lines
.
Trea
tmen
t A
PA
1 (20
10)
NIC
E2 (
2014
) Fi
nlan
d3 (20
15)
Ant
ipsy
chot
ic
med
icat
ion
Firs
t epi
sode
psyc
hosi
s
(FE
P)
Antip
sych
otic
mon
oth
era
py
titra
ted
as
quic
kly
as to
lera
ted
to a
dos
e ra
nge
of 1
60–
1000
CP
Z eq
uiva
lent
s.4
Ora
l antip
sych
otic
monoth
era
py
at a
n op
timum
dosa
ge s
low
ly ti
trate
d up
war
ds w
ithin
the
licen
ced
dose
rang
e.
Antip
sych
otic
mon
oth
era
py
with
a u
sual
dose
rang
e of
100
–300
CP
Z eq
uiva
lent
s.
Mai
nten
ance
treat
men
t
(MT)
Contin
ued a
ntip
sych
otic
tre
atm
ent a
t the
sam
e ef
fect
ive
dose
for ≥
6 m
onth
s, th
en
min
imum
effe
ctiv
e do
se/d
isco
ntin
uatio
n
afte
r at l
east
1 y
ear o
f rem
issi
on.
Indefin
ite a
ntip
sych
otic
tre
atm
ent p
ossi
ble
afte
r FE
P, a
lway
s if
ME
or 2
epi
sode
s in
5
year
s.
Contin
ued a
ntip
sych
otic
tre
atm
ent
– in
form
of a
hig
h ris
k of
rela
pse
if an
tipsy
chot
ics
are
stop
ped
in 1
–2 y
ears
afte
r acu
te p
sych
osis
.
Afte
r with
draw
al o
f ant
ipsy
chot
ics
rela
pse
mon
itorin
g fo
r at l
east
2 y
ears
.
Contin
ued a
ntip
sych
otic
monoth
era
py
with
a m
inim
um e
ffect
ive
dose
(usu
al d
ose
rang
e 15
0–40
0 C
PZ
equi
vale
nts)
for 2
–5
year
s af
ter a
resp
onse
in F
EP
.
Depot in
ject
able
antip
sych
otic
s es
peci
ally
if
poor
insi
ght o
f illn
ess.
Psy
chot
ic
rela
pse
Ora
l antip
sych
otic
s or
long-a
ctin
g in
ject
able
antip
sych
otic
s w
ith n
onad
here
nce.
Ora
l antip
sych
otic
s or
long-a
ctin
g in
ject
able
antip
sych
otic
s.
Inte
rmitt
ent dosa
ge m
ain
tenance
str
ate
gie
s, if
MT
not a
ccep
ted
or c
ontra
indi
cate
d.
Antip
sych
otic
mon
oth
era
py
with
a u
sual
dose
rang
e of
300
–600
CP
Z eq
uiva
lent
s.
Trea
tmen
t
resi
stan
ce
Clo
zap
ine
, if i
nade
quat
e re
spon
se to
2
antip
sych
otic
tria
ls o
f 4–6
wee
ks w
ith a
t
leas
t one
aty
pica
l age
nt.
Clo
zap
ine
for p
ersi
sten
t sui
cida
lity
or
aggr
essi
on.
Aug
men
tatio
n st
rate
gies
.
Clo
zap
ine m
onoth
era
py,
if in
adeq
uate
resp
onse
to ≥
2 a
ntip
sych
otic
tria
ls o
f 4–6
wee
ks (a
t lea
st
one
trial
with
a n
on-c
loza
pine
aty
pica
l
antip
sych
otic
).
Antip
sych
otic
aug
menta
tion
of c
loza
pine
if
inad
equa
te re
spon
se to
clo
zapi
ne m
onot
hera
py.
Clo
zap
ine, i
f ina
dequ
ate
resp
onse
to 2
antip
sych
otic
tria
ls o
f 6 w
eeks
with
suf
ficie
nt
dose
s of
ant
ipsy
chot
ics
of d
iffer
ent
mec
hani
sms.
46
Trea
tmen
t A
PA
1 (20
10)
NIC
E2 (
2014
) Fi
nlan
d3 (20
15)
Ben
zodi
azep
ines
5 C
atat
onia
.
Anx
iety
.
Agi
tatio
n.
Inso
mni
a.
– Rap
id tr
anqu
iliza
tion
guid
elin
e.
Sho
rt-te
rm u
se fo
r sed
atio
n an
d an
xiet
y in
acut
e ps
ycho
sis.
Lora
zepa
m fo
r cat
aton
ia.
Ant
idep
ress
ants
5 M
ajor
dep
ress
ion.
Obs
essi
ve c
ompu
lsiv
e di
sord
er.
– C
linic
al d
epre
ssio
n.
Neg
ativ
e sy
mpt
oms.
SS
RIs
for a
ggre
ssio
n.
Oth
er m
edic
atio
ns
and
biol
ogic
al
inte
rven
tions
5
Moo
d st
abili
sers
for m
ood
labi
lity
and
aggr
essi
on.
Bet
a-bl
ocke
rs fo
r agg
ress
ion.
EC
T in
trea
tmen
t res
ista
nce.
– M
ood
stab
ilise
rs fo
r moo
d la
bilit
y.
Oxc
arba
zepi
ne fo
r agg
ress
ion.
Ant
icho
liner
gics
with
hig
h ty
pica
l dos
es m
ay
impa
ir co
gniti
ve re
cove
ry.
Lam
otrig
ine
with
clo
zapi
ne, r
TMS
in
treat
men
t res
ista
nce.
EC
T fo
r cat
aton
ia a
nd tr
eatm
ent r
esis
tanc
e.
FEP
= fi
rst e
piso
de p
sych
osis
, ME
= m
ultip
le p
sych
otic
epi
sode
s, M
T =
mai
nten
ance
trea
tmen
t, i.m
. = in
tram
uscu
lar,
rTM
S =
repe
titiv
e tra
nscr
ania
l mag
netic
stim
ulat
ion,
EC
T =
elec
tro c
onvu
lsiv
e tre
atm
ent,
SS
RIs
= s
elec
tive
sero
toni
n re
upta
ke in
hibi
tors
. 1 A
mer
ican
Psy
chia
tric
Ass
ocia
tion.
2 N
atio
nal I
nstit
ute
for H
ealth
and
Car
e E
xcel
lenc
e.
3 The
cur
rent
evi
denc
e-ba
sed
Finn
ish
guid
elin
es (w
ww
.kay
paho
ito.fi
). 4 C
PZ
equi
vale
nts
are
give
n on
ly fo
r typ
ical
ant
ipsy
chot
ics.
5 In
dica
tions
of m
edic
atio
ns a
djun
ctiv
e to
ant
ipsy
chot
ics.
47
2.9 Research on schizophrenia, antipsychotics and cognition in the Northern Finland Birth Cohort 1966
The Northern Finland Birth Cohort 1966 (NFBC1966) has offered unique
conditions to study lifetime development and course of cognition in schizophrenia.
Previous studies of the NFBC1966 have investigated neurocognitive performance
and course of cognition during early midlife, and their associations with
developmental predictors, brain volume change, antipsychotic medication and
outcome in schizophrenia in comparison with non-psychotic controls (reviewed by
Jääskeläinen et al., 2015).
Studies on developmental predictors and adult cognition found that delayed
infant motor development was associated with poorer cognitive performance in
executive functions, verbal memory and visuospatial working memory at 34 years
of age (Murray et al., 2006) and deterioration of executive functions with memory
in midlife schizophrenia (Kobayashi et al., 2014). Normative associations between
earlier motor development, better adult executive functions and higher grey matter
density in frontocerebellar systems were disrupted in schizophrenia (Ridler et al.,
2006). Poorer premorbid school performance at 16 years of age and lower
education at 34 years of age predicted a higher rate of decline in cognition during
midlife in schizophrenia, whereas severity of the illness around first-episode or
later symptomatic or functional course did not (Rannikko et al., 2015a).
Several NFBC1966 studies have outlined cognitive performance and course of
cognition in midlife schizophrenia. Cross-sectional global cognition and specific
cognitive functions, such as executive functions, working memory and visual and
verbal memory were poorer in schizophrenia in comparison with non-psychotic
controls at 34 years of age (Kobayashi et al., 2014; Murray et al., 2006; Rannikko
et al., 2015b; Ridler et al., 2006; Veijola et al., 2014) and 43 years of age
(Kobayashi et al., 2014; Rannikko et al., 2015b; Veijola et al., 2014). Cognitive
change during early midlife in schizophrenia mostly followed normative age-
related decline (Rannikko et al., 2015b) in global cognition (Veijola et al., 2014),
verbal learning (Rannikko et al., 2015b), visual learning and executive functions
without memory (Kobayashi et al., 2014). Only in executive functions with the
memory component (Kobayashi et al., 2014) and in 2 out of 20 verbal learning
measures (Rannikko et al., 2015b) was a higher rate of decline observed in
schizophrenia compared with the controls.
48
The associations between cognition and structural brain changes,
antipsychotic treatment and outcome in midlife schizophrenia have also been
studied in the NFBC1966. Long-term antipsychotic exposure was associated with
total (Veijola et al., 2014) and regional brain volume reduction in the
periventricular area (Guo et al., 2015). However, total brain volume reduction was
not significantly associated with a decline in global cognition or executive
functions, working memory, visual or verbal learning (Veijola et al., 2014). Poorer
verbal memory at 34 years of age predicted poorer global outcome and poorer
visual memory predicted poorer vocational outcome in midlife schizophrenia
(Juola et al., 2015). High lifetime exposure to antipsychotics was associated with
poorer outcome in all measures and having no drug-free periods with better
functional outcome (Moilanen et al., 2016).
To summarise, the NFBC1966 studies consistently report developmental
delays and poor premorbid scholastic performance, which predict impairments and
decline in adult cognition in schizophrenia. The findings link abnormal
neurodevelopmental and neurodegenerative processes, both of which may be
relevant in the pathogenesis and midlife course of schizophrenia. However, the
course of cognition in midlife schizophrenia was not progressive in comparison
with controls, but followed normative age-related decline and was not associated
with brain volume loss. Cognition, especially preserved memory, was an important
predictor of long-term functional outcome in midlife schizophrenia. High
antipsychotic exposure was associated with brain volume loss and poorer outcome.
Further study is needed to elucidate the associations between antipsychotic
treatment and cognition in schizophrenia.
49
3 Psychiatric medications and cognition in schizophrenia
3.1 Antipsychotic medication and cognition in schizophrenia
The primary target of antipsychotic treatment are positive psychotic symptoms, for
which antipsychotics have consistently shown efficacy against placebo (Leucht et
al., 2012). However, there are no antipsychotic trials lasting over 2–3 years, which
is why the effects of antipsychotics are known only during first 2 or 3 years of
treatment (Leucht et al., 2012). The efficacy of antipsychotics on other
symptomatic dimensions in schizophrenia, such as negative and cognitive
symptoms, is also less clear (Lally & MacCabe, 2015).
Antipsychotics have been associated with both positive (Désaméricq et al.,
2014) and negative (Knowles, David, & Reichenberg, 2010) cognitive effects
during the first years of treatment. The cognitive effects of antipsychotics are
presumably mediated by their ability to affect neurotransmission in neural networks
of the brain related to cognitive functions, such as the dopaminergic, cholinergic,
glutamatergic, serotonergic and histaminergic systems, and their complex
interactions, with a net result of further impairing or enhancing cognitive
performance (Keefe, Silva, Perkins, & Lieberman, 1999; Tannenbaum, Paquette,
Hilmer, Holroyd-Leduc, & Carnahan, 2012). Major mechanisms behind possible
negative cognitive effects are dopaminergic D2 receptor antagonism in the
hypoactive mesocortical pathways, which can additionally be impaired by
glutamatergic inhibition via serotonergic 5HT2A/2C antagonism and 5HT1A
agonism, as well as anticholinergic and sedative histaminergic mechanisms (Stahl,
2008). Cognitive enhancing mechanisms are related to increasing cholinergic,
5HT2A/2C-serotonergic and dopaminergic functions (Keefe et al., 1999).
Many agents of the first generation of antipsychotics following the discovery
of chlorpromazine (CPZ) in the 1950s, also called typical antipsychotics, were
associated with neurological side-effects, such as extrapyramidal movement
disorders. Typical antipsychotics had poor efficacy or even harmful effects on
cognitive impairments due to the anticholinergic effects and high-potency D2-
antagonism of some agents (Hill, Bishop, Palumbo, & Sweeney, 2010). The arrival
of a newer generation of atypical antipsychotics in the 1990s generated initial
optimism of better cognitive efficacy. They were designed to mimic clozapine with
a wider range of “atypical” mechanisms, especially on the serotonergic
50
transmission, and fewer extrapyramidal side-effects. However, the benefits of
atypical antipsychotics in comparison with typicals remain controversial. The
cognitive effects of antipsychotics have been studied in various settings, these are
reviewed in the following chapters.
3.1.1 Cognition in drug-naïve and medicated persons
In a meta-analysis, the degree and profile of cognitive deficits in antipsychotic
drug-naïve persons with schizophrenia were similar to what has been detected in
persons with schizophrenia treated with antipsychotics in the earlier literature in
comparison with healthy controls (Fatouros-Bergman, Cervenka, Flyckt, Edman,
& Farde, 2014). Impairments were observed in all analysed cognitive functions
(Cohen’s d range from -0.74 to -1.03), indicating a generalised cognitive
impairment. The largest impairments were observed in verbal memory, processing
speed and working memory. The findings confirm the existence of marked
cognitive deficits in the early phase of schizophrenia in the absence of
antipsychotics and imply that antipsychotics may not have much of an influence on
cognition in schizophrenia in the early phase of illness.
3.1.2 Clinical trials on antipsychotics and cognition
Meta-analyses of clinical trials have mostly found mild to moderate positive group
effects on cognition for both typical (Désaméricq et al., 2014; Mishara & Goldberg,
2004) and atypical (Désaméricq et al., 2014; Keefe et al., 1999; Nielsen et al., 2015;
Woodward, Purdon, Meltzer, & Zald, 2005) antipsychotics after treatment, ranging
in duration from 1 week to 2 years (reported medians 23–52 weeks).
In clinical trials the efficacy of a treatment against a control condition is often
quantified as an effect size, calculated as the standardised mean difference between
two groups. Common effect size estimates are, for example, Hedge’s g or Cohen’s
d, for which 0.2 indicates a small, 0.5 a moderate, 0.8 a large and 1.3 a very large
effect size (Cohen, 1992). The mean effect size (Cohen’s d) of typical
antipsychotics compared with a placebo or non-medicated arm was 0.22 for global
cognition and ranged from 0.13 to 0.29 for the majority of cognitive functions with
the only negative effect (-0.11) on motor functions (Mishara & Goldberg, 2004).
Studies reporting the cognitive effects of atypical antipsychotics, conducted with
and without comparisons to other antipsychotics, have produced positive effect
sizes (Cohen’s d) of 0.13–0.43 in all cognitive functions (Harvey & Keefe, 2001).
51
In most older meta-analyses, atypical antipsychotics had more favourable cognitive
effects than typical agents (Keefe et al., 1999) with reported differences in effect
sizes (Hedge’s g) of 0.24 for global cognition and 0.17–0.24 for individual
cognitive domains (Woodward et al., 2005).
The superiority of atypical antipsychotics over typical agents on cognition
found in older clinical trials has been questioned because of methodological issues
of these studies (Harvey & Keefe, 2001). Older trials used relatively higher doses
of comparator than studied medication and controlled insufficiently for
confounders such as anticholinergic use or biases related to industry sponsorship.
Newer large clinical trials with improved methodology were designed to compare
the cognitive effects of typical and atypical agents. In the CATIE trial (Keefe et al.,
2007) all studied atypical antipsychotics and typical agent perphenazine were
associated with small global cognitive improvement without between-group
differences at 2 months, and more improvement with perphenazine than olanzapine
and risperidone at 18 months. The EUFEST trial (Davidson et al., 2009) found
cognitive improvement after 6 months of treatment, with four atypical
antipsychotics and haloperidol without between-group differences. The sample was
younger and less chronic, including persons with first-episode schizophrenia and
schizophreniform disorder, which may explain larger effect sizes (Cohen’s d 0.33–0.56) for global cognition in comparison with the CATIE trial.
Two newer meta-analyses, including the CATIE and EUFEST trials, have
compared the cognitive effects of individual antipsychotic agents with each other
(Désaméricq et al., 2014) and individual atypical agents to grouped typical agents
(Nielsen et al., 2015).
Désaméricq et al. (2014) found small significant differences in mean effect
sizes between agents ranging from small 0.20–0.27 for global cognition and a more
varied range of differences (0.06–0.38) for different cognitive functions.
Quetiapine and olanzapine had the most positive effects on global cognition,
followed by risperidone, ziprasidone, amisulpride and haloperidol (in order from
most effective to least). However, the only significant differences were the
superiority of quetiapine and olanzapine to amisulpride and haloperidol, and
superiority of risperidone to haloperidol. There were also significant differences
between agents in specific cognitive functions. In memory functions, quetiapine
was superior to amisulpride and haloperidol, and olanzapine was superior to
haloperidol. In executive functions quetiapine and olanzapine were superior to
haloperidol. In attention and processing speed, quetiapine was superior to all other
52
agents, ziprasidone and olanzapine were superior to amisulpride, risperidone and
haloperidol, and amisulpride to haloperidol.
In the meta-analysis of Nielsen et al. (2015) there were mostly no significant
differences in the effect sizes between atypical agents and grouped typical agents
(chiefly comprising haloperidol and perphenazine) on global cognition, with the
exception of sertindole, which was superior to clozapine (Cohen’s d 0.87),
quetiapine (Cohen’s d 0.75) and typical agents (Cohen’s d -0.89), which had
negative cognitive effects compared to sertindole. However, there was only one
direct comparison of sertindole and all comparisons with haloperidol were indirect
in the network-meta-analysis.
There were also significant differences between the agents in their effects on
specific cognitive functions (Cohen’s d range 0.26–0.97). The significant effects of
typical agents were negative in all different cognitive functions in comparison with
atypical agents (Nielsen et al., 2015). In verbal working memory, ziprasidone had
a more positive effect than clozapine, olanzapine, quetiapine and typical agents,
and risperidone was also superior to typical antipsychotics. In executive functions,
sertindole was superior to clozapine, olanzapine, ziprasidone and typical agents. In
processing speed, sertindole and quetiapine outperformed typical agents. In long-
term verbal working memory, olanzapine outperformed clozapine. In verbal
fluency, olanzapine and clozapine were superior to typical agents. In visuospatial
skills, olanzapine was superior to typical agents and clozapine. No significant
differences were found in other comparisons or in the effects of studied agents on
motor function, attention, reasoning and long-term non-verbal memory.
To conclude, clinical trials have mostly found mild to moderate positive effects
on global cognition and different cognitive functions with antipsychotic treatment
lasting up to 2 years. There seem to be differences in the cognitive effects between
individual antipsychotic agents, and atypical antipsychotics have been associated
with more positive cognitive effects than typical agents in the majority of studies.
However, due to possible methodological biases, especially in the older studies, the
differences between typical and atypical agents do not seem very clear (Galletly,
2009; Keefe et al., 2007).
3.1.3 Longitudinal studies on antipsychotics and change of
cognition
The clinical trials on antipsychotic medication and cognition in schizophrenia are
almost completely limited to duration of 2 years at most. A search of Medline and
53
PsycINFO was conducted for original study I on 18th October 2013 and updated
for this thesis on 31st May 2017. As a result, only 6 longitudinal studies with at
least 2 years of follow-up analysing the association between antipsychotic
medication and change in cognition were identified (Table 3).
Three of the included studies, comparing medicated groups with each other and
not utilising healthy controls, observed improvement in cognition with the use of
antipsychotics. No significant differences between analysed agents (haloperidol vs.
risperidone or haloperidol vs. olanzapine) or grouped typical and atypical
medications were found after 2 years of follow-up (Green et al., 2002; Keefe et al.,
2006; Selva-Vera et al., 2010). One additional study without controls observed no
significant cognitive change nor association between change of cognition and
several antipsychotic medication variables, including mean daily dose, after 5 years
of follow-up (Waddington, Youssef, & Kinsella, 1990).
The two studies including controls found no differences in the change in
cognitive functioning between any groups, including antipsychotic treatment arms
(haloperidol, olanzapine, risperidone) and controls in 3 years (Ayesa-Arriola et al.,
2013), or additionally to typical, atypical and healthy control arms, a non-
medicated arm in 5 years (Albus et al., 2006). The only significant negative finding
was a decline in verbal fluency with the use of any antipsychotics in comparison
with healthy controls or non-medicated patients after 5 years of follow-up (Albus
et al., 2006).
The findings of longitudinal studies of the association between antipsychotic
treatment of 2–5 years and cognitive change in schizophrenia are inconclusive. The
findings of positive cognitive effects of antipsychotics were all from studies
without a comparison group. Studies including a healthy or non-medicated control
arm or the only study analysing antipsychotic dose and cognition did not find
significant cognitive change with antipsychotics with the exception of a decline in
verbal fluency with antipsychotic use. Based on very limited evidence from
longitudinal studies, the long-term effects of antipsychotics on change of cognition
in schizophrenia mostly seem minimal after up to 5 years of follow-up.
54
Tabl
e 3.
Lon
gitu
dina
l stu
dies
(≥ 2
yea
rs o
f fol
low
-up)
on
the
asso
ciat
ion
betw
een
antip
sych
otic
med
icat
ion
and
chan
ge o
f cog
nitio
n in
sch
izop
hren
ia (m
odifi
ed fr
om o
rigi
nal s
tudy
I O
nlin
e su
pple
men
t Tab
le 1
).
Aut
hor,
year
Stu
dy s
ettin
g,
data
Dia
gnos
tic
syst
em
Leng
th o
f
follo
w-u
p
Mea
sure
men
t of c
ogni
tion
Ana
lysi
s of
ant
ipsy
chot
ic m
edic
atio
n,
conf
ound
ers
Res
ults
Wad
ding
ton
et al.,
199
0
An
obse
rvat
iona
l
stud
y
n =
51 c
hron
ic
schi
zoph
reni
a in
-
patie
nts
Mea
n ag
e (S
D) a
t
base
line
57.2
(13.
7)
Not
men
tione
d
5 ye
ars
Cha
nge
of c
ogni
tion
betw
een
base
line
and
follo
w-u
p m
easu
red
by a
bbre
viat
ed 1
0-qu
estio
n m
enta
l
test
whi
ch e
valu
ated
bas
ic
cogn
itive
func
tions
of o
rient
atio
n,
awar
enes
s an
d im
med
iate
mem
ory
Med
icat
ion
varia
bles
: age
at f
irst
neur
olep
tic tr
eatm
ent,
dura
tion
of
neur
olep
tic tr
eatm
ent,
aver
age
daily
dose
in C
PZ
equi
vale
nts,
dai
ly d
ose
of n
euro
lept
ics
at b
asel
ine,
dur
atio
n
and
use
of a
ntic
holin
ergi
cs.
Con
foun
ders
: age
, gen
der,
onse
t
age,
dur
atio
n of
illn
ess,
fam
ily
hist
ory,
flat
teni
ng o
f affe
ct, A
IMS
(Abn
orm
al In
volu
ntar
y M
ovem
ent
Sca
le)
No
sign
ifica
nt c
hang
e in
cogn
ition
.
No
sign
ifica
nt
asso
ciat
ion
betw
een
chan
ge o
f cog
nitio
n an
d
med
icat
ion,
clin
ical
or
dem
ogra
phic
var
iabl
es.
No
heal
thy
cont
rols
.
Gre
en e
t
al.,
200
2
A ra
ndom
ised
,
doub
le-b
lind
trial
n =
62 (3
3 at
2 y
ears
)
schi
zoph
reni
a or
schi
zoaf
fect
ive
diso
rder
pat
ient
s
Mea
n ag
e (S
D)
-hal
oper
idol
43.
3 (8
.4)
-ris
perid
one
43.2
(8.9
)
DS
M-IV
2
year
s C
hang
e of
cog
nitiv
e cl
uste
r sco
res
and
com
posi
te s
core
bas
e on
:
1. S
patia
l wor
king
and
refe
renc
e
mem
ory
test
s
2. C
alifo
rnia
Ver
bal L
earn
ing
Test
tota
l rec
all s
um, r
ecog
nitio
n er
ror
scor
e
3. D
igit
Spa
n D
istra
ctib
ility
Tes
t
4. V
erba
l Flu
ency
Tes
t
5. S
pan
of A
ppre
hens
ion
6. C
ontin
uous
Per
form
ance
Tes
t
7. P
in T
est
Com
paris
on o
f cha
nge
of c
ogni
tion
betw
een
two
treat
men
t gro
ups:
1. h
alop
erid
ol n
= 1
4
2. ri
sper
idon
e n
= 19
Cov
aria
tes:
bas
elin
e co
gniti
on,
antic
holin
ergi
c st
atus
, med
icat
ion
Impr
ovem
ent i
n cl
uste
r
scor
es a
nd g
loba
l sco
re.
Hal
oper
idol
gro
up
impr
oved
mor
e in
itial
ly,
rispe
ridon
e gr
oup
impr
oved
mor
e
grad
ually
. No
betw
een
grou
p di
ffere
nces
at 2
year
s.
No
heal
thy
cont
rols
.
55
Aut
hor,
year
Stu
dy s
ettin
g,
data
Dia
gnos
tic
syst
em
Leng
th o
f
follo
w-u
p
Mea
sure
men
t of c
ogni
tion
Ana
lysi
s of
ant
ipsy
chot
ic m
edic
atio
n,
conf
ound
ers
Res
ults
8. W
isco
nsin
Car
d S
ortin
g Te
st
9. T
rail
Mak
ing
Test
10. B
lock
Des
ign
Sub
test
(WA
IS-
III)
Alb
us e
t al.,
2006
An
open
-labe
l stu
dy
n =
71 F
E p
atie
nts,
71
heal
thy
cont
rols
Mea
n ag
e 30
yea
rs
DS
M-II
I-R/
DS
M-IV
5 ye
ars
Cha
nge
of e
ach
cogn
itive
dom
ain:
1. V
erba
l lea
rnin
g: C
alifo
rnia
Ver
bal L
earn
ing
Test
, Pai
red
Ass
ocia
te L
earn
ing
Test
(WM
S-R
)
2. V
erba
l int
ellig
ence
3. S
patia
l org
aniz
atio
n
4. V
erba
l flu
ency
5. S
eman
tic m
emor
y
6. V
isua
l mem
ory
7. D
elay
/rete
ntio
n ra
te
8. S
hort-
term
mem
ory
9. V
isua
l-mot
or p
roce
ssin
g an
d
atte
ntio
n
10. A
bstra
ctio
n an
d co
ncep
tual
flexi
bilit
y
Com
paris
on o
f cha
nge
of c
ogni
tion
betw
een
grou
ps w
ith d
iffer
ent
antip
sych
otic
med
icat
ion
stat
us a
t
the
5-ye
ar fo
llow
-up:
1. n
o ne
urol
eptic
s, n
= 1
5
2. c
onve
ntio
nal n
euro
lept
ics,
n =
16
3. a
typi
cal n
euro
lept
ics,
n =
40
Con
foun
ders
: edu
catio
n, g
ende
r,
nega
tive
sym
ptom
s, a
ge a
nd/o
r
posi
tive
sym
ptom
s
No
diffe
renc
e in
the
chan
ge o
f cog
nitio
n
betw
een
treat
men
t
grou
ps o
r con
trols
,
exce
pt fo
r dec
line
in
verb
al fl
uenc
y w
ith
antip
sych
otic
use
of a
ny
type
com
pare
d w
ith n
on-
user
s an
d co
ntro
ls
56
Aut
hor,
year
Stu
dy s
ettin
g,
data
Dia
gnos
tic
syst
em
Leng
th o
f
follo
w-u
p
Mea
sure
men
t of c
ogni
tion
Ana
lysi
s of
ant
ipsy
chot
ic m
edic
atio
n,
conf
ound
ers
Res
ults
Kee
fe e
t al.,
2006
A ra
ndom
ized
dou
ble-
blin
d tri
al
n =
263
FE p
atie
nts
(26
at 2
yea
rs)
Mea
n ag
e (S
D) a
t
base
line:
23.9
(4.6
)
Dia
gnos
tic
syst
em n
ot
men
tione
d,
psyc
hotic
sym
ptom
s
for 1
-60
mon
ths
2 ye
ars
Cha
nge
of c
ogni
tive
com
posi
te
scor
e:
1. V
erba
l mem
ory/
lear
ning
:
Cal
iforn
ia V
erba
l Lea
rnin
g Te
st,
tota
l wor
ds re
calle
d fro
m li
st A
2. A
ttent
ion/
vigi
lanc
e
3. P
roce
ssin
g sp
eed
4. M
otor
func
tion
5. V
erba
l flu
ency
6. W
orki
ng m
emor
y
Com
paris
on o
f cha
nge
of c
ogni
tion
betw
een
two
treat
men
t gro
ups:
1. o
lanz
apin
e, n
= 1
8
2. h
alop
erid
ol, n
= 8
C
ovar
iate
s: b
asel
ine
neur
ocog
nitiv
e
scor
es, d
urat
ion
of il
lnes
s, N
AR
T
scor
es a
s a
prox
y of
read
ing
leve
l,
EP
S (S
imps
on-A
ngus
tota
l sco
res)
,
antic
holin
ergi
c us
e du
ring
test
ing
wee
k
Impr
ovem
ent i
n
com
posi
te c
ogni
tive
scor
e w
ith o
lanz
apin
e (E
S 0
.74,
p <
0.0
01, n
=
18) a
nd h
alop
erid
ol (E
S
0.91
, p =
0.0
08, n
= 8
),
no b
etw
een
grou
p
diffe
renc
es.
No
heal
thy
cont
rols
Sel
va-V
era
et al.,
201
0
A re
trosp
ectiv
e,
natu
ralis
tic s
tudy
n =
39 s
chiz
ophr
enia
patie
nts
Mea
n ag
e (S
D)
32.9
(8.3
)
DS
M-IV
2
year
s C
hang
e in
cog
nitiv
e do
mai
ns:
1. E
xecu
tive
func
tions
/reas
onin
g
and
prob
lem
sol
ving
2. S
hort-
term
mem
ory
3. W
orki
ng m
emor
y
4. V
erba
l mem
ory
(Bab
cock
Sto
ry
Rec
all T
est)
5. V
isua
l mem
ory
6. V
isua
l-mot
or p
roce
ssin
g/S
peed
of p
roce
ssin
g
7. S
eman
tic v
erba
l flu
ency
8. M
otor
Spe
ed
Com
paris
on o
f cha
nge
of c
ogni
tion
betw
een
two
treat
men
t gro
ups:
1. C
onve
ntio
nal a
ntip
sych
otic
s, n
=
13 (f
luph
enaz
ine
n =
7, h
alop
erid
ol n
= 2,
per
phen
azin
e n
= 1,
hal
oper
idol
plus
flup
hena
zine
n =
3)
2. A
typi
cal a
ntip
sych
otic
s, n
= 2
6
(ola
nzap
ine
n =
13, r
ispe
ridon
e n
=
7, q
uetia
pine
n =
6)
Con
foun
ders
: out
com
e, c
linic
al a
nd
treat
men
t var
iabl
es, a
ge, o
nset
age
,
illne
ss le
ngth
, num
ber o
f prio
r
epis
odes
or h
ospi
talis
atio
ns
Impr
ovem
ent i
n ve
rbal
fluen
cy, e
xecu
tive
func
tions
, vis
ual a
nd
verb
al m
emor
y.
No
betw
een
grou
p
diffe
renc
es o
ver 2
yea
rs.
At b
asel
ine
conv
entio
nal
antip
sych
otic
s gr
oup
poor
er in
Tra
il M
akin
g
Test
par
t B a
nd W
CS
T.
No
heal
thy
cont
rols
.
57
Aut
hor,
year
Stu
dy s
ettin
g,
data
Dia
gnos
tic
syst
em
Leng
th o
f
follo
w-u
p
Mea
sure
men
t of c
ogni
tion
Ana
lysi
s of
ant
ipsy
chot
ic m
edic
atio
n,
conf
ound
ers
Res
ults
Aye
sa-
Arr
iola
et
al.,
201
3
A ra
ndom
ized
ope
n-
labe
l stu
dy
n =
79 F
E
schi
zoph
reni
a
spec
trum
pat
ient
s, 4
1
heal
thy
cont
rols
Mea
n A
ge (S
D):
-hal
oper
idol
26.
9 (6
.9)
-ola
nzap
ine
27.4
(7.5
)
-ris
perid
one
27.9
(9.2
)
-con
trols
28.
1 (8
.0)
DS
M-IV
3
year
s 1.
Ver
bal m
emor
y: R
ey A
udito
ry
Ver
bal L
earn
ing
Test
(tot
al n
umbe
r
of w
ords
reca
lled
over
lear
ning
trial
s, n
umbe
r of w
ords
reca
lled
from
the
list a
fter d
elay
)
2. V
isua
l mem
ory
3. M
otor
coo
rdin
atio
n
4. E
xecu
tive
func
tions
5. W
orki
ng m
emor
y
6. S
peed
of p
roce
ssin
g
7. A
ttent
ion
8. D
ecis
ion-
mak
ing
capa
city
9. P
rem
orbi
d IQ
Com
paris
on o
f cha
nge
of c
ogni
tion
betw
een
thre
e tre
atm
ent g
roup
s:
1. h
alop
erid
ol, n
= 2
8
2. o
lanz
apin
e, n
= 2
3
3. ri
sper
idon
e, n
= 2
8
Con
foun
ders
: cog
nitiv
e ba
selin
e
scor
es, o
ther
rele
vant
soci
odem
ogra
phic
and
/or c
linic
al
varia
bles
.
No
diffe
renc
e in
the
chan
ge o
f cog
nitio
n
betw
een
the
thre
e
treat
men
t gro
ups
or
betw
een
them
and
cont
rols
.
The
liter
atur
e se
arch
in M
edlin
e an
d P
sycI
NFO
con
duct
ed 1
8th
Oct
ober
201
3 fo
r orig
inal
stu
dy I
and
upda
ted
31st
May
201
7 in
clud
ed th
e fo
llow
ing
term
s:
(exp
Ant
ipsy
chot
ic A
gent
s/ A
ND
((ex
p *C
ogni
tion/
OR
exp
*C
ogni
tion
Dis
orde
rs/)
AN
D (e
xp *
Sch
izop
hren
ia/ O
R *
Psy
chot
ic D
isor
ders
/) lim
it to
hum
ans)
) OR
((ex
p *C
ogni
tion/
OR
exp
*C
ogni
tion
Dis
orde
rs/)
AN
D (e
xp S
chiz
ophr
enia
/de,
dt [
Dru
g E
ffect
s, D
rug
Ther
apy]
OR
Psy
chot
ic D
isor
ders
/de,
dt [
Dru
g E
ffect
s,
Dru
g Th
erap
y]) l
imit
to h
uman
s).
58
3.1.4 Antipsychotic dose and cognition
Meta-analytical findings of the association between antipsychotic dose and
cognition in schizophrenia are various. One meta-analysis of typical antipsychotics
(Mishara & Goldberg, 2004) and another meta-analysis of older persons with
schizophrenia (Irani et al., 2011) did not find significant associations between
antipsychotic dose and cognition. However, in a meta-analysis of processing speed
deficits in schizophrenia an association was found between higher antipsychotic
dose and poorer cognitive performance and the difference between effect sizes
(Hedge’s g) in the high and low daily CPZ equivalent dose groups was 0.8
(Knowles et al., 2010).
In some trials cognitive improvements have been observed after reduction of
high-dose treatment with typical (Kawai et al., 2006) and atypical antipsychotics
(Takeuchi et al., 2013). In first-episode schizophrenia a guided dose-reduction or
discontinuation of atypical antipsychotic treatment produced cognitive
improvements, especially in processing speed, in comparison with maintenance
treatment (Faber, Smid, Van Gool, Wiersma, & Van Den Bosch, 2012). However,
in chronic patients with schizophrenia, withdrawal of atypical antipsychotic
treatment lead to decline in neurocognitive performance in comparison with
continued antipsychotic treatment (Weickert et al., 2003).
In naturalistic, cross-sectional studies higher antipsychotic doses have been
associated with poorer cognitive performance in schizophrenia (Élie et al., 2010;
Hori et al., 2012; Torniainen et al., 2012).
Most of the studies on the cognitive effects of antipsychotics in schizophrenia
have reported results of antipsychotic treatment on cognition, but analyses of the
association between antipsychotic dose and cognition are rarer. Many of the studies
included in meta-analyses of cognition in schizophrenia have not reported
antipsychotic doses. The number of studies without antipsychotic dose data out of
all included studies have been 40/47 (Mesholam-Gately et al., 2009), 24/29 (Irani
et al., 2011) and 15/47 (Knowles et al., 2010). The lack of reported doses may
explain why more meta-analyses have not analysed or found associations between
antipsychotic dose and cognition.
59
3.1.5 Antipsychotic polypharmacy and cognition
Antipsychotic polypharmacy, i.e. the simultaneous use of 2 or more antipsychotic
agents, is relatively common in the treatment of schizophrenia, with prevalence
rates of 10–30% in most studies (Maayan, Soares-Weiser, Xia, & Adams, 2011).
Antipsychotic polypharmacy is often related to treatment resistance and excessive
dosing (Nielsen et al., 2015; Procyshyn et al., 2010), and there is limited knowledge
of the benefits and risks associated with it (Maayan et al., 2011).
In some clinical trials, antipsychotic polypharmacy has been associated with
poorer performance in several cognitive functions (Hori et al., 2006) and in global
cognition (Hori et al., 2012) in comparison with antipsychotic monotherapy.
Switching to antipsychotic monotherapy enhanced processing speed and attention,
which also translated into better functional outcome (Hori et al., 2013). After
switching from antipsychotic polypharmacy to monotherapy, 69% of persons with
schizophrenia managed equally well clinically and with fewer side-effects (Essock
et al., 2011). One trial, however, did not find a significant connection between
antipsychotic polypharmacy and non-verbal cognitive functions in schizophrenia
(Kontis et al., 2010).
Clozapine monotherapy is the gold standard for treatment resistant
schizophrenia (Elkis & Buckley, 2016), but evidence is limited of the benefits of
augmentation of clozapine with another antipsychotic (Barber, Olotu, Corsi, &
Cipriani, 2017). One meta-analysis based on small and selected samples found no
differences in the cognitive outcomes between clozapine monotherapy and
clozapine treatment augmented with another antipsychotic drug, suggesting no
cognitive benefits or harm resulting from clozapine augmentation (Nielsen et al.,
2015).
The polypharmacy trials mostly study chronic schizophrenia with likely long-
term duration of antipsychotic treatment and possibly also polypharmacy. However,
the duration of or longitudinal exposure to polypharmacy are not analysed. Thus, it
remains inconclusive as to whether only cross-sectional or also long-term exposure
to antipsychotic polypharmacy has cognitive consequences.
3.1.6 Methodological challenges in studying the cognitive effects of
antipsychotic medications in schizophrenia
Several methodological issues have been raised concerning clinical trials on the
cognitive effects of antipsychotic treatment in schizophrenia, which may critically
60
influence the interpretation of their results (Davidson et al., 2009; Harvey & Keefe,
2001; Keefe et al., 1999). Variation in the medication status at the baseline
cognitive assessment, with various durations of previous antipsychotic treatments,
often insufficient discontinuation periods, and poorly reported use of adjunctive
medication, may not enable determining if cognition has changed from old
treatment, medication-free state or combination of other medications (Harvey &
Keefe, 2001).
Trial settings have been heterogeneous, including single arm switch studies,
multiple study arms with randomisation, open label and placebo-controlled designs.
Double-blind randomised controlled trials would be optimal for ruling out, for
example, practice or placebo effects, but due to exclusion criteria may suffer from
selected samples non-representative of clinical practice. Sample sizes have often
been small, which limits the ability to detect significant treatment effects, though
the question of how much cognitive improvement is clinically significant is open.
Short-term trials are the most common, while long-term trials would also be
informative of the cognitive effects of antipsychotics and possibly helpful in
finding out how the cognitive changes may translate to functioning and outcome.
Especially in longitudinal studies, utilising control subjects would be optimal to
control for practice and age-related changes in cognition (Bozikas & Andreou, 2011;
Szöke et al., 2008).
As demonstrated before, antipsychotic doses have not been reported by most
trials limiting the possibility to analyse the association between antipsychotic dose
and cognition. A severe bias in older trials is the use of comparably higher doses of
typical than atypical antipsychotics, limiting the possibility to separate, if cognitive
change was due to switch to atypical agent or dose reduction (Harvey & Keefe,
2001). Additional biases are introduced due to associations of high typical doses
with extrapyramidal side-effects, impaired motor performance and increased use of
anticholinergic medications, which may all impair cognitive test performance as
well as practice-related learning (Keefe et al., 1999). Adjunctive medication during
a trial, though often neglected, are also relevant potential confounders.
The assessment of cognition in the treatment trials has been performed with a
large variety of neuropsychological tests measuring diverse cognitive functions.
Limitations due to this methodological variation have led to the development of
standardised test batteries including the most relevant, affected cognitive domains,
such as the MATRICS Consensus Cognitive Battery (MCCB) (Nuechterlein et al.,
2008), to specifically, reliably assess neurocognitive change in clinical cognitive
enhancement studies of schizophrenia. Additional concerns may arise from, for
61
example, practice effects in repeated administration of memory and problem-
solving tests. The timing of cognitive assessment, after stabilisation of clinical
status as well as antipsychotic treatment and adaptation to possible initial adverse
effects, such as sedation, may cause variation in test performance. Attrition due to
dropping out in the middle of a test or testing session as well as between
longitudinal assessments is a major problem in longitudinal studies of cognition in
schizophrenia, which may result in systematic differences between completers and
dropouts, possibly biasing the results (Barnett et al., 2010).
Discriminating between cognitive enhancement and other clinical changes is
not often possible due to lack of reported data, though it would also be relevant.
Cognitive impairments have been shown to covary with negative (Addington,
Addington, & Maticka-Tyndale, 1991; Aleman, Hijman, De Haan, & Kahn, 1999)
and disorganisation symptoms (Addington et al., 1991), though not as much with
positive symptoms (Mishara & Goldberg, 2004).
Methodological limitations in the treatment studies of cognitive deficits with
antipsychotics in schizophrenia influence the results of the current meta-analyses,
making it challenging to interpret the associations of antipsychotics with cognitive
functioning in schizophrenia as well as differential effects between typical and
atypical agents or individual agents (Davidson et al., 2009). It has been suggested
that practice (Goldberg, Keefe, Goldman, Robinson, & Harvey, 2010) and placebo
effects and the influence of symptomatic improvement on cognition (Keefe &
Harvey, 2012) may mostly explain cognitive improvements found in antipsychotic
trials and that the cognitive effects of antipsychotics are limited in the short-term.
3.2 Benzodiazepines and cognition in schizophrenia
The use of benzodiazepines has been associated with cognitive impairment in
diagnostically heterogeneous samples, both as an acute effect (Tannenbaum et al.,
2012) and after long-term (mean 10 years) exposure (Barker, Greenwood, Jackson,
& Crowe, 2004a). According to a review, memory storage functions have been
most consistently affected, but cognitive deficits have also been found in attention,
reaction time and psychomotor functions after single- and repeated-dose exposure
to benzodiazepines without development of total tolerance during 3 weeks of
administration (Tannenbaum et al., 2012). The short- and long-term harmful
cognitive effects of benzodiazepines may be connected to their activating effects
on the γ-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter
in the brain (Nestler, Hyman, & Malenka, 2009).
62
There are only few studies on the cognitive effects of benzodiazepines
conducted specifically in schizophrenia. These studies have reported cognitive
improvement after tapering down or withdrawal of long-term (mean 4–11 years)
benzodiazepine treatment (Baandrup, Fagerlund, & Glenthoj, 2017; Kitajima et al.,
2012). However, according to meta-analytical findings from non-schizophrenia
samples, even though some degree of cognitive recovery is observed after the
withdrawal of long-term benzodiazepine treatment, there remain cognitive
impairments in comparison with normative data (Barker, Greenwood, Jackson, &
Crowe, 2004b).
In the studies on antipsychotic medication and cognition in schizophrenia,
adjunctive medications have been poorly taken into account. Because
benzodiazepines are commonly used in schizophrenia, including treatment trials,
and they have been described having negative cognitive effects, it would be
important to study if they contribute to some degree to the cognitive effects
associated to antipsychotic treatment.
3.3 Antidepressants and cognition in schizophrenia
One recent meta-analysis (Vernon et al., 2014) and a systematic review (Terevnikov,
Joffe, & Stenberg, 2015) have analysed the cognitive effects of antidepressants in
schizophrenia adjunctive to antipsychotics compared with placebo adjunctive to
antipsychotics. Small positive effects were found for two individual agents
(mirtazapine and mianserin) (Terevnikov et al., 2015) and for pooled
antidepressants on global cognition (Hedge’s g 0.095) and executive functions
(Hedge’s g 0.17), but not on any other cognitive functions (Vernon et al., 2014).
Four additional trials on the cognitive effects of adjunctive antidepressants in
schizophrenia have been published after these reviews with mainly neutral or
positive cognitive effects. In a 16-week trial, a positive effect of agomelatine on
cognition (Bruno et al., 2014a) and a trend of cognitive decline with 12 weeks of
reboxetine were found (Bruno et al., 2014b). Improvement in verbal memory was
found with 6 weeks of adjunctive fluvoxamine, which was also correlated with
changes in the expression of transcripts encoding GABA-A receptor and BDNF
(Silver et al., 2015). Higher serum level of venlafaxine after a median of 6 months
of treatment was associated with better verbal memory in schizophrenia and bipolar
disorder, but no other significant associations between venlafaxine and other
cognitive functions or citalopram or escitalopram and cognition were found (Steen
et al., 2015).
63
Additionally, a review of bupropion treatment in schizophrenia with bupropion
trials in smoking cessation found mostly neutral cognitive effects and some positive
effects on reaction times and preservative errors (Englisch, Morgen, Meyer-
Lindenberg, & Zink, 2013). However, cognition was a secondary outcome in these
trials and reduced nicotinic stimulation may confound the findings, which is why
smoking cessation trials with bupropion were mostly excluded from the meta-
analysis (Vernon et al., 2014).
Antidepressants have been thought to improve cognitive functions, based on
the specific mechanisms of individual agents, which enhance serotonergic,
noradrenergic and dopaminergic transmission (Vernon et al., 2014). Serotonergic
effects include 5-HT2A antagonism of, for example, mirtazapine and mianserin,
facilitating frontal dopamine release and 5-HT1A agonism of mirtazapine,
mianserin and SSRIs (Buoli & Altamura, 2015). Noradrenaline reuptake inhibitors
potentiate noradrenaline transmission, which increases cortical dopamine output
(Masana, Casta, Santana, Bortolozzi, & Artigas, 2012). The noradrenaline and
dopamine reuptake inhibitor buprobion also has more direct central dopaminergic
stimulant qualities (Englisch et al., 2013). Some antidepressants, such as tricyclic
agents, also have marked anticholinergic effects, which are related to less
improvement or impairment of cognition (Vernon et al., 2014).
Cognitive deficits are common also in clinical depression and cognitive
improvement is observed when depressive symptoms are alleviated (Roiser &
Sahakian, 2013). Additional to the effects on neurotransmission, antidepressants
have been connected with pro-cognitive qualities based on their possible
neuroprotective (Dranovsky & Hen, 2006) or hippocampal neurogenesis activating
effects in depression (Sheline, Gado, & Kraemer, 2003).
Despite many positive results, the cognitive effects of antidepressants
adjunctive to antipsychotics in schizophrenia have been small. Characteristics of
the trials, such as a relatively short duration (mostly 4–24 weeks), small and chronic
samples, heterogeneity of studied antidepressants, their doses and adjunctive
antipsychotic treatments, may limit their possibilities to detect significant findings.
Consequently, the reviews consistently conclude that there is no evidence that
antidepressants would provide clear and clinically significant cognitive
improvements in schizophrenia (Buoli & Altamura, 2015; Terevnikov et al., 2015;
Vernon et al., 2014) and the long-term cognitive effects of antidepressants in
schizophrenia remain unknown.
64
3.4 Cognitive effects of other medications in schizophrenia
Pharmacological enhancement of cognitive impairment in schizophrenia has been
studied with a broad variety of substances that have effects on several
neurotransmitter systems related to cognitive functions. The results of these studies
have been covered in several reviews which have been utilised in this section,
concentrating mostly on agents with central nervous system effects.
Agents with dopaminergic effects, such as dopamine enhancers dihydrexidine
and sonepiprazole were not associated with neurocognitive benefits in
schizophrenia in single trials, and there is a lack of neurocognitive data in
schizophrenia concerning psychostimulants (Ahmed & Bhat, 2014). Single dose of
amphetamine, though, was associated with cognitive improvement (Harvey, 2013).
When it comes to cholinergic targets, the cognitive effects of
acetylcholinesterase inhibitors, such as donepezil, rivastigmine and galantamine,
have been mixed with positive effects, for example, on attention and memory, but
also negative effects in comparison with placebo in schizophrenia (Singh, Kour, &
Jayaram, 2012).
Anticholinergic agents used to treat side-effects, such as movement disorders,
caused by antipsychotic medications have been associated with adverse cognitive
effects (Baitz et al., 2012). Additionally, many psychiatric medications as well as
medications used for other medical conditions in persons with schizophrenia, have
varying degrees of anticholinergic activities, which may exert a net anticholinergic
burden with adverse cognitive effects (Eum et al., in press).
Glutamatergic NMDA receptor agonists, including glycine, D-cycloserine and
D-serine, adjunctive to antipsychotics have not offered cognitive benefits (Ahmed
& Bhat, 2014; Tuominen, Tiihonen, & Wahlbeck, 2006). Glutamatergic inhibitors
(not only action mechanism, though) lamotrigine had possible neurocognitive
benefits, whereas memantine did not (Ahmed & Bhat, 2014; Buoli & Altamura,
2015). Additionally, topiramate has glutamate reducing effects mediated via
inhibition of sodium and calcium channels, and adjunctive to clozapine it has been
associated with negative cognitive effects (Buoli & Altamura, 2015).
Among compounds with other mechanisms of actions, a GABAergic agent,
GABAA alpha 2 agonist flumazenil has been associated with cognitive
improvement (Ahmed & Bhat, 2014). Of the serotonergic agents, adjunctive
5HT1A agonist tandospirone improved executive functions and verbal memory,
5HT1A agonist buspirone improved attention, but no other cognitive domains, and
5HT3 antagonist ondansetron also improved cognition (Ahmed & Bhat, 2014). Of
65
noradrenergic compounds, alpha2 receptor agonist quanfacine was associated with
cognitive benefits, for example, in attention, but noradrenaline reuptake inhibitors
atomoxetine or reboxetine had no cognitive effects (Ahmed & Bhat, 2014). The
cannabinoid rimonabant or nicotinic agonists had no cognitive effects (Harvey,
2013), and histamine release promoting modafinil had mostly cognitive benefits
(Ahmed & Bhat, 2014).
Despite extensive research and some positive cognitive results, many trials
suffer from methodological problems, and sufficient evidence of consistent positive
neurocognitive improvements has not been found with psychopharmacological
treatment in schizophrenia (Ahmed & Bhat, 2014; Buoli & Altamura, 2015; Harvey,
2013; Zink, Englisch, & Meyer-Lindenberg, 2010).
3.5 Summary of previous studies on psychiatric medications and cognition in schizophrenia
Meta-analyses on the cognitive effects of antipsychotics in schizophrenia mostly
report mild to moderate positive short-term effects on global cognition and specific
cognitive functions. There are differences in the cognitive effects between
individual agents (Désaméricq et al., 2014; Nielsen et al., 2015). However, even
though there is evidence of more cognitive improvement with atypical
antipsychotics, the differences in the cognitive effects between typical and atypical
agents are not clear (Keefe et al., 2007; Harvey & Keefe, 2001). The cognitive
benefits reported by meta-analyses, limited to at most 2 years of treatment, may to
a great degree be secondary to improvement in other symptoms (Harvey, 2013;
Keefe, 2014) and explained by practice effects (Goldberg et al., 2010). Additionally,
the translation of improvements to real-world functioning is unclear. Thus, the
efficacy of antipsychotics in the treatment of cognitive impairments in
schizophrenia seems limited during first years of treatment.
The few conducted longitudinal studies with 2–5 years of follow-up offer
restricted additional evidence, according to which antipsychotics are mainly not
associated with cognitive change, and longer-term cognitive effects of
antipsychotics remain unknown.
Meta-analyses have mostly not been able to analyse antipsychotic dose and
cognition due to lack of reported doses, and rare existing findings are of neutral
(Irani et al., 2011; Mishara & Goldberg, 2004) or negative effects (Knowles et al.,
2010). Higher cross-sectional antipsychotic dose has been associated with poorer
cognition (Élie et al., 2010; Hori et al., 2012; Torniainen et al., 2012) and dose-
66
reduction mostly with cognitive improvement (Faber et al., 2012; Kawai et al.,
2006; Takeuchi et al., 2013). Antipsychotic polypharmacy has been associated with
poorer cognition (Hori et al., 2006; Hori et al., 2012) or neutral cognitive effects
(Kontis et al., 2010) especially in the case of clozapine augmentation (Nielsen et
al., 2015) and switching to monotherapy with cognitive improvement (Hori et al.,
2013). The effects of antipsychotic dose and polypharmacy on cognition in
schizophrenia seem to be mostly neutral or negative, though based on limited
evidence of cross-sectional use.
Limited evidence of adverse cognitive effects of benzodiazepines in
diagnostically diverse samples (Barker et al., 2004a) and of cognitive improvement
after withdrawal of long-term benzodiazepine use in schizophrenia (Baandrup et
al., 2017; Kitajima et al., 2012) suggest that benzodiazepines may have adverse
cognitive effects in schizophrenia especially in the long-term. Antidepressants may
have mild, but clinically non-significant positive cognitive effects in schizophrenia
during up to 6 months of treatment, after which their effects are largely unknown
(Terevnikov et al., 2015; Vernon et al., 2014). Cognitive enhancement studies in
schizophrenia with a wide spectrum of pharmacological agents have not been
successful (Buoli & Altamura, 2015; Choi, Til, & Kurtz, 2013).
There are currently no approved and clearly effective pharmacologic
treatments for the cognitive impairments in schizophrenia (Ahmed & Bhat, 2014;
Buoli & Altamura, 2015; Choi et al., 2013; Coyle, Balu, Benneyworth, Basu, &
Roseman, 2010; Keefe et al., 2007). However, there have been concerning findings
of possible adverse effects related to high-dose or polypharmacy with
antipsychotics or long-term use of benzodiazepines on cognition in schizophrenia,
considering additionally associations between long-term, high-dose antipsychotic
exposure and structural (Huhtaniska et al., 2017) and functional brain changes
(Abbott, Jaramillo, Wilcox, & Hamilton, 2013).
Evidence of the efficacy and safety of antipsychotic and other psychiatric
medications, as well as appropriate treatment strategies in the long-term, is very
limited (Leucht et al., 2012). Despite this, treatment guidelines recommend even
permanent antipsychotic treatment and adjunctive psychiatric medications are
commonly used in schizophrenia in acute and long-term phases. Because
neurocognitive impairment is a core symptomatic characteristic in schizophrenia
persisting through the lifespan with a key role in determining outcome (Green,
2016), the effects of treatment on cognition during an often lifelong course of
illness are of highest relevance. Lack of knowledge of the long-term effects of
psychiatric medications may partly reflect the challenges in creating a controlled
67
long-term treatment setting. It has been suggested that naturalistic samples would
be optimal and often the only realistic option to study long-term effects of
medications (Wang, Brookhart, Ulbricht, & Schneeweiss, 2011).
This doctoral study attempts to further explore the associations between long-
term, even lifetime exposure (ending at 43 years of age) to antipsychotic medication
and cognition in schizophrenia in the naturalistic NFBC1966 sample, taking also
into account different lifetime trends in use of antipsychotics and the possible
confounding effects of benzodiazepines and antidepressants.
68
69
4 Aims and hypotheses of the study
4.1 Aims of the study
This study aimed to analyse how lifetime exposure to psychiatric medications is
associated with cognition in early midlife in schizophrenia, controlling for potential
confounders related to duration and severity of illness. Non-psychotic controls
formed a reference for normative cognitive development during the same age in
original studies I and II. All participants were from the Northern Finland Birth
Cohort 1966 (NFBC1966). The focus was on the associations of antipsychotics
with cognition (original studies I–III), and benzodiazepines and antidepressants
were studied in original study III. The aims of this study were to:
1. Analyse how cumulative lifetime antipsychotic dose is associated with verbal
learning and memory performance at 34 years of age and its change during a
9-year follow-up between ages 34 and 43 years in schizophrenia and compare
cognitive performance to non-psychotic controls (I).
2. Study the association between cumulative lifetime antipsychotic dose and
cross-sectional global cognition at the age of 43 years in schizophrenia and
compare cognitive performance with non-psychotic controls (II).
3. Analyse the associations of cumulative lifetime benzodiazepine and
antidepressant doses, lifetime trends and timing of antipsychotic use and
antipsychotic polypharmacy with global cognition at the age of 43 years in
schizophrenia (III).
4.2 Hypotheses of the study
The hypotheses tested were:
I. High cumulative antipsychotic exposure is associated with poorer baseline
performance and a decline in verbal learning and memory between ages 34 and
43 years (I).
II. High cumulative exposure to antipsychotics and antipsychotic polypharmacy
are associated with poorer global cognition at the age of 43 years (II, III).
III. High cumulative benzodiazepine exposure is associated with poorer cognition
and high cumulative antidepressant exposure with neutral or positive cognitive
effects at the age of 43 years (III).
70
71
5 Material and methods
5.1 The Northern Finland Birth Cohort 1966
The Northern Finland Birth Cohort 1966 (NFBC1966) is an unselected, general
population birth cohort founded in the mid-1960s by Professor of Public Health,
paediatrician Paula Rantakallio (Rantakallio, 1969). The NFBC1966 consists of
12,058 children born alive in the two northernmost Finnish provinces, Lapland and
Oulu, who had an expected delivery date in 1966. The live-births account for 96%
of all birth in the area.
The NFBC1966 members have been followed up since their mothers’ mid-
pregnancy. The extensive study of this birth cohort primarily focusing on perinatal
health expanding to adolescents in the 1980s, and adult somatic and psychiatric
illnesses since the 1990s has resulted in almost 1,000 peer-reviewed publications
from several medical fields (http://www.oulu.fi/nfbc).
The schizophrenia research in the NFBC1966, launched by Professor
(emeritus) Matti Isohanni in 1990, has been particularly active extending to, for
example, early risk factors, clinical outcome, cognition, brain morphometry,
somatic comorbidity, genetics and pharmacoepidemiology, recently reviewed by
Jääskeläinen et al. (2015).
5.2 Participant identification
5.2.1 Psychiatric baseline study at the age of 34 years (Study I)
The first psychiatric follow-up study of the NFBC1966 was conducted in 1999–2001 when the participants were at an average age of 34 years. The baseline
assessment of original study I is based on this 34-year psychiatric follow-up study.
All NFBC1966 members (n = 10,934) who were living in Finland at 16 years
of age in 1982 and had a diagnosis of any mental health disorder by the end of 1997
in the Care Register for Health Care (CRHC) were included. Their diagnoses were
validated by scrutinisation of their hospital patient history records for DSM-III
criteria (Isohanni et al., 1997; Moilanen et al., 2003). Based on this procedure, 146
subjects (84 males, 58%) with at least one psychotic episode and 187 controls (116
males, 62%) without a history of psychosis randomly selected from the Oulu area
were invited to participate in the baseline study. Ninety-one subjects with a lifetime
72
psychotic disorder and 104 control subjects participated (Haapea et al., 2007). They
went through diagnostic assessment performed by Structured Clinical Interview for
DSM-III-R (SCID I; Spitzer et al., 1989), taking all available anamnestic
information into consideration, after which 61 subjects were diagnosed with
lifetime schizophrenia and 12 subjects with other schizophrenia spectrum disorders,
including schizophreniform disorder, schizoaffective disorder and delusional
disorder.
5.2.2 Psychiatric follow-up study at the age of 43 years (Studies I–III)
The second psychiatric follow-up study of the NFBC1966 was carried out in 2008–2011, when the participants were at an average age of 43 years.
Additional to those who participated in the 34-year baseline study, NFBC1966
members who had developed a psychosis at any time by the end of 2008 were
invited to participate in the 43-year follow-up study. The psychosis diagnoses were
detected by utilising register data on psychosis diagnoses between 1998 and 2008
in the CRHC and Social Insurance Institution of Finland registers on sick leaves,
disability pensions and the right to reimbursement for psychoactive medication due
to psychosis by the end of 2008. Those who reported a psychosis or current
antipsychotic use (at least 300 mg CPZ equivalent) in 1997 in a questionnaire data
collection (Haapea, Miettunen, Lindeman, Joukamaa, & Koponen, 2010) were also
included.
This procedure lead to the detection of 258 NFBC1966 members with a
psychosis diagnosis and known address who were invited to participate in the study.
Ninety-nine (38.5%) individuals participated in the psychiatric interview and
examination including the SCID I interview (First, Spitzer, Gibbon, & Williams,
2002) leading to DSM-IV lifetime diagnosis. Sixty-nine of them were confirmed
with a diagnosis of a schizophrenia spectrum disorder.
The control sample was formed by inviting 450 non-psychotic NFBC1966
members (including the participants of the baseline study) from all around Finland
to participate in the same psychiatric interviews and cognitive assessment.
The follow-up assessment of original study I was performed as a part of the
43-year follow-up (“follow-up study”) and the whole samples of original studies II
and III are based on the 43-year follow-up study (“43-year study”).
73
5.2.3 Study samples
Original study I consisted of 40 schizophrenia spectrum subjects and 73 non-
psychotic controls, who had complete California Verbal Learning Test (CVLT;
Delis, Kramer, Kaplan, & Ober, 1987) data in both the baseline and follow-up
studies. The sample of original study II included 60 schizophrenia spectrum
subjects and 191 non-psychotic controls and original study III the same 60
schizophrenia spectrum subjects as original study II. All of the participants of
original studies II and III had been through cognitive examination in the 43-year
follow-up study. The 40 schizophrenia spectrum subjects and 72 controls of
original study I were also included in the sample of original studies II and III, but
in original study I, only the cognitive measure that was used in the baseline was
included in the follow-up analyses (see section 5.4). Additionally to cognitive test
participation, schizophrenia spectrum subjects of all original studies also had
information on the lifetime use of psychiatric medications. Hereafter in this thesis,
the subjects with a schizophrenia spectrum disorder are called subjects with
schizophrenia. The formation of the study samples (I–III) is described in more
detail in Fig. 1 and Fig. 2.
74
Fig. 1. Flowchart of the formation of the schizophrenia subsample (n = 40) of original study I and the total schizophrenia sample (n = 60) of original studies II and III.
Time
2008–20101999–2001
Sample in study I, N = 40
NFBC1966 members with a psychosis by the end of 1997, according to the Care Register for Health Care, N = 160*
146 subjects were invited to participatein the baseline study in 1999–2001
14 deceased
55 non-participants
91 participants in the baseline study
14 with non-schizophrenic psychosis
3 deceased
22 non-participants in the follow-up study
* Including 1 new outpatient
1 denied the use of data
2 with organic psychosis, 2 with developmental disorder
Missing data:- baseline CVLT, n = 4- follow-up CVLT, n = 1- lifetime antipsychotic use, n = 2
47 participants with schizophrenia in the follow-up study
Time
2008–2010
Sample in studies II & III, N = 60
159 non-participants
99 participants in the follow-up study
1 5 deceased and 1 denied the use of data (not included)2 1 deceased and 5 with no contact information (not included)
811 participants and 492 non-participants of the 34-year follow-upand 128 NFBC1966 members with a psychosisdetected after 1997 were invited to participate
in the 43-year follow-up
30 with non-schizophrenic psychosis
Missing data:- all follow-up cognitive data, n = 1- lifetime antipsychotic use, n = 8
75
Fig. 2. Flowchart of the formation of the control samples in original study I (n = 73) and original study II (n = 191).
Attrition analyses
In original study I, the subjects with schizophrenia who completed both the baseline
and follow-up CVLT assessments did not differ from subjects who did not
participate in the follow-up in gender, baseline performance in the summary
measure of the CVLT (Immediate free recall of trials 1–5), use of antipsychotic
medication, symptoms, age of illness onset or cumulative number of hospital
treatment days. The only significant difference was that participating schizophrenia
subjects had a lower level of education than non-participating ones (p = 0.034). The
only five subjects with schizophrenia who had tertiary education did not participate
in the follow-up study. The participating controls did not differ from non-
Time
2008–20101999–2001
Sample in study I, N = 73
A sample of 187 non-psychotic NFBC1966 memberswere invited to participate in the baseline study in 1999–2001
83 non-participants
104 participants in the baseline study
1 with non-schizoprenic psychosis
27 non-participants in the follow-up study
Missing data:- baseline CVLT, n = 2- follow-up CVLT, n = 1
76 participants in the follow-up study
Time
2008–2010
Sample in studies II & III, N = 191
256 non-participants
194 participants in the follow-up study
1 1 with non-schizophrenic psychosis (not included)2 5 deceased (not included)
1031 participants of the 34-year follow-upand 3472 randomly selected non-psychotic NFBC1966 members
were invited to participate in the 43-year follow-up
2 with organic psychosis
Missing data:- all follow-up cognitive data, n = 1
76
participating controls in gender, baseline summary measure of the CVLT or
education.
In original studies II and III, the participating subjects with schizophrenia and
non-participating NFBC1966 members with a psychosis who were invited to the
follow-up study, did not differ in gender, cumulative number of lifetime hospital
treatment days or occupational status at the follow-up. Compared with the non-
participating schizophrenia subjects, the participating ones had significantly lower
education (basic education 15% vs. 28%, secondary education 85% vs. 62%,
tertiary education 0% vs. 10%) (p = 0.001) and age of illness onset (mean 26.6 vs.
30.1 years) (p = 0.002), more often had a narrow schizophrenia diagnosis (84% vs.
68%) (p = 0.024) and they were more often on a disability pension (50% vs. 26%)
(p = 0.001). There was selective attrition originating from the participating subjects
with schizophrenia having markers related to a more severe illness and poorer
functioning than the non-participating ones. This is why sensitivity analyses were
performed by using inverse probability weighting for the variables that differed
between participants and non-participants. The sensitivity analyses resulted in no
changes to the significant main results between antipsychotic exposure and global
cognition.
The participating controls in original study II compared with all non-psychotic
NFBC1966 members, were not different in gender, educational level or
occupational status, though participating controls were more often working than
non-participants (95% vs. 71%) (p < 0.001).
5.3 Data on psychiatric medications
5.3.1 Collection of medication data
Medical records (I–III)
The data on the lifetime use of psychiatric medications were collected from all
available medical records of the subjects’ hospital and outpatient treatments in
Finland. The medical records were acquired from the subjects’ treatment facilities
identified based on the CRHC information on inpatient and outpatient treatments.
If there was no information in the Care Register, the medical records were ordered
from the outpatient facilities of the subject’s residential area. All medical records
77
were examined and the psychiatric medication agents, doses and time periods of
use were recorded until the 43-year follow-up study date.
Interview (I–III) and register data (I–III)
The information of the use of psychiatric medications was obtained in interviews
in the 34-year and 43-year follow-up studies by asking about the participants’
medication history during the past three months and the previous year. Additionally,
the register of the Social Insurance Institution of Finland containing purchases of
psychiatric medications in 1997 was utilised to check purchased medications. Both
of these information sources were taken into account in combination with medical
records, when estimating the lifetime and current use of psychiatric medications
(described in detail by Moilanen et al., 2016) (I–III).
5.3.2 Classification of medications
The psychiatric medications studied in this thesis were classified according to the
Anatomical Therapeutic Chemical (ATC) classification system (WHO
Collaborating Centre for Drug Statistics Methodology, 2016) to the following
groups: antipsychotics (N05A), benzodiazepines (including benzodiazepine
derivatives N05BA, N03AE and N05CD; and benzodiazepine related drugs
N05CF), antidepressants (N06A) and anticholinergic agents (N04A). Additionally,
antipsychotics were divided to typical and atypical antipsychotics (Leucht et al.,
2012). The ATC codes and dose equivalence values of psychiatric medication
agents are presented in Table 4.
5.3.3 Definitions of the dose of medication
Chlorpromazine equivalents (I, II)
CPZ equivalents are a standardised, quantitative method to compare relative
antipsychotic potencies of different antipsychotic medications (Andreasen, Pressler,
Nopoulos, Miller, & Ho, 2010; Rijcken, Monster, Brouwers, & De Jong-Van Den
Berg, 2003). The equivalency measured by CPZ equivalents is mostly based on
antidopaminergic actions and does not take into account the influences of
antipsychotics on other receptors (Rijcken et al., 2003).
78
The current antipsychotic doses at the baseline and follow-up were transformed
to CPZ equivalents. The cumulative exposure to antipsychotics by the baseline,
between the baseline and follow-up and by the follow-up study was expressed as
CPZ equivalent dose-years. One CPZ dose-year corresponds the exposure of using
a daily dose of 100 mg CPZ for a year.
Defined daily dose (III)
Defined daily dose (DDD) is the average daily maintenance dose of a medication
used for its main indication in adults based on global health statistics evaluated by
the World Health Organization (WHO). DDDs were utilised to compare the doses
of psychiatric medications with each other.
The current used daily doses of antipsychotic, benzodiazepine and
antidepressant medications were divided with their DDDs to calculate DDD ratios.
A DDD ratio below 1 refers to dosage of a medication that is lower than the average
maintenance dose and DDD ratio above 1 to a higher dose. The cumulative lifetime
doses of psychiatric medications were calculated as defined daily dose years (DDD
years). One DDD year corresponds to using one DDD per day for a year.
79
Table 4. Chlorpromazine and defined daily dose equivalents of the psychiatric medications used by all schizophrenia subjects of this study (n = 60).
Psychiatric medication ATC Finnish trade name Administration CPZ
equivalent
DDD
equivalent4
Antipsychotics
Typical antipsychotics
Chlorpromazine N05AA01 Klorproman, Largactil PO 1001 300
Chlorpromazine N05AA01 Klorproman Inj. 1001 100
Levomepromazine N05AA02 Levozin, Nozinan PO 1001 300
Promazine N05AA03 Sparine PO 1002 300
Fluphenazine N05AB02 Siqualone Inj. 1.072 1
Perphenazine N05AB03 Peratsin, Pertriptyl PO 81 30
Perphenazine N05AB03 Peratsin Inj. 1.91 7
Thioridazine N05AC02 Orsanil, Tioridil PO 1001 300
Haloperidol N05AD01 Haloperin, Serenase PO 31 8
Haloperidol N05AD01 Haloperin Inj. 21 8
Flupentixol N05AF01 Fluanxol PO 21 6
Chlorprothixene N05AF03 Truxal, Cloxan PO 501 300
Zuclopenthixol N05AF05 Cisordinol PO 251 30
Zuclopenthixol N05AF05 Cisordinol Inj. 141 15
Zuclopenthixol N05AF05 Cisordinol Acutard Inj. 141 30
Pimozide N05AG02 Orap PO 22 4
Sulpiride N05AL01 Suprium PO 2002 800
Remoxipride N05AL04 Roxiam PO 752 300
Atypical antipsychotics
Sertindole N05AE03 Serdolect PO 5.331 16
Ziprasidone N05AE04 Zeldox PO 601 80
Clozapine N05AH02 Leponex, Froidir PO 1001 300
Olanzapine N05AH03 Zyprexa PO 51 10
Quetiapine N05AH04 Ketipinor, Seroquel PO 751 400
Asenapine N05AH05 Sycrest PO 53 20
Risperidone N05AX08 Risperdal PO 1.51 5
Risperidone N05AX08 Risperdal Consta Inj. 11 2.7
Aripiprazole N05AX12 Abilify PO 7.51 15
Benzodiazepines
Diazepam N05BA01 Diapam, Medipam PO n/a 10
Chlordiazepoxide N05BA02 Risolid PO n/a 30
Oxazepam N05BA04 Opamox, Oxamin PO n/a 50
Potassium
clorazepate
N05BA05 Tranxene PO n/a 20
Lorazepam N05BA06 Ativan, Temesta PO n/a 2.5
Alprazolam N05BA12 Xanor, Alprox PO n/a 1
80
Psychiatric medication ATC Finnish trade name Administration CPZ
equivalent
DDD
equivalent4
Clonazepam N03AE01 Rivatril PO n/a 8
Nitrazepam N05CD02 Insomin PO n/a 5
Triazolam N05CD05 Halcion PO n/a 0.25
Temazepam N05CD07 Tenox PO n/a 20
Midazolam N05CD08 Buccolam, Dormicum PO n/a 15
Zopiclone N05CF01 Imovane, Zopinox, PO n/a 7.5
Zolpidem N05CF02 Somnor, Stella, Stilnoct PO n/a 10
Antidepressants
Clomipramine N06AA04 Anafranil PO n/a 100
Amitriptyline N06AA09 Triptyl PO n/a 75
Nortriptyline N06AA10 Noritren PO n/a 75
Doxepin N06AA12 Doxal PO n/a 100
Maprotiline N06AA21 Ludiomil PO n/a 100
Fluoxetine N06AB03 Fluoxetin, Seronil, Seromex PO n/a 20
Citalopram N06AB04 Sepram, Citalopram PO n/a 20
Paroxetine N06AB05 Optipar, Paroxetin, Seroxat PO n/a 20
Sertraline N06AB06 Sertralin, Zoloft PO n/a 50
Fluvoxamine N06AB08 Fluvosol PO n/a 100
Escitalopram N06AB10 Cipralex, Escitalopram PO n/a 10
Moclobemide N06AG02 Aurorix, Moclobemid PO n/a 300
Mianserin N06AX03 Tolvon PO n/a 60
Mirtazapine N06AX11 Mirtazapin, Remeron Soltab PO n/a 30
Venlafaxine N06AX16 Efexor Depot, Venlafaxin PO n/a 100
Milnacipran N06AX17 Ixel PO n/a 100
Anticholinergic agents
Biperiden N04AA02 Akineton PO, Inj. n/a 10
PO = per oral, Inj. = injection, n/a = not applicable. CPZ and DDD equivalent doses are reported as mg. 1 Kroken, Johnsen, Ruud, Wentzel-Larsen, & Jørgensen, 2009. 2 Bazire, 2003. 3 www.scottwilliamwoods.com. 4 www.whocc.no/atc_ddd_index/
5.3.4 Descriptions of psychiatric medication variables (Studies I–III)
The psychiatric medication variables in this study represent cross-sectional use and
doses of psychiatric medications at the time of the studies, lifetime cumulative
exposure to psychiatric medications and lifetime trends in use of antipsychotic
medication. The variables were calculated for doses used at the time of or until the
follow-up study, but antipsychotic dose as CPZ equivalents was also calculated at
the time of and until the baseline study and between the baseline and follow-up
studies. The analysed psychiatric medication variables are described in Table 5.
81
Table 5. Psychiatric medication variables analysed in original studies (I–III).
Name of the variable Description of the variable (study)
Current use of psychiatric medications
Current CPZ equivalent dose of
antipsychotics
The daily dose of antipsychotics the person used at the time of the
study divided by their CPZ equivalent (I–III).
Current DDD ratio of
antipsychotics
The daily dose of antipsychotics the person used at the follow-up
study divided by their DDD (III).
Current DDD ratio of
benzodiazepines
The daily dose of benzodiazepines the person used at the follow-
up study divided by their DDD (III).
Current DDD ratio of
antidepressants
The daily dose of antidepressants the person used at the follow-up
study divided by their DDD (III).
Current use of antipsychotics The use of antipsychotics at the time of the study (yes/no) (I–III).
Current use of benzodiazepines The use of benzodiazepines at the time of the study (yes/no) (I–III).
Current use of antidepressants The use of antidepressants at the time of the study (yes/no) (I–III).
Current antipsychotic
polypharmacy
Use of two or more antipsychotic medications at the 43-year study
(yes/no) (III).
Lifetime cumulative exposure to
psychiatric medications
CPZ dose-years of
antipsychotics
The sum of CPZ equivalent daily doses of antipsychotic
medications the person had used during the time period, divided by
365.25 days (I–III).
DDD years of antipsychotics The sum of DDD ratios of antipsychotic medications the person
had used until the 43-year study, divided by 365.25 days (III).
DDD years of benzodiazepines The sum of DDD ratios of benzodiazepine medications the person
had used until the 43-year study, divided by 365.25 days (III).
DDD years of antidepressants The sum of DDD ratios of antidepressant medications the person
had used until the follow-up study, divided by 365.25 days (III).
Lifetime trends in antipsychotic use
Proportion of time with
antipsychotic use
Proportion of time during which antipsychotic medication was used
of the whole duration of illness1, 2: 1) < 50 %, 2) 50–95 %, 3) >
95 % of time (III).
Long antipsychotic-free periods
during treatment
Having ≥ 1 period of at least one year without antipsychotic
medication since the start of antipsychotic treatment (yes/no), but
using antipsychotics during the cognitive examination (III).
Being without antipsychotic
medication before the cognitive
examination
Having a break in antipsychotic medication at least 3 months
before and during the cognitive examination (yes/no) (III).
Proportion of time on
antipsychotic polypharmacy
Proportion of time with concomitant use of ≥ 2 antipsychotic
medications of the entire time during which antipsychotic
medication was used2: 1) < 5 %, 2) 5–40%, 3) > 40% of time (III). 1 Duration of illness = time since the onset of illness or first psychiatric medication. 2 The variables were classified into three classes that were chosen based on distribution of the data.
82
5.4 Neuropsychological assessment
The assessment of verbal learning and memory in original study I was performed
by utilising the CVLT (Delis et al., 1987), which was completed by all
schizophrenia subjects and controls at the baseline and follow-up. In addition to the
CVLT, the baseline assessment included the Abstraction, Inhibition and Working
Memory task (AIM; Glahn, Cannon, Gur, Ragland, & Gur, 2000) and the Visual
Object Learning Test (VOLT; Glahn, Gur, Ragland, Censits, & Gur, 1997), but they
were not analysed in original study I. At the follow-up, all the subjects of original
study I were assessed using a more comprehensive neuropsychological test battery
described below, that was analysed in original studies II and III.
In original studies II and III at the 43-year study the participants were assessed
with a neuropsychological test battery, including variables from tests measuring
several, central neurocognitive domains. The neuropsychological test battery
included the AIM, CVLT (Immediate free recall of trials 1–5), VOLT, Verbal
fluency (Lezak, Howieson, & Loring, 2004), Visual series subtest from the
Wechsler Memory Scale III (WMS-III; Wechsler, 2008) and the Vocabulary, Digit
Span and Matrix reasoning subtests from the Wechsler Adult Intelligence Scale III
(WAIS-III; Wechsler, 2005).
The neuropsychological tests were administered at the baseline and follow-up
studies by trained examiners, whose training during the 43-year study was updated
and supervised by two clinical neuropsychologists.
5.4.1 California Verbal Learning Test
The California Verbal Learning Test (CVLT) is a brief, individually administered,
paper and pencil, auditory verbal memory test. It provides an assessment of
numerous strategies and processes associated with learning and remembering
verbal material. It is a validated test method (Delis et al., 1987) and one of the most
widely used cognitive tests in schizophrenia research.
The CVLT consists of 16-item word lists with items from four semantic
categories, four words per category (Delis et al., 1987). The words are presented in
an order in which any word is never followed by another word from the same
category. In a trial, a word list is read to the examinee who then is instructed to
recall in any order as many items as they can. The test begins with 4 trials of the
first word list (List A) followed by one trial of a 16-item interference list (List B)
and a fifth trial of the initial List A, after which in addition to immediate (short-
83
delay) recall there is a long-delay recall trial after a 20-minute interval. All recall
trials include free recall as well as cued recall in which the examinee is asked if
they remember words from the semantic categories.
The descriptions of the CVLT variables quantified from this procedure and
analysed in original study I are shown in Table 6. The total score of the Immediate
free recall of trials 1–5 has had the largest effect size of the CVLT variables in
detecting verbal learning deficits in schizophrenia (Stone et al., 2011) and it
represents verbal learning in the neurocognitive set of original studies II–III.
Table 6. Descriptions of variables obtained in the California Verbal Learning Test (CVLT) analysed in original study I.
Cognitive functions and
variables Description
Verbal learning
Immediate free recall of trials
1–5
Performance (correct responses) on List A provides a sum of trials 1–5.
Learning slope The rate of improvement from first to final trial indicates the amount of
new learning per trial, i.e. reflects the increment in words recalled per
trial over trials 1–5.
Short-term memory
Short-delay free recall After interference List B (a second list with 16 items, presented for one
trial) the subject is asked to recall the items of the List A in any order.
Long-term memory
Long-delay free recall The number of correct responses on List A in any order after 15–20 min
interval (in which the examinee is occupied with other tests to minimize
interference) reflects the ability to retain verbal information over time.
Organisation strategies
Semantic clustering Consecutive recall of List A words grouped by semantic category is the
ratio of correct responses followed by another correct response from
the same category, relative to the expected clustering by chance.
Indicates the degree to which the examinee uses the active learning
strategy of reorganizing the target words into categorical groups.
Recall consistency The ability to recall consistently the same words across repeated
presentations of the same list. This index measures the percentage of
target words recalled on one of the first four trials that are also recalled
on the very next trial.
Recall errors
Intrusions, cued recall The type of recall errors, which are responses not on the target list on
short and long delay.
The descriptions were formulated utilising the following references: Delis et al., 1987; Roofeh et al., 2006;
Rannikko et al., 2012.
84
5.4.2 Other cognitive measures
Abstraction, Inhibition and Working Memory task
The Abstraction, Inhibition and Working Memory task (AIM; Glahn et al., 2000) is
a computerised test of rule-abstraction/category learning in which the examinee
uses information to group stimuli in a meaningful way. Abstracting visual
information about shape and colour and using it in making category judgements
based on shared characteristics is needed for successful performance. AIM is not a
commonly used cognitive measure in schizophrenia research, but it correlates with
other more commonly used tests of executive functions, such as Wisconsin Card
Sorting Test.
In the test two pairs of objects are shown on the screen, one pair in the upper
left corner and one pair in the upper right corner. A fifth object, the target object, is
presented in the centre below the other objects. The task is to group the target object
with the left or right pair. In half of the trials, there is a 2.5 second delay between
the presentation of the target object and other objects, adding a requirement of
maintaining working memory (abstraction + memory). The stimuli vary in colour
(red, yellow or blue) and shape (modified circles, squares or triangles). The correct
answer is to group the target object with the most obvious, least complex set.
Feedback is given after every trial.
The task results in two outcome measures: total score of the abstraction trials
and total score of trials with abstraction and memory, both ranging from 0 to 30
points (Glahn et al., 2000). Participants with below chance performance (scores of
less than half of the maximum score) were excluded. In original studies II and III,
total performance combining both of the scores was included in the analyses to
represent executive functions in the neurocognitive set.
Visual Object Learning Test
The Visual Object Learning Test (VOLT; Glahn et al., 1997) is a computerised test
of visual-spatial learning and memory analogous to verbal tests (for example,
CVLT). It is not a common measure in schizophrenia research, but it is also
correlated with other visual memory tests (Glahn et al., 1997).
The VOLT consists of complex and unfamiliar three-dimensional Euclidean
shapes. In a learning trial a learning set comprising 10 visual objects is shown to a
participant, who then, in a forced choice paradigm, tries to recognise them from a
85
group of 20 objects, of which 10 are distractors. There are 4 learning trials, each of
them with new distractors, and after each trial the learning set is shown again. There
are also short and long delay trials.
The total number of correct answers in the four trials is the outcome measure,
which reflects both correctly recognised and correctly rejected targets. The total
score ranges from 0 to 80 points. Scores with less than half of the maximum points
were considered as below chance performance and excluded. The total VOLT score
was utilised in the neurocognitive set of original studies II and III to represent visual
memory.
Verbal fluency
The Verbal fluency (Lezak et al., 2004) is a short test of verbal functioning. The
expressive or motor semantic fluency tasks were utilised in this study. Semantic
fluency tasks are well-established and useful in the cognitive examination of
schizophrenia patients both in clinical and scientific purposes and they involve
complex cognitive processes, for example, verbal memory, executive and
psychomotor functions (Tyburski, Sokolowski, Chec, Pelka-Wysiecka, &
Samochowiec, 2015).
In the Verbal fluency test, a participant is instructed to say as many words as
they can from three different semantic categories: animals, fruits or berries and
vegetables. The time limit for each category is 60 seconds. The total number of
correct answers from each category is the outcome measure chosen to the
neurocognitive battery in original studies II and III.
Visual series (WMS-III)
Visual series is a test of visuo-spatial working memory and a subtest of the Wechsler
Memory Scale 3rd edition (WMS-III; Wechsler, 2008), a widely-used set of tests to
assess learning, memory and working memory, standardised also in the Finnish
population.
The Visual series test measures the ability to repeat series based on visual
observation by touching dices placed on a white board after the examiner both in
the same order and in the reverse order. The total score of correct answers in both
of these trials was included in the neuropsychological test battery to represent
working memory.
86
Vocabulary (WAIS-III)
Vocabulary is a test of verbal comprehension and a subtest of the Wechsler Adult
Intelligence Scale 3rd edition (WAIS-III; Wechsler, 2005), a widely-used and
standardised IQ test designed to measure intelligence and cognitive ability in adults
and adolescents from 16 years of age onwards.
In the Vocabulary test the examinee is read a list of words one word at a time
and asked to explain the meaning of the words. The total score was included in the
neuropsychological battery to represent verbal intelligence.
Digit span (WAIS-III)
Digit span, also a subtest of WAIS-III, is an auditive-phonological working
memory test. In the Digit span test the task is to repeat the series of numbers read
to the examinee both in the same order and in the reverse order. The total score of
correct answers was included in the neuropsychological set as a measure of
working memory.
Matrix reasoning (WAIS-III)
The Matrix reasoning, a subtest of WAIS-III, is a test of performance intelligence,
more specifically assessing perceptual organisation. It includes four types of
reasoning tasks: completing a series, categorisation, finding similarities and
forming sequences of logical reasoning. The total score of Matrix reasoning was
included in the neuropsychological set to represent performance intelligence.
5.4.3 Global cognitive performance
The eight chosen variables of the neurocognitive test battery were included in a
principal component analysis (PCA), which resulted in a cognitive composite score
representing global cognitive performance of both subjects with schizophrenia (II,
III) and controls (II).
87
Fig. 3. Illustration of the medication and cognitive variables. Variables on cumulative exposure to psychiatric medications were collected from patient history records during the whole illness duration and analysed with interview information of the current use of psychiatric medications and cognitive variables obtained in neuropsychological assessments in the baseline and 43-year/follow-up studies.
1966 1980 1999–2001 2008–2011
34 y 43 y14 y0 y
Lifetime cumulative exposure to psychiatric medications
Cumulative antipsychotic exposure until the baseline Cumulative antipsychotic exposure during the follow-up
Neuropsychological assessmentCalifornia Verbal Learning Test (CVLT)
Neuropsychological assessmentCalifornia Verbal Learning Test (CVLT)Abstraction Inhibition and Working Memory task (AIM) Visual Object Learning Test (VOLT) Verbal fluency Visual series (WMS-III) Vocabulary (WAIS-III)Digit Span (WAIS-III)Matrix reasoning (WAIS-III)
Current use and dose of psychiatric medications
Current use and dose of psychiatric medications
BASELINE STUDY FOLLOW-UP STUDY
88
5.5 Background variables and covariates
The background variables and covariates represent sociodemographic and clinical
characteristics related to duration of illness, symptomatic severity and functional
ability. The more detailed definitions of the variables are presented in Table 7.
Table 7. Background variables and covariates.
Name of the variable Description of the variable (source)
Age of illness onset Age when the first evident psychotic symptoms appeared, which due to the birth
cohort design also indicates the duration of illness (medical records, registers).
Educational level 1) Basic = 9 years or less of basic education and low vocational education
(none, course or school or currently studying)
2) Secondary = 9 years of basic education and high vocational education
(college, polytechnic or university) or 12 years of basic education and low
vocational education
3) Tertiary = 12 years of basic education and high vocational education
(questionnaire information at the baseline and follow-up).
Clinical Global
Impression scale (CGI)
The Severity of Illness subscale ranging from 1 (not ill at all) to 7 (among the
most extremely ill) (interview at the baseline and follow-up).
Cumulative number of
hospital treatment days
Cumulative number of days in psychiatric hospital treatment until the baseline
(I) and follow-up (II, III) (the Care Register for Health Care).
Current or earlier
alcohol use disorder
Comorbid alcohol abuse or dependence diagnosis until the baseline (I) or
follow-up study (II, III) (SCID I interview at the baseline and follow-up).
Current use of alcohol Current use of alcohol (grams per day) at baseline and follow-up studies
(interview at baseline and follow-up).
Occupational status 1) working = studying, on maternity leave or in full-time or part-time work
2) not working/on a disability pension = unemployed, outside of working life for
other reasons or retired due to psychiatric or other illness
(interview at baseline and follow-up, Finnish Centre for Pension registers).
Positive and Negative
Syndrome Scale
(PANSS)
A measure of psychopathological symptoms evaluated from one week before
the baseline and follow-up studies and divided into positive, negative and
disorganisation symptoms based on the model described by van der Gaag et al.
(2006) (SCID I and diagnostic interview at the baseline (I), a PANSS specific
interview at the follow-up (II, III)).
Remission Defined according to the Andreasen et al. (2005) symptomatic criteria without
the duration criteria: no symptoms in PANSS at the baseline or no PANSS
symptoms and no psychiatric hospital treatments 6 months before the follow-up.
Social and Occupational
Functioning
Assessment Scale
(SOFAS)
Scale assessing social activity and work ability ranging from 0 to 100 with
higher scores indicating better functioning (interview at the baseline and follow-
up).
89
5.6 Statistical methods
The characteristics of the samples and current and lifetime use of medications are
presented as frequency distributions, means and standard deviations (SD) for
normally distributed variables and medians and interquartile ranges (IQR) for
variables with skewed distributions. The cognitive performance at the baseline and
follow-up are reported as means with SDs, and the comparisons between
schizophrenia subjects and controls were performed using independent samples t-
test.
The change of verbal learning and memory (I) was calculated by subtracting
the baseline score from the follow-up score in each CVLT variable.
The measure of global cognitive performance of schizophrenia subjects (II, III)
and controls (II) was the result of a principal component analysis (PCA) of the eight
selected cognitive test variables (total scores of Immediate free recall of trials 1–5
of the CVLT, AIM, VOLT, Verbal fluency, Visual series, Vocabulary, Digit Span,
Matrix reasoning). Missing cognitive test scores (reported in original study II,
chapter 2.5, Statistical analyses) were predicted based on the values of the eight
cognitive test variables by multiple imputation (20 datasets) with fully conditional
specification (MCMC) method and linear regression as model type. The PCA
(eigenvalue set as > 1) lead to one cognitive factor (cognitive composite score),
which explained 52.9% of total variance. Communalities ranged between 0.32 and
0.66 and factor loadings between 0.57 and 0.81.
The associations between the medication variables and cognitive variables (I–
III) were analysed in linear regression analyses, in which the medication variables
were used as predictor variables. The natural logarithmic transformation was
applied to the medication variables of cumulative exposure (CPZ equivalent dose-
years or DDD years) to correct for the skewness of their distributions. The
medication variables were used as continuous and classified variables in the
analyses.
For the comparison of verbal learning and memory between schizophrenia
subjects with high and low antipsychotic exposure and controls (I) the
schizophrenia subjects were divided into groups with above and below median CPZ
dose-years antipsychotic exposure. The CVLT change scores were standardised to
the baseline CVLT scores of controls. The differences in the change of verbal
learning and memory between controls and schizophrenia subjects with high- and
low-dose exposure were analysed using analysis of covariance controlling for
baseline performance in each CVLT variable. The effects of the medication
90
variables are presented as unstandardised regression coefficients (B) and their
standard error (SE), standardised regression coefficients (Beta) and p-values.
The association between lifetime dose-years of any antipsychotics and global
cognition (II) was visualised using scatter plot. The global cognitive performance
of schizophrenia subjects in low-, medium- and high-dose groups of psychiatric
medication exposure (III) was analysed by plotting the means of the cognitive
composite score with 95% confidence intervals in the high-dose, medium-dose and
low-dose groups (divided based on tertiles) of cumulative DDD years of the
medications.
P-values < 0.05 were interpreted as statistically significant. IBM SPSS
Statistics 21.0 (I, II) and 24.0 (III) were used to perform the analyses (IBM, 2012,
2016).
91
6 Ethical considerations and personal involvement
6.1 Ethical considerations
The permission to gather data for the NFBC1966 study was obtained from the
Ministry of Social and Health Affairs in 1993. The Ethical Committee of the
Northern Ostrobothnia Hospital District has approved the research design and
supervises the NFBC1966 follow-up studies. The research plan of the NFBC1966
34-year follow-up study was accepted by the Ethical Committee of Oulu University,
Faculty of Medicine, on 30th March 1998, and the research plan of the 43-year
follow-up on 18th February 2008 by the Regional Ethics Committee of the
Northern Ostrobothnia Hospital District. Data protection has been verified by the
Privacy Protection Agency. Informed consent to use data has been ascertained from
all cohort members and written informed consent from each participant of the 34-
year and 43-year follow-up studies. The participants have been designated
individual research ID numbers and their identities are protected from becoming
revealed. All subjects have the right to deny the use of their information at any time.
The Code of Ethics of the World Medical Association for experiments involving
humans (Declaration of Helsinki and its later amendments) has been adhered to
throughout the study.
6.2 Personal involvement
I have participated in the NFBC1966 study since 2012, when I joined the research
group of my principal supervisor, Adjunct Professor, Erika Jääskeläinen and other
supervisors Professor Jouko Miettunen and Professor (emeritus) Matti Isohanni. I
received the doctoral study right of the University of Oulu Graduate School on 9th
October 2012. I have carried out this doctoral research in the Research Unit of
Clinical Neuroscience, University of Oulu and since January 2014 I have
additionally had a doctoral study position of the Medical Research Center Oulu,
Oulu University Hospital and University of Oulu.
Outside of this doctoral thesis, I have been a co-writer on four other
publications as an expert of antipsychotics and cognition (Jääskeläinen et al., 2015;
Rannikko et al., 2015b; Rannikko et al., 2016; Rannikko et al., 2015a).
92
I have designed the original studies in collaboration with my supervisors and
co-authors. Because of the longitudinal nature of this study, I had a limited role in
the collection of the data utilised in this study before 2012. I have participated in
recording cognitive test data, evaluating medical records and collecting data on
lifetime antipsychotic and benzodiazepine medications and evaluating current
doses of psychiatric medications. I was also involved in transforming doses of
psychiatric medications to DDDs and creating medication variables. I have
performed statistical analyses of the original studies with the help and consultation
of statisticians. I conducted all literature searches myself and wrote this compilation
thesis independently. I have, as the first author, written the first and final versions
of all original studies. I was also the corresponding author responsible for
completing the revision and resubmission processes of all the original studies.
93
7 Results
7.1 Characteristics of the samples (I–III)
The schizophrenia subsample in original study I (n = 40) consisted of 19 (48%)
females. The mean age of illness onset was 23.4 years (SD 4.4) and the mean
duration of illness was 10.2 years (SD 4.3) at the baseline. The mean duration of
the follow-up in original study I was 9.1 years (SD 0.6). At the baseline study the
frequencies of persons in low, middle and high educational level classes in the
schizophrenia subsample (study I) were 21 (52%), 12 (30%) and 7 (18%)
respectively and 15 (38%) were working and 25 (63%) were unemployed or on
disability pension.
The total sample of subjects with schizophrenia in original studies II and III (n
= 60) was formed by 27 (45%) females. The mean age of illness onset was 26.6
years (SD 6.3) and mean duration of illness 16.5 years (SD 6.0). Thirty-three (56%)
persons had a low educational level, 15 (25%) middle and 11 (19%) high. In the
total schizophrenia sample (II, III) 18 (30%) schizophrenia subjects were working
and 42 (70%) unemployed or on disability pension. More detailed characteristics
of the samples of schizophrenia subjects are presented in Table 8.
In original study I the sample of control subjects (n = 73) comprised 28 (38%)
females. The educational level of 31 (42%) controls in this sample was low, 13
(18%) were educated to the middle and 29 (40%) to high level. Sixty-eight (93%)
of these controls were working at the time of the baseline study. The mean duration
of follow-up in the control sample in original study I was 8.5 years (SD 0.6).
The control sample of original study II (n = 191) included 97 (51%) females.
Seventy-one (37%) of these controls had a low educational level, 46 (24%) middle
level and 73 (38%) high educational level. 182 (95%) of this control sample were
working during the follow-up study.
94
Table 8. Characteristics of the schizophrenia subjects in original studies I–III.
Background and clinical factors Baseline study
Subsample of
schizophrenia (I),
n = 40
Follow-up study
Subsample of
schizophrenia (I),
n = 40
43-year study
Total
schizophrenia
sample (II, III),
n = 60
Gender, n (%)
Male 21 (53%) 21 (53%) 33 (55%)
Female 19 (48%) 19 (48%) 27 (45%)
Educational level, n (%)1
Low 21 (52%) 19 (49%) 33 (56%)
Middle 12 (30%) 10 (26%) 15 (25%)
High 7 (18%) 10 (26%) 11 (19%)
Occupational status, n (%)
Working 15 (38%) 12 (32%) 18 (30%)
Unemployed/on disability pension 25 (63%) 25 (68%) 42 (70%)
Current use of alcohol (g/day), median (IQR)1 1.6 (0.0–8.0) 1.0 (0.0–11.0) 1.2 (0.0–14.0)
Current or earlier alcohol use disorder, n (%)
Yes 8 (20%) 10 (25%) 6 (10%)
No 32 (80%) 30 (75%) 54 (90%)
Age of illness onset (years), mean (SD) 23.4 (4.4) 26.6 (6.3)
Cumulative number of hospital treatment days,
median (IQR)
163 (45–750) 236 (78–933) 210 (84–687)
Duration of illness (years), mean (SD) 10.2 (4.3) 18.5 (4.6) 16.5 (6.0)
Diagnosis, n (%)
Schizophrenia 33 (83%) 33 (83%) 50 (83%)
Schizophrenia spectrum disorder 7 (17%) 7 (17%) 10 (17%)
SOFAS, mean (SD) 51 (17) 52 (17) 51 (17)
CGI, mean (SD) 4.6 (1.5) 4.4 (1.4) 4.5 (1.4)
PANSS, mean (SD)1
Total 52.6 (19.8) 67.2 (23.9) 66.6 (23.5)
Positive symptoms 12.0 (5.6) 16.3 (8.0) 15.8 (7.7)
Negative symptoms 14.5 (8.6) 18.1 (8.2) 19.1 (9.5)
Remission, n (%)1
Yes 15 (38%) 14 (35%) 16 (28%)
No 25 (63%) 26 (65%) 42 (72%)
IQR = interquartile range, SD = standard deviation, SOFAS = Social and Occupational Functioning
Assessment Scale, CGI = Clinical Global Impression, PANSS = Positive and Negative Syndrome Scale. 1There were missing data at the 43-years study for 1 subject in education, 1 subject in current use of
alcohol, 2 subjects in PANSS and 2 subjects in remission.
95
7.2 The current and lifetime use of psychiatric medications (I-III)
In the schizophrenia subsample (n = 40, original study I) any antipsychotic
medication was used by 27 (68%), benzodiazepines by 12 (30%), antidepressants
by 7 (18%) and anticholinergics by 4 (10%) persons at the baseline study and
respectively by 32 (80%), 9 (23%), 7 (18%) persons and none at the follow-up. The
use of typical antipsychotics was more common at the baseline, whereas at the
follow-up atypical agents were more often used than typical ones. The current use
of psychiatric medications and antipsychotic doses in the schizophrenia subsample
are described in Table 9.
Lifetime cumulative antipsychotic exposure of the schizophrenia subsample
can be found in original study I Table 2. Median exposure to any antipsychotics by
the baseline was 10.2 CPZ dose-years (IQR 2.8–39.3) consisting mostly of typical
antipsychotics (8.4 vs. 0.1 CPZ dose-years). Between the baseline and follow-up
any antipsychotic exposure was 16.7 CPZ dose-years (IQR 4.7–47.3) and atypical
exposure higher than typical exposure (9.6 vs. 1.6 CPZ dose-years).
In the total schizophrenia sample (n = 60, original studies II–III) any
antipsychotics were used by 51 (85%), benzodiazepines by 23 (38%),
antidepressants by 13 (22%) persons and anticholinergic agents by none at the 43-
year study. Compared to typicals, atypical antipsychotics were used more
commonly and with higher doses. During the whole lifetime, until the follow-up
study, any antipsychotics had been used by 59 (98%), benzodiazepines by 43 (72%),
antidepressants by 25 (42%) and anticholinergic agents by 26 (43%) subjects. Most
had used both typical and atypical agents. The cumulative lifetime exposures were
10.4, 4.6, 3.4 and 0.3 DDD years respectively (Table 10), which were relatively
low exposures (0.25 DDDs of benzodiazepines, 0.19 DDDs of antidepressants and
0.01 DDDs of anticholinergics per day during the whole duration of illness in the
user sample) in comparison with global statistics (1 DDD is the average daily dose).
Cumulative atypical exposure was higher than cumulative typical exposure. More
details are shown in Table 10.
Lifetime and current use of psychiatric medication agents in the total
schizophrenia sample is presented in original study III supplement Table 1.
96
Table 9. Current use of psychiatric medications and current antipsychotic doses at the baseline and follow-up in the schizophrenia subsample (n = 40) (baseline use modified from original study I Online supplement Table 2).
Medication Current use at the baseline Current use at the follow-up
n (%) CPZ equivalent
Md (IQR)
n (%) CPZ equivalent
Md (IQR)
Any antipsychotics 27 (68%) 200 (100–451) 32 (80%) 300 (138–655)
Typical antipsychotics 18 (45%) 175 (51–368) 13 (33%) 200 (93–400)
Atypical antipsychotics 13 (33%) 300 (200–400) 26 (65%) 350 (188–600)
Benzodiazepines 12 (30%) n/a 9 (23%) n/a
Antidepressants 7 (18%) n/a 7 (18%) n/a
Anticholinergic agents 4 (10%) n/a 0 (0%) n/a
Md = median, IQR = interquartile range. Medians and interquartile ranges were calculated for the users of
the group of medication.
97
Tabl
e 10
. Cur
rent
use
of p
sych
iatr
ic m
edic
atio
ns a
t the
43-
year
stu
dy a
nd c
umul
ativ
e lif
etim
e ex
posu
re to
psy
chia
tric
med
icat
ions
by
the
43-
year
stu
dy in
the
tot
al s
chiz
ophr
enia
sam
ple
(n =
60)
(m
odifi
ed f
rom
Tab
le 2
in o
rigi
nal s
tudy
II a
nd T
able
3 in
ori
gina
l st
udy
III).
Med
icat
ion
Cur
rent
use
at t
he 4
3-ye
ar s
tudy
Life
time
cum
ulat
ive
expo
sure
by
the
43-y
ear s
tudy
n
(%)
DD
D ra
tio
Md
(IQR
)
CP
Z eq
uiva
lent
Md
(IQR
)
n
(%)
DD
D y
ears
Md
(IQR
)
Dos
e-ye
ars
Md
(IQR
)
Any
ant
ipsy
chot
ics
51 (8
5%)
1.2
(0.7
–2.5
) 30
0 (2
00–6
08)
59
(98%
) 10
.4 (5
.0–2
9.7)
29
.2 (1
2.7–
69.6
)
Typi
cal a
ntip
sych
otic
s 19
(32%
) 0.
5 (0
.3–0
.7)
200
(100
–271
)
54 (9
0%)
5.2
(0.9
–12.
3)
9.6
(0.8
–32.
7)
Aty
pica
l ant
ipsy
chot
ics
43 (7
2%)
1.3
(1.0
–2.0
) 40
0 (2
00–6
00)
49
(82%
) 8.
5 (3
.4–1
5.6)
16
.1 (2
.6–3
7.9)
Ben
zodi
azep
ines
23
(38%
) 1.
0 (0
.4–1
.5)
n/a
43
(72%
) 4.
6 (1
.2–1
6.1)
n/
a
Ant
idep
ress
ants
13
(22%
) 1.
3 (1
.0–1
.8)
n/a
25
(42%
) 3.
4 (0
.8–1
2.9)
n/
a
Ant
icho
liner
gic
agen
ts
0 (0
%)
0.0
n/a
26
(43%
) 0.
3 (0
.04 –
1.3)
n/
a
Md
= m
edia
n, IQ
R =
inte
rqua
rtile
rang
e. M
edia
ns a
nd in
terq
uarti
le ra
nges
wer
e ca
lcul
ated
for u
sers
of t
he g
roup
of m
edic
atio
n
98
7.3 Cognitive performance at the baseline and follow-up (I–III)
Schizophrenia subjects performed significantly poorer than controls in all studied
verbal learning and memory variables at the baseline and follow-up (I) and in global
cognition at the 43-year study (II, III). Only in learning slope were there no
significant differences at baseline. The original scores are shown in Tables 11 and
12.
Table 11. Original values of the CVLT in the subsample of schizophrenia (n = 40) and controls (n = 73) at the baseline and the follow-up studies (Table 3 in original study I).
Cognitive variable Baseline study Follow-up study
Schizophrenia
mean (SD)
Controls
mean
(SD)
Sig Schizophrenia
mean (SD)
Controls
mean
(SD)
Sig1
Immediate free recall of trials 1–5 48.6 (13.5) 60.1 (6.8) <0.001 45.4 (14.4) 55.0 (8.4) <0.001
Short-delay free recall 10.2 (3.9) 13.2 (2.1) <0.001 9.9 (3.9) 12.0 (2.6) 0.003
Long-delay free recall 11.3 (3.7) 13.7 (2.0) <0.001 10.3 (3.7) 12.5 (2.5) 0.001
Semantic clustering 1.8 (0.9) 2.4 (0.7) <0.001 1.8 (0.9) 2.3 (0.9) 0.009
Recall consistency 0.8 (0.1) 0.9 (0.1) 0.002 0.8 (0.2) 0.8 (0.1) 0.010
Learning slope 1.4 (0.7) 1.6 (0.7) 0.218 1.2 (1.1) 1.6 (0.6) 0.049
Intrusions, cued recall 1.1 (1.8) 0.4 (1.0) 0.032 2.1 (3.0) 0.8 (1.2) 0.014
SD = standard deviation, Sig = statistical significance. 1 Difference between schizophrenia subjects and controls.
99
Table 12. Original values of cognitive tests and cognitive composite score in the total schizophrenia sample (n = 60) and controls (n = 191) at the 43-year study (Table 3 in original study II).
Cognitive variable 43-year study
Schizophrenia
mean (SD)
Controls
mean (SD)
Sig1
AIM, Total score 41.5 (8.0) 48.3 (5.0) <0.001
CVLT, Immediate free recall of trials 1–5 43.7 (15.4) 55.2 (9.0) <0.001
VOLT, Total score 60.1 (9.8) 67.7 (5.4) <0.001
Verbal fluency, Total score 47.5 (12.9) 58.4 (12.3) <0.001
Visual series (WMS-III), Total score 15.0 (4.1) 17.8 (2.8) <0.001
Vocabulary (WAIS-III), Total score 34.1 (14.7) 45.3 (11.4) <0.001
Digit span (WAIS-III), Total score 14.1 (3.9) 16.4 (3.9) <0.001
Matrix reasoning (WAIS-III), Total score 14.4 (5.8) 19.5 (3.6) <0.001
Cognitive composite score2 -0.98 (1.2) 0.29 (0.7) <0.001
SD = standard deviation, Sig = statistical significance. 1 Difference between schizophrenia subjects and controls. 2 Principal component analysis.
7.4 Cumulative exposure to antipsychotics and verbal learning and memory at the baseline (I)
Higher cumulative dose-years of any and typical antipsychotics by the baseline
were significantly associated with poorer performance in several verbal learning
and memory variables at the baseline (Table 13). Dose-years of atypical
antipsychotics by the baseline were not associated with verbal learning and memory.
100
Table 13. The association between antipsychotic dose-years by the baseline and baseline verbal learning and memory performance in the schizophrenia subsample (n = 40) (modified Table 4 in original study I).
Medication and cognitive variables B (SE)1 Beta1 Sig1 B (SE)2 Beta2 Sig2
Any antipsychotics
Immediate free recall of trials 1–5 -3.0 (2.1) -0.31 0.160 -5.9 (2.3) -0.62 0.014 Short-delay free recall -1.0 (0.6) -0.34 0.112 -1.6 (0.7) -0.58 0.019 Long-delay free recall -1.2 (0.5) -0.45 0.036 -1.7 (0.6) -0.66 0.007 Semantic clustering 0.01 (0.1) 0.02 0.934 -0.2 (0.2) -0.29 0.241
Recall consistency -0.03 (0.02) -0.28 0.240 -0.1 (0.03) -0.48 0.072
Learning slope -0.2 (0.1) -0.30 0.205 -0.1 (0.1) -0.26 0.309
Intrusions, cued recall3 0.5 (0.3) 0.36 0.108 0.3 (0.3) 0.20 0.450
Typical antipsychotics
Immediate free recall of trials 1–5 -3.0 (2.1) -0.33 0.159 -5.0 (2.1) -0.55 0.024 Short-delay free recall -1.1 (0.6) -0.42 0.067 -1.6 (0.6) -0.59 0.013 Long-delay free recall -1.3 (0.5) -0.52 0.024 -1.6 (0.6) -0.65 0.006 Semantic clustering -0.1 (0.1) -0.11 0.651 -0.2 (0.1) -0.36 0.133
Recall consistency -0.04 (0.02) -0.40 0.112 -0.1 (0.03) -0.55 0.033 Learning slope -0.2 (0.1) -0.38 0.121 -0.2 (0.1) -0.35 0.160
Intrusions, cued recall3 0.3 (0.3) 0.25 0.289 0.05 (0.3) 0.04 0.880
Atypical antipsychotics
Immediate free recall of trials 1–5 -1.2 (1.7) -0.11 0.474 -2.4 (2.0) -0.20 0.245
Short-delay free recall -0.2 (0.5) -0.06 0.701 -0.3 (0.6) -0.10 0.567
Long-delay free recall -0.4 (0.5) -0.11 0.456 -0.5 (0.5) -0.15 0.395
Semantic clustering 0.1 (0.1) 0.09 0.548 -0.01 (0.1) -0.02 0.927
Recall consistency -0.003 (0.02) -0.02 0.880 -0.01 (0.02) -0.06 0.757
Learning slope -0.04 (0.1) -0.07 0.674 -0.003 (0.1) -0.005 0.978
Intrusions, cued recall3 0.3 (0.2) 0.18 0.243 0.2 (0.3) 0.15 0.399
B = regression coefficient, SE = standard error, Beta = standardised regression coefficient, Sig =
statistical significance. 1 Adjusted for gender, age of illness onset and PANSS Total score at the baseline. 2 Adjusted for gender, age of illness onset and logarithmic transformation of cumulative psychiatric
hospital treatment days by the baseline.
3 Inverse score of intrusions, cued recall, was used to help comparison to other CVLT variables.
101
7.5 Cumulative exposure to antipsychotics and change in verbal learning and memory between the baseline and follow-up (I)
Higher dose-years of any and atypical antipsychotics by the baseline were
significantly associated with a greater decline in short-delay free recall during the
9-year follow-up, and higher atypical antipsychotics, also with a greater increase in
intrusions, cued recall during the follow-up (Table 14). In post-hoc analyses, higher
dose-years of clozapine, but not other atypical antipsychotics, were significantly
associated with a greater decline in short-delay free recall, and increase in
intrusions cued recall during the follow-up (supplementary material of original
study I). The direction of the association between higher antipsychotic dose-years
and a decline in verbal learning and memory was the same in almost all analysed
CVLT variables.
Higher dose-years of any antipsychotics during the 9-year follow-up were
significantly associated with a decline in Immediate free recall of trials 1–5 (B = -
4.4, SE = 2.1, Beta = -0.48, Sig = 0.039), when adjusted for baseline cognitive
performance, gender, age of illness onset and logarithmic transformation of
cumulative psychiatric treatment days by the baseline. There were no other
significant associations between antipsychotic dose-years during the 9-year follow-
up and change of CVLT-variables. See original study I Table 6 for more detailed
results.
The schizophrenia subsample was divided to low-dose and high-dose groups
based on median antipsychotic dose-years by the baseline. The baseline
performance and change in verbal learning and memory during the follow-up were
compared between these groups and the non-medicated control subsample. The
subjects exposed to high antipsychotic dose-years had poorer baseline performance
than the two other groups in all CVLT variables except for Intrusions, cued recall
in which there was no significant difference between subjects with high and low
dose-years (Fig. 4). The subjects with high antipsychotic exposure experienced
more cognitive decline than subjects with low-dose exposure in intrusions, cued
recall (p < 0.001), and also more decline than controls in recall consistency (p =
0.02), learning slope (p = 0.03) and cued recall intrusions (p < 0.001) (Fig. 4).
102
Table 14. The association between antipsychotic dose-years by the baseline and change of verbal learning and memory between the baseline and follow-up in the schizophrenia subsample (n=40) (modified Table 5 in original study I).
Medication and cognitive variables B (SE)1 Beta1 Sig1 B (SE)2 Beta2 Sig2
Any antipsychotics
Immediate free recall of trials 1–5 -3.3 (2.2) -0.36 0.143 -4.3 (2.6) -0.46 0.105
Short-delay free recall -1.1 (0.5) -0.50 0.039 -1.3 (0.6) -0.60 0.031
Long-delay free recall -0.9 (0.5) -0.39 0.120 -1.1 (0.6) -0.51 0.079
Semantic clustering -0.1 (0.1) -0.10 0.636 -0.2 (0.2) -0.30 0.229
Recall consistency -0.02 (0.03) -0.12 0.605 -0.02 (0.04) -0.16 0.541
Learning slope -0.1 (0.2) -0.14 0.529 -0.05 (0.2) -0.05 0.837
Intrusions, cued recall3 -0.5 (0.5) -0.26 0.315 -0.8 (0.6) -0.41 0.134
Typical antipsychotics
Immediate free recall of trials 1–5 -1.5 (2.3) -0.17 0.513 -1.8 (2.4) -0.20 0.471
Short-delay free recall -0.6 (0.6) -0.29 0.274 -0.6 (0.6) -0.28 0.320
Long-delay free recall -0.3 (0.6) -0.15 0.574 -0.3 (0.6) -0.15 0.596
Semantic clustering 0.01 (0.1) 0.02 0.946 -0.1 (0.1) -0.13 0.591
Recall consistency -0.01 (0.03) -0.08 0.743 -0.02 (0.03) -0.11 0.664
Learning slope 0.1 (0.2) 0.15 0.528 0.2 (0.2) 0.23 0.335
Intrusions, cued recall3 -0.4 (0.5) -0.19 0.488 -0.5 (0.5) -0.28 0.296
Atypical antipsychotics
Immediate free recall of trials 1–5 -2.6 (1.8) -0.23 0.155 -2.8 (2.0) -0.25 0.163
Short-delay free recall -0.8 (0.4) -0.30 0.054 -1.0 (0.5) -0.34 0.047
Long-delay free recall -0.6 (0.4) -0.23 0.158 -0.8 (0.5) -0.28 0.114
Semantic clustering -0.1 (0.1) -0.11 0.452 -0.1 (0.1) -0.19 0.251
Recall consistency -0.01 (0.03) -0.06 0.688 -0.01 (0.03) -0.06 0.715
Learning slope -0.3 (0.2) -0.25 0.091 -0.3 (0.2) -0.24 0.139
Intrusions, cued recall3 -0.9 (0.4) -0.36 0.031 -1.2 (0.4) -0.47 0.009
B = unstandardised regression coefficient, SE = standard error, Beta = standardised regression
coefficient, Sig = statistical significance. 1 Adjusted for baseline performance, gender, age of illness onset and PANSS Total score at the baseline. 2 Adjusted for baseline performance, gender, age of illness onset and logarithmic transformation of
cumulative psychiatric hospital treatment days by the baseline. 3 Inverse score of intrusions, cued recall, was used to help comparison to other CVLT variables.
103
Fig. 4. Baseline and follow-up verbal learning and memory performance in the schizophrenia subsample (n = 40) with high and low (above and below median) antipsychotic dose-years by the baseline and the control subsample (n = 73). The baseline mean values of controls are indicated by the 0-axis. P-values show the difference in the change of the CVLT variable between the two groups, adjusted for baseline CVLT performance (Fig. 1 in original study I).
104
7.6 The current use of psychiatric medications and global cognition at the 43-year study (III)
The current use and dose of any antipsychotics and current antipsychotic
polypharmacy were significantly associated with poorer global cognition at the 43-
year study. The adjusted associations did not remain significant, except for the use
of any antipsychotics (Table 15). The current use or dose of benzodiazepines or
antidepressants were not significantly associated with global cognition (Table 15).
Table 15. The association between current use and doses of psychiatric medications and global cognition in the total schizophrenia sample (n = 60) at the 43-year study (modified Table 4 and Table 5 in original study III).
Medication variable B (SE)1 Beta1 Sig1 B (SE)2 Beta2 Sig2
Current use of any antipsychotics3 -0.88 (0.35) -0.32 0.012 -0.90 (0.33) -0.32 0.006 Current use of benzodiazepines4 -0.15 (0.27) -0.07 0.571 0.08 (0.26) 0.04 0.761
Current use of antidepressants4 0.48 (0.31) 0.20 0.127 0.19 (0.33) 0.08 0.561
Current DDD ratio of any antipsychotics -0.23 (0.10) -0.30 0.017 -0.14 (0.10) -0.18 0.181
Current DDD ratio of benzodiazepines4 -0.37 (0.24) -0.41 0.115 -0.25 (0.21) -0.27 0.238
Current DDD ratio of antidepressants4 -0.60 (0.42) -0.32 0.148 -0.78 (0.45) -0.42 0.081
Current antipsychotic polypharmacy -0.74 (0.30) -0.31 0.012 -0.49 (0.31) -0.21 0.110
B = unstandardised regression coefficient, SE = standard error, Beta = standardised regression
coefficient, Sig = statistical significance. 1 Unadjusted model. 2 Adjusted for gender and onset age. 3 Current use of any antipsychotics was significantly associated with global cognition also, when adjusted
for gender, onset age and PANSS Positive symptoms (B = -0.81, SE = 0.35, Beta = -0.29, Sig = 0.021)
and gender, onset age and lifetime cumulative psychiatric hospital treatment days (B = -0.98, SE = 0.36,
Beta = -0.35, Sig = 0.007). 4 The analyses were completed in users of the medication and those with no use were excluded.
7.7 Lifetime cumulative exposure to antipsychotics and global cognitive performance at the 43-year study (II, III)
Higher cumulative exposure to any antipsychotics by the 43-year study, expressed
both as CPZ equivalent dose-years and DDD years, was significantly associated
with poorer global cognition at the 43-year study unadjusted and when adjusted for
gender, onset age and lifetime psychiatric hospital treatment days (Table 16). When
adjusted for gender, onset age and PANSS positive symptoms, higher dose-years
of any antipsychotics were significantly associated with global cognition, but there
105
was only a statistical trend between higher DDD years of any antipsychotics and
global cognition (Table 16). The association between higher lifetime antipsychotic
exposure and poorer global cognition remained significant when adjusted for
gender, onset age and the current use of benzodiazepines at the time of the 43-year
study (original study II Table 4 and original study III Table 5). The association
between higher lifetime dose-years of any antipsychotics and poorer global
cognition is also illustrated in Fig. 5.
When analysing type of antipsychotics, both higher dose-years of typical and
atypical antipsychotics had significant unadjusted and adjusted associations with
poorer global cognition (Table 4 in original study II), but in the selected adjusted
models analysed also with DDD years, only higher atypical dose-years were
significantly associated with poorer global cognition (Table 16).
The mean global cognitive performance of the lowest, medium and highest
tertile of cumulative DDD years of antipsychotics, benzodiazepines and
antidepressants by the 43-year study are shown in Fig. 6. Unadjusted associations
between higher exposures to any antipsychotics and benzodiazepines and poorer
global cognition resembled linear connection, but the association between
antidepressant exposure and cognition did not with both low and high cumulative
antidepressant DDD years associating to better global cognition than medium DDD
years.
106
Tabl
e 16
. The
ass
ocia
tion
betw
een
lifet
ime
expo
sure
to
antip
sych
otic
med
icat
ion
and
glob
al c
ogni
tion
in t
he t
otal
sch
izop
hren
ia
sam
ple
(n =
60)
at t
he 4
3-ye
ar s
tudy
(mod
ified
from
Tab
le 4
and
Tab
le 5
in o
rigi
nal s
tudy
II a
nd T
able
5 in
ori
gina
l stu
dy II
I).
Med
icat
ion
varia
ble
CP
Z eq
uiva
lent
dos
e-ye
ars
D
DD
yea
rs
B
(SE
)1 B
eta1
Sig
1 B
(SE
)2 B
eta2
Sig
2
B (S
E)1
Bet
a1 S
ig1
B (S
E)2
Bet
a2 S
ig2
Any
ant
ipsy
chot
ics
-0.2
5 (0
.11)
-0
.32
0.02
0 -0
.33
(0.1
1)
-0.4
3 0.
004
-0
.24
(0.1
3)
-0.2
8 0.
066
-0.3
4 (0
.15)
-0
.39
0.02
0
Typi
cal a
ntip
sych
otic
s -0
.20
(0.1
2)
-0.3
1 0.
098
-0.2
3 (0
.12)
-0
.36
0.05
0
-0.1
7 (0
.16)
-0
.21
0.29
6 -0
.22
(0.1
5)
-0.2
7 0.
162
Aty
pica
l ant
ipsy
chot
ics
-0.1
5 (0
.09)
-0
.23
0.08
7 -0
.19
(0.0
9)
-0.2
9 0.
036
-0
.19
(0.1
2)
-0.2
2 0.
107
-0.2
5 (0
.12)
-0
.28
0.04
8
B =
uns
tand
ardi
sed
regr
essi
on c
oeffi
cien
t, S
E =
sta
ndar
d er
ror,
Bet
a =
stan
dard
ised
regr
essi
on c
oeffi
cien
t, S
ig =
sta
tistic
al s
igni
fican
ce.
1 Adj
uste
d for g
ende
r, ag
e of
illn
ess
onse
t and
PA
NS
S P
ositi
ve s
ympt
oms
at th
e fo
llow
-up.
2 Adj
uste
d fo
r gen
der,
age
of il
lnes
s on
set a
nd lo
garit
hmic
tran
sfor
mat
ion
of c
umul
ativ
e ps
ychi
atric
hos
pita
l tre
atm
ent d
ays
by th
e 43
-yea
r stu
dy.
107
Fig. 5. The association between lifetime CPZ equivalent dose-years of any antipsychotics and global cognition at the 43-year study in the total schizophrenia sample (n = 60). Higher lifetime dose-years of any antipsychotics were connected with poorer cognitive composite score (Fig. 1 in original study II).
108
Fig. 6. Global cognition at the 43-year study in low-, medium- and high-dose groups of DDD years of any antipsychotics, benzodiazepines and antidepressants in the total schizophrenia sample (n = 60). The division to dose-groups is based on tertiles (Fig. 1 in original study III).
7.8 Lifetime trends in use of antipsychotics and global cognition at the 43-year study (III)
Being without antipsychotic medication for a relatively long time (range 0.9–20.3
years, mean 8.7 years) before the cognitive examination was associated with better
global cognition at the 43-year study. Long antipsychotic-free periods earlier during
antipsychotic treatment were not associated with global cognition, if antipsychotic
medication was used at the cognitive examination. The proportion of time with
antipsychotic use or proportion of time on antipsychotic polypharmacy were not
associated with cognition. These results are presented in Table 17.
109
Table 17. The association between lifetime trends of use of any antipsychotics (DDD year based variables) and global cognition in the total schizophrenia sample (n = 60) at the 43-year study (modified from Table 5 in original study III).
Medication variable B (SE)1 Beta1 Sig1 B (SE)2 Beta2 Sig2
Proportion of time with antipsychotic use -0.28 (0.17) -0.20 0.107 -0.31 (0.17) -0.23 0.066
Long antipsychotic-free periods during treatment 0.11 (0.28) 0.05 0.689 0.12 (0.27) 0.06 0.653
Being without antipsychotic medication before
the cognitive examination
0.81 (0.35) 0.29 0.021 0.98 (0.36) 0.35 0.007
Proportion of time on antipsychotic polypharmacy -0.20 (0.17) -0.16 0.235 -0.24 (0.18) -0.19 0.173
B = unstandardised regression coefficient, SE = standard error, Beta = standardised regression
coefficient, Sig = statistical significance. 1 Adjusted for gender, age of illness onset and PANSS Positive symptoms at the follow-up. 2 Adjusted for gender, age of illness onset and logarithmic transformation of cumulative psychiatric
hospital treatment days by the 43-year study.
7.9 Lifetime cumulative exposure to benzodiazepines and antidepressants and global cognition (III)
Lifetime cumulative DDD years of benzodiazepines or antidepressants were not
significantly associated with global cognition in the total schizophrenia sample at
the 43-year study unadjusted (B = -0.16, SE = 0.14, Beta = -0.18, Sig = 0.278 and
B = 0.08, SE = 0.21, Beta = 0.09, Sig = 0.689 respectively) or in adjusted models.
110
111
8 Discussion
8.1 Main findings
This study aimed to analyse the association between lifetime psychiatric
medication exposure and cognitive functioning in midlife schizophrenia. The focus
was on finding out if high antipsychotic exposure is associated with poorer
cognition or cognitive decline. Additionally, the aim was to discover if lifetime
trends or timing of antipsychotic use, antipsychotic polypharmacy or exposure to
benzodiazepines or antidepressants are associated with cognition.
The main finding was that higher cumulative antipsychotic exposure was
associated with poorer cognitive performance and cognitive decline in
schizophrenia. Cumulative exposure to antipsychotic polypharmacy,
benzodiazepines or antidepressants was not associated with cognitive functioning.
8.1.1 Cumulative exposure to antipsychotics and baseline
performance and change in verbal learning and memory
The main findings of this study concerning cumulative antipsychotic exposure and
verbal learning and memory supported the first hypothesis. Higher cumulative
lifetime exposure to any antipsychotics was associated with poorer baseline global,
short-term and long-term verbal memory in schizophrenia. Higher cumulative
exposure to any antipsychotics by the baseline was associated with a greater decline
in the short-term verbal memory during the 9-year follow-up and higher exposure
during the follow-up with a greater decline in global verbal learning and memory
performance during the same follow-up period.
Exposures to both typical and atypical antipsychotics were associated with
negative effects on verbal learning and memory. Typical antipsychotics were
predominantly used until the baseline, which relates to their association with poorer
baseline verbal learning and memory. Atypical antipsychotic exposure was
considerably higher during the follow-up, and atypical exposure was associated
with a decline in short-term verbal memory and an increase in recall errors. These
associations may be related to exposure to clozapine. However, completely
differentiating the cognitive consequences of lifetime exposures to typical, atypical
or individual antipsychotic agents was impossible, because several different agents
of both types had been used by most of the sample during their lifetime.
112
The subjects exposed to high antipsychotic dose-years had poorer baseline
verbal learning and memory performance than subjects with low exposure in all
dimensions. The only exception was recall errors, which was the only measure
high-dose subjects had more cognitive decline in when compared to subjects with
low exposure.
In comparison with controls of the same birth cohort, schizophrenia subjects
had significantly poorer performance in all studied dimensions of verbal learning
and memory in the baseline and follow-up studies, except for one baseline measure.
The subjects exposed to high antipsychotic doses declined more than controls in
several verbal learning and memory measures, whereas there were no significant
differences in the cognitive change experienced by subjects with low exposure and
controls.
8.1.2 Cumulative lifetime antipsychotic exposure and global
cognition
Higher cumulative lifetime exposure to any antipsychotics, measured until the 43-
year study, was significantly associated with poorer global cognition at 43 years of
age in schizophrenia, supporting the second hypothesis. When analysing types of
antipsychotics, higher exposure to both typical and atypical antipsychotics was
significantly associated with poorer global cognition. The different methods used
to quantify cumulative antipsychotic dose in original studies II and III, CPZ
equivalent dose-years and DDD years, resulted mostly in similar findings, except
for one trend-level finding with DDD years, which was significant with dose-years.
Compared with controls, schizophrenia subjects performed significantly
poorer in all studied cognitive test variables and global cognition at the 43-year
study.
8.1.3 Lifetime trends and timing of antipsychotic use, antipsychotic
polypharmacy and global cognition
Of the lifetime trends in use of any antipsychotics, being without antipsychotic
medication for a relatively long time (minimum 11 months) before the cognitive
examination was associated with better global cognition at 43 years of age in
schizophrenia. Other lifetime trends, such as long antipsychotic-free periods earlier
during treatment, proportion of time with antipsychotic use or proportion of time
on antipsychotic polypharmacy, contrary to the second hypothesis, were not
113
associated with cognition. The current use of any antipsychotics at age 43 years,
was also associated with poorer global cognition, even though current dose or
current antipsychotic polypharmacy were not.
8.1.4 Cumulative exposure to benzodiazepines and antidepressants
and global cognition
The relatively low lifetime exposure to benzodiazepines and antidepressants in this
sample was not significantly associated with global cognition in schizophrenia at
43 years of age. This largely contradicted the hypothesised negative cognitive
effects of benzodiazepine and positive or neutral effects of antidepressant exposure.
The current doses of benzodiazepines or antidepressants at the 43-year study were
also not significantly associated with cognition.
8.2 Comparison with earlier research
8.2.1 Cognitive impairment and course of cognition in schizophrenia
and controls
The subjects with schizophrenia were more impaired in specific cognitive measures
at 34 and 43 years of age and in global cognition at 43 years of age in comparison
with the non-psychotic controls of the same NFBC1966 birth cohort. This finding
is in line with extensive and consistent evidence on a group level of moderate to
large global cognitive impairment in schizophrenia persisting in every clinical state
during the lifespan in comparison with age-matched non-affected controls
(Schaefer et al., 2013).
The longitudinal course of cognition in schizophrenia, quantified as change of
verbal learning and memory between 34 and 43 years, was analysed in relation to
antipsychotic exposure. The post-hoc finding of no significant differences between
subjects with low antipsychotic exposure and controls in the midlife course of
cognition, matches with the majority of findings in the literature (Bozikas &
Andreou, 2011; Szöke et al., 2008; Zipursky et al., 2013) as well as in the
NFBC1966 (Rannikko et al., 2015b), according to which the course of cognition is
relatively stable and follows a similar trajectory of age-related decline, though on
a lower level, as in controls.
114
However, subjects with high antipsychotic exposure had more decline than
subjects with low exposure in one measure and controls in several verbal learning
and memory measures. Verbal memory deficits in schizophrenia have been
reported to deteriorate during longer follow-ups, but neither the influence of
antipsychotic medication status nor variation in dosing have been taken into
account (Bozikas & Andreou, 2011). It may not be possible to make further
conclusions on medication effects in such a small subsample of subjects as in the
post-hoc analyses of this study, especially since it was not feasible to control for
other relevant factors that could explain the group differences such as severity of
illness. The possible influence of medication on the course of cognition and specific
neuropsychological functions would warrant more attention in the future research.
8.2.2 Antipsychotic medication and cognition in schizophrenia
Cumulative exposure to antipsychotics
The main findings of this study, of higher long-term and lifetime cumulative
antipsychotic exposure associating with poorer cross-sectional verbal learning and
memory and global cognitive performance and a larger decline in verbal learning
and memory during early midlife in schizophrenia, are novel findings in the
literature. They add up to the previous findings of small positive or limited effects
of antipsychotics on cognition in schizophrenia during first years of treatment, and
rare neutral or negative cross-sectional associations between antipsychotic dose
and cognition, by suggesting that in the long-term high antipsychotic exposure may
be associated with adverse cognitive effects.
This naturalistic study stands alone in comparison with a large bulk of
antipsychotic trials reporting mostly small positive or neutral cognitive effects
(Désaméricq et al., 2014; Keefe et al., 1999; Mishara & Goldberg, 2004; Nielsen
et al., 2015; Woodward et al., 2005). Some negative associations with higher dose
(Knowles et al., 2010) and positive effects with dose-reduction (Kawai et al., 2006;
Takeuchi et al., 2013) have been found, though.
Several unique qualities of this study explain some of the discrepancy between
the findings. Previous clinical trials and longitudinal studies clearly analysing the
association between antipsychotics and cognitive change in schizophrenia are
mostly limited to 2–5 years duration (see Table 3). Additionally, the duration and
dosing of antipsychotic treatment are often poorly reported and mostly not analysed
115
relative to cognition in longitudinal or cross-sectional studies of cognition in
schizophrenia.
This study extends the longitudinal cognitive follow-up to 9 years and,
uniquely to the cognitive studies, was able to analyse long-term and lifetime
cumulative antipsychotic exposure as well as cross-sectional use and dose of
antipsychotics. Long-term cumulative antipsychotic exposure and cross-sectional
current use of antipsychotics were associated with poorer cognition, but current
dose was not. The findings of this study suggest that duration and dosing of
antipsychotic exposure may be relevant for the cognitive effects of antipsychotics.
Differences between typical and atypical antipsychotics
Differences in the cognitive effects between typical and atypical antipsychotics
were not clarified further by this study. Higher exposure to both types of
antipsychotics was associated with poorer cognition or cognitive decline. In this
naturalistic sample, especially when studying the cognitive consequences of
lifetime antipsychotic exposure, separating different types of or individual agents
was not possible, because most subjects had a history of using multiple different
types of agents.
In comparison with the earlier literature, the differences between the cognitive
effects of typical and atypical agents or superiority of atypical agents are not very
clear either because of methodological limitations of many trials, such as industry
sponsorship, unequal comparisons between higher doses of typical than atypical
agents and insufficient controlling for the use of, for example, anticholinergic
agents (Keefe et al., 2007). In this naturalistic study such biases were minimised
and the findings resemble the results of newer, more carefully designed,
independent trials (Davidson et al., 2009; Keefe et al., 2007), which found similar
cognitive effects between atypical and typical agents. However, the direction of the
associations is different (negative vs. earlier positive cognitive effects), which may
be explained by study qualities, such as the long-term nature of this study, discussed
in the previous chapter.
Similar, negative cognitive effects can be understandable, when considering
that both typical and atypical agents have actions which have been associated with
negative cognitive effects, for example, considerable anticholinergic and D2
receptor antagonism. Moreover, it has been suggested that instead of dividing
antipsychotics into two heterogeneous classes, it may be more useful to consider
116
these medications, which have very different effect and side-effect profiles, as
individual agents, especially in clinical decision making (Leucht et al., 2013).
Antipsychotic polypharmacy and lifetime trends and timing of antipsychotic
use
In this study, the current use of antipsychotic polypharmacy at the time of the study
or proportion of time on antipsychotic polypharmacy during lifetime antipsychotic
treatment were not associated with global cognition. At least two studies found an
association between cross-sectional antipsychotic polypharmacy and poorer
cognition (Hori et al., 2006; Hori et al., 2012) and one between switching from
polypharmacy to monotherapy and cognitive improvement (Hori et al., 2013),
whereas other findings of no association have also been reported (Kontis et al.,
2010; Nielsen et al., 2015).
In the studies with comparison of antipsychotic monotherapy and
polypharmacy (Hori et al., 2006; Hori et al., 2012), the doses in both groups were
mostly from almost twice to four times as high as current antipsychotic dose of
antipsychotic users in this study, which is one of the major differences in the study
characteristics and possibly explains some discrepancy in results. The meta-
analysis of clozapine augmentation by another antipsychotic found no differences
in cognitive effects to clozapine monotherapy, though dosage data were not
provided (Nielsen et al., 2015). The meta-analytical results partly support the
findings of this study of no cognitive effects with antipsychotic polypharmacy,
though the previous results may better apply to a more selected, treatment-resistant
sample than the sample of this study.
The associations between cognition and lifetime trends, or timing of use of
antipsychotics, including also proportion of time on antipsychotic polypharmacy
during lifetime treatment, have not to my knowledge been previously studied in
schizophrenia in such a detailed way as in this study. The novel findings that time
on antipsychotic treatment, antipsychotic-free periods or long-term antipsychotic
polypharmacy, at least to the extent it was used in this study, may not be harmful
treatment strategies (though not useful either), when it comes to cognition, can be
clinically important information.
Moreover, considering that a relatively long break in antipsychotic treatment
before the cognitive assessment was associated with better global cognition, the
possibility that the cognitive effects of antipsychotics could to some degree be
reversible, is particularly interesting. However, the latter finding could also be
117
explained by a very low lifetime exposure to antipsychotics of this subsample,
which was antipsychotic-free before and during the cognitive assessment. The
associations between lifetime treatment and cognitive outcomes in schizophrenia
seem complex and would warrant further research.
Chlorpromazine and DDD equivalents
This study utilised two different methods of quantifying exposure to antipsychotics.
CPZ-based measures of equivalence, such as CPZ equivalent dose-years, are
classic and more commonly reported units in the literature, but DDDs have also
been used before (Leucht, Samara, Heres, & Davis, 2016).
Discrepancy has been found between CPZ and DDD equivalents, with DDD
equivalent values demonstrating lower potencies of antipsychotic drugs in
comparison with CPZ equivalents (Rijcken et al., 2003). In this study there were
also slightly less significant findings in analyses of DDD years and cognition in
comparison with CPZ dose-years and cognition, which is in line with earlier results.
CPZ equivalence studies were older and higher doses may have been used in them
(Rijcken et al., 2003). DDD equivalents are more often updated, internationally
accepted and based on global usage data. Though DDDs were standardised
measures of consumption and not originally intended for equivalence measures,
their availability for most medications supports their use (Leucht et al., 2016).
8.2.3 Benzodiazepines and antidepressants and cognition in
schizophrenia
In this study, the lifetime exposure to benzodiazepines and antidepressants or their
current use or doses at the 43-year study were not associated with global cognition
in schizophrenia. These results seem to be in conflict with earlier findings of
adverse cognitive effects of benzodiazepines both immediately (Tannenbaum et al.,
2012) and in the long-term (Barker et al., 2004a). Evidence from schizophrenia,
though, is limited mostly to cognitive improvement (measured as both composite
and subscale scores) observed after withdrawal or tapering down of long-term
benzodiazepine use (Baandrup et al., 2017; Kitajima et al., 2012).
One explanation for the discrepancy could be that the relatively low lifetime
exposure to benzodiazepines was under a threshold which could cause long-term
cognitive consequences. The current dose of benzodiazepines for the users (median
1.0 and mean 1.2 DDD) was on an average level and on a similar level (Kitajima
118
et al., 2012) or about half of the baseline and maintenance treatment dose
(Baandrup et al., 2017) of the studies with benzodiazepine withdrawal.
Additionally, differences in the exposures (long-term use and reduction or
withdrawal vs. cumulative exposure and partly continued use), settings
(comparison of cognition between groups of reduced and continued use vs.
association between dose or use and cognition) and samples (diagnostically
heterogenous clinical vs. naturalistic schizophrenia spectrum) may explain
different results.
Current benzodiazepine use was additionally controlled and it did not reduce
the association between lifetime antipsychotic exposure and poorer cognition. The
extensive medication data in this study is valuable, especially because it enables
control of the use of adjunctive medications that is usually neglected in cognitive
trials with antipsychotics in schizophrenia (Harvey & Keefe, 2001).
When it comes to antidepressants, the results of this study are similar to earlier
meta-analyses or reviews (Terevnikov et al., 2015; Vernon et al., 2014) of no
clinically significant cognitive effects. However, many trials with adjunctive
antipsychotics have found significant cognitive improvement, both in global
cognition (Vernon et al., 2014) and specific functions (Terevnikov et al., 2015;
Vernon et al., 2014), which was not detected in this study. Perhaps one explanation
could be the use of global cognition instead of analysing cognitive functions
separately, which may not allow accurate detection of cognitive change.
The naturalistic sample of this study differs from the usual clinical samples of
trials. The current use of antidepressants in particular was not very common and a
sample of 13 is likely to be too small to find significant associations, though current
dosages were quite average. In the lifetime use, similar to benzodiazepines, an even
lower cumulative lifetime antidepressant exposure was not sufficient to result in
cognitive benefits.
This study also analysed much longer-term exposure than the previous trials
extending the evidence of long-term cognitive effects of antidepressants from 6
months to a much longer lifetime illness duration, even though the measurement of
cognition is cross-sectional. Thus, it may be that, especially in the long-term,
antidepressants have relatively neutral cognitive effects.
It may not be possible to draw firm conclusions on the long-term or current
cognitive effects of benzodiazepines or antidepressants based on such a low
exposure and small subsamples of users as in this study. However, the lifetime or
current use of benzodiazepines or antidepressants likely did not confound the
119
association between higher antipsychotic exposure and poorer cognition in this
study.
8.3 Mechanisms of the cognitive effects of medications
The cognitive effects of medications stem from their potential to affect
neurotransmission in areas and neural networks of the brain responsible for
cognitive functions (Tannenbaum et al., 2012). The effects of psychiatric
medications on neurotransmission are presumably highly complex. Medications
have pharmacological profiles with actions on multiple receptors involved in
neurotransmission, making it difficult to predict net cognitive effects of even a
single compound, let alone several interacting medications. The amount and
location of receptors, for example, pre- or postsynaptically regulated as a response
to medications and receptor occupancy dependent on the concentration of an agent,
also take part in determining the effects. Finally, interactions and balance between
neurotransmitter systems play a key role in determining cognitive performance
(Keefe et al., 1999).
The cognitive impairment in schizophrenia, according to the dopamine
hypothesis, results from a hypodopaminergic state of mesocortical pathways
projecting to prefrontal cortex (Stahl, 2008). Antipsychotics with D2 receptor
antagonist qualities may further impair the hypoactive dopaminergic pathway and
worsen cognitive impairments and negative symptoms (Liemburg, Knegtering,
Klein, Kortekaas, & Aleman, 2012). Additionally, high-potency antagonism of D2
receptors (Hill et al., 2010) or high-occupancy (over 80%) D2 binding caused by
high-dose exposure to antipsychotics have been associated with neurocognitive
deficits (Sakurai et al., 2013).
Another key network for cognition is the cholinergic system, which projects to
the cortex and hippocampus and is connected to memory, perception and attention.
Suppression of the central cholinergic system by antagonism of muscarinic
cholinergic receptors i.e. anticholinergic actions of medications impair cognition
(Eum et al., in press), especially learning and memory functions, encoding, but not
retrieval of information (Hasselmo & Wyble, 1997). Several medications, including
both typical and atypical antipsychotics and antidepressants (for example, tricyclic
agents), have significant anticholinergic actions. Clozapine is the most sedative
antipsychotic (Leucht et al., 2013), possibly due to its high anticholinergic actions,
which may also explain some adverse cognitive effects associated with it. Though
clozapine users of this study were also likely to be a highly selected group with
120
generally more severe and treatment-resistant illness and poorer outcome, possibly
also explaining findings of poorer cognition with clozapine use.
In schizophrenia, glutamatergic regulation is hypothesised to be disturbed
resulting in hyperactivation of mesolimbic pathways and positive symptoms and
hypoactivation of mesocortical pathways and negative and cognitive symptoms
(Stahl, 2008). Because antagonism of 5-HT2A/2C and agonism of 5-HT1A
serotonergic receptors both further inhibit glutamatergic functions, they may also
further impair cognitive functions (Keefe et al., 1999; Stahl, 2008).
Other mechanisms of antipsychotics with adverse cognitive effects include
sedative effects mediated by antagonism of alpha-2A adrenergic or histamine-1
receptors (Stahl, 2008).
The γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in
the brain. GABAergic dysfunction has also been connected with cognitive
impairment in schizophrenia (Nakazawa et al., 2012). The adverse cognitive effects
of benzodiazepines may be mediated by the activating effects of benzodiazepines
on GABAergic transmission (Nestler et al., 2009).
The cognitive enhancing mechanisms of medications, not so relevant in
understanding the findings of this study, are associated mostly with opposite actions
to those mentioned above, such as stimulation of cholinergic, 5HT2A/2C-
serotonergic or alpha-2A actions, or increasing dopaminergic function below
therapeutic window (Keefe et al., 1999). Some antipsychotics (Stahl, 2008) and
antidepressants (Buoli & Altamura, 2015) have these effects. Additionally,
antidepressants have been associated with neuroprotective or neurogenesis
activating effects (Dranovsky & Hen, 2006; Sheline et al., 2003).
Medications influence functioning of the brain when there is a sufficient
concentration of an active agent in the body. This is also the case in continued use
of medication in the long-term. However, it is not as clear, especially if the long-
term use of medications can result in permanent changes in the functioning of
neural networks mediated by, for example, changes in synaptic activity or growth,
or cell death (Shin et al., 2012). Anticholinergic qualities have been hypothesised
to mediate not only the short-term, but also long-term negative cognitive effects of
antipsychotics (Terry & Mahadik, 2007). Additionally, at least benzodiazepines
have been associated before with partly nonreversible cognitive impairments
(Barker et al., 2004b).
121
8.4 Antipsychotic medication, cognition and brain changes
According to a meta-review most of the structural brain changes in schizophrenia
may be associated with either illness stage or antipsychotic medication (Shepherd,
Laurens, Matheson, Carr, & Green, 2012). Antipsychotics may have a role in
increasing basal ganglia volume and possibly also in affecting thalamic and cortical
volumes (Shepherd et al., 2012). More recent meta-analyses have provided further
evidence of the associations between grey matter volume reduction and
antipsychotic medication (Vita, De Peri, Deste, Barlati, & Sacchetti, 2015) or
higher cumulative antipsychotic exposure (Fusar-Poli et al., 2013). A meta-analysis
of long-term studies with at least 2 years of follow-up also suggested an association
between higher long-term antipsychotic exposure and structural brain changes,
including a decrease in parietal lobe and increase in basal ganglia (Huhtaniska et
al., 2017). Additionally, a meta-analysis of structural and functional brain imaging
in first-episode schizophrenia found associations between regional reductions in
grey matter volume and reduced or enhanced functioning, and some of these
abnormalities were influenced by antipsychotic exposure (Radua et al., 2012).
Significant associations between long-term antipsychotic exposure and
reduction in the total (Veijola et al., 2014) and regional brain volume in the
periventricular area (Guo et al., 2015) in midlife schizophrenia have also been
found in the NFBC1966 sample. The total brain volume reduction, though, was not
associated with cognitive change or symptomatic or functional outcomes (Veijola
et al., 2014). At an earlier age in the NFBC1966, cumulative exposure to
antipsychotics did not predict cross-sectional structural brain changes, yet a longer
time without antipsychotic medication before the study was associated with
increases in regional brain structures (Moilanen et al., 2015).
The cognitive and brain structural and functional abnormalities seem inherent
to schizophrenia, reflecting its neurobiological basis and heterogeneous phenotypes
and course during the lifespan. Both neurocognitive and neuroimaging studies,
supporting the findings of this study, have found evidence that, in addition to the
illness process itself, pharmacological treatment, especially high-dose and long-
term antipsychotic exposure, may also contribute to the functional and structural
abnormalities and their progression over time (Flashman & Green, 2004;
Huhtaniska et al., 2017; Radua et al., 2012; Shepherd et al., 2012). Other important
factors with a possible influence on course of cognition include substance abuse
and metabolic syndrome (Harvey & Rosenthal, in press).
122
8.5 Antipsychotic medication, cognition and outcome
The discovery of antipsychotic medications has enabled many people with
schizophrenia to achieve symptomatic remission. However, good outcomes and
recovery rates in schizophrenia have not improved despite available antipsychotic
treatment (Hegarty et al., 1994; Jääskeläinen et al., 2013). Neurocognition and
social cognition in schizophrenia have been largely overlooked in the treatment and
research of schizophrenia until recent decades, when they have risen to attention,
especially due to their key role in predicting the functional outcome in
schizophrenia (Green, 2016). Verbal memory, which is one of the most impaired
cognitive domains in schizophrenia and in a key role in this study, is among the
best predictors (Cirillo & Seidman, 2003; Toulopoulou & Murray, 2004). Cognitive
impairments in schizophrenia are relatively treatment resistant and they may even
influence, how much a person can benefit from rehabilitation programmes
(Spaulding et al., 1999).
The inefficacy of antipsychotic treatment in promoting cognitive and
functional recovery in schizophrenia is not the only concern to be raised. The
associations of antipsychotics with cognitive decline also replicated by this study,
brain volume reduction and dopamine D2 receptor sensitisation, iatrogenically
increasing susceptibility to relapses without antipsychotic treatment (Moncrieff,
2006), have given reason to suspect that antipsychotics might negatively affect
long-term outcomes in schizophrenia (Goff et al., 2017). However, little evidence
has been found that initial or maintenance antipsychotic treatment would have a
negative impact on outcomes in comparison with no treatment. Early intervention
and reduced duration of untreated psychosis are associated with improved long-
term outcomes (Goff et al., 2017).
At the same time, studies have identified subpopulations of people with
schizophrenia, who have a less severe illness course and more beneficial outcome
despite being antipsychotic-free or having a low maintenance antipsychotic dose.
In a 20-year naturalistic follow-up, the users of long-term antipsychotic medication
had more frequent and severe psychotic symptoms and more hospitalisations than
non-medicated people with schizophrenia (Harrow, Jobe, & Faull, 2014).
Wunderink, Nieboer, Wiersma, Sytema, & Nienhuis, (2013) studied first-episode
psychosis patients, who after 6 months of remission were randomised to dose-
reduction/discontinuation of antipsychotic treatment (DR) and maintenance
treatment (MT) groups and followed up for 7 years. The DR group had twice as
123
high recovery rate (due to better social functioning) as the MT group, though also
many in the DR group were adherent to antipsychotic medication.
In the NFBC1966, higher lifetime exposure to antipsychotics and antipsychotic
polypharmacy were associated with a poorer global outcome (Moilanen et al.,
2013). In the same sample, having a low antipsychotic dose was connected with a
better clinical outcome and no drug-free periods with better functional outcome
(Moilanen et al., 2016). With the robust associations between cognition and
outcome, it may be that the group identified in this study, of antipsychotic-free
persons with better cognition, also belongs to this minority within schizophrenia
with a less severe illness and more favourable course of cognition and outcome.
A review of evidence base acknowledged that a subgroup of persons with
schizophrenia may benefit from dose-reduction or discontinuation strategies, but at
the same time, the relapse risk in these strategies may be elevated (Goff et al., 2017).
A critical problem is a lack of neurobiological markers that would guide choosing
optimal, efficient, individualised treatment strategies. It has been hypothesised that
recurrent or persisting psychosis may also have a detrimental effect on cognition
(Harvey et al., 2013) and brain structures, though evidence supporting toxicity of
psychosis is not strong (Rund, 2014). The contradicting findings may describe the
heterogeneity of the neurodevelopmental and neurodegenerative processes
involved in the pathogenesis and illness processes behind schizophrenia and their
interactions with treatment as described in the progressive neurodevelopmental
model of schizophrenia (Pino et al., 2014).
8.6 Strengths and limitations
8.6.1 Strengths
The naturalistic, population-based birth cohort sample and information from
interviews, psychiatric and neuropsychological assessments, medical records and
linkage to register data provide an extensive, reliable, prospective database for this
study. In this epidemiologically sound sample, selection biases may be smaller in
comparison with, for example, selected, clinical populations. The extensive
database with information from the whole illness duration enabled control for
several relevant clinical variables and thus minimised latent confounding often
linked to naturalistic settings. Additionally, the attrition bias, rising from the
participating subjects with schizophrenia having markers of more severe illness and
124
poorer functioning than non-participating subjects, was analysed thoroughly in
inverse probability weighted sensitivity analyses, revealing that the selective
attrition was not likely to influence the results. The results of this study should be
fairly reliable and generalisable to the real-world schizophrenia population.
The detailed longitudinal information on the lifetime use of psychiatric
medications is unique in the literature. The information on the dosing and time
periods of use of medications during the whole lifetime has enabled a novel long-
term perspective on studying the cognitive effects of medication exposures, as well
as analysing cross-sectional current doses. The access to not only register data on
prescriptions and purchases, as in most other studies, but also medical records, has
enabled taking into account known antipsychotic-free periods and medications
during hospital treatments in estimating the cumulative exposure.
Besides antipsychotics information on the use of other psychiatric medications,
has allowed control of the effects of the most commonly used psychiatric
medications, benzodiazepines and antidepressants, which are often not taken into
account in cognition studies. In this study the comparison of different methods of
quantifying equivalent doses of antipsychotics, CPZ and DDD equivalents was
possible, as well as analysing antipsychotics together with other psychiatric
medications by using DDDs and DDD years.
The neuropsychological assessment in this study was performed with validated
and reliable neurocognitive tests. The longitudinal assessment in two time points
comprised only one neuropsychological test, the California Verbal Learning Test
(CVLT), which is a widely used and validated measure (Albus et al., 2006; Keefe
et al., 2006; Tuulio-Henriksson et al., 2011) and one of the most specific
neurocognitive endophenotypes for schizophrenia (Millard et al., 2016), making it
highly relevant to study. The extensive neuropsychological set utilised at the 43-
year study, though non-standard, included valid neuropsychological tests
measuring the most essential neurocognitive domains affected in schizophrenia as
the standardised test batteries (MCCB, CANTAB).
The non-psychotic controls from the same birth cohort formed a reference for
normative cognitive performance and development during the same age period.
This facilitated interpretation of the results, when comparing differences in
cognitive decline in subjects with high and low antipsychotic exposure, and
differentiating age-related changes (Bozikas & Andreou, 2011; Szöke et al., 2008).
125
8.6.2 Limitations
The sample size of the schizophrenia subjects in this study was relatively small,
which is a common limitation in the trials and longitudinal studies on cognition in
schizophrenia (Keefe et al., 1999). Attrition associated with long follow-up times
highlights this issue (Bozikas & Andreou, 2011). The small sample limits the
statistical power of this study to detect significant cognitive effects of medications
(type I error) and rule out, if not finding an association between medication and
cognition, truly means there is no significant association (type II error).
The sample sizes become even smaller, when the total sample is divided into
subgroups based on, for example, the degree of exposure to medications (high,
medium or low), use of other psychiatric medications than antipsychotics or use of
individual medication agents. This limits the conclusions that can reliably be drawn
on the cognitive effects of benzodiazepines and antidepressants. Due to small
sample size it was not feasible to analyse the cognitive effects of other psychiatric
medications and individual drugs in this study. It would have been important to
study, for example, anticholinergic agents, mood stabilisers, antihistamines or
melatonin, but they form too heterogeneous a group to be analysed and their
lifetime and current use was very small, which is why only their use was reported
(original study III, Supplementary Table 1).
The reliability of the medication variables in this study may suffer from issues
related to adherence. Based on a cross-sectional measure, the Drug Attitude
Inventory (DAI-10; Awad, 1993) with some value in predicting medication
adherence (Brain et al., 2013; Yang et al., 2012), the adherence of this sample was
good at the 43-year study. Total score of DAI-10 was not associated with lifetime
antipsychotic dose or cognition, which may further support that adherence did not
significantly confound the main association between antipsychotic medication and
cognition.
Due to analysing multiple medication and cognitive variables, the likelihood
of some of the significant results being chance findings may also increase.
A limitation related to the cognitive measurements is the lack of a standard
neuropsychological assessment before and during the onset of the first psychotic
episode. There was also only one cross-sectional measurement of global cognition.
This may make separating illness and medication related cognitive changes
challenging. Global cognition may have also been too insensitive a measure to
detect effects of medication exposures in comparison with analysing subtests or
cognitive functions, which might have resulted in more findings. Not being able to
126
compare the possibly different cognitive effects of psychiatric medications on
specific cognitive functions also limits the implications and applicability of the
results. However, one of the most impaired cognitive functions in schizophrenia,
verbal memory, was analysed in great detail with robust findings. Moreover, in the
NFBC1966 schizophrenia sample, premorbid school performance was associated
with midlife cognitive course (Rannikko et al., 2015a), which mostly had a
relatively stable trajectory (Rannikko et al., 2015b). Thus, the cross-sectional
measures likely do not reflect only temporal conditions, but may also describe long-
term cognition.
Finally, due to the naturalistic design, which is limited in detecting causal
associations, especially when transversal designs were used, the findings of this
study should be interpreted with some reservations. The results may not be applied
as reliably to clinical populations. The golden standard for studying treatment
effects are double-blind, randomised, controlled trials. However, carrying out a
long-term RCT is difficult and similar challenges related to, for example, attrition,
compromised blinding or confounding as in naturalistic studies, as well as financial
and ethical issues may be encountered in them. Considering this, it has been
suggested that naturalistic studies may be the optimal or at least the most feasible
method to study the long-term effects of medication exposures (Wang et al., 2011).
Another limitation is the lack of information on the psychosocial and cognitive
rehabilitation, which may have influenced cognitive functioning of the participants.
Because of the extensive database of this study, it was possible to control a variety
of the most relevant confounders related to duration and severity of illness. The
symptom measures, PANSS positive, negative and disorganisation symptoms, were
only evaluated cross-sectionally in the baseline and 43-year studies. Lifetime
cumulative psychiatric hospital treatment days form a long-term marker of the
course and severity of illness.
Despite the careful and extensive procedure in controlling for confounders, it
may be possible that higher long-term antipsychotic exposure identifies individuals
with a more severe and earlier onset illness and marks the poorer course of illness
rather than causes cognitive impairment. Similarly, managing for many years
without antipsychotics may be a marker of a more favourable illness course with
preserved cognitive functioning. Nevertheless, the possibility that long-term high-
dose antipsychotic exposure can, in addition to the illness processes, have a further
detrimental effect on the compromised cognitive functioning and its course in
schizophrenia, deserves attention in clinical decision-making and future studies.
127
9 Conclusions
9.1 Main conclusions
This study contributed novel information to schizophrenia research in particular on
the long-term cognitive effects of psychiatric medications, which have previously
been mostly unknown. It was the first study to report an association of higher
cumulative long-term and lifetime exposure to antipsychotics with poorer cognition
and a greater decline in verbal learning and memory in schizophrenia during early
midlife. The cognitive effects of typical and atypical antipsychotics were similar.
Lifetime trends and timing of antipsychotic treatment have not previously been
studied in association with cognition in schizophrenia. A relatively long break in
antipsychotic treatment before the cognitive assessment was associated with better
global cognition. A long antipsychotic-free period earlier in the treatment history,
proportion of time on antipsychotic treatment or on antipsychotic polypharmacy
were not associated with cognition.
Controlling for relevant confounders, related to duration and severity of illness
and treatment with other psychiatric medications, was also possible with
exceptional detail. Small lifetime exposure to benzodiazepines or antidepressants
or cross-sectional use of benzodiazepines did not seem to confound the association
between high antipsychotic exposure and poorer cognition in schizophrenia.
The results of this naturalistic study suggest that high-dose long-term
antipsychotic treatment may have some influence on the clinical course of
schizophrenia, possibly by preventing or attenuating cognitive recovery. Potential
biases related to the naturalistic design may explain some of the findings. More
research on the long-term effects of psychiatric medications is needed to develop
the safe and effective treatment and rehabilitation of schizophrenia and advance the
recovery and wellbeing of people with schizophrenia.
9.2 Clinical implications
The finding that long-term high-dose antipsychotic exposure may be associated
with poorer cognition and cognitive decline has a significant influence on the
treatment practice of schizophrenia. The current treatment guidelines recommend
maintenance antipsychotic treatment, some of them advising for using a lower
antipsychotic dose after the acute phase. The results of this study underline the
128
importance of finding a minimal effective dose of antipsychotics, especially in the
long-term maintenance treatment of schizophrenia to avoid or reduce adverse
effects, including harmful cognitive effects.
Polypharmacy with antipsychotics and other psychiatric medications is a
common practice in the long-term treatment of schizophrenia. The lack of cognitive
effects associated with long-term low exposure to antipsychotic polypharmacy and
adjunctive benzodiazepine and antidepressant treatment in this study, does not
prove their long-term safety. However, it is possible that the use of polypharmacy
or adjunctive medications in specific psychotic or comorbid states with low or
moderate doses for short, determined periods of time may be relatively safe at least
to cognition.
Moreover, even though antipsychotic discontinuation was associated with
better cognitive functioning, the overall benefits and risks associated with tapering
down or discontinuing antipsychotic treatment cannot be answered based on this
study. Most people with schizophrenia have a significantly higher relapse risk
without antipsychotic medication. This study highlights the heterogeneity of
schizophrenia by identifying a subgroup with more preserved cognitive functioning,
who may manage with a smaller dose or even without antipsychotic treatment for
long periods of time. The findings of this study, using population-based and
epidemiologically-representative samples, however, while generalisable to real-
world schizophrenia, may not be applied as reliably to clinical settings with more
concentrated populations of poorer outcome schizophrenia.
Finally, strategies to reduce the cumulative exposure to medications and
support the optimal cognitive and functional outcome, could include more active
utilisation of psychosocial treatments, especially cognitive remediation. Combining
cognitive remediation and rehabilitation with individually tailored
psychopharmacological treatment, primarily with lowest effective dose of
antipsychotic monotherapy and critical use of adjunctive medications, could
advance cognitive, social and occupational recovery and quality of life for people
with schizophrenia.
9.3 Future research
The findings of this study of the long-term effects of medications, which may differ
from those detected in the short-term, emphasise the relevance of a long-term
perspective in the future studies of the treatment of schizophrenia.
129
Further studies exploring the associations between long-term antipsychotic
treatment and cognition in schizophrenia in larger samples from different
populations would be needed to replicate or contradict the suggestive findings of
this study. Longer-term randomised, controlled clinical trials, even if challenging
to carry out, and detailed analysis of duration and dosing of antipsychotics and
other psychiatric medications (perhaps including serum concentrations), would be
of special value, especially in estimating safe dose-ranges and optimal duration of
treatment.
The longitudinal assessment of cognition with a standardised test battery,
differentiating essential cognitive domains, during the premorbid phase, drug-naïve
first-episode and several later stages of the illness with comparison to age-matched
controls, would give optimal information on the course of cognition in
schizophrenia. When combined with adequate controlling for longitudinal
symptoms, substance use, comorbidities, psychosocial treatments and
rehabilitation, as well as medications, the effects of illness process and treatment
effects could be more reliably separated.
Future studies should also combine neurocognitive and neuroimaging data and
perhaps also innovative animal models to identify neural correlates of medication
and illness effects. To determine if the observed cognitive changes in long-term
antipsychotic treatment have a significant impact on the wellbeing and real-life
functioning of people with schizophrenia, future studies should also include
measures of functional and occupational outcome and quality of life.
Further study in larger clinical and naturalistic populations of the optimal
treatment strategies of psychiatric medications in the long-term is also needed. In
general, research further elucidating the heterogeneous neurobiological illness
processes, trajectories and outcomes associated with schizophrenia could help,
especially to identify markers of subpopulations with higher susceptibility to
relapses and poorer outcomes benefiting from continuous maintenance treatment,
as well as those who may manage well with smaller doses or even without
antipsychotic medication.
130
131
References Abbott, C. C., Jaramillo, A., Wilcox, C. E., & Hamilton, D. A. (2013). Antipsychotic drug
effects in schizophrenia: A review of longitudinal FMRI investigations and neural interpretations. Current Medicinal Chemistry, 20(3), 428–437.
Addington, J., Addington, D., & Maticka-Tyndale, E. (1991). Cognitive functioning and positive and negative symptoms in schizophrenia. Schizophrenia Research, 5(2), 123–134. doi:10.1016/0920-9964(91)90039-T
Ahmed, A. O., & Bhat, I. A. (2014). Psychopharmacological treatment of neurocognitive deficits in people with schizophrenia: A review of old and new targets. CNS Drugs, 28(4), 301–318. doi:10.1007/s40263-014-0146-6
Albus, M., Hubmann, W., Mohr, F., Hecht, S., Hinterberger-Weber, P., Seitz, N., & Kchenhoff, H. (2006). Neurocognitive functioning in patients with first-episode schizophrenia. Results of a prospective 5-year follow-up study. European Archives of Psychiatry and Clinical Neuroscience, 256(7), 442–451. doi:10.1007/s00406-006-0667-1
Aleman, A., Hijman, R., De Haan, E. H. F., & Kahn, R. S. (1999). Memory impairment in schizophrenia: A meta-analysis. American Journal of Psychiatry, 156(9), 1358–1366.
Altamura, A. C., Pozzoli, S., Fiorentini, A., & Dell'Osso, B. (2013). Neurodevelopment and inflammatory patterns in schizophrenia in relation to pathophysiology. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 42, 63–70. doi:10.1016/j.pnpbp.2012.08.015
American Psychiatric Association (APA). (1987). American diagnostic and statistical manual of mental disorders (3rd revised ed.). Washington: American Psychiatric Association.
American Psychiatric Association (APA). (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington: American Psychiatric Association.
American Psychiatric Association (APA). (2004). Practice guideline for the treatment of patients with schizophrenia, second edition. American Journal of Psychiatry, 161, S1–56.
American Psychiatric Association (APA). (2013). Diagnostic and statistical manual of mental disorders 5th edition: DSM-5 (5th ed.). Arlington, VA: American Psychiatric Publishing.
American Psychiatric Association (APA). (2010). Practice guideline for the treatment of patients with schizophrenia. Arlington, VA: American Psychiatric Association.
Andreasen, N. C. (2010). The lifetime trajectory of schizophrenia and the concept of neurodevelopment. [El curso vital de la esquizofrenia y el concepto de neurodesarrollo] Dialogues in Clinical Neuroscience, 12(3), 409–415.
Andreasen, N. C., Carpenter Jr., W. T., Kane, J. M., Lasser, R. A., Marder, S. R., & Weinberger, D. R. (2005). Remission in schizophrenia: Proposed criteria and rationale for consensus. American Journal of Psychiatry, 162(3), 441–449. doi:10.1176/appi.ajp.162.3.441
132
Andreasen, N. C., Pressler, M., Nopoulos, P., Miller, D., & Ho, B.-C. (2010). Antipsychotic dose equivalents and dose-years: A standardized method for comparing exposure to different drugs. Biological Psychiatry, 67(3), 255–262. doi:10.1016/j.biopsych.2009.08.040
Awad, A. G. (1993). Subjective response to neuroleptics in schizophrenia. Schizophrenia Bulletin, 19(3), 609–618. doi:10.1093/schbul/19.3.609
Ayesa-Arriola, R., Rodríguez-Sánchez, J. M., Pérez-Iglesias, R., Roiz-Santiáñez, R., Martínez-García, O., Sánchez-Moreno, J., ...Crespo-Facorro, B. (2013). Long-term (3-year) neurocognitive effectiveness of antipsychotic medications in first-episode non-affective psychosis: A randomized comparison of haloperidol, olanzapine, and risperidone. Psychopharmacology, 227(4), 615–625. doi:10.1007/s00213-013-2994-z
Baandrup, L., Fagerlund, B., & Glenthoj, B. (2017). Neurocognitive performance, subjective well-being, and psychosocial functioning after benzodiazepine withdrawal in patients with schizophrenia or bipolar disorder: A randomized clinical trial of add-on melatonin versus placebo. European Archives of Psychiatry and Clinical Neuroscience, 267(2), 163–171. doi:10.1007/s00406-016-0711-8
Baitz, H. A., Thornton, A. E., Procyshyn, R. M., Smith, G. N., MacEwan, G. W., Kopala, L. C., ...Honer, W. G. (2012). Antipsychotic medications: Linking receptor antagonism to neuropsychological functioning in first episode psychosis. Journal of the International Neuropsychological Society, 18(4), 717–727. doi:10.1017/S1355617712000343
Barber, S., Olotu, U., Corsi, M., & Cipriani, A. (2017). Clozapine combined with different antipsychotic drugs for treatment-resistant schizophrenia. Cochrane Database of Systematic Reviews, 2017(3). doi:10.1002/14651858.CD006324.pub3
Barch, D. M. (2009). Neuropsychological abnormalities in schizophrenia and major mood disorders: Similarities and differences. Current Psychiatry Reports, 11(4), 313–319. doi:10.1007/s11920-009-0045-6
Barch, D. M., Bustillo, J., Gaebel, W., Gur, R., Heckers, S., Malaspina, D., ...Carpenter, W. (2013). Logic and justification for dimensional assessment of symptoms and related clinical phenomena in psychosis: Relevance to DSM-5. Schizophrenia Research, 150(1), 15–20. doi:10.1016/j.schres.2013.04.027
Barker, M. J., Greenwood, K. M., Jackson, M., & Crowe, S. F. (2004a). Cognitive effects of long-term benzodiazepine use: A meta-analysis. CNS Drugs, 18(1), 37–48. doi:10.2165/00023210-200418010-00004
Barker, M. J., Greenwood, K. M., Jackson, M., & Crowe, S. F. (2004b). Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: A meta-analysis. Archives of Clinical Neuropsychology, 19(3), 437–454. doi:10.1016/S0887-6177(03)00096-9
Barnett, J. H., Robbins, T. W., Leeson, V. C., Sahakian, B. J., Joyce, E. M., & Blackwell, A. D. (2010). Assessing cognitive function in clinical trials of schizophrenia. Neuroscience and Biobehavioral Reviews, 34(8), 1161–1177. doi:10.1016/j.neubiorev.2010.01.012
Bazire, S. (2003). Psychotropic drug directory 2003/2004. Fivepin publishing, 179–180.
133
Beards, S., Gayer-Anderson, C., Borges, S., Dewey, M. E., Fisher, H. L., & Morgan, C. (2013). Life events and psychosis: A review and meta-analysis. Schizophrenia Bulletin, 39(4), 740–747. doi:10.1093/schbul/sbt065
Bhati, M. T. (2013). Defining psychosis: The evolution of DSM-5 schizophrenia spectrum disorders. Current Psychiatry Reports, 15(11). doi:10.1007/s11920-013-0409-9
Bilder, R. M., Reiter, G., Bates, J., Lencz, T., Szeszko, P., Goldman, R. S., ...Kane, J. M. (2006). Cognitive development in schizophrenia: Follow-back from the first episode. Journal of Clinical and Experimental Neuropsychology, 28(2), 270–282. doi:10.1080/13803390500360554
Bora, E., & Murray, R. M. (2014). Meta-analysis of cognitive deficits in ultra-high risk to psychosis and first-episode psychosis: Do the cognitive deficits progress over, or after, the onset of psychosis? Schizophrenia Bulletin, 40(4), 744–755. doi:10.1093/schbul/sbt085
Bozikas, V. P., & Andreou, C. (2011). Longitudinal studies of cognition in first episode psychosis: A systematic review of the literature. Australian and New Zealand Journal of Psychiatry, 45(2), 93–108. doi:10.3109/00048674.2010.541418
Brain, C., Allerby, K., Sameby, B., Quinlan, P., Joas, E., Karilampi, U., ...Waern, M. (2013). Drug attitude and other predictors of medication adherence in schizophrenia: 12 months of electronic monitoring (MEMS) in the Swedish COAST-study. European Neuropsychopharmacology, 23(12), 1754–1762. doi:10.1016/j.euroneuro.2013.09.001
Brown, A. S. (2011). The environment and susceptibility to schizophrenia. Progress in Neurobiology, 93(1), 23–58. doi:10.1016/j.pneurobio.2010.09.003
Bruno, A., Zoccali, R. A., Abenavoli, E., Pandolfo, G., Scimeca, G., Spina, E., & Muscatello, M. R. A. (2014a). Augmentation of clozapine with agomelatine in partial-responder schizophrenia: A 16-week, open-label, uncontrolled pilot study. Journal of Clinical Psychopharmacology, 34(4), 491–494. doi:10.1097/JCP.0000000000000157
Bruno, A., Zoccali, R., Bellinghieri, P. M., Pandolfo, G., De Fazio, P., Spina, E., & Muscatello, M. R. A. (2014b). Reboxetine adjuvant therapy in patients with schizophrenia showing a suboptimal response to clozapine: A 12-week, open-label, pilot study. Journal of Clinical Psychopharmacology, 34(5), 620–623. doi:10.1097/JCP.0000000000000196
Bryson, G. J., Silverstein, M. L., Nathan, A., & Stephen, L. (1993). Differential rate of neuropsychological dysfunction in psychiatric disorders: Comparison between the halstead-reitan and luria-nebraska batteries. Perceptual and Motor Skills, 76(1), 305–306.
Buoli, M., & Altamura, A. C. (2015). May non-antipsychotic drugs improve cognition of schizophrenia patients? Pharmacopsychiatry, 48(2), 41–50. doi:10.1055/s-0034-1396801
Cannon, M., Jones, P. B., & Murray, R. M. (2002). Obstetric complications and schizophrenia: Historical and meta-analytic review. American Journal of Psychiatry, 159(7), 1080–1092. doi:10.1176/appi.ajp.159.7.1080
134
Cannon, T. D., Kaprio, J., Lönnqvist, J., Huttunen, M., & Koskenvuo, M. (1998). The genetic epidemiology of schizophrenia in a Finnish twin cohort: A population-based modeling study. Archives of General Psychiatry, 55(1), 67–74. doi:10.1001/archpsyc.55.1.67
Carlsson, A. (1988). The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology, 1(3), 179-186.
Choi, K.-H., Til, W., & Kurtz, M. M. (2013). Adjunctive pharmacotherapy for cognitive deficits in schizophrenia: Meta-analytical investigation of efficacy. British Journal of Psychiatry, 203(3), 172–178. doi:10.1192/bjp.bp.111.107359
Chong, H. Y., Teoh, S. L., Wu, D. B.-C., Kotirum, S., Chiou, C.-F., & Chaiyakunapruk, N. (2016). Global economic burden of schizophrenia: A systematic review. Neuropsychiatric Disease and Treatment, 12, 357–373. doi:10.2147/NDT.S96649
Cirillo, M. A., & Seidman, L. J. (2003). Verbal declarative memory dysfunction in schizophrenia: From clinical assessment to genetics and brain mechanisms. Neuropsychology Review, 13(2), 43–77. doi:1023870821631
Clarke, M. C., Kelleher, I., Clancy, M., & Cannon, M. (2012). Predicting risk and the emergence of schizophrenia. Psychiatric Clinics of North America, 35(3), 585–612. doi:10.1016/j.psc.2012.06.003
Cohen, J. (1992). A power primer. Psychological Bulletin, 112(1), 155–159. Coyle, J. T. (2006). Glutamate and schizophrenia: Beyond the dopamine hypothesis.
Cellular and Molecular Neurobiology, 26(4–6), 365–384. Coyle, J. T., Balu, D., Benneyworth, M., Basu, A., & Roseman, A. (2010). Beyond the
dopamine receptor: novel therapeutic targets for treating schizophrenia. [Más allá del receptor de dopamina: Nuevos blancos terapéuticos para tratar la esquizofrenia] Dialogues in Clinical Neuroscience, 12(3), 359–382.
Crossley, N. A., Mechelli, A., Fusar-Poli, P., Broome, M. R., Matthiasson, P., Johns, L. C., ...McGuire, P. K. (2009). Superior temporal lobe dysfunction and frontotemporal dysconnectivity in subjects at risk of psychosis and in first-episode psychosis. Human Brain Mapping, 30(12), 4129–4137. doi:10.1002/hbm.20834
Davidson, M., Galderisi, S., Weiser, M., Werbeloff, N., Fleischhacker, W. W., Keefe, R. S., ...Kahn, R. S. (2009). Cognitive effects of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: A randomized, open-label clinical trial (EUFEST). American Journal of Psychiatry, 166(6), 675–682. doi:10.1176/appi.ajp.2008.08060806
de Paula, A L D, Hallak, J. E. C., Maia-de-Oliveira, J. P., Bressan, R. A., & Machado-de-Sousa, J. P. (2015). Cognition in at-risk mental states for psychosis. Neuroscience and Biobehavioral Reviews, 57, 199–208. doi:10.1016/j.neubiorev.2015.09.006
Delis, D. C., Kramer, J. H., Kaplan, E., & Ober, B. A. (1987). California verbal learning test. New York: Psychological Corporation.
Désaméricq, G., Schurhoff, F., Meary, A., Szöke, A., Macquin-Mavier, I., Bachoud-Lévi, A. C., & Maison, P. (2014). Long-term neurocognitive effects of antipsychotics in schizophrenia: A network meta-analysis. European Journal of Clinical Pharmacology, 70(2), 127–134. doi:10.1007/s00228-013-1600-y
135
Dickinson, D., Ramsey, M. E., & Gold, J. M. (2007). Overlooking the obvious: A meta-analytic comparison of digit symbol coding tasks and other cognitive measures in schizophrenia. Archives of General Psychiatry, 64(5), 532–542. doi:10.1001/archpsyc.64.5.532
Dickson, H., Laurens, K. R., Cullen, A. E., & Hodgins, S. (2012). Meta-analyses of cognitive and motor function in youth aged 16 years and younger who subsequently develop schizophrenia. Psychological Medicine, 42(4), 743–755. doi:10.1017/S0033291711001693
Dietsche, B., Kircher, T., & Falkenberg, I. (2017). Structural brain changes in schizophrenia at different stages of the illness: A selective review of longitudinal magnetic resonance imaging studies. Australian and New Zealand Journal of Psychiatry, 51(5), 500–508. doi:10.1177/0004867417699473
Dold, M., Li, C., Gillies, D., & Leucht, S. (2013). Benzodiazepine augmentation of antipsychotic drugs in schizophrenia: A meta-analysis and cochrane review of randomized controlled trials. European Neuropsychopharmacology, 23(9), 1023–1033. doi:10.1016/j.euroneuro.2013.03.001
Dranovsky, A., & Hen, R. (2006). Hippocampal neurogenesis: Regulation by stress and antidepressants. Biological Psychiatry, 59(12), 1136–1143. doi:10.1016/j.biopsych.2006.03.082
Élie, D., Poirier, M., Chianetta, J. M., Durand, M., Grgoire, C. A., & Grignon, S. (2010). Cognitive effects of antipsychotic dosage and polypharmacy: A study with the BACS in patients with schizophrenia and schizoaffective disorder. Journal of Psychopharmacology, 24(7), 1037–1044. doi:10.1177/0269881108100777
Elkis, H., & Buckley, P. F. (2016). Treatment-resistant schizophrenia. Psychiatric Clinics of North America, 39(2), 239–265. doi:10.1016/j.psc.2016.01.006
Englisch, S., Morgen, K., Meyer-Lindenberg, A., & Zink, M. (2013). Risks and benefits of bupropion treatment in schizophrenia: A systematic review of the current literature. Clinical Neuropharmacology, 36(6), 203–215. doi:10.1097/WNF.0b013e3182a8ea04
Essock, S. M., Schooler, N. R., Stroup, T. S., McEvoy, J. P., Rojas, I., Jackson, C., ...Tapp, A. (2011). Effectiveness of switching from antipsychotic polypharmacy to monotherapy. American Journal of Psychiatry, 168(7), 702–708. doi:10.1176/appi.ajp.2011.10060908
Eum, S., Hill, S. K., Rubin, L. H., Carnahan, R. M., Reilly, J. L., Ivleva, E. I., ...Bishop, J. R. (in press). Cognitive burden of anticholinergic medications in psychotic disorders. Schizophrenia Research. doi:10.1016/j.schres.2017.03.034
Faber, G., Smid, H. G. O. M., Van Gool, A. R., Wiersma, D., & Van Den Bosch, R J. (2012). The effects of guided discontinuation of antipsychotics on neurocognition in first onset psychosis. European Psychiatry, 27(4), 275–280. doi:10.1016/j.eurpsy.2011.02.003
Fatouros-Bergman, H., Cervenka, S., Flyckt, L., Edman, G., & Farde, L. (2014). Meta-analysis of cognitive performance in drug-nave patients with schizophrenia. Schizophrenia Research, 158(1-3), 156–162. doi:10.1016/j.schres.2014.06.034
136
Fioravanti, M., Bianchi, V., & Cinti, M. E. (2012). Cognitive deficits in schizophrenia: An updated metanalysis of the scientific evidence. BMC Psychiatry, 12. doi:10.1186/1471-244X-12-64
First, M., Spitzer, R., Gibbon, M., & Williams, J. (2002). Structured clinical interview for DSM-IV-TR axis I disorders, research version, patient edition with psychotic screen (SCID-I/P W/SPYSCREEN). New York: Biometrics Research, New York State Psychiatric Institute.
Fitzsimmons, J., Kubicki, M., & Shenton, M. E. (2013). Review of functional and anatomical brain connectivity findings in schizophrenia. Current Opinion in Psychiatry, 26(2), 172–187. doi:10.1097/YCO.0b013e32835d9e6a
Flashman, L. A., & Green, M. F. (2004). Review of cognition and brain structure in schizophrenia: Profiles, longitudinal course, and effects of treatment. Psychiatric Clinics of North America, 27(1), 1–18. doi:10.1016/S0193-953X(03)00105-9
Fontanella, C. A., Campo, J. V., Phillips, G. S., Hiance-Steelesmith, D. L., Sweeney, H. A., Tam, K., ...Hurst, M. (2016). Benzodiazepine use and risk of mortality among patients with schizophrenia: A retrospective longitudinal study. Journal of Clinical Psychiatry, 77(5), 661–667. doi:10.4088/JCP.15m10271
Foster, D. J., Jones, C. K., & Conn, P. J. (2012). Emerging approaches for treatment of schizophrenia: Modulation of cholinergic signaling. Discovery Medicine, 14(79), 413–420.
Fusar-Poli, P., Smieskova, R., Kempton, M. J., Ho, B. C., Andreasen, N. C., & Borgwardt, S. (2013). Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies. Neuroscience and Biobehavioral Reviews, 37(8), 1680–1691. doi:10.1016/j.neubiorev.2013.06.001
Gaebel, W., Riesbeck, M., & Wobrock, T. (2011). Schizophrenia guidelines across the world: A selective review and comparison. International Review of Psychiatry, 23(4), 379–387. doi:10.3109/09540261.2011.606801
Gaebel, W., & Zielasek, J. (2015). Schizophrenia in 2020: Trends in diagnosis and therapy. Psychiatry and Clinical Neurosciences, 69(11), 661–673. doi:10.1111/pcn.12322
Galletly, C. (2009). Recent advances in treating cognitive impairment in schizophrenia. Psychopharmacology, 202(1-3), 259–273. doi:10.1007/s00213-008-1302-9
Glahn, D. C., Cannon, T. D., Gur, R. E., Ragland, J. D., & Gur, R. C. (2000). Working memory constrains abstraction in schizophrenia. Biological Psychiatry, 47(1), 34–42. doi:10.1016/S0006-3223(99)00187-0
Glahn, D. C., Gur, R. C., Ragland, J.D., Censits, D. M., & Gur, R. E. (1997). Reliability, performance characteristics, construct validity, and an initial clinical application of a visual object learning test (VOLT). Neuropsychology, 11(4), 602–612. doi:10.1037/0894-4105.11.4.602
Goff, D. C., Falkai, P., Fleischhacker, W. W., Girgis, R. R., Kahn, R. M., Uchida, H., ...Lieberman, J. A. (2017). The long-term effects of antipsychotic medication on clinical course in schizophrenia. American Journal of Psychiatry, 174(9), 840–849. doi:10.1176/appi.ajp.2017.16091016
137
Goldberg, T. E., Keefe, R. S. E., Goldman, R. S., Robinson, D. G., & Harvey, P. D. (2010). Circumstances under which practice does not make perfect: A review of the practice effect literature in schizophrenia and its relevance to clinical treatment studies. Neuropsychopharmacology, 35(5), 1053–1062. doi:10.1038/npp.2009.211
Green, M. F. (2016). Impact of cognitive and social cognitive impairment on functional outcomes in patients with schizophrenia. Journal of Clinical Psychiatry, 77, 8–11. doi:10.4088/JCP.14074su1c.02
Green, M. F., & Harvey, P. D. (2014). Cognition in schizophrenia: Past, present, and future. Schizophrenia Research: Cognition, 1(1), e9. doi:10.1016/j.scog.2014.02.001
Green, M. F., Marder, S. R., Glynn, S. M., McGurk, S. R., Wirshing, W. C., Wirshing, D. A., ...Mintz, J. (2002). The neurocognitive effects of low-dose haloperidol: A two-year comparison with risperidone. Biological Psychiatry, 51(12), 972–978. doi:10.1016/S0006-3223(02)01370-7
Guo, J. Y., Huhtaniska, S., Miettunen, J., Jääskeläinen, E., Kiviniemi, V., Nikkinen, J., ...Murray, G. K. (2015). Longitudinal regional brain volume loss in schizophrenia: Relationship to antipsychotic medication and change in social function. Schizophrenia Research, 168(1–2), 297–304. doi:10.1016/j.schres.2015.06.016
Gur, R. E., Calkins, M. E., Gur, R. C., Horan, W. P., Nuechterlein, K. H., Seidman, L. J., & Stone, W. S. (2007). The consortium on the genetics of schizophrenia: Neurocognitive endophenotypes. Schizophrenia Bulletin, 33(1), 49–68. doi:10.1093/schbul/sbl055
Gurillo, P., Jauhar, S., Murray, R. M., & MacCabe, J. H. (2015). Does tobacco use cause psychosis? systematic review and meta-analysis. The Lancet Psychiatry, 2(8), 718–725. doi:10.1016/S2215-0366(15)00152-2
Haapea, M., Miettunen, J., Lindeman, S., Joukamaa, M., & Koponen, H. (2010). Agreement between self-reported and pharmacy data on medication use in the Northern Finland 1966 Birth Cohort. International Journal of Methods in Psychiatric Research, 19(2), 88–96. doi:10.1002/mpr.304
Haapea, M., Miettunen, J., Veijola, J., Lauronen, E., Tanskanen, P., & Isohanni, M. (2007). Non-participation may bias the results of a psychiatric survey. An analysis from the survey including magnetic resonance imaging within the Northern Finland 1966 Birth Cohort. Social Psychiatry and Psychiatric Epidemiology, 42(5), 403–409. doi:10.1007/s00127-007-0178-z
Haijma, S. V., van Haren, N., Cahn, W., Koolschijn, P. C. M. P., Hulshoff Pol, H. E., & Kahn, R. S. (2013). Brain volumes in schizophrenia: A meta-analysis in over 18 000 subjects. Schizophrenia Bulletin, 39(5), 1129–1138. doi:10.1093/schbul/sbs118
Harrison, G., Fouskakis, D., Rasmussen, F., Tynelius, P., Sipos, A., & Gunnell, D. (2003). Association between psychotic disorder and urban place of birth is not mediated by obstetric complications of childhood socio-economic position: A cohort study. Psychological Medicine, 33(4), 723–731. doi:10.1017/S0033291703007591
Harrow, M., Jobe, T. H., & Faull, R. N. (2014). Does treatment of schizophrenia with antipsychotic medications eliminate or reduce psychosis? A 20-year multi-follow-up study. Psychological Medicine, 44(14), 3007–3016. doi:10.1017/S0033291714000610
138
Harvey, P. D. (2013). Pharmacological approaches to cognitive enhancement. In P. D. Harvey (Ed.), Cognitive impairment in schizophrenia (pp. 266–283). New York: Cambridge University Press.
Harvey, P. D. (2014). Disability in schizophrenia: Contributing factors and validated assessments. Journal of Clinical Psychiatry, 75(SUPPL. 1), 15–20. doi:10.4088/JCP.13049su1c.03
Harvey, P. D., & Keefe, R. S. E. (2001). Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. American Journal of Psychiatry, 158(2), 176–184. doi:10.1176/appi.ajp.158.2.176
Harvey, P. D., Loewenstein, D. A., & Czaja, S. J. (2013). Hospitalization and psychosis: Influences on the course of cognition and everyday functioning in people with schizophrenia. Neurobiology of Disease, 53, 18–25. doi:10.1016/j.nbd.2012.10.022
Harvey, P. D., & Rosenthal, J. B. (in press). Cognitive and functional deficits in people with schizophrenia: Evidence for accelerated or exaggerated aging? Schizophrenia Research. doi:10.1016/j.schres.2017.05.009
Hasselmo, M. E., & Wyble, B. P. (1997). Free recall and recognition in a network model of the hippocampus: Simulating effects of scopolamine on human memory function. Behavioural Brain Research, 89(1–2), 1–34. doi:10.1016/S0166-4328(97)00048-X
Heaton, R. K., Gladsjo, J. A., Palmer, B. W., Kuck, J., Marcotte, T. D., & Jeste, D. V. (2001). Stability and course of neuropsychological deficits in schizophrenia. Archives of General Psychiatry, 58(1), 24–32.
Hegarty, J. D., Baldessarini, R. J., Tohen, M., Waternaux, C., & Oepen, G. (1994). One hundred years of schizophrenia: A meta-analysis of the outcome literature. American Journal of Psychiatry, 151(10), 1409–1416.
Heinrichs, R. W., & Zakzanis, K. K. (1998). Neurocognitive deficit in schizophrenia: A quantitative review of the evidence. Neuropsychology, 12(3), 426–445. doi:10.1037/0894-4105.12.3.426
Hill, S. K., Bishop, J. R., Palumbo, D., & Sweeney, J. A. (2010). Effect of second-generation antipsychotics on cognition: Current issues and future challenges. Expert Review of Neurotherapeutics, 10(1), 43–57. doi:10.1586/ern.09.143
Hori, H., Noguchi, H., Hashimoto, R., Nakabayashi, T., Omori, M., Takahashi, S., ...Kunugi, H. (2006). Antipsychotic medication and cognitive function in schizophrenia. Schizophrenia Research, 86(1-3), 138–146. doi:10.1016/j.schres.2006.05.004
Hori, H., Yoshimura, R., Katsuki, A., Hayashi, K., Ikenouchi-Sugita, A., Umene-Nakano, W., & Nakamura, J. (2012). Several prescription patterns of antipsychotic drugs influence cognitive functions in japanese chronic schizophrenia patients. International Journal of Psychiatry in Clinical Practice, 16(2), 138–142. doi:10.3109/13651501.2011.631018
Hori, H., Yoshimura, R., Katsuki, A., Sugita, A., Atake, K., & Nakamura, J. (2013). Switching to antipsychotic monotherapy can improve attention and processing speed, and social activity in chronic schizophrenia patients. Journal of Psychiatric Research, 47(12), 1843–1848. doi:10.1016/j.jpsychires.2013.08.024
139
Howes, O. D., Kambeitz, J., Kim, E., Stahl, D., Slifstein, M., Abi-Dargham, A., & Kapur, S. (2012). The nature of dopamine dysfunction in schizophrenia and what this means for treatment: Meta-analysisof imaging studies. Archives of General Psychiatry, 69(8), 776–786. doi:10.1001/archgenpsychiatry.2012.169
Howes, O. D., & Murray, R. M. (2014). Schizophrenia: An integrated sociodevelopmental-cognitive model. The Lancet, 383(9929), 1677–1687. doi:10.1016/S0140-6736(13)62036-X
Huhtaniska, S., Jääskeläinen, E., Hirvonen, N., Remes, J., Murray, G. K., Veijola, J., ...Miettunen, J. (2017). Long-term antipsychotic use and brain changes in schizophrenia a systematic review and meta-analysis. Human Psychopharmacology, 32(2) doi:10.1002/hup.2574
Hulshoff Pol, H. E., & Kahn, R. S. (2008). What happens after the first episode? A review of progressive brain changes in chronically ill patients with schizophrenia. Schizophrenia Bulletin, 34(2), 354–366. doi:10.1093/schbul/sbm168
IBM Corp. (2012). IBM SPSS statistics for windows, version 21.0. Armonk, NY: IBM Corp. IBM Corp. (2016). IBM SPSS statistics for windows, version 24.0. Armonk, NY: IBM Corp. Immonen, J., Jääskeläinen, E., Korpela, H., & Miettunen, J. (in press). Age at onset and the
outcomes of schizophrenia: A systematic review and meta-analysis. Early Intervention in Psychiatry. doi:10.1111/eip.12412
Insel, T. R. (2010). Rethinking schizophrenia. Nature, 468(7321), 187–193. doi:10.1038/nature09552
Irani, F., Kalkstein, S., Moberg, E. A., & Moberg, P. J. (2011). Neuropsychological performance in older patients with schizophrenia: A meta-analysis of cross-sectional and longitudinal studies. Schizophrenia Bulletin, 37(6), 1318–1326. doi:10.1093/schbul/sbq057
Isohanni, M., Mäkikyrö, T., Moring, J., Räsänen, P., Hakko, H., Partanen, U., ...Jones, P. (1997). A comparison of clinical and research DSM-III-R diagnoses of schizophrenia in a Finnish national birth cohort. clinical and research diagnoses of schizophrenia. Social Psychiatry and Psychiatric Epidemiology, 32(5), 303–308. doi:10.1007/BF00789044
Juola, P., Miettunen, J., Salo, H., Murray, G. K., Ahmed, A. O., Veijola, J., ...Jääskeläinen, E. (2015). Neurocognition as a predictor of outcome in schizophrenia in the Northern Finland Birth Cohort 1966. Schizophrenia Research: Cognition, 2(3), 113–119. doi:10.1016/j.scog.2015.07.001
Jääskeläinen, E., Haapea, M., Rautio, N., Juola, P., Penttilä, M., Nordström, T., ...Miettunen, J. (2015). Twenty years of schizophrenia research in the Northern Finland Birth Cohort 1966: A systematic review. Schizophrenia Research and Treatment, 2015, 524875. doi:10.1155/2015/524875
Jääskeläinen, E., Juola, P., Hirvonen, N., McGrath, J. J., Saha, S., Isohanni, M., ...Miettunen, J. (2013). A systematic review and meta-analysis of recovery in schizophrenia. Schizophrenia Bulletin, 39(6), 1296–1306. doi:10.1093/schbul/sbs130
140
Kahn, R. S., Sommer, I. E., Murray, R. M., Meyer-Lindenberg, A., Weinberger, D. R., Cannon, T. D., ...Insel, T. R. (2015). Schizophrenia. Nature Reviews Disease Primers, 1. doi:10.1038/nrdp.2015.67
Kawai, N., Yamakawa, Y., Baba, A., Nemoto, K., Tachikawa, H., Hori, T., ...Iidaka, T. (2006). High-dose of multiple antipsychotics and cognitive function in schizophrenia: The effect of dose-reduction. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 30(6), 1009–1014. doi:10.1016/j.pnpbp.2006.03.013
Keefe, R. S. E. (2014). The longitudinal course of cognitive impairment in schizophrenia: An examination of data from premorbid through posttreatment phases of illness. Journal of Clinical Psychiatry, 75(SUPPL. 2), 8–13. doi:10.4088/JCP.13065su1.02
Keefe, R. S. E., Bilder, R. M., Davis, S. M., Harvey, P. D., Palmer, B. W., Gold, J. M., ...Lieberman, J. A. (2007). Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. Archives of General Psychiatry, 64(6), 633–647. doi:10.1001/archpsyc.64.6.633
Keefe, R. S. E., Eesley, C. E., & Poe, M. P. (2005). Defining a cognitive function decrement in schizophrenia. Biological Psychiatry, 57(6), 688–691. doi:10.1016/j.biopsych.2005.01.003
Keefe, R. S. E., & Harvey, P. D. (2012). In Geyer M. A., & Gross G.(Eds.), Cognitive impairment in schizophrenia. doi:10.1007/978-3-642-25758-2_2
Keefe, R. S. E., Seidman, L. J., Christensen, B. K., Hamer, R. M., Sharma, T., Sitskoorn, M. M., ...Lieberman, J. A. (2006). Long-term neurocognitive effects of olanzapine or low-dose haloperidol in first-episode psychosis. Biological Psychiatry, 59(2), 97–105. doi:10.1016/j.biopsych.2005.06.022
Keefe, R. S. E., Silva, S. G., Perkins, D. O., & Lieberman, J. A. (1999). The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: A review and meta-analysis. Schizophrenia Bulletin, 25(2), 201–222.
Kendler, K. S., McGuire, M., Gruenberg, A. M., O'Hare, A., Spellman, M., & Walsh, D. (1993). The Roscommon family study: I. methods, diagnosis of probands, and risk of schizophrenia in relatives. Archives of General Psychiatry, 50(7), 527–540. doi:10.1001/archpsyc.1993.01820190029004
Kirkbride, J. B., Fearon, P., Morgan, C., Dazzan, P., Morgan, K., Tarrant, J., ...Jones, P. B. (2006). Heterogeneity in incidence rates of schizophrenia and other psychotic syndromes: Findings from the 3-center SOP study. Archives of General Psychiatry, 63(3), 250–258. doi:10.1001/archpsyc.63.3.250
Kitajima, R., Miyamoto, S., Tenjin, T., Ojima, K., Ogino, S., Miyake, N., ...Yamaguchi, N. (2012). Effects of tapering of long-term benzodiazepines on cognitive function in patients with schizophrenia receiving a second-generation antipsychotic. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 36(2), 300–306. doi:10.1016/j.pnpbp.2011.11.008
Kiviniemi, M., Suvisaari, J., Pirkola, S., Häkkinen, U., Isohanni, M., & Hakko, H. (2010). Regional differences in five-year mortality after a first episode of schizophrenia in Finland. Psychiatric Services, 61(3), 272–279. doi:10.1176/appi.ps.61.3.272
141
Knowles, E. E. M., David, A. S., & Reichenberg, A. (2010). Processing speed deficits in schizophrenia: Reexamining the evidence. American Journal of Psychiatry, 167(7), 828–835. doi:10.1176/appi.ajp.2010.09070937
Kobayashi, H., Isohanni, M., Jääskeläinen, E., Miettunen, J., Veijola, J., Haapea, M., ...Murray, G. K. (2014). Linking the developmental and degenerative theories of schizophrenia: Association between infant development and adult cognitive decline. Schizophrenia Bulletin, 40(6), 1319–1327. doi:10.1093/schbul/sbu010
Kontis, D., Theochari, E., Kleisas, S., Kalogerakou, S., Andreopoulou, A., Psaras, R., ...Tsaltas, E. (2010). Doubtful association of antipsychotic polypharmacy and high dosage with cognition in chronic schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 34(7), 1333–1341. doi:10.1016/j.pnpbp.2010.07.029
Kroken, R. A., Johnsen, E., Ruud, T., Wentzel-Larsen, T., & Jørgensen, H. A. (2009). Treatment of schizophrenia with antipsychotics in Norwegian emergency wards, a cross-sectional national study. BMC Psychiatry, 9. doi:10.1186/1471-244X-9-24
Kurtz, M. M. (2005). Neurocognitive impairment across the lifespan in schizophrenia: An update. Schizophrenia Research, 74(1), 15–26. doi:10.1016/j.schres.2004.07.005
Lally, J., & MacCabe, J. H. (2015). Antipsychotic medication in schizophrenia: A review. British Medical Bulletin, 114(1), 169–179. doi:10.1093/bmb/ldv017
Lang, F. U., Kösters, M., Lang, S., Becker, T., & Jäger, M. (2013). Psychopathological long-term outcome of schizophrenia – A review. Acta Psychiatrica Scandinavica, 127(3), 173–182. doi:10.1111/acps.12030
Laursen, T. M., Nordentoft, M., & Mortensen, P. B. (2014). Excess early mortality in schizophrenia. Annual Review of Clinical Psychology, 10, 425–48. doi:10.1146/annurev-clinpsy-032813-153657
Leucht, S., Cipriani, A., Spineli, L., Mavridis, D., Örey, D., Richter, F., ...Davis, J. M. (2013). Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis. The Lancet, 382(9896), 951–962. doi:10.1016/S0140-6736(13)60733-3
Leucht, S., Samara, M., Heres, S., & Davis, J. M. (2016). Dose equivalents for antipsychotic drugs: The DDD method. Schizophrenia Bulletin, 42, S94. doi:10.1093/schbul/sbv167
Leucht, S., Tardy, M., Komossa, K., Heres, S., Kissling, W., & Davis, J. M. (2012). Maintenance treatment with antipsychotic drugs for schizophrenia. Cochrane Database of Systematic Reviews (Online), 5.
Lezak, M. D., Howieson, D. B., & Loring, D. W. (2004). Neuropsychological assessment (4. ed. ed.). Oxford: Oxford Univ. Press.
Liemburg, E. J., Knegtering, H., Klein, H. C., Kortekaas, R., & Aleman, A. (2012). Antipsychotic medication and prefrontal cortex activation: A review of neuroimaging findings. European Neuropsychopharmacology, 22(6), 387–400. doi:10.1016/j.euroneuro.2011.12.008
Linscott, R. J., Allardyce, J., & Os, J. (2010). Seeking verisimilitude in a class: A systematic review of evidence that the criterial clinical symptoms of schizophrenia are taxonic. Schizophrenia Bulletin, 36(4), 811–829. doi:10.1093/schbul/sbn181
142
Maayan, N., Soares-Weiser, K., Xia, J., & Adams, C. E. (2011). Antipsychotic combinations for schizophrenia (protocol). Cochrane Database of Systematic Reviews Issue 2. Art. No.:CD009005. doi:10.1002/14651858.CD009005
MacCabe, J. H. (2008). Population-based cohort studies on premorbid cognitive function in schizophrenia. Epidemiologic Reviews, 30, 77–83. doi:10.1093/epirev/mxn007 [doi]
Masana, M., Casta, A., Santana, N., Bortolozzi, A., & Artigas, F. (2012). Noradrenergic antidepressants increase cortical dopamine: Potential use in augmentation strategies. Neuropharmacology, 63(4), 675–684. doi:10.1016/j.neuropharm.2012.05.020
Matheson, S. L., Shepherd, A. M., Laurens, K. R., & Carr, V. J. (2011). A systematic meta-review grading the evidence for non-genetic risk factors and putative antecedents of schizophrenia. Schizophrenia Research, 133(1-3), 133–142. doi:10.1016/j.schres.2011.09.020
Maynard, T. M., Sikich, L., Lieberman, J. A., & LaMantia, A. (2001). Neural development, cell-cell signaling, and the "two-hit" hypothesis of schizophrenia. Schizophrenia Bulletin, 27(3), 457–476.
McGrath, J., Brown, A., & St Clair, D. (2011). Prevention and schizophrenia – the role of dietary factors. Schizophrenia Bulletin, 37(2), 272–283. doi:10.1093/schbul/sbq121
McGrath, J., Saha, S., Chant, D., & Welham, J. (2008). Schizophrenia: A concise overview of incidence, prevalence, and mortality. Epidemiologic Reviews, 30(1), 67–76. doi:10.1093/epirev/mxn001
McGrath, J., Saha, S., Welham, J., El Saadi, O., MacCauley, C., & Chant, D. (2004). A systematic review of the incidence of schizophrenia: The distribution of rates and the influence of sex, urbanicity, migrant status and methodology. BMC Medicine, 2 doi:10.1186/1741-7015-2-13
McGurk, S. R., Twamley, E. W., Sitzer, D. I., McHugo, G. J., & Mueser, K. T. (2007). A meta-analysis of cognitive remediation in schizophrenia. American Journal of Psychiatry, 164(12), 1791–1802. doi:10.1176/appi.ajp.2007.07060906
Mesholam-Gately, R. I., Giuliano, A. J., Goff, K. P., Faraone, S. V., & Seidman, L. J. (2009). Neurocognition in first-episode schizophrenia: A meta-analytic review. Neuropsychology, 23(3), 315–336. doi:10.1037/a0014708
Mestdagh, A., & Hansen, B. (2014). Stigma in patients with schizophrenia receiving community mental health care: A review of qualitative studies. Social Psychiatry and Psychiatric Epidemiology, 49(1), 79–87. doi:10.1007/s00127-013-0729-4
Millard, S. P., Shofer, J., Braff, D., Calkins, M., Cadenhead, K., Freedman, R., ...Tsuang, D. W. (2016). Prioritizing schizophrenia endophenotypes for future genetic studies: An example using data from the COGS-1 family study. Schizophrenia Research, 174(1–3), 1–9. doi:10.1016/j.schres.2016.04.011
Mishara, A. L., & Goldberg, T. E. (2004). A meta-analysis and critical review of the effects of conventional neuroleptic treatment on cognition in schizophrenia: Opening a closed book. Biological Psychiatry, 55(10), 1013–1022. doi:10.1016/j.biopsych.2004.01.027
143
Moilanen, J. M., Haapea, M., Jääskeläinen, E., Veijola, J. M., Isohanni, M. K., Koponen, H. J., & Miettunen, J. (2016). Long-term antipsychotic use and its association with outcomes in schizophrenia – the Northern Finland Birth Cohort 1966. European Psychiatry, 36, 7–14. doi:10.1016/j.eurpsy.2016.03.002
Moilanen, J., Haapea, M., Miettunen, J., Jääskeläinen, E., Veijola, J., Isohanni, M., & Koponen, H. (2013). Characteristics of subjects with schizophrenia spectrum disorder with and without antipsychotic medication - A 10-year follow-up of the Northern Finland 1966 Birth Cohort study. European Psychiatry, 28(1), 53–58. doi:10.1016/j.eurpsy.2011.06.009
Moilanen, J., Huhtaniska, S., Haapea, M., Jääskeläinen, E., Veijola, J., Isohanni, M., ...Miettunen, J. (2015). Brain morphometry of individuals with schizophrenia with and without antipsychotic medication-the Northern Finland Birth Cohort 1966 study. European Psychiatry, 30(5), 598–605. doi:10.1016/j.eurpsy.2015.02.009
Moilanen, K., Veijola, J., Läksy, K., Mäkikyrö, T., Miettunen, J., Kantojärvi, L., ...Isohanni, M. (2003). Reasons for the diagnostic discordance between clinicians and researchers in schizophrenia in Northern Finland 1966 Birth Cohort. Social Psychiatry and Psychiatric Epidemiology, 38(6), 305–310.
Mollon, J., & Reichenberg, A. (in press). Cognitive development prior to onset of psychosis. Psychological Medicine; 1–12. doi:10.1017/S0033291717001970
Moncrieff, J. (2006). Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatrica Scandinavica, 114(1), 3–13. doi:10.1111/j.1600-0447.2006.00787.x
Murray, G. K., Jones, P. B., Moilanen, K., Veijola, J., Miettunen, J., Cannon, T. D., & Isohanni, M. (2006). Infant motor development and adult cognitive functions in schizophrenia. Schizophrenia Research, 81(1), 65–74. doi:10.1016/j.schres.2005.08.016
Nakazawa, K., Zsiros, V., Jiang, Z., Nakao, K., Kolata, S., Zhang, S., & Belforte, J. E. (2012). GABAergic interneuron origin of schizophrenia pathophysiology. Neuropharmacology, 62(3), 1574–1583. doi:10.1016/j.neuropharm.2011.01.022
Negrón-Oyarzo, I., Lara-Vásquez, A., Palacios-García, I., Fuentealba, P., & Aboitiz, F. (2016). Schizophrenia and reelin: A model based on prenatal stress to study epigenetics, brain development and behavior. Biological Research, 49, 16. doi:10.1186/s40659-016-0076-5
Nestler, E. J., Hyman, S. E., & Malenka, R. C. (2009). Molecular neuropharmacology (2nd ed.). New York: McGraw-Hill.
NICE. (2009). Schizophrenia. Core Interventions in the Treatment and Management of Schizophrenia in Adults in Primary and Secondary Care. NICE Clinical Guideline 82. London: National Institute for Health and Clinical Excellence.
NICE. (2014). Psychosis and schizophrenia in adults: prevention and management. National Institute for Health and Care Excellence, Clinical Guideline, 178.
144
Nielsen, R. E., Levander, S., Kjaersdam Tellus, G., Jensen, S. O. W., Østergaard Christensen, T., & Leucht, S. (2015). Second-generation antipsychotic effect on cognition in patients with schizophrenia-a meta-analysis of randomized clinical trials. Acta Psychiatrica Scandinavica, 131(3), 185–196. doi:10.1111/acps.12374
Nuechterlein, K. H., Green, M. F., Kern, R. S., Baade, L. E., Barch, D. M., Cohen, J. D., ...Marder, S. R. (2008). The MATRICS consensus cognitive battery, part 1: Test selection, reliability, and validity. American Journal of Psychiatry, 165(2), 203–213. doi:10.1176/appi.ajp.2007.07010042
Palmer, B. W., Heaton, R. K., Kuck, J., Braff, D., Paulsen, J. S., Jackuelyn Harris, M., ...Jeste, D. V. (1997). Is it possible to be schizophrenic yet neuropsychologically normal? Neuropsychology, 11(3), 437–446. doi:10.1037/0894-4105.11.3.437
Pedersen, C. B., & Mortensen, P. B. (2001). Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Archives of General Psychiatry, 58(11), 1039–1046.
Perälä, J., Saarni, S. I., Ostamo, A., Pirkola, S., Haukka, J., Härkänen, T., ...Suvisaari, J. (2008). Geographic variation and sociodemographic characteristics of psychotic disorders in Finland. Schizophrenia Research, 106(2–3), 337–347. doi:10.1016/j.schres.2008.08.017
Perälä, J., Suvisaari, J., Saarni, S. I., Kuoppasalmi, K., Isometsä, E., Pirkola, S., ...Lönnqvist, J. (2007). Lifetime prevalence of psychotic and bipolar I disorders in a general population. Archives of General Psychiatry, 64(1), 19–28. doi:10.1001/archpsyc.64.1.19
Pino, O., Guilera, G., Gómez-Benito, J., Najas-Garcia, A., Rufián, S., & Rojo, E. (2014). Neurodevelopment or neurodegeneration: Review of theories of schizophrenia. Actas Espanolas De Psiquiatria, 42(4), 185–195.
Procyshyn, R. M., Honer, W. G., Wu, T. K. Y., Ko, R. W. Y., McIsaac, S. A., Young, A. H., ...Barr, A. M. (2010). Persistent antipsychotic polypharmacy and excessive dosing in the community psychiatric treatment setting: A review of medication profiles in 435 Canadian outpatients. Journal of Clinical Psychiatry, 71(5), 566–573. doi:10.4088/JCP.08m04912gre
Radua, J., Borgwardt, S., Crescini, A., Mataix-Cols, D., Meyer-Lindenberg, A., McGuire, P. K., & Fusar-Poli, P. (2012). Multimodal meta-analysis of structural and functional brain changes in first episode psychosis and the effects of antipsychotic medication. Neuroscience and Biobehavioral Reviews, 36(10), 2325–2333. doi:10.1016/j.neubiorev.2012.07.012
Rajji, T. K., Ismail, Z., & Mulsant, B. H. (2009). Age at onset and cognition in schizophrenia: Meta-analysis. British Journal of Psychiatry, 195(4), 286–293. doi:10.1192/bjp.bp.108.060723
Rajji, T. K., & Mulsant, B. H. (2008). Nature and course of cognitive function in late-life schizophrenia: A systematic review. Schizophrenia Research, 102(1–3), 122–140. doi:10.1016/j.schres.2008.03.015
145
Rannikko, I., Haapea, M., Miettunen, J., Veijola, J., Murray, G. K., Barnett, J. H., ...Jääskeläinen, E. (2015b). Changes in verbal learning and memory in schizophrenia and non-psychotic controls in midlife: A nine-year follow-up in the Northern Finland Birth Cohort study 1966. Psychiatry Research, 228(3), 671–679. doi:10.1016/j.psychres.2015.04.048
Rannikko, I., Jääskeläinen, E., Miettunen, J., Ahmed, A. O., Veijola, J., Remes, A. M., ...Haapea, M. (2016). Predictors of long-term change in adult cognitive performance: Systematic review and data from the Northern Finland Birth Cohort 1966. Clinical Neuropsychologist, 30(1), 17–50. doi:10.1080/13854046.2015.1128000
Rannikko, I., Murray, G. K., Juola, P., Salo, H., Haapea, M., Miettunen, J., ...Jääskeläinen, E. (2015a). Poor premorbid school performance, but not severity of illness, predicts cognitive decline in schizophrenia in midlife. Schizophrenia Research: Cognition, 2(3), 120–126. doi:10.1016/j.scog.2015.08.001
Rannikko, I., Paavola, L., Haapea, M., Huhtaniska, S., Miettunen, J., Veijola, J., ...Jääskeläinen, E. (2012). Verbal learning and memory and their associations with brain morphology and illness course in schizophrenia spectrum psychoses. Journal of Clinical and Experimental Neuropsychology, 34(7), 698–713. doi:10.1080/13803395.2012.668875
Rantakallio, P. (1969). Groups at risk in low birth weight infants and perinatal mortality. Acta Paediatrica Scandinavica, 193, Suppl 193:1+.
Rapoport, J. L., Giedd, J. N., & Gogtay, N. (2012). Neurodevelopmental model of schizophrenia: Update 2012. Molecular Psychiatry, 17(12), 1228–1238. doi:10.1038/mp.2012.23
Reichenberg, A., Caspi, A., Harrington, H., Houts, R., Keefe, R. S. E., Murray, R. M., ...Moffitt, T. E. (2010). Static and dynamic cognitive deficits in childhood preceding adult schizophrenia: A 30-year study. American Journal of Psychiatry, 167(2), 160–169. doi:10.1176/appi.ajp.2009.09040574
Reichenberg, A., & Harvey, P. D. (2007). Neuropsychological impairments in schizophrenia: Integration of performance-based and brain imaging findings. Psychological Bulletin, 133(5), 833–858. doi:10.1037/0033-2909.133.5.833
Ridler, K., Veijola, J. M., Tanskanen, P., Miettunen, J., Chitnis, X., Suckling, J., ...Bullmore, E. T. (2006). Fronto-cerebellar systems are associated with infant motor and adult executive functions in healthy adults but not in schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 103(42), 15651–15656. doi:10.1073/pnas.0602639103
Rijcken, C. A. W., Monster, T. B. M., Brouwers, J R B J, & De Jong-Van Den Berg, L T W. (2003). Chlorpromazine equivalents versus defined daily doses: How to compare antipsychotic drug doses? Journal of Clinical Psychopharmacology, 23(6), 657–659. doi:10.1097/01.jcp.0000096247.29231.3a
Ripke, S., Neale, B. M., Corvin, A., Walters, J. T. R., Farh, K.-H., Holmans, P. A., ...O'Donovan, M. C. (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature, 511(7510), 421–427. doi:10.1038/nature13595
146
Roiser, J. P., & Sahakian, B. J. (2013). Hot and cold cognition in depression. CNS Spectrums, 18(3), 139–149. doi:10.1017/S1092852913000072
Roofeh, D., Cottone, J., Burdick, K. E., Lencz, T., Gyato, K., Cervellione, K. L., ...Kumra, S. (2006). Deficits in memory strategy use are related to verbal memory impairments in adolescents with schizophrenia-spectrum disorders. Schizophrenia Research, 85(1–3), 201-212. doi:10.1016/j.schres.2006.03.030
Rund, B. R. (2014). Does active psychosis cause neurobiological pathology? A critical review of the neurotoxicity hypothesis. Psychological Medicine, 44(8), 1577–1590. doi:10.1017/S0033291713002341
Saha, S., Chant, D., & McGrath, J. (2007). A systematic review of mortality in schizophrenia: Is the differential mortality gap worsening over time? Archives of General Psychiatry, 64(10), 1123–1131. doi:10.1001/archpsyc.64.10.1123
Saha, S., Chant, D., Welham, J., & McGrath, J. (2005). A systematic review of the prevalence of schizophrenia. PLoS Medicine, 2(5), 413. doi:10.1371/journal.pmed.0020141
Sakurai, H., Bies, R. R., Stroup, S. T., Keefe, R. S. E., Rajji, T. K., Suzuki, T., ...Uchida, H. (2013). Dopamine D2 receptor occupancy and cognition in schizophrenia: Analysis of the CATIE data. Schizophrenia Bulletin, 39(3), 564–574. doi:10.1093/schbul/sbr189
Schaefer, J., Giangrande, E., Weinberger, D. R., & Dickinson, D. (2013). The global cognitive impairment in schizophrenia: Consistent over decades and around the world. Schizophrenia Research, 150(1), 42–50. doi:10.1016/j.schres.2013.07.009
Selva-Vera, G., Balanzá-Martínez, V., Salazar-Fraile, J., Sánchez-Moreno, J., Martinez-Aran, A., Correa, P., ...Tabarés-Seisdedos, R. (2010). The switch from conventional to atypical antipsychotic treatment should not be based exclusively on the presence of cognitive deficits. A pilot study in individuals with schizophrenia. BMC Psychiatry, 10. doi:10.1186/1471-244X-10-47
Shah, J. N., Qureshi, S. U., Jawaid, A., & Schulz, P. E. (2012). Is there evidence for late cognitive decline in chronic schizophrenia? Psychiatric Quarterly, 83(2), 127–144. doi:10.1007/s11126-011-9189-8
Sheline, Y. I., Gado, M. H., & Kraemer, H. C. (2003). Untreated depression and hippocampal volume loss. American Journal of Psychiatry, 160(8), 1516–1518. doi:10.1176/appi.ajp.160.8.1516
Shenton, M. E., Whitford, T. J., & Kubicki, M. (2010). Structural neuroimaging in schizophrenia: From methods to insights to treatments. [Neuroimgenes estructurales en la esquizofrenia: desde la metodologa hasta la comprensin de los tratamientos] Dialogues in Clinical Neuroscience, 12(3), 317–332.
Shepherd, A. M., Laurens, K. R., Matheson, S. L., Carr, V. J., & Green, M. J. (2012). Systematic meta-review and quality assessment of the structural brain alterations in schizophrenia. Neuroscience and Biobehavioral Reviews, 36(4), 1342–1356. doi:10.1016/j.neubiorev.2011.12.015
147
Shin, J. H., Park, S. J., Kim, E. S., Jo, Y. K., Hong, J., & Cho, D.-H. (2012). Sertindole, a potent antagonist at dopamine D2 receptors, induces autophagy by increasing reactive oxygen species in SH-SY5Y neuroblastoma cells. Biological and Pharmaceutical Bulletin, 35(7), 1069–1075. doi:10.1248/bpb.b12-00009
Silver, H., Mandiuk, N., Einoch, R., Susser, E., Danovich, L., Bilker, W., ...Weinreb, O. (2015). Improvement in verbal memory following SSRI augmentation of antipsychotic treatment is associated with changes in the expression of mRNA encoding for the GABA-A receptor and BDNF in PMC of schizophrenic patients. International Clinical Psychopharmacology, 30(3), 158–166. doi:10.1097/YIC.0000000000000070
Singh, J., Kour, K., & Jayaram, M. B. (2012). Acetylcholinesterase inhibitors for schizophrenia. Cochrane Database of Systematic Reviews (Online), 1.
Singh, S. P., Singh, V., Kar, N., & Chan, K. (2010). Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: Meta-analysis. British Journal of Psychiatry, 197(3), 174–179. doi:10.1192/bjp.bp.109.067710
Smoller, J. W., Ripke, S., Lee, P.H., Neale, B., Nurnberger, J.I., Santangelo, S., …Kendler, K. (2013). Identification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis. The Lancet, 381(9875), 1371–1379. doi:10.1016/S0140-6736(12)62129-1
Spaulding, W. D., Fleming, S. K., Reed, D., Sullivan, M., Storzbach, D., & Lam, M. (1999). Cognitive functioning in schizophrenia: Implications for psychiatric rehabilitation. Schizophrenia Bulletin, 25(2), 275–289.
Spitzer, R. L., Williams, J. B. W., Gibbon, M., & First, M. B. (1989). Structured clinical interview for DSM-III-R -patient edition (SCID-P, 9/1/89 version). New York: Biometrics Research Department, New York State, Psychiatric Institute, NY.
Stahl, S. M. (2008). Antipsychotics and mood stabilizers: Stahl’s essential psychopharmacology (3rd ed.). New York: Cambridge University Press.
Steen, N. E., Aas, M., Simonsen, C., Dieset, I., Tesli, M., Nerhus, M., ...Andreassen, O. A. (2015). Serum level of venlafaxine is associated with better memory in psychotic disorders. Schizophrenia Research, 169(1–3), 386–392. doi:10.1016/j.schres.2015.10.021
Stone, W. S., Giuliano, A. J., Tsuang, M. T., Braff, D. L., Cadenhead, K. S., Calkins, M. E., ...Seidman, L. J. (2011). Group and site differences on the california verbal learning test in persons with schizophrenia and their first-degree relatives: Findings from the consortium on the genetics of schizophrenia (COGS). Schizophrenia Research, 128(1–3), 102–110. doi:10.1016/j.schres.2011.01.005
Szöke, A., Trandafir, A., Dupont, M., Méary, A., Schürhoff, F., & Leboyer, M. (2008). Longitudinal studies of cognition in schizophrenia: Meta-analysis. British Journal of Psychiatry, 192(4), 248–257. doi:10.1192/bjp.bp.106.029009
Takeuchi, H., Suzuki, T., Remington, G., Bies, R. R., Abe, T., Graff-Guerrero, A., ...Uchida, H. (2013). Effects of risperidone and olanzapine dose reduction on cognitive function in stable patients with schizophrenia: An open-label, randomized, controlled, pilot study. Schizophrenia Bulletin, 39(5), 993–998. doi:10.1093/schbul/sbt090
148
Tandon, R., Keshavan, M. S., & Nasrallah, H. A. (2008). Schizophrenia, "just the facts" what we know in 2008. 2. epidemiology and etiology. Schizophrenia Research, 102(1–3), 1–18. doi:10.1016/j.schres.2008.04.011
Tannenbaum, C., Paquette, A., Hilmer, S., Holroyd-Leduc, J., & Carnahan, R. (2012). A systematic review of amnestic and non-amnestic mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid drugs. Drugs and Aging, 29(8), 639–658. doi:10.2165/11633250
Terevnikov, V., Joffe, G., & Stenberg, J.-H. (2015). Randomized controlled trials of add-on antidepressants in schizophrenia. International Journal of Neuropsychopharmacology, 18(9), 1–14. doi:10.1093/ijnp/pyv049
Terry Jr., A. V., & Mahadik, S. P. (2007). Time-dependent cognitive deficits associated with first and second generation antipsychotics: Cholinergic dysregulation as a potential mechanism. Journal of Pharmacology and Experimental Therapeutics, 320(3), 961–968. doi:10.1124/jpet.106.106047
Thomas, E. H. X., Bozaoglu, K., Rossell, S. L., & Gurvich, C. (2017). The influence of the glutamatergic system on cognition in schizophrenia: A systematic review. Neuroscience and Biobehavioral Reviews, 77, 369–387. doi:10.1016/j.neubiorev.2017.04.005
Thorsen, A. L., Johansson, K., & Løberg, E. (2014). Neurobiology of cognitive remediation therapy for schizophrenia: A systematic review. Frontiers in Psychiatry, 5(AUG) doi:10.3389/fpsyt.2014.00103
Tiihonen, J., Mittendorfer-Rutz, E., Torniainen, M., Alexanderson, K., & Tanskanen, A. (2016). Mortality and cumulative exposure to antipsychotics, antidepressants, and benzodiazepines in patients with schizophrenia: An observational follow-up study. American Journal of Psychiatry, 173(6), 600–606. doi:10.1176/appi.ajp.2015.15050618
Torniainen, M., Suvisaari, J., Partonen, T., Castaneda, A. E., Kuha, A., Suokas, J., ...Tuulio-Henriksson, A. (2012). Cognitive impairments in schizophrenia and schizoaffective disorder: Relationship with clinical characteristics. Journal of Nervous and Mental Disease, 200(4), 316–322. doi:10.1097/NMD.0b013e31824cb359
Toulopoulou, T., & Murray, R. M. (2004). Verbal memory deficit in patients with schizophrenia: An important future target for treatment. Expert Review of Neurotherapeutics, 4(1), 43–52. doi:10.1586/14737175.4.1.43
Tuominen, H. J., Tiihonen, J., & Wahlbeck, K. (2006). Glutamatergic drugs for schizophrenia. The Cochrane Database of Systematic Reviews, (2)(2), CD003730. doi:10.1002/14651858.CD003730.pub2 [doi]
Tuulio-Henriksson, A., Perälä, J., Saarni, S. I., Isometsä, E., Koskinen, S., Lönnqvist, J., & Suvisaari, J. (2011). Cognitive functioning in severe psychiatric disorders: A general population study. European Archives of Psychiatry and Clinical Neuroscience, 261(6), 447–456. doi:10.1007/s00406-010-0186-y
Tyburski, E., Sokolowski, A., Chec, M., Pelka-Wysiecka, J., & Samochowiec, A. (2015). Neuropsychological characteristics of verbal and non-verbal fluency in schizophrenia patients. Archives of Psychiatric Nursing, 29(1), 33–38. doi:10.1016/j.apnu.2014.09.009
149
van der Gaag, M., Cuijpers, A., Hoffman, T., Remijsen, M., Hijman, R., de Haan, L., ...Wiersma, D. (2006). The five-factor model of the positive and negative syndrome scale I: Confirmatory factor analysis fails to confirm 25 published five-factor solutions. Schizophrenia Research, 85(1–3), 273–279. doi:10.1016/j.schres.2006.04.001
van Haren, N. E. M., Schnack, H. G., Cahn, W., Van Den Heuvel, M. P., Lepage, C., Collins, L., ...Kahn, R. S. (2011). Changes in cortical thickness during the course of illness in schizophrenia. Archives of General Psychiatry, 68(9), 871–880. doi:10.1001/archgenpsychiatry.2011.88
Veijola, J., Guo, J. Y., Moilanen, J. S., Jääskeläinen, E., Miettunen, J., Kyllönen, M., ...Murray, G. K. (2014). Longitudinal changes in total brain volume in schizophrenia: Relation to symptom severity, cognition and antipsychotic medication. PLoS ONE, 9(7) doi:10.1371/journal.pone.0101689
Vermeulen, J., van Rooijen, G., Doedens, P., Numminen, E., van Tricht, M., & de Haan, L. (in press). Antipsychotic medication and long-term mortality risk in patients with schizophrenia; a systematic review and meta-analysis. Psychological Medicine, 1–12. doi:10.1017/S0033291717000873
Vernon, J. A., Grudnikoff, E., Seidman, A. J., Frazier, T. W., Vemulapalli, M. S., Pareek, P., ...Correll, C. U. (2014). Antidepressants for cognitive impairment in schizophrenia – A systematic review and meta-analysis. Schizophrenia Research, 159(2–3), 385–394. doi:10.1016/j.schres.2014.08.015
Vita, A., De Peri, L., Deste, G., Barlati, S., & Sacchetti, E. (2015). The effect of antipsychotic treatment on cortical gray matter changes in schizophrenia: Does the class matter? A meta-analysis and meta-regression of longitudinal magnetic resonance imaging studies. Biological Psychiatry, 78(6), 403–412. doi:10.1016/j.biopsych.2015.02.008
Vita, A., De Peri, L., Deste, G., & Sacchetti, E. (2012). Progressive loss of cortical gray matter in schizophrenia: A meta-analysis and meta-regression of longitudinal MRI studies. Translational Psychiatry, 2. doi:10.1038/tp.2012.116
Vohora, D., & Bhowmik, M. (2012). Histamine H3 receptor antagonists/ inverse agonists on cognitive and motor processes: Relevance to Alzheimer's disease, ADHD, schizophrenia and drug abuse. Frontiers in Systems Neuroscience, (OCTOBER 2012), 1-27. doi:10.3389/fnsys.2012.00072
Vos, T., Barber, R. M., Bell, B., Bertozzi-Villa, A., Biryukov, S., Bolliger, I., ...Murray, C. J. L. (2015). Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: A systematic analysis for the global burden of disease study 2013. The Lancet, 386(9995), 743–800. doi:10.1016/S0140-6736(15)60692-4
Waddington, J. L., Youssef, H. A., & Kinsella, A. (1990). Cognitive dysfunction in schizophrenia followed up over 5 years, and its longitudinal relationship to the emergence of tardive dyskinesia. Psychological Medicine, 20(4), 835–842. doi:10.1017/S0033291700036527
150
Wahlbeck, K., Westman, J., Nordentoft, M., Gissler, M., & Laursen, T. M. (2011). Outcomes of Nordic mental health systems: Life expectancy of patients with mental disorders. British Journal of Psychiatry, 199(6), 453–458. doi:10.1192/bjp.bp.110.085100
Wang, P. S., Brookhart, A. M., Ulbricht, C., & Schneeweiss, S. (2011). The pharmacoepidemiology of psychiatric medications. Textbook in psychiatric epidemiology: Third edition (pp. 155–165) John Wiley and Sons. doi:10.1002/9780470976739.ch10
Wechsler, D. (2005). Wechsler adult intelligence scale (3rd ed.). Helsinki, Finland: Psykologien Kustannus Oy.
Wechsler, D. (2008). WMS-III – Wechsler memory scale (3rd ed.) New York: The Psychological Corporation. Helsinki, Finland: Psykologien Kustannus Oy.
Weickert, C. S., & Weickert, T. W. (2016). What's hot in schizophrenia research? Psychiatric Clinics of North America, 39(2), 343–351. doi:10.1016/j.psc.2016.01.011
Weickert, T. W., Goldberg, T. E., Marenco, S., Bigelow, L. B., Egan, M. F., & Weinberger, D. R. (2003). Comparison of cognitive performances during a placebo period and an atypical antipsychotic treatment period in schizophrenia: Critical examination of confounds. Neuropsychopharmacology, 28(8), 1491–1500. doi:10.1038/sj.npp.1300216
Weinberger, D. R. (1987). Implications of normal brain development for the pathogenesis of schizophrenia. Archives of General Psychiatry, 44(7), 660–669. doi:10.1001/archpsyc.1987.01800190080012
Whitehead, C., Moss, S., Cardno, A., & Lewis, G. (2003). Antidepressants for the treatment of depression in people with schizophrenia: A systematic review. Psychological Medicine, 33(4), 589–599. doi:10.1017/S0033291703007645
WHO Collaborating Centre for Drug Statistics Methodology. (2016). Guidelines for ATC classification and DDD assignment 2016. Oslo: WHO Collaborating Centre for Drug Statistics Methodology.
Wilkinson, S. T., Radhakrishnan, R., & D'Souza, D. C. (2014). Impact of cannabis use on the development of psychotic disorders. Current Addiction Reports, 1(2), 115–128. doi:10.1007/s40429-014-0018-7 [doi]
Woodward, N. D. (2016). The course of neuropsychological impairment and brain structure abnormalities in psychotic disorders. Neuroscience Research, 102, 39–46. doi:10.1016/j.neures.2014.08.006
Woodward, N. D., Purdon, S. E., Meltzer, H. Y., & Zald, D. H. (2005). A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. International Journal of Neuropsychopharmacology, 8(3), 457–472. doi:10.1017/S146114570500516X
World Health Organization (WHO). (1992). International classification of diseases and related health problems (10th ed.). Geneva: WHO.
151
Wunderink, L., Nieboer, R. M., Wiersma, D., Sytema, S., & Nienhuis, F. J. (2013). Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry, 70(9), 913–920. doi:10.1001/jamapsychiatry.2013.19
Wykes, T., Huddy, V., Cellard, C., McGurk, S. R., & Czobor, P. (2011). A meta-analysis of cognitive remediation for schizophrenia: Methodology and effect sizes. American Journal of Psychiatry, 168(5), 472–485. doi:10.1176/appi.ajp.2010.10060855
Yang, J., Ko, Y.-H., Paik, J.-W., Lee, M.-S., Han, C., Joe, S.-H., ...Kim, S.-H. (2012). Symptom severity and attitudes toward medication: Impacts on adherence in outpatients with schizophrenia. Schizophrenia Research, 134(2–3), 226–231. doi:10.1016/j.schres.2011.11.008
Yung, A. R., & McGorry, P. O. (1996). The prodromal phase of first-episode psychosis: Past and current conceptualizations. Schizophrenia Bulletin, 22(2), 353–370.
Zink, M., Englisch, S., & Meyer-Lindenberg, A. (2010). Polypharmacy in schizophrenia. Current Opinion in Psychiatry, 23(2), 103–111. doi:10.1097/YCO.0b013e3283366427
Zipursky, R. B., Reilly, T. J., & Murray, R. M. (2013). The myth of schizophrenia as a progressive brain disease. Schizophrenia Bulletin, 39(6), 1363–1372. doi:10.1093/schbul/sbs135
Zubin, J., & Spring, B. (1977). Vulnerability – A new view of schizophrenia. Journal of Abnormal Psychology, 86(2), 103–126.
152
153
Original publications
This thesis is based on the following publications, which are referred to throughout
the text by their Roman numerals:
I Husa, A. P., Rannikko, I., Moilanen, J., Haapea, M., Murray, G. K., Barnett, J., Jones, P. B., Isohanni, M., Koponen, H., Miettunen, J., & Jääskeläinen, E. (2014). Lifetime use of antipsychotic medication and its relation to change of verbal learning and memory in midlife schizophrenia – An observational 9-year follow-up study. Schizophrenia Research 158(1–3):134–141. doi: 10.1016/j.schres.2014.06.035
II Husa, A. P., Moilanen, J., Murray, G. K., Marttila, R., Haapea, M., Rannikko, I., Barnett, J. H., Jones, P. B., Isohanni, M., Remes, A. M., Koponen, H., Miettunen, J., & Jääskeläinen, E. (2017). Lifetime antipsychotic medication and cognitive performance in schizophrenia at age 43 years in a general population birth cohort. Psychiatry Research 247:130–138. doi: 10.1016/j.psychres.2016.10.085
III Hulkko, A. P., Murray, G. K., Moilanen, J., Haapea, M., Rannikko, I., Jones, P. B., Barnett, J.H., Huhtaniska, S., Isohanni, M. K., Koponen, H., Jääskeläinen, E., & Miettunen, J. (2017). Lifetime use of psychiatric medications and cognition at 43 years of age in schizophrenia in the Northern Finland Birth Cohort 1966. European Psychiatry 45: 50–58. doi: 10.1016/j.eurpsy.2017.06.004
Reprinted with permission from Elsevier (I, II, III).
Original publications are not included in the electronic version of the dissertation.
154
A C T A U N I V E R S I T A T I S O U L U E N S I S
Book orders:Granum: Virtual book storehttp://granum.uta.fi/granum/
S E R I E S D M E D I C A
1418. Oura, Petteri (2017) Search for lifetime determinants of midlife vertebral size :emphasis on lifetime physical activity and early-life physical growth
1419. Kytövuori, Laura (2017) Genetic causes and risk factors associated withphenotypes occurring in mitochondrial disorders
1420. Herajärvi, Johanna (2017) Remote ischemic preconditioning in aortic surgery :Experimental studies with a porcine model
1421. Lemma, Siria (2017) Migration and adhesion associated molecules in lymphomabiology and their potential roles as biomarkers
1422. Garma, Leonardo D. (2017) Structural bioinformatics tools for the comparisonand classification of protein interactions
1423. Suhonen, Noora- Maria (2017) Cognitive and behavioral characteristics offrontotemporal lobar degeneration
1424. Heikkinen, Juuso (2017) Recovery of calf muscle isokinetic strength after acuteAchilles tendon rupture
1425. Mäkinen, Johanna (2017) Lung adenocarcinoma : histopathological features andtheir association with patient outcome
1426. Karhu, Toni (2017) Isolation of novel ligands for MAS-related G protein-coupledreceptors X1 and X2, and their effect on mast cell degranulation
1427. Mantere, Tuomo (2017) DNA damage response gene mutations and inheritedsusceptibility to breast cancer
1428. Salokorpi, Niina (2017) Treatment of craniosynostoses
1429. Männikkö, Niko (2017) Problematic gaming behavior among adolescents andyoung adults : Relationship between gaming behavior and health
1430. Kortekangas, Tero (2017) The Non-operative treatment of Weber B -type anklefractures and the clinical relevance and treatment of syndesmosis injury
1431. Lavander, Päivi (2017) Nimikesuojattujen ja laillistettujen ammattihenkilöidentyönjako yliopistosairaalan muuttuvassa toimintaympäristössä
1432. Vihanninjoki, Kyösti (2017) The Heidelberg Retina Tomograph in the diagnosis ofglaucoma
1433. Männistö, Jaana (2017) The effects of termination of pregnancy on futurereproduction
UNIVERSITY OF OULU P .O. Box 8000 F I -90014 UNIVERSITY OF OULU FINLAND
A C T A U N I V E R S I T A T I S O U L U E N S I S
University Lecturer Tuomo Glumoff
University Lecturer Santeri Palviainen
Postdoctoral research fellow Sanna Taskila
Professor Olli Vuolteenaho
University Lecturer Veli-Matti Ulvinen
Planning Director Pertti Tikkanen
Professor Jari Juga
University Lecturer Anu Soikkeli
Professor Olli Vuolteenaho
Publications Editor Kirsti Nurkkala
ISBN 978-952-62-1682-9 (Paperback)ISBN 978-952-62-1683-6 (PDF)ISSN 0355-3221 (Print)ISSN 1796-2234 (Online)
U N I V E R S I TAT I S O U L U E N S I S
MEDICA
ACTAD
D 1434
AC
TAA
nja Hulkko
OULU 2017
D 1434
Anja Hulkko
THE ASSOCIATION OF LIFETIME ANTIPSYCHOTIC AND OTHER PSYCHIATRIC MEDICATIONS WITH COGNITION IN SCHIZOPHRENIA
THE NORTHERN FINLAND BIRTH COHORT1966 STUDY
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU,FACULTY OF MEDICINE;MEDICAL RESEARCH CENTER OULU;OULU UNIVERSITY HOSPITAL
![Retro tControlwithApproximateEnvironmentModeling · due to model reduction can be handled as a model uncer-tainty in robust control [Zhou et al., 1995]. However, such a model reduction](https://img.pdfslide.net/doc/110x75/5e7b3bf731766507f4010fc4/retro-tcontrolwithapproximateen-due-to-model-reduction-can-be-handled-as-a-model.jpg)
