Understanding Complexities of SZ

7/31/2019 Understanding Complexities of SZ

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Otoe 2011

SUPPLEMENT TO

Gregory W. Mattingly, MDAssociate Clinical Professor

Department of Psychiatry

Washington University School of Medicine

St. Louis, Missouri

Henry A. Nasrallah, MDProgram Moderator

Professor of Psychiatry and Neuroscience

University of Cincinnati

Director, Schizophrenia Program

UC Health University Hospital

Cincinnati, Ohio

Peter J. Weiden, MDProfessor of Psychiatry

Director, Psychotic Disorders ProgramUniversity of Illinois Medical Center

Chicago, Illinois

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Understanding the

Complexities of Schiophrenia


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SA-3CurrentPsychiatry.com Supplement to Current Psychiatry | Vol 10, No 9 | October 2011

Understanding the Complexitiesof Schizophrenia

A Precipitous DeclineSchizophrenia is a lifelong, degenerative disease that affects individuals

during the most productive period of their lives. Schizophrenia typically

begins during late adolescence, and the prodromal period is characterized

by social withdrawal and other subtle changes in behavior and emotional

responsiveness. What follows formal diagnosis of schizophrenia is a seriesof acute episodes and relapses, during which symptoms persist and often

worsen over time.1-3 The damage associated with schizophrenia begins dur-

ing or even before the prodromal period and appears to continue through-

out the course of the disease. However, the first 5 to 10 years after diagnosis

appear to be particularly destructive to brain tissue.4

Structural Brain Abnormalities in SchizophreniaStructural abnormalities associated with schizophrenia include enlarged

cerebral ventricles, a reduction in the size of the hippocampus and

amygdala, and alterations in other structures such as the entorhinal cor-

tex of the parahippocampal gyrus, superior temporal gyrus, and anteriorcingulate gyrus. Abnormalities in prefrontal white matter may underlie

an altered connection between the prefrontal cortex and anterior cingu-

late cortex or limbic regions. Unlike the hippocampus and amygdala,

which are smaller in patients with schizophrenia compared with the

general population, the size of basal ganglia structures is increased in

this population.5,6

The loss of grey matter is significant and progressive in patients with

schizophrenia, as illustrated by a study performed in patients with an early

onset of the disease (Figure 1, page SA-4). During the 5 years of the study,

grey-matter loss progressed anteriorly into temporal lobes, sensorimotor

and dorsolateral prefrontal cortices, and frontal eye fields. These patternsof loss correlated with psychotic symptom development and reflected the

neuromotor, auditory, visual search, and frontal executive impairments in

schizophrenia. It should be noted that subject choice was a notable limita-

tion of the study, as patients with very early onset of schizophrenia tend to

experience a more severe disease course.6

As previously noted, the hippocampus typically shows a decrease in

size and an alteration in shape in patients with schizophrenia. In humans,

this important structure is thought to mediate the formation of new mem-

ories. The roles for the hippocampus postulated in schizophrenia are var-

ied. Some investigators attribute memory impairments in schizophrenia

to hippocampal pathology. Others cite its high concentration of NMDA

Gregory W. Mattingly, MDAssociate Clinical ProfessorDepartment of PsychiatryWashington UniversitySchool of MedicineSt Louis, Missouri

Henry A. Nasrallah, MD

Professor of Psychiatry andNeuroscienceUniversity of Cincinnati College

of MedicineDirector, Schizophrenia ProgramUC Health University HospitalCincinnati, Ohio

Peter J. Weiden, MDProfessor of PsychiatryDirector, Psychotic Disorders ProgramUniversity of Illinois Medical CenterChicago, Illinois

Disclosures

Dr Mattingly receives research support from Astra

Zeneca; Ayerst; Dainippon Sumitomo Pharma Co. Ltd.;Forest Laboratories, Inc.; GlaxoSmithKline; Janssen; John-

son & Johnson; Eli Lilly and Company; Lundbeck A/S;

Ortho-McNeil-Janssen Pharmaceuticals, Inc.; Merck &

Co.; New River Pharmaceuticals Inc.; Novartis; Organon

Pharmaceuticals USA Inc.; Pfizer Inc; Sanofi-Synthelabo;

Schwabe/Ingenix; Sunovion Pharmaceuticals Inc.; Shire;

Solvay Pharmaceuticals, Inc.; Takeda Pharmaceuticals

North America, Inc.; Vanda Pharmaceuticals Inc.; and Wyeth

Pharmaceuticals Inc. He is or has served on speakers

bureaus for Abbott Laboratories; Forest Pharmaceuti-

cals; GlaxoSmithKline; Janssen; Eli Lilly and Company;

Ortho-McNeil-Janssen Pharmaceuticals, Inc.; and Shire. Dr

Mattingly is or has been a consultant for Forest; Eli Lilly and

Company; Ortho-McNeil-Janssen Pharmaceuticals, Inc.;

Pfizer Inc; Shire; and Vanda Pharmaceuticals Inc.

Dr Nasrallah is a consultant/advisor for AstraZeneca;

Janssen, L.P.; Merck; Novartis; Pfizer Inc.; and Sunovion

Pharmaceuticals Inc. He is an investigator for Forest Phar-

maceuticals; Janssen, L.P.; Otsuka; Roche; and Shire. In ad-

dition, Dr Nasrallah has served as a meeting participant/

leader for Genentech, Inc.; Merck; Novartis; and Sun-

ovion Pharmaceuticals Inc. He has also conducted scien-

tific study/trials for Forest Pharmaceuticals; Janssen, L.P.;

Otsuka; and Roche.

Dr Weiden has received grant support from The National

Institute of Mental Health (NIMH); Novartis; Ortho-McNeil-

Janssen, Inc.; and Sunovion Pharmaceuticals Inc. He has

served as a consultant for Biovail Corporation (now Valeant

Pharmaceuticals International, Inc); Bristol-Myers Squibb;

Delpor, Inc.; Genentech, Inc.; Lundbeck; Novartis; and

Ortho-McNeil-Janssen, Inc. He has also served as a speaker

for Merck; Novartis; Ortho-McNeil-Janssen, Inc.; Pfizer Inc;

and Sunovion Pharmaceuticals Inc.


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UNDSANDNG H CMPS SCHzPHNA

SA-4 October 2011 | Vol 10, No 9 | Supplement to Current Psychiatry

(N-Methyl-D-aspartate) receptors and be-

lieve it is involved in the clinical symptoms

of schizophrenia.7

Although the exact location of hip-pocampal pathology in schizophrenia is

currently a topic of active research, a post-

mortem study by Benes and colleagues

demonstrated alterations in one particular

regionCA2and in one particular cell

typenonpyramidal cells. The hippocam-

pus is a particularly complex structure,

and this study may also be instructive in

the kind of fine-grained analysis that may

be necessary to reveal functionally signifi-

cant brain alterations in a complex diseasesuch as schizophrenia (Figure 2).8

Functional Brain Abnormalitiesin SchizophreniaIn addition to a variety of structural al-

terations, patients with schizophrenia also

show key functional abnormalities in brain

activation during specific tasks. One such

findinghypofrontalityrefers to the dys-

function in prefrontal brain regions associat-

ed with linguistic and emotional expression,

planning and producing new ideas, and

mediating social interactions. The finding

of insufficient activation in this region was

elegantly illustrated by a classic study con-

ducted by Andreasen and colleagues.9

In this study, the Tower of London

task was used to engage prefrontal brain

function in drug-nave patients with

schizophrenia, nondrug-nave patients

with schizophrenia, and control subjects.

Brain activation was measured with single

photon emission computed tomography

(SPECT) imaging. The Tower of London

task requires shifting balls of varying size

between several pegs until they are ar-

ranged in order of decreasing size. Cerebralperfusion with xenon 133 was measured

during the task with a SPECT scanner.9

During the Tower of London task, the

difference in regional cerebral blood flow

between active and control conditions

increased in all three groups, with drug-

nave patients with schizophrenia show-

ing the highest level of cerebral blood

flow in both the control and active condi-

tions. However, when the regional blood

flow within predefined regions of interestwas compared with overall brain perfu-

sion, control subjects showed the greatest

increase in blood flow in the left mesial

frontal region. Neither drug-nave nor

drug-exposed patients with schizophrenia

showed this increase.9

A more recent study by Horga and col-

leagues correlated brain activation, as

measured by fluorodeoxyglucose positron

emission tomography (FDG-PET), with ac-

tive verbal auditory hallucinations in pa-tients with schizophrenia. This study used

patients with schizophrenia without verbal

auditory hallucinations as a control group,

and all patients were drug-naveallowing

the investigators to examine the neurologic

correlates of the disease of schizophrenia

without the confounding factor of neuro-

leptic treatment. Observations included in-

creases in activity in left superior and middle

temporal gyri and hypoactivation in the bi-

lateral hippocampi (Figure 3, page SA-6).10

Although the

exact locationof hippocampal

pathology in

schizophrenia is

currently a topic of

active research, a

postmortem study by

Benes and colleagues

demonstrated

alterations in one

particular region

CA2and in one

particular cell type

nonpyramidal cells.

Figure 1

Loss of Grey Matter in Patients With Schizophrenia6

Thompson PM, et al. PNAS. 2001;98(20):11650-11655.

Copyright 2001 National Academy of Sciences, U.S.A.

Normal Schizophrenic Difference

Significant, progressive grey matter loss in patients with schizophrenia


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A Workout for the HippocampusIn contrast to the many studies show-

ing irreparable damage as schizophre-

nia wreaks havoc on the brain, a recent

study reported the positive effects of asimple interventionmoderate exercise

three times a weekon hippocampal

volume in patients with schizophrenia.

In this randomized, controlled study, pa-

tients with schizophrenia and normal

control subjects exercised in a gym for

30 minutes three times a week for a period of

3 months. The nonexercising control groups

of patients with schizophrenia and healthy

volunteers played table foosball for 30 min-

utes three times a week (Figure 4, page SA-7).11

Patients with schizophrenia who exer-

cised experienced hippocampal volume in-

creases of 12% compared with a further 1%

shrinkage among the nonexercising patients.

Healthy subjects who exercised experienced

a 16% increase in hippocampal volume.

Furthermore, changes in hippocampal vol-

ume correlated with improvement in aerobic

fitness, as measured by change in maximum

oxygen consumption. In the schizophre-

nia exercise group (but not in the controls),change in hippocampal volume was as-

sociated with a 35% increase in the ratio of

N-acetylaspartate (NAA; a neuronal marker

in magnetic resonance spectroscopy) to cre-

atine in the hippocampus. Improvement

in test scores for short-term memory in the

combined exercise and nonexercise schizo-

phrenia groups was correlated with change

in hippocampal volume.11

Approaches to Unlocking theGenetics of SchizophreniaOver the last several decades of active re-

search into the genetic causes of schizo-

phrenia, it has become abundantly clear

that schizophrenia is a complex polygenetic

condition.12-14 Certainly, no one gene has

ever been successfully linked with its onset

or treatment. In the meantime, research con-

tinues to look at the influence of candidate

genes on specific symptoms, developmental

trajectories, and pharmacologic outcomes.

Particularly promising areas of schizophre-

nia research, known as pharmacogenomics,

combine genetic information with pharma-

cologic treatment and evaluate genetic cor-

relates with functional neuroimaging.

Given the importance of dopamine for

the pathophysiology of schizophrenia,

much research has been devoted to exam-

ining genes related to dopamine transport,connectivity, or signal transduction. For

example, the catechol-O-methyltransferase

(COMT) gene is by far the most frequently

studied in association with schizophrenia.

COMT degrades catecholamine, including

dopamine, and has been linked to an in-

creased risk of psychosis. It is particularly

concentrated in the extrasynaptic spaces of

the prefrontal cortex and hippocampus

two areas shown to sustain damage in pa-

tients with schizophrenia.15,16

Figure 2

Scatterplot of Hippocampal Neurons in the StratumPyramidale8

P=0.037

A scattergram plot of the x,y coordinates of every pyramidal neuron (upper panel) and

nonpyramidal neuron (lower panel) in the stratum pyramidale of sectors CA14 in thehippocampal formation of a normal control (left) and schizophrenic (right) subject. There

was on average approximately 2000 pyramidal neurons (small dots) and 200 nonpyramidal

neurons (filled circles) throughout the cornu ammonis subfields of the subjects in both groups.

Benes FM, et al. Biol Psychiatry. 1998;44:88-97. 1998 Society of Biological Psychiatry.

CA2 CA2

CA2 CA2

It has become

abundantly clear that

schizophrenia is a

complex polygenetic

condition.

Control Schizophrenic

Pyramidal Pyramidal

Nonpyramidal Nonpyramidal


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Other genes related to dopamine func-

tioning currently under investigation in

schizophrenia areto name a fewDRD2,

which encodes the dopamine receptors

D2 subtype and enhances engagement of

prefrontal-striatal pathways; RGSR, which

encodes the RGS protein, which is thought

to modulate postsynaptic dopamine sig-

nal transduction via G alpha-GTP binding;

PPP1R1B, which encodes the dopamine-and cAMP-regulated phosphoprotein of

molecular weight 32 kDa (DARPP-32),

which is a key integrator of information

in dopaminoceptive neurons; and AKT1,

which encodes the AKT1 protein putatively

involved in signal transduction in the non-

canonical dopaminergic pathway.17-20

As the disease of schizophrenia becomes

better understood, genes related to other

neurotransmitters are receiving more atten-

tion. Dysbindin is one example. It is a pro-tein whose gene is located at chromosome

6p22.3, one of the most promising suscep-

tibility loci in schizophrenia linkage stud-

ies. In one animal study, overexpression

of dysbindin increased extracellular basal

glutamate levels and release of glutamate.

Conversely, dysbindin protein knockout re-

duced the release of glutamate, suggesting

that dysbindin may affect glutamate release

by upregulating molecules in presynaptic

machinery.21

Other approaches to understanding the

genetic basis of schizophrenia include identi-

fication of genes through genome-wide asso-

ciation studies and investigation of epistatic

relationships.15

Research examining the roleof genetics in determining response to anti-

psychotics has yielded practical clinical in-

formation about potential dose adjustments

and side effects modulated via CYP enzyme

metabolization.22

As a clinical and neuropathologic entity,

schizophrenia currently may be as difficult

to characterize as it is to treat. However, all of

its complexities and challenges also provide

enticement for researchers and clinicians

who work at the forefront of psychiatry, andwho uncover new aspects of this disease on

a regular basis.

Clinical Challenges in theTreatment of SchizophreniaThe disease of schizophrenia is associated

with severe disabilities and poses numer-

ous treatment challenges. Research con-

ducted by the World Health Organization,

the World Bank, and the Harvard School of

Public Health demonstrated that among de-veloped regions schizophrenia ranks fourth

in diseases contributing to global burden of

disease for ages 15 through 44 years.23 These

years are typically the most productive for

individuals and their contributions to so-

ciety, so the personal and societal costs of

schizophrenia must be appreciated in this

context.24

Both patients with schizophrenia and the

clinicians who treat them face substantial

challenges. A large majority of patients withschizophrenia are unable to maintain inde-

pendent living or gainful employment for

any significant period of time after the onset

of illness. The onset of schizophrenia is usu-

ally during adolescence, when individuals

normally are beginning to achieve a firm

sense of self, establish enduring relation-

ships, and make productive contributions

to society. Even during quiescent periods of

the illness, patients continue to experience

social disturbances that severely limit their

COMT degrades

catecholamine,

including dopamine,

and has been linked

to an increased risk

of psychosis.

Figure 3

Activation During Auditory Verbal Hallucinations10

Brain regions showing differences in relative glucose metabolic rate (rGMR) in patients

with schizophrenia with auditory verbal hallucinations (multivariate analysis using partialleast squares).

Horga G, et al.J Psychiatry Neurosci. 2011. doi: 10.1503/jpn.100085. [Epub ahead of print.]

2011 Canadian Medical Association.

A2


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capacity for recovery and integration into

the community.24

Several factors contribute to the disease

burden in schizophrenia, including persist-

ing symptom burden, comorbid substanceabuse, poor social skills, and unsupportive

family and community environments.25

For these and other reasons, many pa-

tients with schizophrenia are nonadherent

with pharmacotherapy, which can lead

to poor outcomes, including relapse and

hospitalization.26,27

In 2005, Andreasen and colleagues chal-

lenged the field of psychiatry by propos-

ing a consensus definition of remission

in schizophrenia, suggesting, althoughthere is no cure, that this outcome is pos-

sible even in such a difficult population.

This consensus definition of remission re-

quires scores of mild or less for a period

of 6 or more months on select items of the

Brief Psychiatric Rating Scale (BPRS), the

Positive and Negative Syndrome Scale

(PANSS), the Scale for the Assessment of

Negative Symptoms (SANS), and the Scale

for the Assessment of Positive Symptoms

(SAPS).28

This definition did spur muchfurther research, but reported rates of re-

mission have been varied (no higher than

38% in recent studies).29,30

A Shift in Clinical ConcernIn addition to challenges to effective treat-

ment, the management of side effects

has been of paramount importance since

atypical antipsychotics were introduced.

At that time, the side effects of great-

est concern to clinicians were the extra-pyramidal symptoms (EPS) and tardive

dyskinesia (TD) thought to be associated

with the more typical antipsychotics.

Although these particular issues are still

important, the use of atypical antipsy-

chotics has increased the focus on other

adverse events (Figure 5, page SA-8); those

of great concern to clinicians include coro-

nary heart disease, diabetes, hyperlipid-

emia, insulin resistance, weight change,

and elevated glucose.31,32

Elevated cardiovascular risk factors

in patients with schizophrenia include

elevated body-mass index, smoking,

diabetes, hypertension, and metabolic

syndrome.33-35 It should be noted, how-

ever, that metabolic disturbances in pa-

tients with schizophrenia are not solely

the result of treatment with antipsychotic

agents, as some increased risk factors were

documented in this population before theadvent of antipsychotics as well as in treat-

ment-nave patients.31

The consequences of increased metabolic

and cardiovascular risk factors in patients

with schizophrenia are severe. Compared

with the general population, patients with

schizophrenia die as many as 30 years

earlier.36,37 Heart disease is the most com-

mon cause of death in this population.36

In addition to increased metabolic and

cardiovascular risk factors, patients with

Figure 4

Hippocampal Plasticity in Response to Exercise11

Metabolic

disturbances

in patients with

schizophrenia

are not solely the

result of treatment

with antipsychotic

agents.

T1-weighted magnetic resonance images in the sagittal and coronal plane, with the

right hippocampus marked in blue, comparing baseline (A and B) and endpoint (C

and D) of the patient in the schizophrenia exercise group with the largest increase inhippocampal volume (from 3.898 cm3 to 4.667 cm3; +19.7%).

Pajonk F-G, et al.Arch Gen Psychiatry. 2010;67(2):133-143. 2010 American Medical

Association. All Rights Reserved.

A B

C D


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schizophrenia also have a higher burden of

medical illness.38,39

Unfortunately, despite the elevated riskfactors and poor outcomes from comorbid

cardiovascular and metabolic illnesses, pa-

tients with schizophrenia receive very little

treatment for these disorders. In 2009, the

UNITE survey found that many psychia-

trists who treat patients with schizophrenia

do not follow guidelines for the monitoring

of cardiovascular and metabolic disorders.

Thus, according to this study, only 30% of

patients with schizophrenia reported ever

having been weighed, and only 12% report-ed ever having had their waist measured.40

Both patients with schizophrenia and their

psychiatrists face significant challenges when

it comes to treating the disorder and caring

for the individuals overall physical health.

Adherence Considerations:Scope of the ProblemWhile nonadherence, or noncompliance,

with pharmacotherapy is a common prob-

lem in medicine, the rate of compliance in

psychiatric patients is lower than in pa-

tients with physical disorders. A study by

Cramer and colleagues found that, on aver-

age, patients receiving antipsychotics took

approximately 58% of the recommendedamount of medication, whereas patients

with physical disorders took 76%.41 In the

treatment of schizophrenia, nonadherence

presents a particularly challenging barrier

to improving patient outcomes, because

some elements of the disease itselfsuch

as poor insightcontribute to a lack of

adherence.26

Expert consensus clinical guidelines

published in 2003 reported the surveyed re-

sponses of nearly 50 well-known researchersregarding the definition and rates of nonad-

herence in patients with schizophrenia. The

authors of the study defined noncompliance

in the following way42:

Compliant: misses 80% of

medication

According to the above definition, the

experts estimated that 43% of their patientswere compliant. However, the average rate

of compliance in the research literature is

only 28%. The survey summary leading to

the expert consensus guidelines demon-

strates that even experts in schizophrenia

may overestimate compliance in their pa-

tients, and that definitions of compliance

may vary considerably.

Nonadherence in patients with schizo-

phrenia begins early and increases with

time. Velligan and colleagues describedtheir experience with the first 68 patients re-

cruited into a 5-year study of adherence in

patients with schizophrenia.43 During the

first 2 weeks after hospital discharge, 25% of

patients with schizophrenia, including those

living in group homes, missed one or more

doses of antipsychotic medications. This rate

of nonadherence was demonstrated even

under close supervision (staff monitoring,

pill counts, and blood-level analysis). Home

visits by the investigators revealed numer-

Even experts in

schizophrenia

may overestimate

compliance in their

patients.

EPS=extrapyramidal symptoms; TD=tardive dyskinesia.

Nasrallah HA, Smeltzer DJ. Contemporary Diagnosis and Management of the Patient

With Schizophrenia. Newtown, PA: Handbooks in Health Care; 2003.

Young AS, et al. Schizophr Bull. 2010;36:732-739.

Shift in Concerns With Side-Effect Profile31,32

Figure 5

Side effects of greater

historical concern

Side effects of greater

current concern

EPS and TD

CoronaryHeart Disease

EPS and TD

ElevatedGlucose

InsulinResistance

WeightGain

Diabetes

Hyperlipidemia

WeightGain

CHD

Hyper-lipidemia

ElevatedGlucose

InsulinResistance


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ous barriers to adherence, including poor

understanding of drug regimen and the roles

of prior and current medications, as well as

chaotic living arrangements.43 A review of

the literature regarding outpatient nonad-herence in patients with schizophrenia noted

that, by 1 year after hospital discharge, non-

adherence rates rose to at least 50%, and by

2 years after discharge, to at least 75%.44

From the clinicians perspective, the per-

ception of good adherence in their practice

may not be consistent with the reality that

many patients who seem adherent are in

fact not. It is difficult to predict which pa-

tients are going to take their medications

as prescribed. Clinicians usually base theirassessment of adherence on patient re-

ports and apparent clinical state. However,

it is not always the case that, if a patient is

in a good clinical state, he or she is adher-

ent. This example of backward reasoning

(ie, the patient is better so he/she must be taking

the medication as prescribed) can have a signifi-

cant consequence on prescribing behavior.

The Consequences of

NonadherencePoor adherence to antipsychotic medica-

tions can contribute to a vicious cycle of

poor outcomes for patients with schizo-

phrenia. Within 3 to 10 months of discon-

tinuing their medication, approximately

50% of patients experience a relapse.45-47

In a meta-analysis of published studies of

antipsychotic medication discontinuation

in patients with schizophrenia (N=1,006),

time-to-relapse, and indicator of clinical

stability, deteriorated markedly within 3 to6 months (Figure 6). Risk of relapse reached

25% within 10.2 weeks and 50% within

30.3 weeks.45 In a study by Morken and col-

leagues, patients who were not adherent to

oral antipsychotics (those with more than

1 month of missed medications) relapsed

at a rate of 64% compared with 11% for pa-

tients who remained adherent.47

The impact of nonadherence on outcome

cuts across different phases of illness. In re-

cently diagnosed first-episode patients,

where adherence was carefully tracked over

follow-up, Subotnick and colleagues dem-

onstrated that periods of partial adherence

(50%75% of prescribed dosage) and rela-

tively brief periods (24 weeks) of partial orfull nonadherence with oral antipsychotic

therapy put patients with schizophrenia

at significant risk for relapse (hazard ratio,

3.728.5).48

Even relatively smaller medication gaps in

otherwise stable patients with schizophrenia

can have a noticeable impact on the likeli-

hood of relapse. In a pharmacy refill study

of Medicaid patients with schizophrenia

chosen for their relative stability during the

previous year, a study by Weiden and col-leagues demonstrated that, in patients with

schizophrenia with partial adherence to oral

antipsychotic therapy, the length of the ther-

apy gap predicted rehospitalization(Figure 7,

page SA-10).49

In addition to directly affecting patient

outcomes by allowing psychotic symptoms

to continue unabated, nonadherence has sev-

eral indirect but deleterious effects. The 2009

consensus guidelines that addressed the

problem of nonadherence in patients with

Even relatively

smaller medication

gaps in otherwise

stable patients with

schizophrenia can

have a noticeable

impact on the

likelihood of relapse.

Computed survival functions based on findings from studies that discontinuedmaintenance oral neuroleptic drugs in patients with schizophrenia. Data are thepercentage of patients whose conditions remained stable vs the weeks after the

abrupt stoppage of treatment (n=1006). Dashed lines indicate 95% confidenceintervals. Inset: time to a 50% relapse risk (7.5 months).

Viguera AC, et al.Arch Gen Psychiatry. 1997;54:49-55. 1997 American Medical Association.

All Rights Reserved.

Clinical Stability in Patients With Schizophrenia WhoDiscontinued Oral Medication45

Figure 6

100

90

80

70

60

50

40

30

20

100

90

80

70

60

50

%R

emainingstable

%Remainingstable

Weeks after stopping oral neuroleptic therapy abruptly

Weeks after stopping neuroleptic therapy

Time to 50% risk

0

0 4 8 12 16 20 24 28 32

24 48 72 96 120 144 168 192


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schizophrenia summarized the research lit-

erature on this topic. Incorrect inferences by

the clinician can result in inappropriate treat-

ment plans for the patient. When a patient

appears to not respond to treatment with a

particular agent, the psychiatrist may con-

clude that the patient needs augmentation or

switching, whereas the poor response may

be due to the patient simply not taking his orher medication.27

It is also important to consider the effect

that nonadherence can have on the physi-

cian/patient relationship. If the psychiatrist

approaches adherence as a type of behavior

in which the patient obeys the clinician,

the therapeutic relationship may be dam-

aged, leading to potential further negative

repercussions for the patients treatment.27

Patient and clinician responses to factors

that affect adherence can differ considerably.As shown in Figure 8, when a potentially

troublesome side effect emerges, the patient

can experience acute distress and respond

by reducing adherence to the antipsychotic

regimen. The clinician may focus more on

the objective severity of the side effect rather

than on the subjective distress it causes the

patient. The clinicians behavior typically is

motivated by evaluating the safety concern

that the particular side effect poses, rather

than how much it interferes with the pa-

tients life. Because the patients subjective

experience can affect adherence, it is impor-

tant for clinicians to also take both objective

safety and subjective distress very seriously

in overall pharmacologic management.50

Strategies for ImprovingAdherenceNumerous strategies have been proposed

for improving adherence to treatment in pa-

tients with schizophrenia. In 2003, Dolder

and colleagues reviewed the recent litera-

ture to evaluate which interventions were

most successful. They concluded that, of

the psychosocial interventions using a sin-

gle approach, educational strategies wereleast successful. The most successful strate-

gies used a combination of educational, af-

fective, and behavioral approaches. These

combined approaches also were more

likely to improve secondary outcomes (eg,

medication knowledge, insight into treat-

ment, hospitalization, psychopathology,

and functioning) in addition to adherence

to antipsychotic therapy. Interventions that

led to improvements in adherence tended

to be of longer duration and performed ina group setting, demonstrating the impor-

tance of sufficient intensity and length of

therapy as well as a large enough sample

size for evaluation.51

As with pharmacologic interventions

with antipsychotics, matching behavioral

interventions to increase adherence with

pharmacotherapy to the needs of specific

patients is desirable. Different factors af-

fecting adherence require different inter-

ventions by the clinician. For example,if a patient has an unfavorable attitude

toward taking or staying on medication,

it is important to: routinely assess adher-

ence; emphasize the therapeutic alliance;

use a patient-centered approach, starting

with the patients point of view; and stay

symptom-focused rather than relying on

the disease-model of interaction, in which

the clinician lectures the patient. Specific

interventions include: cognitive-behavioral

therapy (CBT) to emphasize working on

Risk for Rehospitalization Increases With Lengthof Therapy Gap49

Figure 7

25

20

15

10

5

0

%P

atientsrehospitalized

Maximum therapy gap, days within 1 year

0

6

1-10

12

11-30

16

>30

22

It is important for

clinicians to also

take both objective

safety andsubjective

distress very

seriously in overall

pharmacologic

management.

Weiden PJ, et al. Psychiatr Serv. 2004;55:886-891. Adapted with permission from PsychiatricServices (Copyright 2004). American Psychiatric Association.


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problems as identified by the patient rather

than the clinician; motivational interview-

ing to help facilitate motivation for positive

change; and family intervention to help ed-

ucate and motivate family members in en-couraging ongoing medication adherence.

In fact, involving family members in treat-

ment and offering family psychoeducation

may encourage adherence and reduce hos-

pitalizations and relapses.52

It is also important to appreciate the po-

tential role of persistent symptoms as bar-

riers to adherence and to address them not

only with pharmacotherapy but also with

effective behavioral interventions. Likewise,

many patients have environmental barriersto adherence, such as difficulty remember-

ing to take medication without supervision,

getting to appointments, and refilling pre-

scriptions. Interventions such as cognitive

adaptation training (CAT) may be helpful

in addressing these barriers, together with

good case management.52

Although adherence is driven by multiple

factors, recent research provides some guid-

ance for understanding and addressing this

complex component of improved outcomesin patients with schizophrenia.

Acknowledgement

The faculty wish to acknowledge Katia Zalkind,

MS, for her contributions to this manuscript.

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Many patients haveenvironmental

barriers to adherence,

such as difficulty

remembering to take

medication without

supervision.

An Example of How Patient and Clinician ResponsesMay Differ50

Figure 8

Inuenci

ngpatien

trespons

e

Inuencingclinicianresponse

Reverberations from side effects

Side Effect

Appears

Subjective

Distress

Objective

Severity

Adherence

Impact

Safety and

Risk

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