ROMANIAN JOURNAL OF PSYCHOPHARMACOLOGY · Romanian Journal of Psychopharmacology (2009) 9, 59-64 59 “CLINICAL DEPRESSION” VS. “UNDERSTANDABLE SADNESS”: IS THE DIFFERENCE CLEAR,

Volume 9, Issue 2, Year 2009

ROMANIAN JOURNAL OF

PSYCHOPHARMACOLOGY

Editura Medicală Universitară Craiova

2009

CONTENTS Editorial

“Clinical Depression” vs. “Understandable Sadness”: Is the Difference Clear, and is it Relevant To Treatment Decisions ? Prof. Mario Maj, President of the World Psychiatric Association .................................................................. 59 Original articles

Diabetes and the Risk for Cognitive Decline and Dementia Ramit Ravona-Springer, Michael Davidson, Michal Schnaider Beeri ............................................................ 65 Homocysteine – Biomarker in Neuropsychiatric Disorders Elena Buteica, Emilia Burada, Sandra Alice Buteica ...................................................................................... 83 Long-Acting Risperidone Injection – A Path to Remission in Schizophrenia Cristinel Stefanescu, Carina Persson, Roxana Chirita, Vasile Chirita ............................................................ 89 Neurobiological Arguments for a Degenerative Model in Schizophrenia Dragos Marinescu, Tudor Udristoiu, Ion Udristoiu, Ileana Marinescu ......................................................... 103 The Cambridge Cognitive Examination (CAMCOG) in Early Assessment of Post-Stroke Cognitive Impairment Denisa Pirscoveanu, Cornelia Zaharia, Valerica Tudorica, Elena Albu, Diana Stanca ................................ 110

Romanian Journal of Psychopharmacology

EDITOR-IN-CHIEF: Tudor UDRISTOIU DEPUTY EDITOR: Dragos MARINESCU

EDITORIAL BOARD

Michel BOURIN (France) Vasile CHIRITA (Romania) Michael DAVIDSON (Israel) Virgil ENATESCU (Romania) Carol FRIEDMANN (Romania) Ion FULGA (Romania) Iosif GABOS-GRECU (Romania) Alexandru GRIGORIU (Romania) Siegfried KASPER (Austria) Dragos MARINESCU (Romania) Ioana MICLUTIA (Romania) Radu MIHAILESCU (Romania) Hans-Jürgen MÖLLER (Germany) Dan PRELIPCEANU (Romania) Pedro RUIZ (United States) Ghiorghe TALAU (Romania) Tudor UDRISTOIU (Romania) Victor VOICU (Romania) Joseph ZOHAR (Israel)

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Romanian Journal of Psychopharmacology (2009) 9, 59-64

59

“CLINICAL DEPRESSION” VS. “UNDERSTANDABLE SADNESS”: IS THE DIFFERENCE CLEAR, AND IS IT RELEVANT

TO TREATMENT DECISIONS? Mario Maj1

Department of Psychiatry, University of Naples, Italy

One of the items of the “neo-kraepelinian credo”, articulated in the 1970s, was that “there is

a boundary between the normal and the sick”. In other terms, it was maintained that there is a clear,

qualitative distinction between persons who have a mental disorder and persons who have not (1). A

corollary to this item was the statement that “depression, when carefully defined as a clinical entity,

is qualitatively different from the mild episodes of sadness that everyone experiences at some point

in his or her life” (1). Apparently in line with this statement was the observation that tricyclic

antidepressants were active only in people who were clinically depressed; when administered to

other people, they did not act as stimulant and did not alter their mood.

Today, the picture appears much less clear, and this is certainly in part a consequence of the

evolution of psychiatric treatments. Guidelines for treatment of major depression often contain

contradictory statements in this respect: on the one hand, the assertion that it is important to clearly

differentiate clinical depression from normal adaptive responses to stress; on the other, the warning

that antidepressant medications are effective even in the presence of significant life stress, and should

not be withheld solely because the condition is understandable. These statements beget two questions:

a) Are we really able to distinguish between a “dysfunctional” and an “adaptive” response to an

adverse life event? b) Is this distinction clinically relevant, since treatment decisions are expected not

to be influenced by whether the condition is understandable or not, but only by its clinical picture,

severity, duration and by the degree of impairment of social functioning? These are questions with

significant political, ethical, scientific and clinical implications, which have become particularly

visible and pressing in the past few decades, in parallel to the escalation of the prevalence rates of

depression in community studies, of the estimated social costs of depression, of the number of

patients in treatment for depression, and of the prescriptions of antidepressant medications.

The National Comorbidity Survey, published in 1994, reported that the one-year prevalence

of major depression in the US adult community was about 10%, and the lifetime prevalence about

17% (which means that 1 out of 10 Americans currently suffers from major depression and almost 1

1 Correspondence: Mario Maj, University of Naples SUN, Italy. E-mail: [email protected].

Mario Maj

60

out of 5 has suffered from this disorder during his or her lifetime) (2). The World Health

Organization estimated that depression will become by 2020 the second leading cause of worldwide

disability, and is already the leading cause of disability for people aged from 15 to 44 years: these

estimates were based on the above data on the prevalence of depression in the community and on a

severity score according to which depression was placed in the second most severe category of

illness, the same category as paraplegia and blindness (3). In the US, the number of patients with

depression treated in outpatient settings increased by 300% between 1987 and 1997, the use of

antidepressant medications among adults tripled between 1988 and 2000, and the spending for

antidepressants increased by 600% during the 1990s (4).

This situation has generated concerns from both outside and within the psychiatric profession.

On the one hand, psychiatry has been accused to inappropriately medicalize ordinary life

problems in order to expand the range of its jurisdiction. This criticism was well articulated in a

book entitled “Making us crazy. DSM: the psychiatric bible and the creation of mental disorders”

(5): “Determining when relatively common experiences such as sadness should be considered

evidence of some disorder requires the setting of boundaries that are largely arbitrary, not scientific,

unlike setting boundaries for what constitutes cancer or pneumonia”. “Rather than gaining any

substantive understanding of your difficulties, you gain [from the DSM-IV] a far more interesting

glimpse of psychiatry’s struggle to define its domain and expand its range”.

On the other hand, the above-mentioned prevalence rates of depression in the community

have been regarded as unbelievable even from within the psychiatric profession: “Based on the high

prevalence rates in both the ECA and the NCS, it is reasonable to hypothesize that some syndromes

in the community represent transient homeostatic responses to internal or external stimuli that do

not represent true psychopathologic disorders” (6); “The criteria diagnosed many individuals who

were exhibiting normal reactions to a difficult environment as having a mental disorder” (7).

Particularly articulated has been the critique by Jerome Wakefield, an extensive version of

which can be found in his book “The Loss of Sadness. How Psychiatry Transformed Normal

Sorrow into Depressive Disorder” (4). The basic argument of this book is that the above-mentioned

high prevalence rates of major depression, the WHO estimates about the social costs of this

disorder, the high number of patients in treatment for depression and the increasing prescription of

antidepressant medications are all consequences of the failure by DSM criteria to distinguish

between true depression, a medical disorder which occurs despite there being no appropriate reason

in the patient’s circumstances, and normal sadness, which represents a normal reaction to a major

loss. What Wakefield proposes is either that the diagnosis of depression be “excluded if the sadness

response is caused by a real loss that is proportional in magnitude to the intensity and duration of

the response” or that the diagnosis of depression require that “despite there being no real recent loss

„Clinical Depression” vs. „Understandable Sadness”: Is the Difference Clear, and Is It Relevant to Treatment Decision?

61

(or only losses of minor magnitude), the individual nonetheless experiences a sufficient number and

intensity of symptoms” (8). Thus, the proposal is to extend the current exclusion criterion

concerning bereavement to other major losses.

This approach may sound reasonable, but is of doubtful feasibility and reliability. In the

community, it is almost the rule that major depression is preceded by an adverse event, as reported by

the patient. Wakefield himself, in a recent study (9), found that as many as 94% of cases of single

episode major depression had been preceded by a loss. An additional contextual criterion may exclude

from treatment a substantial proportion of people in need of it. The decision on whether there is a

causal relationship between the event and the response and on whether the response is proportional to

the event is often difficult, and would be left to the subjective judgement of the clinician, with a high

risk of low reliability (10). Even worse, the ideological orientation of the clinician may sometimes be

decisive: there are psychiatrists who do believe that every psychopathological manifestation can be

explained by looking at the individual’s environmental conditions. Moreover, even when confronted

with the most severe life events, only a small minority of individuals develop major depression,

raising the issue of what is meant by a “normal” reaction to stressors (11).

Actually, the point raised by Wakefield is not a new one. It was extensively explored by

British psychiatry in the 1960s. In particular, Aubrey Lewis described in a classical paper his

attempt to apply a set of criteria to distinguish contextual versus endogenous depression (12). He

reported that: “The criteria were applied… But the more one knew about the patient, the harder this

became. A very small group of nine cases emerged where… it could be said the situation had been

an indispensable efficient cause for the attack… There was a small group of 10 in whom one could

not in the least discover anything in their environment which could have been held responsible for

the outbreak of the attacks. But all the others were understandable examples of the interaction of

organism and environment, i.e., personality and situation; it was impossible to say which of the

factors was decidedly preponderant”.

It is useful to report that, although Wakefield maintains that the distinction between

depression and normal sadness has to be done on the basis of the context in which the symptoms

occur, because there are no significant symptomatological differences between the two conditions,

there are some studies suggesting that the two conditions may actually be qualitatively different.

“Normal forms of negative mood such as despair or sadness must not be mistaken as depressed

mood, characterized by a lack of holothymia and being an emotional feeling only known to

depressed persons” (13). Along the same line, some studies carried out in patients with severe or

chronic physical illness have described the differential features between clinical depression and

understandable demoralization. A depressed person has lost the ability to experience pleasure

generally, whereas a demoralized person is able to experience pleasure normally when he is

distracted from thoughts concerning the demoralizing circumstance or event. The demoralized

Mario Maj

62

person feels inhibited in action by not knowing what to do, feeling helpless and incompetent; the

depressed person has lost motivation and drive even when an appropriate direction of action is

known. Moreover, persons with clinical depression suffer from psychomotor, neurovegetative and

cognitive symptoms which are not typically present in demoralization (14).

However, the evidence provided by taxometric analyses of depression carried out in large

clinical samples suggests that major depression is not qualitatively distinguishable from less severe

mood states, although these analyses do not completely exclude the existence of a latent depression

taxon corresponding to “endogenous” or “nuclear” depression (15).

Another critical point concerning Wakefield’s approach is that the treatment implications of a

distinction between intense understandable sadness and non-contextual depression are currently

unclear. Actually, there are studies showing a high rate of response to antidepressant medication in

people who meet diagnostic criteria for a major depression episode during the first two months of

bereavement, which has led Zisook and his co-workers to conclude that even the current DSM-IV

exclusion criterion concerning bereavement may not be valid (so, rather than extended to other losses

as proposed by Wakefield, it should be eliminated) (16). Furthermore, some psychotherapeutic

techniques which have been proven to be effective in major depression, namely interpersonal

psychotherapies, are based on the assumption that the individual is currently experiencing problematic

environmental situations, of which the depressive condition is an understandable consequence.

In his book, Wakefield mentions the argument that treating intense understandable sadness

may disrupt normal coping processes and the use of informal support networks. In fact, it has been

repeatedly pointed out in the literature that externally elicited, mild to moderate, depressive states

may have an adaptive role that has developed through the evolution of the human species. They

may warn a person that past or ongoing strategies have failed and new strategies are needed.

Physiological slowing and social withdrawal may remove a person from high-cost, low-benefit

social interactions, and signalling one’s state to others may initiate others’ help without requiring

long-term payback. In this light, the experience of mental suffering is developmentally useful and

even necessary for human growth and self-actualization. By medicalizing this condition and treating

it with drugs we may undermine the coping strategies of the individual (17). The opposite view,

however, is that suffering in itself does not promote any growth and self-actualization, and that

what makes sense from an outside, universal philosophical perspective becomes unacceptable if we

try to say that the intense suffering of that particular person in real time and space ultimately exists

for his own good. In this light, the relief of severe mental suffering by appropriate, clinically sound

means becomes a legitimate medical purpose, exactly like the relief of severe physical pain (18).

This is, if you wish, the philosophical side of the problem. The clinical and scientific side is that the

effectiveness and cost-effectiveness of pharmacological and non-pharmacological interventions for

intense understandable sadness has to be proved by research.

„Clinical Depression” vs. „Understandable Sadness”: Is the Difference Clear, and Is It Relevant to Treatment Decision?

63

One view which has been repeatedly expressed in recent years is that the boundary between

mental disorders and normality can be decided only arbitrarily on pragmatic grounds (19). The

boundary will be regarded as clinically valid if it has significant predictive implications in terms of

response to treatment and clinical outcome. However, if prediction of treatment response is going to

be one of our validating criteria in the case of the diagnosis of major depression, it is unlikely that

the threshold for the diagnosis will be the same for all the various treatment modalities which are

currently available. The threshold for response to an interpersonal psychotherapy, for instance, may

be different from the threshold for response to an SSRI, which may be different from the threshold

for response to a tricyclic antidepressant. This provides a rationale for the recent proposal of

sequential stepwise treatment algorithms for people with depressive symptoms (20). Should we

ignore the issue of the differential diagnosis between true depression and understandable sadness

and simply apply one of these algorithms to all people presenting with depressive symptoms? In a

community setting, this could be a reasonable response to the current state of affairs.

So, in conclusion, our initial questions, whether we are able to distinguish between a

“dysfunctional” and an “adaptive” response to an adverse life event, and whether this distinction

has significant treatment implications, remain without a clear answer at the moment. What we really

need is further research evidence concerning the feasibility and reliability of the addition of a

“contextual” criterion in the diagnosis of major depression, the clinical utility of this additional

criterion in terms of prognosis and prediction of treatment response, and the biological correlates of

non-contextual depression versus normal sadness, and probably also further research efforts aimed

to operationalize that “distinct quality of mood” which may distinguish at least some forms of

depression from normal sadness. The more these issues appear to be loaded with political and

ethical implications, the more they require objective and convincing research evidence.

References

1. Blashfield R.K., 1984 – The Classification of Psychopathology. New York: Plenum.

2. Kessler R.C., McGonagle K.A., Zhao S. et al., 1994 – Lifetime and 12-month

prevalence of DSM-III-R psychiatric disorders in the United States: results from the

National Comorbidity Survey. Arch Gen Psychiatry; 51:8-19.

3. World Health Organization, 2001 – The World Health Report 2001. Mental Health:

New Understanding, New Hope. Geneva: World Health Organization.

4. Horwitz A.V., Wakefield J.C., 2007 – The Loss of Sadness. How Psychiatry Transformed

Normal Sorrow Into Depressive Disorder. Oxford: Oxford University Press.

5. Kutchins H., Kirk S.A., 1997 – Making Us Crazy. DSM: The Psychiatric Bible and the

Creation of Mental Disorders. New York: The Free Press.

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64

6. Regier D.A., Kaelber C.T., Rae D.S. et al., 1998 – Limitations of diagnostic criteria and

assessment instruments for mental disorders. Implications for research and policy. Arch

Gen Psychiatry; 55:109-115.

7. Spitzer R.L., Wakefield J.C., 1999 – DSM-IV diagnostic criterion for clinical significance:

does it help solve the false positives problem? Am J Psychiatry; 156:1856-1864.

8. Wakefield J.C., 1997 – Diagnosing DSM-IV - Part I: DSM-IV and the concept of

disorder. Behav Res Ther; 35:633-649.

9. Wakefield J.C., Schmitz M.F., First M.B., Horwitz A.V., 2007 – Extending the

bereavement exclusion for major depression to other losses. Evidence from the National

Comorbidity Survey. Arch Gen Psychiatry; 64:433-440.

10. Maj M., 2008 – Depression, bereavement, and “understandable” intense sadness: should

the DSM-IV approach be revised? (Editorial). Am J Psychiatry; 165:1373-1375.

11. Kendler K.S., 1999 – Setting boundaries for psychiatric disorders. Am J Psychiatry;

156: 1845-1848.

12. Lewis A., 1967 – Melancholia: a clinical survey of depressive states, in Inquiries in

Psychiatry: Clinical and Social Investigations. Edited by Lewis A. New York, Science

House, Inc., 30-72.

13. Helmchen H., Linden M., 2000 – Subthreshold disorders in psychiatry: clinical reality,

methodological artefact, and the double-threshold problem. Compr Psychiatry; 41:1-7.

14. Clarke D.M., Kissane D.W., 2002 – Demoralization: its phenomenology and

importance. Aust N Zeal J Psychiatry; 36:733-742.

15. Grove W.M., Andreasen N.C., Young M. et al., 1987 – Isolation and characterization of

a nuclear depressive syndrome. Psychol Med; 17:471-484.

16. Zisook S., Shear K. Kendler K.S., 2007 – Validity of the bereavement exclusion

criterion for the diagnosis of major depressive episode. World Psychiatry; 6:102-107.

17. McGuire M.T., Troisi A., 1998 – Darwinian psychiatry. New York: Oxford University Press.

18. Bjorklund P., 2005 – Can there be a “cosmetic” psychopharmacology? Prozac

unplugged: the search for an ontologically distinct cosmetic psychopharmacology.

Nursing Philosophy: 6:131-143.

19. Kendell R., Jablensky A., 2003 – Distinguishing between the validity and utility of

psychiatric diagnoses. Am J Psychiatry; 160:4-12.

20. Linden M., Helmchen H., Mackert A., Müller-Oerlinghausen B., 1994 – Structure and

feasibility of a standardized stepwise drug treatment regimen (SSTR) for depressed

inpatients. Pharmacopsychiatry; 27(Suppl.):51-53.


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DIABETES AND THE RISK FOR COGNITIVE DECLINE AND DEMENTIA

Ramit Ravona-Springer1, Michael Davidson1, 2, Michal Schnaider Beeri2 1Sheba Medical Center, Ramat Gan, Israel.

2Mount Sinai School of Medicine, New York, NY.

Abstract Life expectancy is rising with increasing numbers of elderly people who develop dementia. In the absence of effective treatments for dementia, it is important to identify risk factors that are potentially modifiable, thus enabling development of treatment strategies that can prevent dementia, ameliorate it's rate of deterioration or postpone it's onset. Several cardiovascular risk factors such as type 2 diabetes, hypertension, cholesterol, and inflammation have been demonstrated in longitudinal epidemiological studies to increase risk of dementia, Alzheimer’s disease (AD), mild cognitive impairment (MCI), and cognitive decline. In this article, the association of diabetes with dementia and cognitive decline will be reviewed. Key words: Alzheimer’s disease, cognitive decline, metabolic alterations.

Introduction

Alzheimer’s disease (AD) remains the most common cause of dementia in the elderly. The

risk factors for AD, other than age, include female gender, family history, and at least one

apolipoprotein E4 (APOE4) allele 1. In addition, cardiovascular risk factors, established as risk

factors for vascular dementia, have also been associated with AD 3. These risk factors are of special

interest since their potential for modification may affect the course of dementia. This paper reviews

the most well established cardiovascular risk factor for dementia- diabetes, for which there is

longitudinal epidemiological evidence of increased risk of dementia, Alzheimer’s disease (AD),

mild cognitive impairment (MCI), and cognitive decline.

The association of diabetes with increased risk for dementia has been demonstrated relatively

consistently, nevertheless, there is variability between studies which should be viewed in light of

methodological differences between them; for example, differences in populations studied (age, gender,

community or nursing home residence), duration of follow up, time at which diabetes was measured,

(e.g. midlife vs. closer to ascertainment of dementia), proportions of people carrying diabetes,

proportion of people being treated for diabetes, the methods by which the diabetes was measured (e.g.

1 Correspondence: Michael Davidson, Department of Psychiatry, Tel Aviv University. Tel.: +972 526666565; e-mail: [email protected].

Ramit Ravona-Springer et al.

66

direct measure, self report, medical charts), in the confounders accounted for, and of course, in the

outcome measures (typically AD, vascular dementia, all cause dementia, MCI, or cognitive decline).

The association of diabetes and dementia, mild cognitive impairment and cognitive decline Type 2 diabetes has been demonstrated to increase risk for dementia in most 5, 6, but not

all8,9 prospective epidemiological studies, with the highest odds ratios approaching 3-fold increased

risk of dementia for diabetic individuals compared to non-diabetics6. Many studies have also

shown increased risk for Alzheimer's disease (AD) and vascular dementia (VaD) (eg. 11). Recently,

even pre-diabetes (defined as glucose >7.8mmol/l but <11.0 mmol/l) was associated with dementia

(HR 1.77; 95% CI 1.02-3.12) and AD (HR 1.98; 1.12-3.50)12.

Diabetes 7 as well as impaired fasting glucose, a pre-diabetic condition 14 , have also been

demonstrated to be associated with increased risk for Mild Cognitive Impairment (MCI)16, a state of

cognitive compromise considered to be a transitional phase between normal aging and dementia 17 .

Several studies have reported increased risk of cognitive decline in diabetes19. In a cohort of

independent diabetic subjects, duration of diabetes and glycemic control (measured by HbA1c) were

significantly associated with some cognitive dysfunction 20. Higher hemoglobin A1c was also

associated with lower cognitive function in primarily non demented subjects of the ACCORD study22.

Diabetes has also been demonstrated by some 23 24 but not all 27, 28. to be associated with

faster cognitive decline in patients with incident AD 23 and in non demented subject 24.

Proposed Mechanisms

Several mechanisms have been proposed for the association between diabetes and dementia:

1) diabetes is associated with micro and/or macrovascular disease 30 which in turn increase the risk

of cognitive decline and dementia31,32. Interestingly however, brain imaging studies have

demonstrated conflicting results regarding the association of diabetes with cerebrovascular changes 33 34. 2) Brain atrophy has been demonstrated relatively consistently in diabetic subjects, with some

demonstrating an accelerating effect of greater hemoglobin A1c on brain atrophy rates 35 while

others demonstrated increased brain atrophy only in subjects with co-morbidity of diabetes and

hypertension and not in subjects with either diabetes or hypertension alone 33 34. 3) Another

mechanism proposed for the association of diabetes with dementia and cognitive impairment is a

defective insulin receptor signaling pathway (IRSP) in the central nervous system 40; the IRSP is

associated with vital brain processes including synaptic plasticity 41-43, neuroprotection,

neurodegeneration, survival, growth, energy metabolism, and longevity 45, 46. Insulin receptors (IR)

are abundant throughout the brain 47 and are expressed in especially high abundance in regions that

support cognitive function 48. Amiloid Beta (Aβ), the main component of neuritic plaques, hallmark

Diabetes and the Risk for Cognitive Decline and Dementia

67

lesions of AD, decreases insulin affinity and reduces the binding of insulin to its receptor 50

preventing rapid activation of specific kinases required for multiple cellular functions, including

long term potentiation (LTP) 51. Soluble Aβ oligomers were recently shown to significantly lower

IR responses to insulin and to cause rapid and substantial loss of neuronal surface IRs 52. The IR

desensitization found in AD brains 53, hampers the release of Aβ from the intracellular to the

extracellular compartment 55, which may be a mechanism for its neurotoxicity 56. 4) Advanced

glycation end products (AGEs) may have a crucial role in the relationship between diabetes and

dementia 59-62. AGEs, which normally increase with age and faster with diabetes, are the products of

naturally occurring reactions between reducing sugars, e.g. glucose, and free amine-containing

proteins or lipids 61. AD brains have significantly higher levels of AGEs than normal controls 63 and

in in-vitro studies, AGEs contribute to the formation of amyloid plaques and neurofibrillary tangles 64, 65. 5) Insulin has been hypothesized to compete with Amyloid on it's main depurative

mechanism – the Insulin-Degrading Enzyme (IDE). Since IDE is much more selective for insulin

than for Abeta, brain hyperinsulinism may deprive Abeta of its main clearance mechanism28,67 6)

Finally, Hypoglycemia, a common complication of anti-diabetic treatments, has been demonstrated

to increase risk for dementia (Whitmer et al. JAMA April 2009) .

Table 1. Risk of dementia, MCI and cognitive decline in parients with Type 2 diabetes

Reference Results (95% CI) Dementia studies

Schnaider Been2 OR 2.8 (1.4-5.7) Brayne4 OR 2.6 (0.9-7.8) Yaffe7 OR 2.4 (0.9-6.1) Ott10 RR 1.9 (1.3-2.8) Leibson13 SMR 1.6 (1.3-2.0) Whitmer15 HR 1.5 (1.2-1.8) Xu18 HR 1.5 (1.1-2.1) Peila21 RR 1.5 (1.0-2.2) Curb25, 26 RR 1.4 (0.97-1.95) MacKnight29 RR 1.3 (0.9-1.7) Hassing19, 36-39 RR 1.2 (0.8-1.7)

MCI studiesYaffe7 OR 1.8 (1.1-2.8) Luchsinger44 HR 1.5 (1.0-2.3) Luchsinger49 HR 1.4 (1.0-1.9)

Cognitive declineGregg19, 54 OR 1.7 (1.3-2.4) Logroscino57, 58 OR 1.3 (1.1-1.6) Fontbonne58, 66 OR >2 for 4 of 9 tests Knopman70-72 37% to 165% greater rate of cognitive decline in diabetics (depending on the test) Okereke77, 78 Diabetics decline faster; global cognition D-.09 (-.15, -.04) Hassing83, 84 Diabetics decline over twice as fast as non diabetics Arvanitakis87, 88 44% greater rate of cognitive decline in diabetics Hassing93, 94 Diabetics decline twice as fast as non diabetics Van den Berg97 Diabetes was not associated with cognitive decline

OR=odds ratio; RR=relative risc; HR=hayard ratio; SMR=standard morbidity ratio; D=difference rates


68

Hypoglycemic events may impair nutrient delivery to the brain, increase amount of

glutamate, a neurtoxic neuro-transmitter, and down regulate markers of neuronal plasticity 68, 69

Hypoglycemia may increase risk for vascular complications in the brain by inducing platelet

aggregation and fibrinogen formation 73.

Moderating Factors

Diabetes is closely associated with other risk factors for dementia, such as age,

hypertension, and the metabolic syndrome—a clustering of several commonly occurring disorders

(including abdominal obesity, hypertriglyceridemia, low high-density lipoprotein (HDL) level, and

hypertension)74. The combination of these risk factors, together with diabetes-specific

characteristics (e.g. age of onset, glycemic control, use of anti-diabetes medications), demographic

and socioeconomic factors, and genetic factors, might be important determinants of the increased

risk of cognitive decline and dementia in individuals with diabetes 75, 76.

Abdominal distribution of fat, an independent and potent risk factor for type II diabetes 79 80

has been shown to be associated with increased risk for dementia 81. This association was

independent of demographics, diabetes, cardiovascular comorbidities and body mass index (BMI).

Insulin resistance, a consequence of central obesity, may be the mechanism by which central

obesity affects cognition. Thus, this subset of prediabetic subjects may be possible candidates for

early dementia prevention interventions.

The co-occurrence of diabetes and hypertension, has been demonstrated to significantly

increase the risk of dementia 82 and of cognitive decline 85. High systolic blood pressure interacted

with borderline diabetes12 and with frank diabetes 12 multiplying the risk of AD. Another modifying

effect for the association of diabetes and dementia may be type of antidiabetic treatment: the risk for

AD was doubled in diabetics compared to non diabetics in the Rotterdam study; however, within

diabetics, those treated with insulin were at the highest risk (RR 4.3, 1.7-10.5) 86 suggesting that more

severe diabetes increases dementia risk. Consistent with these observations, subjects with longer

duration of diabetes19, 89, 90 or with diabetes complications 91, 92 had steeper cognitive decline.

The mediating effect of other risk factors such as APOE4 genotype age on the association of

diabetes with dementia has been less consistent. Participants with diabetes and the APOE4 allele had

a risk ratio of 5.5 (CI 2.2-13.7) for AD compared with those with neither risk factors in the Honolulu

Asia Aging Study 95 and this was consistent with neuropathological findings. However, borderline

diabetes was associated with AD only in non-APOE4 carriers in the Kongsholmen study. The effect

of age on the relationships between diabetes and dementia is also difficult to interpret. The

relationship between diabetes and dementia in the Framingham study was strongest for participants

older than 75 96 but diabetes was not associated with accelerated cognitive decline in 85+ years of age


69

participants in another study 98. This suggests that factors other than cardio-vascular risk factors (i.e.

age, APOE genotype) interact with diabetes to increase the risk of cognitive compromise.

Inflammation is another potential mediator of the association of diabetes with cognitive

decline99 and dementia100. Inflammation is increased in diabetes and may have a role in

diabetogenesis 101. Chronic hyperinsulinemia102 and obesity may both elicit chronic systemic

inflammation. Although the main physiological abnormalities in type 2 diabetes are insulin

resistance and impaired insulin secretion103, the specific underlying determinants of these metabolic

defects remain uncertain. An accumulating body of evidence suggests that inflammation may play a

crucial intermediary role in pathogenesis of diabetes. Substantial experimental evidence suggests

that interleukin-6 (IL-6) and C-reactive protein (CRP), two sensitive physiological markers of sub-

clinical systemic inflammation, are associated with the development of hyperglycemia, insulin

resistance, and overt diabetes104-107. Several studies have demonstrated elevated levels of IL-6 and

CRP among individuals both with features of the insulin resistance syndrome and with overt

diabetes108-110. These associations are often found after adjustment for obesity and cardiovascular

disease, and even in non-obese individuals 110. Furthermore, a reinforcement cycle might exist since

poor glycemic control is associated with increased inflammation 111, 112. Improving glycemic control

in turn, has been shown by some 111, 112 but not all 113 to be associated with reduced inflammation .

Figure 1. Conceptual Model

There are several lines of evidence that support the importance of inflammation in the

pathogenesis of cognitive impairment and AD. Acute-phase proteins, cytokines, chemokines, and

their receptors are up-regulated in brains of AD patients 100, 113. The abundance of activated

microglia, the primary neuronal immune surveillance cell, is a relatively early pathogenic event in

patients with AD 113, 114. Proinflammatory cytokines augment amyloid precursor protein (APP) 113,


70

115, 116, and in turn, β amyloid (Aβ) induces further release of cytokines113, 117. Furthermore, gene

polymorphisms of several inflammatory mediators have been associated with increased risk of AD 113, 118. Blood elevations of inflammatory markers, specifically CRP and IL-6, have been shown to

be risk factors for cognitive decline (generally assessed by a global cognition measure) and

dementia 113, 119-126. These epidemiological studies are consistent with the in vitro and in vivo

studies suggesting a potential role of inflammation in the development of cognitive compromise.

Depression may be an additional modifier between diabetes and dementia. Diabetes is

associated with 50-100% increased risk for depression 127, with severe symptoms of depression in

approximately 30% of diabetic subjects. It is unknown whether diabetes, through cerebro-vascular

complications128, causes depression, or whether depression itself129, 130 or antidepressant

medications {Rubin, 2008 1117 /id} induce diabetes. Depression is associated with worse glycemic

control and increased risk for diabetes related complications, potentially affecting cognition.

Depression per se is also a risk factor for dementia. Future studies should assess optimal cognitive

screening strategies and optimal antidepressant treatments in depressed diabetic patients.

Effects of anti-diabetic treatments on cognition

Interestingly, results of preclinical as well as clinical studies using antidiabetic treatments,

have demonstrated potential efficacy on cognitive compromise. Rosiglitazone treatment of Tg2576

mice (transgenic mice over-expressing amyloid precursor protein) resulted in better spatial learning

and memory abilities and an approximately 25% reduction in Aβ42 levels 131. In a 24 double blind

study in older diabetic adults randomized to Roziglytazone or glyburide treatment as add on

treatments to metformin, achievement of better glycemic control was associated with improved

cognitive performance132. Rosiglitazone therapy resulted in improved memory and selective

attention while not affecting glucose levels in a study of 30 AD or MCI non-diabetic subjects during

a period of 6 months 133. A trial with 518 mild to moderate AD patients treated with rosiglitazone

for six months reported significant improvement in cognition only in patients who did not possess

an APOE4 allele134. Craft et al.135-140 performed several investigations examining the effect of

intravenous insulin in non-diabetic elderly adults with AD. Mild to moderate AD patients’

immediate and delayed recall were improved in hyperglycemic and hyperinsulinemic conditions

compared to a saline control condition. However, normal controls had no change in their cognition 135. Intranasal insulin administration has recently shown some promising effects on memory141, 142.

Substantially reduced neuritic plaques (NPs), the hallmark lesions of the AD brain, were found in

the brains of diabetic subjects who during life received a combination of insulin and another anti-

diabetic medication143. Recently, the SALSA study reported decreased rates of cognitive decline in

diabetic subjects receiving anti-diabetic medications (insulin or oral hypoglycemic) compared to

untreated diabetic subjects {Wu, 2003 1122 /id}.


71

These studies are encouraging, especially in light of the beneficial effect of diabetes control

on non cognitive complications of diabetes 144 . Nevertheless, they are not sufficient to draw

conclusions. In a recent search of the literature by the Cochrane control trial register, no appropriate

studies were found for meta-analysis regarding the effect of treatment for type 2 diabetes and

degree of metabolic control on the development of dementia145. Many questions should be answered

prior to implementation of antidiabetic treatments as strategies for dementia prevention; for

example, at what stage/ severity of diabetes should treatment be initiated? What degree of glycemic

control should be aimed for? What medications should be used? Should treatment strategies change

with patients' age? Etc. The importance of these questions is stressed by evidences showing that

severe hypoglycemic episodes, which are complications of antidiabetic treatments, are associated

with cognitive decline in older subjects with type II diabetes 146. Additionally, very strict diabetes

control has been demonstrated to increase mortality 28. Increased myocardial infarction and death

from cardiovascular causes were reported in rosiglitazone users 147

Conclusions

Diabetes and pre-diabetic states are risk factors for cognitive decline and dementia and may

increase rate of dementia deterioration. As these are potentially modifiable risk factors, their

treatment may serve as a strategy for dementia prevention or postponement. Several mechanisms

and modifying factors may be involved in this association, suggesting pathways for interventions.

As diabetes is a heterogeneous disease, further studies should detect diabetic subjects at increased

risk for cognitive impairment, optimal screening tools and optimal intervention strategies.

References

1. Rocca WA. Frequency, distribution, and risk factors for Alzheimer's disease. Nurs Clin

North Am 1994 March;29(1):101-11.

2. Schnaider BM, Goldbourt U, Silverman JM et al. Diabetes mellitus in midlife and the

risk of dementia three decades later. Neurology 2004 November 23;63(10):1902-7.

3. Luchsinger JA, Mayeux R. Cardiovascular risk factors and Alzheimer's disease. Curr

Atheroscler Rep 2004 July;6(4):261-6.

4. Brayne C, Gao L, Matthews F. Challenges in the epidemiological investigation of the

relationships between physical activity, obesity, diabetes, dementia and depression.

Neurobiol Aging 2005 December;26 Suppl 1:6-10.

5. Brayne C, Gao L, Matthews F. Challenges in the epidemiological investigation of the

relationships between physical activity, obesity, diabetes, dementia and depression.

Neurobiol Aging 2005 December;26 Suppl 1:6-10.


72

6. Schnaider BM, Goldbourt U, Silverman JM et al. Diabetes mellitus in midlife and the

risk of dementia three decades later. Neurology 2004 November 23;63(10):1902-7.

7. Yaffe K, Blackwell T, Kanaya AM, Davidowitz N, Barrett-Connor E, Krueger K.

Diabetes, impaired fasting glucose, and development of cognitive impairment in older

women. Neurology 2004 August 24;63(4):658-63.

8. Hassing LB, Johansson B, Nilsson SE et al. Diabetes mellitus is a risk factor for

vascular dementia, but not for Alzheimer's disease: a population-based study of the

oldest old. Int Psychogeriatr 2002 September;14(3):239-48.

9. MacKnight C, Rockwood K, Awalt E, McDowell I. Diabetes mellitus and the risk of

dementia, Alzheimer's disease and vascular cognitive impairment in the Canadian Study

of Health and Aging. Dement Geriatr Cogn Disord 2002;14(2):77-83.

10. Ott A, Stolk RP, van HF, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the

risk of dementia: The Rotterdam Study. Neurology 1999 December 10;53(9):1937-42.

11. Luchsinger JA, Tang MX, Stern Y, Shea S, Mayeux R. Diabetes mellitus and risk of

Alzheimer's disease and dementia with stroke in a multiethnic cohort. Am J Epidemiol

2001 October 1;154(7):635-41.

12. Xu W, Qiu C, Winblad B, Fratiglioni L. The effect of borderline diabetes on the risk of

dementia and Alzheimer's disease. Diabetes 2007 January;56(1):211-6.

13. Leibson CL, Rocca WA, Hanson VA et al. The risk of dementia among persons with

diabetes mellitus: a population-based cohort study. Ann N Y Acad Sci 1997 September

26; 826:422-7.

14. Kanaya AM, Barrett-Connor E, Gildengorin G, Yaffe K. Change in cognitive function

by glucose tolerance status in older adults: a 4-year prospective study of the Rancho

Bernardo study cohort. Arch Intern Med 2004 June 28;164(12):1327-33.

15. Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K. Midlife cardiovascular risk

factors and risk of dementia in late life. Neurology 2005 January 25;64(2):277-81.

16. Yaffe K, Blackwell T, Kanaya AM, Davidowitz N, Barrett-Connor E, Krueger K.

Diabetes, impaired fasting glucose, and development of cognitive impairment in older

women. Neurology 2004 August 24;63(4):658-63.

17. Petersen RC, Morris JC. Mild cognitive impairment as a clinical entity and treatment

target. Arch Neurol 2005 July;62(7):1160-3.

18. Xu WL, Qiu CX, Wahlin A, Winblad B, Fratiglioni L. Diabetes mellitus and risk of

dementia in the Kungsholmen project: a 6-year follow-up study. Neurology 2004

October 12;63(7):1181-6.


73

19. Gregg EW, Yaffe K, Cauley JA et al. Is diabetes associated with cognitive impairment

and cognitive decline among older women? Study of Osteoporotic Fractures Research

Group. Arch Intern Med 2000 January 24;160(2):174-80.

20. van HB, Oosterman J, Muslimovic D, van Loon BJ, Scheltens P, Weinstein HC.

Cognitive impairment and MRI correlates in the elderly patients with type 2 diabetes

mellitus. Age Ageing 2007 March;36(2):164-70.

21. Peila R, Rodriguez BL, Launer LJ. Type 2 diabetes, APOE gene, and the risk for

dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes 2002

April;51(4):1256-62.

22. Cukierman-Yaffe T, Gerstein HC, Williamson JD et al. Relationship between baseline

glycemic control and cognitive function in individuals with type 2 diabetes and other

cardiovascular risk factors: the action to control cardiovascular risk in diabetes-memory

in diabetes (ACCORD-MIND) trial. Diabetes Care 2009 February;32(2):221-6.

23. Helzner EP, Luchsinger JA, Scarmeas N et al. Contribution of vascular risk factors to

the progression in Alzheimer disease. Arch Neurol 2009 March;66(3):343-8.

24. Cukierman T, Gerstein HC, Williamson JD. Cognitive decline and dementia in

diabetes--systematic overview of prospective observational studies. Diabetologia 2005

December;48(12):2460-9.

25. Curb JD, Rodriguez BL, Abbott RD et al. Longitudinal association of vascular and

Alzheimer's dementias, diabetes, and glucose tolerance. Neurology 1999 March

23;52(5):971-5.



October 12;63(7):1181-6.

27. bellan van KG, Rolland Y, Nourhashemi F, Coley N, Andrieu S, Vellas B.

Cardiovascular disease risk factors and progression of Alzheimer's disease. Dement

Geriatr Cogn Disord 2009;27(3):240-6.

28. Gerstein HC, Miller ME, Byington RP et al. Effects of intensive glucose lowering in

type 2 diabetes. N Engl J Med 2008 June 12;358(24):2545-59.

29. MacKnight C, Rockwood K, Awalt E, McDowell I. Diabetes mellitus and the risk of

dementia, Alzheimer's disease and vascular cognitive impairment in the Canadian Study

of Health and Aging. Dement Geriatr Cogn Disord 2002;14(2):77-83.

30. Stratton IM, Adler AI, Neil HA et al. Association of glycaemia with macrovascular and

microvascular complications of type 2 diabetes (UKPDS 35): prospective observational

study. BMJ 2000 August 12;321(7258):405-12.


74

31. Arvanitakis Z, Schneider JA, Wilson RS et al. Diabetes is related to cerebral infarction

but not to AD pathology in older persons. Neurology 2006 December 12;67(11):1960-5.

32. Lazarus R, Prettyman R, Cherryman G. White matter lesions on magnetic resonance

imaging and their relationship with vascular risk factors in memory clinic attenders. Int

J Geriatr Psychiatry 2005 March;20(3):274-9.

33. Schmidt R, Launer LJ, Nilsson LG et al. Magnetic resonance imaging of the brain in

diabetes: the Cardiovascular Determinants of Dementia (CASCADE) Study. Diabetes

2004 March;53(3):687-92.

34. Vermeer SE, Den HT, Koudstaal PJ, Oudkerk M, Hofman A, Breteler MM. Incidence

and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study.

Stroke 2003 February;34(2):392-6.

35. Enzinger C, Fazekas F, Matthews PM et al. Risk factors for progression of brain

atrophy in aging: six-year follow-up of normal subjects. Neurology 2005 May

24;64(10):1704-11.

36. Hassing LB, Johansson B, Nilsson SE et al. Diabetes mellitus is a risk factor for

vascular dementia, but not for Alzheimer's disease: a population-based study of the

oldest old. Int Psychogeriatr 2002 September;14(3):239-48.



23;52(5):971-5.



23;52(5):971-5.



October 12;63(7):1181-6.

40. Frolich L, Blum-Degen D, Bernstein HG et al. Brain insulin and insulin receptors in

aging and sporadic Alzheimer's disease. J Neural Transm 1998;105(4-5):423-38.

41. Artola A, Kamal A, Ramakers GM et al. Synaptic plasticity in the diabetic brain:

advanced aging? Prog Brain Res 2002;138:305-14.

42. Chiu SL, Chen CM, Cline HT. Insulin receptor signaling regulates synapse number,

dendritic plasticity, and circuit function in vivo. Neuron 2008 June 12;58(5):708-19.

43. van der Heide LP, Kamal A, Artola A, Gispen WH, Ramakers GM. Insulin modulates

hippocampal activity-dependent synaptic plasticity in a N-methyl-d-aspartate receptor

and phosphatidyl-inositol-3-kinase-dependent manner. J Neurochem 2005

August;94(4):1158-66.


75

44. Luchsinger JA, Tang MX, Stern Y, Shea S, Mayeux R. Diabetes mellitus and risk of

Alzheimer's disease and dementia with stroke in a multiethnic cohort. Am J Epidemiol

2001 October 1;154(7):635-41.

45. Plum L, Schubert M, Bruning JC. The role of insulin receptor signaling in the brain.

Trends Endocrinol Metab 2005 March;16(2):59-65.

46. van der Heide LP, Ramakers GM, Smidt MP. Insulin signaling in the central nervous

system: learning to survive. Prog Neurobiol 2006 July;79(4):205-21.

47. Unger JW, Livingston JN, Moss AM. Insulin receptors in the central nervous system:

localization, signalling mechanisms and functional aspects. Prog Neurobiol 1991;

36(5):343-62.

48. Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific

mechanisms. Lancet Neurol 2004 March;3(3):169-78.

49. Luchsinger JA, Reitz C, Patel B, Tang MX, Manly JJ, Mayeux R. Relation of diabetes

to mild cognitive impairment. Arch Neurol 2007 April;64(4):570-5.

50. Xie L, Helmerhorst E, Taddei K, Plewright B, Van BW, Martins R. Alzheimer's beta-

amyloid peptides compete for insulin binding to the insulin receptor. J Neurosci 2002

May 15; 22(10):RC221.

51. Townsend M, Mehta T, Selkoe DJ. Soluble Abeta inhibits specific signal transduction

cascades common to the insulin receptor pathway. J Biol Chem 2007 September 13.

52. Zhao WQ, De Felice FG, Fernandez S et al. Amyloid beta oligomers induce impairment

of neuronal insulin receptors. FASEB J. 2007.Ref Type: Generic

53. Hoyer S. Glucose metabolism and insulin receptor signal transduction in Alzheimer

disease. Eur J Pharmacol 2004 April 19;490(1-3):115-25.

54. Logroscino G, Kang JH, Grodstein F. Prospective study of type 2 diabetes and cognitive

decline in women aged 70-81 years. BMJ 2004 March 6;328(7439):548.

55. Solano DC, Sironi M, Bonfini C, Solerte SB, Govoni S, Racchi M. Insulin regulates

soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent

pathway. FASEB J 2000 May;14(7):1015-22.

56. Gouras GK, Tsai J, Naslund J et al. Intraneuronal Abeta42 accumulation in human

brain. Am J Pathol 2000 January;156(1):15-20.



58. Fontbonne A, Berr C, Ducimetiere P, Alperovitch A. Changes in cognitive abilities over

a 4-year period are unfavorably affected in elderly diabetic subjects: results of the

Epidemiology of Vascular Aging Study. Diabetes Care 2001 February;24(2):366-70.


76

59. Dickson DW, Sinicropi S, Yen SH et al. Glycation and microglial reaction in lesions of

Alzheimer's disease. Neurobiol Aging 1996 September;17(5):733-43.

60. Ledesma MD, Perez M, Colaco C, Avila J. Tau glycation is involved in aggregation of

the protein but not in the formation of filaments. Cell Mol Biol (Noisy -le-grand) 1998

November;44(7):1111-6.

61. Vlassara H. Intervening in atherogenesis: lessons from diabetes. Hosp Pract (Off Ed)

2000 November 15;35(11):25-9.

62. Yan SD, Chen X, Fu J et al. RAGE and amyloid-beta peptide neurotoxicity in

Alzheimer's disease. Nature 1996 August 22;382(6593):685-91.

63. Vitek MP, Bhattacharya K, Glendening JM et al. Advanced glycation end products

contribute to amyloidosis in Alzheimer disease. Proc Natl Acad Sci U S A 1994 May

24;91(11):4766-70.

64. Smith MA, Taneda S, Richey PL et al. Advanced Maillard reaction end products are

associated with Alzheimer disease pathology. Proc Natl Acad Sci U S A 1994 June 7;

91(12):5710-4.

65. Smith MA, Richey PL, Taneda S et al. Advanced Maillard reaction end products, free

radicals, and protein oxidation in Alzheimer's disease. Ann N Y Acad Sci 1994

November 17;738:447-54.

66. Knopman D, Boland LL, Mosley T et al. Cardiovascular risk factors and cognitive

decline in middle-aged adults. Neurology 2001 January 9;56(1):42-8.

67. Roriz-Filho S, Sa-Roriz TM, Rosset I et al. (Pre)diabetes, brain aging, and cognition.

Biochim Biophys Acta 2009 May;1792(5):432-43.

68. Wredling R, Levander S, Adamson U, Lins PE. Permanent neuropsychological

impairment after recurrent episodes of severe hypoglycaemia in man. Diabetologia 1990

March; 33(3):152-7.

69. Ryan CM, Williams TM, Finegold DN, Orchard TJ. Cognitive dysfunction in adults

with type 1 (insulin-dependent) diabetes mellitus of long duration: effects of recurrent

hypoglycaemia and other chronic complications. Diabetologia 1993 April;36(4):329-34.

70. Knopman D, Boland LL, Mosley T et al. Cardiovascular risk factors and cognitive

decline in middle-aged adults. Neurology 2001 January 9;56(1):42-8.

71. Okereke OI, Kang JH, Cook NR et al. Type 2 diabetes mellitus and cognitive decline in

two large cohorts of community-dwelling older adults. J Am Geriatr Soc 2008

June;56(6):1028-36.

72. Suh SW, Hamby AM, Swanson RA. Hypoglycemia, brain energetics, and

hypoglycemic neuronal death. Glia 2007 September;55(12):1280-6.


77

73. Wright RJ, Frier BM. Vascular disease and diabetes: is hypoglycaemia an aggravating

factor? Diabetes Metab Res Rev 2008 July;24(5):353-63.

74. Kalofoutis C, Piperi C, Zisaki A et al. Differences in Expression of Cardiovascular Risk

Factors among Type 2 Diabetes Mellitus Patients of Different Age. Ann N Y Acad Sci

2006 November;1084:166-77.

75. Stewart R, Liolitsa D. Type 2 diabetes mellitus, cognitive impairment and dementia.

Diabet Med 1999 February;16(2):93-112.

76. Strachan MW, Deary IJ, Ewing FM, Frier BM. Is type II diabetes associated with an

increased risk of cognitive dysfunction? A critical review of published studies. Diabetes

Care 1997 March;20(3):438-45.



June;56(6):1028-36.

78. Hassing LB, Hofer SM, Nilsson SE et al. Comorbid type 2 diabetes mellitus and

hypertension exacerbates cognitive decline: evidence from a longitudinal study. Age

Ageing 2004 July;33(4):355-61.

79. Yarnell JW, Patterson CC, Thomas HF, Sweetnam PM. Central obesity: predictive

value of skinfold measurements for subsequent ischaemic heart disease at 14 years

follow-up in the Caerphilly Study. Int J Obes Relat Metab Disord 2001

October;25(10):1546-9.

80. Ramachandran A, Snehalatha C, Viswanathan V, Viswanathan M, Haffner SM. Risk of

noninsulin dependent diabetes mellitus conferred by obesity and central adiposity in

different ethnic groups: a comparative analysis between Asian Indians, Mexican

Americans and Whites. Diabetes Res Clin Pract 1997 May;36(2):121-5.

81. Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson EP, Yaffe K.

Central obesity and increased risk of dementia more than three decades later. Neurology

2008 September 30;71(14):1057-64.

82. Posner HB, Tang MX, Luchsinger J, Lantigua R, Stern Y, Mayeux R. The relationship

of hypertension in the elderly to AD, vascular dementia, and cognitive function.

Neurology 2002 April 23;58(8):1175-81.

83. Hassing LB, Grant MD, Hofer SM et al. Type 2 diabetes mellitus contributes to

cognitive decline in old age: a longitudinal population-based study. J Int Neuropsychol

Soc 2004 July;10(4):599-607.

84. Hassing LB, Grant MD, Hofer SM et al. Type 2 diabetes mellitus contributes to

cognitive decline in old age: a longitudinal population-based study. J Int Neuropsychol

Soc 2004 July;10(4):599-607.


78



Ageing 2004 July; 33(4):355-61.

86. Ott A, Stolk RP, van HF, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the

risk of dementia: The Rotterdam Study. Neurology 1999 December 10; 53(9):1937-42.

87. Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes mellitus and

risk of Alzheimer disease and decline in cognitive function. Arch Neurol 2004 May;

61(5):661-6.

88. Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes mellitus and

risk of Alzheimer disease and decline in cognitive function. Arch Neurol 2004

May;61(5):661-6.





June;56(6):1028-36.

91. Rotkiewicz-Piorun AM, Al SS, Raji MA, Kuo YF, Markides KS. Cognitive decline in

older Mexican Americans with diabetes. J Natl Med Assoc 2006 November;

98(11):1840-7.

92. Wu JH, Haan MN, Liang J, Ghosh D, Gonzalez HM, Herman WH. Impact of

antidiabetic medications on physical and cognitive functioning of older Mexican

Americans with diabetes mellitus: a population-based cohort study. Ann Epidemiol

2003 May;13(5):369-76.



Ageing 2004 July;33(4):355-61.

94. van den BE, de Craen AJ, Biessels GJ, Gussekloo J, Westendorp RG. The impact of

diabetes mellitus on cognitive decline in the oldest of the old: a prospective population-

based study. Diabetologia 2006 September;49(9):2015-23.

95. Peila R, White LR, Masaki K, Petrovitch H, Launer LJ. Reducing the risk of dementia:

efficacy of long-term treatment of hypertension. Stroke 2006 May;37(5):1165-70.

96. Akomolafe A, Beiser A, Meigs JB et al. Diabetes mellitus and risk of developing

Alzheimer disease: results from the Framingham Study. Arch Neurol 2006

November;63(11):1551-5.


79







99. Rafnsson SB, Deary IJ, Smith FB et al. Cognitive decline and markers of inflammation

and hemostasis: the Edinburgh Artery Study. J Am Geriatr Soc 2007 May;55(5):700-7.

100. Weisman D, Hakimian E, Ho GJ. Interleukins, inflammation, and mechanisms of

Alzheimer's disease. Vitam Horm 2006;74:505-30.

101. Prince MJ, Bird AS, Blizard RA, Mann AH. Is the cognitive function of older patients

affected by antihypertensive treatment? Results from 54 months of the Medical

Research Council's trial of hypertension in older adults. BMJ 1996 March

30;312(7034):801-5.

102. Krogh-Madsen R, Plomgaard P, Keller P, Keller C, Pedersen BK. Insulin stimulates

interleukin-6 and tumor necrosis factor-alpha gene expression in human subcutaneous

adipose tissue. Am J Physiol Endocrinol Metab 2004 February;286(2):E234-E238.

103. Reaven GM. Insulin resistance and human disease: a short history. J Basic Clin Physiol

Pharmacol 1998;9(2-4):387-406.

104. Festa A, D'Agostino R, Jr., Howard G, Mykkanen L, Tracy RP, Haffner SM. Chronic

subclinical inflammation as part of the insulin resistance syndrome: the Insulin

Resistance Atherosclerosis Study (IRAS). Circulation 2000 July 4;102(1):42-7.

105. Frohlich M, Imhof A, Berg G et al. Association between C-reactive protein and features

of the metabolic syndrome: a population-based study. Diabetes Care 2000

December;23(12):1835-9.

106. Kanemaki T, Kitade H, Kaibori M et al. Interleukin 1beta and interleukin 6, but not

tumor necrosis factor alpha, inhibit insulin-stimulated glycogen synthesis in rat

hepatocytes. Hepatology 1998 May;27(5):1296-303.

107. Sandler S, Bendtzen K, Eizirik DL, Welsh M. Interleukin-6 affects insulin secretion and

glucose metabolism of rat pancreatic islets in vitro. Endocrinology 1990

February;126(2):1288-94.

108. Ford ES. Body mass index, diabetes, and C-reactive protein among U.S. adults.

Diabetes Care 1999 December;22(12):1971-7.

109. Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate

immune system: association of acute-phase reactants and interleukin-6 with metabolic

syndrome X. Diabetologia 1997 November;40(11):1286-92.


80

110. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein,

interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001 July

18;286(3):327-34.

111. Jain SK, Rains JL, Croad JL. High glucose and ketosis (acetoacetate) increases, and

chromium niacinate decreases, IL-6, IL-8, and MCP-1 secretion and oxidative stress in

U937 monocytes. Antioxid Redox Signal 2007 October;9(10):1581-90.

112. Rota S, Yildirim B, Kaleli B, Aybek H, Duman K, Kaptanoglu B. C-reactive protein

levels in non-obese pregnant women with gestational diabetes. Tohoku J Exp Med 2005

August;206(4):341-5.

113. Md Isa SH, Najihah I, Nazaimoon WM et al. Improvement in C-reactive protein and

advanced glycosylation end-products in poorly controlled diabetics is independent of

glucose control. Diabetes Res Clin Pract 2006 April;72(1):48-52.

114. Eikelenboom P, Bate C, van Gool WA et al. Neuroinflammation in Alzheimer's disease

and prion disease. Glia 2002 November;40(2):232-9.

115. Brugg B, Dubreuil YL, Huber G, Wollman EE, haye-Bouchaud N, Mariani J.

Inflammatory processes induce beta-amyloid precursor protein changes in mouse brain.

Proc Natl Acad Sci U S A 1995 March 28;92(7):3032-5.

116. Sheng JG, Bora SH, Xu G, Borchelt DR, Price DL, Koliatsos VE. Lipopolysaccharide-

induced-neuroinflammation increases intracellular accumulation of amyloid precursor

protein and amyloid beta peptide in APPswe transgenic mice. Neurobiol Dis 2003

October;14(1):133-45.

117. McGeer PL, McGeer EG. Inflammation, autotoxicity and Alzheimer disease. Neurobiol

Aging 2001 November;22(6):799-809.

118. Vasto S, Candore G, Duro G, Lio D, Grimaldi MP, Caruso C. Alzheimer's disease and

genetics of inflammation: a pharmacogenomic vision. Pharmacogenomics 2007

December; 8(12):1735-45.

119. Engelhart MJ, Geerlings MI, Meijer J et al. Inflammatory proteins in plasma and the

risk of dementia: the rotterdam study. Arch Neurol 2004 May;61(5):668-72.

120. Ravaglia G, Forti P, Maioli F et al. Blood inflammatory markers and risk of dementia:

The Conselice Study of Brain Aging. Neurobiol Aging 2007 December;28(12):1810-20.

121. Schmidt R, Schmidt H, Curb JD, Masaki K, White LR, Launer LJ. Early inflammation

and dementia: a 25-year follow-up of the Honolulu-Asia Aging Study. Ann Neurol 2002

August;52(2):168-74.

122. Schram MT, Euser SM, de Craen AJ et al. Systemic markers of inflammation and

cognitive decline in old age. J Am Geriatr Soc 2007 May;55(5):708-16.


81

123. Tilvis RS, Kahonen-Vare MH, Jolkkonen J, Valvanne J, Pitkala KH, Strandberg TE.

Predictors of cognitive decline and mortality of aged people over a 10-year period. J

Gerontol A Biol Sci Med Sci 2004 March;59(3):268-74.

124. Weaver JD, Huang MH, Albert M, Harris T, Rowe JW, Seeman TE. Interleukin-6 and

risk of cognitive decline: MacArthur studies of successful aging. Neurology 2002

August 13;59(3):371-8.

125. Yaffe K, Lindquist K, Penninx BW et al. Inflammatory markers and cognition in well-

functioning African-American and white elders. Neurology 2003 July 8;61(1):76-80.

126. Yaffe K, Kanaya A, Lindquist K et al. The metabolic syndrome, inflammation, and risk

of cognitive decline. JAMA 2004 November 10;292(18):2237-42.

127. Gonzalez JS, Safren SA, Delahanty LM et al. Symptoms of depression prospectively

predict poorer self-care in patients with Type 2 diabetes. Diabet Med 2008

September;25(9):1102-7.

128. Mast BT, Miles T, Penninx BW et al. Vascular disease and future risk of depressive

symptomatology in older adults: findings from the Health, Aging, and Body

Composition study. Biol Psychiatry 2008 August 15;64(4):320-6.

129. Mezuk B, Eaton WW, Albrecht S, Golden SH. Depression and type 2 diabetes over the

lifespan: a meta-analysis. Diabetes Care 2008 December;31(12):2383-90.

130. Knol MJ, Twisk JW, Beekman AT, Heine RJ, Snoek FJ, Pouwer F. Depression as a risk

factor for the onset of type 2 diabetes mellitus. A meta-analysis. Diabetologia 2006

May;49(5):837-45.

131. Pedersen WA, McMillan PJ, Kulstad JJ, Leverenz JB, Craft S, Haynatzki GR.

Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp

Neurol 2006 June;199(2):265-73.

132. Ryan CM, Freed MI, Rood JA, Cobitz AR, Waterhouse BR, Strachan MW. Improving

metabolic control leads to better working memory in adults with type 2 diabetes.

Diabetes Care 2006 February;29(2):345-51.

133. Watson GS, Cholerton BA, Reger MA et al. Preserved cognition in patients with early

Alzheimer disease and amnestic mild cognitive impairment during treatment with

rosiglitazone: a preliminary study. Am J Geriatr Psychiatry 2005 November;

13(11):950-8.

134. Risner ME, Saunders AM, Altman JF et al. Efficacy of rosiglitazone in a genetically

defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J

2006 July;6(4):246-54.

135. Craft S, Newcomer J, Kanne S et al. Memory improvement following induced

hyperinsulinemia in Alzheimer's disease. Neurobiol Aging 1996 January;17(1):123-30.


82

136. Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D, Jr.

Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to

severity of dementia and apolipoprotein E genotype. Neurology 1998 January;

50(1):164-8.

137. Craft S, Asthana S, Schellenberg G et al. Insulin metabolism in Alzheimer's disease

differs according to apolipoprotein E genotype and gender. Neuroendocrinology 1999

August; 70(2):146-52.

138. Craft S, Asthana S, Newcomer JW et al. Enhancement of memory in Alzheimer disease

with insulin and somatostatin, but not glucose. Arch Gen Psychiatry 1999

December;56(12):1135-40.

139. Craft S, Asthana S, Schellenberg G et al. Insulin effects on glucose metabolism,

memory, and plasma amyloid precursor protein in Alzheimer's disease differ according

to apolipoprotein-E genotype. Ann N Y Acad Sci 2000 April;903:222-8.

140. Craft S, Asthana S, Cook DG et al. Insulin dose-response effects on memory and

plasma amyloid precursor protein in Alzheimer's disease: interactions with

apolipoprotein E genotype. Psychoneuroendocrinology 2003 August;28(6):809-22.

141. Benedict C, Hallschmid M, Schmitz K et al. Intranasal insulin improves memory in

humans: superiority of insulin aspart. Neuropsychopharmacology 2007 January;

32(1):239-43.

142. Reger MA, Watson GS, Frey WH et al. Effects of intranasal insulin on cognition in

memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging 2006

March; 27(3):451-8.

143. Beeri MS, Schmeidler J, Silverman JM et al. Combination of insulin with other diabetes

medication is associated with lower Alzheimer's neuropathology. Neurology. In press 2008.

144. Standards of Medical Care in Diabetes--2007: American Diabetes Association. Diabetes

Care 30, s4-s41. 2007. Ref Type: Generic.

145. Areosa SA, Grimley EV. Effect of the treatment of Type II diabetes mellitus on the

development of cognitive impairment and dementia. Cochrane Database Syst Rev 2002;

(4):CD003804.

146. Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP, Jr., Selby JV. Hypoglycemic

episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA

2009 April 15; 301(15):1565-72.

147. Nissen SE, Wolski K. Effects of rosigitazone on the risk of myocardial infarction and

death from cardiovasculr causes. New England Journal of Medicine , Ahead. 2007.

Ref Type: Generic.


83

HOMOCYSTEINE – BIOMARKER IN NEUROPSYCHIATRIC DISORDERS Elena Buteica1, Emilia Burada2, Sandra Alice Buteica1

1University of Medicine and Pharmacy Craiova, Romania 2County Emergency Hospital Craiova, Romania

Abstract Hyperhomocysteinemia has an important role in the pathogenesis of some neuropsychiatric diseases, some studies suggest that homocysteine is a biological marker of neurodegeneration, and its level may accelerate the progression of the neurodegenerative disorders. Associations between homocysteine concentration and the severity of extrapyramidal effects at patients treated with antipsychotics, given findings linking homocysteine to dopamine-mediated toxicity or between the level of homocysteine and the degree of brain atrophy at patients with schizophrenia, having in mind the fact that the polymorphisms of the MTHFR gene determine high levels of homocysteine that affects NMDA glutamatergic systems and produces DNA breakage and apoptosis in the cell brain followed by brain atrophy sustain the idea that homocysteine is a biomarker for neuropsychiatric diseases and its measurement could be used as a way of monitoring the response to therapy or, in some cases, as a predictor to the severity of adverse effects of the therapy. Other studies consider that homocysteine is just a risk factor for a variety of central nervous system diseases including Alzheimer disease, schizophrenia, cognitive impairment in the elderly, neuroleptic-induced movement disorders, including tardive Parkinsonism and tardive dyskinesia, other movement disorders such as idiopathic Parkinson's disease, Huntington's disease and primary dystonia. Key words: homocysteine, neuropsychiatric diseases, vitamin B12.

Introduction

Homocysteine can be a biomarker for neuropsychiatric diseases and its measurement could

be used as a way of monitoring the response to therapy or, in some cases, as a predictor to the

severity of adverse effects of the therapy, or its high level is just a risk factor for a variety of central

nervous system diseases including Alzheimer disease, schizophrenia, cognitive impairment in the

elderly, neuroleptic-induced movement disorders, including tardive parkinsonism and tardive

dyskinesia, other movement disorders such as idiopathic Parkinson's disease, Huntington's disease

and primary dystonia. Elevated plasma levels of homocysteine are also proved to be a risk factor for

systemic vascular diseases, stroke and vascular dementia.

1 Correspondence: Elena Buteica, U.M.Ph. Craiova, 2, Petru Rares St., 200349. e-mail: [email protected]; tele. +40 722570333.

Elena Buteica et al.

84

Metabolism

Homocysteine is a sulphur-containing aminoacid that is closely related to methionine and

cysteine. It cannot be obtained from food and it is the result of the methylation cycle. In human

cells, homocysteine is formed by the demethylation of the essential amino acid methionine and an

abnormality in the methylation pathway may have a role in the pathogenesis of schizophrenia.

Three enzymes are directly involved in the homocysteine metabolism: methionine synthase,

betaine homocysteine methyltransferase, and cystathionine β-synthase. Several other enzymes are

indirectly involved. Vitamins B6 and B12 are cofactors to these enzymes and folate is a substrate in

the methionine synthase-mediated reaction. Methionine is converted by methionine-

adenosyltransferase into S-adenosylmethionine that is the most important methyl donor in humans,

and donates its methyl group in numerous transmethylation reactions, such as methylation of DNA,

RNA, proteins and lipids, hormones and neurotransmitters. These transmethylation reactions,

catalyzed by methyltransferases, form S-adenosylhomocysteine, which is an inhibitor of many

methyltransferases, such as catechol-O-methyltransferase (COMT). In its turn, S-

adenosylhomocysteine hydrolyses to adenosine and homocysteine. Homocysteine can then be

metabolised via three metabolic pathways that function to maintain low intracellular concentrations

of homocysteine. Firstly, homocysteine can be remethylated to methionine via the enzyme

methionine synthase (MTR), which uses vitamin B12 as co-factor. In this remethylation reaction 5-

methyltetrahydrofolate donates its methyl group to vitamin B12, which, in its turn, transfers it to

homocysteine to form methionine and tetrahydrofolate.

Folate is obtained via the diet and is reduced via several steps involving enzymes such as

serine-hydroxymethyltransferase and methylenetetrahydrofolate reductase (MTHFR) into 5-

methyltetrahydrofolate, the predominant form of folate in plasma (1). Secondly, in the liver and

kidney homocysteine can also be remethylated into dimethylglycine by the enzyme betaine-

homocysteine methyltransferase with betaine as methyl donor. Thirdly, intracellular homocysteine

can be irreversibly degraded to cysteine through the transsulphuration pathway that is mainly

limited to cells of the liver and kidneys. Vitamin B6 dependent cystathionine β-synthase has an

important role in this reaction. As betaine-homocysteine methyltransferase and cystathionine β-

synthase are absent in central nervous tissue, 5-methyltetrahydrofolate is the only methyl donor

involved in the methylation of homocysteine in central nervous tissue.

Causes of hyperhomocysteinemia

Disturbances in this metabolism, caused by a genetic enzyme defect (polymorphisms of the

MTHFR gene) or by deficiency of cofactors (vitamin B12, vitamins B6, folat, vitamin B2), normally

result in cellular accumulation of homocysteine, and secondary causes hyperhomocysteinemia.

Homocysteine – Biomarker in Neuropsychiatric Disorders

85

Hyperhomocysteinemia is frequently associated with low levels of folate, vitamin B12 and

B6. Moderate elevations of homocysteine may often be caused by one or more unhealthy lifestyle

factors that influence vitamin metabolism, such as smoking, high alcohol consumption, low

nutritional intake of vitamins, high coffee consume and lack of physical exercise. Increased

homocysteine plasma levels seem to have an important role at patients with these basal ganglia

disturbances, by exerting neurotoxic effects, contributing to neurotransmitter imbalance in motor

circuits, and increasing the risk for vascular insults and cognitive dysfunctions.

Increased homocysteine plasma levels seem to have an important role at patients with these

basal ganglia disturbances, by exerting neurotoxic effects, contributing to neurotransmitter

imbalance in motor circuits, and increasing the risk for vascular insults and cognitive dysfunctions.

The most commonly toxic mechansims of homocysteine is oxidative injury realized by

different mechanisms such as abnormalities in folate metabolism or excitotoxic effects mediated by

N-methyl-D-aspartate (NMDA) glutamate subreceptors that could also oxidize membrane lipids and

proteins and determine abnormal methylation, damaged DNA synthesis/repair. The vascular effect

of homocysteine is very important. And it is caused by direct damage to endothelial cells, increased

platelet activity, pro-coagulant effects, increased collagen synthesis, and enhanced proliferation of

smooth muscle cells.

Oxidative stress may induce various vascular and neurological damages, and seem to play a

major role in aging and neurodegenerative disorders such as Alzheimer disease and Huntington´s

disease, amyotrophic lateral sclerosis, Parkinson´s disease. Elevated homocysteine and nitrite (a

metabolite of NO) levels were found in multiple sclerosis patients, in both L-dopa-treated and non-

treated Parkinson disease patients and in patients with cerebrovascular disorders.

Oxidation of homocysteine leads to the formation of homocysteine sulphinic acid and

homocysteic acid, both shown to have potent excitotoxic effects on different subtypes of N-methyl-

D-aspartate (NMDA) glutamate receptors (2, 3). Homocysteine is an endogenous glutamate

receptor agonist, and is proved to act on N-methyl-d-aspartate (NMDA) receptor subtype. An

interaction between excitotoxic NMDA activity and NO-related oxidative damage has been

proposed in aging, neurodegenerative disease, and other neurological disorders (4, 5). Homocysteic

acid and cysteine sulphinic acid can activate NO formation by interaction with the NMDA

receptors. This has also been associated with homocysteine-related neurological damage (6).

Homocysteine and neuropsychiatric diseases

Recent studies showed a positive correlation between the levels of homocysteine and the

severity of the symptoms from different neuropsychiatric diseases such as the following: Alzheimer

disease, schizophrenia, neuroleptic-induced movement disorders, including tardive parkinsonism


86

and tardive dyskinesia, other movement disorders such as idiopathic Parkinson's disease,

Huntington's disease and primary dystonia.

Hogervorst et al. (2002) showed a significant negative association between homocysteine

and minimal hippocampal width, and also a significant positive association between homocysteine

and cerebral infarction, white matter changes, and degree of atrophy at patients with Alzheimer

disease (7). Elevated homocysteine levels in schizophrenics in connection with the C677T

polymorphism of the MTHFR gene and low folate status are described (8). Homocysteine affects

NMDA glutamatergic systems (9), and seems to play some role in the pathogenesis of

schizophrenia. Homocysteine may enhance oxidative stress processes (10) that also may be a risk

factor for schizophrenia.

Homocysteine was also suggested to induce DNA strand breakage and apoptosis (11) and

some authors suggested a link between apopotic processes and schizophrenia (12). High

homocysteine levels are accompanied by high S-adenosyl-homocysteine levels. Elevation of S-

adenosyl-homocysteine was suggested to be associated with DNA hypomethylation and alterations

in gene expression (13). Altered gene expression may be associated with the pathogenesis of

schizophrenia. Significantly elevated plasma levels of homocysteine have been reported in patients

with Parkinson’s disease (PD) (13, 14).

In one study the levels of homocysteine were elevated by 60% in levodopa-treated patients

with a marked elevation occuring in patients with the MTHFR 677TT genotype. The homocysteine

and folate levels were inversely correlated in this group (13). Additional data from this group and

other recently reported data firmly support that this polymorphism is a significant factor for

hyperhomocysteinemia in L-dopa-treated patients.

Homocysteine monitoring may be of particular value for Parkinson disease as it is neurotoxic

to the nigrostriatal dopaminergic system. Because of the neurotoxicity nature of homocysteine to

dopaminergic neurons there was suggested that elevated level of this molecule in patients with

Parkinsonism may lead to accelerate the progression of the disease. Hyperhomocysteinemia in

Parkinson disease could be explain by levodopa administration and it may be implicated in the

development of motor complications and non-motor symptoms, such as dementia.

Hyperhomocysteinemia has been evidenced in Huntington disease and dystonic patients

(14). High serum total homocysteine level may constitute a risk factor for certain variants of

neuroleptic-induced movement disorder especially in young schizophrenic or schizo-affective male

patients and studies have been made in these direction (15).

Homocysteine – Biomarker in Neuropsychiatric Disorders

87

Conclusions

Hyperhomocysteinemia has an important role in the pathogenesis of some neuropsychiatric

diseases, some authors consider that homocysteine is a biological marker of neurodegeneration, and

its level may accelerate the progression of the neurodegenerative disorders.

It is possible a correlation between the level of homocysteine and the degree of brain

atrophy at patients with schizophrenia, having in mind the fact that the polymorphisms of the

MTHFR gene determine high levels of homocysteine that affects NMDA glutamatergic systems,

and produces DNA breakage and apoptosis in the cell brain followed by brain atrophy.

References

1. Bolander-Gouaille C., Bottiglieri T. 2007. Homocysteine Related Vitamins and

Neuropsychiatric Disorders, Second edition, Springer-Verlag France.

2. Lipton S., Rosenberg P. 1994. Excitatory amino acids as a final common pathway for

neurologic disorders. New Engl J Med 330, 613-622.

3. Flott-Rahmel B. 1998. Homocysteic and homocysteine sulphic acid exhibit exitotoxicity

in organotypic cultures from rat brain. Eur J Pediatrics 157, 112- 117.

4. Garthwaite J. 1991. Glutamate, nitric oxide and cell signalling in the nervous system.

TINS, 14:60-7.

5. Bondy S, Le Bel C. 1993. The relationship between exitotoxicity and oxidative stress in

the central nervous system. Free Rad Biol Med, 14:633-42.

6. Adachi K.1998. Inhibition of NMDA receptors and nitric oxide synthase reduces

ischemic injury of the retina. Eur J Pharmacol 29:53-7.

7. Hogervorst E. 2002. Plasma homocysteine levels, cerebrovascular risk factors, and

cerebral white matter changes in patients with Alzheimer´s disease. Arch Neurol 59,

787-93.

8. Regland B., Germgard T., Gottfries C.G, Grenfeldt B., Koch- Schmidt A.C. 1997

Homozygous thermolabile methylenetetrahydrofolate reductase in schizophrenialike

psychosis. J Neural Transm 104, 931-41.

9. Ho P.I., Ortiz D., Rogers E., Shea T.B. 2002. Multiple aspects of homocysteine

neurotoxicity: glutamate excitotoxicity, kinase hyperactivation and DNA damage.

Journal of Neuroscience Research 70:694–702.

10. Huang R.F., Huang S.M., Lin B.S., Wei J.S., Liu T.Z. 2001. Homocysteine thiolactone

induces apoptotic DNA damage mediated by increased intracellular hydrogen peroxide

and caspase 3 activation in HL-60 cells. Life Sciences 68:2799–811.


88

11. Mattson M.P., Shea T.B. 2003. Folate and homocysteine metabolism in neural plasticity

and neurodegenerative disorders. Trends in Neuroscience 26, 137–46.

12. James S.J., Melnyk S., Pogribna M., Pogribny I.P., Caudill M.A. 2002. Elevation in S-

adenosylhomocysteine and DNA hypomethylation: Potential epigenetic mechanism for

homocysteine-related pathology. Journal of Nutrition 132.

13. Yasui K. 2002 Plasma homocysteine and MTHFR C677T genotype in levodopa-treated

patients with PD. Neurology 55, 437-40.

14. Müller T. 2002. 3-OMD and homocysteine plasma levels in parkinsonian patients. J

Neural Transm 109, 175-9.

15. Lerner V., Miodownik C., Kaptsan A., Vishne T., Sela B.A., Levine J. 2005. High

serum homocysteine levels in young male schizophrenic and schizoaffective patients

with tardive parkinsonism and/or tardive dyskinesia. J Clin Psychiatry 66(12):1558-63.


89

LONG-ACTING RISPERIDONE INJECTION – A PATH TO REMISSION IN SCHIZOPHRENIA

Cristinel Stefanescu1, Carina Persson2, Roxana Chirita1, Vasile Chirita1 1University of Medicine and Pharmacy “Gr. T. Popa” Iasi, Romania

2Psykiatriska kliniken Kungälv, Sweden

Abstract Aim. The clinical efficacy, adverse effects, cost, and dosage of long-acting risperidone injection are reviewed. Summary. Risperidone is the first atypical antipsychotic available in a long-acting injectable formulation. After a single injection, significant plasma levels of the drug are achieved at week 3 and sustained through week 6. Our review demonstrates the efficacy, safety, and tolerability of long-acting risperidone injection in patients with schizophrenia. According to the reviewed data, risperidone injection was well tolerated, with low adverse-effect rates. Weight gain with long-acting risperidone injection was insignificant. Extrapyramidal symptom ratings are comparable with other novel antipsychotics. Conclusion. With its tolerability and efficacy, long-acting risperidone injection has the potential to extend the benefits of antipsychotic medication in patients with schizophrenia, achieving the remission criteria with a good economic imbalance. Key words: schizophrenia, antipsychotics.

Introduction

Schizophrenia is a chronic, severe and disabling brain disorder that seriously impairs a

person’s ability to think clearly, relate to others and to function productively in society.

Schizophrenia typically develops in adolescence or the early 20s, although symptoms may not

become obvious until later life (33). While most males first become ill between the ages of 16 and

25, the majority of females develop symptoms between ages 23 and 36 (1). Schizophrenia is

marked by ‘positive’ and ‘negative’ symptoms, characterized by psychotic episodes. When

symptoms worsen, these episodes often recur which is known as a relapse. The severity and

regularity of these episodes vary from person to person. Each successive relapse will often become

worse over time and harder to control. After several relapses, the patient’s overall condition can

deteriorate to such an extent that he/she may not be able to reach the same level of health and

functioning they had before becoming ill, as the graph below demonstrates. In addition, during

1 Correspondence: Cristinel Stefanescu. e-mail: [email protected].

Cristinel Stefanescu et al.

90

these relapses, patients have an increased risk of hospitalization. The disruption caused by a relapse

can be devastating for a patient and their family.

Socio-economic impact of schizophrenia

Approximately 25 percent of people with schizophrenia will recover after one psychotic

episode. However, for many, schizophrenia is a life-long illness and a severe burden to both the

patient and their family and friends. Many patients will be out of work as a result of the illness, and

it may also seriously impact on their relationships and social life. Moreover, people with

schizophrenia will often be in poor physical health and they are more likely to eat poorly, smoke

and drink alcohol to excess. Family life is also disrupted as on average carers spend 15 hours a

week looking after a family member with schizophrenia.

Treatment challenges in schizophrenia

While there is no real cure for schizophrenia, the psychiatrist has to manage the appropriate

treatment, particularly when intervention is sought and received early in the illness. According to the

United States’ National Alliance for the Mentally Ill (NAMI), the current treatment-success rate for

schizophrenia is about 60 percent, compared to just 41-52 percent for patients with heart disease (37).

However, recovery to the maximum extent possible depends on maintenance of treatment.

Data show that about 75 percent of people with schizophrenia relapse within a year to 18 months if

antipsychotic drug therapy is stopped or taken inconsistently (32, 23). Unfortunately, it is estimated

that as few as 25 percent of people with schizophrenia take their medication on a continuous,

consistent basis (11).

Improving compliance

When patients stop taking their medication it is likely that their symptoms may return. These

relapses can result in serious problems and hospitalization. Non-compliance to medication is among

the most common causes of relapse in schizophrenia (16), and relapse rates are up to four times

higher in patients who are non-adherent to their medication (15). Non-adherence to medication is

actually the most important factor related to readmission of the patient in the hospital.

Patients who relapse can take over a year to return to their pre-relapse level of social

functioning (12), and with each successive relapse, the person’s condition may deteriorate and

previous levels of health and functioning may not be reached again (18).

One potential aid in addressing these challenges is long-acting injectable antipsychotic that

require less frequent administration and facilitate regular interchange with a physician or other

healthcare professional.

Long-Acting Risperidone Injection – A Path to Remission in Schizophrenia

91

While replacing daily pills with long-acting injections isn’t a perfect and unique solution for

treatment non-adherence, unlike pills or liquids that are taken privately, a missed appointment for

an injection is often evident to the family or carers. This can help the social supporting group and

the therapeutic team to identify any problems the patient may have with their treatment regimen and

provide the individual with the appropriate follow-up in an effective time frame.

The introduction in the 1960s of long-acting, intra-muscular injections of older,

conventional antipsychotics or so called “depot” formulations was specifically intended to address

the problem of non-adherence. Many studies show that patients prefer long-acting injections to oral

treatment (40). However, the incidence of movement-related side effects is a significant

disadvantage of these older formulations. A further drawback is that, because the older injections

are typically oil-based, they are often associated with pain and/or irritation (28).

The next generation of long-acting injections combine the advantages of the newer

generation antipsychotics with the benefits of a long-acting formulation, which are less painful to

receive. These medications may help to improve symptoms and adherence which may lead to

reduced relapse rates, hospitalization and improve quality of life (33).

Pharmacology

Long-acting risperidone is a suspension administered by intramuscular injection in the

upper-outer gluteal area. It consists of risperidone impregnated in microspheres composed of a

biodegradable, high-molecular-weight, glycolic acid- lactic acid (polyactide-glycolide) matrix (39).

The long-acting risperidone powder requires refrigeration at 2-8 °C. However, the vial is stable for

up to seven days at 25 °C or below (17). Since the suspension is not uniform and the syringe is

ungraduated, it is not possible to accurately inject a partial dose in order to reduce the dose given.

Clinical Efficacy

Several studies have been conducted to evaluate the efficacy and safety of long-acting

risperidone in patients with schizophrenia or schizoaffective disorder (22,7,13). In a 12-week, double-

blind, placebo-controlled U.S. trial, Kane et al. (22) used the PANSS and the Clinical Global

Impressions scale (CGI) to assess efficacy in 400 outpatients and inpatients with schizophrenia. The

PANSS is a 30-item scale with ratings of 1-7; the CGI also uses ratings of 1- 7 to rate overall severity

of illness. The mean baseline PANSS score for subjects was 82, and the mean age was 38 years.

Significant improvements in positive symptoms (such as delusions and hallucinations), negative

symptoms (such as blunted affect and social withdrawal), total PANSS scores, and CGI ratings were

produced by all three doses of long-acting risperidone injection evaluated (25, 50, and 75 mg)

administered every two weeks. Regardless of the baseline severity of illness, improvements were

greater in the subjects receiving 25 or 50 mg than in those receiving 75 mg. This suggests that there is


92

no added benefit from the 75-mg dose. Clinical improvement at the end of the study (≥20% reduction

in total PANSS scores) was seen in 17% of placebo recipients and 47%, 48%, and 39% of subjects in

the 25-, 50-, and 75-mg risperidone groups, respectively (p < 0.001).

A further analysis of this 12-week trial focused on patients who received oral olanzapine

prior to the initiation of therapy with long-acting risperidone injection (19). Compared with

baseline, these patients demonstrated significant improvement in total PANSS scores (p = 0.03),

positive symptoms (p < 0.05), negative symptoms (p < 0.05), and anxiety and depression (p < 0.05)

when they were switched to the risperidone formulation.

Chue et al. (7) conducted a randomized, double-blind, 12-week trial in 640 patients to

establish whether long-acting risperidone injection was as effective as oral risperidone. After

stabilization on oral medication for 8 weeks, the subjects were randomly assigned to receive either (1)

oral risperidone and placebo injection or (2) long-acting risperidone injection and oral placebo and

monitored for 12 weeks. Patients receiving long-acting risperidone injection every two weeks also

received three weeks of active oral medication following the first injection. The study was completed

by 84% of those given oral medication and 80% of those who received risperidone injection.

Significant improvements from baseline to the end of the study in total PANSS scores, positive

symptoms, negative symptoms, disorganized thoughts, and anxiety and depression were seen in both

groups (p < 0.05). Non-inferiority testing further demonstrated that the injectable formulation was not

inferior to oral risperidone and that subjects could be switched to it without loss of efficacy.

Fleischhacker et al. (13) conducted an international one-year open-label trial in 615 patients

with schizophrenia. The mean PANSS score was 66, and the mean age was 42 years. Compared with

baseline, patients receiving long-acting risperidone injection every two weeks at all doses had

improvements in total PANSS scores (p < 0.01), positive symptoms (p < 0.01), and negative

symptoms (p < 0.001) at the end of the study. Since the subjects were considered stable at baseline,

these improvements are especially noteworthy. Clinical improvement, defined as a reduction in total

PANSS scores of at least 20%, was seen in 49% of the risperidone recipients. Furthermore, 34% and

18% of these patients achieved >40% and >60% reductions in total PANSS scores, respectively, after

one year of treatment (29). As in the Kane et al. (22) trial, subjects in this one-year study receiving 25

or 50 mg of long-acting risperidone injection had greater improvement than those given 75 mg.

A number of subanalyses of the data from the study by Fleischhacker et al. (13) were

conducted. One looked at the effect of prior antipsychotic therapy on the efficacy of long-acting

risperidone (42). Patients who had previously been treated with oral risperidone accounted for

approximately 50% of the population studied, while approximately 25% had received “depot”

conventional antipsychotic agents. Eighteen percent, 33%, and 10% of the patients whose illness


93

had been stable on oral risperidone, “depot” conventional antipsychotics, and oral conventional

antipsychotics, respectively, showed more than 60% improvement in PANSS scores when they

were switched to long-acting risperidone (27,14,34,35).

Analysis of a further 110 patients with schizoaffective disorder who had participated in the

Fleischhacker et al. (13) study found that they had benefited significantly from long-acting

risperidone (20). Total PANSS scores improved by a mean ± S.D. of 9.0 ± 1.6 points between

baseline and the end of the study (p < 0.001). Clinical improvement -- measured as ≥20%, 40%, or

60% reduction in total PANSS scores from baseline -- occurred in 58%, 39%, and 18% of the

subjects, respectively.

The definition of remission

The exact definition of the word ‘remission’ is ‘the state of absence of disease activity in

patients with a chronic illness. Remission of symptoms is not a new concept, and definitions of

remission criteria currently exist for both psychiatric and non-psychiatric illnesses. However, in

psychiatric illnesses remission is usually defined by a low level of symptoms with mild disability.

The concept of remission in schizophrenia begins to move the somewhat negative

perception of being ill to the much more positive assertion of being well. At the simplest level, the

concept begins to accept the idea that patients can have periods of time when they are well and

although the condition can fluctuate, the possibility of long-term recovery is very real.

An important part of remission in schizophrenia is the improved quality of life it gives

patients and the proposal that ‘symptomatic remission is an achievable objective for a significant

proportion of patients with a diagnosis of this illness (9). With the advances in medication,

remission is now considered to be clinically relevant in the treatment of schizophrenia, where

patients are able to progress beyond stability (26).

The development of the concept of remission

Unfortunately, schizophrenia is a somewhat stigmatised condition, which is mainly

attributed to a lack of knowledge, and for many years it has been regarded as a disease with little or

no hope of recovery. In fact, dramatic improvement in people diagnosed with schizophrenia was

regarded by many clinicians as evidence of an original misdiagnosis.

However, this view has altered over time due to advances in knowledge, improvements in

psychotherapeutic techniques and the introduction of antipsychotic medications.

Due to advancements in the understanding of schizophrenia, the treatment goals have

evolved significantly. The diagram below illustrates how these objectives have evolved over time,


94

for example, before the 1960s, the treatment goal was to improve self-care, reduce aggression and

reduce self-injury. However, by 2000 this goal had changed to focus on improving a patients’

ability to function within society and the potential for remission.

Improve self-care Reduce aggression Reduce self-injury

‘Survive’ out of hospitalDe-institutionalisation

Reduce relapseMinimise positive symptoms

Increase ‘stable’ periodsMinimise negative symptoms

Pre-1960s

1960-70s

1980s

1990s

Focus on functionalityPotential for Remission

2000+

A consensus for remission in schizophrenia

In April 2003, an international remission expert group convened to develop a consensus

definition of remission as applied to schizophrenia. The consensus aimed at developing a criterion for

sustained symptomatic remission in patients with schizophrenia, similar to the remission consensus

developed in mood and anxiety disorder (34). Sustained remission was defined by using an absolute

threshold of severity of the diagnostic symptoms of schizophrenia and a duration component.

The need for a consensus came about due to a growing understanding of the disease course and

advancements in treatment options, including oral and long-acting injectable atypical medications.

The working group established that the remission criteria for schizophrenia needed to be an

attainable clinical goal that was easily measurable. It needed to employ a time component and

support alignment of the views of patients, caregivers and clinicians.

The Positive and Negative Syndrome Scale (PANNS) consists of eight specific items

reflecting all three dimensions and core symptoms of the illness, all of which were selected by the

working group as a criterion for remission in schizophrenia. In order to achieve symptomatic

remission, patients would need to score mild or less simultaneously on all of the eight core

symptoms and maintain this score for a minimum of six months.

According to the consensus, a patient can be considered in remission when during a period

of at least six months; all of the core symptoms are either absent, minimal or mild enough so as not

to interfere with the patient’s day to day life (34).


95

Core symptoms:

Delusions

Conceptual disorganisation

Hallucinatory behaviour

Unusual thought content

Mannerisms and posturing

Blunted affect

Social withdrawal

Lack of spontaneity or flow of conversation

The table below highlights both the advantages of having clearly defined remission criteria

and the benefits of achieving remission for patients, carers and psychiatrists.

ADVANTAGES OF A CLEARLY DEFINED REMISSION CRITERIA PATIENTS AND CARERS: PSYCHIATRISTS:

Patients have clear expectations of what is achievable in the long-term and challenge their treatment expectations ‘beyond stability’ Patients and carers are better enabled to communicate long-term goals to psychiatrists Provides clinicians with a robust, well-defined and achievable outcome goal in the long-term treatment of schizophrenia Helps to facilitate comparisons of effectiveness across the range of available therapeutic options and clinical trials They can help patients reach sustained remission

ADVANTAGES OF ACHIEVING SUSTAINED REMISSION PATIENTS & CARERS:

There is a reduced burden on the carers Patients improve in their overall daily living… Personal hygiene Domestic activities Managing finances Daily activities/work Executive functioning Improved cognitive ability Vigilance Working memory Long-term memory

Obstacles in remission: adherence to treatment

Although remission is an achievable goal in the treatment of schizophrenia, it is important to

recognise the obstacles that can delay the patient in reaching this goal. There are at least two major

obstacles in achieving continuous improvement in patients with schizophrenia.

The first obstacle is ensuring patient adherence with medication. Patients who fail to take their

prescribed medication will reduce the effectiveness of their treatment and this will contribute to the

worsening of their condition, possible deficits in cognition and psychosocial functioning, and ultimately

relapse. This can cause further problems as research has shown that patients not in remission have a

reduced cognitive ability and consequently experience difficulty complying with their treatment.


96

The second obstacle is treatment efficacy and tolerability. It is important to ensure that the

medication prescribed to the patient is effective and well-tolerated.

Safety and Tolerability

Long-acting risperidone injection is generally well tolerated and has an adverse-effect

profile similar to that of oral risperidone. In the Kane et al. (22) trial, similar proportions of

individuals receiving long-acting injection and placebo reported adverse events. The rate of serious

adverse effects was 23.5% in the placebo group and 13%, 14%, and 15% in the risperidone 25-, 50-,

and 75-mg groups, respectively. Serious adverse effects were defined as those that resulted in death

or were life threatening, required hospitalization or prolonged hospitalization with persistent or

significant disability, or resulted in incapacity, congenital anomaly, or a birth defect (22). Overall,

the rate of patient withdrawal from the study because of adverse effects was 12% in the placebo

group and 11-14% in the risperidone recipients. The most frequently reported adverse effects were

headache, agitation, psychosis, insomnia, and anxiety.

Long-acting risperidone injection was also well tolerated in the trial by Fleischhacker et al.

(13); two thirds of the patients completed the study, and less than 6% of any of the treatment groups

withdrew because of adverse effects. The percentage of patients with adverse effects declined from

68% in the first three months of the study to 43% in the last three months, with the most frequently

reported problems being anxiety (24%), insomnia (21%), psychosis (17%), and depression (15%).

Because of their activities as D2-receptor antagonists, EPSs are a potential concern with all

atypical antipsychotics. Both Kane et al. (22) and Fleischhacker et al. (13) used the 55-item

Extrapyramidal Symptom Rating Scale (ESRS) to evaluate the severity of EPSs. This scale assesses

the objective frequency, objective severity, and subjective severity of parkinsonism, dyskinesia,

akathisia, and dystonia (5).

In both the 12-week Kane et al. (22) and one-year Fleischhacker et al. (13) trials, baseline

ESRS scores were low. EPS severity decreased in all groups during the Kane et al. trial, with the

greatest improvement observed in the 25-mg long-acting risperidone group. After completion of the

concomitant oral treatment phase (the first three weeks after the first injection of long-acting

risperidone), the EPS rate was 9% in those receiving placebo and 3% in those receiving risperidone

25 mg. The rates for the 50- and 75-mg doses were 14% and 23%, respectively. In the

Fleischhacker et al. study, according both to patients’ subjective ratings and physicians' ratings, the

severity of movement disorders was low at baseline and improved significantly during treatment

with long-acting risperidone injection. Patients previously treated with oral risperidone and those

who had previously received depot conventional agents both had significant improvements in

movement disorders at week 50, as determined by the subjective and objective ratings on the ESRS


97

(p <0.05) (14,37). Treatment-emergent tardive dyskinesia occurred in only 0.68% of patients in the

one-year trial by Fleischhacker et al., while 28.4% of the patients diagnosed with dyskinesia at

baseline (n = 102) improved significantly after treatment with long-acting risperidone (4).

Other important adverse effects of atypical antipsychotic agents include increases in body

weight (8), glucose intolerance (25), and prolactin elevation (2, 3). Body-weight changes by the end

of the 12-week trial by Kane et al. (22) were small (gains of 0.05, 1.2, and 1.9 kg in the 25-, 50-, and

75-mg groups, respectively), while the mean weight change in the placebo group was a loss of 1.4 kg.

Weight gain in the one-year study by Fleischhacker et al. (13) was 1.7, 2.6, and 1.9 kg in the 25-, 50-,

and 75-mg groups, respectively. This could indicate that the weight gain occurs early in treatment but

does not increase dramatically with continued use. Glucose levels were not specifically reported, but

there were no clinically significant changes from baseline in the one-year trial (13).

Additional clinical assessments during treatment with long-acting risperidone injection

included electrocardiograms to assess cardiovascular safety. No significant differences in

cardiovascular function between risperidone and placebo, or detrimental effects of long-term

treatment, were observed, including in patients 65 years of age or older (22,13,36).

Cost Benefit Considerations

The duration and frequency of hospitalization can markedly affect the cost of treating a

patient with psychosis. Hospitalization is the largest component of the direct cost of treating

schizophrenia (24). Chue and colleagues (6) evaluated rehospitalization rates in 397 patients with

stable schizophrenia or schizoaffective disorder who were treated with long-acting risperidone

injection in the Fleischhacker et al. study (13). The sample included individuals who had been

stable on their previous antipsychotic medication for at least four weeks before study entry and who

were outpatients or who were inpatients and subsequently discharged. The overall hospitalization

rate at one year was 17.6%; the rehospitalization rate for those beginning as outpatients and treated

with risperi-done was 15.9%. This rate is notably lower than that reported for people receiving

conventional long-acting agents (30-50%) or oral atypical antipsychotic agents (20-30%)

(43,38,31,10). There was also a significant decrease in the percentage of patients requiring

hospitalization (38% at baseline, 12% at the end of the study) (p < 0.0001) (6). Given the proportion

of treatment costs due to hospitalization, use of long-acting risperidone injection could lead to an

over-all reduction in the cost of treating schizophrenia.

Dosage and administration

On the basis of data from the studies by Kane et al. (22) and Fleischhacker et al. (13), the

recommended starting dosage of long-acting risperidone is 25 mg administered every two weeks by

deep intramuscular injection in the upper-outer gluteal area. Kane and colleagues (22) found that

this dosage produced the optimum risk-benefit profile for most individuals with schizophrenia.


98

Given the lack of incremental benefits and the higher rate of EPSs seen with the 75-mg dose

(22,13), the manufacturer recommends a maximum dosage of 50 mg every two weeks (17). Since

the achievement of appreciable blood levels is delayed, supplementation with an antipsychotic

should occur during the first three weeks after the initial injection. Because there is minimal release

of risperidone from the long-acting formulation in the first three weeks, adverse effects arising from

the presence of both oral and injectable medication are unlikely.

Steady state is reached after four injections of long-acting risperidone are administered

every two weeks (six weeks of treatment). If breakthrough psychotic symptoms occur before steady

state is reached, clinicians should treat them with an oral antipsychotic, rather than with increasing

doses of long-acting risperidone. Clinicians should avoid giving rapidly escalating doses or extra

injections in an effort to produce a quick response, since the effects of the dosage adjustments will

not be evident for several weeks. Dosage adjustments should not be made more frequently than

once every four weeks.

Patients with schizophrenia who are switched from an oral antipsychotic to long-acting

risperidone injection should continue to receive their oral antipsychotic medication for the first

three weeks of long-acting risperidone treatment. The duration of action of depot conventional

antipsychotics is such that most patients who are switched from these agents can be directly

switched to long-acting risperidone, substituting the long-acting risperidone for their next scheduled

injection (30). Once steady state has been achieved, any missed doses should be administered as

soon as possible. If the last dose was administered less than six weeks earlier, oral supplementation

may not be necessary. However, if more than six weeks has elapsed since the last dose, oral

supplementation should be considered. If doses are missed before the achievement of steady state,

the clinician should provide oral supplementation when reinitiating therapy with the long-acting

formulation. All patients should be carefully monitored (41).

Before patients are given long-acting risperidone injection for the first time, it is good

clinical practice to rule out potential hypersensitivity. Clinicians can give a test dose of oral

risperidone to evaluate hypersensitivity (21). Finally, since long-acting risperidone is injected in the

form of a suspension, it should never be administered intravenously.

Conclusion

Long-acting injectable antipsychotic agents can limit the impact of partial compliance by

helping to en-sure delivery of antipsychotic medication. Depot conventional antipsychotics are

usually reserved for people with disorders that are severe or difficult to manage. With its unique

tolerability and efficacy, long-acting risperidone injection has the potential to extend the benefits of

assured medication delivery and improved long-term outcomes to more patients with schizophrenia.


99

References

1. American Psychiatric Association. ‘Practice guideline for the treatment of patients with

schizophrenia’ Supplement to Am J Psychiatry. 1997;154: 4.

2. Canuso C, Lasser R. Significantly reduced serum prolactin levels following treatment

with long-acting risperidone. Paper presented at American Psychiatric Association

Meeting. San Francisco, CA; 2003 May 17-22.

3. Canuso CM, Goldstein JM, Wojcik J et al. Antipsychotic medication, prolactin

elevation, and ovarian function in women with schizophrenia and schizoaffective

disorder. Psychiatry Res. 2002; 111: 11-20.

4. Chouinard G, Lasser R, Bossie C et al. Does a long-acting atypical antipsychotic offer a

low risk of tardive dyskinesia in patients with schizophrenia? Paper presented at

American College of Neuropsychopharmacology 41st Annual Meeting. San Juan, PR;

2002 Feb 2-5.

5. Chouinard G, Ross-Chouinard A, Annable L et al. Extrapyramidal symptom rating

scale. Can J Neurol Sci. 1980; 7:233. Abstract.

6. Chue P, Devos E, Duchesne I et al. One-year hospitalization rates in patients during

long-term treatment with long-acting risperidone injection. Value Health. 2002;

5(3):229. Abstract.

7. Chue P, Eerdekens M, Augustyns I et al. Comparative efficacy and safety of long-acting

risperidone and risperidone oral tablets. Schizophrenia Res. 2002; 53(suppl 3):S174-5.

8. Clinical guidelines on the identification, evaluation, and treatment of overweight and

obesity in adults: the evidence report. Bethesda, MD: National Institutes of Am J

Health-Syst Pharm Vol 61 Sep 1, 2004

9. Cockshut G, Progress in Neurology and Psychiatry, January/February 07 Supplement.

10. Conley RR, Love RC, Kelley DL et al. Rehospitalization rates of patients recently

discharged on a regimen of risperidone or clozapine. Am J Psychol. 1999; 156:863-8.

11. Davis JM, Matalon L, Watanabe MD, Blake L. ‘Depot antipsychotic drugs: place in

therapy’. Drugs 1994; 47:741-73.

12. Fenton WS et al. ‘Determinants of medication compliance in schizophrenia: empirical

and clinical findings’. Schizophrenia Bull. 1997. 23, 637-651

13. Fleischhacker W, Eerdekens M, Karcher K et al. Treatment of schizophrenia with long-

acting injectable risperidone: a 12 month evaluation of the first long-acting 2nd

generation antipsychotic. J Clin Psychiatry. 2003; 64:1250-7.

14. Gharabawi G, Lasser R, Bossie C et al. Enhanced one-year outcomes with three doses

of long-acting injectable risperi-done in 336 chronically psychotic, stable patients


100

switched from oral risperidone. Paper presented at American College of

Neuropsychopharmacology 41st Annual Meeting. San Juan, PR; 2002 Feb 2-5.

15. Haywood TW et al. ‘Predicting the "revolving door" phenomenon among patients with

schizophrenic, schizoaffective, and affective disorders’. Am J Psychiatry 1995; 152, 856-861

16. Hogarty GE, Schooler NR, Ulrich R, Mussare F et al. ‘Fluphenazine and social therapy

in the aftercare of schizophrenic patients: relapse analyses of a two-year controlled

study of fluphenazine decanoate and fluphenazine hydrochloride’. Arch Gen Psychiatry.

1979; 36:1283-1294

17. Janssen Pharmaceutical Products, Inc. Risperidone long-acting injection (Risperdal

Consta) U.S. prescribing information. www.risperdalconsta.com (accessed 2004 Mar 1).

18. Johnson DAW et al. ‘The discontinuance of maintenance neuroleptic therapy in chronic

schizophrenic patients: drug and social consequences’. Acta Psychiatr Scand. 1983. 67,

339-352.

19. Jones R, Bossie C, Lasser R. Clinical improvement with long-acting risperidone in

patients previously receiving oral olanzapine. Paper presented at American Psychiatric

Association Meeting. San Francisco, CA; 2003 May 17-22.

20. Kane J, Gharabawi G, Bossie CA et al. Effect of a novel long-acting antipsychotic

formulation in stable patients with schizoaffective disorder. Paper presented at

American College of Neuropsycho-pharmacology 41st Annual Meeting. San Juan, PR;

2002 Feb 2-5.

21. Kane JM, Conley RC, Keith SJ et al. Guidelines for the use of long-acting injectable

atypical antipsychotics. J Clin Psychiatry. 2004; 65:1-12.

22. Kane JM, Eerdekens M, Lindenmayer JP et al. Long-acting injectable risperidone:

efficacy and safety of the first long-acting atypical antipsychotics. Am J Psychiatry.

2003; 160:1125-32.

23. Kissling W, ed. ‘Guidelines for neuroleptic relapse prevention in schizophrenia’. Berlin,

Germany: Springer-Verlag, 1991.

24. Knapp M. Schizophrenia costs and treatment cost-effectiveness. Acta Psychiatr Scand

Suppl. 2000; 102:15-8.

25. Koller EA, Cross JT, Doraiswamy PM et al. Risperidone-associated diabetes mellitus: a

pharmacovigilance study. Pharmacotherapy. 2003; 23:735-44.

26. Lars Helldin et al., Remission and cognitive ability in a cohort of patients with

schizophrenia, J Psychiat Res 2006; 40: 738-45.


101

27. Lasser R, Bossie CA, Gharabawi G et al. Patients with schizophrenia previously stabilized

on conventional depot antipsychotics experience significant clinical improvements

following treatment with long-acting risperidone. Eur Psychiatry. 2004; 19:219-25.

28. Lindenmayer, Jean-Pierre; Jarboe. ‘Minimal injection site pain and high patient

satisfaction during treatment with long-acting risperidone’. International Clinical

Psychopharmacology. 20(4):213-221, July 2005

29. Lonchena C, Lasser R, Bossie C et al. Can stable patients with schizophrenia improve?

The impact of partial compliance vs. constant therapy. Paper presented at American

Psychiatric Association Meeting. San Francisco, CA; 2003 May 17-22.

30. Marder S, Conley R, Ereshefsky L et al. Dosing and switching strategies for long-acting

risperidone. J Clin Psychiatry. 2003; 64:S43-8.

31. Moore D, Kelly D, Dherr J et al. Rehospitalization rates for depot antipsychotics and

pharmacoeconomic implications: comparison with risperidone. Am J Health-Syst

Pharm. 1998; 55(suppl 4): S17-9.

32. NAMI website. www.nami.org/helpline/schizo.htm

33. NIH Publication No. 99-3517

34. Os J V, Burns T, Cavallaro, R, Leucht, S, Peuskens, J, Helldin, L, Bernardo, M, Arango,

C, Fleischhacker, W, Lachaux, B, Kane, JM Acta Psychiatr Scan 2006; 113: 91-95.

35. Os JV, Bossie CA, Lasser R. Improvements in stable patients with psychotic disorders

switched from oral conventional antipsychotics therapy to long-acting risperidone. Int

Clin Psychopharmacol. 2004; 19:229-32.

36. Pandina G, Gharabawi G, Eerdekens M et al. Long-acting risperidone for the management

of elderly patients with psychotic disorders: a favourable benefit/risk ratio. Paper presented

at American Psychiatric Association Meeting. San Francisco, CA; 2002 May 18-23.

37. Perkins DO et al. ‘Relationship between duration of untreated psychosis and outcome in

first-episode schizophrenia: A critical review and meta-analysis. Am J Psychiatry 2005;

162:1785-1804

38. Rabinowitz J, Lichtenberg P, Kaplan Z et al. Rehospitalization rates of chronically ill

schizophrenic patients discharged on a regimen of risperidone, olanzapine, or

conventional antipsychotics. Am J Psychiatry. 2001; 158:266-9.

39. Ramstack J, Grandolfi G, D'Hoore P et al. Risperdal Consta: prolonged-release

injectable delivery of risperidone using Medisorb microsphere technology. Paper

presented at Ninth International Congress on Schizophrenia Research. Colorado

Springs, CO; 2003.


102

40. Shepherd M et al. ‘The natural history of schizophrenia: a five-year follow-up study of

outcome and prediction in a representative sample of schizophrenics’. Psychol Med

Monogr Suppl 1989;15:1-46

41. Turner M, Eerdekens M, Jacko M. Long-acting injectable risperidone: safety and

efficacy in patients switched from conventional depot antipsychotics. Schizophr Res.

2003; 60(suppl 1):305.

42. Urioste R, Bossie CA, Gharabani G et al. Suboptimal pharmacotherapy and partial

compliance: barriers to continued improvement. Paper presented at American

Psychiatric Association Meeting. San Francisco, CA; 2003 May 17-22.

43. Weiden P, Aquila R, Standard J. Atypical antipsychotic drugs and long-term out-come

in schizophrenia. J Clin Psychiatry. 1996; 57:53-60.


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NEUROBIOLOGICAL ARGUMENTS FOR A DEGENERATIVE MODEL IN SCHIZOPHRENIA Dragos Marinescu1, Tudor Udristoiu1, Ion Udristoiu1, Ileana Marinescu2

1University of Medicine and Pharmacy Craiova, Romania 2University Clinic of Psychiatry Craiova, Romania

Abstract The cognitive dysfunction and structural alterations in the cortical and subcortical areas of the brain, as well as schizophrenia-like symptoms that appear in the course of neurodegenerative disorders, such as Alzheimer’s, Parkinson or Huntington diseases raise the question of possible etiopathogenic relationships between schizophrenia and neurodegenerative diseases. Based on different types of vulnerability, we try to elaborate a comparison between the two categories of disorders, leading to a model that could facilitate the development of primary and secondary prophylactic strategies and a individualized, neuroprotective therapeutic approach, based on the neurobiological submodel. Keywords: schizophrenia, neurodegenerative disorders.

Several arguments that involve symptoms of schizophrenia such as cognitive dysfunction,

progressive structural alterations of the cortical and subcortical areas, “schizophrenia-like” psychotic

features in neurodegenerative disorders – dementia in Alzheimer’s, Parkinson or Huntington diseases

bring once more into discussion the neurodegenerative elements in schizophrenia.

The involvement of neurodegenerative elements is sustained by at least two different

sources of cerebral vulnerability, thus suggesting separate neurobiological models. The first source

does not show structural alterations and is correlated with a short prodromal symptomatology

without cognitive dysfunction, while during the active phase the positive symptoms are prominent

(non-microlesional source). The other source associates frequently neurostructural changes,

especially in thalamic, hippocampal and prefrontal areas, which are significantly correlated with

toxic and traumatic aggressions during the intra-, peri- and postnatal periods (neurodevelopment

abnormalities). The prodromal phase is long (more than 5 years) and the active phase is dominated

by the cognitive, negative and depressive symptoms (microlesional source).

The structural microlesions represent the first trigger of the neurodegenerative potential, being

similar to the notions of “minimal brain dysfunction” or “minimal brain damage”. Their impact in the

1 Correspondence: Dragos Marinescu, University Clinic of Psychiatry, 24 Aleea Potelu 200331. e-mail: [email protected]; tel. +40 251 426161.

Dragos Marinescu et al.

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etiopathogeny of schizophrenia has raised proportionally with the neurobiological investigation

techniques and was associated with birth trauma and metabolic or hypoxic alterations in the perinatal

period. They constitute the first neurobiological model – the microlesional model (Figure 1).

Fig. 1. Cerebral abnormalities in first episode of schizophrenia. (adapted after Okubo, 2001)

Frequent neurological “soft signs” were identified for this model. Their existence, combined

with minimal prodromal symptoms, represents a high risk for schizophrenia in child and adolescent

(Erlenmeyer-Kimling & Cornblatt, 1987, Leask, Done & Crow, 2002). Adding to these cases

structural abnormalities of the anterior cingulate cortex may transform into an ”ultra high risk”

factor for the development of psychotic symptoms (Yucel, 2003).

Longitudinal studies regarding the evolution of patients with schizophrenia have shown that

structural abnormalities progress together with the cognitive decline and the amplification of

negative symptoms even in the absence of microlesional sources. This is a characteristic of

schizophrenia that sustains the neurodegenerative model (Figure 2).

The progression of schizophrenia depends on the level of neuroprotection and intersynaptic

connectivity, both between dopaminergic neurons and between their junctions with other

neurotransmission systems. Protecting the functional structures represents an important objective in

elaborating the therapeutic strategy.

The appearance of the disconnective model may be primary – correlated with the

microlesional vulnerability source – or secondary – through neurobiochemical alterations of

regulation following disturbances in neurotransmission. Since there is a genetic predisposition similar

to the neurodevelopment abnormalities, the early onset may constitute an indicator of the genetic

Neurobiological Arguments for the Degenerative Model in Schizophrenia

105

disconnective vulnerability and could also explain the rapid progression of neuronal loss (Figure 3).

This may bring another argument in the favor of the neurodegenerative model in schizophrenia.

Fig. 2. Comparison of ventricular enlargement volume changes for 10 years between a patient with schizophrenia and a control (adapted after Okubo, 2001).

Fig. 3. Average rates of grey matter loss in normal adolescents and in schizophrenia (adapted after Thompson, 2001)

The neurodegenerative elements in the Alzheimer’s disease determine an almost similar

progression compared with the control (Figure 4).


106

Fig. 4. Average grey matter loss rates in healthy aging (a, b, c, d) and AD (e, f, g, h) (adapted after Thompson, 2003)

The neurobiochemical vulnerability is potentiated by the genetic vulnerability that is

correlated with the decrease in the capacity of neurotransmitters synthesis in the presynaptic pole.

This dysfunction is revealed by presynaptic genetic markers (COMT, DBH and MAO). The pre-

and post-synaptic vulnerability for dopamine triggers glutamate activatory mechanisms, which

determine glutamatergic hyperactivity that is a crossing point between schizophrenia and

neurodegenerative disorders.

Fig. 5. Neurobiological consequences of increased glutamatergic neurotransmission in schizophrenia

The primary deficit in dopamine is corrected by an exaggerated activity of glutamate, which

first becomes excito-toxic with multiple secondary activations in the different neurotransmission

systems. Thus, the initial hypodopaminergy is replaced with a hyperdopaminergic-like activity with

polymorphic psychotic symptoms with neurotoxic risk. The increased glutamatergic activity

reduces the GABA protection in the neuronal membranes, raising the excitability, altering the intra-

and extracellular balance, the mitochondrial activity and the oxidative mechanisms. The result is the


107

appearance of the oxidative stress and the triggering of apoptotic mechanisms, common both for

schizophrenia and neurodegenerative disorders. For both types of disorders, the clinical

consequences may be frequent psychotic manifestations, while the neurobiological effect is the

progression of atrophy in the white and grey matter.

Fig. 6. Progressive reduction of grey matter in schizophrenia is proportional with the duration

of disorder and the number of relapses (after Kahn, 2006)

The reduction in dopamine activity following antipsychotic medication may be determined

by the intense blockade of D2 receptors, generating extrapiramidal effects that are markers of

disconnectivity and neurodegenerescence in schizophrenia.

Moreover, beside the hipodopaminergy a hiperglutamatergy, the decrease in the cholinergic

activity and the cholinergic blockade appear to be a common model for schizophrenia and

Alzheimer’s disease, based on the following arguments:

The behavioural, non-cognitive or hallucinatory symptoms in the history of Alzheimer’s

disease could be controlled with cholinergic-like medication of glutamate modulators.

Dopamine is proven to play an important role in the cognitive process

Hipodopaminergy is correlated with the extrapiramidal induced symptoms

As a conclusion, the acceptance of a neurodegenerative model in the etiopathogeny of

schizophrenia would facilitate the development of primary and secondary prophylactic strategies and

an individualized, neuroprotective therapeutic approach, based on the neurobiological submodel.

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References

1. Carlsson, A., Lecrubier, Y., 2004 – Progress in dopamine research in schizophrenia. A

guide for physicians, Taylor & Francis Group, London.

2. Carter, C., McDonald, A., Ross, L., Stenger, V.A., 2001 – Anterior cingulate cortex

activity and impaired self-monitoring of performance in patients with schizophrenia: an

event-related fMRI study. Am. J. Psych.; 158:1423-1428

3. Csemansky, J. Q., Bardgett, M.E., 1998 – Limbic-Cortical Neuronal Damage and the

Pathophysiology of Schizophrenia, Sch. Bul., 24(2):231-248.

4. Cummings, J.L., Benson, D.F., 1992 – Dementia: a clinical approach. 2nd Edition,

Butter Worths, London.

5. Cummings, J.L., Saloway, S., 1997 – The limbic system: An anatomic phylogenetic and

clinical perspective. Journal Neurology, Psychiatry and Clinical Neurosch.,; 9:315-350

6. Erlenmeyer-Kimling, L., Cornblatt, B., 1987 – The New York high-risk project.

Schizophrenia Bull., 13, 451-462.

7. Heckers, S., 1997 – Neuropathology of schizophrenia: cortex, thalamus, basal ganglia,

and neurotransmiters-specific projection systems. Schizophr. Bull., 23:403-421.

8. Kahn, R., 2006 – Schizophrenia as a progressive brain disorder, Educational

Symposium, Schizophrenia: Future perspective and insight into day to day treatment.

9. Leask, S.J., Done, D.J., Crow, T.J., 2002 – Adult psychosis, common childhood

infections and neurological soft signs in a national birth cohort, BMJ, 181, 387-392.

10. Marinescu, D., Udriştoiu, T., Mogoantă, L., 2006 – The action of antypsychotics on

hippocampus and prefrontal cortex, 19th ECNP Congress, Paris, France, 16-20

september, (poster).

11. Maynard, T.M., Sikich, L., Lieberman, J.A., LaMantia, A.S., 2001 – Neural

development, cell-cell signaling ant the two-hit hypothesis of schizophrenia. Schizophr

Bull, 273:457-476.

12. Nakazono, Y., Abe, H., Murakami, H., Koyabu, N., Isaka, Y., Nemoto, Y., Murata, S.,

Tsutsumi, Y., Ohtani, H., Sawada, Y., 2005 – Association between neuroleptic drug-

induced extrapyramidal symptoms and dopamine D2-receptor polymorphisms in

Japanese schizophrenic patients. Int. J. Clin. Pharmacol. Ther., 43(4), 163-71.

13. Perry, E., Lee, M., et al., 2001 – Cholinergic activity in autism: abnormalities in the

cerebral cortex and basal forebrain. Am. J. Psych.; 158:1058-1066

14. Pulver, A.E., Brown, C.H., 1992 – Risk factors in schizophrenia. Brit. J. Psychiat.,

160, 65-71.


109

15. Sim, K., DeWitt, I., Ditman, T., Zalesak, M., Greenhouse, I., Goff, D., Weiss, A.P.,

Heckers, S., 2006 – Hippocampal and Parahippocampal Volumes in Schizophrenia: A

Structural MR Study, Schizophrenia Bulletin, vol. 32, no.2, pp. 332-340.

16. Thompson, P. M., Vidal, Ch., Giedd, J.N., Gochman, P., Blumenthal, J., Nicolson, R.,

Toga, A.W., Rapoport, J.L., 2001 – Mapping adolescent brain change reveals dynamic

wave of accelerated gray matter loss in very early-onset schizophrenia, 11650–11655,

PNAS, September 25, vol. 98, no. 20.

17. Thompson, P.M., Hayashi, K.M., de Zubicaray, G., Janke, A.L., Rose, S.E., Semple, S.,

Herman, D., Hong, M.S., Dittmer, S.S. , Doddrell, D.M. , Toga, A.W., 2003 –

Dynamics of Gray Matter Loss in Alzheimer’s Disease The Journal of Neuroscience,

February 1, 23(3):994 –1005.

18. Weinberger, D.L., 1987 – Implications of normal brain development for the pathogenesis

of schizophrenia, Arch Gen Psych, 44:660-669.

19. Yucel, M., Wodd, S.J., Phillips, L.J., Stuart, G.W., Smith, D.J., Yung, A., Velakoulis,

D., McGorry, P.D., Pantelis, C., 2003 – Morphology of the anterior cingulate cortex in

young men at ultra-high risk of developing a psychotic illness, BMJ, 182, 518-524.


110

THE CAMBRIDGE COGNITIVE EXAMINATION (CAMCOG) IN EARLY ASSESSMENT OF POST-STROKE

COGNITIVE IMPAIRMENT Denisa Pirscoveanu1, Cornelia Zaharia1 ,Valerica Tudorica1, Elena Albu2, Diana Stanca1

1University of Medicine and Pharmacy Craiova, Romania 2Clinical Hospital of Neuropsychiatry Craiova, Romania

Abstract Stroke is one of the most common causes of cognitive impairment and dementia. The cognitive assessment of patients with stroke is very important in the early evaluation of the cognitive decline, thus preventing the severe dementia. The objective of our study is to assess the cognitive state in a group of 76 patients with ischemic stroke using the Cambridge Cognitive Examination (CAMCOG). We have also investigated the most affected cognitive domains. The patients in the group were between 72 and 84 years old, with an average educational level of 9 years and no aphasia. For comparison, a control group of 90 subjects was used, having the same range of educational level and age. Three assessments were done: at the beginning of the study, after 3 months and after 6 months. For the statistical analysis, the Student test (p<0,05) was used. The CT scan examination was performed in all patients. The patients with ischemic stroke have shown higher cognitive impairment than the control group and the cognitive decline increased after 6 months compared to baseline. Also, patients with ischemic stroke in left carotid territory have shown a higher cognitive decline compared with patients with ischemic stroke in right carotid territory or vertebro-basilar territory. The most affected cognitive domains were the memory, the praxis and the orientation. Key words: cognitive decline, ischemic stroke, CAMCOG.

Introduction

Stroke is one of the most common causes of cognitive impairment and dementia. The

cognitive decline installed after stroke is named "vascular cognitive impairment". It appears due to

a complex interaction between vascular factors, the risk factors of stroke and neuronal damage of

the brain. . The cognitive assessment of patients with stroke is very important in the early evaluation

of the cognitive decline, thus preventing the severe dementia.

1 Correspondence: Denisa Pirscoveanu, Clinical Hospital of Neuropsychiatry, 149 Calea Bucuresti. e-mail: [email protected]; tel.: +40 744541398

The Cambridge Cognitive Examination (CAMCOG) in Early Assessment of Post-Stroke Cognitive Impairment

111

Objective

The main aim of our study was to follow-up the cognitive performances of the patients who

suffered an ischemic stroke, using CAMCOG. This scale assesses a wide area of cognitive domains,

therefore we study which cognitive functions are the most impaired.

Material and methods

We studied a group composed of 76 patients aged between 72 and 84 years, and the mean

level of education of 9,3±2,12 years. The patients were admitted to The Clinic of Neurology

Craiova during 2007 year, for first ever ischemic stroke. We also studied a group composed of 90

control subjects without clinical signs of cerebro-vascular disease, with the same age and the same

range of the educational level. 35 patients had an ischemic stroke in the left carotid artery territory,

30 in the right carotid artery territory and 11 of the patients in the vertebro-basilar territory. The

diagnosis was confirmed by the CT scan examination. In all control subjects the brain computed

tomography scans were normal. Data on conventional vascular risk factors were recorded for all the

study subjects including arterial hypertension, diabetes mellitus, atrial fibrillation, dyslipidemia and

smoking. Upon giving an informative consent, both groups (patients and controls) were tested using

CAMCOG. It forms a part of a standardized psychiatric assessment schedule, CAMDEX

(Cambridge Examination for Mental Disorders of the Elderly), devised by Roth and colleagues and

published by Cambridge University Press. CAMCOG assess a wide range of cognitive domains

such as attention, memory, abstraction, language, praxis, orientation and perception. The maximum

overall score is 105. A cut-off of 80 was found to discriminate between demented and normal

subjects. Our evaluations were made in the beginning of the study (baseline), then 3 months and

respectively 6 months later. We compared the results obtained in the patients group with those from

control group and we have also followed-up which are the most impaired cognitive functions

assessed by CAMCOG. Then, we estimated the cognitive performances related to the vascular

territory of stroke. The results were analyzed by Student test (p<0,05).

Results

At baseline, mean CAMCOG score in the patient group was 92,5 points and for the control

group 94,2 points. After 3 months, the patients stroke showed a mean CAMCOG score of 88,4

points and the control group 92,2 points. Six months later, in the patients group we obtained a mean

score of 83,5 points and in control group 90,1 points. The cognitive assessment related to the

vascular territory showed the next mean CAMCOG values: the patients with ischemic stroke in the

left carotid artery territory had at baseline a mean score of 90,1, after 3 months 86,8 points and at

the end of the study 81,1 points. The patients with ischemic stroke in the right carotid artery

territory had at baseline 92,8 points, after 3 months 90,8 points and 6 months later 88,7 points. In

Denisa Pirscoveanu et al.

112

the group of patients with stroke in the vertebro-basilar territory we obtained the next mean scores:

at baseline 94,6 points, after 3 months 92,5 points and after 6 months 90,7 points. The statistical

analysis regarding the most affected cognitive domains is represented on Table I.

Table I. The cognitive domains impaired in the patients and control group,

using CAMCOG evaluation

Cognitive domain impaired Patients group (N=76) n% Control group ( N=90) n% Abstract thinking 41 ( 53,94 %) 31 (34,44 %) Orientation 61 (80,26 %) 70 (77,77%) Language 37 (48,68 %) 49 (54,44%) Memory 68 (89,47%) 79 (87,77%) Attention and calculation 37 (48,68 %) 42 (46,66%) Praxis 57 ( 75%) 68 (75,55%) Perception 33 (43,42%) 28 (31,11%)

Conclusion and discussions

Given the increased number of elderly population, dementia of any type represents a

common illness today, and efforts are made to enable early diagnosis and treatment as soon as

possible. The studies of neuro-epidemiology suggested that the vascular factor is very important for

starting and progression of dementia. As vascular pathology appears to be a common characteristic

of both vascular dementia and Alzheimer disease, the early diagnosis of mild cognitive impairment

must play an important role. This is one of the reasons to study the vascular cognitive decline.

Using CAMCOG for the cognitive assessment, we observed that the stroke patients group

showed a higher cognitive decline than control group, both after 3 and 6 months (Fig. no. 1).

78

80

82

84

86

88

90

92

94

96

Mea

n C

AM

CO

G s

core

Baseline 3 months 6 months

Fig. no. 1. Mean CAMCOG score in patients group and control groupat baseline, at 3 months and 6 months later

Patients group

Control group

Our study in dynamics show that in the patients group there are not considerable

statistically differences between cognitive state at baseline and 3 months later. After 6 months of

The Cambridge Cognitive Examination (CAMCOG) in Early Assessment of Post-Stroke Cognitive Impairment

113

study we observed a considerable cognitive impairment in the patients group (p <0,05) , therefore

our conclusion is that a considerable cognitive decline appears in the evolution of the patients

with ischemic stroke. Regarding the relationship between the vascular artery territory and the

range of the cognitive decline , our data shows a higher cognitive impairment in patients with

ischemic stroke in the left carotid territory than in those patients with ischemic stroke in the right

carotid territory and vertebrobasilar territory (Fig. no. 2).

70

75

80

85

90

95

Mea

n C

AM

CO

G s

core

Baseline 3 months 6 months

Fig. no. 2. Mean score CAMCOG relatedto the vascular territory of ischemic stroke

Left carotid territory

Right carotid territory

Vertebrobasilar territory

As CAMCOG assess a wide area of cognitive domains, it gives the opportunity to observe

which cognitive functions are the most affected in patients with ischemic stroke compared with

those in the control group during the 6 months of study. The results pointed to the orientation,

praxis and memory (Fig. no. 3 and 4).

Fig. no. 3. The impaired cognitive domains in patients group

53,94

48,68

89,47

48,68

75

43,42

80,26

Abstract thinking

Orientation

Language

Memory

Attention/calcul

Praxis

Perception

Denisa Pirscoveanu et al.

114

Fig. no. 4. The impaired cognitive domains in control group

34,44

77,77

54,44

87,77

46,66

75,55

31,11

Abstract thinking

Orientation

Language

Memory

Attention/calcul

Praxis

Perception

Our results are in concordance with other studies that demonstrated CAMCOG as a very

useful tool in the assessment of cognitive decline. Using CAMCOG scale may offer an early detection

of the cognitive impairment, thus preventing or slowing the progression to severe dementia.

References

1. Bowler JV, Hachinski V, 1995 – Vascular cognitive impairment: A new approach to

vascular dementia Baillieres. Clin Neurol 4:357-376.

2. De Carli C, 2004 – Vascular factors in dementia: An overview. J Neurol Sci 226:19-23.

3. Hodges J., 2007 – Cognitive Assessment for Clinicians: Oxford University Press, 152-

155

4. O`Brien JT, Erkinjuntti T, Reisberg B, et al, 2003 – Vascular cognitive impairment.

Lancet Neurology 2:89-98.

5. Skoog I, Gustafson D., 2003 – Vascular disorders and Alzheimer Disease In: Bowler

JW,Hachinski V, eds. Vascular cognitive impairment: preventable dementia, New York:

Oxford University Press, 261-276.

6. Tatemichi TK, Desmond DW, Stern Y et al., 1994 – Cognitive impairment after stroke:

frequency, patterns and relationship to functional abilities: Journal of Neurology,

Neurosurgery and Psychiatry, 57:202-207.

Romanian Journal of Psychopharmacology (2009) Vol. 9, No. 2

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