Utilization of olanzapine and risperidone in Hungary with special concern to the treatment of schizophrenia in the

psychiatric rehabilitation

Ph.D. Thesis

András Klebovich

Semmelweis University Doctoral School of Pharmaceutical and Pharmacological Sciences

Supervisor: Dr. Romána Zelkó, D.Sc.

Head of examining committee: Dr. Sándor Kerpel-Fronius, D.Sc. Examinig committee: Dr. Kornélia Tekes, Ph.D. Dr. Gábor Simon Kis, Ph.D.

Budapest 2008

2

CONTENTS

Összefoglalás 5

Summary 6

Abbreviations 7

List of Figures and Tables 8

A INTRODUCTION 9

B OBJECTIVES 11

C LITERATURE REVIEW 12

C.1 Aetiology and pathogenesis of schizophrenia 12

C.1.1 Genetic and environmental factors 12

C.1.2 Epidemiology 12

C.1.3 Causes 14

C.1.4 Genetic causes 14

C.1.5 Prenatal causes 15

C.1.6 Social causes 15

C.1.7 Substance use 15

C.1.8 Psychological causes 16

C.1.9 Neural causes 17

C.1.10 Neurochemical theories 18

C.1.11 Dopamine theory 19

C.1.12 Glutamate theory 19

C.1.13 Other theories 20

C.1.14 Summary of cause theories 20

C.2 The nature of schizophrenia 20

C.3 Diagnosis of schizophrenia 21

C.3.1 DSM IV-TR criteria 21

C.3.2 Subtypes 22

C.4 Treatment of schizophrenia 23

C.4.1 Medication 24

C.4.2 Psychological and social interventions 25

3

C.5 Screening and prevention 26

C.6 Psychiatric rehabilitation 26

C.7 Antipsychotic drugs 27

C.7.1 Terminology 27

C.7.2 Classification of antipsychotic drugs 28

C.7.3 General properties 29

C.7.4 Mechanism of action 29

C.7.5 Drug action 31

C.7.6 Pharmacological effects 32

C.7.6.1 Behavioural effects 32

C.7.6.2 Unwanted effects 33

C.7.6.2.1 Extrapyramidal motor disturbances and tardive dyskinesia 33

C.7.6.2.2 Acute dystonias 34

C.7.6.2.3 Tardive dyskinesia 34

C.7.6.2.4 Endocrine effects 36

C.7.6.2.5 Other unwanted effects 36

C.7.6.2.6 Pharmacokinetic aspects 38

C.7.6.2.7 Clinical use and clinical efficacy of typical and atypical

antipsychotic drugs 38

C.7.7 Application of typical agents 39

C.7.7.1 Side effects of typical antipsychotics 40

C.7.7.2 Typical antipsychotics (trade names appear in parentheses) 41

C.7.8 Application of atypical agents 42

C.7.8.1 Pharmacology of the atypicals 43

C.7.8.2 Side effects of atypical antipsychotics 44

C.7.8.3 Tardive Dyskinesia 44

C.7.8.4 Metabolic side effects with atypical antipsychotics 44

C.7.8.5 Atypical antipsychotics 45

C.7.9 Antipsychotics in Hungary 46

C.7.10 Typical versus atypical 47

C.7.11 Schizophrenia and diabetes mellitus 48

C.7.11.1 Antipsychotic treatment and diabetes mellitus 49

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D EXPERIMENTAL PART 51

D.1 Study design and methods 51

D.1.1 Utilization study of olanzapine and risperidone in psychiatric

rehabilitation within 1999-2007 51

D.1.2 Utilization study of clozapine, olanzapine and risperidone

in Hungary 52

D.1.3 Sample selection for the study of the diabetes prevalence

among elderly patients in psychiatric rehabilitation 52

D.1.3.1. Hypothesis testing 55

E RESULTS 56

E.1. Utilization study of olanzapine and risperidone

in psychiatric rehabilitation within 1999-2007

in comparison with the country data 56

E.1.1. Utilization study of clozapine, olanzapine and risperidone 61

E.2. Diabetes prevalence among elderly patients in psychiatric

rehabilitation 63

F DISCUSSION

F.1. Evaluation of the results of the utilization study of olanzapine

and risperidone 65

F.2. Evaluation of the diabetes prevalence among elderly patients in

psychiatric rehabilitation 66

G NEW SCIENTIFIC RESULTS AND CONCLUSIONS 67

REFERENCES 69

ACKNOWLEDGEMENTS 84

PUBLICATIONS AND LECTURES 85

OFFPRINTS OF THE PUBLICATIONS 87

5

Összefoglalás

Olanzapin és riszperidon utilizációs vizsgálata Magyarországon különös tekintettel a szkizofrénia kezelésére a pszichiátriai rehabilitációban

Mivel az olanzapin és a riszperidon hasonló hatékonysággal és tolerálhatósággal

rendelkezik és a szkizofrénia kezelésében ez a két hatóanyag a leggyakrabban rendelt

atípusos antipszichotikum Magyarországon, ezért utilizációs vizsgálatukkal meghatározó

következtetések nyerhetők. A vizsgálat célkitűzése az olanzapin és riszperidon

használatának vizsgálata volt Magyarországon és a gerontopszichiátriai profilú Gálfi Béla

Gyógyító és Rehabilitációs Kht. Szakkórházában. Az adagolás és a gyógyszerrendelési

preferenciák meghatározásához az adatokat a Gálfi Béla Szakkórház kórlapjainak

elemzésével gyűjtöttük az 1999 és 2007 közötti időszakban. Az utilizációs vizsgálat

eredményeként megállapítható volt, hogy a teljes vizsgált időszakra növekvő felhasználás

jellemző, bár jelentős növekedés csak 2001-től volt megfigyelhető. A kórlapok elemzése

rámutatott, hogy mindkét hatóanyag felhasználása növekvő trend dominanciát mutat,

ugyanakkor a riszperidon felhasználása gyorsabban növekszik, amit a Gálfi Béla

Szakkórház gerontopszichiátriai profilja magyaráz.

Vizsgálataim további célja volt a diabétesz kockázatának összehasonlítása az atípusos

antipszichotikummal kezelt szkizofrén betegpopuláció és a nem-szkizofrén magyar

populáció között, nem és életkor szerinti megoszlás figyelembevételével. A szkizofrén

betegpopulációt a Gálfi Béla Gyógyító és Rehabilitációs Kht. Szakkórházában kórlapok

elemzésével vizsgáltuk. Az országos gyógyszerfelhasználási adatok az Országos

Egészségbiztosítási Pénztár nyilvántartásából származtak, míg a magyar populáció

diabétesz prevalencia adatait a Központi Statisztikai Hivataltól kaptuk a 2000-2006

időszakra vonatkozóan. A hipotézis vizsgálat binomiális disztribúcióval történt. A vizsgálat

magasabb diabétesz előfordulást mutat szkizofrén betegek között (12,72%) mindkét nem

esetében, mint a magyar populáció egészében (6,85%) a 18-64 éves korosztályban, míg a

65 év feletti populációban nem volt magasabb a diabétesz előfordulásának kockázata. Az

eredményeim alapján megállapítható, hogy az atípusos antipszichotikummal kezelt betegek

esetében folyamatos testsúly, vércukor és lipidszint monitorozás indokolt minden

korcsoportban, mégha a vizsgálat idős betegeknél nem is mutatott nagyobb diabétesz

kialakulási kockázatot.

6

Summary

Because olanzapine and risperidone have similar efficacy and tolerability in the treatment

of schizophrenia and these two agents are the most widely used atypical antipsychotics in

Hungary, the utilisation of the drugs is a relevant consideration. The purpose of this study

was to follow the utilisation trend of olanzapine and risperidone in Hungary and in the

Gálfi Béla Hospital, which is a specialised institute on psychiatric rehabilitation. Data

regarding dosages and psychiatrists' clinical preferences were collected through studying

hospital charts in the Gálfi Béla Hospital during the period 1999-2007. Utilisation of the

agents indicated that there was an increase of use for the whole examined period in the

Gálfi Béla Hospital, although unambiguous growth began only in 2001. Hospital chart

analysis shows that both drugs were used to a large extent and risperidone use is increasing

more rapidly, which is justified by the gerontopsychiatric profile of the hospital.

The further aim of the study was to compare the risk of diabetes in a Hungarian

schizophrenic population treated with atypical antipsychotics with that of the non-

schizophrenic population. We wished to reveal the effects of gender and age. A

schizophrenic population was examined by studying hospital charts in the Gálfi Béla

Hospital. Data were given by the National Health Insurance Fund registry in the period of

2000-2006, while the Hungarian Central Statistical Office presented data on the prevalence

of diabetes in the Hungarian population. Binomial distribution was used for the hypothesis

testing. The examination shows higher prevalence of diabetes among schizophrenic

patients (12.72%) in comparison with the Hungarian population (6.85%) in the age group

of 18-64 among both sexes, while there was no higher risk of diabetes found in the age

group of above 65 among both sexes. As a conclusion, we emphasize that continuous

weight, glucose and lipid level monitoring should be considered during treatment with

antipsychotics in all age groups, even if our study does not show higher risk of diabetes

among elderly schizophrenic patients.

The results of my investigations did not show higher risk of diabetes among elderly

schizophrenic patients treated with atypical antipsychotics, while continuous weight,

glucose and lipid level monitoring should be indicated during treatment with antipsychotics

in other age groups.

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Abbreviations

5-HT Serotonin receptors (5-hydroxytryptamine)

ATC Anathomic Therapeutic Chemical

CATIE Clinical Antipsychotic Trials of Intervention Effectiveness

CBT Cognitive Behavioural Therapy

Cl clearance

D- Dopamine receptors

DDD Defined Daily Dose

DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders Fourth Edition

Text Revision

EPS Extrapyramidal Syndrome

FDA Food and Drug Administration

fMRI Functional Magnetic Resonance Imaging

ICD-10 International Classification of Diseases 10th Edition

MRI Magnetic Resonance Imaging

NMDA N-methyl-D-asparate

NMS Neuroleptic Malignant Syndrome

OLA Olanzapine

PANSS Positive and Negative Syndrome Scale

PDD Prescribed Daily Dose

PET Positron Emission Tomography

RIS Risperidone

t½ Plasma half-life

TD Tardive Dyskinesia

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List of Figures and Tables

Figure 1 PET image of brain in a patient diagnosed with schizophrenia

Figure 2 Antipsychotics in Hungary

Figure 3 The use of olanzapine and risperidone (DDD/100 beds/day) in the

examined period in the Gálfi Béla Hospital

Figure 4 The use of olanzapine and risperidone (DDD/1000 persons/day)

in the examined period in Hungary

Figure 5 The use of olanzapine, risperidone and clozapine (DDD/100 beds/day)

in the Gálfi Béla Hospital

Figure 6 The use of olanzapine, risperidone and clozapine (DDD/1000 persons/day)

in Hungary

Table 1 Mean ± S.D. daily dosages (mg/day) of olanzapine and risperidone

in the Gálfi Béla Hospital

Table 2 Number of hospital charts in the most prevalent schizophrenic

disorders and the number of charts with olanzapine (OLA) or

risperidone (RIS) treatment in the Gálfi Béla Hospital

Table 3 Diabetes average prevalence in Hungary in all age groups within 2000-2006

and in the examined patient population treated with antipsychotics

Table 4 Results of the hypothesis testing at a 5% of significance level

9

A INTRODUCTION

Schizophrenia affects about 1% of the population. It is one of the most important forms

of psychiatric illness, because it affects young people, is often chronic and usually

highly disabling. There is a strong hereditary factor in its aetiology, and evidence

suggestive of a fundamental biological disorder. The main clinical features of the disease

are:

• Positive symptomps:

o Delusions (often paranoid in nature)

o Hallucinations, usually in the form of voices, and often exhortatory in

their message

o Thought disorder, comprising wild trains of thought, garbled sentences

and irrational conclusions, sometimes associated with the feeling that

thoughts are inserted or withdrawn by an outside agency.

o Abnormal behaviours, such as stereotyped or occasionally aggressive

behaviours.

• Negative symptomps:

o Withdrawal from social contacts

o Flattening of emotional responses.

In addition, deficits in cognitive function (e.g. attention, memory) are often present,

together with anxiety and depression, leading to suicide in 10% of cases. The clinical

phenotype varies greatly, particularly with respect to balance between negative and

positive symptoms, and this may have a bearing on the efficacy of antipsychotic drugs in

individual cases.

A characteristic feature of schizophrenia is a defect in ‘selective attention’. The ability of

schizophrenic patients to discriminate between significant and insignificant stimuli

seems to be impaired. ‘Latent inhibition’ is a form of behavioural testing in animals that

can be used as a model for this type of sensory habituation. Latent inhibition is a

measure of the inhibitory effect of pre-exposure to the conditioned stimulus on

acquisition of the conditioned response.

10

Schizophrenia often begins in adolescence or young adult life; it can follow a relapsing

or remitting course, or be chronic and progressive, particularly in cases with a later

onset. Chronic schizophrenia used to account for most of the patients in long-stay

psychiatric hospitals [1].

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B OBJECTIVES

Data showed that in accordance with the latest professional guidelines the use of novel

antipsychotics is increasing. Based on analysis of the antipsychotic use in clinical

practices there were characteristic patterns found that show that the conventional

antipsychotic use is still notable.

Because olanzapine and risperidone have similar efficacy and tolerability in the

treatment of schizophrenia and these two agents are the most widely used atypical

antipsychotics in Hungary the utilization of the drugs becomes a relevant consideration.

The purposes of the thesis were the followings:

1. To study retrospectively the use of olanzapine and risperidone between

1999 and 2007 and to have a clear view on their utilization with respect

to the gerontopsychiatric profile of the Gálfi Béla Hospital which is a

specialised institute on psychiatric rehabilitation,

2. To follow the temporal development trends of use of olanzapine and

risperidone in Hungary between 1999 and 2007,

3. To study the relationship between the antipsychotic treatment and the

prevalence of diabetes among elderly patients in psychiatric

rehabilitation.

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C LITERATURE REVIEW

C.1 Aetiology and pathogenesis of schizophrenia

C.1.1 Genetic and environmental factors

The cause of schizophrenia remains unclear, but it involves a combination of genetic and

environmental factors. The disease shows, a strong, but incomplete hereditary tendency.

In first-degree relatives, the risk is about 10%; even in monozygotic twins, one of whom

has schizophrenia, the probability of the other being affected is only about 50%. Genetic

linkage studies aimed at identifying schizophrenia susceptibility genes have identified

likely chromosomes, but not yet any specific genes. Some environmental influences

early in development have been identified as possible predisposing factors, including

maternal virus infections and high blood pressure during pregnancy. This and other

evidence suggests that schizophrenia is associated with a neurodevelopment disorder,

affecting mainly the cerebral cortex, and occurring in the first few months of prenatal

development. This view is supported by brain imaging studies showing cortical atrophy,

with enlargement of the cerebral ventricles. These structural changes are present in

schizophrenic patients presenting for the first time and are probably not progressive,

suggesting that they represent an early irreversible aberration in brain development

rather than a gradual neurodegeneration. Studies of post-mortem schizophrenic brains

show evidence of misplaced cortical neurons with abnormal morphology. Psychological

factors, such as stress, may precipitate acute episodes but are not underlying cause [1,2].

C.1.2 Epidemiology

Schizophrenia occurs equally in males and females although typically appears earlier in

men with the peak ages of onset being 20–28 years for males and 26–32 years for

13

females [1,3]. Much rarer are instances of childhood-onset and late- (middle age) or

very-late-onset (old age) schizophrenia [4,5]. The lifetime prevalence of schizophrenia,

that is, the proportion of individuals expected to experience the disease at any time in

their lives, is commonly given at 1%. A 2002 systematic review of many studies,

however, found a lifetime prevalence of 0.55% [6]. Despite the received wisdom that

schizophrenia occurs at similar rates throughout the world, its prevalence varies across

the world, within countries, and at the local and neighbourhood level [7-9]. One

particularly stable and replicable finding has been the association between living in an

urban environment and schizophrenia diagnosis, even after factors such as drug use,

ethnic group and size of social group has been controlled for [10]. Schizophrenia is

known to be a major cause of disability. In a 1999 study of 14 countries, active

psychosis was ranked the third-most-disabling condition, after quadriplegia and

dementia and before paraplegia and blindness [11].

Sex differences in schizophrenia can be caused by the disease process itself, by genetic

and hormonal differences, by differences in the maturation and morphology of the brain

and in age- and gender-specific behavioural patterns.

Symptomatology, lifetime risk and symptom-related course of illness—the latter without

consideration of age—show no gender differences. However, until menopause illness

onset is delayed and severity of illness is reduced by oestrogen on the level of gene

expression and transmitter functioning. Oestrogen has an antagonistic effect on the—

familial or exogenous—predisposition to illness. As a result, the age distribution of onset

and the severity of first-episode illness in young men and post-menopausal women differ

from the normal. First intervention trials with oestrogen substitution of neuroleptic

therapy have demonstrated antipsychotic effects.

The poorer social course of schizophrenia in men than in premenopausal women is

accounted for by men’s lower level of social development at illness onset and the

subsequent impediment of their further development. Men’s socially adverse illness

behaviour, too, is a contributing factor. Scarcity of the knowledge of differences in the

development, morphology and functioning of the male and female brain does not yet

allow any definitive conclusions about gender differences in schizophrenia [12,13].

14

C.1.3 Causes

Data from a PET study suggests that the less the frontal lobes are activated during a

working memory task, the greater the increase in abnormal dopamine activity in the

striatum, thought to be related to the neurocognitive deficits in schizophrenia [14].

While the reliability of the diagnosis introduces difficulties in measuring the relative

effect of genes and environment (for example, symptoms overlap to some extent with

severe bipolar disorder or major depression), evidence suggests that genetic and

environmental factors can act in combination to result in schizophrenia [15]. Evidence

suggests that the diagnosis of schizophrenia has a significant heritable component but

that onset is significantly influenced by environmental factors or stressors [16]. The idea

of an inherent vulnerability (or diathesis) in some people, which can be unmasked by

biological, psychological or environmental stressors, is known as the stress-diathesis

model [17]. The idea that biological, psychological and social factors are all important is

known as the "biopsychosocial" model.

C.1.4 Genetic causes

Estimates of the heritability of schizophrenia tend to vary owing to the difficulty of

separating the effects of genetics and the environment although twin studies have

suggested a high level of heritability [18]. It is likely that schizophrenia is a condition of

complex inheritance, with several genes possibly interacting to generate risk for

schizophrenia or the separate components that can co-occur leading to a diagnosis [19].

Recent work has suggested that genes that raise the risk for developing schizophrenia are

non-specific, and may also raise the risk of developing other psychotic disorders such as

bipolar disorder [20,21].

15

C.1.5 Prenatal causes

It is thought that causal factors can initially come together in early neurodevelopment,

including during pregnancy, to increase the risk of later developing schizophrenia. One

curious finding is that people diagnosed with schizophrenia are more likely to have been

born in winter or spring, (at least in the northern hemisphere) [22]. There is now

evidence that prenatal exposure to infections increases the risk for developing

schizophrenia later in life, providing additional evidence for a link between in utero

developmental pathology and risk of developing the condition [23].

C.1.6 Social causes

Living in an urban environment has been consistently found to be a risk factor for

schizophrenia [24]. Social disadvantage has been found to be a risk factor, including

poverty and migration related to social adversity, racial discrimination, family

dysfunction, unemployment or poor housing conditions [25,26]. Childhood experiences

of abuse or trauma have also been implicated as risk factors for a diagnosis of

schizophrenia later in life [27,28]. Parenting is not held responsible for schizophrenia but

unsupportive dysfunctional relationships may contribute to an increased risk [29,30].

C.1.7 Substance use

The relationship between schizophrenia and drug use is complex, meaning that a clear

causal connection between drug use and schizophrenia has been difficult to tease apart.

There is strong evidence that using certain drugs can trigger either the onset or relapse of

schizophrenia in some people. It may also be the case, however, that people with

schizophrenia use drugs to overcome negative feelings associated with both the

commonly prescribed antipsychotic medication and the condition itself, where negative

emotion, paranoia and anhedonia are all considered to be core features [31].

16

Amphetamines trigger the release of dopamine and excessive dopamine function is

believed to be responsible for many symptoms of schizophrenia (known as the dopamine

hypothesis of schizophrenia), amphetamines may worsen schizophrenia symptoms [32].

Schizophrenia can be triggered by heavy use of hallucinogenic or stimulant drugs [33].

One study suggests that cannabis use can contribute to psychosis, though the researchers

suspected cannabis use was only a small component in a broad range of factors that can

cause psychosis [34].

C.1.8 Psychological causes

A number of psychological mechanisms have been implicated in the development and

maintenance of schizophrenia. Cognitive biases that have been identified in those with a

diagnosis or those at risk, especially when under stress or in confusing situations,

include excessive attention to potential threats, jumping to conclusions, making external

attributions, impaired reasoning about social situations and mental states, difficulty

distinguishing inner speech from speech from an external source, and difficulties with

early visual processing and maintaining concentration [35-38]. Some cognitive features

may reflect global neurocognitive deficits in memory, attention, problem-solving,

executive function or social cognition, while others may be related to particular issues

and experiences [29,39]. Despite a common appearance of "blunted affect", recent

findings indicate that many individuals diagnosed with schizophrenia are highly

emotionally responsive, particularly to stressful or negative stimuli, and that such

sensitivity may cause vulnerability to symptoms or to the disorder [40-42]. Some

evidence suggests that the content of delusional beliefs and psychotic experiences can

reflect emotional causes of the disorder, and that how a person interprets such

experiences can influence symptomology [43-46]. Further evidence for the role of

psychological mechanisms comes from the effects of therapies on symptoms of

schizophrenia [47].

17

C.1.9 Neural causes

Functional magnetic resonance imaging and other brain imaging technologies allow for

the study of differences in brain activity among people diagnosed with schizophrenia.

Studies using neuropsychological tests and brain imaging technologies such as fMRI and

PET to examine functional differences in brain activity have shown that differences

seem to most commonly occur in the frontal lobes, hippocampus, and temporal lobes

[48].

Figure 1 - PET image of brain in a patient diagnosed with schizophrenia [48]

These differences have been linked to the neurocognitive deficits often associated with

schizophrenia [49]. The role of antipsychotic medication, which nearly all those studied

had taken, in causing such abnormalities is also unclear [50].

Particular focus has been placed upon the function of dopamine in the mesolimbic

pathway of the brain. This focus largely resulted from the accidental finding that a drug

group which blocks dopamine function, known as the phenothiazines, could reduce

psychotic symptoms. An influential theory, known as the Dopamine hypothesis of

schizophrenia, proposed that a malfunction involving dopamine pathways was the cause

of (the positive symptoms of) schizophrenia. This theory is now thought to be overly

simplistic as a complete explanation, partly because newer antipsychotic medication

(called atypical antipsychotic medication) can be equally effective as older medication

(called typical antipsychotic medication), but also affects serotonin function and may

have slightly less of a dopamine blocking effect [51].

18

Interest has also focused on the neurotransmitter glutamate and the reduced function of

the NMDA glutamate receptor in schizophrenia. This has largely been suggested by

abnormally low levels of glutamate receptors found in postmortem brains of people

previously diagnosed with schizophrenia and the discovery that the glutamate blocking

drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive

problems associated with the condition [52, 53]. The fact that reduced glutamate

function is linked to poor performance on tests requiring frontal lobe and hippocampal

function and that glutamate can affect dopamine function, all of which have been

implicated in schizophrenia, have suggested an important mediating (and possibly

causal) role of glutamate pathways in schizophrenia [54]. Further support of this theory

has come from preliminary trials suggesting the efficacy of coagonists at the NMDA

receptor complex in reducing some of the positive symptoms of schizophrenia [55].

There have also been findings of differences in the size and structure of certain brain

areas in schizophrenia, starting with the discovery of ventricular enlargement in those

for whom negative symptoms were most prominent [56]. However, this has not proven

particularly reliable on the level of the individual person, with considerable variation

between patients. More recent studies have shown various differences in brain structure

between people with and without diagnoses of schizophrenia [57]. However, as with

earlier studies, many of these differences are only reliably detected when comparing

groups of people, and are unlikely to predict any differences in brain structure of an

individual person with schizophrenia.

C.1.10 Neurochemical theories

Current ideas about neurochemical mechanisms in schizophrenia came from analysing

the effects of antipsychotic and propsychotic drugs – from pharmacology rather than

from neurochemistry. Instead of neurochemical theory providing the basis for rational

drug treatment, the opposite occurred: drugs found by chance to be effective have

provided the main clues about the nature of the disorder. The main neurochemical

19

theories centre on dopamine and glutamate, though other mediators, particularly 5-HT,

are also receiving attention [1].

C.1.11 Dopamine theory

The dopamine theory was proposed by Carlsson – awarded a Nobel prize in 2000 – on

the basis of indirect pharmacological evidence in humans and experimental animals.

Amphetamine releases dopamine in the brain and can produce in humans a behavioural

syndrome indistinguishable from an acute schizophrenic episode. Potent D2-receptor

agonists (e.g. apomorphine and bromocriptine) produce similar effects in animals, and

these drugs, like amphetamine, exacerbate the symptoms of schizophrenic patients.

Furthermore, dopamine antagonists and drugs that block neuronal dopamine storage

(e.g. reserpine) are effective in controlling the positive symptoms of schizophrenia, and

in preventing amphetamine-induced behavioural changes. There is a strong correlation

between clinical antipsychotic potency and activity in blocking D2-receptors, and

receptor imaging studies have shown that clinical efficacy of antipsychotic drugs is

consistently achieved when D2-receptor occupancy reaches about 80% [58].

C.1.12 Glutamate theory

Another transmitter implicated in the pathophysiology of schizophrenia is glutamate.

The glutamate NMDA (N-methyl-D-asparate) receptor agonists such as phencyclidine,

ketamine and dizocilpine produce psychotic symptoms in humans and reduced glutamate

concentrations and glutamate receptor densities have been reported in post-mortem

brains of schizophrenics – one of the few fairly consistent findings [1].

20

C.1.13 Other theories

Other transmitters that may be important include 5-HT and noradrenaline. The idea that

5-HT dysfunction could be involved in schizophrenia was based on the fact that LSD

produces schizophrenia-like symptoms, and this idea has drifted in and out of favour

many times.

Many effective antipsychotic drugs, in addition to blocking dopamine receptors, also act

as 5-HT receptor antagonists. 5-HT has a modulatory effect on dopamine pathways, so

the two theories are not incompatible. Affinity for 5-HT2A-receptors is a feature of many

of the recently developed ‘atypical’ antipsychotic drugs, which produce fewer

extrapyramidal side-effects than earlier dopamine-selective compounds, controversy

exists as to whether the 5-HT2-receptor block contributes to the antipsychotic effect or

merely reduces the undesirable side-effects associated with D2-receptor antagonists

[1,59].

C.1.14 Summary of cause theories

In conclusion the dopamine hyperactivity theory of schizophrenia is supported by

considerable evidence. Though it is undoubtedly an oversimplification, and relates only

to the positive symptoms, it provides the best framework for understanding the action of

antipsychotic drugs, though effects on 5-HT and other receptors may contribute

significantly to the clinical profile of some of the newer drugs [1,60,61].

C.2 The nature of schizophrenia

• Schizophrenia psychotic illness is characterised by delusions, hallucinations and

thought disorder (positive symptoms), together with social withdrawal, flattening of

emotional responses and cognitive impairment (negative symptoms).

21

• Acute episodes (mainly positive symptoms) frequently recur and develop into

chronic schizophrenia, with predominantly negative symptoms.

• Incidence is about 1% of population, with a strong, but not invariable, hereditary

component.

• Pharmacological evidence is generally consistent with dopamine overactivity

hypothesis, supported by biochemical findings and imaging studies.

• There is also evidence for involvement of glutamate and 5-HT.

C.3 Diagnosis of schizophrenia

The most widely used criteria for diagnosing schizophrenia are from the American

Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, the

current version being DSM-IV-TR, and the World Health Organization's International

Statistical Classification of Diseases and Related Health Problems, currently the ICD-10.

The latter criteria are typically used in European countries while the DSM criteria are

used in the USA or the rest of the world, as well as prevailing in research studies.

C.3.1 DSM IV-TR criteria

To be diagnosed with schizophrenia, a person must display [62]:

• Characteristic symptoms: Two or more of the following, each present for a

significant portion of time during a one-month period (or less, if successfully

treated)

o delusions

o hallucinations

o disorganized speech (e.g., frequent derailment or incoherence; speaking

in abstracts). See thought disorder.

o grossly disorganized behaviour (e.g. dressing inappropriately, crying

frequently) or catatonic behaviour

22

o negative symptoms, i.e., affective flattening (lack or decline in emotional

response), alogia (lack or decline in speech), or avolition (lack or decline

in motivation).

Note: Only one of these symptoms is required if delusions are bizarre or hallucinations

consist of hearing one voice participating in a running commentary of the patient's

actions or of hearing two or more voices conversing with each other.

• Social/occupational dysfunction: For a significant portion of the time since the

onset of the disturbance, one or more major areas of functioning such as work,

interpersonal relations, or self-care, are markedly below the level achieved prior

to the onset.

• Duration: Continuous signs of the disturbance persist for at least six months. This

six-month period must include at least one month of symptoms (or less, if

successfully treated).

Additional criteria are also given that exclude the diagnosis; thus schizophrenia cannot

be diagnosed if symptoms of mood disorder or pervasive developmental disorder are

present, or the symptoms are the direct result of a substance (e.g., abuse of a drug,

medication) or a general medical condition.

C.3.2 Subtypes

Historically, schizophrenia in the West was classified into simple, catatonic, hebephrenic

(now known as disorganized), and paranoid. The DSM contains five sub-classifications

of schizophrenia:

• paranoid type: where delusions and hallucinations are present but thought

disorder, disorganized behaviour, and affective flattening are absent (DSM code

295.3/ICD code F20.0)

• disorganized type: named 'hebephrenic schizophrenia' in the ICD. Where thought

disorder and flat affect are present together (DSM code 295.1/ICD code F20.1)

23

• catatonic type: prominent psychomotor disturbances are evident. Symptoms can

include catatonic stupor and waxy flexibility (DSM code 295.2/ICD code F20.2)

• undifferentiated type: psychotic symptoms are present but the criteria for

paranoid, disorganized, or catatonic types have not been met (DSM code

295.9/ICD code F20.3)

• residual type: where positive symptoms are present at a low intensity only (DSM

code 295.6/ICD code F20.5)

The ICD-10 recognises a further two subtypes:

• post-schizophrenic depression: a depressive episode arising in the aftermath of a

schizophrenic illness where some low-level schizophrenic symptoms may still be

present (ICD code F20.4)

• simple schizophrenia: insidious but progressive development of prominent

negative symptoms with no history of psychotic episodes (ICD code F20.6)

C.4 Treatment of schizophrenia

The concept of a cure as such remains controversial, as there is no consensus on the

definition, although some criteria for the remission of symptoms have recently been

suggested [63]. The effectiveness of schizophrenia treatment is often assessed using

standardized methods, one of the most common being the positive and negative

syndrome scale (PANSS) [64]. Management of symptoms and improving function is

thought to be more achievable than a cure. Treatment was revolutionized in the mid

1950s with the development and introduction of chlorpromazine [65]. A recovery model

is increasingly adopted, emphasizing hope, empowerment and social inclusion [66].

Hospitalization may occur with severe episodes of schizophrenia. This can be voluntary

or (if mental health legislation allows it) involuntary (called civil or involuntary

commitment). Long-term inpatient stays are now less common due to

deinstitutionalization, although can still occur [67]. Following a hospital admission,

support services available can include drop-in centers, visits from members of a

24

community mental health team or Assertive Community Treatment team, supported

employment and patient-led support groups [68].

In many non-Western societies, schizophrenia may only be treated with more informal,

community-led methods. The outcome for people diagnosed with schizophrenia in non-

Western countries may actually be better than for people in the West [69]. The reasons

for this effect are not clear, although cross-cultural studies are being conducted.

C.4.1 Medication

The mainstay of psychiatric treatment for schizophrenia is an antipsychotic medication

[70]. These can reduce the "positive" symptoms of psychosis. Most antipsychotics take

around 7–14 days to have their main effect.

Though expensive, the newer atypical antipsychotic drugs are usually preferred for

initial treatment over the older typical antipsychotics; they are often better tolerated and

associated with lower rates of tardive dyskinesia, although they are more likely to induce

weight gain and obesity-related diseases [71]. Prolactin elevations have been reported in

women with schizophrenia taking atypical antipsychotics [72]. It remains unclear

whether the newer antipsychotics reduce the chances of developing neuroleptic

malignant syndrome, a rare but serious and potentially fatal neurological disorder most

often caused by an adverse reaction to neuroleptic or antipsychotic drugs [73].

The two classes of antipsychotics are generally thought equally effective for the

treatment of the positive symptoms. Some researchers have suggested that the atypicals

offer additional benefit for the negative symptoms and cognitive deficits associated with

schizophrenia, although the clinical significance of these effects has yet to be

established. Recent reviews have refuted the claim that atypical antipsychotics have

fewer extrapyramidal side effects than typical antipsychotics, especially when the latter

are used in low doses or when low potency antipsychotics are chosen [74].

Response of symptoms to medication is variable; "Treatment-resistant schizophrenia" is

a term used for the failure of symptoms to respond satisfactorily to at least two different

antipsychotics [75]. Patients in this category may be prescribed clozapine, a medication

25

of superior effectiveness but several potentially lethal side effects including

agranulocytosis and myocarditis [76,77]. Clozapine may have the additional benefit of

reducing propensity for substance abuse in schizophrenic patients [78]. For other

patients who are unwilling or unable to take medication regularly, long-acting depot

preparations of antipsychotics may be given every two weeks to achieve control.

America and Australia are two countries with laws allowing the forced administration of

this type of medication on those who refuse but are otherwise stable and living in the

community. Some findings have found that in the longer-term some individuals may do

better not taking antipsychotics [79]. Despite the promising results of early pilot trials,

omega-3 fatty acids failed to improve schizophrenic symptoms, according to the most

recent meta-analysis [80].

C.4.2 Psychological and social interventions

Psychotherapy is also widely recommended and used in the treatment of schizophrenia,

although services may often be confined to pharmacotherapy because of reimbursement

problems or lack of training [81].

Cognitive behavioural therapy (CBT) is used to reduce symptoms and improve related

issues such as self-esteem, social functioning, and insight. Although the results of early

trials were inconclusive, more recent reviews suggest that CBT can be an effective

treatment for the psychotic symptoms of schizophrenia [82,83]. Another approach is

cognitive remediation therapy, a technique aimed at remediating the neurocognitive

deficits sometimes present in schizophrenia. Based on techniques of neuropsychological

rehabilitation, early evidence has shown it to be cognitively effective, with some

improvements related to measurable changes in brain activation as measured by fMRI

[84]. A similar approach known as cognitive enhancement therapy, which focuses on

social cognition as well as neurocognition, has shown efficacy [85].

Family Therapy or Education, which addresses the whole family system of an individual

with a diagnosis of schizophrenia, has been consistently found to be beneficial, at least if

the duration of intervention is longer-term [86-88]. Aside from therapy, the impact of

26

schizophrenia on families and the burden on carers has been recognized, with the

increasing availability of self-help books on the subject [89-90]. There is also some

evidence for benefits from social skills training, although there have also been

significant negative findings [91,92]. Some studies have explored the possible benefits

of music therapy and other creative therapies [93-95].

C.5 Screening and prevention

There are no reliable markers for the later development of schizophrenia although

research is being conducted into how well a combination of genetic risk plus non-

disabling psychosis-like experience predicts later diagnosis [96]. People who fulfil the

'ultra high-risk mental state' criteria, that include a family history of schizophrenia plus

the presence of transient or self-limiting psychotic experiences, have a 20–40% chance

of being diagnosed with the condition after one year [97]. The use of psychological

treatments and medication has been found effective in reducing the chances of people

who fulfill the 'high-risk' criteria from developing full-blown schizophrenia [98].

However, the treatment of people who may never develop schizophrenia is

controversial, in light of the side-effects of antipsychotic medication; particularly with

respect to the potentially disfiguring tardive dyskinesia and the rare but potentially lethal

neuroleptic malignant syndrome [99]. The most widely used form of preventative health

care for schizophrenia takes the form of public education campaigns that provide

information on risk factors, early detection and treatment options [100].

C.6 Psychiatric rehabilitation

Psychiatric rehabilitation, also known as Psychosocial rehabilitation, is the process of

restoration of community functioning and wellbeing of an individual who has a

psychiatric disability (been diagnosed with a mental disorder). Rehabilitation work

undertaken by psychiatrists, social workers and other mental health professionals seeks

27

to effect changes in a person’s environment and in a person’s ability to deal with their

environment, so as to factiliate improvement in symptoms or personal distress. These

services often combine pharmacologic treatment, independent living and social skills

training, psychological support to clients and their families, housing, vocational

rehabilitation, social support and network enhancement, and access to leisure activities

[101]. There is often a focus on challenging stigma and prejudice to enable social

inclusion, on working collaboratively in order to empower clients, and sometimes on a

goal of full psychosocial recovery.

Psychiatric rehabilitation promotes recovery, full community integration and improved

quality of life for persons who have been diagnosed with any mental health condition

that seriously impairs their ability to lead meaningful lives. Psychiatric rehabilitation

services are collaborative, person directed and individualized. These services are an

essential element of the health care and human services spectrum, and should be

evidence-based. They focus on helping individuals develop skills and access resources

needed to increase their capacity to be successful and satisfied in the living, working,

learning, and social environments of their choice [102].

C.7 Antipsychotic drugs

C.7.1 Terminology

Antipsychotics are also referred to as neuroleptic drugs, neuroleptics. The lower doses

used currently have resulted in reduced incidence of motor side-effects and sedation, and

the term is less commonly used than in the past.

Antipsychotics are broadly divided into two groups, the typical or first-generation

antipsychotics and the atypical or second-generation antipsychotics. There are also

dopamine partial agonists, which are often categorized as atypicals.

Typical antipsychotics are also sometimes referred to as major tranquilizers, because

some of them can tranquilize and sedate. This term is increasingly disused, as the

28

terminology implies a connection with benzodiazepines ("minor" tranquilizers) when

none exists.

Common conditions with which antipsychotics might be used include schizophrenia,

mania and delusional disorder. They might be used to counter psychosis associated with

a wide range of other diagnoses. Antipsychotics may also be used in mood disorder (e.g.

bipolar disorder) even when no signs of psychosis are present. In addition, these drugs

are used to treat non-psychotic disorders. For example, some antipsychotics

(haloperidol, pimozide) are used off-label to treat Tourette syndrome; while aripiprazole

is prescribed in some cases of Asperger's syndrome.

In routine clinical practice, antipsychotics may be used as part of risk management, and

to control difficult patients, although this is controversial [103].

C.7.2 Classification of antipsychotic drugs

More than 20 different antipsychotic drugs are available for clinical use, but with certain

exceptions the differences between them are minor.

A distinction is drawn between the drugs that were originally developed (e.g.

chlorpromazine, haloperidol and many similar compounds), often referred to as classical

or typical antipsychotic drugs, and more recently developed agents (e.g. clozapine,

risperidone), which are termed atypical antipsychotic drugs. These terms are widely

used, but not clearly defined, what ‘atypical’ actually means. It often refers to the

diminished tendency of some newer compounds to cause unwanted motor side-effects,

but it is also used to describe compounds with a pharmacological profile somewhat

different from that of ‘classical’ compounds, or to describe compounds which improve

the negative as well as the positive symptoms. In practice, it merely serves to distinguish

the large group of ‘classical’ drugs (phenothiazines, thioxanthenes and butyrophenones),

which are very similar in their properties, from a more diverse group of newer

compounds.

29

Classification of antipsychotic drugs

• Main categories are:

o Classical ‘typical’ antipsychotics (e.g. chlorpromazine, haloperidol,

fluphenazine, thioridazine, flupenthixol, clopenthixol)

o Recent ‘atypical’ antipsychotic (e.g. clozapine, risperidone,

sertindole, quetiapine)

• Distinction between typical and atypical groups is not clearly defined, but

rests on:

o Receptor profile

o Incidence of Extrapyramidal side-effects (less in atypical group)

o Efficacy in treatment-resistant group of patients

o Efficacy against negative symptoms

C.7.3 General properties

The therapeutic activity of the prototype drug, chlorpromazine, in schizophrenic patients

was discovered through the acute observations of a French surgeon Laborit, in 1947. The

clinical efficacy of phenotiazines was discovered long before their mechanism of action

was understood. Pharmacological investigation showed that phenothiazines blocked the

actions of many different mediators, including histamine, catecholamine, acetylcholine

and 5-HT, and this multiplicity of actions led to trade name Largactil for

chlorpromazine. It is now clear that antagonism at dopamine receptors is the main

determinant of antipsychotic action [1].

C.7.4 Mechanism of action

There are five subtypes of dopamine receptors, which fall into two functional classes:

the D1-type, comprising D1 and D5 and the D2-type, comprising D2, D3 and D4. The

30

antipsychotic drugs owe their therapeutic effects mainly to blockade of D2-receptors.

Antipsychotic effects require about 80% block of D2-receptors. Antagonism at D2-

receptors can be measured in experimental animals by various tests, such as inhibition of

amphetamine –induced stereotypic behaviour, or of apomorphine-induced turning

behaviour in animals with unilateral striatal lesions, and in vitro by the ability to inhibit

the binding of a radioactive D2-antagonist (e.g. spiroperidol) to brain membrane

fragments. The earlier compounds, phenothiazines, thioxanthenes and butyrophenones,

showshow some preference to D2- over D1-receptors; some of the newer agents (e.g.

sulpiride, remoxipride) are highly selective for D2-receptors, whereas clozapine is

relatively non-selective between D1 and D2 but has high affinity for D4 [1].

In animal tests, all antipsychotic drugs initially increase and later decrease the electrical

activity of midbrain dopaminergic neurons in the substantia nigra and ventral tegmentum

and also release of dopamine in regions containing dopaminergic nerve terminals. These

changes are possibly associated with changes in dopamine receptor expression. Effects

on the mesolimbic/mesocortical dopamine pathways are believed to correlate with

antipsychotic effects, whereas effects on the nigrostriatal pathways are responsible for

the unwanted motor effects produced by antipsychotic drugs. Antipsychotic drugs, like

many neuroactive compounds take several weeks to take effect, even though their

receptor-blocking action is immediate. When antipsychotic drugs are administered

chronically, the increase in activity of dopaminergic neurons is transient and gives way

after about 3 weeks to inhibition, at which time both the biochemical and

electrophysiological markers of activity decline. Another delayed effect seen with

chronic administration of antipsychotic drugs is proliferation of dopamine receptors,

detectable as an increase in haloperidol binding; there is a supersenitivity to dopamine,

somewhat akin to the phenomenon of denervation supersensitivity. At present neither the

mechanism of the delayed effects nor their relationship to the clinical response is at all

well understood. Antipsychotic drugs show varying patterns of selectivity in their

receptor-blocking effects, some having high affinity for 5-HT and/or D4-receptors. The

connection between their receptor specificity and their functional and therapeutic effects,

despite a wealth of fine argument, remains hidden.

31

Mechanism of action of antipsychotic drugs

• All antipsychotic drugs are antagonists at dopamine D2-recptors but most also

block other monoamine receptors, especially 5-HT2. Clozapine also blocks

D4-receptors.

• Antipsychotic potency generally runs parallel to activity on D2-receptors, but

other activities may determine side-effect profile.

• Antipsychotics take days or weeks to work, suggesting that secondary effects

(e.g. increase number of D2-receptors in limbic structure) may be important

than direct effect of D2-receptor block.

C.7.5 Drug action

All antipsychotic drugs tend to block D2-receptors in the dopamine pathways of the

brain. This means that dopamine released in these pathways has less effect. Excess

release of dopamine in the mesolimbic pathway has been linked to psychotic

experiences. It is the blockade of dopamine receptors in this pathway which is thought to

control psychotic experiences.

Typical antipsychotics are not particularly selective and also block Dopamine receptors

in the mesocortical pathway, tuberoinfundibular pathway and the nigrostriatal pathway.

Blocking D2-receptors in these other pathways is thought to produce some of the

unwanted side effects that the typical antipsychotics can produce. They were commonly

classified on a spectrum of low potency to high potency, where potency referred to the

ability of the drug to bind to dopamine receptors, and not to the effectiveness of the

drug. High potency antipsychotics such as haloperidol typically have doses of a few

milligrams and cause less sleepiness and calming effects than low potency

antipsychotics such as chlorpromazine and thioridazine, which have dosages of several

hundred milligrams. The latter have a greater degree of anticholinergic and

antihistaminergic activity which can counteract dopamine-related side effects.

Atypical antipsychotic drugs have a similar blocking effect on D2-receptors. Some also

block or partially block serotonin receptors (particularly 5-HT2A,C and 5-HT1A-receptors)

32

ranging from risperidone which acts overwhelmingly on serotonin receptors, to

amisulpride which has no serotonergic activity. The additional effects on serotonin

receptors may be why some of them can benefit the 'negative symptoms' of

schizophrenia [104].

C.7.6 Pharmacological effects

C.7.6.1 Behavioural effects

Antipsychotic drugs produce many behavioural effects in experimental animals, but no

single test is known that distinguishes them clearly from other types of antipsychotic

drug. Antipsychotic drugs reduce spontaneous motor activity and in larger doses cause

catalepsy, a state in which the animal remains immobile even when placed in an

unnatural position. Inhibition of the locomotor hyperactivity induced by amphetamine is

used as an indicator of the required antipsychotic action of these drugs, whereas ability

to cause catalepsy is used as an indicator of their tendency to cause unwanted

extrapyramidal symptoms in clinical use. These effects probably reflect D2-receptor

antagonism in the mesocortical/mesolimbic and the striatonigral pathways respectively.

Other tests reveal effects that are not associated with motor inhibition. For example, in a

conditioned avoidance model, a rat may be trained to respond to a conditioned stimulus,

such as a buzzer, by remaining immobile and thereby avoiding a painful shock;

chlorpromazine impairs performance in this test, as well as in tests that demand active

motor responses. In doses too small to reduce spontaneous motor activity,

chlorpromazine reduces social interactions (grooming, mating, fighting, etc.) and also

impairs performance in discriminant tests. (e.g. requiring the animal to respond

differently to red and green lights.)

Inhibition of amphetamine-induced behavioural changes occurs with all of the classical

antipsychotic drugs, reflecting their action on D2-receptors. Some of the atypical drugs,

which have less activity on D2-receptors, are less active in such models, and also in the

33

catalepsy model, but are equally efficacious in conditioned avoidance tests. Both

classical and atypical drugs, moreover, reduce the hyperactivity caused by phencyclidine

(a glutamate antagonist), which causes a schizophrenia-like syndrome in humans.

Conditioned avoidance and phencyclidine tests in animals are, therefore, used as guides

to antipsychotic activity in humans.

In humans, the effect of antipsychotic drugs is to produce a state of apathy and reduced

initiative. The subject displays few emotions, is to slow to respond to external stimuli

and tends to drowse off. The patient is, however, easily aroused and can respond to

questions accurately, with no marked loss of intellectual function. Aggressive tendencies

are strongly inhibited. The effects in humans differ from those of hypnotic and

anxiolytic drugs, which cause drowsiness and confusion, with euphoria rather than

apathy.

Many antipsychotic drugs show antiemetic activity, reflecting antagonism at dopamine

receptors. The antihistamine activity of many phenothiazines are also important [1].

C.7.6.2 Unwanted effects

C.7.6.2.1 Extrapyramidal motor disturbances and tardive dyskinesia

Antipsychotic drugs produce two main kinds of motor disturbance in humans, acute

dystonias, and tardive dyskynesia, collectively termed extrapyramidal side-effects,

which result directly or indirectly from D2-receptor blockade. These effects constitute

one of the main disadvantages of all the classical antipsychotic drugs. The term

‘atypical’ was originally applied to some of the newer compounds that show much less

tendency to produce extrapyramidal effects.

34

C.7.6.2.2 Acute dystonias

Acute dystonias are involuntary movements (muscle spasms, protruding tongue,

torticollis, etc.) and often Parkinson-type syndrome. They occur commonly in the first

few weeks, often declining with the time, and they are reversible on stopping drug

treatment. The occurrence of acute dystonias is consistent with block of the

dopaminergic nigrostriatal pathway, and there is evidence that the relative selectivity of

atypical antipsychotic drugs for mesolimbic/mesocortical pathway accounts for the

diminished risk of acute dystonias. Concomitant block of muscarinic acetylcholine

receptors may also mitigate the motor effects of dopamine receptor block, since the two

receptor systems act in opposite ways.

C.7.6.2.3 Tardive dyskinesia

Tardive dyskinesia develops after months or years (hence ‘tardive’) in 20-40% of

patients treated with classical antipsychotic drugs and is one of the main problems of

antipsychotic therapy. Its seriousness lies in the fact that it is a disabling and often

irreversible condition, which often gets worse when antipsychotic therapy is stopped,

and is resistant to treatment. The syndrome consists in voluntary movements, often of

the face and tongue, but also of the trunk and limbs, which can be severely disabling. It

resembles that seen after prolonged treatment of Parkinson’s disease with levodopa. The

incidence depends on greatly on the drug dosage, the age of patient (commonest in

patients over 50) and on the drug used. There are several theories about the mechanism

of tarive dyskinesia. One is that is associated with a gradual increase in the number of

D2-receptor sites in the striatum, which is less marked with the antipsychotic drugs.

Another possibility is that chronic block of inhibitory dopamine receptors enhances

catecholamine and/or glutamate release in the striatum, leading to excitotoxic

neurodegeneration. The reason why atypical antipsychotic drugs (e.g. clozapine,

olanzapine, sertindole) are better in this regard is not clear. A possible explanation lies in

differences in the rate at which compounds dissociate from D2-receptors. With a rapidly

35

dissociating compound, a brief surge of dopamine can effectively overcome the block by

competition, whereas with a slowly dissociating compound, the level of blocks takes a

long time to respond to the presence of endogenous dopamine and is in practice non-

competitive. It could therefore, be that motor effects are avoided if the level of receptor

block can give way readily to competition from physiological surges of dopamine,

whereas this is not a factor of importance for the psychotropic effects. Whether this

kinetic explanation will prove more sustainable than the many attempts to relate the

tendency to cause motor side-effects to the receptor profile of different compounds

remains to be seen. Clozapine has relatively high affinity for D1-and D4-receptors,

compared with D2-receptors, and also has marked antimuscarinic activity, as do some

other antipsychotic drugs, such as thioridazine, which may counteract its effects on the

motor system [1].

Antipsychotic-induced motor disturbances

• Major problem of antipsychotic drug treatment.

• Two main types of disturbance occur:

o Acute, reversible dystonias and Parkinson-like symptoms

o Slowly developing tardive dyskinesia, often irreversible.

• Acute symptoms comprise involuntary movements, of tremor and rigidity, and

are probably the direct consequence of block of nigrostriatal dopamine receptors.

• Tardive dyskinesia comprises mainly involuntary movements of face and limbs,

appearing after months or years of antipsychotic treatment. It may be associated

with proliferation of dopamine receptors (possibly presynaptic) in corpus

striatum. Treatment is generally unsuccessful.

• Incidence of acute dystonias and tardive dyskinesia is less with atypical

antipsychotics, and particularly low with clozapine. This may reflect relatively

strong muscarinic receptor block with these drugs, or a degree of selectivity for

the mesolimbic, as opposed to the nigrostriatal, dopamine pathways [1].

36

C.7.6.2.4 Endocrine effects

Dopamine, released in the median eminence by neurons of the tuberohypophyseal

pathway acts physiologically via D2-receptors as an inhibitor of prolactine secretion. The

result of blocking D2-receptors by antipsychotic drugs is thus to increase the plasma

prolactine concentration, resulting in breast swelling, pain and lactation, which can occur

in men as well as women.

Unwanted effects of antipsychotic drugs

• Important side-effects common to most drugs are extrapyramidal motor

disturbances and endocrine disturbances (increased prolactin disease); these are

secondary to dopamine receptor block. Sedation, hypotension and weight gain

are also common.

• Other side-effects (dry mouth, blurred vision, hypotension, etc) result from

blockade of other receptors, particularly α-adrenoceptors and muscarinic

acetylcholine receptors.

• Obstructive jaundice sometimes occurs with phenothiazines.

• Some antipsychotics cause agranulocytosis as a rare and serious idiosyncratic

reaction. With clozapine leucopenia is common and requires routine monitoring.

• Antipsychotic malignant syndrome is a rare but potentially dangerous

idiosyncratic reaction [1].

C.7.6.2.5 Other unwanted effects

Sedation which tends to decrease with continued use, occurs with many antipsychotic

drugs. Antihistamine (H1) activity is a property of phenotiazines and contributes to their

sedative and antiemetic properties, but not to their antipsychotic action.

Blocking muscarinic receptors produces a variety of peripheral effects, including

blurring of vision and increased intraocular pressure, dry mouth and eyes, constipation

and urinary retention. It may, however, also be beneficial in relation to extrapyramidal

37

side-effects. Acetylcholine acts in opposition to dopamine in the basal ganglia and it is

possible that the relative lack of Extrapyramidal side-effects with clozapine and

thioridazine is a consequence of their high antimuscarinic potency.

Blocking α-adrenoceptors results in the important side effect in humans of orthostatic

hypotension, but it does not seem to be important for the antipsychotic action.

Weight gain is common and troublesome side-effect, particularly associated with some

of atypical drugs, and probably related to 5-HT antagonism.

Various idiosyncratic and hypersensitivity reactions can occur, the most

important being:

• Jaundice, which occurs with older phenotiazines, such as chlorpromazine.

The jaundice is usually mild, and of obstructive origin, and disappears

quickly when the drug is stopped or substituted by an antipsychotic drug

of a different class.

• Leucopenia and agranulocytosis are rare, but potentially fatal, and occur

in the first few weeks of treatment. The incidence of leukopenia is less

than 1 in 10000 for most antipsychotics, but much higher (1-2%) with

clozapine, the use of which, therefore, requires regular monitoring of

blood cell counts. Provided the drug is stopped at the first sign of

leucopenia or anaemia, the effect is reversible. Olanzapine appears to be

free of this disadvantage.

• Urticarial skin reactions are common but usually mild. Excessive

sensitivity to ultraviolet light may also occur.

• Antipsychotic malignant syndrome is rare but serious complication,

similar to the malignant hyperthermia syndrome seen with certain

anaesthetics. Muscle rigidity is accompanied by a rapid rise in body

temperature and mental confusion. It is usually reversible, but death from

renal or cardiovascular failure occurs in 10-20%.

38

C.7.6.2.6 Pharmacokinetic aspects

The relation between the plasma concentration and the clinical effect of antipsychotic

drugs is also highly variable. The plasma half-life (t½) of most antipsychotic drugs is 15-

30 hours, clearance (Cl) depending entirely on hepatic transformation by a combination

of oxidative and conjugative reactions.

Most antipsychotic drugs can be given orally or by intramuscular injection, once or

twice a day. Slow-release (depot) preparations of many are available, in which the active

drug is esterified with heptanoic or decanoic acid and dissolved in oil. Given as an

intramuscular injection, the drug acts for 2-4 weeks but initially may produce acute side-

effects. These preparations are widely used as a means of overcoming compliance

problems [1].

C.7.6.2.7 Clinical use and clinical efficacy of typical and atypical antipsychotic drugs

The major use of antipsychotic drugs is in the treatment of schizophrenia, and acute

behavioural emergencies, but they are also widely used as adjunct therapy in the

treatment of other illnesses, such as psychotic depression and mania. Antipsychotic

drugs, apart from their side-effects, have two main shortcomings.

• They are effective in only about 70% of schizophrenic patients; for any single

drug the success rate is lower. The remaining 30% are classed as “treatment-

resistant”, and present a major therapeutic problem.

• While they control the positive symptoms effectively, they are less effective in

relieving the negative symptoms.

The newer atypical antipsychotic drugs, particularly clozapine, may overcome these

shortcomings to some degree, showing efficacy in treatment-resistant patients and

improving negative, as well as positive, symptoms.

39

Clinical efficacy of antipsychotic drugs

• Antipsychotic drugs are effective in controlling symptoms of acute

schizophrenia, when large doses may be needed.

• Long-term antipsychotic treatment is often effective in preventing recurrence of

schizophrenic attacks, and this is a major factor in allowing schizophrenic

patients to lead normal lives.

• Depot preparations are often used for maintenance therapy.

• Antipsychotic drugs are not generally effective in improving negative

schizophrenic symptoms, though newer drugs are claimed to relieve these

symptoms.

• Approximately 40% of chronic schizophrenic patients are poorly controlled by

antipsychotic drugs; clozapine may be effective in some of these ‘antipsychotic-

resistant’ patients.

• There are small, if any, overall differences in efficacy between different

antipsychotic drugs, though side-effects differ significantly.

C.7.7 Application of typical agents

Typical antipsychotics (sometimes referred to as first generation antipsychotics,

conventional antipsychotics, classical neuroleptics, or major tranquilizers) are a class of

antipsychotic drugs first developed in the 1950s and used to treat psychosis (in

particular, schizophrenia), and are generally being replaced by atypical antipsychotic

drugs. Typical antipsychotics may also be used for the treatment of acute mania,

agitation, and other conditions. The first typical antipsychotics to enter clinical use were

the phenothiazines.

Traditional antipsychotics are broken down into low-potency and high-potency

classifications.

Some of the high-potency antipsychotics have been formulated as the decanoate ester

(e.g. fluphenazine decanoate) to allow for a slow release of the active drug when given

as a deep, intramuscular injection. This has the advantage of providing reliable dosing

40

for a person who doesn't want to be drugged. Depot injections can also be used for

involuntary community treatment patients to ensure compliance with a community

treatment order when the patient would refuse to take daily oral medication. Depot

preparations were limited to high-potency antipsychotics so choice was limited. It is

therefore preferable to use oral medications if the cooperation and compliance of the

patient can be assured.

The oldest depots available were haloperidol and fluphenazine, with flupenthixol and

zuclopenthixol as more recent additions. All have a similar, predominantly

extrapyramidal, side effect profile though there are some variations between patients.

More recently a long acting preparation of the atypical antipsychotic risperidone has

become available, offering a new choice. Risperidone still has a higher incidence of

extrapyramidal effects than some other drugs available however.

C.7.7.1 Side effects of typical antipsychotics

Side effects vary among the various agents in this class of medications, but common side

effects include: dry mouth, muscle stiffness, muscle cramping, tremors, EPS and weight-

gain. EPS is a cluster of symptoms consisting of parkinsonism, dystonias, and akathisia.

Anticholinergics such as benztropine and diphenhydramine are commonly prescribed to

treat the symptoms of EPS.

There is a significant risk of the serious condition tardive dyskinesia developing as a side

effect of typical antipsychotics. The risk of developing tardive dyskinesia after chronic

typical antipsychotic usage varies on several factors, such as age and gender. The

commonly reported incidence of TD among younger patients is about 5% per year.

Among older patients incidence rates as high than 20% per year have been reported. The

average prevalence is approximately 30%. [105]. There are no treatments that have

consistently been shown to be effective for the treatment of tardive dyskinesias, however

branched chain amino acids, melatonin, and vitamin E have been suggested as possible

treatments. The atypical antipsychotic clozapine has also been suggested as an

41

alternative antipsychotic for patients experiencing tardive dyskinesia. Tardive dyskinesia

may reverse upon discontinuation of the offending agent or it may be irreversible.

Neuroleptic malignant syndrome (NMS), is a rare, but potentially fatal side effect of

antipsychotic treatment. NMS is characterized by fever, muscle rigidity, autonomic

dysfunction, and altered mental status. Treatment includes discontinuation of the

offending agent and supportive care.

The role of typical antipsychotics has come into question recently as studies have

suggested that atypical antipsychotics may increase the risk of death in elderly patients.

A retrospective cohort study showed an increase in risk of death with the use of typical

antipsychotics that was on par with the increase shown with atypical antipsychotics

[106]. This has led some to question the common use of antipsychotics for the treatment

of agitation in the elderly, particularly with the availability of alternatives such as mood

stabilizing and antiepileptic drugs.

C.7.7.2 Typical antipsychotics

• Phenothiazines

o Chlorpromazine

o Fluphenazine

o Perphenazine

o Prochlorperazine

o Thioridazine

o Trifluoperazine

o Mesoridazine

o Promazine

o Triflupromazine

o Levomepromazine

• Thioxanthenes

o Chlorprothixene

o Flupenthixol

42

o Thiothixene

o Zuclopenthixol

• Butyrophenones

o Haloperidol

o Droperidol

o Pimozide

o Melperone

C.7.8 Application of atypical agents

The atypical antipsychotics (also known as second generation antipsychotics) are a class

of prescription medications used to treat psychiatric conditions. Some atypical

antipsychotics are FDA approved for use in the treatment of schizophrenia. Some carry

FDA approved indications for acute mania, bipolar mania, psychotic agitation, bipolar

maintenance, and other indications.

Atypicals are a heterogeneous group of otherwise unrelated drugs united by the fact they

work differently from typical antipsychotics. Most share a common attribute of working

on serotonin receptors as well as dopamine receptors. Two drugs, aripiprazole and

amisulpride, don't have serotonergic activity, instead having some partial dopamine

agonism [1].

The first atypical anti-psychotic medication, clozapine, was discovered in the 1950s, and

introduced in clinical practice in the 1970s. Clozapine fell out of favour due to concerns

over drug-induced agranulocytosis. With research indicating its effectiveness in

treatment-resistant schizophrenia and the development of an adverse event monitoring

system, clozapine reemerged as a viable antipsychotic. Despite the effectiveness of

clozapine for treatment-resistant schizophrenia, agents with a more favourable side

effect profile were sought after for widespread use. During the 1990s, olanzapine,

risperidone, and quetiapine were introduced, with ziprasidone and aripiprazole following

in the early 2000s. The newest atypical anti-psychotic, paliperidone, was approved by

the FDA in late 2006.

43

The atypical anti-psychotics have found favour among clinicians and are now considered

to be first line treatments for schizophrenia and are gradually replacing the typical

antipsychotics. Most researchers agree that the defining characteristic of an atypical

antipsychotic is the decreased propensity of these agents to cause extrapyramidal side

effects and an absence of sustained prolactin elevation.

C.7.8.1 Pharmacology of the atypicals

The mechanism of action of these agents is unknown, and differs greatly from drug to

drug. The variation in the receptor binding profile is such that the only effect all have in

common is an anti-psychotic effect; the side effect profiles vary tremendously. While

modulation of the dopamine neurotransmitter system is the most important mechanism

by which anti-psychotics exert their benefits, the role of the serotonergic activity of the

atypicals is debated. Some researchers believe that D2-receptor antagonism, coupled

with 5-HT2A-receptor antagonism, is responsible for the "atypicality" of atypical anti-

psychotics. Others believe that fast dissociation (a fast Koff) from the D2-receptor,

allowing for better transmission of normal physiological dopamine surges, better

explains the pharmacological evidence.

There is extensive evidence that atypical anti-psychotics have less of an affinity for D2-

receptors and more of an affinity for the D4-receptors [1]. This is primarily because

atypical antipsychotics are somewhat less likely to cause tardive dyskinesia [1]. The idea

is that D2-receptors are dopaminergically ubiquitous and affect the motor system as

much as the motivational aspect of the dopamine system. On the other hand, D4 is a

more accurate dopamine receptor subtype. Atypical anti-psychotics also affect the

norepinephrine, acetylcholine, and histamine receptors of various subtypes. However,

studies have shown that D4 selective antagonism has no anti-psychotic effect [1].

44

C.7.8.2 Side effects of the atypical antipsychotics

The side effects reportedly associated with the various atypical antipsychotics vary and

are medication-specific. Generally speaking, atypical antipsychotics are hoped to have a

lower likelihood for the development of tardive dyskinesia than the typical

antipsychotics. However, tardive dyskinesia typically develops after long term (possibly

decades) use of antipsychotics. It is not clear, then, if atypical antipsychotics, having

been in use for a relatively short time, produce a lower incidence of tardive dyskinesia.

Akathisia is more likely to be less intense with these drugs then the typical

antipsychotics although many patients would dispute this claim.

C.7.8.3 Tardive Dyskinesia

All the atypical antipsychotics warn about the possibility of tardive dyskinesia in their

package inserts and in the PDR. It is not possible to truly know the risks of tardive

dyskinesia when taking atypicals, because tardive dyskinesia can take many decades to

develop and the atypical antipsychotics are not old enough to have been tested over a

long enough period of time to determine all of the long-term risks.

However, the atypicals may cause serious metabolic disorders to make them equally

dangerous as the older anti-psychotic drugs [1].

C.7.8.4 Metabolic side effects with atypical antipsychotics

Recently, metabolic concerns have been of grave concern to clinicians, patients and the

FDA. In 2003, the Food and Drug Administration (FDA) required all manufacturers of

atypical antipsychotics to change their labeling to include a warning about the risks of

hyperglycaemia and diabetes with atypical antipsychotics. It must also be pointed out

45

that although all atypicals must carry the warning on their labeling, some evidence

shows that all atypicals are not equal in their effects of weight and insulin sensitivity

[107,108]. The general consensus is that clozapine and olanzapine are associated with

the greatest effects on weight gain and decreased insulin sensitivity, followed by

risperidone and quetiapine [109-112]. Ziprasidone and aripiprazole are thought to have

the smallest effects on weight and insulin resistance but clinical experience with these

newer agents is not as developed as that with the older agents [1].

C.7.8.5 Atypical antipsychotics

• Clozapine - Available only in oral tablets.

• Risperidone - Available in oral tablets, dissolving tablets, liquid form, and

extended release intramusclar injection.

• Olanzapine - Available in oral tablets, dissolving tablets, and

intramuscular injection.

• Quetiapine - Available only in oral tablets.

• Ziprasidone - Available in oral capsules and intramuscular injection.

• Aripiprazole - Available in oral tablets and dissolving tablets.

• Paliperidone - Available in extended-release oral tablets.

• Asenapine

• Iloperidone

• Sertindole

• Zotepine

• Amisulpride

• Bifeprunox

• Melperone

46

Figu

re 2

-

Ant

ipsy

chot

ics

in H

unga

ry (

trad

e na

mes

app

ear

in p

aren

thes

es)

C.7.9. Antipsychotics in Hungary

Figure 2 summarizes the antipsychotics marketing authorized in Hungary.

47

C.7.10 Typical versus atypical

While the atypical, second-generation medications were marketed as offering greater

efficacy in reducing psychotic symptoms while reducting side effects (and extra-

pyramidal symptoms in particular) than typical medications, these results showing these

effects often lack robustness. To remediate this problem, the NIMH conducted a recent

multi-site, double-blind, study (the CATIE project), which was published in 2005

[71,113]. This study compared several atypical antipsychotics to an older typical

antipsychotic, perphenazine, among 1493 persons with schizophrenia. Perphenazine was

chosen because of its lower potency and moderate side-effect profile. The study found

that only olanzapine outperformed perphenazine in the researchers' principal outcome,

the discontinuation rate. The authors also noted the apparent superior efficacy of

olanzapine to the other drugs for greater reduction in psychopathology, longer duration

of successful treatment, and lower rate of hospitalizations for an exacerbation of

schizophrenia. In contrast, no other atypical studied (risperidone, quetiapine, and

ziprasidone) did better than the typical perphenazine on those measures. Olanzapine,

however, was associated with relatively severe metabolic effects: subjects with

olanzapine showed a major weight gain problem and increases in glucose, cholesterol,

and triglycerides. The average weight gain (1.1 kg/month, or 44 pounds for the 18

months that lasted the study) casts serious doubt on the potentiality of long-term use of

this drug.

Clozapine indeed proved to be more effective at reducing medication drop-outs than

other neuroleptic agents. Researchers also observed a trend showing clozapine with a

greater reduction of symptoms. However, the potential of clozapine to cause toxic side

effects, including agranulocytosis, limits the prescription to persons with schizophrenia

[114,115].

48

C.7.11 Schizophrenia and diabetes mellitus

Several major mental illnesses, including depression, schizophrenia, Alzheimer’s

dementia and bipolar affective disorder have been associated with impaired glucose

regulation and elevated rates of diabetes mellitus [116,117]. Abnormalities in glucose

regulation were first reported in schizophrenia prior to the introduction of antipsychotic

medications, with early reports indicating a pattern of insulin resistance in untreated

patients [118]. These early reports suggested that patients with psychotic disorders might

have some elevated baseline risk for glucoregulatory disturbances, prior to any

consideration of adverse medication effects. However, these early studies had a number

of weaknesses, including failure to control for or consider age, weight, adiposity,

ethnicity or diet. Nevertheless, a number of early reports of impaired glucose

metabolism suggested an association with various mental illnesses, independent of

medication effects. Despite the limitations of these early reports and the lack of large-

scale population studies, current investigators tend to conclude that this patient group

may be at increased risk for glucoregulatory disturbances and type 2 diabetes mellitus,

independent of medication effects. The number and the relative consistency of

observations of increased rates of insulin resistance and type 2, rather than type 1,

diabetes in unmedicated patients have suggested that disease-related disturbance in

whole-body glucose metabolism can occur more frequently in schizophrenia patients

than in control subjects. If this conclusion is correct, one can hypothesize that this is

somehow directly related to the disease process, and/or secondary to disease-related

changes in diet, exercise and weight regulation. Primary effects of disease might involve

shared genetic vulnerability for both psychosis and diabetes mellitus, or one of many

changes in cellular, endocrine and immune function in schizophrenia which could affect

whole-body glucose regulation. Limitations in resolving these issues include the

difficulties of conducting unmedicated studies of patients with schizophrenia when

highly effective medications are available and the difficulties of obtaining appropriate

tissue specimens for genetic studies.

Metabolic abnormalities such as obesity, diabetes and dyslipidaemia increase the risk of

cardiovascular disease, as well as a number of other adverse long-term health

49

consequences. There is increasing evidence from case studies, retrospective analyses and

clinical trials to suggest that second-generation antipsychotics can increase the risk of

metabolic abnormalities in patients with schizophrenia, with indications that the level of

risk may vary among antipsychotic medications. Comparison of weight gain data for the

second-generation antipsychotics provides strong evidence to indicate differences in the

weight gain liability, with clozapine and olanzapine being associated with the greatest

weight gain over 1 year. Data suggest that these treatment-induced changes in weight are

primarily responsible for treatment-related changes in glucose metabolism; however,

there is also evidence to suggest that some impairments in glucose metabolism may be

independent of adiposity. Studies investigating the effects of atypical antipsychotics on

glucose metabolism have used a number of techniques of varying sensitivity and quality

in an attempt to assign causality. Recent studies using gold standard methodologies, for

both insulin sensitivity and adiposity, have shown that psychiatric patients receiving

antipsychotics are at least as sensitive to the adverse effects of adiposity on glucose and

lipid metabolism as non-psychiatric controls. This demonstrates the importance of

weight gain prevention in psychiatry to help reduce long-term risk. There is also

growing evidence to suggest that the differential effects of second-generation

antipsychotics on metabolic parameters also result in differences in the risk of metabolic

syndrome, with olanzapine having a significantly higher risk than either aripiprazole or

ziprasidone. This differential risk highlights the need for adequate monitoring in patients

receiving treatment with second-generation antipsychotics and careful selection of

treatment in high-risk patients [119].

C.7.11.1 Antipsychotic treatment and diabetes mellitus

Glucoregulatory disturbances in schizophrenia can be worsened by treatment with

antipsychotic medications. With the introduction of chlorpromazine, phenothiazine

treatment was observed to contribute to abnormalities in glucose regulation, including

reports of aggravation of existing diabetes and new onset type 2 diabetes mellitus [117].

The introduction of chlorpromazine in one setting increased the prevalence of diabetes

from 4.2% to 17.2%, an increase similar to that noted in some recent reports concerning

50

the introduction of newer antipsychotic medications [120]. Phenothiazine treatment has

also been associated with increases in plasma lipids and weight gain [121,122]. These

and other reports prompted the National Diabetes Data Group in the late 1970s to add

phenothiazines to the list of medications that can disturb whole-body glucose

metabolism [123]. While low potency phenothiazine treatment has most frequently been

associated with abnormalities in glucose regulation, this association is not consistently

observed for all older antipsychotics [124-126]. Higher potency older antipsychotic

agents like haloperidol are less consistently associated with diabetes mellitus, suggesting

that medication effects on glucose regulation may vary in magnitude across individual

agents. In general, these early studies of medication effects on glucose metabolism, like

earlier studies of glucose metabolism in unmedicated schizophrenia patients, suffered

from a lack of controls and limited assessment of confounding variables (e.g., adiposity).

The increased use of older high potency antipsychotics, versus low potency

phenothiazines, in the years prior to the introduction of newer antipsychotic medications

may have contributed to the reduction in the number of reports concerning

antipsychotic-related hyperglycemia over that same period. The relative lack of attention

to this issue may have been one of the factors that allowed pivotal clinical trials for

recently approved antipsychotic medications to be conducted with random plasma

glucose as the only measure of medication effects on glucose metabolism (i.e., no fasting

or postload plasma glucose measurements). Since the marketing of newer antipsychotics,

a number of reports indicate that treatment with these medications, as with older agents,

can be associated with the occurrence of clinically significant hyperglycemia. Weight

gain has been a major challenge in the treatment of mental illness. On one hand, weight

gain is a major factor contributing to antipsychotic noncompliance, but the weight gain

associated with compliance is associated with increased risk of early mortality [116].

51

D EXPERIMENTAL PART

D.1 Study design and methods

D.1.1 Utilization study of olanzapine and risperidone in psychiatric rehabilitation

within 1999-2007

There is a growing trend in the use of atypical antipsychotics in the medication of

schizophrenia [127-129]. Olanzapine and risperidone have become widely used atypical

agents in Hungary. Although there is a significant cost-difference between the two drugs

the degrees of efficacy and tolerability are similar [130-138]. To control pharmacy costs

the National Health Insurance Fund (Országos Egészségbiztosítási Pénztár) has issued

guidelines for the use of these drugs, restricting their use to patients with a diagnosis of

schizophrenia who have failed to respond to conventional neuroleptics or who

experienced severe side effects from previous treatments. Risperidone is preferred over

olanzapine for first-episode patients and elderly psychosis, and olanzapine for patients

sensitive to Extrapyramidal symptomps (EPS) [139]. The prescribed daily doses (PDD)

of olanzapine are 15mg and 4-6mg of risperidone [132-140]. Data regarding dosages and

psychiatrists’ clinical preferences were collected through studying hospital charts in the

Gálfi Béla Hospital which is specialized on gerontopsychiatric attendance with a main

profile of rehabilitation. The location of the Gálfi Béla Hospital is in Pest County with a

distance of 25 km from Budapest. In the examined period there was psychiatric

attendance on 420 beds.

As a first step of the examination all diagnosed schizophrenic disorders (ICD-10 F20xx

– F29) were surveyed between 1999 and 2007 in the Gálfi Béla Hospital including over

2000 hospital charts [141]. Hospital charts are electronically registered documents that

can be filled out only by the prescribing doctors. There were 14 psychiatrists’

prescriptions surveyed in the period of 1999-2007. Patients show a view of a typical

polymorbide population, thus they were treated with ACE inhibitors, Ca-channel

blockers, beta-blockers, oral and parenteral antidiabetics, non-steroid antiinflammatory

drugs (NSAIDs), antibiotics.

52

All charts refer to some cases of schizophrenia - including paranoid, disorganized,

undifferentiated or residual types - or schizoaffective disorder of unknown type

receiving antipsychotic treatment (conventional neuroleptics or atypical antipsychotics).

A smaller number of charts indicate when patients received antipsychotic medication of

olanzapine (OLA) or risperidone (RIS).

The defined daily dose of olanzapine (DDDOLA) is 10 mg/day (ATCOLA N05AH03) and

risperidone (DDDRIS) is 5 mg/day (ATCRIS N05AX08), while PDDs for olanzapine and

risperidone are 15 mg and 4-6 mg, respectively [132-140].

Polynomials have been fitted to both sets of data and analysis of variance has also been

applied to check the results. The statistical program package SPSS 13.0 (SPSS Inc.,

Chicago, IL, USA) has been used.

D.1.2 Utilization study of clozapine, olanzapine and risperidone

The utilization data of the country study were obtained by the National Health Insurance

Fund registry in the period of 1999-2003. Data were given in the Gálfi Béla Hospital by

hospital chart analysis.

Olanzapine and risperidone were the most widely used atypical antipsychotics in

Hungary between 1999 and 2003, while the special indication of clozapine indicated its

participation in the utilization study.

D.1.3 Sample selection for the study of the diabetes prevalence among elderly patients

in psychiatric rehabilitation

Metabolic complications are a major issue in patients receiving antipsychotic therapy

[142]. Diabetes is known to occur occasionally with conventional antipsychotics, but has

been more often associated with atypical antipsychotics [143]. A body of evidence

suggests that atypical antipsychotics, apart from clozapine, are more disadvantageous

from the aspect of glucose regulation and diabetes than conventional drugs. Atypical

53

antipsychotics should be administered with great care to patients with risk factors for

diabetes [144]. Diabetes is associated with increased morbidity and mortality for

cardiovascular disease [145]. An increasing number of reports concerning diabetes,

ketoacidosis, hyperglycaemia and lipid dysregulation in patients treated with atypical

antipsychotics have raised concerns about a possible association between these

metabolic effects and treatment with these medications [146]. Reports and clinical

experience suggest that in the case of atypical antipsychotics associated diabetes,

discontinuation of the antipsychotic agent may result in complete resolution of the

hyperglycaemia [147].

Metabolic side effects have been increasingly noted during therapy with novel

antipsychotics, but there is a dearth of comprehensive comparative data in this area

[148]. Weight gain is a common and troublesome side-effect, particularly associated

with some of the atypical drugs, and probably related to 5-HT antagonism [1]. Several

mental illnesses including schizophrenia have been associated with impaired glucose

regulation and elevated rates of diabetes mellitus [116].

Data regarding dosages and psychiatrists’ clinical preferences were collected through

studying hospital charts in the Gálfi Béla Hospital which is specialized on

gerontopsychiatric attendance with a main profile of rehabilitation. In the examined

period there was psychiatric attendance on 420 beds.

As a first step of the examination, all diagnosed schizophrenic disorders (International

Classification of Diseases ICD-10 F20xx – F29) were surveyed between 2000 and 2006

in the Gálfi Béla Hospital including over 2,500 hospital charts [149]. Hospital charts are

electronically registered documents that can be filled out only by the prescribing doctors.

There were 14 psychiatrists’ prescriptions surveyed in the period of 2000-2006.

As a result of the hospital chart analysis we admitted a population of schizophrenic

patients (n = 245). The examined population came together with fulfilling the following

criteria. Each patient was treated continuously with antipsychotics between 2000 and

2006. There would be a near number of the male and female patients in the

examination. All ages should have been represented. All patients were diagnosed as

54

schizophrenic (according to ICD-10 F20xx – F29). Patients preferably would come from

all parts of Hungary. Patients were not diagnosed as diabetics before 2000 in the Gálfi

Béla Hospital.

The research in consideration of the hospital chart analysis received approval from the

ethics approval committee of the Gálfi Béla Hospital.

The ATC-A10A parenteral and ATC-A10 B oral antidiabetic use of each patient was

examined by using the National Health Insurance Fund registry by checking the personal

insurance numbers and the related medication in the examined period. The medication of

those patients who were treated continuously in hospital was documented in their

hospital charts. Most diabetic patients in the examined population were treated with

olanzapine, risperidone, quetiapine and clozapine, only one patient with ziprasidone.

However there is little evidence to link risperidone and the newer drug ziprasidone with

diabetes mellitus, appear not to cause significant weight gain [150]. Olanzapine and

risperidone have become the most widely used atypical agents in Hungary. Although

there is a significant cost-difference between the two drugs, the degrees of efficacy and

tolerability are similar [132,151]. To control pharmacy costs, the National Health

Insurance Fund has issued guidelines for the use of these drugs, restricting their use to

patients with a diagnosis of schizophrenia who have failed to respond to conventional

neuroleptics or who experienced severe side effects on previous treatments. Risperidone

is preferred over olanzapine for first-episode patients and elderly psychosis, and

olanzapine for patients sensitive to extrapyramidal symptomps [127]. The Defined Daily

Dose (DDD) of olanzapine is DDDOLA = 10 mg/day (ATCOLAN05AH03) and DDDRIS =

5 mg/day (ATCRIS N05AX08) of risperidone, while the Prescribed Daily Doses (PDD)

of olanzapine are 15 mg and 4-6 mg of risperidone [132].

We aimed to compare the risk of diabetes in a Hungarian schizophrenic population

treated with atypical antipsychotics with that of the non-schizophrenic population. We

wished to reveal the effects of gender and age. A schizophrenic population (n = 135

male and n = 110 female patients of different age groups) was examined by studying

hospital charts in the Gálfi Béla Hospital specialized on gerontopsychiatric attendance

with a main profile of rehabilitation. Data were given by the National Health Insurance

55

Fund registry in the period of 2000-2006, while the Hungarian Central Statistical Office

presented data on the prevalence of diabetes in the Hungarian population. Binomial

distribution was used for the hypothesis testing.

D.1.3.1 Hypothesis testing

Binomial tests were made, with the zero hypothesis that there is no difference between

the schizophrenic and normal Hungarian population in diabetes rates and with the

alternative hypothesis that the diabetic rate is higher in the schizophrenic group. In cases

of all female and male groups, the age-adjusted population prevalence data (based on

census information, 2001) were applied in the binomial tests. Microsoft Excel software

was used for the calculations. Level of significance was taken as 5%.

56

E RESULTS

E.1 Results of the utilization study of olanzapine and risperidone in psychiatric

rehabilitation within 1999-2007 in comparison with the country data

Because olanzapine and risperidone have similar efficacy and tolerability in the

treatment of schizophrenia and these two agents are the most widely used atypical

antipsychotics in Hungary, the utilisation of the drugs is a relevant consideration [152].

Data regarding dosages and psychiatrists’ clinical preferences were collected through

studying hospital charts in the Gálfi Béla Hospital during the period of 1999–2007.

Utilisation of the agents indicated that there was an increase of use for the whole

examined period in the Gálfi Béla Hospital, although unambiguous growth began only in

2001 [153]. Hospital chart analysis shows that both drugs were used to a large extent and

risperidone use is increasing more rapidly, which is justified by the gerontopsychiatric

profile of the hospital.

Table 2 presents the results of the surveyed charts, showing both the number of patients

with the most prevalent schizophrenic disorders (n = 2545) and, of those, the number

receiving either olanzapine or risperidone (n = 1472). Following from the chart

examination, Table 1 presents the mean daily dosages (mg/day) in each disorder given to

patients in the Gálfi Béla Hospital in the period surveyed.

Only oral doses were counted, i.e. risperidone and olanzapine film coated tablets and

risperidone solution. The depot injection of risperidone was not registered until 2003 in

Hungary, and although the intramuscular olanzapine injection was registered in 2001, it

was not used before 2003 in the Gálfi Béla Hospital. Even if the depot injection of

risperidone were to be included, the degree of use is so low that its omission does not

cause a significant difference to the utilisation in 2003. In the period of 2004-2007 the

depot preparation of risperidone was included in the survey.

Figure 3 summarises the daily dosages of olanzapine and risperidone as a mean value

weighted with the number of hospital charts in the most prevalent schizophrenic

disorders treated with one of the agents.

57

Table 1 Mean ± S.D. daily dosages (mg/day) of olanzapine and risperidone in the Gálfi Béla Hospital

Disorders OLA RIS OLA RIS OLA RIS OLA RIS OLA RIS

Schizophrenia, Paranoid Type 10,8 ± 2,8 5,6 ± 1,7 11,7 ± 3,1 4,6 ± 1,5 11,3 ± 3,0 4,8 ± 1,4 11,8 ± 3,3 5,7 ± 1,9 11,8 ± 3,4 5,7 ± 1,8

Schizophrenia, Disorganized Type 12,4 ± 3,1 5,3 ± 1,5 11,8 ± 3,1 4,5 ± 1,4 12,7 ± 3,1 5,6 ± 1,8 13,4 ± 4,8 6,3 ± 2,0 13,5 ± 4,5 6,2 ± 2,1

Schizophrenia, Undifferentiated Type 13,4 ± 3,3 3,8 ± 1,4 12,8 ± 3,2 3,7 ± 1,3 14,2 ± 5,1 5,2 ± 1,6 14,1 ± 5,1 5,8 ± 1,9 14,2 ± 5,2 5,6 ± 1,9

Schizophrenia, Residual Type 13,7 ± 3,5 3,9 ± 1,4 13,8 ± 3,5 5,3 ± 1,7 12.8 ± 3,1 5,2 ± 1,7 14,0 ± 5,0 5,3 ± 1,4 13,9 ± 5,0 5,3 ± 1,5

Schizoaffective Disorder, Unknown Type 13,6 ± 3,4 3,7 ± 1,2 13,8 ± 3,6 3,9 ± 1,3 13,8 ± 3,5 5,2 ± 1,6 12,9 ± 3,2 5,1 ± 1,4 13,3 ± 4,8 4,8 ± 1,3

20031999 2000 2001 2002

58

Table 2 Number of hospital charts in the most prevalent schizophrenic disorders and the number of charts with olanzapine (OLA) or risperidone (RIS)

treatment in the Gálfi Béla Hospital

ICD-10 Disorders OLA or RIS All OLA or RIS All OLA or RIS All

F20.0 Schizophrenia, Paranoid Type 41 92 50 105 43 82

F20.1 Schizophrenia, Disorganized Type 16 22 7 10 17 26

F20.3 Schizophrenia, Undifferentiated Type 20 42 10 18 9 21

F20.5 Schizophrenia, Residual Type 49 87 41 76 43 74

F25.9 Schizoaffective Disorder, Unknown Type 15 33 30 55 16 29

Total number of hospital charts 141 276 138 264 128 232

Number of charts with OLA or RIS treatment as a 51% 52% 55%

percentage of all charts in the most prevalent disorders

ICD-10 = International Classification of Diseases, 10th edition

ICD-10 Disorders OLA or RIS All OLA or RIS All OLA or RIS All

F20.0 Schizophrenia, Paranoid Type 69 122 72 129 47 99

F20.1 Schizophrenia, Disorganized Type 13 24 15 25 20 23

F20.3 Schizophrenia, Undifferentiated Type 11 16 14 17 25 33

F20.5 Schizophrenia, Residual Type 42 84 47 83 39 85

F25.9 Schizoaffective Disorder, Unknown Type 19 36 31 41 39 50

Total number of hospital charts 154 282 179 295 170 290

Number of charts with OLA or RIS treatment as a 55% 61% 59%

percentage of all charts in the most prevalent disorders

ICD-10 = International Classification of Diseases, 10th edition

ICD-10 Disorders OLA or RIS All OLA or RIS All OLA or RIS All

F20.0 Schizophrenia, Paranoid Type 63 101 50 89 51 103

F20.1 Schizophrenia, Disorganized Type 11 20 11 24 21 27

F20.3 Schizophrenia, Undifferentiated Type 13 18 9 20 6 15

F20.5 Schizophrenia, Residual Type 49 82 62 79 52 83

F25.9 Schizoaffective Disorder, Unknown Type 43 77 61 97 60 73

Total number of hospital charts 179 298 193 309 190 301

Number of charts with OLA or RIS treatment as a 60% 62% 63%

percentage of all charts in the most prevalent disorders

ICD-10 = International Classification of Diseases, 10th edition

2007

2003 2004

2005 2006

1999 2000 2001

2002

59

Figure 3 - The use of olanzapine and risperidone (DDD/100 beds/day) in the examined

period in the Gálfi Béla Hospital

3,973,99

3,56

1,59

1,25

0,83

0,400,60

1,10

0,47 0,580,73 0,83

1,04 1,111,37 1,35

0,41

0,00

0,50

1,00

1,50

2,00

2,50

3,00

3,50

4,00

4,50

1999 2000 2001 2002 2003 2004 2005 2006 2007

olanzapine risperidone

Figure 4 - The use of olanzapine and risperidone (DDD/1000 persons/day) in the

examined period in Hungary

19,718,5

25,9

29,9 29,030,4

29,3 29,9

17,5

14,615,7 15,4

20,018,6

19,4

24,0 23,5

19,1

0,0

5,0

10,0

15,0

20,0

25,0

30,0

35,0

1999 2000 2001 2002 2003 2004 2005 2006 2007

olanzapine risperidone

60

E.1.1 Utilization study of clozapine, olanzapine and risperidone

Figure 5 summarizes the use of olanzapine, risperidone and clozapine (DDD/100 beds/day)

in the Gálfi Béla Hospital, while figure 6 represents the use of olanzapine, risperidone and

clozapine (DDD/1000 persons/day) in Hungary between 1999 and 2003. The use of

olanzapine and risperidon was increasing in the Gálfi Béla Hospital and Hungary in the

examined period. Figure 6 shows that the use of clozapine was decreasing in the country

study.

Figure 5 – The use of olanzapine, risperidone and clozapine (DDD/100 beds/day) in the

Gálfi Béla Hospital

0.00

5.00

10.00

15.00

20.00

25.00

30.00

35.00

1998 1999 2000 2001 2002 2003 2004

risperidone olanzapine clozapine

61

Figure 6 – The use of olanzapine, risperidone and clozapine (DDD/1000 persons/day) in

Hungary

0,00

0,20

0,40

0,60

0,80

1,00

1,20

1,40

1999 2000 2001 2002 2003

olanzapin risperidon c lozapin

62

E.2 Diabetes prevalence among elderly patients in psychiatric rehabilitation

The examination shows higher prevalence of diabetes among schizophrenic patients

(12.72%) in comparison with the Hungarian population (6.85%) in the age group of 18-64

among both sexes, while there was no higher risk of diabetes found in the age group of

above 65 among both sexes [154]. Table 3 presents diabetes prevalence in all age groups in

Hungary and in the examined patient population treated with antipsychotics. Diabetes

prevalence in the sample population shows almost a double value (12.72%) in comparison

to the Hungarian population prevalence (6.85%). The Hungarian Central Statistical Office

and the National Institute for Strategic Health Research presented data on the prevalence of

diabetes in the Hungarian population. Table 4 summarizes the results of the hypothesis test.

The hypothesis test shows that in the age group of 18-64 significantly higher diabetic rates

were found among both sexes. In the age group above 65 there was no significant

difference between the treated and the normal population rates neither among the male nor

the female patients. We could miss the effect because of the small number of patients (n =

245) fulfilling the criteria in those groups. Schizophrenic patients have higher mortality and

the population prevalence of diabetes is higher in the age group of 18-65, while in the non-

schizophrenic population the prevalence of diabetes is higher over the age of 65. Sex

differences in schizophrenia can be caused by the disease process itself, by genetic and

hormonal differences, by differences in the maturation and morphology of the brain and in

age- and gender- specific behavioral patterns [13]. However, in our study no significant

differences were observed between the two sexes.

Calculations on the all, male and female groups are made with age adjusted prevalence

based on 2001 Census.

The study is based on a survey of hospital charts in the Gálfi Béla Hospital and the National

Health Insurance Fund registry.

63

Table 3

Diabetes average prevalence in Hungary in all age groups within 2000-2006 and in the

examined patient population treated with antipsychotics

Population prevalence (%) Sample prevalence (%)

Age Male Female Male Female

All 6.16 7.47 14.17 10.89

All 6.85 12.72

64

Table 4.

Results of the hypothesis testing at a 5% of significance level

Diabetic patients All patients Population Probability Significance n

prevalence p(n) Yes +

No –

(age adjusted

all 18+ 46 245 0.0694 p(0-45) = 0.9999 +

(0.0886)

Female s 20 110 0.0758 p(0-19) = 0.9948 +

(0.0985)

Males 26 135 0.0620 p(0-25) = 0.9999 +

(0.0792)

Female s 13 67 0.0450 p(0-12) = 0.9999 +

18-64 years

Females 7 43 0.1819 p(0-7) = 0.4663 -

65+ years

Males 17 88 0.0488 p(0-16)=0.9999 +

18-64 years

Males 9 47 0.136 p(0-9)=0.9023 -

65+ years

65

F DISCUSSION

F.1 Evaluation of the results of the utilization study of olanzapine and

risperidone

There was an increase in the use of both atypical antipsychotics over the examined period.

Figure 3 shows that although there was a stagnancy of the use in 2000 and 2001 for

olanzapine and in 2001 for risperidone, there was a gross increase in the use of both agents

over the whole surveyed period. An increase of 1.142 mg/day/year (p = 0.0004) was found

for olanzapine and 1.6483 mg/day/year (p = 0.002) for risperidone. Therefore, it might

justly be concluded that risperidone use increased more rapidly. Figure 4 indicates country

data of the National Health Insurance Fund, showing an increase with both agents. An

increase of 0.507 mg/day/year (p = 0.0002) was found for olanzapine and 0.130

mg/day/year (p = 0.0001) for risperidone. Even if the use of both agents shows a dynamic

accession, the growth with olanzapine was significantly higher (p=0.026) in the examined

period on a country level, while the gerontopsychiatric profile of the hospital supports more

use of risperidone. It was observed that the clinical preferences are consistent with the

literature, which suggests that the drugs have similar indications and are equally effective.

While the use of olanzapine shows a greater growth at a country level, the

gerontopsychiatric profile of the hospital supports more use of risperidone.

Concerning the the daily therapy costs of clozapine in comparison with olanzapine and

risperidon, it could be stated that although the daily therapy costs of clozapine are much

lower than that of olanzapine and risperidon, the reason of the decrease could be the serious

side-effect profile of clozapine. Calculations on linear regression showed strong relation

between the calculated values. The latter was also proved by the high values of correlation

coefficients (rCLO=0,9008, rOLA=0,9966, rRIS=0,9922). Because of its side-effect profile

clozapine remains the atypical agent in case of therapy resistance.

In the Gálfi Béla Hospital the use of clozapine showed a small increase, what could be

indicated by the relative big number of therapy resistance.

66

F.2. Evaluation of the diabetes prevalence among elderly patients in

psychiatric rehabilitation

Country data give a clear view on the growing utilization trend of atypical antipsychotics in

Hungary. A large study of 38,600 patients with schizophrenia suggested that patients on

atypical treatment were 9% more likely to have diabetes than conventionally treated

patients [155]. Risperidone however was not associated with an increased risk across the

entire age group, just in patients under 40 years old [156].

The examination shows higher prevalence of diabetes among schizophrenic patients treated

with antipsychotics (12.72%) in comparison with the Hungarian population (6.85%) while

there was no higher risk of diabetes found in the age group of 65+ among both sexes.

Nevertheless the difference was found significant; the latent diabetes prevalence of the

Hungarian non-schizophrenic population is higher than the officially published value.

Based on the results it would seem prudent to monitor patients’ weight, glucose and lipid

levels, especially in the age group of 18-64, whatever antipsychotics are prescribed for

them. The limitation of this study was the relatively small number of schizophrenic patients

in the examined sample (n = 245).

67

G NEW SCIENTIFIC RESULTS AND CONCLUSION

1. Analysis on the data sources showed a clear accession for olanzapine and

risperidone in the examined term. There was a growth in use of the agents over the

whole study term, although an unambiguous increase started only in 2001. In

general, the clinical preferences as revealed by the study are consistent with the

literature, which suggests that the drugs have similar indications and are equally

effective.

2. The use of olanzapine and risperidone show a dynamic accession between 1999 and

2007 in the Gálfi Béla Hospital and in Hungary. Country data clearly show the

growing utilisation trend of atypical antipsychotics in Hungary. Even if the use of

olanzapine shows a greater growth at a country level, the gerontopsychiatric profile

of the hospital supports more use of risperidone.

3. Our results did not show higher risk of diabetes among elderly schizophrenic

patients treated with atypical antipsychotics. Nevertheless it would seem prudent to

monitor patients’ weight, glucose and lipid levels, especially in the age group of 18-

64, whatever antipsychotics are prescribed for them. Although there is a growing

trend in the use of atypical antipsychotics in the medication of schizophrenia in

Hungary, no relevant data can be found in the literature considering the metabolic

effects of these drugs in the Hungarian population. Atypical antipsychotics, which

have a better side-effect profile are more suitable for elderly people [155]. This

paper includes an assessment of the potential contributory role of treatment-induced

ATC-A10A parenteral and ATC-A10 B oral antidiabetic use during treatment with

atypical antipsychotics in psychiatric rehabilitation among elderly patients in

Hungary.

68

Practical aspects of the results

Daily therapy costs of olanzapine and risperidone as the most often ordered atypical

antipsychotics and of all other atypical agents are higher in comparison with typical

agents. Whereas drug costs are the smaller part of therapy costs of psychotic

diseases, hospitalization can take the half of all costs. With the use of atypical

antipsychotics all costs of the therapy can be decreased and the quality of life of the

treated patient is significantly better than in patients treated with classical agents.

Country data show growing utilisation trend of atypical antipsychotics in Hungary,

while the use of clozapine is decreasing. Clozapine remains the antipsichotic agent

of therapy resistant schizophrenic patients. The incidence of hyperglycaemia and

lipid abnormalities can be higher among patients treated with atypical

antipsychotics. Therefore schizophrenic patients with one or more risk factors of

diabetes should be regularly controlled in point of weight, blood pressure, glucose

and lipid levels.

69

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84

ACKNOWLEDGEMENT

First of all I wish to express my sincere thanks to my tutor Dr. Romána Zelkó, the

Director of the University Pharmacy Department of Pharmacy Administration of the

Semmelweis University, for providing me with the opportunity to work in the

Institute.

Furthermore, I express my special thanks to Csilla Andrea Reszegi and Dr. Balázs

Hankó for their help in the data collection.

Sincere thanks to Dr. Zoltán Bujdosó (Medical Director of the Gálfi Béla Hospital)

for his

effective participation in the clinical part of my work, and for the opportunity to

support the

studies in the Gálfi Béla Hospital.

85

PUBLICATIONS AND LECTURES

Publications

1. Klebovich A, Bujdosó Z, Zelkó R. (2003) Utilization and comparision study

of antipsychotics at the Department of Psychiatry and Psychotherapy of the

Semmelweis University and the Gálfi Béla Hospital. Acta Pharm. Hung., 73:

131-135.

2. Klebovich A, Reszegi CsA, Zelkó R. (2004) Utilization study of clozapine,

olanzapine and risperidone in Hungary. Acta Pharm. Hung., 74: 233-236.

3. Klebovich A, Bujdosó Z, Meskó A, Zelkó R. (2005) Comparison of

olanzapine and risperidone use in psychiatric rehabilitation. Therapie, 60

(6): 573-576.

4. Klebovich A, Hankó B, Orbán K, Zelkó R. (2007) Antipsychotic treatment

and the prevalence of diabetes among elderly patients in psychiatric

rehabilitation. Arch. Gerontol. Geriatr., Közlés alatt,

DOI::10.1016/j.archger.2007.09.005

Lectures

1. Klebovich A.: Az Európai Únió Gyógyszerészeti Csoportja a PGEU

(Pharmaceutical Group of the European Union) bemutatása néhány aktuális

gyógyszerészeti kérdés tükrében

XXXVII. Rozsnyai Mátyás Emlékverseny, Kaposvár, 2002. május 23-25.

86

2. Klebovich A., Bujdosó Z., Zelkó R.:

Antipszichotikumok utilizációs vizsgálata a Gálfi Béla Gyógyító és

Rehabilitációs Kht. Szakkórházában.

Magyar Kórházi Gyógyszerészek XIV. Kongresszusa, Debrecen,

2004. május 13-15.

3. Klebovich A.: Antipszichotikumok alkalmazása a gerontopszichiátriai

gyakorlatban.

Ph. D. Tudományos Napok 2005, Semmelweis Egyetem Doktori

Iskola, Budapest, 2005.

87

OFFPRINTS OF THE PUBLICATIONS