Download 2.1 About schizophrenia

KAUNAS UNIVERSITY OF MEDICINE
FACULTY OF PHARMACY
DEPARTMENT OF BASIC AND CLINICAL PHARMACOLOGY
Trends in the use of antipsychotic drugs in Lithuania on 2003-2005 year.
Evaluation of effectiveness of antipsychotics.
Meta-analysis
MASTER WORK
Done by: L. Katajceva, 5th course of Pharmacy studies
Supervised by: E. Kaduševičius, MD., Pharm. D., Assoc. prof.
Kaunas, 2006
Adam "was a wonderfully, sweet young man," his mother said. He was a high school
athlete and captain of his team, active in his college fraternity, a good student. He had graduated
from college and started working while studying for a professional certification exam when
something inside him changed. . .
Adam stopped being careful about his personal appearance. He told his parents he
suspected them of communicating with each other in secret ways, such as in sign language which
he couldn't understand. He began to hear his mother's voice in his head and he asked her why she
was sending him messages. . . he was diagnosed with schizophrenia.
Dr. W.A.F. Browne
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TABLE OF CONTENTS
ABBREVIATIONS.........................................................................................................................5
1. INTRODUCTION AND THE NOVELTY OF STUDY ………...............................................6
2. SCHIZOPHRENIA: DIAGNOSIS, CLASSIFICATION AND TREATMENT.........................8
2.1 About schizophrenia..............................................................................................................8
2.2 Diagnosis and classification...................................................................................................9
2.3 Brief Psychiatric Rating Scale.............................................................................................10
2.4 Getting treatment.................................................................................................................11
2.5 What is the outlook..............................................................................................................12
2.6 Medication update................................................................................................................12
3. OBJECTIVE AND AIMS.........................................................................................................26
4. MATERIAL AND METHODS.................................................................................................27
4.1 The ATC classification – structure and principles……………...…………………….…...27
4.2 History of the ATC/DDD system…………………………………………………………27
4.3 The purpose of the ATC/DDD system................................................................................28
4.4 The DDD- definition and principles....................................................................................28
4.5 DDD for comparison of consumption.................................................................................29
4.6 Utilisation studies................................................................................................................32
4.7 Outcome studies...................................................................................................................33
4.8 Pharmacoeconomic studies..................................................................................................34
4.9 Cost benefit analysis............................................................................................................36
4.10 Data sources.......................................................................................................................38
4.11 Meta-analysis of antipsychotic drugs................................................................................38
5. RESULTS..................................................................................................................................41
5.1 Main results of meta-analysis of antipsychotic drugs..........................................................41
5.2 Comparison of consumption over the three years period....................................................50
5.3 Pharmacoeconomic calculations suggesting the reference price.........................................53
6. DISCUSSION............................................................................................................................62
6.1 Plasma concentration monitoring for antipsychotic............................................................63
6.2 Therapeutic drug monitoring of antipsychotic.....................................................................64
6.3 Reduction of hospital days for schizophrenic patients........................................................65
6.4 The introduction of new antipsychotic medicines...............................................................65
6.5 Supporting different pharmaceutical formulations..............................................................67
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6.6 The introduction of already existing antipsychotic agents into the list of
reimbursement...............................................................................................................................68
7. CONCLUSIONS.......................................................................................................................69
8. SUMMARY...............................................................................................................................70
9. SANTRAUKA...........................................................................................................................71
10. REFERENCES........................................................................................................................72
ANNEXES 1- 9………………………………………………..…………………………...…79
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ABBREVIATIONS
AIDS
Acquired Immune Deficiency Syndrome
APS
Antipsychotics
ATC
Anatomical Therapeutic Chemical classification
BNF
British National Formulary
BPRS
Brief Psychiatric Rating Scale
CBA
Cost Benefit Analysis
CEA
Cost Effectiveness Analysis
CI
Confidence Interval
CNS
Central Nervous System
CMA
Cost Minimisation Analysis
CUA
Cost Utility Analysis
DDD
Defined Daily Dose
ECG
Electrocardiogram
ECHO
Economic, Clinical and Humanistic Outcomes
ECT
Electroconvulsive Therapy
EPS
Extrapyramidal Symptoms
EU
European Union
FDA
Food and Drug Administration
FEP
First-Episode Psychosis
GP
General practitioner
IMS
International Marketing Service
NA
Not Assessed
NICE
National Institute for Health and Clinical Excellence
MS
Multiple Sclerosis
OR
Odds Ratio
SIDS
Sudden Infant Death Syndrome
QUALY Quality Adjusted Life Year
WHO
World Health Organization
WMD
Weighted Mean Differences
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1. INTRODUCTION AND THE NOVELTY OF STUDY
In economic theory, prices are determined by the invisible hand of self-interest as buyers
and sellers participate in the marketplace. But such theories are not relevant to the current market
for pharmaceuticals, where neither the consumer nor the prescriber are paying for medication.
There is enormous inequality in the availability of information regarding value, and almost
complete opacity regarding the real price of a particular drug. Furthermore, the great majority of
sales involve patented items, creating a legal monopoly. There would seem to be real need for
the third party payer to know the value of what they are purchasing. Pharmacoeconomics should
help [1].
Prior to statements approval, manufacturers are required to carry out sophisticated studies
of a drug’s safety and efficacy, but there are no requirements for comparable pharmacoeconomic
studies. In the absence of such a requirement, post-launch studies are generally a marketing tool.
Not surprisingly, the most consistent finding in the pharmacoeconomic literature on atypical
antipsychotics is a highly significant correlation between funding source and which product is
found to be most cost-effective [2].
The issue of cost-effectiveness in the pharmacoeconomics of mental illness is a new
concept. As methodologies for exploring this subject unfold, the most fundamental objective for
health care professionals and managed care officials is to find ways in which currently available
resources can be used most effectively. The managed care perspective is highly cost-based
within the market it serves. In addition to cost, other factors that influence the managed care
perspective are a short-term focus, segmentation of budgets, and measurable indicators of
outcome, cost, and quality of care [3].
Schizophrenia generates important costs for society direct, as a consequence of
hospitalization and outpatient treatment, and indirect; related to loss of productivity. The atypical
antipsychotics, such as olanzapine, have supposed an important advance in the treatment of
schizophrenia. The greater cost of atypical antipsychotics with respect to conventional drugs has
led to the conduction of pharmacoeconomic studies to determine its efficiency.
The cornerstone of recent pharmacoeconomic work in schizophrenia is the hypothesis
that the improved efficacy of novel antipsychotic medications will lead to a reduction in medical
services utilization, thereby reducing direct medical costs associated with treatment. Creating the
most valid design to prospectively examine the effectiveness and costs of competing
pharmacotherapies requires dialectic of opposing research paradigms. The final protocol must
represent a series of decisions that strike a careful balance between being scientifically sound
(internal validity) and generalizable to the real world of clinical treatment (external validity). The
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results must be useful to decision-makers in determining to what extent reductions in healthcare
expenditures can offset higher drug acquisition costs within their type of treatment environment.
Cost-effectiveness studies of novel antipsychotic medications will increase in importance
as the use of second-generation agents continues to expand [4].
Over the past 50 years, antipsychotic medications have emerged as the cornerstone of
management in concert with other important interventions, such as psychosocial and economic
support and rehabilitation efforts. However, the unrivalled role of conventional antipsychotic
medications has been continuously challenged by the wide range of adverse effects of these
medications and their lack of usefulness in the treatment of neurocognitive deficits as well as
deficit and negative symptoms. In addition, the lack of subjective tolerability of these agents and
their negative impact on quality of life has complicated management for a large number of
patients. Over the last 15 years, several new atypical antipsychotic medications have been
introduced, including amisulpride, remoxipride, risperidone, sertindole, olanzapine, zotepine,
quetiapine, ziprasidone and aripiprazole. In general, the new antipsychotics have shown
themselves to be at least comparable in efficacy to conventional antipsychotics but with superior
subjective tolerability and a more favourable adverse effect profile. The majority of quality of
life studies involving new antipsychotic agents have evaluated the benefits of risperidone,
olanzapine and clozapine; only a few studies have examined the effects of other new
antipsychotics [5].
Formal pharmacoeconomic studies are needed to confirm the expected cost benefit of
atypical antipsychotics in reducing aggressive behaviour in residents with schizophrenia [6].
This Master work suggests ways in which available resources can be used more
effectively to treat mental illness within the present health care system.
Novelty of study
We did not find data about utilisation of antipsychotic drugs in Lithuania at any time
period. Also the same we can say about pharmacoeconomics studies on antipsychotic drugs
evaluation in Lithuania.
This paper reviews the possibility to control expenses on antipsychotics drugs, to
improve treatment results and the same for outcomes and to keep budget of schizophrenia
treatment very effective in reducing expenditures or limiting their growth and brings
reimbursement of antipsychotics clarity. On the other hand implementation of reference price
system in the reimbursement can improve market transparency by eliminating gaps between
therapeutically equivalent medicines.
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2. SCHIZOPHRENIA: DIAGNOSIS, CLASSIFICATION AND TREATMENT
2.1 About schizophrenia

1 in 200 babies born will develop schizophrenia during their lifetime.

The onset is typically between the ages of 15 and 25 and often confused with adolescent
behaviour thereby delaying diagnosis.

Current antipsychotic treatments are only partially effective and can have serious side
effects.

10% of patients suicide accounting for more deaths than AIDS, SIDS and MS combined.

Schizophrenia can affect any family and in most cases arises where there is no previous
history of the illness.

It often leads to long-term disability, unemployment, drug and alcohol abuse, family
trauma, homelessness, crime and imprisonment [7].

It costs the Lithuanian community nearly 40 mln Litas each year.
Schizophrenia is a severe, disabling and relative common psychiatric disorder, estimated
to affect approximately 1% of the population. Its course is generally chronic, with acute
psychotic exacerbations that may frequently require hospitalisation.
The clinical picture, depending on the stage of the illness, includes a wide range of
symptoms:
delusions,
hallucinations,
agitation,
suspiciousness,
hostility,
conceptual
disorganisation, blunted affect, emotional and social withdrawal, lack of spontaneity, poverty of
speech and a wide range of neurocognitive deficits. However, in addition to the suffering the
condition causes patients and their families, schizophrenia has a major economic impact in terms
of health and psychosocial services required, lost productivity due to unemployment and longterm disability [8].
Schizophrenia is a cluster of related difficulties in behaviour, thoughts and feelings.
Commonly encountered symptoms of schizophrenia include Bleuler’s 4 As: autism
(preoccupation with internal stimuli), inappropriate affect (external manifestations of mood),
associational disturbances (illogical or idiosyncratic thought process), and ambivalence
(simultaneous, contradictory thinking). Mendel, in seeking to establish precision to the diagnosis
of schizophrenia, has identified three basic disabilities of function which are the trademarks of
schizophrenia. Whether in psychotic exacerbation or remission, schizophrenics show difficulties
in anxiety management, interpersonal relationships and learning from experience (failure of
historicity).
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In spite of extensive research, the aetiology of schizophrenia remains mostly unclear.
However, it is recognised that schizophrenia is likely to be a heterogeneous disorder with
variable aetiological and treatment response patterns. It follows, then, that current approaches to
the management of schizophrenia require a range or interventions directed or ameliorating
symptoms, forestalling further deterioration throughout the long-term course of the disorder, and
enhancing the patient’s already compromised quality of life and functional state.
Over the past five decades, the pharmacological approach has evolved as the comer stone
of clinical management of schizophrenia; other approaches in the spectrum of interventions
include rehabilitative efforts and psychosocial support for both the individual and the family [9].
2.2. Diagnosis and classification
The patient’s presentation during a psychotic episode does not clearly dictate the
diagnosis. Differentiation of manic episodes and drug-induced psychosis from schizophrenia is
one of the most commonly encountered diagnostic and treatment dilemmas. The course of the
illness is more important in the differential diagnosis than the number and severity of presenting
symptoms. The signs of illness should be present for at least six months, and a residual
impairment should be observed in the spheres of social behaviour perceptual experiences
affective responses and thought process.
The classification categories for diagnosis of schizophrenia are described below:
-
Paranoid schizophrenia - manifested by prominent persecutory or grandiose delusions, or
hallucinations with a persecutory or grandiose content;
-
Disorganized schizophrenia - characterized by marked incoherence with an unresponsive
inappropriate or silly affective presentation;
-
Catatonic schizophrenia - characterized by marked psychomotor disturbances which can
present as stupor, rigidity, strange body language, or excitement;
-
Undifferentiated schizophrenia, the largest category, is used whenever prominent
psychotic symptoms cannot be classified in any category previously listed.
-
Residual schizophrenia - a category which is used when there has been at least one
previous episode [10].
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2.3. Brief Psychiatric Rating Scale
Many theories exist regarding the causes of schizophrenia, though none have been
confirmed. Over the years, theories have ranged from the alienating behaviour of the
schizophrenogenic (cold, distant, dominant) mother to a viral infection, and finally genetics.
Although schizophrenia is not fully understood, the toll on its victims is undeniable. The
evaluation of treatment effectiveness depends on accurate measurement of symptoms and other
relevant outcomes.
The Brief Psychiatric Rating Scale (BPRS) is a clinician-administered tool designed to
assess psychiatric symptoms in a rapid and efficient way. A skilled clinician should be able to
administer the instrument in 30 minutes or less. Ratings on the BPRS scale are based upon
observation of the patient and verbal report by the patient.
The observations are based on the physical, intellectual, and social behaviour of the
patient as well as verbal report by the patient. The BPRS results in a total score, where higher
scores indicate greater symptom severity [11].
This form consists of 24 symptom constructs, each to be rated in a 7-point scale of
severity ranging from 'not present' to 'extremely severe'. If a specific symptom is not rated, mark
'NA' (not assessed). Circle the number headed by the term that best describes the patient's present
condition.
The BPRS has been the most frequently used psychiatric rating scale for the past four
decades and only a highly selected number of studies that used the BPRS can be quoted. It has
been successfully used to demonstrate efficacy of antipsychotic drugs, including the newer
antipsychotics.
The BPRS is most frequently used in schizophrenia. It is still considered to provide at
least as good a measure of the deficit syndrome as the more recently developed scales that were
designed specifically for that purpose, which makes the use of extra 'specific' scales superfluous.
Needless to say that the BPRS has an excellent sensitivity to change, i.e. to identify the
therapeutic effects of drugs or other systematic interventions (See Annex 1 for BPRS scale) [12].
2.4. Getting treatment
Although schizophrenia is not yet a "curable" disease, it is treatable. The proper treatment
of schizophrenia includes the following:
1. Medication;
2. Education;
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3. Family Counselling;
4. Hospitalization and Regular Follow-up;
5. Residential and Rehabilitation Programs;
6. Self-Help Groups;
7. Nutrition and Rest;
8. Electroconvulsive Therapy (ECT) [13].
The introduction of the first antipsychotic medication, chlorpromazine, in the early 1950s
ushers in era of optimism in the management of schizophrenia. Development of chlorpromazine
and other subsequent antipsychotic medications, collectively known as typical or conventional
antipsychotics, provided for the first time more specific and effective management of psychotic
symptoms, both in the acute and chronic phases of the illness. However, their pre-eminent role in
the treatment of psychotic disorders was to be challenged on several accounts, particularly with
respect to their wide range of physical and subjective adverse effects. Furthermore, increasing
recognition of the limited usefulness of typical antipsychotics in the treatment of the broad
spectrum of psychotic symptoms and neurocognitive deficits, as well as the lack of response to
these agents demonstrated by at least 30% of patients with schizophrenia, limited their role and
accelerated the search for better antipsychotic medications.
Since schizophrenia may not be a single condition and its causes are not yet known,
current treatment methods are based on both clinical research and experience. These approaches
are chosen on the basis of their ability to reduce the symptoms of schizophrenia and to lessen the
chances that symptoms will return. During the 1990s there were dramatic advances in the
treatment of schizophrenia. The first of the new (post-clozapine) atypical antipsychotic
medications, risperidone, was introduced in1994, and followed by olanzapine, sertindole and
ziprasidone. The pharmacologic profiles of these newer antipsychotic medications in some ways
resemble that of clozapine, but they are not associated with the more severe side effects of
clozapine. Thus, the new atypical medications may be effective for the symptoms of
schizophrenia, but with fewer troublesome and possibly severe extrapyramidal symptoms (EPS)
and other side effects.
2.5. What is the outlook?
The outlook for people with schizophrenia has improved over the last 25 years. Although
no totally effective therapy has yet been devised, it is important to remember that many people
with the illness improve enough to lead independent, satisfying lives. As we learn more about the
causes and treatments of schizophrenia, we should be able to help more patients achieve
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successful outcomes. Given the complexity of schizophrenia, the major questions about this
disorder - its cause or causes, prevention, and treatment - must be addressed with research.
Although progress has been made toward better understanding and treatment of schizophrenia,
continued investigation is urgently needed. This is a time of hope for people with schizophrenia
and their families. Research is gradually leading to new and safer medications and to unravelling
the complex causes of the disease. Scientists are using many approaches from the study of
molecular genetics to the study of populations to learn about schizophrenia. Methods of imaging
the brain's structure and function also hold the promise of new insights into the disorder [14].
2.6 Medication update
Use of antipsychotic medications
Antipsychotic drugs relieve florid psychotic symptoms such as thought disorder,
hallucinations, and delusions, and prevent relapse. Although they are usually less effective in
apathetic withdrawn patients, they sometimes appear to have an activating influence. Patients
with acute schizophrenia generally respond better than those with chronic symptoms.
Long-term treatment of a patient with a definite diagnosis of schizophrenia may be
necessary even after the first episode of illness in order to prevent the manifest illness from
becoming chronic. Withdrawal of drug treatment requires careful surveillance because the
patient who appears well on medication may suffer a disastrous relapse if treatment is withdrawn
inappropriately. In addition the need for continuation of treatment may not become immediately
evident because relapse is often delayed for several weeks after cessation of treatment.
Conventional antipsychotic drugs are considered to act by interfering with dopaminergic
transmission in the brain by blocking dopamine D2 receptors, which may give rise to the
extrapyramidal effects described below, and also to hyperprolactinaemia. Antipsychotic drugs
may also affect cholinergic, alpha-adrenergic, histaminergic, and serotonergic receptors.
Antipsychotics should be used with caution in patients with hepatic impairment, renal
impairment, cardiovascular disease, Parkinson’s disease (may be exacerbated by antipsychotics),
epilepsy (and conditions predisposing to epilepsy), depression, myasthenia gravis, prostatic
hypertrophy, or a personal or family history of angle-closure glaucoma (avoid chlorpromazine,
pericyazine and prochlorperazine in these conditions). Caution is also required in severe
respiratory disease and in patients with a history of jaundice or who have blood dyscrasias
(perform blood counts if unexplained infection or fever develops). Antipsychotics should be used
with caution in the elderly, who are particularly susceptible to postural hypotension and to hyper12
or hypothermia in very hot or cold weather. Serious consideration should be given before
prescribing these drugs for elderly patients. As photosensitisation may occur with higher
dosages, patients should avoid direct sunlight.
Antipsychotic drugs may be contra-indicated in comatose states, CNS depression, and
phaeochromocytoma. Most antipsychotics are best avoided during pregnancy, unless essential
and it is advisable to discontinue breast-feeding during treatment.
Drowsiness may affect performance of skilled tasks (e.g. driving or operating
machinery), especially at start of treatment; effects of alcohol are enhanced
Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and
closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.
Extrapyramidal symptoms are the most troublesome. They occur most frequently with
the
piperazine
phenothiazines
(fluphenazine,
perphenazine,
prochlorperazine,
and
trifluoperazine), the butyrophenones (benperidol and haloperidol), and the depot preparations.
They are easy to recognise but cannot be predicted accurately because they depend on the dose,
the type of drug, and on individual susceptibility.
Extrapyramidal symptoms consist of:

parkinsonian symptoms (including tremor), which may occur more commonly in adults
or the elderly and may appear gradually;

dystonia (abnormal face and body movements) and dyskinesia, which occur more
commonly in children or young adults and appear after only a few doses;

akathisia (restlessness), which characteristically occurs after large initial doses and may
resemble an exacerbation of the condition being treated; and

tardive dyskinesia (rhythmic, involuntary movements of tongue, face, and jaw), which
usually develops on long-term therapy or with high dosage, but it may develop on shortterm treatment with low doses—short-lived tardive dyskinesia may occur after
withdrawal of the drug.
Parkinsonian symptoms remit if the drug is withdrawn and may be suppressed by the
administration of antimuscarinic drugs. However, routine administration of such drugs is not
justified because not all patients are affected and because they may unmask or worsen tardive
dyskinesia.
Tardive dyskinesia is of particular concern because it may be irreversible on withdrawing
therapy and treatment is usually ineffective. However, some manufacturers suggest that drug
withdrawal at the earliest signs of tardive dyskinesia (fine vermicular movements of the tongue)
may halt its full development. Tardive dyskinesia occurs fairly frequently, especially in the
elderly, and treatment must be carefully and regularly reviewed.
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Hypotension and interference with temperature regulation are dose-related side-effects
and are liable to cause dangerous falls and hypothermia or hyperthermia in the elderly.
Neuroleptic malignant syndrome (hyperthermia, fluctuating level of consciousness,
muscular rigidity, and autonomic dysfunction with pallor, tachycardia, labile blood pressure,
sweating, and urinary incontinence) is a rare but potentially fatal side-effect of some drugs.
Discontinuation of the antipsychotic is essential because there is no proven effective treatment,
but cooling, bromocriptine, and dantrolene have been used. The syndrome, which usually lasts
for 5–7 days after drug discontinuation, may be unduly prolonged if depot preparations have
been used.
Other side-effects include: drowsiness; apathy; agitation, excitement and insomnia;
convulsions; dizziness; headache; confusion; gastro-intestinal disturbances; nasal congestion;
antimuscarinic symptoms (such as dry mouth, constipation, difficulty with micturition, and
blurred vision); cardiovascular symptoms (such as hypotension, tachycardia, and arrhythmias);
ECG changes (cases of sudden death have occurred); endocrine effects such as menstrual
disturbances, galactorrhoea, gynaecomastia, impotence, and weight gain; blood dyscrasias (such
as agranulocytosis and leucopenia), photosensitisation, contact sensitisation and rashes, and
jaundice (including cholestatic); corneal and lens opacities, and purplish pigmentation of the
skin, cornea, conjunctiva, and retina [15].
Classification of antipsychotics
Until antipsychotics can be subdivided according to differentiated effects on psychic
functions (for example on positive/negative symptoms and cognitive functions), the best
classification seems to be one based upon receptor-binding profiles and the side effects that
follow. Nowadays the most popular classification seems to be separating all antipsychotics to
conventional and atypical. Such a combined pharmacological-clinical approach appears fruitful
to clinicians as well as pharmacologists. According to the receptor-binding classification new
antipsychotics can be subdivided into three main categories: the relatively pure dopamine
antagonists (D2 antagonists, including sulpiride and amisulpiride); the dopamine (D2)-serotonin
(5-HT2)-norepinephrine (alpha 1) antagonists (risperidone, ziprazidone and sertindole); and the
multireceptor antagonists (clozapine, olanzapine and seroquel). Clozapine is still the most potent
antipsychotic and the least potent at inducing extrapyramidal symptoms. New drugs such as
olanzapine, seroquel and sertindole represent the further development of clozapine's positive
qualities, while risperidone and ziprasidone are dominated to a greater extent by relatively
traditional dopamine D2 receptor blockade [ 16].
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The phenothiazine derivatives can be divided into 3 main groups.

Group 1: chlorpromazine, levomepromazine (methotrimeprazine), and promazine,
generally characterised by pronounced sedative effects and moderate antimuscarinic and
extrapyramidal side-effects.

Group 2: pericyazine and pipotiazine, generally characterised by moderate sedative
effects, marked antimuscarinic effects, but fewer extrapyramidal side-effects than groups
1 or 3.

Group 3: fluphenazine, perphenazine, prochlorperazine, and trifluoperazine, generally
characterised by fewer sedative effects, fewer antimuscarinic effects, but more
pronounced extrapyramidal side-effects than groups 1 and 2.
Drugs of other chemical groups tend to resemble the phenothiazines of group 3. They
include the butyrophenones
(benperidol
and haloperidol);
diphenylbutylpiperidines
(pimozide); thioxanthenes (flupentixol and zuclopenthixol); and the substituted benzamides
(sulpiride).
The goals of antipsychotic medications:

Efficacy without adverse effects;

Improved subjective tolerability and quality of life;

Positive long-term outcome;

Cost effectiveness.
Stages of Response:
There are four stages to the schizophrenic’s response to drug therapy:
1. Medicated cooperation- the patient responds to the calming properties of the major
tranquilizers. This stage usually occurs within the first week of therapy.
2. Improved socialization- the patient begins to obey ward or society rules and begins to act
in a socially appropriate fashion. Occurs within the first two to six weeks of drug therapy.
3. Elimination of thought disorder occurs within any time frame. The individual begins to
think and behave more normally.
4. Maintenance therapy stage- an individual can most benefit from no drug therapies [17].
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Choice of antipsychotic medications
Previous response is the best prognosticator for the therapeutic success in subsequent
exacerbations of a schizophrenic process. Additionally, the metabolic and pharmacodynamic
variables affecting an antipsychotic drug‘s effects appear to be genetically transmitted.
Clinician choice of an atypical antipsychotic may depend on a number of factors such as
perceived efficacy, tolerability and cost. It is also important that the choice of treatment takes
into consideration the previous response to treatment, experience of side-effects and personal
clinical characteristics. The receptor-affinity profiles of the atypical antipsychotics differ; with
the exception of amisulpride, a selective D2/D3 antagonist, all the atypical antipsychotics exhibit
a greater affinity for the serotonin-2A receptors than dopamine receptors. However, there is no
evidence that the variation in receptor affinities is relevant to efficacy. Indeed, the crucial factor
may be fast dissociation from low affinity for the D2 receptor. Tolerability also varies between
the atypical antipsychotics and the side-effect profile may be related to the receptor-affinity
profile of the individual drugs. Extrapyramidal side-effects are generally less of a problem with
most atypical drugs than with conventional drugs, but weight gain, loss of glycaemic control,
sedation and hyperprolactinaemia remain problematic in some patients [18].
As indicated above, the various drugs differ somewhat in predominant actions and sideeffects. Selection is influenced by the degree of sedation required and the patient's susceptibility
to extrapyramidal side-effects. However, the differences between antipsychotic drugs are less
important than the great variability in patient response; moreover, tolerance to secondary effects
such as sedation usually develops. The atypical antipsychotics may be appropriate if
extrapyramidal side-effects are a particular concern (see under Atypical Antipsychotics, below).
Clozapine is used for schizophrenia when other antipsychotics are ineffective or not tolerated.
Prescribing of more than one antipsychotic at the same time is not recommended; it may
constitute a hazard and there is no significant evidence that side-effects are minimised.
Chlorpromazine is still widely used despite the wide range of adverse effects associated
with it. It has a marked sedating effect and is useful for treating violent patients without causing
stupor. Agitated states in the elderly can be controlled without confusion, a dose of 10 to 25 mg
once or twice daily usually being adequate.
Flupentixol (flupenthixol) and pimozide are less sedating than chlorpromazine.
Sulpiride in high doses controls florid positive symptoms, but in lower doses it has an
alerting effect on apathetic withdrawn schizophrenics.
16
Fluphenazine, haloperidol, and trifluoperazine are also of value but their use is limited
by the high incidence of extrapyramidal symptoms. Haloperidol may be preferred for the rapid
control of hyperactive psychotic states; it causes less hypotension than chlorpromazine and is
therefore also popular for agitation and restlessness in the elderly, despite the high incidence of
extrapyramidal side-effects.
Promazine is not sufficiently active by mouth to be used as an antipsychotic drug; it has
been used to treat agitation and restlessness in the elderly [19].
Table 1. Equivalent doses of oral antipsychotics
These equivalences are intended only as an approximate guide; individual dosage instructions
should also be checked; patients should be carefully monitored after any change in medication
Antipsychotic
Daily dose
Chlorpromazine
100 mg
Clozapine
50 mg
Haloperidol
2–3 mg
Pimozide
2 mg
Risperidone
0.5–1 mg
Sulpiride
200 mg
These equivalences must not be extrapolated beyond the maximum dose for the drug.
Higher doses require careful titration in specialist units and the equivalences shown here may not
be appropriate.
17
After an initial period of stabilisation, in most patients, the long half-life of antipsychotic
drugs allows the total daily oral dose to be given as a single dose [20].
Conventional antipsychotics
Antipsychotics are now classified as conventional (typical) and atypical and are generally
differentiated by their pharmacologic mechanism of action. Most conventional antipsychotics are
thought to act primarily by blocking dopamine D2 receptors. The conventional agents are often
grouped according to their relative high affinity for the D2 receptor (high-potency, haloperidol;
low-potency, thioridazine) compared with their lower affinity for cholinergic, histaminic, and
alpha-adrenergic receptors. Conventional antipsychotics were previously termed "major
tranquilizers" because many of them had significant sedative effects. The selectivity of the highpotency antipsychotics for D2 receptors is responsible for the higher rate of EPS associated with
their use.
Despite their shortcomings, conventional antipsychotics have been used more than any
other single class of psychotropic drugs to treat behavioural disturbances with or without
psychosis [21]. Although many agitated patients improve with treatment, the response is usually
modest, and some patients actually become worse. In the best-designed studies, about a third of
the patients with unspecified agitation or aggression had a good response to antipsychotics [22],
The specific symptoms that consistently improve with conventional antipsychotics include
delusions, hallucinations, and severe or aggressive agitation. Behaviours that respond poorly are
repetitive, non-aggressive behaviours such as the inappropriate indications. Clinicians seem to
prefer using the low-dose, high-potency antipsychotics in geriatric patients because the elderly
are less likely to have multiple anticholinergic, histaminergic, and alpha-adrenergic side effects.
However, these patients are at a higher risk for EPS and need frequent assessments for these
effects [23].
Side effects of conventional antipsychotics
Patients with dementia, especially those with Alzheimer's disease, may be more
susceptible to the adverse effects of antipsychotics because of pharmacokinetic and neuronal
18
changes that result from aging and the disease process. This is evidenced by noting that both the
doses and plasma levels of antipsychotics necessary for clinical effect are lower in patients with
dementia than in age-matched schizophrenic patients [24]. Older patients are highly sensitive to
the emergence of EPS on exposure to antipsychotics for two reasons: dopaminergic neurons and
D2 receptors diminish throughout life, leaving the elderly with fewer receptors to antagonize; and
the older adult is less able to up-regulate D2 receptors in the presence of a receptor-blocking drug
such as an antipsychotic agent [25].
Side effects of conventional antipsychotics in the elderly include acute EPS such as
parkinsonism and akathisia as well as the more insidious tardive dyskinesia [26]. Jeste and
Caligiuri [27] have estimated that older patients exposed to these agents develop tardive
dyskinesia at alarming rates: 26% of their elderly patients developed this disorder after one year
of exposure, 52% after two years, and 60% after three years. These drug-induced movement
disorders can compound the declining praxis, mobility, and functional abilities of a demented
patient. Anticholinergic (e.g., benztropine) or dopaminergic (e.g., amantadine) medications are
used to combat drug-induced parkinsonism in younger adults, but in older adults they can
contribute to confusion, declining cognition, and increased delirium or psychosis and should
therefore be avoided. Residents most at risk for tardive dyskinesia appear to be elderly women
with dementia and prominent affective symptoms.
Antipsychotic drugs used to treat agitation in residents with dementia may also impair
cognition. Residents with Alzheimer's disease not only have an age-related decline in dopamine
receptors, making them susceptible to EPS, but they also have a profound loss of acetylcholineproducing neurons in various brain regions, particularly in the nucleus basalis of Meynert. The
latter deficit serves as the basis for all current Food and Drug Administration (FDA) approved
treatments for Alzheimer's disease. Thus the use of antipsychotic agents with significant
anticholinergic effects may further impair cognition in residents with Alzheimer's disease [28].
Orthostatic hypotension is a serious side effect associated with low-potency conventional
antipsychotics. This drop in blood pressure is attributed to an alpha1-adrenergic receptor
blockade and can result in falls, fractures, and increased morbidity and mortality. With elderly
residents particularly sensitive to the side effects of antipsychotics, it is critical that the
indications for use and the dose be carefully regulated [29].
Dosing conventional agents
Because of the physiologic changes associated with aging, starting doses of conventional
antipsychotic agents should be approximately 50% of those recommended for younger adults
19
and should be increased slowly [30]. Many patients with the behavioural disturbances of
dementia do not comply with pharmacotherapy, so that intramuscular injections of short-acting
or long-acting (depot) antipsychotics are sometimes used. The efficacy of depot antipsychotics in
the elderly, however, has not been determined, and most oral-to-intramuscular dose-conversion
studies have been done in younger schizophrenic patients. Clinicians should use depot
antipsychotics cautiously in the elderly. Elderly residents may develop a high incidence of side
effects, even with lower doses, because their decreased muscle mass can make intramuscular
injections impractical and because of the different pharmacokinetics of these agents in this age
group. The greatest disadvantages to the use of these agents are the lack of flexibility in dose
adjustments and the increased potential and prolonged time course of side effects.
Because many elderly are highly sensitive to side effects, individual dose adjustment may
be the best method to achieve a reasonable balance between efficacy and adverse effects. If this
is not feasible, then a change to a different class of antipsychotic or an alternate type of
medication may be in order. Rational pharmacotherapy for elderly residents requires an attempt
to reduce polypharmacy and the use of the lowest appropriate doses of antipsychotics to avoid
the subsequent need for concomitant medications. It is also best to avoid giving certain
conventional antipsychotics in inconvenient and unnecessary divided doses [31]. At times,
however, rational co-prescribing of different classes of medications (e.g., buspirone, trazodone,
selective serotonin re-uptake inhibitors, divalproex) may be necessary until agitation is
adequately reduced.
Increasing recognition of the limited action or usefulness of typical antipsychotics in the
treatment the broad spectrum of psychotic symptoms and ably neurocognitive deficits, as well as
the lack of response to these agents demonstrated by at least 30% of patients with schizophrenia,
limited their role and accelerated the search for better antipsychotic medications.
Atypical antipsychotics
A new era in the development of modern psychopharmacology of schizophrenia began in
the early 1990s with the development of a number of new atypical antipsychotic medications,
many of them have already been introduced for clinical use. The includes: amisulpride (approved
for use in Europe), remoxipride (withdrawn after approval available data about quality of life and
cost effects), clozapine (reintroduced for patients tiveness of these drugs appears to have been
collected with treatment-resistance illness), risperidone, olanzapine, sertindole (available in
Europe), quetiapine, zotepine, deziprasidone, and more recently, aripiprazole.
20
In general, compared with conventional antipsychotics, all of the new atypical
antipsychotics are over the comparable with respect to efficacy in the treatment of positive
symptoms, and some show a trend to ideal superior efficacy in the management of negative
symptoms and neurocognitive deficits. There is also general agreement that new atypical
antipsychotics, overall, have a more favourable adverse effect profile and much improved
subjective tolerability compared with conventional agents [32].
What makes these agents "atypical" or "novel" rests with several properties of these
drugs. First, in contrast to conventional antipsychotics, the atypical antipsychotics combine
blockade of both dopamine and serotonin receptors. This dual mechanism of action is believed to
combat both the positive and negative symptoms of schizophrenia. The positive symptoms (e.g.,
hallucinations, delusions, and thought disturbances) are believed to respond to dopamine D2
receptor blockade, while the negative symptoms (e.g., flat affect and social withdrawal) respond
to serotonin 5-HT2 receptor blockade [33]. Moreover, the atypical antipsychotics elicit fewer
EPS, and thus the rate of tardive dyskinesia is expected to be much lower with this group of
drugs than with the conventional agents. Other, less-tested characteristics of the novel drugs
include their effects on cognition and their use in treating treatment-resistant schizophrenia.
These effects have not been confirmed for all agents in this class.
Theoretically, the atypical agents' mechanism of action should be useful for residents
with dementia who are cognitively impaired and who often have both behavioural disturbances
and flattened affect. Clozapine has demonstrated pharmacotherapeutic efficacy for treatmentresistant schizophrenia [34] and a reduced propensity for EPS and the development of tardive
dyskinesia [35]. These benefits may be the result of a higher affinity ratio of dopamine Dl to D2
receptors. Clozapine, however, is not without its liabilities. Its use is associated with significant
anticholinergic, histaminergic, and alpha-adrenergic adverse effects. Elderly residents are often
unable to tolerate clozapine dose titration because of significant orthostatic hypotension,
sedation, confusion, and sialorrhea [36]. However, it is the increased risk of seizures and 1%
incident of agranulocytosis with subsequent need for blood monitoring, that generally limit its
use in the elderly [37]. Starting doses of clozapine in the elderly are typically low (6.25-12.5
mg/day) and are increased to a maximum of 400 mg/day. Case reports involving geriatric
patients have described improvements in schizophrenia, psychosis secondary to organic mental
syndrome, psychosis secondary to Parkinson's disease, and movement disorders [38].
Risperidone has a much more favourable pattern of receptor blockade than clozapine for
use in older adults. While it has potent D2 and 5-HT2 blocking properties, it has weak
anticholinergic properties [39]. The latter feature should prove useful in treating residents with
dementia of the Alzheimer's type. Moreover, owing to its strong serotonin-blocking activity,
21
risperidone ameliorates both positive and negative symptoms and has a relatively benign sideeffect profile.
Comparative trials of risperidone and haloperidol in patients with schizophrenia showed
that risperidone was as effective as haloperidol and was associated with a lower risk of EPS [40].
The emergence of EPS is dose dependent with risperidone; thus doses should be slowly
increased to clinical effect. Risperidone has been used to treat a variety of disorders in the elderly
[41], including schizophrenia and other psychoses [42], psychosis associated with Parkinson's
disease and psychotic and behavioural disturbances associated with dementia [43]. Risperidone
has also been shown to improve cognitive functioning in elderly patients with psychosis [44].
The efficacious and well-tolerated dose of risperidone has been reported to be <3 mg/day in most
elderly patients with schizophrenia [45] and 1-2.5 mg/day in demented patients [46]. Risperidone
has shown promise in the treatment of psychosis and behavioural disturbances in elderly patients
with dementia. In a recent placebo-controlled, randomized study of risperidone in more than 600
elderly demented patients, it was found to be significantly more effective than placebo in
controlling psychotic symptoms and in reducing both the severity and frequency of aggressive
behaviour. The optimal dose of risperidone, in terms of both efficacy and tolerability, was 1
mg/day. In an analysis of data from 27 trials of risperidone, only four cases of tardive dyskinesia
were identified among 3,298 patients treated with risperidone (probability of tardive dyskinesia =
0.0034 per treatment year) [47].
Olanzapine is structurally similar to clozapine and, like clozapine, blocks a broad
spectrum of receptors and may have a side-effect profile that is difficult for elderly residents to
tolerate (i.e., anticholinergic symptoms, sedation, dizziness, and orthostatic hypotension). This
must be explored in upcoming clinical trials. When compared with haloperidol, olanzapine was
associated with fewer EPS, but its propensity to cause EPS appears to be dose related and EPS
may be seen with higher doses [48]. Olanzapine is not associated with persistent increased
plasma prolactin levels or agranulocytosis. The efficacy of this novel antipsychotic in the
treatment of schizophrenia has been demonstrated in double-blind trials that compared doses of
2.5-17.5 mg/day versus haloperidol and placebo [49]. Olanzapine has also been used
successfully in patients with Parkinson's disease [48]. However, in a study of patients with
psychotic and behavioural symptoms secondary to Alzheimer's dementia, no improvement was
seen with olanzapine compared with placebo.
Quetiapine, the most recently introduced atypical antipsychotic, has moderate 5-HT2
receptor and weak D2 blockade and reportedly lacks D1 receptor activity [49]. In pre-clinical
trials [50], quetiapine was found to cause minimal EPS, anticholinergic effects, and orthostatic
hypotension. There was no increase in prolactin levels and no apparent risk of agranulocytosis,
22
but sedation was reported and judged to be due to an antihistaminic effect. A transient
asymptomatic increase in liver enzymes of more than three times the upper limit of normal
requires monitoring during therapy. The half-life of quetiapine (approximately 6.5 hours)
necessitates twice-daily dosing. Results of controlled clinical trials demonstrate that quetiapine at
doses of 150-750 mg/day was efficacious and safe in the treatment of schizophrenia [51]. Its
efficacy was not significantly better than that of haloperidol, but the severity of EPS was
significantly less with quetiapine than with haloperidol. The efficacy, safety, and tolerability of
quetiapine were studied in 151 elderly patients diagnosed with idiopathic (schizophrenia, bipolar
disorder) and organic (psychoses associated with Alzheimer's disease and vascular dementia)
psychoses [52]. Patients were treated with 25-800 mg/day of quetiapine for one year. Overall
psychotic symptoms and positive and negative symptoms improved, with no difference between
the two groups. Patients exhibited negligible EPS, and the drug was generally well-tolerated
[53].
The ‘atypical antipsychotics' amisulpride, aripiprazole, clozapine, olanzapine,
quetiapine, risperidone, and zotepine may be better tolerated than other antipsychotics;
extrapyramidal symptoms may be less frequent than with older antipsychotics.
Aripiprazole, clozapine, olanzapine, quetiapine, and sertindole cause little or no elevation
of prolactin concentration; when changing from other antipsychotics, a reduction in prolactin
may increase fertility.
Clozapine is licensed for the treatment of schizophrenia only in patients unresponsive to,
or intolerant of, conventional antipsychotic drugs. It can cause agranulocytosis and its use is
restricted to patients registered with a clozapine patient monitoring service.
Sertindole has been reintroduced following an earlier suspension of the drug because of
concerns about arrhythmias; its use is restricted to patients who are enrolled in clinical studies
and who are intolerant of at least one other antipsychotic.
Acute phase of schizophrenia: impact of atypical antipsychotics
The acute phase of schizophrenia is characterized by the presence of positive, negative
and affective symptoms. After recovery, patients still may suffer distressing residual symptoms;
they also carry a high risk of relapse which may be associated with further deterioration in their
condition. Prompt, early and continued treatment with an effective, well-tolerated antipsychotic
agent, is therefore crucial. Typical antipsychotics are poorly tolerated, leading to lack of
compliance and relapse. They also lack efficacy in controlling negative and affective symptoms.
Atypical compounds such as amisulpride or risperidone are better tolerated. In addition, when
23
compared with either haloperidol or risperidone, amisulpride has been shown to be at least as
effective in controlling positive symptoms and significantly superior in alleviating negative
symptoms. The onset of action of amisulpride appears more rapid than that of haloperidol.
Amisulpride therefore fulfils all the requirements of a first-line agent for the treatment of the
acute phase of schizophrenia [54].
NICE guidance (atypical antipsychotics for schizophrenia)
National Institute for Health and Clinical Excellence (NICE) has recommended (June 2002) that:

the atypical antipsychotics (amisulpride, olanzapine, quetiapine, risperidone, and
zotepine) should be considered when choosing first-line treatment of newly diagnosed
schizophrenia;

an atypical antipsychotic is considered the treatment option of choice for managing an
acute schizophrenic episode when discussion with the individual is not possible;

an atypical antipsychotic should be considered for an individual who is suffering
unacceptable side-effects from a conventional antipsychotic;

an atypical antipsychotic should be considered for an individual in relapse whose
symptoms were previously inadequately controlled;

changing to an atypical antipsychotic is not necessary if a conventional antipsychotic
controls symptoms adequately and the individual does not suffer unacceptable sideeffects;

clozapine should be introduced if schizophrenia is inadequately controlled despite the
sequential use of two or more antipsychotics (one of which should be an atypical
antipsychotic) each for at least 6–8 weeks.
While atypical antipsychotics have not generally been associated with clinically
significant prolongation of the QT interval, they should be used with care if prescribed with
other drugs that increase the QT interval. Atypical antipsychotics should be used with caution in
patients with cardiovascular disease, or a history of epilepsy; they should be used with caution in
the elderly;
Atypical antipsychotics may affect performance of skilled tasks (e.g. driving); effects of
alcohol are enhanced.
Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and
closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.
24
Side-effects of the atypical antipsychotics include weight gain, dizziness, postural
hypotension (especially during initial dose titration) which may be associated with syncope or
reflex tachycardia in some patients, extrapyramidal symptoms (usually mild and transient and
which respond to dose reduction or to an antimuscarinic drug), and occasionally tardive
dyskinesia on long-term administration (discontinue drug on appearance of early signs).
Hyperglycaemia and sometimes diabetes can occur, particularly with clozapine and olanzapine;
monitoring weight and plasma glucose may identify the development of hyperglycaemia.
Neuroleptic malignant syndrome has been reported rarely [20].
Several other new atypical antipsychotics (e.g., ziprasidone) are nearing release into the
market or are under investigation. These agents are likely to follow the success of the currently
available antipsychotics (clozapine, risperidone, olanzapine, and quetiapine) in the treatment of
the symptoms of schizophrenia. Success depends on these agents' ability to surpass the typical
agents in efficacy yet cause significantly fewer EPS [55].
3. OBJECTIVE AND AIMS
Objective:
To evaluate trends in the use of antipsychotic drugs in Lithuania during 2003 - 2005 years.
Aims:
1. To assess antipsychotic medicines sales in Lithuania during 2003 - 2005 years period from the
IMS Health Inc. data base and to evaluate the consumption of antipsychotics by the DDD
methodology.
2. To analyse the consumption within antipsychotic drugs classes and the changes in the use of
antipsychotics over three years period (2003-2005) and to compare results with the similar
studies data in other countries.
3. To perform the meta-analysis of antipsychotic medicines on the point of effectiveness.
4. To perform the pharmacoeconomic analysis of antipsychotics by the cost minimization
method and reference price methodology.
25
4. MATERIAL AND METHODS
4.1 The ATC classification – structure and principles
In the Anatomical Therapeutic Chemical (ATC) classification system, the drugs are
divided into different groups according to the organ or system on which they act and their
chemical, pharmacological and therapeutic properties. Drugs are classified in groups at five
different levels. The drugs are divided into fourteen main groups (1st level), with one
pharmacological/therapeutic
subgroup
(2nd
level).
The
3rd
and
4th
levels
are
chemical/pharmacological/therapeutic subgroups and the 5th level is the chemical substance. The
2nd, 3rd and 4th levels are often used to identify pharmacological subgroups when that is
considered more appropriate than therapeutic or chemical subgroups.
4.2 History of the ATC/DDD system
In 1981, the WHO Regional Office for Europe recommended the ATC/DDD system
for international drug utilization studies. In connection with this, and to make the methodology
more widely used, there was a need for a central body responsible for co-ordinating the use of
the methodology. The WHO Collaborating Centre for Drug Statistics Methodology was
accordingly established in Oslo in 1982. The Centre is now located at the Norwegian Institute of
Public Health. The Norwegian government funds the Centre.
In 1996, WHO recognised the need to develop use of the ATC/DDD system as an
international standard for drug utilization studies. The Centre was therefore linked directly to
26
WHO Headquarters in Geneva instead of the WHO Regional Office for Europe in Copenhagen.
This was seen as important to allow close integration of international drug utilization studies and
WHO’s initiatives to achieve universal access to needed drugs and rational use of drugs
particularly in developing countries. Access to standardised and validated information on drug
use is essential to allow audit of patterns of drug utilization, identification of problems,
educational or other interventions and monitoring of the outcomes of the interventions.
When the decision on globalizing the ATC/DDD system was taken, the WHO Division of Drug
Management and Policies established the WHO International Working Group for Drug Statistics
Methodology. The WHO Collaborating Centre for Drug Statistics Methodology receives expert
advice from the Working Group.
4.3 The purpose of the ATC/DDD system
The purpose of the ATC/DDD system is to serve as a tool for drug utilization research in
order to improve quality of drug use. One component of this is the presentation and comparison
of drug consumption statistics at international and other levels.
A major aim of the Centre and Working Group is to maintain stable ATC codes and
DDDs over time to allow trends in drug consumption to be studied without the complication of
frequent changes to the system. There is a strong reluctance to make changes to classifications or
DDDs where such changes are requested for reasons not directly related to drug consumption
studies. For this reason the ATC/DDD system by itself is not suitable for guiding decisions about
reimbursement, pricing and therapeutic substitution.
4.4 The DDD – definition and principles
The basic definition of the unit is:
The DDD is the assumed average maintenance dose per day for a drug used for its main
indication in adults.
A DDD will only be assigned for drugs that already have an ATC code.
It should be emphasised that the defined daily dose is a unit of measurement and does not
necessarily reflect the recommended or prescribed daily dose. Doses for individual patients and
patient groups will often differ from the DDD and will necessarily have to be based on
individual characteristics (e.g. age and weight) and pharmacokinetic considerations.
27
Drug consumption data presented in DDDs only give a rough estimate of consumption and not
an exact picture of actual use. DDDs provide a fixed unit of measurement independent of price
and formulation enabling the researcher to assess trends in drug consumption and to perform
comparisons between population groups.
DDDs are not established for topical preparations, sera, vaccines, antineoplastic agents,
allergen extracts, general and local anaesthetics and contrast media.
Principles for DDD assignment
DDDs for plain substances are normally based on monotherapy. Exceptions to this rule
are given in the guidelines.
A DDD will normally not be assigned for a substance before a product is approved and
marketed in at least one country.
The assigned DDD is based on the following principles:

The average adult dose used for the main indication as reflected by the ATC code. When
the recommended dose refers to body weight, an adult is considered to be a person of 70
kg. It should be emphasised that even special pharmaceutical forms mainly intended for
children (e.g. mixtures, suppositories) are assigned the DDD used for adults. Exceptions
are made for some preparations mainly used by children, e.g. growth hormones and
fluoride tablets.

The maintenance dose is usually preferred when establishing the DDD. Some drugs are
used in different initial doses but this is not reflected in the DDD.

The treatment dose is generally used. If, however, prophylaxis is the main indication, this
dose is used, e.g. for fluoride tablets (A01AA01) and some antimalarials.

A DDD is usually established according to the declared content (strength) of the product.
Various salts of a substance are usually not given different DDDs. Exceptions are
described in the guidelines for the different ATC groups.
The DDD is nearly always a compromise based on a review of the available information
including doses used in various countries when this information is available. The DDD is
sometimes a dose that is rarely if ever prescribed, because it is an average of two or more
commonly used dose sizes [56].
4.5 DDD for comparison of consumption
28
This is a contribution to the ongoing discussion on the suitability of the DDD in such
different
areas
as
drug
consumption
statistics
and
pricing
and
reimbursement.
There is the WHO Collaborating Centre for Drug Statistics Methodology in Oslo, which is
actually assigning all official ATC codes and DDDs. We want to point out some of the main
principles one has to be aware of when planning to use the DDDs for some purposes.
The basic definition of the DDD is: The DDD is the assumed average maintenance dose per day
for a drug used for its main indication in adults.
It should be emphasized that the defined daily dose is a unit of measurement and does not
necessarily reflect the recommended or Prescribed Daily Dose. Doses for individual patients and
patient groups will often differ from the DDD and will necessarily have to be based on
individual characteristics (e.g. age and weight) and pharmacokinetic considerations.
Drug consumption data presented in DDDs only give a rough estimate of consumption and not
an exact picture of actual use. DDDs provide a fixed unit of measurement independent of price
and formulation enabling the researcher to assess trends in drug consumption and to perform
comparisons between population groups [57].
The DDD is the assumed average maintenance dose per day for a drug used for its main
indication in adults. The DDD is often a compromise based on a review of the available
information about doses used in various countries. The DDD may even be a dose that is rarely
prescribed, because it is an average of two or more commonly used dose sizes. Drug utilization
figures should preferably be presented as numbers of DDDs/1000 inhabitants/day or, when inhospital drug use is considered, as DDDs per 100 bed days. For anti-infectives (or other drugs
used in short periods), it is often considered most appropriate to present the figures as numbers
of DDDs per inhabitant per year.
These terms are explained in the following.
DDDs/1000 inhabitants/day
Sales or prescription data presented in DDD/1000 inhabitants/day may provide a rough
estimate of the proportion of the study population that may be treated daily with certain drugs.
As an example, the figure 10 DDDs/1000 inhabitants/day indicates that 1% of the population on
average might get a certain drug or group of drugs every day. This estimate is most useful for
chronically used drugs when there is good agreement between the average prescribed daily dose
and DDD. It may also be important to consider the size of the population including all age
groups. Some drug groups have very limited use among young people, with most users above the
age of 45. To correct for utilization differences due to differing age structures between countries,
29
simple age adjustments can be made by using the number of inhabitants in the relevant age group
as denominator.
DDDs per 100 bed years
This unit may be applied when in-hospital drug use is considered. As an example, 70
DDD/100 bed days of hypnotics provide an estimate of the therapeutic intensity and suggest that
70% of the in-patient might receive a DDD of a hypnotic every day. This unit is quite useful for
benchmarking in hospitals.
DDDs per inhabitant per year
DDD term may give an estimate of the number of days for witch each inhabitant is, on
average, treated annually. For example, 5 DDDs/inhabitant/year indicates that the utilisation is
equivalent to the treatment to the treatment period is known, the total number of DDDs can be
calculated as the number of treatment courses, and the number of treatment courses can then be
related to the total population [58].
In Europe the DDD-system has been applied to some extent within current parts of the
health sector for more than 20 years. It functions through centrally, as well as locally based
initiatives - depending on the follow-up from either of these levels. The system has evolved as an
indispensable tool for review of drug utilisation, as well as future drug selection. In addition,
assessment of the procurement and pricing of drugs to a major part of public hospitals in is
totally based on software containing price per DDD-unit for all drug substances.
In Norway, the Drug Utilisation Statistics at the national level have been published with data on
drug consumption in value of money, - and quantity (DDD) for more than 2 decades. However,
the same figures have hardly been analysed and reviewed by any representative and extensive
cross-professional setting as a follow-up.
In my opinion, the DDD-system is no more complicated to introduce than normal price
figures for the drugs. However, to experience this fact one has to try for oneself. A few key
points should be highlighted to experience a successful start:
1. The concept of DDD must be well known - not only by pharmacists, but also by
prescribes, economists and health administrators in the setting being involved. The fact
30
that 1 DDD is a mean calculated volume figure, - not containing any professional dosage
recommendation, must be repeatedly stressed.
2. Globally - most drug substances have a DDD definition. Any setting planning to make
use of the DDD-measure, must distribute written information to current personnel. The
information should include a listing with the DDD-definitions for all drugs being used in
the setting.
3. A plan on the production of statistics on drug consumption (containing figures of volume
- DDD and economic expenditure) should be regularly elaborated. These figures may
also be related to the number of patients receiving the different drugs, or (in a hospital
setting) - the number of treatment days for the respective drugs.
4.6 Utilisation studies
Discrepancies between clinical trials and utilisation in naturalistic conditions need to be
identified because of their potential clinical and economic impact. These discrepancies may
concern prescription characteristics associated with lower efficacy (e.g. insufficient dosage or
duration) or with increased risk of adverse effects (e.g. hazardous co-prescription). The gap
between guidelines and utilisation is well established for psychotropic medications that are
mainly prescribed by specialists, such as anti-psychotics.
Utilisation studies are also fundamental to identifying possibly unfounded or hazardous
extensions of the indications for psychotropic medications. The widening of the boundaries of
treatable illness, often favoured by the marketing pressure of pharmaceutical companies, is not
specific to psychiatry [57], but it is a phenomenon to which the specialty is particularly
vulnerable; uncertainty regarding the boundaries between normality and cosiness allows the
creation of new diagnostic categories of putatively treatable psychiatric disorders [59]. Early
intervention in psychosis provides an illustration of extension of indication generated by the
creation of a new diagnostic category with need of care. Owing to the lack of valid screening
tests, it is not yet clearly established at the population level whether the benefits of antipsychotic
medication in people with preclinical psychosis are superior to the risks linked to unjustified
prescription in cases with a false-positive diagnosis [60]. However, it is striking that interest in
early intervention markedly increased when new antipsychotic drugs became available, and the
enthusiastic support of early intervention programmes by pharmaceutical companies suggests
that they at least have little doubt about the benefits they can obtain from this strategy. The
31
current promotion of the use of antipsychotics not only in preclinical psychosis but also in
bipolar disorder and behavioural disturbances of dementia may reassure prescribes about the
safety of these drugs, inducing their even more widespread use. It is thus necessary to explore at
the population level whether the utilisation pattern of these drugs is altered, not only in
psychiatric settings, but also in primary care. Several other examples could be given for each
class of psychotropic medication, pointing to the need for studies examining utilisation patterns
in naturalistic conditions in order to identify discrepancies between guidelines based on clinical
trials and actual use.
4.7 Outcome studies
Although clinical trials may identify the most frequent adverse effects associated with the
use of psychotropic medications, they are of limited value in detecting delayed or less prevalent
risks linked to exposure to a new drug. Such adverse reactions have to be identified as early as
possible, since even a small increase in risk may have a serious impact on the health of the
population if many people are exposed to the drug. Surveillance by centralised pooling of
spontaneous reports facilitates the detection of previously unidentified drug-related risks, which
can be subsequently confirmed or dismissed by field and database studies. The availability of
population-based databases documenting drug exposure is therefore crucial for the identification
of risks associated with psychotropic drug use. Such databases have the advantage of meeting a
major need in pharmaco-epidemiology - the observational nature of the data. Furthermore,
studies using these databases are less prone to selection bias, and are therefore more
representative, than pre-marketing clinical studies [61].
Another major issue addressed by out-come studies is the risk of psychiatric disorders
induced by prescription of psychotropic or non-psychotropic drugs. A further example of the
usefulness of population-based studies is provided by the debate on the suspected link between
autism and exposure to the measles, mumps and rubella triple vaccination. Findings obtained in
clinical samples of uncertain representatively generated a huge scientific controversy, widely
amplified by the media. There is now strong evidence against this hypothesis, as rigorous
32
population-based studies have failed to find such an association. A markedly underdeveloped
field of investigation concerns the delayed psychiatric risks associated with psychotropic use; for
example, the possible risk of dementia associated with exposure to benzodiazepines needs to be
further explored owing to the public health consequences of such a finding [62].
Another major public health issue concerns the psychiatric consequences of medication
prescription during pregnancy. Although the association between exposure to perinatal risk
factors and increased vulnerability for psychiatric disorder is well documented, knowledge is
strikingly sparse regarding the impact of prenatal exposure to prescribed drugs on the delayed
risk of psychiatric disorder [63]. Owing to their methodological limitations, no definite
conclusion regarding behavioural teratogenicity can be drawn from most studies exploring the
risk associated with prenatal exposure to psychotropic medication [64]. Sparse findings suggest
that exposure to xenoestrogens such as diethylstilbestrol may be a risk factor for psychiatric
disorders, mediated by a possible deleterious impact of these substances on foetal
neurodevelopment, but this hypothesis is speculative owing to the small number of studies and
their methodological limitations [65]. The most convincing pharmaco-epidemiological study to
date is one using data on drug exposure prospectively collected on 7866 persons in the
Copenhagen Perinatal Cohort (1959-1961), cases of schizophrenia being identified through the
Danish Psychiatric Central Register. After adjustment for confounding factors, risk of
schizophrenia was found to be increased in people exposed to maternal diuretic treatment during
the third trimester of pregnancy and was especially marked in individuals also exposed to
maternal hypertension [66].
4.8 Pharmacoeconomic studies
Treatment cost can have a dramatic effect on treatment availability, and clinicians may
find themselves unable to provide expensive treatments they believe their patients should
receive. The introduction of new, premium-priced antipsychotic medications has provided
visible examples of this problem. Cost considerations must be part of treatment decisions, since
resources are often insufficient to provide all potentially helpful treatments. However, the key
question regarding expensive drugs is whether other savings can be expected to offset the higher
drug price, or if not, whether improved effectiveness justifies the added cost. Pharmacoeconomic
research attempts to integrate relevant information on both effectiveness and cost so that
clinicians, patients, and other decision-makers can make meaningful treatment choices. This
work
presents
a
conceptual
framework
for
cost-effectiveness
analysis,
illustrates
33
pharmacoeconomic methods with studies of the cost-effectiveness of treatment, and describes
the steps in designing cost-effectiveness research on novel antipsychotic agents [67].
Pharmacoeconomics can be defined as the branch of economics that uses cost-benefit,
cost-effectiveness, cost-minimization, cost-of-illness and cost-utility analyses to compare
pharmaceutical products and treatment strategies. Economic evaluations provide healthcare
decision-makers with valuable information, allowing optimal allocation of limited resources.
However, pharmacoeconomics is based on long-term benefits, whereas physicians are typically
forced to seek immediate savings [68].
Pharmacoeconomic research is the process of identifying, measuring, and comparing the
costs, risks and benefits of programs, services or therapies and determining which alternative
procedures the best health outcome for the resource invested. For most pharmacists this
translates into weighing the cost of providing a pharmacy product or service against the
consequences realized by using the product or service, to determine which alternative yields the
optimal outcome.
Pharmacoeconomics is not the synonymous with outcome research. Although
pharmacoeconomics is a division of outcomes research, not all outcomes research is
pharmacoeconomic research. Outcomes research is defined more broadly as studies that attempt
to identify measure and evaluate the results of health care services in general. Cost is defined as
the value of the resources consumed by a program or drug therapy of interest. Consequence is
defined as the effects, outputs or outcomes of the program of drug therapy of interest.
Consideration of both costs and consequences differentiates most pharmacoeconomic evaluation
methods from traditional cost-containment strategies and drug-use evaluations [69].
Antipsychotics are the keystone in schizophrenia treatment. Although the benefits of the
new generation of antipsychotics has been demonstrated over the last decade, the issues of
patient compliance and higher purchasing price of atypical antipsychotics remain unresolved.The
higher acquisition costs of the new atypical antipsychotics compared with conventional
antipsychotics have given rise to some urgency into the study of cost effectiveness in
schizophrenia [70].
Emerging data and clinical experience with the new atypical antipsychotics has
demonstrated their efficacy, improved adverse effect profile and much better subjective
tolerability. However, medications by themselves cannot raise the level of quality of life in
patients with schizophrenia; this also depends on the availability of other important
interventions, such as psychological rehabilitation. Thus should result in higher costs, at least
initially, because of the costs of psychological support and rehabilitation programmes [71].
34
The cornerstone of recent pharmacoeconomic work in schizophrenia is the hypothesis
that the improved efficacy of novel antipsychotic medications will lead to a reduction in medical
services utilization, thereby reducing direct medical costs associated with treatment. Creating the
most valid design to prospectively examine the effectiveness and costs of competing
pharmacotherapies requires dialectic of opposing research paradigms. The final protocol must
represent a series of decisions that strike a careful balance between being scientifically sound
(internal validity) and generalizable to the real world of clinical treatment (external validity). The
results must be useful to decision-makers in determining to what extent reductions in healthcare
expenditures can offset higher drug acquisition costs within their type of treatment environment
[72].
The principles, methods, and applications of pharmacoeconomics and pharmaceutical
outcomes evaluations are discussed. Pharmacoeconomics may be defined as balancing the cost
with the consequences (outcomes) of pharmaceutical therapies and services. As a type of
outcomes evaluation, pharmacoeconomics looks beyond just the direct or acquisition cost of a
pharmaceutical by including its impact on total health resource utilization and costs. Outcomes
research attempts to answer the question, what difference does the pharmaceutical make in
patient outcomes under real-world conditions? The economic, clinical, and humanistic outcomes
(ECHO) model for a pharmacoeconomic evaluation views the drug as some combination of its
clinical, economic, and humanistic attributes. Safety and effectiveness are no longer the only
salient attributes of a drug; the effect on total health resource utilization, cost, and quality of life
must also be evaluated. The four types of pharmacoeconomic methods are cost-minimization
analysis, cost-benefit analysis, cost-effectiveness analysis, and cost-utility analysis. As disease
state management continues to emerge as a cost-management, quality assurance strategy,
formularies per se will wane in importance and pharmacoeconomic and outcomes data will
increase in relevance as health professionals endeavour to find the most efficient and effective
combinations of medical care. Pharmacoeconomics as a component of outcomes research will
help pharmacists decide which clinical circumstances, patient characteristics, and practice
settings are most suitable for particular interventions [73].
4.9. Cost benefit analysis
Cost benefit analysis is the explicit consideration of the perceived costs and benefits of a
proposed course of action. We implicitly weigh the costs and benefits of courses of action on a
daily basis. The analysis discussed in this paper merely extends this weighing up process by
35
clarifying the values used and assumptions made in valuing the attractiveness of a proposed
action.
Within the health system, we don’t have the resources to do everything we want to do.
Consequently, we need a means of deciding how to allocate resources to those activities that we
most desire. Cost benefit analysis provides guidance for resource allocation decisions. The
explicit nature of this analysis allows for clear definition of issues. This clarity is an essential
prerequisite for a robust decision making process. Assumptions are open to scrutiny and debate,
allowing all relevant issues to be considered and weighed when coming to a decision.
Also, the explicit listing of costs and benefits creates a record against which future (and
past) decisions can be reviewed, thereby, aiding consistency [74].
Types of cost benefit analysis
Difference types of analyses reflect the different levels of analysis that can be performed
in pharmacoeconomic cost benefit analysis. They are listed in order from the least complex to
the most.
Cost Minimisation Analysis (CMA): where no benefit changes are involved (i.e. assuming
the same levels of the outcome). Hence, the decision can be made on the basis of costs alone.
The benefits from listing a generic pharmaceutical at a lower price than the original brand
product, delivering the same health benefits for less cost, is an example of a “cost minimisation”
decision.
Cost effectiveness Analysis (CEA): where we assess the costs of achieving directly
comparable outcomes. The resulting cost effectiveness measure can be compared with those for
other interventions that also enable people to avoid heart attacks. This analysis has a major
drawback in that we cannot directly compare interventions that treat different disorders.
Cost Utility Analysis (CUA): where we compare the possible health outcomes using a
common currency. Rather than having a certain end-point relevant to the treatment in question,
such as heart attacks avoided, the analysis has a common value end-point, such as a quality
adjusted life year (QALY). CUA has the advantage that investment opportunities in different
areas of health care can be compared. For example, the cost effectiveness of interventions to
prevent heart attacks can be compared with the cost effectiveness of drugs to cure gastric ulcers.
In contrast, CEA can compare investment opportunities for only one area of health care, in the
example above, that of avoiding heart attacks. We note that there are still some issues to be
addressed in using cost-utility analysis. For example, there is currently no commonly agreed
36
technique for measuring quality of life. Secondly, there are issues involved in interpreting
QALYs.
Full Cost Benefit Analysis (CBA): Where we set out all costs and benefits in dollar terms.
Investment opportunities can be compared across all areas of government spending, extending
beyond health. However, it has two major drawbacks. Firstly, there are significant difficulties in
placing a dollar value on health benefits. We know of no robust technique for doing this that is
systematically used by funding authorities in any country. We note that there is interest in
developing techniques for valuing benefits, but that further research is required before such
approaches can be considered more seriously. Secondly, it implicitly assigns different values
(weights) to different types of health benefits. For example, people may be willing to pay more
for life saving interventions over those that raise quality of life. We aim to do this explicitly,
which is more easily done using cost-utility analysis [75].
4.10 Data sources
The data on total sales of antipsychotic drugs in all Lithuanian regions over three years
(2003-2005) were obtained from IMS (Intercontinental Marketing Service) Health Incorporated.
Data were retrieved as units of antipsychotic drugs and costs for the drugs. System and use was
quantified in terms of defined daily doses (DDDs). Data were calculated by DDD methodology
and expressed in DDDs per 1.000 inhabitants per day. Meta-analysis of observational studies
retrieved through systematic search of all available electronic data sources. 1651 abstracts were
found and checked. 76 randomised double-blind studies were identified for the meta-analysis.
4.11 Meta-analysis
A statistical method when all data from all available studies of something are combined,
regardless of data quality. The technique is used by researchers to get a maximum of statistical
information without worrying about distortion in the results.
Meta-analysis is the quantitative combination of results from multiple research studies.
There are three steps in a typical meta-analysis model.
1. Extract individual estimates and standard errors from each study
2. Combine these estimates using a fixed or random effects model
3. Display the results graphically.
Odds ratio
37
A meta-analysis integrates the quantitative findings from separate but similar studies and
provides a numerical estimate of both overall effect of interest.
Under the fixed effects model, we assumed that all studies come from a common
population and that the effect size (odds ratio) is not significantly different among the different
trials. This assumption is tested by the “Heterogeneity test”. If this test yields a low p-value
(p<0,05), then the fixed effects model may be invalid. In this case, the random effects model
may be more appropriate, in which both the random variation within the studies and the
evaluation between the different studies is incorporated.
MedCalc is the program used in this work. MedCalc uses the Mantel-Haenszel method
for calculating the weighted summary Odds ratio under the fixed effects model. Next the
heterogeneity statistic is incorporated to calculate the summary Odds ratio under the random
effects model.
Required input:
Study
1
2
3
Quetiapine_Pos
214
75
520
Quetiapine_N
224
144
812
Haloperidol_Pos
203
55
512
Haloperidol_N
224
144
812
Pos – positive outcome, N- number of patients
In this example, in a first study 224 patients were treated with Quetiapine and of these,
214 had a positive outcome (in our study the effectiveness according to the Brief Psychiatric
Rating Scale, when BPRS reduction of > or = 20%). 224 cases received Haloperidol and 203 of
these had a positive outcome. On the next rows of the spreadsheet follow the data of other
studies.
Results:
Variable for studies: Study
1. Intervention groups
Variable for total number of cases: Quetiapine N
Variable for number of positive cases: Quetiapine Pos
2. Control groups
Variable for total number of cases: Haloperidol N
Variable for number of positive cases: Haloperidol Pos
------------------------------------------------------------------------------------Study
Intervention Controls Odds
95% CI
------------------------------------------------------------------------------------1
214/224
203/224 2,214 1,018 4,816
2
75/144
55/144
1,759 1,100 2,811
3
520/812
512/812 1,043 0,852 1,277
Total (fixed effects)
809/1180
770/1180
1,178
0,984
1,409
38
Total (random effects) 809/1180 770/1180 1,457 0,907 2,341
-------------------------------------------------------------------------------------Test for heterogeneity
Q = 6,7219, DF = 2, P = 0,0347
The program lists the results of the individual studies: number of positive cases, total
number of cases, the odds ratio with 5% C.
The Total Odds ratio with 95% C is given both for the Fixed effects model and the
Random effects model. In our study the Odds ratio is statistically significant when p<0,05 [75].
39
Graph:
The results of the different studies are shown in the following graph:
Meta-analysis
1
2
3
Total (fixed effects)
Total (random effects)
0,1
1
10
100
Odds ratio
The odds ratio is a way of comparing whether the probability of a certain event is the
same for two groups.
An odds ratio of 1 implies that the event is equally likely in both groups. An odds ratio
greater than one imply that the event is more likely in the first group. An odds ratio less than one
imply that the event is less likely in the first group [76].
40
5. RESULTS
5.1 Main results of meta-analysis of antipsychotic drugs
BACKGROUND: The treatment of schizophrenia with old, conventional antipsychotic
drugs such as haloperidol can be problematic, because many people treated with these drugs will
suffer from it‘s side effects. Atypical antipsychotics which become more and more popular in the
treatment of schizophrenia induce less unfavourable side effects and are effective for both
positive and negative symptoms of schizophrenia. The search for novel antipsychotic agents has
led to a variety of investigational compounds exhibiting different pharmacologic profiles.
Criteria for comparison of antipsychotic drugs include an efficacy profile. Comparing the novel
antipsychotics, they differ in their chemical structure, profile of receptor binding affinities,
animal neuropharmacology, pharmacokinetics, etc. Based on preclinical and clinical differences,
it was hypothesized that both conventional and atypical antipsychotics would differentiate from
each other in vivo on features of efficacy.
OBJECTIVES: To evaluate the effectiveness of atypical antipsychotics compared with
conventional and within the pharmacological group of atypical and to select the most effective
antipsychotic drugs for schizophrenia treatment.
SEARCH STRATEGY: Meta-analysis of observational studies retrieved through
systematic search of all available electronic data sources (Medline database). 1651 abstracts were
found and checked. 76 randomised double-blind studies were identified for the meta-analysis.
SETTING: Retrospective and prospective studies published in the English-language
literature from 1966 to present.
SELECTION CRITERIA: All randomised controlled trials comparing atypical
antipsychotics to conventional and comparing both atypical antipsychotics for schizophrenia for
periods ranging from 3 weeks to 2 years. Response rates based on percentage of improvement in
BPRS total score. In this study 20% of improvement means the response.
DATA COLLECTION AND ANALYSIS: Data were independently extracted and
analysed on an intention-to-treat basis. The odds ratio (OR) and 95% confidence intervals (CI) of
dichotomous data were calculated using a odds ratio model. The mean change in Brief
Psychiatric Response Scale (BPRS) was used in the efficacy analysis. The primary of efficacy
analysis involved the mean change from baseline to endpoint in total scores on the BPRS.
41
Table 2. The comparison of antipsychotics efficacy according to BPRS Total Scores of
schizophrenic patients
Medicines
Number
of trials
Number of
participants
Odds
Ratio
Confidence
Interval
P
value
Olanzapine-Ziprasidone
2
633
3,34
1,038-10,731
0,02
Clozapine-Haloperidol
2
519
3,12
2,159-4,510
0,40
Olanzapine-Haloperidol
10
2439
2,67
1,847-3,857
0,06
Risperidone-Haloperidol
18
4972
2,44
1,604-3,714
0,01
Clozapine-Risperidone
2
110
2,43
1,043-5,660
0,58
Ziprasidone-Haloperidol
2
866
2,24
1,275-3,947
0,25
Aripiprazole-Haloperidol
2
500
1,99
0,405-2,459
0,60
Olanzapine-Amisulpride
2
178
1,94
0,330-2,670
0,49
Remoxipride-Haloperidol
6
569
1,87
0,555-1,377
0,25
Zotepine-Haloperidol
2
199
1,83
1,034-3,232
0,87
Olanzapine-Clozapine
5
1513
1,82
0,467-1,445
0,03
Risperidone-Olanzapine
9
3791
1,23
0,822-1,853
0,02
Amisulpride-Haloperidol
3
878
1,65
1,013-2,694
0,07
Quetiapine-Haloperidol
3
2360
1,46
0,907-2,341
0,03
Amisulpride-Risperidone
3
585
1,45
0,943-2,225
0,88
Sertindole-Risperidone
2
477
1,35
0,854-2,120
0,47
Quetiapine-Risperidone
3
1494
1,05
0,625-1,765
0,29
42
MAIN RESULTS: This review currently includes 76 randomised studies with a total of 22083
participants. Most trials were of long duration. Data from 48 trials with 13302 participants with
positive and negative symptoms suggest that haloperidol is less effective than atypical
antipsychotics. The results of a total of ten trials suggest that olanzapine was more effective in
improving BPRS scale than haloperidol (n=2439, OR 2,67, CI 1,847 to 3,857, p=0,06), eighteen
trials show that risperidone is more effective than haloperidol (n=4972, OR 2,44, CI 1,604 to
3,714, p<0,0001 ), three studies points the priority of amisulpride to haloperidol (n=878, OR
1,652, CI 1,013 to 2,694, p=0,07), three next trials shows that quetiapine is more effective than
haloperidol (n=2360, OR 1,457, CI 0,907 to 2,341, p=0,034), five studies-that clozapine is less
effective than olanzapine (n=1513, OR 0,822, CI 0,467 to 1,445, p=0,03 ), the results of nine
trials-that risperidone is more effective than olanzapine (n=3791, OR 1,234, CI 0,82 to 1,85,
p=0,02 ) and two studies shows the priority of olanzapine to ziprasidone (n=633, OR 3,338, CI
1,038 to 10,731, p=0,02). The results of all other studies show the differences between clozapine
and risperidone (n=110, OR 2,43, CI 1,043 to 5,66, p=0,58), amisulpride and risperidone (n=585,
OR 1,448, CI 0,943 to 2,225, p=0,88), quetiapine and risperidone (n=1494, OR 1,051, CI 0,625
to 1,765, p=0,295), sertindole and risperidone (n=477, OR 1,346, CI 0,854 to 2,120, p=0,4685),
remoxipride and haloperidol (n=569, OR 0,874, CI 0,555 to 1,377, p=0,25), ziprasidone and
haloperidol (n=866, OR 2,243, CI 1,275 to 3,947, p=0,25), zotepine and haloperidol (n=199, OR
1,828, CI 1,034 to 3,232, p=0,873), aripiprazole and haloperidol (n=500, OR 0,998, CI 0,405 to
2,459, p=0,601), amisulpride and olanzapine (n=178, OR 0,939, CI 0,330 to 2,670, p=0,488),
clozapine and haloperidol (n=519, OR 3,121, CI 2,1959 to 4,510, p=0,398). But the differences
accounted are not statistically significant because of insufficient amount of trials carried out for
these medicines (See Annex 2 for all data collected, Annex 3 for meta-analysis results and
calculations and Annex 4 for the example of abstracts collected for meta-analysis).
43
4
Effectiveness
3,5
3,34
3,12
2,67
3
2,5
2,44 2,43
2,24
2
2,00 1,94 1,87
1,83 1,82
1,65
1,5
1,46 1,45 1,35
1,23
1,05
1
Quet-Risp
Risp-Olanz
Sert-Risp
Ams-Risp
Quet-Hal
Ams-Hal
Olanz-Cloz
Zot-Hal
Remox-Hal
Olanz-Ams
Arip-Hal
Zipr-Hal
Cloz-Risp
Risp-Hal
Olanz-Hal
Cloz-Hal
0
Olanz-Zipr
0,5
Medicines
Figure 1. Comparison of certain antipsychotic drugs effectiveness
Risp-Hal
Risp-Olanz
Olanz-Zipr
Quet-Hal
Olanz-Cloz
Olanz-Hal
Ams-Hal
Remox-Hal
Zipr-Hal
Quet-Risp
Cloz-Hal
Sert-Risp
Olanz-Ams
Cloz-Risp
Arip-Hal
Zot-Hal
Ams-Risp
0,9 0,880,87
0,8
0,7
0,6 0,58
0,6
0,490,47
0,5
P
0,4
0,4
0,3
0,3
0,250,25
0,2
0,070,060,030,03
0,1
0,020,020,01
0
Medicines
Figure 2. Comparison of probability of the results of effectiveness
The odds ratio is a way of comparing whether the probability of a certain event is the
same for two groups. An odds ratio of 1 implies that the event is equally likely in both groups.
An odds ratio greater than one imply that the event is more likely in the first group. An odds
ratio less than one imply that the event is less likely in the first group.
44
Table 3. The comparison of statistically significant meanings
Medicines
Odds Ratio
P values
Olanzapine-Ziprasidone
3,34
0,02
Risperidone-Haloperidol
2,44
0,01
Olanzapine-Clozapine
1,82
0,03
Quetiapine-Haloperidol
1,46
0,03
Risperidone-Olanzapine
1,23
0,02
3,50
3,34
3,00
2,44
2,50
Odds
1,82
2,00
1,46
1,50
1,23
1,00
RisperidoneOlanzapine
QuetiapineHaloperidol
OlanzapineClozapine
RisperidoneHaloperidol
0,00
OlanzapineZiprasidone
0,50
Medicines
Figure 3. The comparison of statistically significant meanings
45
The main results of certain antipsychotic drugs meta-analysis:
Amisulpride-Haloperidol
(Odds ratio=1,652)
Amisulpride - Risperidone
(Odds ratio=1,448)
Meta-analysis
Meta-analysis
1
1
2
2
3
3
Total (fixed effects)
Total (fixed effects)
Total (random effects)
Total (random effects)
0,1
1
10
100
0,1
Odds ratio
1
10
100
Odds ratio
Amisulpride – Olanzapine
(Odds ratio=0,939)
Clozapine - Haloperidol
(Odds ratio=3,121)
Meta-analysis
Meta-analysis
1
2
1
2
Total (fixed effects)
Total (fixed effects)
Total (random effects)
Total (random effects)
0,01
0,1
1
10
Odds ratio
0,1
1
10
100
Odds ratio
Clozapine – Olanzapine
(Odds ratio=0,822)
Aripiprazole – Haloperidol
(Odds ratio=1,998)
Meta-analysis
Meta-analysis
1
2
1
3
4
2
5
Total (fixed effects)
Total (fixed effects)
Total (random effects)
Total (random effects)
0,01
0,1
1
10
100
0,1
1
10
Odds ratio
Odds ratio
46
Clozapine – Risperidone
(Odds ratio=2,430)
Olanzapine – Ziprasidone
(Odds ratio=3,338)
Meta-analysis
Meta-analysis
1
1
2
2
Total (fixed effects)
Total (fixed effects)
Total (random effects)
Total (random effects)
0,1
1
10
0,1
100
1
100
Odds ratio
Odds ratio
Olanzapine – Haloperidol
(Odds ratio=2,669)
10
Quetiapine – Haloperidol
(Odds ratio=1,457)
Meta-analysis
Meta-analysis
1
2
3
4
5
6
7
8
9
10
Total (fixed effects)
Total (random effects)
1
2
3
Total (fixed effects)
0,1
10
1000
Odds ratio
Total (random effects)
0,1
1
10
100
Odds ratio
Olanzapine – Risperidone
(Odds ratio=0,810)
Quetiapine – Risperidone
(Odds ratio=1,051)
Meta-analysis
Meta-analysis
1
2
3
1
4
5
2
6
3
7
8
9
Total (fixed effects)
Total (fixed effects)
Total (random effects)
Total (random effects)
0,1
1
10
Odds ratio
100
0,1
1
10
100
Odds ratio
47
Remoxiprode – Haloperidol
(Odds ratio=0,874)
Ziprasidone
–
(Odds ratio=2,243)
Haloperidol
Meta-analysis
Meta-analysis
1
2
3
4
5
6
1
2
Total (fixed effects)
Total (random effects)
Total (fixed effects)
Total (random effects)
0,1
1
10
100
Odds ratio
0,1
1
10
100
Zotepine – Haloperidol
(Odds ratio=1,828)
Odds ratio
Risperidone – Haloperidol
(Odds ratio=2,441)
Meta-analysis
Meta-analysis
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Total (fixed effects)
Total (random effects)
1
2
Total (fixed effects)
Total (random effects)
0,1
10
1000
0,1
1
10
100
Odds ratio
Odds ratio
Sertindole – Risperidone
(Odds ratio=1,346)
Meta-analysis
1
2
Total (fixed effects)
Total (random effects)
0,1
1
10
100
Odds ratio
48
CONCLUSIONS: This systematic review confirms that novel antipsychotics are more
effective than conventional antipsychotic drugs for those with schizophrenia. Atypical
antipsychotics offer a good general profile, at least compared to high-potency typical
antipsychotics. They may also yield better results in some specific outcomes related to efficacy,
such as improvement of global state and general negative symptoms.
Long term randomised trials evaluate the comparative value of atypical antipsychotics,
particularly compared to other expensive atypical antipsychotics. The results of comparison
between atypical antipsychotics effectiveness show that the most effective is risperidone, then
olanzapine, clozapine, quetiapine and ziprasidone. The differences between all other new novel
medicines are not statistically significant. These focus on important outcomes which have not
been sufficiently monitored such as service use, family burden and quality of life.
In the present analysis that included 22083 patients, risperidone treatment demonstrated
significant advantages for schizophrenia.
On the basis of that meta-analysis, risperidone meets a number of the criteria for a novel
atypical antipsychotic. While the robustness of these advantages should be replicated in a usualcare setting, these data represent an encouraging advance for the victims of schizophrenia.
According to the results of meta-analysis, pharmacoeconomic evaluations were carried
out. As it comes form the conclusions of meta-analysis of atypical antipsychotic medicines,
risperidone is the most effective agent for schizophrenia treatment.
All other atypical antipsychotics comparing their effectiveness are rather similar and the
differences are not statistically significant. That is why it was decided to use risperidone price as
reference price for atypical antipsychotics.
49
5.2 Comparison of consumption over the three years period (2003-2005)
All the calculated data of antipsychotics consumption over the three years period (20032005) are shown in the Annexes 5, 6, 7, 8.
5,48
5,6
5,4
5,07
5,2
DDD/1000
5
inhabitants/1
4,8
day
4,73
4,6
4,4
4,2
2003 Year
2004 Year
2005 Year
Figure 4. The total consumption of antipsychotic drugs in Lithuania, 2003-2005
Figure 4 illustrates how the total consumption of antipsychotic drugs in Lithuania
increased by 16 % in three years period from 4,73 DDD/1000 inhabitants/1 day (in 2003) to 5,48
DDD/1000 inhabitants/1 day (in 2005).
6,00
5,00
4,00
DDD/1000
inhabitants/1 3,00
day
2,00
1,00
2,74
2,69
2,82
Conventional
Atypical
1,99
2,38
2,66
0,00
2003 Year 2004 Year 2005 Year
Figure 5. The consumption of conventional ant atypical antipsychotics in three years, 2003-2005
50
The Figure 4 shows changes of consumption of conventional and atypical antipsychotics
in three years (2003-2005). The proportion of consumption of conventional antipsychotics
increased only by 3 % (from 2,74 to 2,82 DDD/1000 inhabitants/1 day). In contrast the
consumption of atypical antipsychotics showed the pronounced increase of 34 % (from 1,99 to
2,66 DDD/1000 inhabitants/1 day).
Table 4. The proportions of conventional and atypical antipsychotics over three years
Antipsychotics
Conventional
Atypical
2003
57,96%
42,04%
Year
2004
53,12%
46,88%
2005
51,52%
48,48%
In comparison among proportions of conventional and atypical antipsychotics, it
appeared that the proportion of conventional antipsychotics decreased by 6% because of atypical
antipsychotics increasing. In 2005 there are almost the same proportions of total market (Table
4).
Table 5. Data about the certain antipsychotics consumption in three years, 2003-2005
Antipsychotic agent
Haloperidol (solid oral form)
Olanzapine (solid oral form)
Risperidone (solid oral form)
Amisulpride (solid oral form)
Haloperidol (liquid oral form)
Chlorpromazine (solid oral form)
Flupentixol (solid oral form)
Melperone (solid oral form)
Tiapride (solid oral form)
Quetiapine (solid oral form)
Clozapine (solid oral form)
Levomepromazine (solid oral form)
Zuklopentixol (solid oral form)
Chlorprotixene (solid oral form)
Sulpiride (solid oral form)
Trifluoperazine (solid oral form)
Thioridazine (solid oral form)
Risperidone (liquid oral form)
Ziprasidone (solid oral form)
2003
17,65%
12,56%
11,42%
11,30%
9,02%
7,00%
4,55%
3,87%
3,50%
3,41%
3,35%
3,06%
3,03%
2,46%
1,46%
1,29%
1,04%
-
Year
2004
16,33%
13,91%
12,09%
10,55%
8,38%
6,46%
2,06%
4,39%
4,63%
6,56%
3,51%
2,77%
2,81
2,89%
1,20%
0,91%
0,26%
-
2005
19,65%
15,60%
10,50%
10,33%
7,35%
2,41%
1,78%
3,53%
6,75%
7,25%
4,03%
3,24%
2,69%
4,08%
1,10%
0,03%
0,17%
0,15%
0,63%
Over the studied period the consumption of haloperidol, olanzapine and risperidone
remained in the top of the list, respectively the first, the second and the third (Table 5). The
51
results show that the proportion of haloperidol decreased in 2004 and increased in 2005 making
almost fifth part of all antipsychotics consumption. The proportion of olanzapine increased by
3% over three years, the consumption of risperidone and amisulpride declined and in parallel the
proportion of quetiapine and clozapine increased. Ziprasidone appeared in 2005 taking 0,63% of
all antipsychotics consumption. Most of conventional antipsychotics, such as haloperidol liquid
form, chlorpromazine, flupentixol, melperone, zuklopentixol, sulpiride and trifluoperazine
consumption declined. Only tiapride, levomepromazine, chlorprotixene and thioridazine
proportion increased. The interesting fact is that all of those antipsychotic agents that have an
increased consumption are out of reimbursement (Table 5).
39,21
36,71
40,00
35,00
30,96
30,00
25,00
Million Litas 20,00
15,00
10,00
5,00
0,00
2003 Year
2004 Year
2005 Year
Figure 6. Total costs of antipsychotics in three years, 2003-2005
45000000
40000000
32450126
35000000
30000000
34472979
27118723
25000000
Atypical
20000000
Conventional
15000000
10000000
5000000
3836881
4257090
4734283
0
2003
2004
2005
Figure 7. Costs by conventional and atypical antipsychotics in three years, 2003-2005
52
The findings show that the expenditure of antipsychotics increased from 30,96 mln Litas
(in 2003) to 39,21 mln Litas (in 2005) (Figure 6). As it is shown in Figure 7, the costs of atypical
antipsychotics increased from 27,12 mln Litas to 34,47 mln Litas that makes 87% of all
expenditures of antipsychotic medicines in 2005 year.
5.3. Pharmacoeconomic calculations suggesting the reference price for antipsychotics
The aim of the study was to examine the costs of schizophrenia treatment using the
reference price for atypical antipsychotics.
Table 6 shows us the differences between antipsychotic drugs according to DDD/1000
inhabitants/1 day. Sales data presented in this table provide a rough estimate of the proportion of
the study population that may be treated daily with certain drugs. The biggest part of population
on average might get haloperidol every day. This estimate is most useful for chronically used
drugs. The consumption measuring according to the DDD/1000 inhabitants/1 day shows the
general utilization. The biggest meaning for conventional antipsychotics is for haloperidol
(1,007) and for atypical antipsychotics for olanzapine (0,885). Also there is a great difference
between hard (0,576) and liquid (0,008) pharmaceutical forms consumption. It shows that liquid
form is not popular in Lithuania in spite of the effectiveness of this drug.
53
Table 6. Data about consumption of antipsychotics according to the DDD/1000 inhabitants/1
day method in 2005 year in Lithuania
Nr. Active substance
DDD/1000
inhabitants/
1 day
DDD/1000
inhabitants/1
day (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Haloperidol
Olanzapine
Risperidone
Amisulpride
Haloperidol (liquid)
Quetiapine
Tiapride
Chlorprotixene
Clozapine
Melperone
Levomepromazine
Zuklopentixol
Flupentixol
Chlorpromazine
Sulpiride
Ziprasidone
Thioridazine
Risperidone (liquid)
1,077
0,855
0,576
0,566
0,403
0,397
0,370
0,223
0,221
0,194
0,178
0,148
0,097
0,064
0,060
0,035
0,009
0,008
19,65
15,60
10,50
10,33
7,35
7,25
6,75
4,08
4,03
3,53
3,24
2,69
1,78
1,17
1,10
0,63
0,17
0,15
19
Trifluoperazine
0,002
0,03
5,481
100,00
Comparing the prices of one DDD, the atypical antipsychotic prices range from 5,18
Litas/DDD (clozapine) to 14,58 Litas/DDD (olanzapine) (Table 7). The cheapest antipsychotic
among conventional agents is haloperidol (0,18 Litas/DDD) and the most expensive sulpiride
(4,46 Litas/DDD). So total prices of antipsychotic agents in Lithuania in 2005 balances between
0,18 Litas and 14,58 Litas/DDD.
54
Table 7. DDD price for the certain antipsychotics in 2005
Nr.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Active Substance
Olanzapine
Quetiapine
Ziprasidone
Risperidone (liquid)
Risperidone
Amisulpride
Clozapine
Sulpiride
Tiapride
Levomepromazine
Melperone
Chlorprotixene
Flupentixol
Thioridazine
Trifluoperazine
Zuklopentixol
Chlorpromazine
Haloperidol (liquid)
Haloperidol
One DDD
Price (LTL)
14,58
13,05
12,19
11,64
7,34
6,48
5,18
4,46
3,66
3,07
2,91
2,32
2,32
2,14
1,72
1,55
0,79
0,19
0,18
The consumption of antipsychotic agents according to the DDD/1000 inhabitants/1 day
and the costs of DDD help to understand the reasons of total costs of antipsychotics (Table 8).
As we can see from the following table, the sum of money spent on antipsychotic medicines in
Lithuania in 2005 is 39 207 262 Litas. The biggest part takes olanzapine, quetiapine and
risperidone.
Other important point is that some medicines for schizophrenia treating is out of
reimbursement in spite of their wide consumption and popularity. It is levomepromazine,
chlorprotixene, sulpiride, chlorpromazine, thioridazine and trifluoperazine. All together they take
5% of all antipsychotics sales in 2005.
55
Table 8. The total costs of the certain antipsychotics in 2005 in Lithuania
Nr.
1
2
3
4
5
6
7
8
9
10
11
12
Active Substance
Olanzapine
Quetiapine
Risperidone
Amisulpride
Tiapride
Clozapine
Melperone
Levomepromazine
Chlorprotixene
Ziprasidone
Sulpiride
Zuklopentixol
Price, LTL
15641649,07
6508092,41
5298612,81
4606066,82
1696438,84
1436309,62
708277,56
683602,20
650798,39
528747,08
337146,68
286968,28
%
39,89
16,60
13,51
11,75
4,33
3,66
1,81
1,74
1,66
1,35
0,86
0,73
13
14
15
16
17
18
19
Flupentixol
Haloperidol
Risperidone (liquid)
Haloperidol (liquid)
Chlorpromazine
Thioridazine
Trifluoperazine
283145,36
238838,87
116355,00
94399,38
63769,00
24351,00
3694,00
39207262,37
1763361,27
0,72
0,61
0,30
0,24
0,16
0,06
0,01
100,00
4,50
All:
Out of reimbursement:
* Medicines out of reimbursement are bolded.
Figures 8 and 9 show the percentage of certain antipsychotics according to DDD/1000
inhabitants/1 day separately for conventional and atypical antipsychotics. The most popular
between conventional antipsychotics is haloperidol (both hard and liquid pharmaceutical forms),
then tiapride, chlorprotixene, melperone, etc.
Conventional antipsychotics DDD/1000 gyventojų/ 1 dieną
2%
2%
Haloperidolum
3%
Haloperidolum (skystis)
5%
Tiapridum
Chlorprotixenum
6%
39%
7%
Melperonum
Levomepromazinum
Zuklopentixolum
Flupentixolum
8%
Chlorpromazinum
13%
Sulpiridum
15%
Thioridazinum
Trifluoperazinum
Figure 8. The part of certain conventional antipsychotics in DDD/1000 inhabitants/1 day for
schizophrenia in 2005
56
The most popular medicines between atypical antipsychotics are olanzapine, risperidone,
amisulpride, quetiapine, etc. All results of this work show that olanzapine is the lieder in
antipsychotic medicines market in spite of their less effectiveness and big price comparing to
risperidone.
Atypical antipsychotics DDD/1000 inhabitants/1day
0%
1%
8%
33%
15%
Olanzapinum
Risperidonum
Amisulpridum
Quetiapinum
Clozapinum
Ziprasidonum
Risperidonum (liquid)
21%
22%
Figure 9. The part of certain atypical antipsychotics in DDD/1000 inhabitants/1 day
for schizophrenia in 2005
Next two figures (Figure 8 and Figure 9) demonstrate the differences between DDD
prices of both conventional and atypical antipsychotics in Lithuania in 2005. The values of
conventional agents vary between haloperidol and sulpiride. Accordingly the consumption of
haloperidol comparing DDD/1000 inhabitants/1 day is biggest, at the same time sulpiride
consumption percent is almost the last.
Talking about atypical antipsychotics, the biggest DDD price is for olanzapine, it takes
two times biggest part comparing to risperidone solid form, but the consumption of olanzapine is
also on the first place that doesn’t accompany to the pharmacoeconomic theory. The reason of
this also still stays unclear.
57
One DDD price for conventional antipsychotics in 2005
1%
Sulpiridum
1%
Tiapridum
3%
Levomepromazinum
6%
18%
Melperonum
7%
Chlorprotixenum
8%
Flupentixolum
14%
9%
Thioridazinum
Trifluoperazinum
Zuklopentixolum
12%
9%
Chlorpromazinum
12%
Haloperidolum (liquid)
Haloperidolum
Figure 10. DDD price (LTL) for conventional antipsychotics in 2005
One DDD Price for atypical antipsychotics in 2005
7%
21%
9%
Olanzapinum
Quetiapinum
Ziprasidonum
10%
Risperidonum (liquid)
19%
Risperidonum
Amisulpridum
Clozapinum
17%
17%
Figure 11. DDD price (LTL) for atypical antipsychotics in 2005
During this study an attempt was made in order to indicate the pricing limits for the
antipsychotics and especially for atypical antipsychotics considering the similar therapeutic
effects. According to the results, the most part of money spent for the treatment of schizophrenia
takes atypical antipsychotics.
58
Table 9. The distribution of money spent on atypical antipsychotics on 2005 in Lithuania
Name of Agent
Olanzapine
Quetiapine
Risperidone
Amisulpride
Clozapine
Ziprasidone
Price, Lt
15641649
6508092
5414968
4606067
1436310
528747
34135833
Percentage, %
46
19
16
13
4
2
100
20000000
15000000
10000000
5000000
Ziprasidonum
Clozapinum
Amisulpridum
Risperidonum
Quetiapinum
0
Olanzapinum
Sum of money, Lt
Money spent on atypical antipsychotics in 2005
distribution
Name of agent
Figure 12. The distribution of money spent on atypical antipsychotics on 2005 in Lithuania
As we can see from the figure 12, the biggest amount of money was spent on Olanzapine,
Quetiapine, Risperidone and Amisulpride. Reference price would probably help.
Pharmacoeconomic calculations were done using the meta-analysis results of atypical
antipsychotics. As the meta-analysis showed, risperidone is the most effective among atypical
antipsychotics, differences between risperidone and other new antipsychotic drugs are not
significant and that is why the decision was to set the risperidone price as reference. Setting the
reference price of atypical antipsychotics class (by risperidone 7,34 Lt/DDD), the total savings
estimated respectively as 10 868 316,11 Lt (Table 10).
59
Table 10. Pharmacoeconomic calculations suggesting the risperidone price of the atypical
antipsychotic agent as the reference price
Name of agent
DDD
Cost, LT
Price/DDD
(LT)
Reference
price/DDD
(LT)
Conventional antipsychotics
Chlorpromazine
80.340,00
63769,00
0,79
0,79
Chlorprotixene
280450,00
650798,39
2,32
2,32
Flupentixol
122183,33
283145,36
2,32
2,32
Haloperidol
1351681,25
238838,87
0,18
0,18
Haloperidol (liquid)
505350,00
94399,38
0,19
0,19
Levomepromazine
222875,00
683602,20
3,07
3,07
Melperone
243116,67
708277,56
2,91
2,91
Sulpiride
75611,25
337146,68
4,46
4,46
Tiapride
464015,00
1696438,84
3,66
3,66
Thioridazine
11384,00
24351,00
2,14
2,14
Trifluoperazine
2152,50
3694,00
1,72
1,72
Zuklopentixol
185363,33
286968,28
1,55
1,55
Atypical antipsychotics (using risperidone price as reference)
Medicines with reference prices are bolded
Amisulpride
710360,00
4606066,82
6,48
6,48
Clozapine
277083,33
1436309,62
5,18
5,18
Olanzapine
1072960,00 15641649,07
14,58
7,34
Quetiapine
498535,00
6508092,41
13,05
7,34
Risperidone
722368,00
5298612,81
7,34
7,34
Risperidone (liquid)
10000,00
116355,00
11,64
7,34
Ziprasidone
43372,50
528747,08
12,19
7,34
Total:
39 207 262,37
Saved by: 10 868 316,11
Cost using
reference
price (7,34),
LTL
63769,00
650798,39
283145,36
238838,87
94399,38
683602,20
708277,56
337146,68
1696438,84
24351,00
3694,00
286968,28
4606066,82
1436309,62
7875526,40
3659246,90
5298612,81
73400,00
318354,15
28 338 946,26
The total amount spent for antipsychotic drugs is over 39 mln Litas in 2005. The
calculations show that it would be possible to reduce the total costs of antipsychotics almost by
11 mln Litas setting the reference price for atypical antipsychotics as the risperidone price.
Figure 13 and 14 demonstrate total costs of antipsychotic medicines over three years
comparing to the possible savings setting reference price of risperidone during three years for
atypical antipsychotics. Total amount of budget saved during 2003-2005 years could reach 20
mln Litas.
60
40,00
35,00
30,00
39,21
36,71
30,96
27,51
30,76
28,34
25,00
Money spent, mln
Litas
Money spent using
reference price, mln
Litas
Million Litas 20,00
15,00
10,00
5,00
0,00
2003 Year
2004 Year
2005 Year
Figure 13. Total costs of antipsychotics comparing to possible costs using reference price over
three years
12,00
10,87
Million Litas
10,00
8,00
6,00
4,00
Saved amount
5,95
3,44
2,00
0,00
2003 Year
2004 Year
2005 Year
Figure 14. Money saved by introducing reference price for atypical antipsychotics over three
years
61
6. DISCUSSION
Schizophrenia is a disease affecting the young adults and amounts to approximately
20,000 people in Lithuania. Schizophrenia represents the first diagnosis that psychiatric sectors
take in charge. The costs associated with schizophrenia, mainly hospital costs, are important and
take a big part of the total medical costs in Lithuania. In the social welfare system, the social
costs (pensions, allowances, managements of custody or guardianship by social workers) are also
to be taken into account: it amounts to a third of the global direct cost. Schizophrenia also
generates indirect costs (losses of productivity and premature deaths) which would be at least
equal, or even more important, than direct medical costs. The non-compliance to the
antipsychotic treatment is a major problem with people suffering from schizophrenia. Indeed the
lack of compliance to the treatment is a major handicap for schizophrenic patient stabilization.
The poor level of compliance is due to many various causes: adverse effects that are considered
unbearable, medicine viewed as persecutory, negation of the disease, nostalgia for the productive
phases of the disease, lack of social support, complexity of the prescription, relapse itself [77].
Since 2003 the total antipsychotics consumption increased by 16% reaching the value of
5,5 DDD/1000 inhabitants/day (Figure 4). In fact the results of the similar studies in other
countries also indicate the increasing use of antipsychotics agents [78]. However in comparison
with these reports the consumption of antipsychotics sold in Lithuania was still low (Figure 15).
9
8,4
8
8,2
7,8
6,9
7
6,4
6
6
5,8
DDD/1000 5
inhabitants/1
4
day
3
5,5
4,2
2
Latvia
Lithuania
Hungary
Spain
Italy
France
UK
Sweden
0
Germany
1
Figure 15. The total sales of antipsychotics in various countries in 2005
The reason of these results is probably that patients are frequently neither recognized nor
treated adequately. Under-diagnosis and under-treatment of major depression can be associated
62
with factors relating to patients, their physicians, and the health care systems that provide their
care [67].
The results of pharmacoeconomic analysis show that the total amount spent for
antipsychotic drugs in 2005 is over 39 mln Litas. According to the meta-analysis and
calculations above, introduction of risperidone price as reference price for atypical
antipsychotics let save almost by 11 mln Litas.
The point of this discussion is to define the main possible directions of additional budget
saved and the roots of perfection of schizophrenia treatment in Lithuania. Probably, the
introduction of additional sum of money in the treatment quality will lead to bigger savings.
6.1. Plasma concentration monitoring for antipsychotics
Antipsychotic drugs are candidates for plasma concentration monitoring, but not all
agents have the same potential in this respect. Although some of the antipsychotic drugs have
been in use for many years, knowledge of their pharmacokinetics is still only approximate. This
is primarily because determination in biological fluids is not always feasible. Accordingly,
analytical methods useful for pharmacokinetic studies or plasma concentration monitoring of
these antipsychotic drugs are discussed. All the neuroleptics should review some basic
pharmacokinetic properties: good gastrointestinal absorption but reduced systemic availability
because of hepatic first-pass metabolism, high hepatic clearance and a large apparent volume of
distribution leading to an apparent elimination half-life of about 24 hours for most of these
compounds. The renal elimination is negligible and it seems that these drugs do not possess
active metabolites. The pharmacokinetic properties of antipsychotic drugs are important for the
inclusion of a set of drugs in a psychiatric institution where there is a possibility of drug
concentration monitoring. It is important to point, that every fifth patient tolerates medicines
differently. That is why side effects or insufficient treatment appear. Talking about mental
illnesses it is not easy to evaluate the effect of drugs and the results of treatment mistakes are too
serious.
It is known that 20% of all patients have a different metabolism of medicines. European
countries have already developed the plasma concentration monitoring systems and show better
treatment results. It is definitely important to introduce this practice in Lithuania. Some
methodologies offer to check the plasma concentration every month or ever often. In Lithuania it
would be enough to prepare it at least every three months for every patient and to find out the
level of concentration of antipsychotic and to correct the dosage if it is needed [79].
63
As the calculating of this work shows there are about 17000 patients affected
schizophrenia in Lithuania in 2005. Also it was accounted that reference price introduction
would help Lithuanian government to rationalize health system budget. The best way to use
saved budget is to accept plasma concentration monitoring requirement in Lithuania and
rationalize the treatment of schizophrenia.
The total resources needed for antipsychotic drugs plasma concentration monitoring and
to find out the level of rationality of schizophrenia treatment can be accounted. Introducing the
measuring of plasma concentration of antipsychotics every three months would lead to 4
measuring in year, probably there will appear one or two extra measurements, so, let us take 5
measuring in a year for every patient. The cost of one plasma concentration determination is
about 30-40 Litas. According to the results above there is almost 11 mln Litas extra money
saved. That is why we can let ourselves to account in a following way:
17000 patients * 5 measurements a year * 40 Litas = 3 400 000 Litas
It shows that Lithuanian government has a real possibility to induce the antipsychotic
medicines plasma concentration measurement, to avoid a lot of side effects and successfully
rationalize the treatment of schizophrenia in Lithuania.
6.2. Therapeutic drug monitoring of antipsychotics
Use of antipsychotic drugs, especially known as second-generation antipsychotics, has
soared in recent years for the treatment of a variety of mental illnesses, among them is
schizophrenia.
For those who respond well to these drugs, they can mean the difference between leading
a fulfilling life and being severely disabled. But researchers say use of these drugs has also been
associated with dramatic weight gain, diabetes, and unhealthy cholesterol levels.
People who take antipsychotic drugs to treat a wide range of mental illnesses may suffer
from potentially rapid weight gain that could put them at risk for diabetes, high cholesterol, and
heart disease.
Because of those risks, experts are now calling for more careful screening and monitoring
of the use of antipsychotic drugs.
Therapeutic drug monitoring of conventional and atypical antipsychotics offers numerous
clinical advantages to the clinician. These include cost savings, decreased risk of toxicity, and
improved compliance. Among these drugs, studies of haloperidol, olanzapine, and clozapine
have provided the most compelling data to justify therapeutic drug monitoring. Among atypical
antipsychotics, although data document the utility of routine monitoring of clozapine and
64
olanzapine blood levels, there are no similar data available for either risperidone or quetiapine.
Additionally, the utility of therapeutic drug monitoring is enhanced by the availability of
prospective dosing schemes for haloperidol, olanzapine, and clozapine [80].
See Annex 9 for Antipsychotic Therapy Monitoring Sheet.
6.3. Reduction of hospital days for schizophrenic patients
Hospital costs for chronic schizophrenic patients consume a major share of the cost of
mental health care. Despite the success of numerous community mental health programs,
repeated hospital admission of schizophrenic patients is a significant problem. Effective therapy
and compliance with that therapy are two important factors in reducing hospitalization. Adverse
effects of antipsychotic agents, particularly extrapyramidal symptoms (EPS), negatively
influence compliance. A new antipsychotic agent, risperidone, has demonstrated efficacy against
both positive and negative symptoms of schizophrenia and has been associated with a low
incidence of EPS. Risperidone may have a role in reducing hospital days for the chronic
schizophrenic population [81].
An ideal study would explicitly measure direct and indirect medical costs associated with
the use of newer antipsychotic medications.
6.4. The introduction of new antipsychotic medications
In recent years, new atypical antipsychotic drugs have been marketed. Unfortunately,
new antipsychotic medicines have been introduced in too little researches to determine their real
efficacy and safety level. Nowadays more and more antipsychotics are being introduced in
Europe market. According to BNF there are some new drugs for schizophrenia treatment that are
already accepted in other European countries but not in Lithuania yet.
This work introduces the comparison of effectiveness of antipsychotic drugs. But another
side of view are increasing numbers of reports concerning diabetes, ketoacidosis,
hyperglycaemia and lipid dysregulation in patients treated with second-generation (or atypical)
antipsychotics. This have raised concerns about a possible association between these metabolic
effects and treatment with these medications and looking for newer medications.
Theories of nowadays considers the evidence for and against an association between
glucose or lipid dysregulation and eight separate second-generation antipsychotics currently
available in Europe, specifically clozapine, olanzapine, risperidone, quetiapine, zotepine,
amisulpride, sertindole, ziprasidone and aripiprazole.
65
Clozapine and olanzapine treatment are associated with the greatest risk of clinically
significant weight gain, with other agents producing relatively lower levels of risk. Risperidone,
quetiapine, amisulpride and zotepine generally show low to moderate levels of mean weight gain
and a modest risk of clinically significant increases in weight. Ziprasidone and aripiprazole
treatment are generally associated with minimal mean weight gain and the lowest risk of more
significant increases. Clozapine and olanzapine treatment are associated with an increased risk of
diabetes mellitus and dyslipidaemia. The absence of retrospective database studies, and little or
no relevant published data from clinical trials, makes it difficult to draw conclusions concerning
risk for zotepine or amisulpride, although amisulpride appears to have less risk of treatmentemergent dyslipidaemia in comparison to olanzapine. There is no evidence at this time to suggest
ziprasidone and aripiprazole treatment association with an increase in risk for diabetes,
dyslipidaemia or other adverse effects on glucose or lipid metabolism [82].
Olanzapine, risperidone and ziprasidone are associated with extrapyramidal symptoms in
a dose-dependent manner, whereas quetiapine has been shown to produce a significantly lower
incidence of substantial EPS effects than haloperidol, and less EPS requiring treatment than
risperidone. Similarly, unlike risperidone and haloperidol, quetiapine treatment has been
associated with a significant reduction in serum prolactin levels, and has normalized raised
prolactin levels after discontinuation of previous treatment. Weight gain is also one of the major
unwanted adverse effects of treatment with many antipsychotic drugs but, in contrast, quetiapine
has demonstrated a neutral or 'normalizing' effect on body weight. In comparison with other
antipsychotics, quetiapine has been shown to possess a favourable safety profile, with no
requirement for routine blood, thyroid, or liver monitoring during treatment. Overall, quetiapine
therapy has produced high levels of patient satisfaction and compliance and this, coupled with its
efficacy in reducing psychoses of various origins, has made it an attractive treatment option in
both patients at increased risk of EPS, and the general population [83].
According to this, the part of money saved can be spent on new novel antipsychotics
introduction into Lithuanian market. Comparing BNF and the list of antipsychotics in Lithuania
there are some that don’t figure in the last one. New antipsychotics introduced should be:

Aripiprazole (Abilify) 5/10/15/30 mg tablets – in comparison to other atypical
antipsychotics, aripiprazole shows less risk of raised prolactin and prolongation of the
QTc interval [84].

Sertindole (Serdolect) 4/12/16/20 mg film coated tablets - an atypical antipsychotic
approved in the EU for once-daily use in patients with schizophrenia, improves negative
symptoms, and is also effective for the treatment of neuroleptic-resistant schizophrenia,
66
generally well tolerated and is associated with a low rate of extrapyramidal symptoms
[85].
As the meta-analysis shows, they are rather effective, sometimes even more than
risperidone and olanzapine, but the data to state this results is insufficient and more clinical
studies required.
The fact that these new novel antipsychotics are at least as effective as risperidone or
olanzapine is clear and according to their favourable safety profile the attention to them should
be paid.
6.5. Supporting different pharmaceutical formulations
Pharmacoeconomic analysis and meta-analysis provided in this work involves the oral
formulations of antipsychotics. This is because of too small part of other pharmaceutical forms
existing in Lithuania that is used for schizophrenia treatment. Most of them are out of
reimbursement. This could be another side of usefulness of extra money saved.
Comparing already existing medicines and pharmaceutical forms it is easy to recognise
that probably there could be other treatment possibilities that are refused because of resources
insufficiency. Some offers can be made.
Long-acting injectable antipsychotics and oral soluble forms allow a better therapeutic
compliance and thus better efficacy of the treatment all around the world. The main objective of
next pharmacoeconomic analysis would be to evaluate the impact in terms of medical benefits
and costs of the following strategies:
1. Risperidone long-acting injection: first long-acting injectable atypical antipsychotic;
2. Risperidone orodispersible tablets.
The main hypothesis of the model would be that an increase in compliance linked to the
use of long-acting injectable formulation or oral soluble form could lead to an increased efficacy
and a modification of the cost-effectiveness ratio. The hypotheses for long acting forms shows
that increase of efficacy which can be expected for the long-acting injectable formulations varies
between 5% to more than 30% according to the literature data. The soluble forms are also
recognised as one of the most effective oral forms in Europe [86].
67
6.6. The introduction of already existing antipsychotic drugs into the list of
reimbursement
Accounting the consumption of antipsychotic medicines demonstrated the part of drugs
that are not introduced into the list of reimbursement. In 2005 these medicines are:
chlorpromazine,
chlorprotixene,
droperidole,
fluphenazine,
haloperidol
injections,
levomepromazine, olanzapine injections, sulpiride, thioridazine, trifluoperazine, some forms of
ziprasidone. The sum of money spent on these medicines in 2005 reaches almost 2 mln Litas.
Most of medicines pointed are conventional antipsychotics but they are still being prescribed and
it should be the main reason for their reimbursement.
All these let us evaluate the reasonable consumption and administration of antipsychotic
medicines during introduction of reference price for atypical antipsychotics. Money saved seems
to be indispensable for the perfecting of schizophrenia treatment.
Schizophrenia generates important costs for society direct, as a consequence of
hospitalization and outpatient treatment, and indirect; related to loss of productivity. The atypical
antipsychotics, such as risperidone, have supposed an important advance in the treatment of
schizophrenia. The greater cost of atypical antipsychotics with respect to conventional drugs has
led to the conduction of pharmacoeconomic studies to determine its efficiency. This work
reviews the complete pharmacoeconomic studies that compare conventional and novel
antipsychotics in the treatment of schizophrenia [87].
Until now, there has been no sufficient evidence for the superior cost-effectiveness of
atypical antipsychotics in European countries. Considering the importance of this topic for health
politics, more cost-effectiveness studies in European countries are urgently needed. But even if
economic superiority of the second-generation antipsychotics cannot be demonstrated in such
studies,
their
use
is
nevertheless
indicated
with
respect
to
patient's
well-being.
More and more people are exposed to prescribe psychotropic drugs at all stages of the life cycle,
from prenatal life to old age. Beyond the societal questions raised by this medical practice, the
utilisation and impact of psychotropic drugs have to be further explored at the population level.
Pharmaco-epidemiological research conducted independently of drug companies is therefore
required to explore crucial public health issues related to psychotropic drug use, such as the
medical and economic impact of unjustified extension of use, the identification of infrequent or
delayed adverse effects, and the efficiency of new marketed products in naturalistic conditions
[88].
68
7. CONCLUSIONS

The total antipsychotics consumption increased by 16% over three years (2003-2005)
period reaching the value of 5,5 DDD/1000 inhabitants/day. The use of total
antipsychotic drugs continues to increase because of the increased use of atypical
antipsychotics. Since 2003 the proportion of use of antipsychotics has increased by 34%,
while the use of conventional has increased only by 3%.

The expenditure of antipsychotics increased from 30,96 mln Litas (in 2003) to 39,21 mln
Litas (in 2005), the costs of atypical antipsychotics increased from 27,12 mln Litas to
34,47 mln Litas that made 87% of all expenditures of antipsychotic medicines in 2005
year.

The total prices of one DDD of antipsychotic agents in Lithuania in 2005 balances
between 0,18 Litas/DDD (Haloperidol) and 14,58 Litas/DDD (Olanzapine).

On the basis of our meta-analysis, that included 22083 patients, risperidone treatment
demonstrated significant advantages for schizophrenia.

Setting the reference price for atypical antipsychotics by risperidone price 7,34 Lt/DDD,
the total savings estimated respectively as 10,86 mln Litas. Total amount of budget saved
by introducing the reference price of risperidone during 2003-2005 years could reach
20,26 mln Litas.

Performed cost-minimization analysis using the reference-based pricing estimated the
possible reduction of total antipsychotics expenditures in 2005 by 28%.

Extra money saved by reference price could be used for the antipsychotic drugs plasma
concentration ant therapeutic monitoring and increase their efficacy, for the introduction
of new antipsychotic agents into the Lithuanian market (aripiprazole, sertindole), for the
supporting of different pharmaceutical formulations of already existing drugs (depot
injections and dispersible tablets), for the introduction of already existing antipsychotics
into the list of medicines on compensation. These would lead to the perfection of
schizophrenia treatment in Lithuania.
69
8. SUMMARY
Objective: To evaluate trends in the use of antipsychotic drugs in Lithuania between
2003 and 2005 years.
Methods: The data on total sales of antipsychotic drugs in all Lithuanian regions over
three years (2003-2005) were obtained from IMS Health Inc. Drugs were classified according to
the Anatomic Therapeutic Chemical system and use was quantified in terms of defined daily
doses. Meta-analysis of observational studies retrieved through systematic search of all available
electronic data sources. 1651 abstracts were found and checked. 76 randomised double-blind
studies were identified for the met-analysis. Data were calculated by DDD methodology and
expressed in DDDs per 1.000 inhabitants per day. The pharmacoeconomic analysis of
antipsychotics was performed by cost minimization and reference price methodology.
Results: In Lithuania the total antipsychotics consumption increased by 16% over three
years (2003-2005) period reaching the value of 5,5 DDD/1000 inhabitants/day. Since 2003 the
proportion of use of conventional antipsychotics has increased by 2%, while the use of atypical
antipsychotics has increased by 14%. The expenditures of antipsychotics has reached 39 mln
Litas (in 2005), of which 87% was costs for atypical antipsychotic agents. Setting the reference
price of risperidone (according to the meta-analysis results of effectiveness) for atypical
antipsychotics (7,34 Lt/DDD) it would be possible to rationalize schizophrenia treatment using
10,68 mln Litas extra money.
Conclusions: The findings suggest that the use of total antipsychotic drugs continues to
increase because of the increased use of atypical antipsychotics and some conventional
antipsychotics. According to the meta-analysis results risperidone is the most effective drug for
schizophrenia treatment. Considering the similar efficacy of other atypical antipsychotics and the
increased high expenditures of atypical antipsychotics it is extremely important to consider the
cost-effectiveness of antipsychotics. Performed cost-minimization analysis using the referencebased pricing estimated the possible reduction of total antipsychotics expenditures by 28% and
the possible schizophrenia treatment rationalization.
70
9. SANTRAUKA
Antipsichotinių vaistų suvartojimo tendencijos Lietuvoje 2003-2005 m.
Antipsichotikų efektyvumo įvertinimas. Metanalizė
Tikslas: Įvertinti antipsichotinių vaistų suvartojimo tendencijas Lietuvoje 2003-2005 m.
Metodai: Duomenys apie antipsichotinių vaistų pardavimus Lietuvoje 2003-2005 metų
laikotarpyje buvo surinkti iš IMS Health Inc. duomenų bazės. Vaistai buvo suklasifikuoti pagal
anatominę terapinę cheminę (ATC) klasifikaciją. Vaistų suvartojimas buvo vertinamas pagal
apibrėžtos dienos dozės (DDD – daily defined dose) metodiką, o duomenys išreikšti DDD
tūkstančiui gyventojų dienai. Duomenys metanalizei buvo sistematiškai surinkti iš visų įmanomų
elektroninių doumenų šaltinių. Buvo atrinktas ir išanalizuotas 1651 straipsnis. 76 randomizuotos
dvigubai-aklos
studijos
buvo
panaudotos
metanalizės
atlikimui.
Antipsichotikų
farmakoekonominei analizei atlikti buvo taikytas kainų mažinimo bei standartinės kainos
nustatymo principas.
Rezultatai: Per tris metus (2003-2005 m.) Lietuvoje antipsichotinių vaistų vartojimas
išaugo 16% ir pasiekė 5,5 DDD/tūkstančiui gyventojų/dieną rodiklį. Nuo 2003 metų tipinių
antipsichotikų suvartojimas padidėjo 2%, tuo metu kai atipinių antipsichotikų vartojimas išaugo
14%. Išlaidos antipsichotikams pasiekė 39 mln litų (2005 metais), iš kurių net 87% buvo skirta
atipiniams antipsichotiniams vaistams. Taikant standartinę kainą pagal metanalizės nustatytą
efektyviausią šizofrenijos gydymui antipsichotinį vaistą risperidoną atipiniams antipsichotikams
(7,34 Lt/DDD), būtų įmanoma racionalizuoti šizofrenijos gydymą is atitinkamai sutaupyti 10,68
mln litų suma.
Išvados: Antipsichotinių vaistų vartojimas Lietuvoje nenustoja didėti ir daugiausiai dėl
to, kad auga atipinių antipsichotikų bei kai kurių tiesiogiai veikiančių antipsichotikų vartojimas.
Atsižvelgiant į metanalizės rezultatus, risperidonas yra efektyviausias preparatas šizofrenijos
gydymui. Todėl, remiantis panašiu naujųjų atipinių antipsichotinių vaistų efektyvumu ir žymiai
padidėjusiomis išlaidomis atipiniams antipsichotikams yra svarbu akcentuoti antipsichotinių
vaistų kainų efektyvumo sąvoką. Atlikta farmakoekonominė analizė parodė, kad nustačius
standartines antipsichotinių vaistų kainas įmanoma šių vaistų išlaidas sumažinti 28%, kuo
remiantis racionalizuoti šizofrenijos gydymą.
71
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