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 WORKDone by: L. Katajceva, 5th course of Pharmacy studies
Supervised by: E. Kaduševičius, MD., Pharm. D., Assoc. prof.
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.
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
6.6 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
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
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
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.
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 long-term 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).
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].
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;
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
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 hyper-
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 short-term 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.
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].
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.
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 side-effects. 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.
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.
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 high-potency 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
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 acetylcholine-producing 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
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.
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 treatment-resistant 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,
risperidone ameliorates both positive and negative symptoms and has a relatively benign side-effect 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,
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
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 side-effects;
• 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.
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.
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
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.
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].
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 in-hospital 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,
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
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 naturalisticconditions 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 possiblyunfounded or hazardous extensions of the indications for psychotropicmedications. The widening of the boundaries of treatable illness,often favoured by the marketing pressure of pharmaceuticalcompanies, 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 categoriesof 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 clearlyestablished at the population level whether the benefits ofantipsychotic medication in people with preclinical psychosis are superior to the risks linked to unjustified prescriptionin cases with a false-positive diagnosis [60].However, it is striking that interest in early interventionmarkedly increased when new antipsychotic drugs became available,and the enthusiastic support of early intervention programmes by pharmaceutical companies suggests that they at least havelittle doubt about the benefits they can obtain from this strategy. The
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 widespreaduse. 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 psychotropicmedication, pointing to the need for studies examining utilisationpatterns in naturalistic conditions in order to identify discrepanciesbetween guidelines based on clinical trials and actual use.
4.7 Outcome studies
Although clinical trials may identify the most frequent adverseeffects 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 reactionshave to be identified as early as possible, since even a small increase in risk may have a serious impact on the health ofthe population if many people are exposed to the drug. Surveillance by centralised pooling of spontaneous reports facilitates thedetection of previously unidentified drug-related risks, which can be subsequently confirmed or dismissed by field and databasestudies. The availability of population-based databases documentingdrug exposure is therefore crucial for the identification ofrisks associated with psychotropic drug use. Such databaseshave 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 clinicalstudies [61].
Another major issue addressed by out-come studies is the riskof psychiatric disorders induced by prescription of psychotropicor non-psychotropic drugs. A further example of the usefulnessof population-based studies is provided by the debate on thesuspected link between autism and exposure to the measles,mumps and rubella triple vaccination. Findings obtained in clinical samples of uncertain representatively generated ahuge scientific controversy, widely amplified by the media. There is now strong evidence against this hypothesis, as rigorous
population-based studies have failed to find such an association. A markedlyunderdeveloped field of investigation concerns the delayedpsychiatric risks associated with psychotropic use; for example,the possible risk of dementia associated with exposure to benzodiazepinesneeds to be further explored owing to the public health consequencesof such a finding [62].
Another major public health issue concerns the psychiatric consequencesof medication prescription during pregnancy. Although the association between exposure to perinatal risk factors and increased vulnerabilityfor psychiatric disorder is well documented, knowledge is strikinglysparse regarding the impact of prenatal exposure to prescribeddrugs on the delayed risk of psychiatric disorder [63]. Owing to their methodological limitations, no definite conclusion regarding behavioural teratogenicity can be drawnfrom most studies exploring the risk associated with prenatalexposure 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 hypothesisis speculative owing to the small number of studies and theirmethodological limitations [65]. The most convincingpharmaco-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 schizophreniabeing identified through the Danish Psychiatric Central Register. After adjustment for confounding factors, risk of schizophrenia was found to be increased in people exposedto 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
