PHARMACOECONOMIC ASPECTS OF SCHIZOPHRENIA

Schizophrenia is one of the most seriouspsychiatric illnesses belonging to the group of non-affective psychoses. It is characterized by distortions of thought, perception, emotions and behavior. Twenty-four million people around the world suffer from schizophrenia. Schizophrenia is a chronic illness connected to significant expenses which are imposed on both the health system, extended social community and family, as well.Cost of illness studies of schizophrenia conducted around the world show wide range of material resources that countries set aside from their health budgets in order to cure schizophrenia. They range from 1.6% to 2.5%.International cost of illness studies came to the conclusion that the costs of this disease are high, depending on the health system and location and that intangible costs per se already justify investments in research and development of new treatments.Majority of published papers suggest that atypical antipsychoticshave better cost-effectiveness profile in comparison to the first generation of antipsychotics. Olanzapine, clozapine and risperidone are atypical antipsychotics generally found to be most costeffective in treating schizophrenia.


INTRODUCTION
Schizophrenia is one of the most serious psychiatric illnesses belonging to the group of non-affective psychoses.It is characterized by distortions of thought, perception, emotions and behavior.It is inherited poligenically.Various external factors contribute to the emergence of this disease, whilst the symptoms and the clinical manifestations are consequence of malfunctions in biochemical brain processes 1 .Twenty-four million people around the world suffer from schizophrenia 2 .Its prevalence is estimated between 0.3 and 1% worldwide, and its incidence is from 15.2 to 20.0 per 100,000 populations/year [3][4][5] .Schizophrenia is chronic illness associated with significant expenses which are imposed on both the health system, extended social community and family, as well 6,7 .
Treating schizophrenia is huge challenge for clinical doctors, due to its complex symptomatology and unpredictable, patientdependent course of illness.The illness outlook is good in 40% of cases, extremely unfavorable in 40%, whereas in the remaining 20% it has moderately progressive course.The patients suffering from this illness have higher risk of comorbidity and social isolation, they have problems finding employment, while the death rate is double that of general population, which makes this illness one of the most expensive psychiatric illnesses 8,9 .
Discovery of the mechanism of actionfor the first antipsychotic druug 60 years ago opened a path to synthesis of new group of drugs with similar profile (antipsychotics of the first generation), which, together with psychotherapeutic and socio-therapeutic interventions were significant step forward in the treatment of schizophrenia.Thirty-five years later, many antipsychotics of the second generation have been synthesized, and turned to be as efficient as the conventional antipsychotics, but with significantly better profile of side effects and superior tolerance, offering wider range of possibilities for treating this illness 10,11 .Nevertheless, despite modern pharmacotherapy, 20-30% of patients have weak response to the therapy, 15-20% of the patients have relapses every year, while certain patients relapse when taking maintenance therapy [12][13][14] .

SCHIZOPHRENIA AND ECONOMIC CONSEQUENCES
Cost of illness studies of schizophrenia conducted around the world show wide range of material resources that countries set aside from their health budgets in order to treat schizophrenia [15][16][17][18] .They range from 1.6% to 2.5% 19,20 .According to the general conclusion of the analysis of several cost of illness studies of schizophrenia given by Knapp, these costs are high, dependent on the health system and location, and intangible costs per se already justify investment in research and development of new treatments 7 .
Results of the costs-of-schizophrenia study conducted by Mangalor and associatesin England during 2004 and 2005, showedthat total expenses were 6.7 billion pounds, where 2 billion pounds represent direct expenses.Out of 4.7 billion pounds set aside for indirect expenses, the largest part of 3.4 billion pounds was used for expenses due to productivity loss for the reasons of sick leave, unemployment and deaths connected to schizophrenia, while the expenses of the productivity loss of caregivers amounted to 32 million pounds.The expenses of patients' families and private care were 615 million pounds.The cost of criminal proceedings with the patients suffering from schizophrenia amounted to expenses (72%) was in relation to unemployment and the productivity loss of caregivers.

ECONOMIC EVALUATION OF ANTIPSYCHOTICS RELATED TO THE TREATMENT OF SCHIZOPHRENIA
Pharmacotherapy of schizophrenia is based on antipsychotic drugs.However, their effectiveness is limited, often connected with discontinuation of treatment, relapses and hospitalization 21,22,23   .Drug prescriptions appear to contribute little to total costs 7,24,25 , but drugs may influence hospitalization rates and productivity, thus becoming rather significant for the economics of schizophrenia 26,27 .
McEvoy 28 came to a conclusion that hospitalization costs decreased in the United States of America between 1991.and 2002.However, the costs of outpatient treatment and medication went up.The decrease of inpatient costs could be explained by changes of policy and availability of new drugs for treatment of schizophrenia.In fact, there was a trend todecrease number of psychiatric beds all round the world over the last few decades,as a result of reforms in mental health care concepts and practices 29 .However, in spite of that, the costs of hospitalization are still the main direct cost driver of schizophrenia.Limiting length of stay and decreasing probability of relapse reduce treatment costs of schizophrenia 3,24,25 .Adverse effects of these drugs can vary, primarily considering higher risk of extrapyramidal syndrome concerning the firstgeneration antipsychotics (FGA) and risperidone, metabolic syndrome with olanzapine and clozapine, hyperprolactinemia with risperidone and agranulocytosis with clozapine 26,30,31 .
If one takes into account limited productivityof pharmacological treatment of schizophrenia, which is associated with high costs of the disease and increasingly higher expenses for medicines by health systems, it is necessary to evaluate cost-effectiveness profile of antipsychotic drugs in order to allow an adequate choice of pharmacotherapy for patients, in line with the financial reality of health systems.
Majority of published papers suggest that atypical antipsychotics have more beneficial cost-effectiveness profile in comparison to the first generation antipsychotics.According to the study conducted by Santos and associates in 2016 32 , which evaluated cost-effectiveness of atypical antipsychotics in Brazilian public health system, it was found that olanzapine was domi-nant over the other drugs.Nevertheless, validity of these study was not completely proven due to limited number of antipsychotic drugs included, but also due to the fact that quality of used data could not be checked.
Furthermore,randomized controlled study conducted by Davies and associates 33 showed that economic costs were lower and number of quality-adjusted life years gained higher when antipsychoticsof the first generation were used in the therapy of schizophrenic populationthat was responding poorly to previous treatment, instead of atypical antipsychotics.Two more studies conducted in Great Britain came up with similar conclusions 34,35 .
However, the systematic review of literature related to cost-effectiveness analysis of head-tohead comparisons of antipsychotics in schizophrenic populations that encompassed 24 studies with data from 14 countries, showed that clozapine, risperidone and olanzapine were the most cost-effective in treating schizophrenia 36 .
Validity of existing literature data should be carefully checked in regard to the manner of selection of subjects, method of estimation of direct and indirect treatment expenses, as well as interests of financiers.Namely, pharmaceutical companies provide studies whose results show an undoubted advantage of new medicines being placed on the market, while the research groups financed by Ministries of health or certain bureaus and funds, generally emphasize apparently cheaper and older antipsychotics 37 .Not only pharmacoeconomic studies, but also numerous clinical studies that analyze the problems falling within the domain of pharmacoeconomics, were the basis for modern schizophrenia treatment guidelines which give advantage to newer antipsychotics, pointing out that there are differences even among these medicines.According to the literature search, pharmacoeconomic analysis related to schizophrenia treatment as well as the cost effectiveness study of antipsychotics used in therapy still have not been conducted in Serbia.

CONCLUSION
Schizophrenia is chronic illness associated with significant expenses which are imposed on both the health system, extended social community and family, as well.International cost-of-illness studies on schizophrenia came to the conclusion that the costs are high, dependent on the health system and location and that the intangible costs per se already justify inve-stments in research and development of new treatments.The majority of published papers suggested that atypical antipsychoticshave more beneficial cost-effectiveness profile in comparison to the first generation drugs.Olanzapine, clozapine and risperidone are atypical antipsychotics that were generally found to be the most cost-effective in treating schizophrenia.