Analysis of Antidepressant Use in Republic of Serbia from 2013 to 2015 A

Introduction: Depression is a chronic mental disorder that causes changes in mood, thoughts, behavior and physical health. According to the World Health Organization (WHO) 350 million people worldwide are said to suff er from this mental disorder. This explains why antidepressants are widely used. Aim: The aim of this study was to analyze the use of antidepressants in Serbia, Norway and Finland from 2013 to 2015. Methods: The data about the use of antidepressants in Serbia, Norway and Finland in 2013, 2014 and 2015 was taken from the Agency for Drugs and Medical Devices of the Republic of Serbia, the sites of Norwegian Institute of Public Health, and Finish Agency for Drugs Fimea. Results: Large number of depressed patients and smaller number of antidepressants used in Serbia compared to Finland and Norway in 2013, 2014 and 2015 can be explained by a diff erent socioeconomic status and diff erent health system in those three countries. Patients in Serbia are underdiagnosed and undertreated due to a failure of the primary care physicians to identify depressed patients, so that those can be treated by a psychiatrist at the secondary health care level. Sertralin is the fi rst-choice medication in Serbia compared to escitalopram in Norway and Finland. Escitalopram has the highest probability of remission of the investigated antidepressants and is the most eff ective and cost-eff ective pharmacological treatment strategy for depression in a primary care setting. Conclusion: The consumption of antidepressants in Serbia increased in 2015 compared to 2013, but was still signifi cantly less in Serbia in 2013, 2014 and 2015 compared to Finland and Norway, pharmacotherapeutically developed countries. Medications consumed the most in all 3 countries in 2013, 2014 and 2015 were selective serotonin reuptake inhibitors. Sertraline was the most widely used antidepressant in Serbia in 2015, while escitalopram was mostly used antidepressant in Norway and Finland.


INTRODUCTION
Depression is a chronic mental disorder that causes changes in mood, thoughts, behavior and physical health.According to the World Health Organization (WHO) 350 million people worldwide are said to suff er from this mental disorder.Th e lifetime prevalence for major depression is reported to be as high as 14-17% and the one-year prevalence is 4-8%.Th e lifetime prevalence rates of major depressive disorders among women are 10-25%, and for men 5-12%.Depression is one of the leading causes of disability-adjusted life year (DALY) [1,2].
Th e most common forms of depression are the following: Persistent depressive disorder (also called dysthymia) is a depressed mood that lasts for at least two years.A person diagnosed with persistent depressive disorder may have episodes of major depression along with periods of less severe symptoms, but symptoms must last for two years to be considered persistent depressive disorder.
Postpartum depression -women with postpartum depression experience full-blown major depression during pregnancy or aft er delivery (postpartum depression).Th e feelings of extreme sadness, anxiety, and exhaustion that accompany postpartum depression may make it diffi cult for these new mothers to complete daily care activities for themselves and/or for their babies.
Psychotic depression occurs when a person has severe depression plus some form of psychosis, such as having disturbing false fi xed beliefs (delusions) or hearing or seeing upsetting things that others cannot hear or see (hallucinations).Th e psychotic symptoms typically have a depressive "theme, " such as delusions of guilt.
Seasonal aff ective disorder is characterized by the onset of depression during the winter months, when there is less natural sunlight.Th is depression generally lift s during spring and summer.Winter depression, typically accompanied by social withdrawal, increased sleep, and weight gain, predictably returns every year in seasonal aff ective disorder.
Bipolar disorder is diff erent from depression, but it is included in this list is because someone with bipolar disorder experiences episodes of extremely low moods that meet the criteria for major depression (called "bipolar depression").But a person with bipolar disorder also experiences extreme high -euphoric or irritable -moods called "mania" or a less severe form called "hypomania" [1].
Depression can only be diagnosed if the following symptoms are present most of the day, almost every day for at least 2 weeks: loss of interest or pleasure in hobbies and activities and persistent sad, anxious, or "empty" mood.Th ese symptoms have to be accompanied by at least 4 of the following symptoms: feelings of hopelessness, or pessimism, irritability, feelings of guilt, worthlessness, or helplessness, decreased energy or fatigue, moving or talking slowly, feeling restless or having trouble sitting still, diffi culty concentrating, remembering, or making decisions, diffi culty sleeping, earlymorning awakening, or oversleeping, appetite and/or weight changes, thoughts of death or suicide, or suicide attempts, aches or pains, headaches, cramps, or digestive problems without a clear physical cause and/or that do not ease even with treatment [1,2].
Current research suggests that depression is caused by a combination of genetic, biological, environmental, and psychological factors.Depression can happen at any age, but oft en begins in adulthood [1].
Depression, especially in midlife or older adults, can co-occur with other serious medical illnesses, such as diabetes, cancer, heart disease, and Parkinson's disease.But, in younger people, depression is oft en associated with rheumatoid arthritis and other chronic infl ammatory disorders [3].Th ese conditions are oft en worse when depression is present.Sometimes medications taken for these physical illnesses may cause side eff ects that contribute to depression [1].
Risk factors include: personal or family history of depression, major life changes, trauma, or stress and certain physical illnesses and medications [1].
Depression is usually treated with medications, psychotherapy, or a combination of the two.If these treatments do not reduce symptoms, electroconvulsive therapy (ECT) and other brain stimulation therapies may be options to explore [1].
Th e most popular types of antidepressants are called selective serotonin reuptake inhibitors (SSRIs).Accumulation of data on serotonergic organization and function of the Central Nervous System in healthy and morbid conditions has largely improved the understanding of etiopathogenesis of the affective and cognitive disorders.Concurrently, therapeutic approach has become more selective, specifi c and effi cient, yet not more causal.[5].Examples of SSRIs include: fl uoxetine, citalopram, sertraline, paroxetine, escitalopram.Other types of antidepressants are serotonin and norepinephrine reuptake inhibitors (SN-RIs).SNRIs are similar to SSRIs and include venlafaxine and duloxetine [1].
Another antidepressant that is commonly used is bupropion.Bupropion is a third type of antidepressant which works diff erently than either SSRIs or SNRIs.Bupropion is also used to treat seasonal aff ective disorder and to help people stop smoking [1].
SSRIs, SNRIs, and bupropion are popular because they do not cause as many side eff ects as older classes of antidepressants, and seem to help a broader group of depressive and anxiety disorders.Older antidepressant medications include tricyclics, tetracyclics, and monoamine oxidase inhibitors (MAOIs).For some people, tricyclics, tetracyclics, or MAOIs may be the best medications [1].

AIM
Th e aim of this study was to analyze the use of antidepressants from pharmacotherapeutic point of view in Serbia, Norway and Finland from 2013 to 2015 as well as to compare results of antidepressant use from Serbia with results of antidepressant use in Norway and Finland, countries with developed pharmacotherapeutic practice.

METHODS
Th e data about the use of antidepressants in Serbia in 2013, 2014 and 2015 was taken from the Agency for Drugs and Medical Devices of the Republic of Serbia [6][7][8].Th e data on use of antidepressants in Norway and Finland was taken from the offi cial site of the Norwegian Institute of Public Health and the offi cial site of the Finish Agency for Drugs Fimea, respectively [9,10].Analysis of the use of drugs was done from the point of social perspective and there was no infl uence of any factors or any interest groups.
Internationally recognized and widely accepted methodology in the study of drug use is based on the concept of anatomicaltherapeutic-chemical classifi cation of drugs (ATC) and defi ned daily doses.According to the ATC classifi cation the drugs that we use in treatment of nervous system belong to the N group, whereas psychoanaleptics are belonging to a group of N06.Antidepressants are further analyzed in N06A group.
In order to facilitate comparison of the intensity of use of certain drugs in time and in diff erent geographical areas scientist created a separate statistical unit of measurement of drug use, labeled as defi ned daily doses (DDD).Th e unit is independent of price, size, packaging, protected names of individual manufacturers and even from the pharmaceutical dosage form.Th e concept of DDD off ered as a statistical unit of use the agreed amount of drug that is commonly used for the most common indication.DDD is defi ned, whenever its possible, in weight units (or units of activity).Th e amount of the drug used is expressed in the number of defi ned daily doses (DDD) per 1000 inhabitants per day (DDD/1000 inhabitants/day) [11]. is 4.7% of the population while Finland had 293,921 cases identifi ed or 5.6% of the population.Depression is one of the leading causes of the disability among the psychiatric diseases in Europe with the annual cost of 115 billion € [12].Th e use of antidepressants (N06A) in Serbia in 2015 was 26.13 DDD/1000 inhabitants/day, while in Norway it was 56.48 DDD/1000 inhabitants/day.Th e use of antidepressants in Finland was 68.16 DDD/1000 inhabitants/day in 2015.

Consumption of antidepressants (N06A) in
According to the previously given information, the number of patients suff ering from depression is much higher in Serbia than in Scandinavian countries, but the use of antidepressants is much lower.
According to Harhai's research, it was shown that barriers in diagnosing and treating depression are mostly due to the following reasons: general practitioners are overloaded with many visits, lack of competence to manage depression, and patient refusal to accept the diagnosis and treatment.To improve the recognition and treatment of depression in primary health care, it is necessary to provide better education programs for general practitioners, more time for work (by decreasing number of visits), and destigmatization, to motivate patients to talk about mental health problems and to accept the recommended treatment [13].
According to Stojancevic at al, the diff erences in antidepressant utilization between Serbia and Finland are partly consequential to diff erent socioeconomic and health policy factors.Th e considerably lower utilization of antidepressants in Serbia implies possible underdiagnosing of aff ective disorders in general practice.Serious consequences may be reduced by early diagnosis, timely, adequate, and eff ective management of depression [14].
Th ere is realitively small number of patients currently treated on the primary care level for depression in Serbia, meaning that only 39% of the patients who visits psychiatrist contact the primary care physician beforehand.Th e knowledge of the primary care physicians about the prevention and treatment of mental health disorders are not suffi cient and the communication with the secondary health care level is inadequate or it does not exist at all.National budget for mental health is insuffi cient and the fi nancing is still based on the number of bed days, while the preven-tion and the promotion of the mental health is inadequately supported.Centers for the mental health protection should be formed in certain territories of the country for mental health of the patients to be protected.Th ose centers should have teams for helping vulnerabile population, especially children, and adolescents through the support system outside of the health care insitututions, in schools and boarding schools.Th ere are no protected apartments for these patients and there is no system in place that would guarantee employment of the psychiatric patients, so the circle of unemployment -poverty -depression cannot be stopped [15].
Th e Nordic countries are all established welfare states, and there has for some time existed a notion of a distinctive Nordic or Scandinavian welfare state; it is oft en understood in terms of broad, tax-fi nanced public responsibility and legislated, collective, and universalistic solutions that respect employment interest yet aim at welfare and equity goals.Lately, the Nordic countries have performed well in comparative research of health policy in European countries but also regarding health care system in OECD countries.However, while it appears that the case for the existence of a Nordic model is strong there is no consensus of the precise specifi cation of the feature that defi nes the model [16].
For example, considerable diff erences seem to exist between the psychiatric services within, as well as between Nordic countries when it comes to history, mental health acts and allocation of resources.Furthermore, some scholars argue that it is not even possible to speak of a common Nordic political approach to public health, since the public health programs in diff erent Nordic countries contain contradictory policies and ideological statements Th is is especially evident for depression and sales of antidepressants in diff erent Nordic countries [16].
Several factors such as accessibility of drugs, available treatment alternatives, clinical practice and national guidelines, may infl uence patterns of prescribing and use of antidepressant drugs in Nordic countries [16].
Further research is therefore needed to scrutinize as to why diff erences in prevalence of depression and antidepressant sales exist between the Nordic countries, despite the Nordic model.Th e Nordic countries do for some reason have a high consumption of anti-depressants compared to OECD despite relatively moderate or low depression prevalence patterns.Th is is especially important, since the increase in antidepressants consumption has spurred an ongoing debate whether antidepressants are overprescribed (medicalization) or under-prescribed (poor access to treatment) [16].
If we are to compare the use of antidepressants in Serbia, Norway and Finland in 2015, it was determined that the use of selective serotonin reuptake inhibitors is the highest and these results correspond to national gudeliens for depression treatment.Sertralin was moslty used medication in Serbia with 8.20 DDD/1000 inhabitants/day or 31.38%.In Norway and Finland that was escitalopram with 20.44 DDD/1000 inhabitants/day or 36.19% and 13.80 DDD/1000 inhabitants/day or 20.25%, respectively.
According to Ramsber at al, employing a large body of randomized head-tohead evidence, escitalopram has the highest probability of remission of the investigated antidepressants and is the most eff ective and cost-eff ective pharmacological treatment strategy for moderate to severe depression in a primary care setting, when evaluated over a one-year time-horizon [17].According to the data obtained from the Republic of Serbia Health Insurance Funds, both escitalopram and sertraline are on the A list of medications.According to the documentation from the list of medications that have been funded by the obligated health insurance in 2015, the price of sertraline in bulk per DDD was 11.91 dinars and the price of escitalopram was 11.92 dinars.Copay for both medications was 50.00 dinars [18].

CONCLUSION
Th e use of antidepressants in Serbia increased in 2015 compared to 2013 and was signifi cantly less in Serbia in 2013, 2014 and 2015 compared to Finland and Norway, pharmacotherapeutically developed countries.Medications used the most in all 3 counrties in 2013, 2014 and 2015 were selective serotonin reuptake inhibitors.Sertralin was the most widely used antidepressant in Serbia in 2015, while escitalopram was mostly used antidepressant in Norway and Finland.

Table 1 .
Comparative review of antidepressant use (N06A) in Serbia from 2013 to 2015 expressed in DDD/inhabitants/ day and percentage

Table 3 .
Comparative review of antidepressant use (N06A) in Finalnd from 2013 to 2015 expressed in DDD/inhabitants/ day and percentage DDD -DDD/1000 inhabitants/ day