Pharmacotherapy of Depressive Disorders in Conditions of Coronavirus Disease: Pharmacoeconomic Experimental Study

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disorders. This is due to the lack of such a link in Ukraine as a family doctor in the diagnosis and treatment of depression associated with coronavirus infection and somatic diseases [14,15].
The pharmacotherapy and epidemiology of depression are constantly being studied. In the pharmacotherapy of depression against the background of the coronavirus epidemic, the use of available drugs by the method of off-label clinical re-profiling (according to unconfirmed indicators) has become widespread [16,17].
In the context of the coronavirus epidemic, given the prevalence of depression among patients with chronic somatic diseases, as well as the circulation in the pharmaceutical market of new, more effective, safer antidepressants, diagnosis, and treatment of mild and moderate depression in most European and North American countries. primary care (general practitionersfamily doctors, therapists) and specialists (neurologists, cardiologists, gastroenterologists), not psychiatrists.
The purpose of the study was to conduct comprehensive pharmacoeconomic, clinical and pharmacological, marketing, documentary, regulatory and legal studies of pharmacotherapy of depressive disorders, as it is important to use modern, effective, and safe drugs for pharmacotherapy of depression.
Material and methods. For complex pharmaceutical and economical, clinical, and pharmacological, normative, and legal analysis authors used international and national medical and technological documents on standardization of medical care for depression, as well as scientific sources. The complex experimental research was based on the study of the following materials: the International Classification of Diseases of the 10 th edition; the International Classification for Primary Care; international and national medical and technological documents on standardization of medical care for depression; normative documents (medical care standards, clinical protocols, drug forms, National List of Essential Medicines); drugs of clinical and pharmacological groups for pharmacotherapy of depression according to the ATC codes.
The information base of the study consisted of scientific works of foreign and domestic scientists on the topic of the article. The review of scientific sources of literature was carried out considering the recommendations of the Cochrane Society for PICO: P (population)the population suffering from depression diseases; I (intervention)pharmacotherapy, effective, safe, affordable drugs; C (comparator)research technology; O (outcomes)research results [18][19][20][21][22].
Drugs clinical and pharmacological groups for pharmacotherapy of depression diseases with diagnostic code of the ATC -Classification (ATC) ATC was selected. The objects of the study were drugs, which are registered in the State Register of drugs of Ukraine as of June 2021 [23,24].
The names of drugs were systematized by International nonproprietary name (INN), trade names, the number of drugs, dosage forms. All drugs were registered in the State Register of drugs of Ukraine as of June 2021 [23][24][25].
The analysis based on production was performed with the determination of the share of domestic and foreign drugs, by individual countries, manufacturing companies. Drugs clinical and pharmacological groups for pharmacotherapy of депресії with diagnostic codes ATC -Classification (ATC) were selected [23]. International and national medical and technological documents on standardization of medical care of depression, as well as scientific sources were used for regulatory, documentary and pharmacoeconomic analysis. The objects of the study the codes of the International Classification of Diseases 10 edition (ICD-10) -F32, F33, F34.1 and the code of the International Classification for Primary Care (ICPC-2) -P76.
The current research was carried out using the system approach during 2018-2021. Study design is based on pharmacoeconomic, organizational and legal, forensic, and pharmaceutical approaches to pharmacotherapy using literature review. The anonymous analysis of medical cards of patients with depressive disorders was carried out (33 medical cards). Drugs for the pharmacotherapy of depression are systematized. The experimental study was conducted on the clinical bases of Kharkiv Medical Academy of Postgraduate Education, Lviv Medical Institute (hospitals, pharmacies), Department of Medical and Pharmaceutical Law, General and Clinical Pharmacy of Kharkiv Medical Academy of Postgraduate Education, and Luhansk State Medical University.
Marketing research of medicines that are allowed for medical use in Ukraine was conducted by trade names of medicines, manufacturers, dosage forms, registration certificates and terms of their registration in Ukraine by clinical-pharmacological, regulatory, and documentary methods of analysis.
Pharmacoeconomic experimental study based on ABC/VEN analysis was used to select effective and safe drugs. To assess the cost of pharmacotherapy for depression, ABC analysis was conducted as a tool to study the cost of purchasing drugs in healthcare facilities through tender or other procurement. ABC-analysis provides for the distribution of drugs from the most expensive to the least expensive depending on their share among the indicators of the total cost of pharmacotherapy of depression. The procedure included a step-by-step algorithm: systematization of drugs by INN for ABC analysis; calculation of the share of the total cost of the drug in descending order of value in UAN, starting from the top of the population with a higher value (category Athe most expensive; category Bless expensive, average cost; category Cthe cheapest). Price indicators were calculated on average as of June 2021. Next, the total percentage of value was calculated, as well as determine the cut-off points for drugs in categories A, B, C based on the Pareto principle. A structured data collection from Management Science for Health was used to collect the necessary data for ABC analysis. ABC analysis involves the distribution of drugs from the most to the least expensive depending on their share among the indicators of the general purpose of drugs [20].
To assess the effectiveness of drug use, a vital-essential-nonessential (VEN) analysis was performed to classify drugs into categories V (Vital), E (Essential) and N (Non-Essential), considering regulatory documents (medical care standards, clinical protocols, State Form of Medicines, National List of Essential Medicines) and the principles of evidence-based medicine та evidence-based фармації (quality, safety, economy, accessibility). According to ABC/VEN analysis, a matrix of consolidated ABC/VEN for pharmacotherapy of depression was constructed.
Modern research methods were used: pharmacoeconomic, clinical and pharmacological, ABC/VEN, normative and legal, documentary, bibliographic, systemic, comparative, marketing, graphic, mathematical analysis. Mathematical processing and statistical evaluation of data was performed using Microsoft Excel.
The research of the article is a fragment of research works of Luhansk State Medical University "Conceptual interdisciplinary approaches to pharmaceutical provision and availability of drugs, taking into account organizational and legal, technological, analytical, pharmacognostic, forensic and pharmaceutical, clinical and pharmacological, pharmacoeconomic, marketing, social and economic competencies" (state registration number 0123U101632, terms 2023-2027); Kharkiv Medical Academy of Postgraduate Education on "Improving the organizational and legal procedure for providing patients with drugs from the standpoint of forensic pharmacy, organization and management of pharmacy" (state registration number 0116U003137, terms 2016-2020) and "Pharmaceutical and medical law: integrated approaches to the system of drug circulation from the standpoint of forensic pharmacy and organization of pharmaceutical business" (state registration number 0121U000031, terms 2021-2026); Petro Mohyla Black Sea National University on the topic "Conceptual interdisciplinary approaches to the drug circulation system, taking into account organizational and legal, technological, biopharmaceutical, analytical, pharmacognostic, forensic and pharmaceutical, clinical and pharmacological, pharmacoeconomic, pharmacotherapeutic aspects" (state registration number 0123U100468, implementation period 2023-2028).
Results and discussion. Depression is on the rise globally. In May 2013, the World Health Assembly adopted a resolution calling for a comprehensive, coordinated national response to mental disorders. In low-and middle-income countries, 76% to 85% of depressed patients do not receive the required pharmacotherapy. Barriers to obtaining effective pharmacotherapy include a lack of resources, a shortage of drugs, and social stigma. Another obstacle is inaccurate diagnosis in the context of the spread of coronavirus disease. Depression, in turn, can exacerbate stress, disrupt normal functioning, worsen the life situation of the person suffering from it, and lead to even more severe depression. There is a relationship between depression and physical health. For example, cardiovascular diseases can lead to the development of depression and vice versa [26,27]. Depression problems have increased in the context of the global pandemic due to many factors (social distancing, fear of infection and death, fear of losing a job, family, and friends due to illness, loss of finances). Symptoms of depression and anxiety are exacerbated by fear, insecurity, and social isolation under quarantine Pharmacotherapy for depression is individually tailored to co-morbid conditions, interactions and patient needs Telemedicine solutions are used in inpatient and outpatient settings to provide mental health services A systematic review of the impact of the COVID-19 pandemic has shown the prevalence of depression symptoms in the general population from 14,6% to 48.3%. Regarding depression and other mental health conditions in the general population, there is also a serious concern for those hospitalized with COVID-19. Hospitalized patients face the previously mentioned risk factors for depression with COVID-19. They also isolated from visitors when fighting disease in a stationary setting. A hospital in Wuhan, China, the city, and country where the virus was suspected of origin, reported depressive symptoms in 13.4% of hospitalized COVID-19 patients. Infectious epidemics are associated with anxiety, panic, and stress. It is believed that patients with COVID-19 may suffer from anxiety, impaired mood regulation and exacerbation of preexisting mental illness [26,28,29].
Among patients who have undergone coronavirus disease, direct and indirect negative effects of COVID-19 on the nervous system are found. Among the mediated subjectively significant stress factors of the pandemic, a long-term potential threat to life, long-term quarantine measures with selfisolation, lack of stable immunity, limited access to medical services, etc. are of particular importance. up to 50.9%) and mixed anxiety-depressive disorders. When conducting psychopharmacotherapy in patients with COVID-19, preference should be given to drugs not only with minimally expressed undesirable effects and adverse drug interactions, but also with additional therapeutic procognitive and somatotropic particularities [30,31].
The COVID-19 pandemic has negatively impacted the psychological well-being of people around the world, especially in low-and middle-income countries such as Bangladesh. Conducted an online cross-sectional study among Bangladeshi citizens. A total of 13,654 participants (61.0% male; mean age 24.0 years; age range 18-65) completed the survey between May and June (2020). The survey included socio-demographic data and questions related to COVID-19, as well as lifestyle, suicidal and psychometric indicators. Hierarchical regression was performed to determine a significant association between depression and the studied variables. The score for depressive symptoms during the COVID-19 pandemic was 43.5%. According to hierarchical regression analysis, depression was significantly associated with withdrawal from COVID-19 prevention measures, daily activities in home quarantine (such as playing video games), and suicidal behavior. The score for suicidal thoughts during the pandemic was 8.2%, slightly higher than the 5% prevalence of suicidal thoughts found in a pre-COVID-19 study conducted in Bangladesh, and 4.3% in Turkey earlier for the COVID-19 pandemic. A broader study in seventeen countries found that suicidal ideation was prevalent at 9.2%. While none of these recent studies were conducted during the COVID-19 pandemic, the results of this study demonstrate that the pandemic may be affecting suicidal ideation. A study from Bangladesh found that 12.8% of suicidal thoughts are present among university students during the COVID-19 pandemic. During the pandemic, the percentage of people with suicidal ideation and past suicidal thoughts was much higher among people with depression than among people without depression, and home quarantine and feelings of social isolation can be a co-problem among people and a possible vulnerability to suicide [28].
In Ukraine, medical care for patients with depression in the context of the spread of coronavirus disease is provided in accordance with the provisions of the Unified Clinical Protocol of primary, secondary (specialized) and tertiary (highly specialized) medical care "Depression (mild, moderate, severe depressive episodes without somatic syndrome or somatic syndrome recurrent depressive disorder) " [32].
According to the results of normative-legal and documentary analysis of international and national Ukrainian clinical protocols, it was found that four drugs (Amitriptyline, Lithium, Risperidone, Fluoxetine) were included in all normative and legal documents, which testifies to their recognition and use both internationally, and at the Ukrainian level [23,25,[32][33][34][35][36][37].
The above indicates the existence of certain contradictions and inconsistencies between domestic and international regulations regarding the pharmacotherapy of depression.
Pharmacotherapy of depression includes drugs of different clinical and pharmacological groups. Clinical and pharmacological group's drugs for pharmacotherapy of depression by International nonproprietary name (INN) are given in Table 1. According to clinical and pharmacological characteristics, drugs are divided into two groups according to the ATC code: N05 "Antipsychotics"four drugs (Lithium, Olanzapine, Risperidone, Sulpiride) and N06 "Antidepressants"other fourteen drugs.
Marketing research of drugs for the pharmacotherapy of depression (Table 2) was carried out. According to the results of marketing analysis, it was found that: the largest share of producers belongs to domestic production (30.3%); ranking of manufacturers from other countries -Denmark, India, Ireland, Italy, Cyprus, Latvia, Portugal, Hungary, Switzerland (5.5% each); Germany, Poland (10.1% each). For the pharmacotherapy of depression, doctors prescribe 77.7% tablets and 22.3% capsules. 94.5% of drugs have an unlimited period of validity on the territory of Ukraine.
The next stage of research was to conduct pharmacoeconomic studies using ABC/VEN analysis, which involves the distribution of drugs by the cost of pharmacotherapy and evaluation of the effectiveness of drug use in a healthcare setting. ABC analysis was applied as a method for classifying drugs based on cost incurred (Table 3). Table 3. ABC analysis of International nonproprietary name of drugs for pharmacotherapy of depression.
According to the results of ABC analysis, group A included drugs, the use of which was equal to 81.76% of the total rate of use; to group B -14.21%, and to group C -4.03%.
Category A included ten INN drugs (Citalopram, Risperidone, Duloxetine, Paroxetine, Mirtazapine, Trazodone, Olanzapin, Venlafaxine, Agomelatine, Fluvoxamine), the cost of which is 4956.50 UAH i.e., 81.76% of the total cost of treatment of the patient. Group B included four INN drugs (Sertralin, Escitalopram, Mianserin, Sulpiride) whose total cost is 861.30 UAH (14.21%). The group C includes four INN drugs (Doxepin, Lithium, Fluoxetine, Amitriptyline) with a cost of UAH 244.54 (4.03%). VEN analysis was applied as a method of prioritizing pharmaceuticals based on public health importance as vital, essential, and non-essential (  Table 4. Vital-essential-nonessential analysis of International nonproprietary name of drugs for pharmacotherapy of depression. According to the results of VEN analysis, found that four INN drugs (Risperidone, Lithium, Fluoxetine, Amitriptyline) belong to category V (Vital). Category E (Essential) includes fourteen INN drugs (Citalopram, Duloxetine, Paroxetine, Mirtazapine, Trazodone, Olanzapine, Venlafaxine F, Sertraline, Escitalopram, Mianserin, Sulpiride, Doxepin). Category N (Non-essential) did not include any drug.
Distribution according to the results of VEN-analysis of studied drugs for pharmacotherapy of depression shown on Fig. 1.   Fig. 1 Based on the ABC/VEN analysis, a matrix of the consolidated ABC/VEN analysis was formed (Table 5). According to the results of pharmacoeconomic analysis, the following indicators were established ( Table 5). The group of essential drugs (group E) took the largest share of costs (85.75%).
In group E, 69.4% of the most expensive drugs (for example, Citaloprame) are prescribed by doctors; 14.21%drugs at the average price (for example, Sertraline); 2.14% are the cheapest drugs (for example, Doxepine).
According to doctors, the niche of the matrix of vital drugs (group V) had a share of 14.25% in the pharmacotherapy of depression. In group V, the largest costs (12.35%) were drugs of group A (e.g., Risperidone). Only 1.9% (e.g., Fluoxetine) is the cheapest drug (group C).
Thus, comprehensive pharmacoeconomic, clinical-pharmacological, marketing, documentary and regulatory studies have made it possible to study the cost component of pharmacotherapy of depression, to systematize the risks of purchasing drugs using budgetary and non-budgetary funds and to predict the effectiveness of drugs in healthcare facilities based on the principles of evidencebased medicine and pharmacy.
Conclusions. Complex pharmacoeconomic, clinical and pharmacological, marketing, documentary, and normative and legal researches of pharmacotherapy of depression in the conditions of spread of coronavirus disease were carried out. The obtained results make it possible to make administrative and managerial decisions in determining the pharmacotherapy of patients with depressive disorders. The introduction of information on pharmacoeconomic components for the pharmacotherapy of depression will ensure proper organization of the circulation of medicines at the stages of appointment, purchase, storage, accounting, quality control, transportation, release, destruction, licensing in accordance with current medical and pharmaceutical legislation in healthcare facilities. Ultimately, further research is needed on the long-term effects of the COVID-19 pandemic on mental health.
Funding. The author state, that this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Ethical notice. As editor-in-chief's publication, there were only guest editors invited for the review.