[Association of anhedonia with comorbid mental disorders, suicidality and personality traits in patients with depression]. / Vzaimosvyaz' angedonii s komorbidnymi psikhicheskimi rasstroistvami, suitsidal'nost'yu i chertami lichnosti u patsientov s depressiei.

OBJECTIVE: A comprehensive assessment of anhedonia in patients with depression, considering their demographic, clinical and personality characteristics. MATERIAL AND METHODS: This cross-sectional, multicenter study included 190 patients with depression (63.7% women, mean age (Me) 31 (24-46.5) years) diagnosed with a depressive episode (F32) and recurrent depressive disorder (F33) according to the ICD criteria regardless of the disease stage (exacerbation or remission). Comorbid mental disorders of the anxiety spectrum, eating behavior, substance abuse, and psychotic symptoms were assessed and recorded. The Snaith-Hamilton Pleasure Scale (SHAPS) was used to assess the severity of anhedonia. RESULTS: Patients with an earlier onset of depression (p=0.037) and a history of suicide attempts (p=0.001) showed higher scores for anhedonia. The generalized anxiety disorder, panic disorder, bulimia nervosa, and alcohol dependence in patients with current depression were associated with higher anhedonia. The anhedonia scores had moderate positive correlations with a number of personality traits on TCI-125: Harm Avoidance (r=0.30; p<0.01), as well as weak negative correlations with Reward dependence (r= -0.20; p<0.05) and Cooperativeness (r= -0.26; p<0.05). There were also weak positive correlations of anhedonia scores with the severity of suicidal ideation and suicidal risk (for the last month and throughout life) and moderate positive correlations with the severity of suicidal behavior throughout life. CONCLUSIONS: The study confirms and expands the information about the complex nature of the anhedonia phenomenon in patients with depression. Further research on anhedonia may help in clinical practice and become the basis for the search for new biomarkers of depression.

[Comorbidity patterns and structure of depressive episodes in patients with bipolar disorder and major depressive disorder]. / Patterny komorbidnosti i struktura depressivnykh epizodov u patsientov s bipolyarnym i depressivnym rasstroistvami.

OBJECTIVE: To conduct an exploratory analysis of comorbidity patterns and the structure of depressive episodes among Russian patients with bipolar disorder (BD) and major depressive disorder (MDD). MATERIAL AND METHODS: This multicenter cross-sectional study included 178 patients with mood disorders, of which 78.1% (n=139) were women. The diagnosis of BD was made in 68.0% (n=121) patients, of them 37.1% (n=66) were diagnosed with BD type I. All study participants underwent a structured Mini International Neuropsychiatric Interview to verify the clinical diagnosis and identify concomitant mental disorders, and also filled out an electronic case report form. Statistical analysis was performed in RStudio v. 1.4.1717 using the standard R package and the «psych¼ package. RESULTS: According to the results of stepwise regression, comorbid diagnoses of panic disorder (OR=5.3; 95% CI 1.9-19.1) and eating disorders (OR=7.7; 95% CI 2.8-27.4) were more associated with BD. In addition, depressive episodes in BD were more associated with symptoms of hypersomnia (OR=2.5; 95% CI 1.2-5.3) and psychomotor retardation (OR=3.2; 95% CI 1.5-7.6). Symptoms such as increased appetite (47.1% (n=57) vs 26.3% (n=15); p=0.009), ideas of guilt (92.6% (n=112) vs 7.2% (n=44); p=0.006) and thoughts of self-harm or death (70.2% (n=85) vs 45.6% (n=25); p=0.003) were also nominally more common in depressive episodes within the BD compared to MDD. CONCLUSIONS: Mood disorders such as BD and MDD have significant differences in the patterns of comorbidity and the structure of depressive episodes, which is important to consider when conducting differential diagnosis of these disorders. The results also indicate the need for a comprehensive diagnostic interview with patients with mood disorders to assess the presence of comorbid mental disorders during life and the structure of depressive episodes throughout the clinical course from the moment of onset.

Pterin metabolism, inflammation and oxidative stress biochemical markers in schizophrenia: Factor analysis and assessment of clinical symptoms associations.

Various aspects of folate and tetrahydrobiopterin (BH4) metabolism disturbances have been detected in patients with schizophrenia.Data were obtained that disturbances in the pterins (folates and BH4) metabolism can be associated with oxidative stress and inflammation, but has not yet been confirmed in clinical studies in schizophrenia. Within the framework of this study, a correlation and factor analysis of biochemical markersof pterin metabolism, inflammation and redox imbalance in patients with schizophrenia was performed in order to test the hypothesis of the single etiopathogenetic node, including the studied biochemical processes. Methods: 125 patients with schizophrenia and 95 healthy volunteers were randomly selected and evaluated with a biochemical examination of BH4, folate, B12, homocysteine, C-reactive protein, interleukin-6, reduced glutathione levels in the blood serum; activity of superoxide dismutase and catalase - in erythrocytes; malondialdehyde - in blood plasma. All patients underwent an examination using standardized psychopathology rating scales. Spearman rank coefficient (ρ) with Benjamini-Hochberg correction was used for the correlation analysis. The principal components analysis (PCA) was used as a factor analysis. Results: Significant correlations were found within groups of pterin metabolism, inflammatory markers and redox-imbalance, and also between separate inflammation, oxidative stress and markers of pterin metabolism. The performed factor analysis made it possible to distinguish two components: 1 - pterin metabolism, 2 - oxidativeinflammatory markers. Despite the weak statistical associations and, possibly, functional relationships between pterin metabolism and oxidative/inflammation markers, each of the components has its own clinical correlates and, probably, a separate contribution to the pathology of schizophrenia.

[Anhedonia in mood disorders and somatic diseases: results of exploratory Mendelian randomization analysis]. / Angedoniya pri rasstroistvakh nastroeniya i somaticheskikh zabolevaniyakh: rezul'taty razvedochnogo Mendelevskogo randomizatsionnogo analiza.

OBJECTIVE: To conduct an exploratory Mendelian randomization analysis of the causal relationships of anhedonia with a wide range of psychiatric and somatic phenotypes based on the genetic data of participants in a population study. MATERIAL AND METHODS: This cross-sectional study included 4520 participants, of which 50.4% (n=2280) were female. The mean age was 36.8 (S.D.=9.8) years. Participants were pheno-nailed based on the DSM-5 criteria for anhedonia in the framework of depression. An episode of anhedonia exceeding 2 weeks during life was reported by 57.6% (n=2604) of participants. A genome-wide association study (GWAS) of the anhedonia phenotype was performed, as well as a Mendelian randomization analysis using summary statistics of large-scale GWASs on psychiatric and somatic phenotypes. RESULTS: The GWAS on anhedonia did not reveal the variants with genome-wide significant association (p<10-8). The most significant (p=9.71×10-7) was the variant rs296009 (chr5:168513184) in an intron of the slit guidance ligand 3 (SLIT3) gene. Using Mendelian randomization, nominally significant (p<0.05) causal associations of anhedonia with 24 phenotypes were identified, which can be divided into 5 main groups: psychiatric/neurological diseases, inflammatory diseases of the digestive system, respiratory diseases, oncological diseases and metabolic disorders. The most significant causal effects of anhedonia were found for breast cancer (p=0.0004, OR=0.9986, 95% confidence interval (CI) (0.9978-0.999)), minimal depression phenotype (p=0.009, OR=1.004, 95% CI (1.001-1.007)), as well as for apolipoprotein A (p=0.01, OR=0.973, 95% CI (0.952-0.993)) and respiratory diseases (p=0.01, OR=0.9988, 95% CI (0.9980-0.9997)). CONCLUSION: The polygenic nature of anhedonia may cause the risks of comorbidity of this phenotype with a wide range of somatic diseases, as well as may be associated with mood disorders.

[Association of depression and anxiety with somatic diseases: negative lifestyle factors impact]. / Svyaz' depressii i trevogi s somaticheskimi zabolevaniyami: rol' negativnykh vneshnikh faktorov.

OBJECTIVE: To assess the associations of various depression and anxiety phenotypes with manifestations of different somatic disorders and negative lifestyle factors. MATERIAL AND METHODS: The study involved 5116 people. In the online questionnaire, participants provided information about age, sex, height and weight, as well as a history of smoking, alcohol use, physical activity and diagnoses/symptoms of various physical diseases. Self-questions based on the DSM-5 criteria and the online version of the HADS were used to screen for phenotypes of affective and anxiety disorders in a population sample. RESULTS: An association of both subclinical and clinical depressive symptoms on HADS-D was noted for respondents with weight gain (OR 1.43; CI: 1.29-1.58, p<0.05 and OR 1,CI: 1.05-1.52, p<0.05, respectively), increased BMI (OR 1.36; CI: 1.24-1.48, p<0.05 OR 1.27; CI: 1.09-1.47, p<0.05 respectively), and decreased physical activity (OR 1.67; CI: 1.35-2.07, p<0.05 and OR 2.35; CI: 1.59-3.57, p<0.05, respectively) at the time of testing. The phenotypes of depression, anxiety disorders, and bipolar disorder by DSM criteria were associated with a history of smoking. (OR 1.37; CI: 1.18-1.62, p<0.001; OR 1.36; CI: 1.24-1.48, p<0.05 and OR 1.59; CI: 1.26-2.01, p<0.001, respectively). For higher BMI the association was reported only for the bipolar depression phenotype (OR 1.16; CI: 1.04-1.29, p<0.05), and with a decrease in physical activity - for the phenotypes of major depression and anxiety disorders (OR 1.27; CI: 1.07-1.52, p<0.05 and OR 1.61; CI: 1.31-1.99, p<0.001, respectively). A significant association with various somatic disorders was noted for all phenotype variants, but to the greatest extent for those based on DSM criteria. CONCLUSIONS: The study confirmed the association of negative external factors and various somatic disorders with depression. These associations were noted for various phenotypes of anxiety and depression, both in severity and structure, and may be due to complex mechanisms that have shared biological and environmental mechanisms.

[Low doses of quetiapine (Seroquel) as an impulsivity corrector in patients with bipolar affective disorder in remission]. / Nizkie dozy kvetiapina (Serokvelya) v kachestve korrektora impul'sivnosti u patsientov s bipolyarnym affektivnym rasstroistvom v remissii.

OBJECTIVE: To evaluate the effectiveness of low doses (25-75 mg/day) of quetiapine (Seroquel) in patients with bipolar affective disorders in a euthymic state with signs of impaired impulse control. MATERIAL AND METHODS: The main criteria for patients' selection were as follows: both sex, diagnoses of bipolar affective disorders, remission (euthymic state), adult age (from 18 to 60 years old), stable basic therapy. The duration of the study was 6 weeks, a dose of quetiapine (Seroquel) varied from 25 to 75 mg. The examinations were carried out with the Barratt scale, computerized Go-No-Go and Balloon tests. RESULTS: The study group included 32 patients (11 men and 21 women), mean age 31.2±9.7 years (minimum 18, maximum 60 years). The changes in Barratt total score (p=0.000014, Wilcoxon test, effect size 0.48) and Balloon total earnings (p=0.03, Wilcoxon test, effect size 0.22) were statistically significant and reflected clinically significant improvement. The changes of the indices of the Go-No-Go test were not significant. The data of fMRI showed an increase in the connectivity of the cortex of the central and parietal tegmentum of the left hemisphere with other areas of the brain, which correlated with the changes in psychometric and test parameters. CONCLUSION: The results of the study showed that add-on of the low doses of quetiapine (Seroquel) significantly decreases impaired impulse control in remitted patients with bipolar affective disorders both in self-evaluation and in risk-taking experimental test. The drop of high level of impulsivity can improve the quality and stability of remission and reduce behavioral risks due to impaired impulse control.

[The association of serum folate levels with schizophrenia symptoms]. / Assotsiatsiya urovnya folatov syvorotki krovi s klinicheskimi simptomami shizofrenii.

OBJECTIVE: To evaluate the association of serum folate levels with schizophrenia and its clinical characteristics in patients from a Russian sample. MATERIAL AND METHODS: Ninety-three patients with schizophrenia and 60 healthy volunteers were examined. Determination of serum folate levels was performed by chemiluminescent immunoassay on microparticles (Architect, Abbott Lab SA). Symptoms of schizophrenia were assessed with the Positive and Negative Syndrome Scale, the Calgary Schizophrenia Depression Scale, the Snight-Hamilton Anhedonia Scale, the Brief Assessment of Cognition in Schizophrenia, the Personal and Social Performance Scale, the Scale for Therapy Side-Effects assessment, Simpson-Angus scales, abnormal involuntary movements scale, Barnes akathisia rating scale. Statistical analysis was performed using the Statistica 6.0. Since the data distribution was different from normal, non-parametric criteria were used. RESULTS: Patients had significantly lower folate levels than healthy controls (p=0.00053), mainly in women (p=0.0025). At the same time, in all the subgroups (including healthy ones), the vast majority of the participants had folate levels below the median (9.95 ng/ml) and in the lower quartile of the reference values. In patients, folate levels are inversely correlated with the severity of most negative symptoms and directly correlated with all measures of cognitive functions. Patients with folate levels below the reference values differed from other patients by a greater severity of the total score of negative symptoms (p=0.023), Marder's factors of negative symptoms (p=0.046) and disorganized thinking (p=0.033), a greater severity of general side effects of therapy (p=0.021) and all measures of cognitive functions except for verbal memory. Smoking has a significant effect on serum folate levels in all participants (p=0.016). There was also an inverse association of folate levels with the selectivity of antipsychotics (p=0.035), and more severe folate deficiency in inpatients than outpatients (p=0.0063). CONCLUSION: The results obtained in the Russian sample on the association of folate deficiency with schizophrenia and a wide range of clinical indicators, including those affecting the prognosis of schizophrenia, indicate the high relevance of further study of this topic and the introduction of approaches to augmentation of antipsychotic therapy for schizophrenia with folates.

[Validation of a DSM-5-based screening test using digital phenotyping in the Russian population]. / Validatsiya skriningovogo testa, osnovannogo na kriteriyakh DSM-5, metodom tsifrovogo fenotipirovaniya na rossiiskoi populyatsii.

OBJECTIVE: To evaluate the validity of a depression and anxiety screening test based on DSM-5 diagnostic criteria to identify cases of these conditions simultaneously assessed with the validated Hospital Anxiety and Depression Scale (HADS) in a population sample by digital phenotyping. MATERIAL AND METHODS: This cross-validation study included 5.116 respondents (mean age 36.9 (9.8)), of which 49.4% (2526) were women. The depression and anxiety screening test was done in electronic form and based on the DSM-5 diagnostic criteria for major depressive disorder and generalized anxiety disorder. The validated HADS scale was used as a standard test. The categories of depression (HADS-D) and anxiety (HADS-A) phenotypes were formed with a cutoff of ≥8 points and ≥11 points. The main parameters of the validity of the screening test were calculated, including accuracy (Ac), sensitivity (Sn) and specificity (Sp) with their 95% confidence intervals [CI]. RESULTS: The prevalence of current depression and anxiety according to the screening test was 7.8% (400) and 12.5% (639), respectively. The prevalence of lifetime depression was 25.9% (1327). For the HADS-D depression subscale with cut-offs of ≥11 and ≥8 points, the prevalence of depression was 3.4% (174) and 15% (766), respectively. For the HADS-A anxiety subscale with cut-offs of ≥11 and ≥8 points, the prevalence of anxiety was 8.9% (456) and 31.8% (1628), respectively. For HADS-D and HADS-A with a cutoff of ≥11 points, the parameters of current depression were Ac=92%, Sn=47% (CI 95% [39-54]), Sp=94% (CI 95% [93-94]), lifetime depression - Ac=75%, Sn=63% (CI 95% [56-70]), Sp=75% (CI 95% [74-77]) and current anxiety - Ac=88%, Sn=54% (CI 95% [50-59]) and Sp=92% (CI 95% [90-92]). For HADS-D and HADS-A with a cutoff of ≥8 points, the parameters of current depression were Ac=86%, Sn=30% (CI 95% [27-33]), Sp=96% (CI 95% [95-97]), lifetime depression - Ac=74%, Sn=51% (CI 95% [48-55]), Sp=75% 79% (CI 95% [77-80]) and current anxiety - Ac=75%, Sn=31% (CI 95% [29-33]), Sp=96% (95% CI [95-97]). CONCLUSION: The high Ac and Sp of this test allows it to be used for screening purposes to identify (but not exclude) cases of depression and anxiety in the population. However, further studies are needed to validate the screening test using a diagnostic interview with a physician.

[Family history of mood disorders may weaken the link between adverse childhood experience and suicidality in patients with depression]. / Svyaz' semeinoi otyagoshchennosti rasstroistvami nastroeniya s neblagopriyatnym detskim opytom i suitsidal'nost'yu u patsientov s depressiei.

OBJECTIVE: To study the impact of family history of mood disorders (FHMD), comprising genetic factors associated with depression, on the association between adverse childhood experience (ACE) and suicidality in depression. MATERIAL AND METHODS: This multicenter cross-sectional study included 200 in- and outpatients (64% (n=128) women, mean age - (M (SD)) 36.21 (15.09) yrs.) with depression. Self-reports about FHMD and lifetime suicide attempts were obtained in clinical interview. The lifetime intensity of suicidal ideas and behavior was assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS), ACE - by the Adverse Childhood Experience International Questionnaire (ACE-IQ). RESULTS: FHMD did not affect the prevalence of ACE, suicide attempts and C-SSRS scores. We found that FHMD weakens the link between ACE and the risk of suicide attempt. The emotional neglect itself increased the risk of suicide attempt (p=0.001, OR=4.428, CI 95% [1.797-10.911]), but reduced it in patients with FHMD (p=0.03, OR=0.128, CI 95% [0.018-0.893]). GLM analysis revealed that FHMD significantly affected the association between suicidal ideas and domestic violence (p=0.045) and between suicidal behavior and emotional neglect (p=0.015) and abuse (p=0.044). CONCLUSION: FHMD may weaken the link between ACE and suicidality in patients with depression. Suicidality in these patients may be underlined by mechanisms not involved in the response to ACE although more studies are needed.

Tetrahydrobiopterin deficiency in schizophrenia: Biochemical and clinical aspects.

It was reported that the levels of tetrahydrobiopterin (BH4) are reduced in schizophrenia. However, mechanisms of BH4 deficiency in schizophrenia had not been studied precisely. OBJECTIVE: the search of the association between BH4 deficiency in schizophrenia and a range of biochemical and clinical parameters for the evaluation of the possible mechanisms of BH4 loss and its role in the development of the symptoms. METHODS: 93 patients with schizophrenia and 60 healthy volunteers were randomly selected and evaluated with a biochemical examination of BH4, folate, cobalamin (B12), homocysteine, C-reactive protein (CRP), reduced glutathione (GSH) levels in the blood serum.Patients underwent standardized psychopathological examination. RESULTS: In patients, the levels of BH4 and folate were lower (p = 0.001 and p = 0.054, respectively), and the levels of homocysteine were higher (p = 0.012) compared to the control group. BH4 levels directly moderately correlated with folate (ρ = 0.43; p = 0.0029) and B12 levels (ρ = 0.43; p = 0.0020) and inversely moderately correlated with homocysteine levels (ρ = -0.54; p = 0.00015) in patients. Cluster analysis identified schizophrenia biotype characterized by a deficiency of BH4, folate, B12, and hyperhomocysteinemia. The clinical characteristics of this biotype were not specific. CRP and GSH were higher in patients compared to controls, but their association with serum BH4 was not confirmed.

[Contemporary GWAS studies of depression: the critical role of phenotyping]. / Sovremennye issledovaniya po polnogenomnomu poisku assotsiatsii pri depressii: kriticheskaya rol' fenotipirovaniya.

The need to use large samples to identify the genetic risk loci of mental disorders has led us to the dilemma of phenotyping quality. Especially this problem relates to such common mental disorders as depression (lifetime prevalence 16.2%). On the one hand, there is a very resource-intensive method of capturing patient data by physicians using diagnostic criteria of mental disorders (DSM-V/ICD-10). On the other, there is a popular method of minimal phenotyping using hospital registers, self-reports of respondents on symptoms, diagnosis and treatment of depression. To date, there is no ideal method for phenotyping depression because all of them focus only on its clinical symptoms. The active usage of minimal phenotyping in Genome-Wide Association Study (GWAS) has led to a significant increase in both clinical and genetic heterogeneity of depression. However, an important limitation of using DSM-V/ICD-10 is the high cost of phenotyping due to the involvement of medical specialists. Thus, the most rational is to use electronic diagnostic questionnaires based on DSM-V/ICD-10 criteria. Such an approach will accelerate the increase in research capacity, but will preserve all internal contradictions inherent in official diagnostic classifications (heterogeneity of phenotypes, absence of objective diagnostic criteria, categorical approach, etc.). In this regard, the critical role of psychiatric epidemiology is growing both in the development of standardized tools for operationalized diagnostic criteria and in future GWAS by introducing new phenotypic subtypes of depression and its dimensions.

[Modern approaches to the genetics of depression: scopes and limitations]. / Sovremennye podkhody k izucheniyu genetiki depressii: vozmozhnosti i ogranicheniya.

Recent findings in candidate genes for depression showed significant replication failures and thus appeared irrelevant. Much of the earlier studies' limitations can be overcome by the strategy of genome-wide association studies (GWAS), which aims to identify associations between different genomic variants and phenotypic traits without pathophysiological hypotheses application. With the use of such studies, it seems possible to calculate polygenic risk scores (PRS) as a promising approach for predicting depression risk. The aim of this review is to analyze modern approaches of genetic research used to assess the risk of depression in a population.

[Family history of affective disorders, the gender factor and clinical characteristics of depression]. / Semeinaya otyagoshchennost' affektivnymi rasstroistvami, gendernyi faktor i klinicheskie kharakteristiki depressii.

OBJECTIVE: Analysis of clinical features of development and course of depression in patients with FH of mood disorders taking into account sex differences. MATERIAL AND METHODS: This multicenter cross-sectional study included patients over 18 years of age with depressive episode/recurrent depressive disorder. Clinical characteristics of depression, presence of comorbid mental illness and family history (FH) information were obtained in a structured clinical interview. RESULTS: One hundred and seventy-one patients (mean age (M (SD)) 40.87 (15.86) y.o.), including 64.5% of women, were enrolled in the study. FH was revealed in 30.2% of patients. The proportion of FH did not differ in men and women (p=0.375). Generalized anxiety disorder (GAD) was more frequent in FH positive patients (p=0.016). Logistic regression also revealed that FH is a risk factor for concomitant GAD (p=0.019, OR=2.4). The GLM demonstrated a significant joint effect of FH and sex on the maximum duration of a depressive episode (p=0.044), as well on the number of suicide attempts (p=0.055) and the number of depressive episodes as a trend (p=0.072). CONCLUSION: We have demonstrated the specific interaction of FH of mood disorders with sex on clinical course of depression. Thus, the manifestation of a genetic influence on the clinical phenotype of depression can be significantly moderated by sex.

[Schizophrenia and cardiometabolic disorders]. / Shizofreniya i kardiometabolicheskie narusheniya.

The aim of this review is to analyze the basic biological mechanisms of comorbidity of schizophrenia and metabolic, cardiovascular diseases, which are not directly associated with external risk factors. The study of the general pathophysiological mechanisms of schizophrenia and metabolic disorders can provide a significant basis not only for the fundamentally novel therapeutic, preventive and diagnostic measures, but also for a better understanding of the etiopathogenesis of these diseases. It seems likely that schizophrenia represents a heterogeneous group with a varying genetic basis for both mental symptoms and neuroendocrine, inflammatory processes that form concomitant somatic disorders. Thus, the new integrated approaches to the study of this problem with the latest methods of genetic and molecular research are relevant.

[GWAS-based polygenic risk scores for depression with clinical validation: methods and study design in the Russian population]. / Poligennye shkaly riska razvitiya depressii na osnove GWAS s klinicheskoi validatsiei: metodologiya i dizain issledovaniya v rossiiskoi populyatsii.

Depression is one of the leading causes of decreased quality of life and social functioning of patients. In the context of preventive medicine, the prevention of depression becomes a priority. To achieve the goals of prevention, it is necessary to identify specific population risk groups - individuals with a high genetic risk of depression. The paper describes the project aimed at developing a genetic test system based on polygenic risk scores (PRS) for depression, considering the multi-ethnicity and multicultural diversity of the Russian population. As a result of the study, data on the genetic architecture of depression (GWAS) and PRS for depression will be obtained for the first time. The emergence of a genetic test system developed in the study of the Russian population and in the conditions of a constant decrease in the cost of genetic research will allow an effective transition to preventive medicine in the area of mental health.

[The role of family studies in research of neurobiological basis of depressive disorders]. / Rol' semeinykh issledovanii v izuchenii neirobiologicheskogo bazisa depressivnykh rasstroistv.

Depression belongs to a large class of multifactorial diseases and genetic factors play a significant role in its formation, development and clinical manifestations. The authors present an overview of current studies of recurrent depressive disorder (RDD), a heterogeneous group of disorders with phenotypically similar psychopathological symptoms. A study of families with a high risk for RDD using clinical and biological (including genetic) approaches can greatly help in understanding of the neurobiological basis of depressive disorders, as well as in the identification of endophenotypes of depression. The most important criterion of the endophenotype is its heritability, which can be proved only within the framework of family design research. Comprehensive clinical and molecular genetic studies based on family design have the best prospects.