The prognostic role of depression as a predictor of chronic somatic diseases manifestation.

The negative impact of depression on the course and outcome of somatic disorders is well-known and has a solid theoretical basis. The analyses of prospective studies confirm the role of depression as an independent and significant risk factor for widespread chronic somatic disorders including such severe and life-threatening conditions as cardiovascular diseases, diabetes and oncological pathology. The majority of somatic disorders and depression are the part of the big class of hereditary diseases with multifactorial character and polygenic nature. It is likely, that the genetic risk diversity of these diseases in population is close. There is also a high probability of genetic risks levels overlap (or of common «cluster¼) of two or more diseases in one individual, with one disorder being major depression. In that case such diseases could be considered «genetically comorbid¼ and manifestation of one disease could alter the risks of other. Precise and informative diagnostic tools could detect subsyndromal depression that could be the prognostic sign of the high risk and rapid manifestation of somatic diseases. Thus, patients with depressive disorder could be considered as a group with high risks of diverse range of somatic pathology. The coalescence of fundamental biomedical scientists and internists (psychiatrists and other physicians) could lead to the elaboration of specific complex preventative measures including social ones.

[Psychosomatic medicine: old resources and new technologies]. / Psikhosomaticheskaya meditsina: starye resursy i novye tekhnologii.

Two primary research directions closely coexist in psychosomatic medicine. One is the most traditional, associated with an assessment of the psychological aspects of the connection, interconnection and mutual impact of mental and somatic pathology. The second, based on the rapid development of biological medicine in the last decade, studies causal associations and looks for shared mechanisms. In our review, we consider the previous main stages in the psychosomatic medicine and the prospective approaches to its further study. Evaluation of the etiopathogenesis of the entire set of mental and somatic symptoms in their interaction and dynamics can help identify individual subpopulations of patients with shared pathobiochemical and neurophysiological disorders. The recent interpretation of the biopsychosocial model is mainly related to the etiology and pathogenesis of mental disorders and also provides a good perspective for research on these issues. Today, there are sufficient opportunities to study all three domains of the model. Productive study of the biological, personal and social domains is also possible on the base of evidence-based design using modern research technologies.

[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.

[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.

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.

[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.

[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.

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.

[Microbiota and autoimmune processes as potential therapeutic targets in comorbid depression and inflammatory bowel disease]. / Mikrobiota i autoimmunnye protsessy kak potentsial'nye terapevticheskie «misheni¼ pri komorbidnosti depressii i vospalitel'nykh zabolevanii kishechnika.

The aim of this review is to evaluate current information on the shared pathologic mechanisms of inflammatory bowel disease (IBD) and depression, with an emphasis on inflammatory mechanisms and the role of the gut microbiota. According to the recent data, abovementioned elements play an important role in the risks of depression and anxiety in IBD. The impact on inflammatory processes and microbiota can be used to develop new therapeutic approaches both in cases of comorbid and isolated mental pathology. Despite this, the number of high-quality clinical studies in this area is currently extremely small. Further research into colitis-associated inflammation and dysbiosis may be the key to further understanding and creating optimal treatment of comorbid diseases.

[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.

[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.

[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.

[Genetic comorbidity of depression and somatic disorders]. / Geneticheskaia determinirovannost' komorbidnosti depressii i somaticheskikh zabolevanii.

The aim of our review was to evaluate the perspectives of new therapeutic approaches in comorbid depressive and somatic disorders based on common pathological mechanisms and their genetic risk factors. Literature analysis showed that depression was a complex heterogeneous condition associated with significant prevalence of metabolic, cardiovascular and immune disturbances. The understanding of common molecular mechanisms of risks and course of abovementioned disorders could provide a new strategy for early diagnosis and therapeutic optimization and give the opportunity of 'targeted' approach to different pathological elements.