[Gender characteristics of depressive disorders: clinical, psychological, neurobiological and translational aspects]. / Gendernye osobennosti depressivnykh rasstroistv: kliniko-psikhologicheskie, neirobiologicheskie i translyatsionnye aspekty.

Various studies have indicated that the prevalence of depression is almost twice as high among women as among men. A major factor associated with the development of depression and other affective disorders are adverse and psychologically traumatic life events that contribute to changes in the neuroendocrine system, altering the capacity to adapt to stress. These changes are involved in the pathogenesis of mental disorders, along with genetic and other factors, and are to a significant degree regulated by gender dependent mechanisms. While women have a high prevalence of depressive disorders, men show a higher rate of alcohol and substance abuse. These differences in the epidemiology are most likely explained by different predisposition to mental disorders in men and women and a diversity of biological consequences to adverse life events. Taking this into account, there is a need for a critical review of currently used approaches to modeling depressive disorders in preclinical studies, including the use of animals of both sexes. Adaptation of experimental models and protocols taking into account gender characteristics of neuroendocrine changes in response to stress, as well as structural-morphological, electrophysiological, molecular, genetic and epigenetic features, will significantly increase the translational validity of experimental work.

Methylation Patterns of the FKBP5 Gene in Association with Childhood Maltreatment and Depressive Disorders.

Childhood maltreatment is an important risk factor for adult depression and has been associated with changes in the hypothalamic pituitary adrenal (HPA) axis, including cortisol secretion and methylation of the FKBP5 gene. Furthermore, associations between depression and HPA changes have been reported. This study investigated the associations of whole-blood FKBP5 mRNA levels, serum cortisol levels, childhood maltreatment, and depressive symptoms with the whole-blood methylation status (assessed via target bisulfite sequencing) of 105 CpGs at the FKBP5 locus using data from the general population-based Study of Health in Pomerania (SHIP) (N = 203). Both direct and interaction effects with the rs1360780 single-nucleotide polymorphism were investigated. Nominally significant associations of main effects on methylation of a single CpG site were observed at intron 3, intron 7, and the 3'-end of the gene. Additionally, methylation at two clusters at the 3'-end and intron 7 were nominally associated with childhood maltreatment × rs1360780 and depressive symptoms × rs1360780, respectively. The results add to the understanding of molecular mechanisms underlying the emergence of depression and could aid the development of personalised depression therapy and drug development.

CYP2D6 Genotyping and Inhibition as Predictors of Adverse Drug Reactions in Depressive Disorders.

Objective: The primary aim of this study was to examine the association between the different predicted phenotypes of the polymorphic CYP2D6 gene and the prevalence of adverse drug reactions in patients suffering from depressive disorders. The secondary aim was to investigate if comedication with CYP2D6 inhibitors resulted in more adverse drug reactions due to phenoconversion.Methods: Between January 2012 and December 2021, 415 patients with a depressive disorder and insufficient treatment response in secondary psychiatric care were included in the naturalistic observational study Genes, Depression, and Suicidality (GEN-DS). The patients were subjected to a semistructured interview and diagnosed according to DSM-IV. Patients were also required to complete the self-rating version of the UKU Side Effect Rating Scale. All patients were genotyped for CYP2D6 and assigned a corresponding predicted CYP2D6 phenotype.Results: Out of the 415 patients, 147 patients with available genotyping and UKU scale results were also prescribed 1 or more drugs metabolized by CYP2D6. We did not find any evidence of an effect of the predicted CYP2D6 phenotype on the total burden of adverse drug reactions or in any of the specific symptom domains as measured with the UKU scale among these patients. We also investigated if comedication with 1 or more substances that inhibited the effect of the CYP2D6 enzyme resulted in more reported adverse drug reactions due to phenoconversion. Even though the rate of phenotypic PMs increased from 13 to 38 patients, we did not find any support for increased adverse drug reactions in this group.Conclusions: We did not find that CYP2D6 phenotype could predict the occurrence of adverse drug reactions in patients with depressive disorders in this naturalistic setting. However, information about CYP2D6 genotype may still be important in antidepressant treatment for the selection of appropriate drugs, for dosing recommendations of certain medications, or when the patient is suffering from severe adverse reactions.

CASP3 gene expression and the role of caspase 3 in the pathogenesis of depressive disorders.

BACKGROUND: The aim of our study was to evaluate the expression of the CASP3 gene at both mRNA and protein levels in patients with depressive disorders and to determine the impact of caspase 3 in the pathogenesis of depression; METHODS: A total of 290 subjects, including 190 depressed patients and 100 healthy controls, participated in the study. Socio-demographic and clinical data were collected, and the severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale. Venous blood was collected and gene expression was evaluated using RT-PCR and ELISA at the mRNA and protein levels, respectively; RESULTS: The expression of the CASP3 gene was significantly lower in depressed patients compared to healthy controls at both the mRNA and protein levels. Additionally, a positive correlation was observed between CASP3 gene expression and disease duration as well as the number of depressive episodes; CONCLUSIONS: Further studies are needed to investigate the role of caspase 3 in depressive disorders.

Circuit-wide proteomics profiling reveals brain region-specific protein signatures in the male WKY rats with endogenous depression.

BACKGROUND: Although the Wistar Kyoto (WKY) rat has been consistently recognized as an animal model with endogenous depression, the exact molecular mechanisms underlying its genetic susceptibility to depression remain undetermined. METHODS: Compared with the Wistar rats, the depression-like behaviors of the male WKY ones were evaluated by both the sucrose preference test and forced swimming test. Golgi staining analysis was conducted to access the dendritic morphology. TMT-labelled quantitative proteomics analyses were respectively performed in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and hippocampus (Hip), followed by KEGG enrichment-based clustering analysis, Venn diagram analysis, and Pearson correlation analysis. RESULTS: The WKY strain showed significant differences in both the depression-like behaviors and synaptic plasticity. Moreover, the WKY model displayed markedly distinct differentially-expressed protein (DEP) profiles, with minor differences between the WKY subgroups. A cerebral regional commonality and specificity were evident in the signaling pathways enriched in the WKY model, and a total of 15 brain region-specific DEPs were identified to closely correlate with the depression-like phenotypes (in the mPFC: Lrrc8d, Dcun1d2, and Mtnd5; in the NAc: Ccdc154, Sec14l2, Kif2a, LOC680322, Me1, Mknk1, and Ret7; in the Hip: Sec14l2, Serpinf2, LOC103694855, Fam13c, and Loxl1). Data were available via ProteomeXchange with identifier PXD029079. LIMITATIONS: Female WKY rats are not included, and the roles of these candidate DEPs in depression remain further elucidation. CONCLUSION: The present study further evidences the brain region-specific protein signatures in the male WKY model with endogenous depression, providing novel insights into the pathogenesis of depression in males.

Therapeutic Implications of microRNAs in Depressive Disorders: A Review.

MicroRNAs are hidden players in complex psychophysical phenomena such as depression and anxiety related disorders though the activation and deactivation of multiple proteins in signaling cascades. Depression is classified as a mood disorder and described as feelings of sadness, loss, or anger that interfere with a person's everyday activities. In this review, we have focused on exploration of the significant role of miRNAs in depression by affecting associated target proteins (cellular and synaptic) and their signaling pathways which can be controlled by the attachment of miRNAs at transcriptional and translational levels. Moreover, miRNAs have potential role as biomarkers and may help to cure depression through involvement and interactions with multiple pharmacological and physiological therapies. Taken together, miRNAs might be considered as promising novel therapy targets themselves and may interfere with currently available antidepressant treatments.

A game changer for bipolar disorder diagnosis using RNA editing-based biomarkers.

In clinical practice, differentiating Bipolar Disorder (BD) from unipolar depression is a challenge due to the depressive symptoms, which are the core presentations of both disorders. This misdiagnosis during depressive episodes results in a delay in proper treatment and a poor management of their condition. In a first step, using A-to-I RNA editome analysis, we discovered 646 variants (366 genes) differentially edited between depressed patients and healthy volunteers in a discovery cohort of 57 participants. After using stringent criteria and biological pathway analysis, candidate biomarkers from 8 genes were singled out and tested in a validation cohort of 410 participants. Combining the selected biomarkers with a machine learning approach achieved to discriminate depressed patients (n = 267) versus controls (n = 143) with an AUC of 0.930 (CI 95% [0.879-0.982]), a sensitivity of 84.0% and a specificity of 87.1%. In a second step by selecting among the depressed patients those with unipolar depression (n = 160) or BD (n = 95), we identified a combination of 6 biomarkers which allowed a differential diagnosis of bipolar disorder with an AUC of 0.935 and high specificity (Sp = 84.6%) and sensitivity (Se = 90.9%). The association of RNA editing variants modifications with depression subtypes and the use of artificial intelligence allowed developing a new tool to identify, among depressed patients, those suffering from BD. This test will help to reduce the misdiagnosis delay of bipolar patients, leading to an earlier implementation of a proper treatment.

The Inflammatory Effect of Epigenetic Factors and Modifications in Depressive Disorder: A Review.

BACKGROUND: Depressive disorder is one of the most common mental diseases and has become one of the three major causes of disability worldwide. Although some of the pathological mechanisms have been analyzed, the corresponding drug therapy has only achieved about 30% of curative effects. However, the pathological mechanism of depression is very complex, and the relationship between its complicated pathological mechanisms is still elusive. In recent years, more and more evidence shows that environmental stress induces stable changes in gene expression through the epigenetic mechanism which plays a vital role in the pathogenesis of the disease. Neuroinflammation is considered to be a key pathological mechanism of depression. OBJECTIVE: The aim of the study was to explore the relationship between epigenetic mechanism and neuroinflammation in the pathological process of depression. METHODS: In this paper, we review the crucial role of neuroinflammation in complex pathological mechanisms, especially its complex interrelationship with neurotransmitters, neuroendocrine, neurogenesis, and neuronal plasticity, which play a key role in the pathology of depression. RESULTS: The relationship between epigenetic mechanism and neuroinflammation in the pathological process of depression has been discussed, which mainly involves histone acetylation, histone methylation, DNA methylation, and non-coding RNA association. CONCLUSION: This review will help to understand the role of epigenetic mechanisms in depression and its related inflammatory responses and provide direction and guidance for future research.

Understanding the biological basis of psychiatric disease: What's next?

Psychiatric disease is one of the greatest health challenges of our time. The pipeline for conceptually novel therapeutics remains low, in part because uncovering the biological mechanisms of psychiatric disease has been difficult. We asked experts researching different aspects of psychiatric disease: what do you see as the major urgent questions that need to be addressed? Where are the next frontiers, and what are the current hurdles to understanding the biological basis of psychiatric disease?

A replication study separates polymorphisms behind migraine with and without depression.

The largest migraine genome-wide association study identified 38 candidate loci. In this study we assessed whether these results replicate on a gene level in our European cohort and whether effects are altered by lifetime depression. We tested SNPs of the loci and their vicinity with or without interaction with depression in regression models. Advanced analysis methods such as Bayesian relevance analysis and a neural network based classifier were used to confirm findings. Main effects were found for rs2455107 of PRDM16 (OR = 1.304, p = 0.007) and five intergenic polymorphisms in 1p31.1 region: two of them showed risk effect (OR = 1.277, p = 0.003 for both rs11209657 and rs6686879), while the other three variants were protective factors (OR = 0.4956, p = 0.006 for both rs12090642 and rs72948266; OR = 0.4756, p = 0.005 for rs77864828). Additionally, 26 polymorphisms within ADGRL2, 2 in REST, 1 in HPSE2 and 33 mostly intergenic SNPs from 1p31.1 showed interaction effects. Among clumped results representing these significant regions, only rs11163394 of ADGRL2 showed a protective effect (OR = 0.607, p = 0.002), all other variants were risk factors (rs1043215 of REST with the strongest effect: OR = 6.596, p = 0.003). Bayesian relevance analysis confirmed the relevance of intergenic rs6660757 and rs12128399 (p31.1), rs1043215 (REST), rs1889974 (HPSE2) and rs11163394 (ADGRL2) from depression interaction results, and the moderate relevance of rs77864828 and rs2455107 of PRDM16 from main effect analysis. Both main and interaction effect SNPs could enhance predictive power with the neural network based classifier. In summary, we replicated p31.1, PRDM16, REST, HPSE2 and ADGRL2 genes with classic genetic and advanced analysis methods. While the p31.1 region and PRDM16 are worthy of further investigations in migraine in general, REST, HPSE2 and ADGRL2 may be prime candidates behind migraine pathophysiology in patients with comorbid depression.

Use of the PsycheMERGE Network to Investigate the Association Between Depression Polygenic Scores and White Blood Cell Count.

Importance: Although depression is a common psychiatric disorder, its underlying biological basis remains poorly understood. Pairing depression polygenic scores with the results of clinical laboratory tests can reveal biological processes involved in depression etiology and in the physiological changes resulting from depression. Objective: To characterize the association between depression polygenic scores and an inflammatory biomarker, ie, white blood cell count. Design, Setting, and Participants: This genetic association study was conducted from May 19, 2019, to June 5, 2021, using electronic health record data from 382 452 patients across 4 health care systems. Analyses were conducted separately in each health care system and meta-analyzed across all systems. Primary analyses were conducted in Vanderbilt University Medical Center's biobank. Replication analyses were conducted across 3 other PsycheMERGE sites: Icahn School of Medicine at Mount Sinai, Mass General Brigham, and the Million Veteran Program. All patients with available genetic data and recorded white blood cell count measurements were included in the analyses. Primary analyses were conducted in individuals of European descent and then repeated in a population of individuals of African descent. Exposures: Depression polygenic scores. Main Outcomes and Measures: White blood cell count. Results: Across the 4 PsycheMERGE sites, there were 382 452 total participants of European ancestry (18.7% female; median age, 57.9 years) and 12 383 participants of African ancestry (61.1% female; median age, 39.0 [range, birth-90.0 years]). A laboratory-wide association scan revealed a robust association between depression polygenic scores and white blood cell count (ß, 0.03; SE, 0.004; P = 1.07 × 10-17), which was replicated in a meta-analysis across the 4 health care systems (ß, 0.03; SE, 0.002; P = 1.03 × 10-136). Mediation analyses suggested a bidirectional association, with white blood cell count accounting for 2.5% of the association of depression polygenic score with depression diagnosis (95% CI, 2.2%-20.8%; P = 2.84 × 10-70) and depression diagnosis accounting for 9.8% of the association of depression polygenic score with white blood cell count (95% CI, 8.4%-11.1%; P = 1.78 × 10-44). Mendelian randomization provided additional support for an association between increased white blood count and depression risk, but depression modeled as the exposure showed no evidence of an influence on white blood cell counts. Conclusions and Relevance: This genetic association study found that increased depression polygenic scores were associated with increased white blood cell count, and suggests that this association may be bidirectional. These findings highlight the potential importance of the immune system in the etiology of depression and may motivate future development of clinical biomarkers and targeted treatment options for depression.

Assessing the effect of interaction between C-reactive protein and gut microbiome on the risks of anxiety and depression.

Cumulative evidence shows that gut microbiome can influence brain function and behavior via the inflammatory processes. However, the role of interaction between gut dysbiosis and C-reactive protein (CRP) in the development of anxiety and depression remains to be elucidated. In this study, a total of 3321 independent single nucleotide polymorphism (SNP) loci associated with gut microbiome were driven from genome-wide association study (GWAS). Using individual level genotype data from UK Biobank, we then calculated the polygenetic risk scoring (PRS) of 114 gut microbiome related traits. Moreover, regression analysis was conducted to evaluate the possible effect of interaction between gut microbiome and CRP on the risks of Patient Health Questionnaire-9 (PHQ-9) (N = 113,693) and Generalized Anxiety Disorder-7 (GAD-7) (N = 114,219). At last, 11 candidate CRP × gut microbiome interaction with suggestive significance was detected for PHQ-9 score, such as F_Ruminococcaceae (ß = - 0.009, P = 2.2 × 10-3), G_Akkermansia (ß = - 0.008, P = 7.60 × 10-3), F_Acidaminococcaceae (ß = 0.008, P = 1.22 × 10-2), G_Holdemanella (ß = - 0.007, P = 1.39 × 10-2) and O_Lactobacillales (ß = 0.006, P = 1.79× 10-2). 16 candidate CRP × gut microbiome interaction with suggestive significance was detected for GAD-7 score, such as O_Bacteroidales (ß = 0.010, P = 4.00× 10-4), O_Selenomonadales (ß = - 0.010, P = 1.20 × 10-3), O_Clostridiales (ß = 0.009, P = 2.70 × 10-3) and G_Holdemanella (ß = - 0.008, P = 4.20 × 10-3). Our results support the significant effect of interaction between CRP and gut microbiome on the risks of anxiety and depression, and identified several candidate gut microbiomes for them.

The Genetic Architecture of Depression in Individuals of East Asian Ancestry: A Genome-Wide Association Study.

Importance: Most previous genome-wide association studies (GWAS) of depression have used data from individuals of European descent. This limits the understanding of the underlying biology of depression and raises questions about the transferability of findings between populations. Objective: To investigate the genetics of depression among individuals of East Asian and European descent living in different geographic locations, and with different outcome definitions for depression. Design, Setting, and Participants: Genome-wide association analyses followed by meta-analysis, which included data from 9 cohort and case-control data sets comprising individuals with depression and control individuals of East Asian descent. This study was conducted between January 2019 and May 2021. Exposures: Associations of genetic variants with depression risk were assessed using generalized linear mixed models and logistic regression. The results were combined across studies using fixed-effects meta-analyses. These were subsequently also meta-analyzed with the largest published GWAS for depression among individuals of European descent. Additional meta-analyses were carried out separately by outcome definition (clinical depression vs symptom-based depression) and region (East Asian countries vs Western countries) for East Asian ancestry cohorts. Main Outcomes and Measures: Depression status was defined based on health records and self-report questionnaires. Results: There were a total of 194 548 study participants (approximate mean age, 51.3 years; 62.8% women). Participants included 15 771 individuals with depression and 178 777 control individuals of East Asian descent. Five novel associations were identified, including 1 in the meta-analysis for broad depression among those of East Asian descent: rs4656484 (ß = -0.018, SE = 0.003, P = 4.43x10-8) at 1q24.1. Another locus at 7p21.2 was associated in a meta-analysis restricted to geographically East Asian studies (ß = 0.028, SE = 0.005, P = 6.48x10-9 for rs10240457). The lead variants of these 2 novel loci were not associated with depression risk in European ancestry cohorts (ß = -0.003, SE = 0.005, P = .53 for rs4656484 and ß = -0.005, SE = 0.004, P = .28 for rs10240457). Only 11% of depression loci previously identified in individuals of European descent reached nominal significance levels in the individuals of East Asian descent. The transancestry genetic correlation between cohorts of East Asian and European descent for clinical depression was r = 0.413 (SE = 0.159). Clinical depression risk was negatively genetically correlated with body mass index in individuals of East Asian descent (r = -0.212, SE = 0.084), contrary to findings for individuals of European descent. Conclusions and Relevance: These results support caution against generalizing findings about depression risk factors across populations and highlight the need to increase the ancestral and geographic diversity of samples with consistent phenotyping.

Aging-Dependent Downregulation of SUV39H1 Histone Methyltransferase Increases Susceptibility to Stress-Induced Depressive Behavior.

Aging induces cellular and molecular changes including gene expression alteration in the brain, which might be associated with aging-induced decrease in stress coping ability. In the present study, we investigate how aging changes the ability to cope with stress and increases sensitivity to stress. Aged mice show decreased expression of SUV39H1 histone methyltransferase and increased expression of Mkp-1 in the hippocampus. The siRNA-mediated knockdown of SUV39H1 increases Mkp-1 expression and suppresses p-CREB and Bdnf expression in HT22 cells and in the hippocampus of mice. Chromatin immunoprecipitation assays indicate that the levels of SUV39H1 and methylated histone-H3 bound to the promoter of the Mkp-1 in the hippocampus are reduced in aged mice. Aged mice exhibit depression-like behavior following weak stress that does not induce depressive behavior in young mice. Rosmarinic acid, a phenolic compound that increases SUV39H1 expression, reverses stress-induced changes of SUV39H1, Mkp-1, and Bdnf expression in the hippocampus via an overlapping but distinct mechanism from those of fluoxetine and imipramine and produces anti-depressive effects. These results suggest that aging increases susceptibility to stress via downregulation of SUV39H1 and resulting changes in SUV39H1-regulated signaling pathways in the hippocampus.

Neuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior.

Epitranscriptomic mechanisms linking tRNA function and the brain proteome to cognition and complex behaviors are not well described. Here, we report bi-directional changes in depression-related behaviors after genetic disruption of neuronal tRNA cytosine methylation, including conditional ablation and transgene-derived overexpression of Nsun2 in the mouse prefrontal cortex (PFC). Neuronal Nsun2-deficiency was associated with a decrease in tRNA m5C levels, resulting in deficits in expression of 70% of tRNAGly isodecoders. Altogether, 1488/5820 proteins changed upon neuronal Nsun2-deficiency, in conjunction with glycine codon-specific defects in translational efficiencies. Loss of Gly-rich proteins critical for glutamatergic neurotransmission was associated with impaired synaptic signaling at PFC pyramidal neurons and defective contextual fear memory. Changes in the neuronal translatome were also associated with a 146% increase in glycine biosynthesis. These findings highlight the methylation sensitivity of glycinergic tRNAs in the adult PFC. Furthermore, they link synaptic plasticity and complex behaviors to epitranscriptomic modifications of cognate tRNAs and the proteomic homeostasis associated with specific amino acids.

Relationship between SIRT1 gene and adolescent depressive disorder with nonsuicidal self-injury behavior: Based on gene methylation and mRNA expression.

OBJECTIVE: The incidence of non-suicidal self-injury (NSSI) behavior in adolescents is increasing year by year. Patients with a history of both depression and NSSI behavior tend to be at greater risk for suicide. At present, the mechanism of adolescent depressive disorder with NSSI behavior is not clear and still in research and exploration. The expression of the Silent Information Regulator 2 Related Enzyme 1 (SIRT1) gene is closely related to the level of serotonin in molecular mechanisms, and may be closely related to the occurrence and development of depressive disorder. This study aimed to explore the relationship between the SIRT1 gene and NSSI behaviors in adolescents with depressive disorder. METHODS: A total of 15 adolescent depressed patients with NSSI behavior and 15 healthy controls were enrolled in the study. Bisulfite Sequencing PCR (BSP) was used to test the methylation level of SIRT1 gene promoter region of the participants. The real-time fluorescent quantitative PCR was conducted to measure the mRNA expression level of SIRT1 gene. RESULTS: Our study found that the methylation level of SIRT1 gene promoter region at cytosine-guanine dinucleotide 5 (CpG5) site in depression group was higher than that of control group. Compared with that of control group, the plasma concentration of Sirt1 protein significantly decreased in depression group. CONCLUSION: Our study investigated the methylation level and the mRNA expression of SIRT1 gene in adolescent depressive patients with NSSI behavior. The study points towards finding an in vivo molecular marker for those adolescent patients.

CYP2C19 polymorphisms are associated with severity of depression at initial evaluation and after the treatment independently of the prescribed medications: 4 weeks prospective study.

BACKGROUND: The cytochrome P-450 2C19 (CYP2C19) enzyme is involved in the metabolism of numerous antidepressants. It also metabolises some endogenous substrates, which could also confer to vulnerability. We aimed to establish whether the severity of depression and treatment response are associated with the genetically predicted CYP2C19 phenotype. METHODS: We assessed the CYP2C19 genotype-predicted metabolic phenotypes (normal, intermediate or ultrarapid, there were no poor metabolisers) in patients with moderate or severe depression. We used the self-rated Beck Depression Inventory-II (BDI-II) scale and the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline, after 2 and 4 weeks of an empirical treatment trial. Patients and clinicians were blind to the genetic testing results. RESULTS: Seventy-six patients participated in the present study. At baseline, impaired CYP2C19 metabolisers, compared to normal metabolisers, had higher BDI-II (P = 0.046; ηp2 = 0.08) but not MADRS score. Intermediate metabolisers more often had a diagnosis of severe depression than normal metabolisers (P = 0.003). After 4 weeks of empirical treatment, intermediate metabolisers had significantly higher MADRS and BDI-II scores than normal metabolisers (P = 0.006; ηp2 = 0.131 and P = 0.030; ηp2 = 0.091). These differences were independent of the use of CYP2C19-metabolised medications in the treatment trial, as well as the treatment discrepancy status. CONCLUSIONS: Intermediate CYP2C19 polymorphism-predicted activity was associated with more severe depression after an empirical treatment trial. The lack of association between the prescription of CYP2C19-metabolised drugs and treatment response calls for a further look into the role of endogenous substrates of CYP2C19.

Association of Multigenerational Family History of Depression With Lifetime Depressive and Other Psychiatric Disorders in Children: Results from the Adolescent Brain Cognitive Development (ABCD) Study.

Importance: Three-generation family studies of depression have established added risk of psychopathology for offspring with 2 previous generations affected with depression compared with 1 or none. Because of their rigorous methodology, there are few of these studies, and existing studies are limited by sample sizes. Consequently, the 3-generation family risk paradigm established in family studies can be a critical neuropsychiatric tool if similar transmission patterns are reliably demonstrated with the family history method. Objective: To examine the association of multigenerational family history of depression with lifetime depressive disorders and other psychopathology in children. Design, Setting, and Participants: In this analysis of the Adolescent Brain Cognitive Development (ABCD) study data, retrospective, cross-sectional reports on psychiatric functioning among 11 200 children (generation 3 [G3]) and parent reports on parents' (G2) and grandparents' (G1) depression histories were analyzed. The ABCD study sampling weights were used for generalized estimating equation models and descriptive analyses. Data were collected from September 2016 to November 2018, and data were analyzed from July to November 2020. Main Outcomes and Measures: Four risk categories were created, reflecting how many prior generations had history of depression: (1) neither G1 nor G2 (G1-/G2-), (2) only G1 (G1+/G2-), (3) only G2 (G1-/G2+), and (4) both G1 and G2 (G1+/G2+). Child lifetime prevalence and relative risks of psychiatric disorders were based on child and caregiver reports and grouped according to familial risk category derived from G1 and G2 depression history. Results: Among 11 200 included children, 5355 (47.8%) were female, and the mean (SD) age was 9.9 (0.6) years. By parent reports, the weighted prevalence of depressive disorder among children was 3.8% (95% CI, 3.2-4.3) for G1-/G2- children, 5.5% (95% CI, 4.3-7.1) for G1+/G2- children, 10.4% (95% CI, 8.6-12.6) for G1-/G2+ children, and 13.3% (95% CI, 11.6-15.2) for G1+/G2+ children (Cochran-Armitage trend = 243.77; P < .001). The weighted suicidal behavior prevalence among children was 5.0% (95% CI, 4.5-5.6) for G1-/G2- children, 7.2% (95% CI, 5.8-8.9) for G1+/G2- children, 12.1% (95% CI, 10.1-14.4) for G1-/G2+ children, and 15.0% (95% CI, 13.2-17.0) for G1+/G2+ children (Cochran-Armitage trend = 188.66; P < .001). By child reports, the weighted prevalence of depressive disorder was 4.8% (95% CI, 4.3-5.5) for G1-/G2- children, 4.3% (95% CI, 3.2-5.7) for G1+/G2- children, 6.3% (95% CI, 4.9-8.1) for G1-/G2+ children, and 7.0% (95% CI, 5.8-8.5) for G1+/G2+ children (Cochran-Armitage trend = 9.01; P = .002), and the weighted prevalence of suicidal behaviors was 7.4% (95% CI, 6.7-8.2) for G1-/G2- children, 7.0% (95% CI, 5.6-8.6) for G1+/G2- children, 9.8% (95% CI, 8.1-12.0) for G1-/G2+ children, and 13.8% (95% CI, 12.1-15.8) for G1+/G2+ children (Cochran-Armitage trend = 46.69; P < .001). Similar patterns were observed for other disorders for both parent and child reports and across sex, socioeconomic status, and race/ethnicity. Conclusions and Relevance: In this study, having multiple prior affected generations was associated with increased risk of childhood psychopathology. Furthermore, these findings were detectable even at prepubertal ages and existed in diverse racial/ethnic and socioeconomic groups. Clinically, they underscore the need for screening for family history in pediatric settings and highlight implications for biological research with homogenous subgroups using magnetic resonance imaging or genetic analyses.