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Importance: Cognitive impairment in depression is poorly understood. Family history of depression is a potentially useful risk marker for cognitive impairment, facilitating early identification and targeted intervention in those at highest risk, even if they do not themselves have depression. Several research cohorts have emerged recently that enable findings to be compared according to varying depths of family history phenotyping, in some cases also with genetic data, across the life span., Objective: To investigate associations between familial risk of depression and cognitive performance in 4 independent cohorts with varied depth of assessment, using both family history and genetic risk measures., Design, Setting, and Participants: This study used data from the Three Generations at High and Low Risk of Depression Followed Longitudinally (TGS) family study (data collected from 1982 to 2015) and 3 large population cohorts, including the Adolescent Brain Cognitive Development (ABCD) study (data collected from 2016 to 2021), National Longitudinal Study of Adolescent to Adult Health (Add Health; data collected from 1994 to 2018), and UK Biobank (data collected from 2006 to 2022). Children and adults with or without familial risk of depression were included. Cross-sectional analyses were conducted from March to June 2022., Exposures: Family history (across 1 or 2 prior generations) and polygenic risk of depression., Main Outcomes and Measures: Neurocognitive tests at follow-up. Regression models were adjusted for confounders and corrected for multiple comparisons., Results: A total of 57 308 participants were studied, including 87 from TGS (42 [48%] female; mean [SD] age, 19.7 [6.6] years), 10 258 from ABCD (4899 [48%] female; mean [SD] age, 12.0 [0.7] years), 1064 from Add Health (584 [49%] female; mean [SD] age, 37.8 [1.9] years), and 45 899 from UK Biobank (23 605 [51%] female; mean [SD] age, 64.0 [7.7] years). In the younger cohorts (TGS, ABCD, and Add Health), family history of depression was primarily associated with lower performance in the memory domain, and there were indications that this may be partly associated with educational and socioeconomic factors. In the older UK Biobank cohort, there were associations with processing speed, attention, and executive function, with little evidence of education or socioeconomic influences. These associations were evident even in participants who had never been depressed themselves. Effect sizes between familial risk of depression and neurocognitive test performance were largest in TGS; the largest standardized mean differences in primary analyses were -0.55 (95% CI, -1.49 to 0.38) in TGS, -0.09 (95% CI, -0.15 to -0.03) in ABCD, -0.16 (95% CI, -0.31 to -0.01) in Add Health, and -0.10 (95% CI, -0.13 to -0.06) in UK Biobank. Results were generally similar in the polygenic risk score analyses. In UK Biobank, several tasks showed statistically significant associations in the polygenic risk score analysis that were not evident in the family history models., Conclusions and Relevance: In this study, whether assessed by family history or genetic data, depression in prior generations was associated with lower cognitive performance in offspring. There are opportunities to generate hypotheses about how this arises through genetic and environmental determinants, moderators of brain development and brain aging, and potentially modifiable social and lifestyle factors across the life span.

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.

The last 40 years of JAMA Psychiatry are reviewed as a celebration of its achievements. The focus of this article is on the evolution of big data as reflected in key journal articles. The review begins in 1984 with the introduction of the Epidemiology Catchment Area (ECA) study and Freedman's editorial "Psychiatric Epidemiology Counts." The ECA study (N = 17 000), for the first time in a survey, used clinical diagnosis in 5 urban communities, thus linking research and care to population rates of psychiatric diagnosis. The review then traces the subsequent evolution of big data to 5 overlapping phases, other population surveys in the US and globally, cohort studies, administrative claims, large genetic data sets, and electronic health records. Each of these topics are illustrated in articles in JAMA Psychiatry. The many caveats to these choices, the historical roots before 1984, as well as the controversy around the choice of topics and the term big data are acknowledged. The foundation for big data in psychiatry was built on the development of defined and reliable diagnosis, assessment tools that could be used in large samples, the computational evolution for handling large data sets, hypothesis generated by smaller studies of humans and animals with carefully crafted phenotypes, the welcoming of investigators from all over the world with calls for broader diversity, open access and the sharing of data, and introduction of electronic health records more recently. Future directions as well as the opportunities for the complementary roles of big and little data are described. JAMA Psychiatry will continue to be a rich resource of these publications.

Importance: Despite the widespread awareness of functional magnetic resonance imaging findings suggesting a role for cortical connectivity networks in treatment selection for major depressive disorder, its clinical utility remains limited. Recent methodological advances have revealed functional magnetic resonance imaging-like connectivity networks using electroencephalography (EEG), a tool more easily implemented in clinical practice., Objective: To determine whether EEG connectivity could reveal neural moderators of antidepressant treatment., Design, Setting, and Participants: In this nonprespecified secondary analysis, data were analyzed from the Establishing Moderators and Biosignatures of Antidepressant Response in Clinic Care study, a placebo-controlled, double-blinded randomized clinical trial. Recruitment began July 29, 2011, and was completed December 15, 2015. A random sample of 221 outpatients with depression aged 18 to 65 years who were not taking medication for depression was recruited and assessed at 4 clinical sites. Analysis was performed on an intent-to-treat basis. Statistical analysis was performed from November 16, 2018, to May 23, 2019., Interventions: Patients received either the selective serotonin reuptake inhibitor sertraline hydrochloride or placebo for 8 weeks., Main Outcomes and Measures: Electroencephalographic orthogonalized power envelope connectivity analyses were applied to resting-state EEG data. Intent-to-treat prediction linear mixed models were used to determine which pretreatment connectivity patterns were associated with response to sertraline vs placebo. The primary clinical outcome was the total score on the 17-item Hamilton Rating Scale for Depression, administered at each study visit., Results: Of the participants recruited, 9 withdrew after first dose owing to reported adverse effects, and 221 participants (150 women; mean [SD] age, 37.8 [12.7] years) underwent EEG recordings and had high-quality pretreatment EEG data. After correction for multiple comparisons, connectome-wide analyses revealed moderation by connections within and between widespread cortical regions-most prominently parietal-for both the antidepressant and placebo groups. Greater alpha-band and lower gamma-band connectivity predicted better placebo outcomes and worse antidepressant outcomes. Lower connectivity levels in these moderating connections were associated with higher levels of anhedonia. Connectivity features that moderate treatment response differentially by treatment group were distinct from connectivity features that change from baseline to 1 week into treatment. The group mean (SD) score on the 17-item Hamilton Rating Scale for Depression was 18.35 (4.58) at baseline and 26.14 (30.37) across all time points., Conclusions and Relevance: These findings establish the utility of EEG-based network functional connectivity analyses for differentiating between responses to an antidepressant vs placebo. A role emerged for parietal cortical regions in predicting placebo outcome. From a treatment perspective, capitalizing on the therapeutic components leading to placebo response differentially from antidepressant response should provide an alternative direction toward establishing a placebo signature in clinical trials, thereby enhancing the signal detection in randomized clinical trials., Trial Registration: ClinicalTrials.gov identifier: NCT01407094.

Importance: Previous studies have shown an inverse association between offspring religiosity and suicidal ideation/attempts, but the association of parent religiosity on offspring suicidal ideation/attempts has not been examined., Objective: To examine associations of parent and offspring religiosity with suicide ideation and attempts in offspring., Design, Setting, and Participants: The study is based on offspring (generation 3) from a 3-generation family study at New York State Psychiatric Institute and Columbia University, in which generations 2 and 3 were defined as being at high risk or low risk for major depressive disorder because of the presence or absence of major depressive disorder in generation 1. The association between suicidal behaviors (ideation/attempts) and parent and offspring religiosity in generation 3 offspring aged 6 to 18 years (214 offspring from 112 nuclear families) was examined., Main Outcomes and Measures: Parents' psychiatric diagnoses and suicidal behaviors were assessed with the Schedule for Affective Disorders and Schizophrenia, and offspring were independently assessed using the child version. Two measures of religiosity were assessed: religious importance and religious attendance. Logistic regressions in the framework of generalized estimation equations were performed to analyze offspring suicidal behaviors while adjusting for sibling correlation and offspring age, sex, and familial depression risk status., Results: Of 214 offspring, 112 (52.3%) were girls. Offspring religious importance was associated with a lower risk for suicidal behavior in girls (odds ratio [OR], 0.48; 95% CI, 0.33-0.70) but not in boys (OR, 1.15; 95% CI, 0.74-1.80) (religiosity by sex interaction, P = .05). Religious attendance was associated with a lower risk for suicidal behavior in girls (OR, 0.64; 95% CI, 0.49-0.84) but not boys (OR, 0.94; 95% CI, 0.69-1.27) (religiosity by sex interaction, P = .17). Parent religious importance was associated with a lower risk for offspring suicidal behavior (OR, 0.61; 95% CI, 0.41-0.91) but not parent religious attendance. When parent and offspring religious importance were considered simultaneously, we found a lower risk associated with parental religious importance (OR, 0.61; 95% CI, 0.39-0.96) independent of offspring importance. These associations were independent of parental depression, marital status, and parental suicide ideation., Conclusions and Relevance: In this study, parental belief in religious importance was associated with lower risk for suicidal behavior in offspring independent of an offspring's own belief about religious importance and other known parental factors, such as parental depression, suicidal behavior, and divorce.

Importance: Major depressive disorder (MDD) and alcohol dependence (AD) are heritable disorders with significant public health burdens, and they are frequently comorbid. Common genetic factors that influence the co-occurrence of MDD and AD have been sought in family, twin, and adoption studies, and results to date have been promising but inconclusive., Objective: To examine whether AD and MDD overlap genetically, using a polygenic score approach., Design, Settings, and Participants: Association analyses were conducted between MDD polygenic risk score (PRS) and AD case-control status in European ancestry samples from 4 independent genome-wide association study (GWAS) data sets: the Collaborative Study on the Genetics of Alcoholism (COGA); the Study of Addiction, Genetics, and Environment (SAGE); the Yale-Penn genetic study of substance dependence; and the National Health and Resilience in Veterans Study (NHRVS). Results from a meta-analysis of MDD (9240 patients with MDD and 9519 controls) from the Psychiatric Genomics Consortium were applied to calculate PRS at thresholds from P < .05 to P ≤ .99 in each AD GWAS data set., Main Outcomes and Measures: Association between MDD PRS and AD., Results: Participants analyzed included 788 cases (548 [69.5%] men; mean [SD] age, 38.2 [10.8] years) and 522 controls (151 [28.9.%] men; age [SD], 43.9 [11.6] years) from COGA; 631 cases (333 [52.8%] men; age [SD], 35.0 [7.7] years) and 756 controls (260 [34.4%] male; age [SD] 36.1 [7.7] years) from SAGE; 2135 cases (1375 [64.4%] men; age [SD], 39.4 [11.5] years) and 350 controls (126 [36.0%] men; age [SD], 43.5 [13.9] years) from Yale-Penn; and 317 cases (295 [93.1%] men; age [SD], 59.1 [13.1] years) and 1719 controls (1545 [89.9%] men; age [SD], 64.5 [13.3] years) from NHRVS. Higher MDD PRS was associated with a significantly increased risk of AD in all samples (COGA: best P = 1.7 × 10-6, R2 = 0.026; SAGE: best P = .001, R2 = 0.01; Yale-Penn: best P = .035, R2 = 0.0018; and NHRVS: best P = .004, R2 = 0.0074), with stronger evidence for association after meta-analysis of the 4 samples (best P = 3.3 × 10-9). In analyses adjusted for MDD status in 3 AD GWAS data sets, similar patterns of association were observed (COGA: best P = 7.6 × 10-6, R2 = 0.023; Yale-Penn: best P = .08, R2 = 0.0013; and NHRVS: best P = .006, R2 = 0.0072). After recalculating MDD PRS using MDD GWAS data sets without comorbid MDD-AD cases, significant evidence was observed for an association between the MDD PRS and AD in the meta-analysis of 3 GWAS AD samples without MDD cases (best P = .007)., Conclusions and Relevance: These results suggest that shared genetic susceptibility contributes modestly to MDD and AD comorbidity. Individuals with elevated polygenic risk for MDD may also be at risk for AD.

Importance: Speech/language, scholastic, and motor disorders are common in children. It is unknown whether exposure to selective serotonin reuptake inhibitors (SSRIs) during pregnancy influences susceptibility to these disorders., Objective: To examine whether SSRI exposure during pregnancy is associated with speech/language, scholastic, and motor disorders in offspring up to early adolescence., Design, Setting, and Participants: This prospective birth cohort study examined national population-based register data in Finland from 1996 to 2010. The sampling frame includes 845 345 pregnant women and their singleton offspring with data on maternal use of antidepressants and depression-related psychiatric disorders during pregnancy., Exposures: There were 3 groups of offspring: 15 596 were in the SSRI-exposed group, ie, had mothers diagnosed as having depression-related psychiatric disorders with a history of purchasing SSRIs during pregnancy; 9537 were in the unmedicated group, ie, had mothers diagnosed as having depression-related psychiatric disorders without a history of purchasing SSRIs during pregnancy; and 31 207 were in the unexposed group, ie, had mothers without a psychiatric diagnosis or a history of purchasing SSRIs., Main Outcomes and Measures: Cumulative incidence of speech/language, scholastic, or motor disorders (829, 187, and 285 instances, respectively) from birth to 14 years. All hypotheses tested were formulated before data collection., Results: Of the 56 340 infants included in the final cohort, 28 684 (50.9%) were male and 48 782 (86.6%) were 9 years or younger. The mean (SD) ages of children at diagnosis were 4.43 (1.67), 3.55 (2.67), and 7.73 (2.38) for speech/language, scholastic, and motor disorders, respectively. Offspring of mothers who purchased SSRIs at least twice during pregnancy had a significant 37% increased risk of speech/language disorders compared with offspring in the unmedicated group. The cumulative hazard of speech/language disorders was 0.0087 in the SSRI-exposed group vs 0.0061 in the unmedicated group (hazard ratio, 1.37; 95% CI, 1.11-1.70; P = .004). There was a significantly increased risk of these disorders in offspring in the SSRI-exposed and unmedicated groups compared with offspring in the unexposed group. For scholastic and motor disorders, there were no differences between offspring in the SSRI-exposed group and in the unmedicated group., Conclusions and Relevance: Exposure to SSRIs during pregnancy was associated with an increased risk of speech/language disorders. This finding may have implications for understanding associations between SSRIs and child development.

Importance: The increased risk of major depression in the offspring of depressed parents is well known. Whether the risk is transmitted beyond 2 generations is less well known. To our knowledge, no published study with direct interviews of family members and the generations in the age of risk for depression has evaluated beyond 2 generations. This information is important for detecting individuals at highest risk who may benefit from early intervention., Objective: To examine the familial aggregation of psychiatric disorder and functioning in grandchildren by their biological parents' and grandparents' depression status., Design, Setting, and Participants: Longitudinal retrospective cohort family study of 251 grandchildren (generation 3 [mean age, 18 years]) interviewed a mean of 2.0 times and their biological parents (generation 2) interviewed a mean of 4.6 times and grandparents (generation 1) interviewed up to 30 years. The study dates were January 1982 (wave 1) to June 2015 (wave 6)., Main Outcomes and Measures: Cumulative rates of psychiatric disorders and functioning collected for all generations by clinically trained interviewers and best-estimate diagnosis made blind to diagnoses in members of previous generations., Results: There were 91 families (G1) in the original sample, of whom 77 were eligible for inclusion (had a grandchild older than 5 years), and 80.5% (62 of 77) participated in the study. When first examining only 2 generations, the biological children (generation 3) of depressed compared with nondepressed parents (generation 2) had 2-fold increased risk for major depressive disorder (MDD) (hazard ratio [HR], 2.02; 95% CI, 1.08-3.79; P = .03), any disruptive disorder (HR, 1.70; 95% CI, 1.05-2.75; P = .03), substance dependence (HR, 2.96; 95% CI, 1.24-7.08; P = .01), any suicidal ideation or gesture (HR, 2.44; 95% CI, 1.28-4.66; P = .007), and poor functioning (F = 38.25, P < .001). When 3 generations were examined stratified by parental and grandparental depression status, association of a parent's MDD on the grandchild's MDD but not other disorders varied with the grandparent's depression status: grandchildren with both a depressed parent and grandparent (n = 38) were at highest risk for MDD. Among grandchildren without a depressed grandparent, those with (n = 14) vs without (n = 74) a depressed parent had overall poorer functioning (F = 6.31, P = .01) but not higher rates of any of the disorders. Potential confounding variables did not have a meaningful effect on the association between grandchild outcomes and parental or grandparental depression., Conclusions and Relevance: In this study, biological offspring with 2 previous generations affected with major depression were at highest risk for major depression, suggesting the potential value of determining family history of depression in children and adolescents beyond 2 generations. Early intervention in offspring of 2 generations affected with moderate to severely impairing MDD seems warranted. The specificity of the transmission of depression across 3 generations may make this group a homogeneous sample for biological marker studies.

Importance: We previously reported a 90% decreased risk in major depression, assessed prospectively, in adult offspring of depressed probands who reported that religion or spirituality was highly important to them. Frequency of church attendance was not significantly related to depression risk. Our previous brain imaging findings in adult offspring in these high-risk families also revealed large expanses of cortical thinning across the lateral surface of the right cerebral hemisphere., Objective: To determine whether high-risk adults who reported high importance of religion or spirituality had thicker cortices than those who reported moderate or low importance of religion or spirituality and whether this effect varied by family risk status., Design, Setting, and Participants: Longitudinal, retrospective cohort, familial study of 103 adults (aged 18-54 years) who were the second- or third-generation offspring of depressed (high familial risk) or nondepressed (low familiar risk) probands (first generation). Religious or spiritual importance and church attendance were assessed at 2 time points during 5 years, and cortical thickness was measured on anatomical images of the brain acquired with magnetic resonance imaging at the second time point., Main Outcomes and Measures: Cortical thickness in the parietal regions by risk status., Results: Importance of religion or spirituality, but not frequency of attendance, was associated with thicker cortices in the left and right parietal and occipital regions, the mesial frontal lobe of the right hemisphere, and the cuneus and precuneus in the left hemisphere, independent of familial risk. In addition, the effects of importance on cortical thickness were significantly stronger in the high-risk than in the low-risk group, particularly along the mesial wall of the left hemisphere, in the same region where we previously reported a significant thinner cortex associated with a familial risk of developing depressive illness. We note that these findings are correlational and therefore do not prove a causal association between importance and cortical thickness., Conclusions and Relevance: A thicker cortex associated with a high importance of religion or spirituality may confer resilience to the development of depressive illness in individuals at high familial risk for major depression, possibly by expanding a cortical reserve that counters to some extent the vulnerability that cortical thinning poses for developing familial depressive illness.

Importance: The neural systems that confer risk or vulnerability for developing familial depression, and those that protect against or confer resilience to becoming ill, can be disentangled from the effects of prior illness by comparing brain imaging measures in previously ill and never ill persons who have either a high or low familial risk for depression., Objective: To distinguish risk and resilience endophenotypes for major depression from the effects of prior lifetime illness., Design, Setting, and Participants: We used functional magnetic resonance imaging to measure and compare brain function during performance of an attentional, self-regulatory task across a large sample of multigenerational families ascertained specifically to be at either high or low risk for developing major depression. Study procedures were performed in a university setting. A total of 143 community participants were followed up prospectively for more than 20 years in a university setting. The sample was enriched with persons who were at higher or lower familial risk for developing depression based on being biological offspring of either a clinical sample of persons with major depression or a community control sample of persons with no discernible lifetime illness., Main Outcomes and Measures: Task-related change in blood oxygen level-dependent functional magnetic resonance imaging signal., Results: A risk endophenotype included greater activation of cortical attention circuits. A resilience endophenotype included greater activation of the dorsal anterior cingulate cortex. The effects of prior lifetime illness were common to both risk groups and included greater deactivation of default-mode circuits., Conclusions and Relevance: These findings identify neural systems that increase risk for depression, those that protect from illness, and those that endure following illness onset, and they suggest circuits to target for developing novel preventive and therapeutic interventions.