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Suicide is the second leading cause of death among college students, yet many students with elevated suicide risk do not seek professional help. This study identified suicide risk profiles among college students and examined these in relation to students' perceived barriers to professional help-seeking. Data were obtained from college students (n = 1689) identified to be at elevated risk for suicide based at four US universities. Latent class analysis was performed to determine risk profiles, followed by examinations of differences in help-seeking barriers by profile groupings. Results revealed three student groupings: (1) moderate internalizing and externalizing symptoms (with low alcohol misuse), (2) highest internalizing and externalizing symptoms (with highest social disconnection), and (3) lowest internalizing symptoms and low externalizing (with highest social connection and alcohol misuse). Group 1 included the youngest and most racially and sexually diverse students, Group 2 endorsed the most help-seeking barriers, and Group 3 endorsed the fewest barriers. Group 2 is especially concerning, considering the severe clinical characteristics, high number of barriers, and low connectedness to others for potential support. Understanding these differences across risk and barrier profiles is an important step towards developing tailored approaches to increase mental health care in college populations.

Bipolar disorder (BD) is characterized by mood episodes, disrupted circadian rhythms and gray matter reduction in the brain. Lithium is an effective pharmacotherapy for BD, but not all patients respond to treatment. Lithium has neuroprotective properties and beneficial effects on circadian rhythms that may distinguish lithium responders (Li-R) from non-responders (Li-NR). The circadian clock regulates molecular pathways involved in apoptosis and cell survival, but how this overlap impacts BD and/or lithium responsiveness is unknown. In primary fibroblasts from Li-R/Li-NR BD patients and controls, we found patterns of co-expression among circadian clock and cell survival genes that distinguished BD vs. control, and Li-R vs. Li-NR cells. In cellular models of apoptosis using staurosporine (STS), lithium preferentially protected fibroblasts against apoptosis in BD vs. control samples, regardless of Li-R/Li-NR status. When examining the effects of lithium treatment of cells in vitro, caspase activation by lithium correlated with period alteration, but the relationship differed in control, Li-R and Li-NR samples. Knockdown of Per1 and Per3 in mouse fibroblasts altered caspase activity, cell death and circadian rhythms in an opposite manner. In BD cells, genetic variation in PER1 and PER3 predicted sensitivity to apoptosis in a manner consistent with knockdown studies. We conclude that distinct patterns of coordination between circadian clock and cell survival genes in BD may help predict lithium response.

Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30-40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of "clock genes" and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.

Background : It has not been established that suicide risk with mixed symptoms is any greater than the depressive component or if there is synergy between depressive and manic symptoms in conveying suicide risk. Methods : The National Network of Depression Centers Mood Outcomes Program collected data from measurement-based care for 17,179 visits from 6,105 unique individuals with clinically diagnosed mood disorders (998 bipolar disorder, 5,117 major depression). The Patient Health Questionaire-8 (PHQ-8) captured depressive symptoms and the Altman Self-Rating Mania scale (ASRM) measured hypomanic/manic symptoms. Generalized linear mixed models assessed associations between depressive symptoms, manic symptoms, and their interaction (to test for synergistic effects of mixed symptoms) on the primary outcome of suicidal ideation or behavior (secondarily suicidal behavior only) from the Columbia-Suicide Severity Rating Scale (C-SSRS). Moderation was assessed. Results : PHQ-8 scores were strongly associated with suicide-related outcomes across diagnoses. ASRM scores showed no association with suicidal ideation/behavior in bipolar disorder and an inverse association in major depression. There was no evidence of synergy between depressive and manic symptoms. There was no moderation by sex, race, or mood disorder polarity. Those over 55 years of age showed a protective effect of manic symptoms, which was lost when depressive symptoms were also present (mixed symptoms). Discussion : Mixed depressive and manic symptoms convey no excess risk of suicidal ideation or behavior beyond the risk conveyed by the depressive symptoms alone. Depressive symptoms are strongly linked to suicidal ideation and suicidal behavior and represent an important and potentially modifiable risk factor for suicide.

Depression and suicidal ideation have substantially increased among college students, yet many students with clinically significant symptoms do not perceive their distress as warranting mental health services. Personalized feedback (PF) interventions deliver objective data, often electronically, comparing an individual’s reported symptoms or behaviors to a group norm. Several studies have shown promise for PF interventions in the context of mood and depression, yet little is known regarding how, and for whom, mood-focused PF interventions might be best deployed. The primary aim of this study was to examine the sociodemographic, clinical, and treatment-seeking factors associated with reviewing PF reports on emotional distress among college students (N=1,673) screening positive for elevated suicide risk and not receiving mental health treatment. Results indicated that PF engagement was greatest among those with higher depression scores, and those reporting privacy/stigma concerns as barriers to treatment. Sexual minority students were more likely to review their PF than heterosexual students. Taken together, PF interventions may be a useful tool for engaging those with greater clinical acuity, and those hesitant to seek in-person care. Further research is warranted to examine the circumstances in which PF interventions might be used in isolation, or as part of a multi-tiered intervention strategy.

Suicide is the second leading cause of death among college students in the United States, and the percentage of students reporting suicidal thoughts is increasing. Nevertheless, many students at risk do not seek mental health (MH) services. This randomized controlled trial (RCT) examined the efficacy of Electronic Bridge to Mental Health for College Students (eBridge) for increasing at-risk students' linkage to MH services.Students from four universities were recruited via email; 40,347 (22.6%) completed the online suicide risk screen; and 3,363 (8.3%) met criteria for randomization based on suicide risk factors and lack of current treatment (62.2% female, 35.0% male, 2.8% transgender/nonbinary; 73.2% White, 7.0% Black, 19.9% Asian, 11.7% other; 12.4% Hispanic, 76.2% undergraduate). These students were randomized to eBridge [personalized feedback (PF) with option of online counseling] or Control (PF). The primary outcome was linkage to MH services within 6 months.Among students assigned to eBridge, 355 students (21.0%) posted ≥1 message, and 168 (10.0%) posted ≥2 messages to the counselor. In intent-to-treat analyses, there was no eBridge effect on obtaining MH services. However, within the eBridge group, students who posted ≥1 message were significantly more likely to link to MH services.eBridge shows promise for reaching a relatively small subset of college students at risk for suicide; however, engagement in eBridge was low. This study underscores the urgent need for more effective strategies to engage young adults in online mental health interventions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Aims There has been a marked increase in suicide fatalities among college-age students in recent years. Moreover, heavy alcohol use, a well-known risk factor for suicide, is present on most campuses. Yet, no prospective studies have examined alcohol use patterns among college students as predictors of suicidal behaviors. Methods Online of 40,335 students at four universities took place at the beginning of four academic years, 2015–2018. Of these, 2296 met criteria for an increased risk of suicidal behavior and completed 1- and/or 6-month follow-up evaluation(s). Baseline assessments included the Alcohol Use Disorders Identification Test to quantify alcohol consumption and resulting problems, and measures of depression, suicidal ideation and suicidal behavior. Results Suicide attempts during follow-up were reported by 35 (1.5%) of high-risk students. Regression analyses indicated that baseline severity of alcohol use consequences, but not amount of alcohol consumption, was associated with greater odds of a follow-up suicide attempt after controlling for baseline suicidal ideation, functional impairment and history of suicide attempts. Conclusions Among college students at elevated risk for suicide, the severity of alcohol-related consequences was a significant predictor of future suicide attempts. Alcohol consumption was not a significant predictor, suggesting that the amount students drink is less of a concern for suicidal behavior than are the problems (e.g. failing to meet expectations, experiencing blackouts) associated with drinking.

Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

Background Numerous reports have described increased rates of exposure to Toxoplasma gondii levels in individuals with a history of suicide attempts in comparison with well controls, or psychiatrically ill individuals, with no suicide attempt history. Such findings suggest that the behavioral effects this parasite exerts on rodent hosts extends to humans though few studies have searched for underlying mechanisms. Methods The present study compared 96 patients with an active depressive disorder and a history of at least two suicide attempts to 126 depressed patients with no history of suicide attempts by IgG and IgM levels of Toxoplasma gondii and cytomegalovirus (CMV). The groups were also compared by IL_1b, TNF-alpha, CRP, IL_6, and IL_1ra titers. Results Toxoplasma gondii IgM levels were higher, and seropositivity more likely, in the suicide attempt group. CMV IgG levels were also higher among suicide attempters. Several of these immunoglobulin measures were more robustly associated with the number of suicide attempts than with the dichotomy of suicide attempter and non-attempter. These two antibody levels were also additive in their association with suicide attempter status. IL_1a levels were lower in suicide attempters and correlated negatively with levels of antibodies to Toxoplasma gondii and CMV. Limitations These include a sample size insufficient to explore differences across mood disorder diagnoses or demographic groupings. Conclusions These results indicate that exposure to common infectious agents such as Toxoplasma gondii and CMV are associated with increased risk of suicide attempts but the mechanism of association does not appear to involve the activation of cytokines. Elucidation of the mechanisms which define the relationship between infections and suicide attempts may lead to new methods for the prediction and prevention of suicide attempts.

Mood disorders are among the most burdensome public health concerns. The National Network of Depression Centers (NNDC) is a nonprofit consortium of 26 leading clinical and academic member centers in the United States providing care for patients with mood disorders, including depression and bipolar disorder. The NNDC has established a measurement-based care program called the Mood Outcomes Program whereby participating sites follow a standard protocol to electronically collect patient-reported outcome assessments on depression, anxiety, and suicidal ideation in routine clinical care. This article describes the approaches taken to develop and implement the program.Since 2015, eight pilot sites have implemented the program and followed more than 10,000 patients. This pilot study presents descriptive statistics based on the first 24-month period of data collection.In this sample, 58.6% of patients with bipolar disorder (N=849) and 57.5% of patients with unipolar depression (N=3,998) remained symptomatic at follow-up. Lifetime rates of planned or actual suicide attempts were high, ranging from 27.6% for patients with unipolar mood disorders to 33.5% for patients with bipolar disorder. Men, unmarried individuals, and those with comorbid anxiety had a poorer longitudinal course. This initial snapshot of clinical burden is consistent with public health data indicating that mood disorders are severely debilitating.This study demonstrates the potential of the Mood Outcomes Program to create a nationwide "learning health system" for mood disorders. This goal will be further realized as the program expands in reach and scope across additional NNDC sites.

BackgroundGroup-based trajectory modeling holds promise for the study of prognostic indicators in the mood disorders because the courses that the individuals with these disorders follow are so highly variable. However, trajectory analyses of major depressive disorder have so far not included some of the more robust predictors of mood disorder outcome, nor have they described interactions between these predictors.MethodsA group of 186 individuals aged 15–20 years with past or current depressive symptoms, who had recently begun taking a serotonin reuptake inhibitors antidepressant, underwent extensive baseline evaluations and were then followed for up to 2 years. Trajectory analyses used weekly ratings of depressive symptoms and the resulting groups were compared by the risk factors of sex, psychiatric comorbidity, negative emotionality, and childhood adversity.ResultsA three-group solution provided the best statistical fit to the 2-year symptom trajectory. Negative emotionality and childhood adversity, though correlated, independently predicted membership in higher-morbidity groups. Female sex and comorbidity with generalized anxiety disorder (GAD) were also significantly more likely in the trajectory groups with higher symptom levels. However, the presence of GAD, rather than female sex, was the most important determinant of group membership. Negative emotionality was predictive of group membership only among women.ConclusionsTrajectory analyses indicated that week-to-week variations in depressive symptoms across individuals could best be condensed into low, remitting and persistent symptom patterns. Female sex, anxiety symptoms, negative emotionality and childhood adversity were each independently associated with trajectories of higher morbidity but negative emotionality may be prognostically important only among women.

Significance COVID-19 is taking a major toll on personal health, healthcare systems, and the global economy. With three betacoronavirus epidemics in less than 20 y, there is an urgent need for therapies to combat new and existing coronavirus outbreaks. Our analysis of clinical data from over 300,000 patients in three major health systems demonstrates a 50% reduced risk of COVID-19 in patients taking lithium, a direct inhibitor of glycogen synthase kinase-3 (GSK-3). We further show that GSK-3 is essential for phosphorylation of the SARS-CoV-2 nucleocapsid protein and that GSK-3 inhibition blocks SARS-CoV-2 infection in human lung epithelial cells. These findings suggest an antiviral strategy for COVID-19 and new coronaviruses that may arise in the future., The coronaviruses responsible for severe acute respiratory syndrome (SARS-CoV), COVID-19 (SARS-CoV-2), Middle East respiratory syndrome-CoV, and other coronavirus infections express a nucleocapsid protein (N) that is essential for viral replication, transcription, and virion assembly. Phosphorylation of N from SARS-CoV by glycogen synthase kinase 3 (GSK-3) is required for its function and inhibition of GSK-3 with lithium impairs N phosphorylation, viral transcription, and replication. Here we report that the SARS-CoV-2 N protein contains GSK-3 consensus sequences and that this motif is conserved in diverse coronaviruses, raising the possibility that SARS-CoV-2 may be sensitive to GSK-3 inhibitors, including lithium. We conducted a retrospective analysis of lithium use in patients from three major health systems who were PCR-tested for SARS-CoV-2. We found that patients taking lithium have a significantly reduced risk of COVID-19 (odds ratio = 0.51 [0.35–0.74], P = 0.005). We also show that the SARS-CoV-2 N protein is phosphorylated by GSK-3. Knockout of GSK3A and GSK3B demonstrates that GSK-3 is essential for N phosphorylation. Alternative GSK-3 inhibitors block N phosphorylation and impair replication in SARS-CoV-2 infected lung epithelial cells in a cell-type–dependent manner. Targeting GSK-3 may therefore provide an approach to treat COVID-19 and future coronavirus outbreaks.

The efficacy of subanesthetic intravenous ketamine for treatment resistant depression (TRD) has spurred a growth of clinics nationwide that provide this service. Ketamine is an FDA-approved drug as an anesthetic but remains unapproved for psychiatric indications, and this status raises a number of short- and long-term safety and efficacy concerns that need to be addressed when implementing and developing this type of clinic. Using a framework of systems, provider, and patient domains, we provide a review of the key challenges in providing ketamine infusions and suggest potential approaches. Under systems issues, we highlight broad stakeholder engagement involving cross-departmental and multidisciplinary considerations, business case development, and delineation of administrative standard operating procedures. In the provider domain, we highlight specific roles for different treatment team members as well as suggested training requirements. In the patient domain, we identify a variety of standard operating procedures involving initial patient assessment parameters, ketamine dosing and administration guidelines, and safety monitoring procedures. Together, this review provides key considerations for developing a ketamine clinic for depression, in an effort to meet the pressing demand for this novel treatment option while helping to ensure its safe implementation.

Heavy alcohol use has been clearly linked to risk for suicidal behaviors and is also prevalent on many American college campuses. This report uses a large sample of college students to explore relationships between alcohol use, depressive symptoms, and suicidality.

BackgroundStudying the phenotypic and genetic characteristics of age and polarity at onset (AAO, PAO) in bipolar disorder (BD) can provide new insights into disease pathology and facilitate the development of screening tools.AimsTo examine the genetic architecture of AAO and PAO and their association with BD disease characteristics.MethodsGenome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (N=12977) and PAO (N=6773) were conducted in BD patients of 34 cohorts and a replication sample (N=2237). The association of onset with disease characteristics was investigated in two of these cohorts.ResultsEarlier AAO was associated with an increased risk of psychotic symptoms, suicidality, and fewer episodes. A depressive onset correlated with lifetime suicidality and a manic onset with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in SNV-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased polygenic scores for autism spectrum disorder (β=-0.34 years, SE=0.08), major depression (β=-0.34 years, SE=0.08), schizophrenia (β=-0.39 years, SE=0.08), and educational attainment (β=-0.31 years, SE=0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.ConclusionsAAO and PAO are associated with indicators of BD severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents, and phenotype definitions introduce significant heterogeneity, affecting analyses.RELEVANCE STATEMENTIn the largest study to systematically characterize age at onset (N=12977) and polarity at onset (N=6773) in bipolar disorder, we describe an association between illness onset characteristics and indicators of severity, confirming their clinical relevance. Our study shows that that early illness onset is associated with genetic liability for a broad range of psychiatric disorders. However, we also highlight systematic differences in age at onset across cohorts, continents, and phenotype definitions. This heterogeneity results in reduced heritability and affects genetic analyses, underscoring the need for the development of standardized phenotype definitions.

Background Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. Methods The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. Results A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. Conclusions In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy. publishedVersion

Objective We have previously shown that the severity of anxiety symptoms during major depressive episodes is associated in a linear fashion with the proportion of weeks in depressive episodes during a subsequent 25 years of follow-up. Here, we test whether the negative prognostic implications of anxiety comorbidity extend to higher likelihoods of suicidal behavior. Methods We used the NIMH Collaborative Depression Study (CDS) cohort to test both the severity of eight anxiety symptoms and the presence or absence of four anxiety disorders as risk factors for suicide attempts or completions over a mean (SD) follow-up of 16.6 (8.5) years. Separate analyses tested potential predictors of events that occurred within 2 years and those that occurred later. Results None of the baseline anxiety manifestations were significantly associated with overall risks for past or future suicide attempts. Only the diagnosis of phobic disorder was overrepresented in the 36 who committed suicide. Psychic anxiety was a risk factor for suicide attempts beyond 2 years of follow-up, and phobic anxiety was protective of suicides within this period. Conclusions These results did not show anxiety comorbidity to be an important risk factor for suicide attempts or completions.

Bipolar disorder is typified by episodes of manic/hypomanic and depressive symptoms, either distinctly or concurrently as mixed symptoms. While depressive symptoms are the major driver of risk, it is unclear whether specific combinations of manic and anxiety symptoms contribute differentially to suicidal ideation and behavior in individuals with bipolar disorder during a depressive state. This study uses a quantitative application of Rothman's theoretical framework of causation, or ‘causal pies’ model. Data were obtained from the National Network of Depression Centers Mood Outcomes Program for 1028 visits from 626 individuals with bipolar disorder with current moderate-to-severe depressive symptoms, operationalized as a Patient Health Questionnaire-8 (PHQ-8) score ≥10. Mania symptoms were captured using the Altman Self-Rating Mania scale (ASRM) and anxiety symptoms were captured using the Generalized Anxiety Disorder-7 scale (GAD-7). The outcome of suicidal ideation or behavior was captured using the Columbia Suicide Severity Rating Scale (C-SSRS). In this cohort of individuals with bipolar disorder and at least moderate depressive symptoms, we found no increased risk of suicidal ideation or behavior attributable to manic and anxiety symptom clusters in individuals with bipolar disorder during depressive state. A small amount (4%) of risk was attributable to having severe depressive symptoms. These findings, however, may be influenced by limitations in sample size and measurement instruments. Future studies would benefit from larger samples and more rigorous assessments, including clinician-rated measures.

Bipolar disorder (BD) is a neuropsychiatric disorder with genetic risk factors defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. While lithium is an effective drug for BD, 30-40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of clock genes and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, rhythm abnormalities in BD have not been evaluated in neurons and it is unknown if neuronal rhythms differ between Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients and controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R. NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low-amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein expression was higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.

BackgroundMood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders.MethodsTo clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424).ResultsSeventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder.ConclusionsThe mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum.

Background College student mental health (MH) problems and suicide risk have steadily increased over the past decade and a significant number of students with MH problems do not seek treatment. While some barriers to mental health care service utilization (MHSU) have been identified, very little is known regarding how these barriers differ among sociodemographic subgroups of students. Method Participants were 3,358 college students from four US universities who screened positive for elevated suicide risk (defined as 2 or more of: depression, alcohol misuse, suicidal ideation, suicide attempt) and were not actively receiving MH services. Reported barriers to MHSU were categorized into: Low perceived need, privacy/stigma concerns, questioning helpfulness of treatment, logistics, time constraints, finances, and cultural issues. Results Adjusted odds ratios indicated that finances were a greater barrier for women, sexual and gender minority students, and Black and Hispanic students. Privacy/stigma concerns were more prominent for men and young undergraduate students. White students and older undergraduate and graduate students were more likely to report a lack of time, and cultural sensitivity issues were significant barriers for sexual and gender minority, and racial/ethnic minority, students. Limitations Participating sites were not nationally representative. The barriers assessment did not examine the degree to which a specific barrier contributed to lack of MHSU relative to others. Conclusions In light of the significant variation in barriers based on age, gender identity, race/ethnicity, and sexual orientation, efforts to increase MHSU should be tailored to meet the unique needs of specific sociodemographic student subgroups.

Lithium remains the gold standard for the treatment of bipolar disorder (BD); however, its use has declined over the years mainly due to the side effects and the subjective experience of cognitive numbness reported by patients. In the present study, we aim to methodically test the effects of lithium on neurocognitive functioning in the largest single cohort (n = 262) of BD patients reported to date by harnessing the power of a multi-site, ongoing clinical trial of lithium monotherapy. At the cross-sectional level, multivariate analysis of covariance (MANCOVA) was conducted to examine potential group differences across neurocognitive tests [California Verbal Learning Test (CVLT trials 1–5,CVLT delayed recall), Wechsler Digit Symbol, Trail-making Test parts A and B (TMT-A; TMT-B), and a global cognition index]. At the longitudinal level, on a subset of patients (n = 88) who achieved mood stabilization with lithium monotherapy, we explored the effect of lithium treatment across time on neurocognitive functioning. There were no differences at baseline between BD patients that were taking lithium compared with those that were not. At follow-up a significant neurocognitive improvement in the global cognitive index score [F = 31.69; p

To examine differences between Black students who do and do not screen positive for suicide risk; to describe barriers to mental health service utilization (MHSU) among participants with a positive screen and no current MHSU and; to determine if barriers vary by student characteristics.

Childhood experiences, personality, and polyunsaturated essential fatty acid (PUFA) composition have all been shown to affect the likelihood of depressive symptoms. Few studies have addressed relationships between these factors in their influence on the occurrence or course of depressive symptoms. The following analysis was designed to do so. Subjects, 15-20 years old, had either begun antidepressant treatment within the preceding month (n = 88), or had never taken psychiatric medications (n = 92). Baseline assessments included a structured diagnostic interview, the self-completed Multiphasic Personality Questionnaire, and a determination of plasma PUFA phospholipid composition. Depressive symptom levels were assessed at baseline and again at 4, 8 and 12 months. Omega-3 composition and general childhood trauma scores were unrelated to each other but both correlated, in predicted directions, with negative emotionality. Low omega-3 composition and history of childhood trauma were associated with persistence of depressive symptoms during follow-up, largely through their effects on negative emotionality. Negative emotionality appears to comprise a final common pathway to depressive disorder through which the diverse risk factors of childhood adversity and low omega-3 composition are expressed.

The purpose of this study was to prospectively examine the independent contribution of major depressive disorder (MDD), generalized anxiety disorder (GAD), and selective serotonin reuptake inhibitors (SSRIs) use to changes in bone metabolism in older adolescents and emerging adults. Medically healthy 15- to 20-year-olds who were unmedicated or within 1 month of starting an SSRI were prospectively followed. Psychiatric functioning and medication treatment were assessed monthly. Every 4 months, trabecular and cortical volumetric bone mineral density (vBMD) at the radius and markers of bone metabolism were evaluated. Every 8 months, total body less head areal bone mineral content and lumbar spine (LS) areal BMD (aBMD) were determined. Linear mixed-effects regression analysis examined associations between bone measures on the one hand and MDD, GAD, and SSRI indices on the other. A total of 264 participants were followed for 1.51 ± 0.76 years. After adjusting for age, sex, vitamin D concentration, physical activity, lean mass or grip strength, and time in the study, MDD severity was associated with increasing LS aBMD. Similarly, SSRI use was associated with increasing LS aBMD and bone formation in female participants. In contrast, SSRI use was associated with decreasing LS aBMD in males. After accounting for depression, GAD was independently, albeit weakly, associated with increased bone mineralization. In older adolescents and emerging adults, MDD and GAD are associated with increasing bone mass, particularly in the lumbar spine and in females, whereas SSRIs are associated with increasing bone mass in females but decreasing bone mass in males. © 2017 American Society for Bone and Mineral Research.

OBJECTIVE Sexual and gender minorities are at elevated risk for suicide, yet few studies have examined differences in risk within many sexual and gender minority subgroups. The purpose of this study was to examine differences in prevalence for suicide risk factors among a wide range of sexual orientations and gender identities. METHOD Forty-one thousand four hundred and twelve college students (62% cis-female, 37% cis-male, 1% transgender/genderqueer) completed a wellness screen that included four suicide risk factors (depression, heavy alcohol use, suicide ideation, suicide attempt). RESULTS Gender minority students (i.e., transgender, genderqueer/non-binary) had significantly higher rates of depression, suicide ideation, and suicide attempts relative to cisgender peers, although there were no within-group differences among gender minority students. Adjusted odds ratios for endorsing two or more (2+) suicide risk factors were substantially higher for all sexual minority subgroups relative to heterosexuals. Among sexual minorities, those identifying as pansexual, bisexual, queer, or mostly gay/lesbian had greater odds of endorsing 2+ suicide risk factors relative to students identifying as mostly heterosexual, gay/lesbian, asexual, or 'other sexual minority'. Pansexual students had 33% greater odds of endorsing 2+ suicide risk factors relative to bisexual students. CONCLUSIONS These findings highlight significant variation in suicide risk among sexual minority subgroups and the need for targeted interventions for subgroups at highest risk.

This section provides summaries of the epidemiology, phenomenology, nosology, and the suspected biological substrates of the depressive disorders. It particularly emphasizes the historical evolution of the pertinent diagnostic constructs and the prognostic import both of the various diagnostic groupings and of the individual symptoms and symptom clusters.

Bipolar disorder (BD) is characterized by recurrent mood episodes, and circadian rhythm disturbances. Past studies have identified calcium channel genes as risk loci for BD. CACNA1C encodes an L-type calcium channel (LTCC) involved in the entrainment of circadian rhythms to light. Another calcium channel, i.e., the ryanodine receptor (RYR), is involved in ­circadian phase delays. It is unknown whether variants in CACNA1C or other calcium channels contribute to the circadian phenotype in BD. We hypothesized that, by using temperature cycles, we could model circadian entrainment in fibroblasts from BD patients and controls to interrogate the circadian functions of LTCCs. Using Per2-luc, a bioluminescent reporter, we verified that cells entrain to temperature rhythms in vitro. Under constant temperature conditions, the LTCC antagonist verapamil shortened the circadian period, and the RYR antagonist dantrolene lengthened the period. However, neither drug affected temperature entrainment. Fibroblasts from BD patients and controls also entrained to temperature. In cells from BD patients, the rhythm amplitude was lower under entrained, but not constant, conditions. Temperature entrainment was otherwise similar between BD and control cells. However, the CACNA1C genotype among BD cells predicted the degree to which cells entrained. We conclude that assessment of rhythms under entrained conditions reveals additional rhythm abnormalities in BD that are not observable under constant temperature conditions.

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patients, we measured circadian rhythms in fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-R patients were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD. © 2018. This is the authors’ accepted and refereed manuscript to the article. Locked until 16.5.2019 due to copyright restrictions.

Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders., Simone de Jong et al. examine the balance of common and rare risk for psychiatric disorders in a large family with high incidence of Bipolar Disorder and Major Depressive Disorder. They find that increased polygenic risk over generations could be partially due to assortative mating, which may explain the observation of anticipation in mood disorders.

Latent infection with toxoplasmosis is a prevalent condition that has been linked in animal studies to high-risk behaviors, and in humans, to suicide and suicide attempts. This analysis investigated a relationship between suicide attempt history and toxoplasmosis titers in a group of older adolescents who had recently begun treatment with an SSRI. Of 108 participants, 17 (15.7 %) had a lifetime history of at least one suicide attempt. All were given structured and unstructured diagnostic interviews and provided blood samples. Two individuals (11.9%) with a past suicide attempt, and two (2.1%) without this history, had toxoplasmosis titers ≥ 10 IU/ml (p = 0.166). Those with a past suicide attempt had mean toxoplasmosis titers that were significantly different (p = 0.018) from those of patients who lacked this history. An ROC analysis suggested a lower optimal threshold for distinguishing patients with and without suicide attempts (3.6 IU/ml) than that customarily used to identify seropositivity. Toxoplasmosis titers may quantify a proneness to suicidal behavior in younger individuals being treated with antidepressants.

Background Bipolar disorder is a heterogeneous mood disorder associated with several important clinical comorbidities, such as eating disorders. This clinical heterogeneity complicates the identification of genetic variants contributing to bipolar susceptibility. Here we investigate comorbidity of eating disorders as a subphenotype of bipolar disorder to identify genetic variation that is common and unique to both disorders. Methods We performed a genome-wide association analysis contrasting 184 bipolar subjects with eating disorder comorbidity against both 1370 controls and 2006 subjects with bipolar disorder only from the Bipolar Genome Study (BiGS). Results The most significant genome-wide finding was observed bipolar with comorbid eating disorder vs. controls within SOX2-OT (p=8.9×10−8 for rs4854912) with a secondary peak in the adjacent FXR1 gene (p=1.2×10−6 for rs1805576) on chromosome 3q26.33. This region was also the most prominent finding in the case-only analysis (p=3.5×10−7 and 4.3×10−6, respectively). Several regions of interest containing genes involved in neurodevelopment and neuroprotection processes were also identified. Limitations While our primary finding did not quite reach genome-wide significance, likely due to the relatively limited sample size, these results can be viewed as a replication of a recent study of eating disorders in a large cohort. Conclusions These findings replicate the prior association of SOX2-OT with eating disorders and broadly support the involvement of neurodevelopmental/neuroprotective mechanisms in the pathophysiology of both disorders. They further suggest that different clinical manifestations of bipolar disorder may reflect differential genetic contributions and argue for the utility of clinical subphenotypes in identifying additional molecular pathways leading to illness.

Background These analyses were undertaken to determine whether similar risk factors for suicide emerged across two prospectively studied cohorts of individuals with bipolar I disorder. Methods The NIMH Collaborative Study of Depression (CDS) recruited 288 patients with bipolar I disorder from 1978–1981 as they sought treatment. Subjects were followed semiannually and then annually for up to 30 years. The Bipolar Genomics studies identified individuals through clinical referrals and advertisement. Clinical follow-up did not occur but personal identifiers of 1748 were matched with National Death Index (NDI) records. Kaplan–Meier survival analyses tested ten potential risk factors. Results The CDS and Genomic follow-ups encompassed 12,667 and 4529 person-years, respectively. Suicides/100 person-years were 0.26 and 0.055. The demographic or clinical variables that predicted suicide differed considerably in the two cohorts. The odds ratio for suicide for those with any history of suicide attempt was 2.3 and 2.8, respectively, and was the third highest odds ratio of the tested risk factors in both studies. Limitations 1. In one of the two cohorts, matching to the NDI was the only means available to ascertain death and cause of death. 2. In one of the two cohorts, depressive symptom ratings were, in most cases, applied to those of a past major depressive episode. Conclusions Differences in the sources of participants in studies of suicide risk may result in marked differences across studies in both rates of suicide and in risk factors. A history of suicide attempt is a relatively robust risk factor across samples.

OBJECTIVE To provide the first head-to-head test of the predictive validity of 2 resolution levels included in the current consensus definition of major depressive episode (MDE) recovery and provide an empirically based, clinically useful definition of the end of an MDE. METHOD 322 participants entering the National Institute of Mental Health Collaborative Depression Study with MDE (diagnosed by Research Diagnostic Criteria) in 1978-1981, and followed thereafter for up to 31 years, were divided into those with 8 consecutive weeks of asymptomatic MDE recovery or residual subsyndromal depressive symptom (SSD) resolution of their index MDE. These 2 levels of recovery were defined based on weekly symptom status on all depressive conditions, assessed by Longitudinal Interval Follow-Up Evaluation (LIFE) interviews conducted every 6 months. Primary measures of validity of these 2 alternative definitions were first well interval duration and long-term depressive illness burden. Groups were also compared on clinical variables, antidepressant treatment, and psychosocial function. RESULTS 61.2% of subjects recovered asymptomatically from their index MDE. By survival analysis, they remained free of a depressive episode relapse or recurrence 4.2 times longer than those with SSD resolution (median = 135 vs 32 weeks; χ² = 70.65; P < .0001). This was not attributable to a difference in intensity of antidepressant medication. Compared to asymptomatic recovery, SSD resolution was associated with significantly longer and more severe index MDEs, with more miscellaneous psychopathology as well as increased long-term psychosocial dysfunction and a greater depressive illness burden during the ensuing 10 or 20 years. Asymptomatic MDE resolution was a stronger predictor of time well than any of 18 other predictors, singly or combined. Eight consecutive weeks of asymptomatic recovery had 93% overlap with a 4-week definition and conferred little benefit over 4 weeks. CONCLUSIONS Four consecutive weeks of asymptomatic recovery defines the end of an MDE and the beginning of a stable well state with improved psychosocial function. Residual symptom resolution is a continuation of an active state of the episode, not the end of an MDE.

OBJECTIVE Substantial evidence exists to indicate bidirectional relationships between obesity and depressive disorders and the importance of fat distribution to this relationship. This analysis used a well-characterized sample of individuals in late adolescence to determine the association between depressive illness and fat distribution. METHOD Medically healthy 15- to 20-year-olds, one-half of whom had recently begun treatment with a selective serotonin reuptake inhibitor, underwent a comprehensive psychiatric evaluation that resulted in diagnostic classification and weekly psychiatric disorder ratings over the prior 4 months using the Longitudinal Interval Follow-Up Evaluation. A whole-body scan, using dual-energy x-ray absorptiometry, allowed estimations of total body less head (TBLH), total mass, fat mass, and visceral adipose tissue (VAT) mass. Assessments occurred between September 2010 and April 2014. Multivariable linear regression analyses, adjusted for relevant covariates, examined the association between DSM-IV-TR-diagnosed major depressive disorder (MDD) and VAT, the primary outcome of interest. These procedures also determined whether significant associations were confined to overweight/obese participants. RESULTS The analysis included data from 200 participants (71% female; mean age = 19.0 ± 1.6 years), of whom 128 had current MDD. The presence of MDD was associated with increased fat mass among overweight/obese participants (Cohen d = 0.79, P < .02), but not normal weight participants. This was true of both visceral and nonvisceral fat mass measures. Accounting for the presence of generalized anxiety disorder (GAD) did not alter the findings. CONCLUSION In adolescents, relationships between central adiposity and MDD may be confined to those who are overweight/obese. Despite the high comorbidity of GAD and depressive disorders, only the latter appeared to be significantly associated with central adiposity.

Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 - 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 - rs2086256 - rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data. peerReviewed

BACKGROUND: There is considerable evidence that many complex traits have a partially shared genetic basis, termed pleiotropy. It is therefore useful to consider integrating genome-wide association study (GWAS) data across several traits, usually at the summary statistic level. A major practical challenge arises when these GWAS have overlapping subjects. This is particularly an issue when estimating pleiotropy using methods that condition the significance of one trait on the signficance of a second, such as the covariate-modulated false discovery rate (cmfdr). RESULTS: We propose a method for correcting for sample overlap at the summary statistic level. We quantify the expected amount of spurious correlation between the summary statistics from two GWAS due to sample overlap, and use this estimated correlation in a simple linear correction that adjusts the joint distribution of test statistics from the two GWAS. The correction is appropriate for GWAS with case-control or quantitative outcomes. Our simulations and data example show that without correcting for sample overlap, the cmfdr is not properly controlled, leading to an excessive number of false discoveries and an excessive false discovery proportion. Our correction for sample overlap is effective in that it restores proper control of the false discovery rate, at very little loss in power. CONCLUSIONS: With our proposed correction, it is possible to integrate GWAS summary statistics with overlapping samples in a statistical framework that is dependent on the joint distribution of the two GWAS. Verena Zuber is supported by the Wellcome Trust and the Royal Society (Grant Number 204623/Z/16/Z) and the UK Medical Research Council (Grant Number MC_UU_00002/7).

The authors conducted a systematic review and meta-analysis to determine whether the risk of psychosis is higher in past or future episodes in patients with major depression with psychotic features than in patients with nonpsychotic depression.PubMed, Embase, and PsycINFO were searched, and studies were selected that 1) identified patients with unipolar major depression, 2) made diagnoses of psychosis based on the presence of delusions or hallucinations, 3) characterized past or subsequent episodes as psychotic or nonpsychotic, and 4) were published in English. Two meta-analyses were then conducted using data from patients having index depressive episodes with or without psychosis at study entry to determine the risk of any prior or subsequent psychotic episode and the risk of psychosis in all episodes.Twelve studies met the inclusion criteria, and altogether they included 546 psychotic and 1,583 nonpsychotic patients with unipolar depression. In seven of the studies, the risk ratio for a prior or subsequent psychotic episode in patients whose index depressive episode was psychotic compared with those whose index episode was nonpsychotic was 9.98 (95% CI=4.75, 20.94). In eight studies, the risk ratio for psychosis among all episodes of depression in the subgroups with psychotic and nonpsychotic index episodes was 7.24 (95% CI=5.03, 10.43). Differences in risk of psychosis between these subgroups remained robust when potential sources of heterogeneity were explored.The findings support the hypothesis that psychotic depression runs true to form, and they support the distinction between psychotic and nonpsychotic depression. Because patients with psychotic depression are at high risk for psychosis in future episodes, determination of effective preventive treatments is imperative.

Background Increased inflammatory markers have been linked to suicidal behavior in numerous studies. Measures of aggression and of impulsivity also comprise risks factors for suicidal behavior and there is evidence that inflammatory markers correlate with these traits. The following analyses compare suicide attempters and non-attempters to determine whether inflammatory markers mediate relationships between aggression or impulsivity and proclivities to suicidal behavior. Methods Investigators at three academic centers recruited patients in major depressive episodes who had a history of two or more suicide attempts (n = 79), or who had no history of suicide attempts (n = 123). Analyses compared these groups by five inflammatory marker levels and by measures of aggression and of impulsivity. Results These results did not confirm the hypotheses that cytokine levels would explain relationships between aggressive behavior and suicide attempt history. However, scores for aggressive behavior and for impulsivity were significantly higher among suicide attempters. One of five of the inflammatory markers, (IL-1β), distinguished the two groups with lower values in the suicide attempt group. IL-1β levels correlated inversely with measures of aggression but neither impulsivity or aggressive behavior appear to explain the association between IL-1β levels and suicide attempt status. Conclusion These results identify recent aggressive behavior, higher levels of impulsivity, and lower levels of IL-1β as risk factors for a history of multiple suicide attempts in a group suffering from major depressive episodes. These measures appear to be additive in their effects.

This section provides summaries of the epidemiology, phenomenology, nosology, and the suspected biological substrates of the depressive disorders. It particularly emphasizes the historical evolution of the pertinent diagnostic constructs and the prognostic import both of the various diagnostic groupings and of the individual symptoms and symptom clusters.

Bipolar disorder is a complex neuropsychiatric disorder presenting with episodic mood disturbances. In this study we use a transcriptomic imputation approach to identify novel genes and pathways associated with bipolar disorder, as well as three diagnostically and genetically distinct subtypes. Transcriptomic imputation approaches leverage well-curated and publicly available eQTL reference panels to create gene-expression prediction models, which may then be applied to “impute” genetically regulated gene expression (GREX) in large GWAS datasets. By testing for association between phenotype and GREX, rather than genotype, we hope to identify more biologically interpretable associations, and thus elucidate more of the genetic architecture of bipolar disorder.We applied GREX prediction models for 13 brain regions (derived from CommonMind Consortium and GTEx eQTL reference panels) to 21,488 bipolar cases and 54,303 matched controls, constituting the largest transcriptomic imputation study of bipolar disorder (BPD) to date. Additionally, we analyzed three specific BPD subtypes, including 14,938 individuals with subtype 1 (BD-I), 3,543 individuals with subtype 2 (BD-II), and 1,500 individuals with schizoaffective subtype (SAB).We identified 125 gene-tissue associations with BPD, of which 53 represent independent associations after FINEMAP analysis. 29/53 associations were novel; i.e., did not lie within 1Mb of a locus identified in the recent PGC-BD GWAS. We identified 37 independent BD-I gene-tissue associations (10 novel), 2 BD-II associations, and 2 SAB associations. Our BPD, BD-I and BD-II associations were significantly more likely to be differentially expressed in post-mortem brain tissue of BPD, BD-I and BD-II cases than we might expect by chance. Together with our pathway analysis, our results support long-standing hypotheses about bipolar disorder risk, including a role for oxidative stress and mitochondrial dysfunction, the post-synaptic density, and an enrichment of circadian rhythm and clock genes within our results.

OBJECTIVES: To determine whether the risk of suicidal ideation or behavior during mixed states exceeds that attributable to the depressive components of these states alone in bipolar disorder. METHODS: We utilized real-world, longitudinal clinical data collected on 290 patients with bipolar disorders (bipolar I, bipolar II, and bipolar not otherwise specified (NOS)) from the National Network of Depression Centers (NNDC) Clinical Care Registry (CCR) seen for 891 visits over a mean of 27.5 weeks. Depressive symptoms were measured with the Patient Health Questionnaire-9 (PHQ-9), manic symptoms with the Altman Self-Rating Mania (ASRM), and suicidal ideation and behavior with the Columbia-Suicide Severity Rating Scale (C-SSRS), obtained as part of the routine, measurement-based care provided across the NNDC. The relations between depressive symptoms, manic symptoms, and the interaction thereof (mixed symptoms) on coinciding suicidal ideation and behavior were modeled in generalized linear mixed models. RESULTS: Depressive symptoms, as measured by the PHQ-9, were strongly associated with suicidal ideation and behavior (p

Background Pathological gambling (PG) is a prevalent and impairing public health problem. In this study we assessed age at onset in men and women with PG and compared the demographic and clinical picture of early- vs. later-onset individuals. We also compared age at onset in PG subjects and their first-degree relatives with PG. Method Subjects with DSM-IV PG were recruited during the conduct of two non-treatment clinical studies. Subjects were evaluated with structured interviews and validated questionnaires. Early-onset was defined as PG starting prior to age 33 years. Results Age at onset of PG in the 255 subjects ranged from 8 to 80 years with a mean (SD) of 34.0 (15.3) years. Men had an earlier onset than women. 84% of all subjects with PG had developed the disorder by age 50 years. Early-onset subjects were more likely to be male, to prefer action games, and to have substance use disorders, antisocial personality disorder, attention deficit/hyperactivity disorder, trait impulsiveness, and social anxiety disorder. Later-onset was more common in women and was associated with a preference for slots and a history of sexual abuse. Conclusions Age at onset of PG is bimodal and differs for men and women. Early-onset PG and later-onset PG have important demographic and clinical differences. The implications of the findings are discussed.

We examined the relationship between suicidal ideations and attempts in 95 probands with pathological gambling (PG), 91 controls, and 1075 first-degree relatives. The results were analyzed using logistic regression with generalized estimating equations. Thirty-four PG probands (35.8%) and 4 controls (4.4%) had attempted suicide (OR = 12.12, p

BackgroundThe first aim was to use confirmatory factor analysis (CFA) to test a hypothesis that two factors (internalizing and externalizing) account for lifetime co-morbid DSM-IV diagnoses among adults with bipolar I (BPI) disorder. The second aim was to use confirmatory latent class analysis (CLCA) to test the hypothesis that four clinical subtypes are detectible: pure BPI; BPI plus internalizing disorders only; BPI plus externalizing disorders only; and BPI plus internalizing and externalizing disorders.MethodA cohort of 699 multiplex BPI families was studied, ascertained and assessed (1998–2003) by the National Institute of Mental Health Genetics Initiative Bipolar Consortium: 1156 with BPI disorder (504 adult probands; 594 first-degree relatives; and 58 more distant relatives) and 563 first-degree relatives without BPI. Best-estimate consensus DSM-IV diagnoses were based on structured interviews, family history and medical records. MPLUS software was used for CFA and CLCA.ResultsThe two-factor CFA model fit the data very well, and could not be improved by adding or removing paths. The four-class CLCA model fit better than exploratory LCA models or post-hoc-modified CLCA models. The two factors and four classes were associated with distinctive clinical course and severity variables, adjusted for proband gender. Co-morbidity, especially more than one internalizing and/or externalizing disorder, was associated with a more severe and complicated course of illness. The four classes demonstrated significant familial aggregation, adjusted for gender and age of relatives.ConclusionsThe BPI two-factor and four-cluster hypotheses demonstrated substantial confirmatory support. These models may be useful for subtyping BPI disorders, predicting course of illness and refining the phenotype in genetic studies.

This study investigates the possible relationship between pathological gambling (PG) and potential spectrum disorders including the DSM-IV impulse control disorders (intermittent explosive disorder, kleptomania, pyromania, trichotillomania) and several non-DSM disorders (compulsive buying disorder, compulsive sexual behavior, Internet addiction). PG probands, controls, and their first-degree relatives were assessed with instruments of known reliability. Detailed family history information was collected on relatives who were deceased or unavailable. Best estimate diagnoses were assigned blind to family status. The results were analyzed using logistic regression by the method of generalized estimating equations. The sample included 95 probands with PG, 91 controls, and 1075 first-degree relatives (537 PG, 538 control). Compulsive buying disorder, having 1–2 spectrum disorder(s), and having “any spectrum disorder” were more frequent in the PG probands and their first-degree relatives vs. controls and their relatives. Spectrum disorders were significantly more prevalent among PG relatives compared to control relatives (adjusted OR = 8.37), though much of this difference was attributable to the contribution from compulsive buying disorder. We conclude that compulsive buying disorder is likely part of familial PG spectrum.