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Previous studies have suggested that alterations in white matter (WM) microstructure are implicated in suicidal thoughts and behaviours (STBs). However, findings of diffusion tensor imaging (DTI) studies have been inconsistent. In this large-scale mega-analysis conducted by the ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium, we examined WM alterations associated with STBs. Data processing was standardised across sites, and resulting WM microstructure measures (fractional anisotropy, axial diffusivity, mean diffusivity and radial diffusivity) for 25 WM tracts were pooled across 40 cohorts. We compared these measures among individuals with a psychiatric diagnosis and lifetime history of suicide attempt ( n =652; mean age=35.4±14.7; female=71.8%), individuals with a psychiatric diagnosis but no STB (i.e., clinical controls; n =1871; mean age=34±14.8; female=59.8%), and individuals with no mental disorder diagnosis and no STB (i.e., healthy controls; n =642; mean age=29.6±13.1; female=62.9%). We also compared these measures among individuals with recent suicidal ideation ( n =714; mean age=36.3±15.3; female=66.1%), clinical controls ( n =1184; mean age=36.8±15.6; female=63.1%), and healthy controls ( n =1240; mean age= 31.6±15.5; female=61.0%). We found subtle but statistically significant effects, such as lower fractional anisotropy associated with a history of suicide attempt, over and above the effect of psychiatric diagnoses. These effects were strongest in the corona radiata, thalamic radiation, fornix/stria terminalis, corpus callosum and superior longitudinal fasciculus. Effect sizes were small (Cohen's d < 0.25). Recent suicidal ideation was not associated with alterations in WM microstructure. This large-scale coordinated mega-analysis revealed subtle regional and global alterations in WM microstructure in individuals with a history of suicide attempt. Longitudinal studies are needed to confirm whether these alterations are a risk factor for suicidal behaviour., Competing Interests: Conflicts of interest ALvH receives consultancy fees from the Augeo foundation. CAZ is a full-time US government employee. He is listed as a co-inventor on a patent for the use of ketamine and its metabolites in major depression and suicidal ideation. Dr. Zarate has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. HPB has consulted to the Milken Institute. MW is a member of the following advisory boards and gave presentations to the following companies: Bayer AG, Germany; Boehringer Ingelheim, Germany; and Biologische Heilmittel Heel GmbH, Germany. MW has further conducted studies with institutional research support from HEEL and Janssen Pharmaceutical Research for a clinical trial (IIT) on ketamine in patients with MDD, unrelated to this investigation. MW did not receive any financial compensation from the companies mentioned above. IA received speakers honorarium from Lundbeck. IBH is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. He is the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell Pty Ltd which aims to transform mental health services through the use of innovative technologies. AC reports being currently an employee of the Regeneron Genetics Center, and may own Regeneron stock or stock options. JCS acknowledge to be related with the next companies ALKERMES (Advisory Board), BOEHRINGER Ingelheim (Consultant), COMPASS Pathways (Research Grant), JOHNSON & JOHNSON (Consultant), LIVANOVA (Consultant), RELMADA (Research Grant), SUNOVION (Research Grant),Mind Med (Research Grant). PMP received payment or honoraria for lectures and presentations in educational events for Sandoz, Daiichi Sankyo, Eurofarma, Abbot, Libbs, Instituto Israelita de Pesquisa e Ensino Albert Einstein, Instituto D’Or de Pesquisa e Ensino. All other authors report no biomedical financial interests, disclosures or potential conflicts of interest.

Bipolar disorder co-occurs with alcohol use disorder at a rate 3-5 times higher than the general population. We recently reported that individuals with bipolar disorder differ in the positive stimulating and anxiolytic effects of alcohol compared with healthy peers. This study used a randomized, placebo-controlled, cross-over, within-subject alcohol administration design to investigate neurobiological mechanisms within ventral prefrontal cortical (vPFC) systems that may underlie altered sensitivity to alcohol in bipolar disorder (NCT04063384). Forty-seven young adults (n = 23 with bipolar disorder, 64% women) completed clinical assessment and two beverage administration sessions (alcohol and placebo, counter-balanced). Participants were dosed to 0.08 g% breath alcohol concentration during the alcohol condition and completed measures of subjective response to alcohol and an emotional processing fMRI task during the ascending limb. Timing during the placebo condition mirrored the alcohol session. Acute alcohol was associated with reduced functional connectivity between the insula - subcallosal cingulate cortex, and increased connectivity between the left nucleus accumbens - ventromedial PFC in bipolar disorder, but with no change in functional connectivity between these regions in healthy peers. Alcohol-related increases in nucleus accumbens - ventromedial PFC functional connectivity was associated with greater positive stimulating effects of alcohol in bipolar disorder and heavier recent alcohol use. Results suggest vPFC brain systems respond differently to acute alcohol during emotional processing in young adults with bipolar disorder compared with healthy peers, and that vPFC system responses relate to the subjective experience of intoxication and recent alcohol use., (© 2023. American College of Neuropsychopharmacology.)

Early life stress, specifically childhood maltreatment, and parental risk for mood and substance use disorders (SUDs) are associated with increased risk for alcohol use disorder (AUD). There is limited data on how these factors interact to contribute to alcohol-related outcomes. Prior work has suggested early life stress may increase sensitivity to psychostimulants and that subjective response to alcohol is heritable. It is unclear if early life stress alters sensitivity to alcohol and interacts with parental risk for mood/SUDs, which in turn may act as a risk factor for AUD. The current study uses within-subjects placebo-controlled alcohol administration methods to investigate the effects of childhood maltreatment on subjective response to alcohol in young adults with and without parental risk of mood/SUDs. Additionally, we explored interactions with drinking context (i.e., drinking in a bar vs. non-bar context). Within individuals with parental risk for mood/SUDs, there was a positive relation between total Childhood Trauma Questionnaire (CTQ) score and how drunk individuals reported feeling across both alcohol and placebo conditions (parental risk group-by-CTQ interaction p = .01; main effect of CTQ within individuals with parental risk for mood/SUDs p = .005). When exploring interactions with drinking context (bar vs. non-bar context), we observed a significant drinking context-by-parental risk-by-CTQ interaction (p = .03), with CTQ score positively associated with greater positive valence/positive arousal feelings in the parental risk group if they consumed their beverages in the bar context (p = .004) but not if they consumed their beverages in the non-bar context. Results suggest childhood maltreatment may contribute to variation in subjective response to the positive effects of alcohol-possibly mediated by alcohol cues and/or expectancies-in young adults with parental risk for mood/SUDs., Competing Interests: Declaration of competing interest We do not believe this relationship could influence the reported results, but we report them for transparency. ETCL received funding for a Janssen-sponsored study through University of Texas at Austin. All other authors report no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

A large body of evidence has demonstrated that exposure to childhood maltreatment at any stage of development can have long-lasting consequences. It is associated with a marked increase in risk for psychiatric and medical disorders. This review summarizes the literature investigating the effects of childhood maltreatment on disease vulnerability for mood disorders, specifically summarizing cross-sectional and more recent longitudinal studies demonstrating that childhood maltreatment is more prevalent and is associated with increased risk for first mood episode, episode recurrence, greater comorbidities, and increased risk for suicidal ideation and attempts in individuals with mood disorders. It summarizes the persistent alterations associated with childhood maltreatment, including alterations in the hypothalamic-pituitary-adrenal axis and inflammatory cytokines, which may contribute to disease vulnerability and a more pernicious disease course. The authors discuss several candidate genes and environmental factors (for example, substance use) that may alter disease vulnerability and illness course and neurobiological associations that may mediate these relationships following childhood maltreatment. Studies provide insight into modifiable mechanisms and provide direction to improve both treatment and prevention strategies.

Limited data exists on mechanisms contributing to elevated risk for alcohol use disorder (AUD) in bipolar disorder. Variation in subjective response to alcohol may relate to alcohol use and risk for AUD. This study used a randomized, placebo-controlled, cross-over, within-subjects design to investigate differences in subjective response to alcohol in 50 euthymic young adults (n = 24 with and n = 26 without bipolar disorder type I). Eighty-three percent of participants with bipolar disorder were medicated. Participants completed assessments of clinical history, alcohol expectancies, and recent alcohol use. Participants were dosed to a .08 g% breath alcohol concentration. The placebo condition occurred on a separate counter-balanced day. Subjective response to alcohol was investigated at similar time points during both conditions. Group, condition, and group-by-condition interactions were modeled, with condition and time of subjective response assessment as repeated within-subject variables, and subjective response to alcohol as the dependent variable. Greater stimulating effects and liking of alcohol were reported in people with bipolar disorder (group-by-condition interactions, p < .05) than healthy young adults. While young adults with bipolar disorder reported anticipating feeling less "mellow/relaxed" when drinking (p = .02), during both beverage conditions they reported feeling more "mellow/relaxed" (main effect of group, p = .006). Feeling more "mellow/relaxed" during the alcohol condition related to greater recent alcohol use in bipolar disorder (p = .001). Exploratory analyses suggested anticonvulsants and sedatives/antihistamines may relate to differences in subjective response to alcohol in bipolar disorder. Results suggest young adults with bipolar disorder may differ in alcohol expectancies and experience alcohol intoxication differently-with distinct relations between subjective response to alcohol and alcohol use-compared to healthy young adults., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Using balanced placebo designs, seminal alcohol administration research has shown individuals' beliefs about whether they have consumed alcohol, irrespective of the actual presence of alcohol, can determine level of alcohol consumption and impact social behavior. Despite the known effect of expecting alcohol on drinking behavior, few studies have used the placebo manipulation to directly investigate the neural underpinnings of the expectancy-related effects that occur following perceived alcohol consumption in humans. The present paper examined placebo responses in the laboratory to better understand the neural basis for the psychological phenomenon of expectancies., Methods: As part of a larger within-subjects study design, healthy young adults (N = 22, age mean+SD =23 +1) completed resting state fMRI scans and measures of subjective response before and after consuming placebo beverages. Effect of placebo beverage consumption (pre- versus post-beverage consumption) on functional connectivity within prefrontal cortical networks was examined using the CONN Toolbox. Relations between perceived subjective response to alcohol with functional connectivity response following placebo beverage consumption were examined., Results: Compared to pre-beverage scan, placebo beverage consumption was associated with increased positive functional connectivity between right nucleus accumbens - ventromedial prefrontal cortex and subcallosal cingulate cortex (p FDR <0.05). Subjective ratings of intoxication (i.e., feeling 'drunk') positively correlated with placebo beverage-related increases in nucleus accumbens - subcallosal cingulate cortex functional connectivity., Conclusion: Results suggest placebo response to alcohol is associated with increased functional connectivity within a key reward network (nucleus accumbens - ventromedial prefrontal cortex and subcallosal cingulate cortex) and put forth a mechanism by which alcohol expectancies may contribute to the subjective experience of intoxication., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Multiple trans-synaptic complexes organize synapse development, yet their roles in the mature brain and cooperation remain unclear. We analyzed the postsynaptic adhesion protein LRRTM1 in the prefrontal cortex (PFC), a region relevant to cognition and disorders. LRRTM1 knockout (KO) mice had fewer synapses, and we asked whether other synapse organizers counteract further loss. This determined that the immunoglobulin family member SynCAM 1 controls synapse number in PFC and was upregulated upon LRRTM1 loss. Combined LRRTM1 and SynCAM 1 deletion substantially lowered dendritic spine number in PFC, but not hippocampus, more than the sum of single KO impairments. Their cooperation extended presynaptically, and puncta of Neurexins, LRRTM1 partners, were less abundant in double KO (DKO) PFC. Electrophysiology and fMRI demonstrated aberrant neuronal activity in DKO mice. Further, DKO mice were impaired in social interactions and cognitive tasks. Our results reveal concerted roles of LRRTM1 and SynCAM 1 across synaptic, network, and behavioral domains., (© 2023. The Author(s).)

Identifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth. We performed analyses in three separate stages, in samples ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a sample of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a sample of young people with mood disorders, in which STB were assessed using different instruments, MRI metrics were compared among healthy controls without STBs (HC; N = 519), clinical controls with a mood disorder but without STBs (CC; N = 246) and young people with current suicidal ideation (N = 223). In separate analyses, MRI metrics were compared among HCs (N = 253), CCs (N = 217), and suicide attempters (N = 64). Third, in a larger transdiagnostic sample with various assessment instruments (HC = 606; CC = 419; Ideation = 289; HC = 253; CC = 432; Attempt=91). In the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and a history of actual suicide attempts (N = 163) than those without a lifetime suicide attempt (N = 323; FDR-p = 0.035, Cohen's d = 0.34). No associations with suicidal ideation were found. When examining more heterogeneous samples, we did not observe significant associations. Lower frontal pole surface area may represent a vulnerability for a (non-interrupted and non-aborted) suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk., (© 2022. Crown.)

Bipolar disorder (BD) and exposure to childhood maltreatment (CM), which is present at high rates in BD, are both associated with hippocampus and prefrontal cortex structural alterations thought to contribute to clinical features. Gender-related differences are implicated in BD for CM exposure, brain structure and clinical features. However, relationships among these factors in BD are understudied. This study aimed to investigate associations among gender, CM, hippocampus and prefrontal gray matter structure and clinical features in BD. Childhood trauma questionnaire, structured clinical assessments and 3 Tesla structural magnetic resonance imaging were obtained for 236 adults (18-63 years, 32.0 ± 12.6): 119 with BD (58.8% women) and 117 healthy controls (HCs, 50.4% women). Women with BD reported higher CM severity than men with BD and HCs (B=-14.34, 95% confidence intervals (CI)[-22.71,-5.97], p<.001). CM and gender showed a significant interaction for left hippocampus (B=-7.41, 95% CI[-14.10,-0.71], p<.05); CM severity was negatively associated with left hippocampus only in women with BD. In women with BD, CM was associated with post-traumatic stress disorder comorbidity (B = 25.68, 95% CI[15.11,36.25], p<.001). In men with BD, CM severity was associated with lower left frontal pole (B=-0.71, 95% CI[-1.14,-0.28], p<.05) and right superior frontal (B=-17.78, 95% CI[-30.66,-4.90], p<.05) surface area; the latter related to earlier age of first mood symptoms (B = 33.97, 95% CI[7.61, 60.33], p<.05). Findings support gender-related effects of CM on frontotemporal structure and clinical features of BD. The findings bring novel perspectives for gendered pathophysiological models of effects of CM in BD., Competing Interests: Declaration of Competing Interest Dr. Lippard receives funding for a Janssen-sponsored study through University of Texas-Austin. Dr. Blumberg received an honorarium for a talk at Aetna. All other authors declare that they have no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Rates of alcohol use disorders in individuals with bipolar disorder are 3 to 5 times greater than in the general population and exceed rates of alcohol use disorders reported in other affective and anxiety disorders. Despite this high rate of comorbidity, our understanding of the psychosocial and neural mechanisms that underlie the initiation of alcohol misuse in young adults with bipolar disorder remains limited. Prior work suggests that individuals with bipolar disorder may misuse alcohol as a coping mechanism, yet the neural correlates of coping drinking motives and associated alcohol use have not been previously investigated in this population., Methods: Forty-eight young adults (22 bipolar disorder type I, 26 typically developing; 71% women; average age ± standard deviation = 22 ± 2 years) completed the Drinking Motives and Daily Drinking Questionnaires, and a Continuous Performance Functional magnetic resonance imaging (fMRI) Task with Emotional and Neutral Distracters. We calculated the relative difference in anterior cingulate cortex (ACC) functional coupling with the anterior insula and amygdala in response to emotional distracters compared with neutral stimuli and investigated the relations with coping drinking motives and alcohol use., Results: Across all participants, coping drinking motives were associated with greater quantity of recent alcohol use. In individuals with bipolar disorder, greater ACC-anterior insula functional coupling was associated with greater coping drinking motives, and greater quantity and frequency of recent alcohol use. The relative difference in ACC-anterior insula functional coupling was not associated with coping drinking motives or alcohol use in the typically developing group. Greater ACC-anterior insula functional coupling in individuals with bipolar disorder was also associated with greater anxiety symptoms and recent perceived psychological stress. Exploratory analyses suggest that the relations between ACC-anterior insula functional coupling and coping drinking motives may be confounded by anticonvulsant use., Conclusion: Results suggest that a difference in ACC-anterior insula functional coupling during emotion processing may underlie alcohol use as a maladaptive coping mechanism in young adults with bipolar disorder., (© 2022 Research Society on Alcoholism.)

A considerable number of studies have documented associations between peer victimization and concurrent and prospective increase in alcohol and substance use. Only a handful have investigated the psychological (e.g., internalizing behavior) and biological (e.g., neural systems) factors that contribute to this relation. Emerging studies provide clues as to mechanisms that may underlie increased risk for alcohol and substance use and associated problems in peer victimized youth, which may serve as potential targets for intervention. This review proposes a conceptual framework of increased alcohol/substance use in peer victimized youth as sequelae of alterations in the structure and/or function of neural regions broadly implicated in cognitive control and emotion processing/regulation. Studies are outlined linking peer victimization with alcohol/substance use, associations with internalizing symptoms, and differential structure and function in, and connectivity among, neural regions implicated in alcohol/substance use disorders. Further, the role(s) of neuroendocrine dysfunction, comorbid mental illness, and genetics are discussed as risk factors for substance use following peer victimization. This review concludes with the identification of gaps in the literature and suggestions for further investigation, such as the need for more studies examining the neural correlates of peer victimization, including cyberbullying, and greater consistency in how peer victimization and alcohol/substance use are operationalized and measured across studies. Prospective investigations of biological and psychosocial factors that contribute to alcohol and substance use and development of alcohol/substance use problems are needed to inform novel intervention and prevention strategies in typically developing youth and in populations with high rates of peer victimization, such as individuals with comorbid mental illness and those at high risk for psychiatric disorders., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Stress-related mechanisms are implicated in the pathophysiology of bipolar disorder and may contribute to heterogeneity in illness course. Yet, there is a lack of study investigating the neural mechanisms underlying the stress response in this condition. This study investigated changes in amygdala activation and functional connectivity in response to acute psychosocial stress in young adults with bipolar disorder and explored relations with clinical phenotype and prospective mood symptoms., Methods: 42 young adults [19 with bipolar disorder, age mean  ± SD =21.4 ± 2.2 years] completed a modified version of the Montreal Imaging Stress Task. Amygdala activation and functional connectivity with prefrontal cortex (PFC) regions of interest was calculated for control and stress conditions. Main effects of group, condition, and group by condition interaction on amygdala activation and connectivity were modeled. A subset of bipolar participants completed 1-year follow-up assessments. Relations between neural responses to stress with concurrent substance use and prospective mood symptoms were explored., Results: There were no between-group differences in amygdala activation or functional connectivity during the control condition. Increased right amygdala-right rostral PFC (rPFC) functional connectivity to stress was observed in bipolar disorder, compared to typically developing controls. In bipolar disorder, greater increase in right amygdala-right rPFC functional connectivity to stress was associated with less frequent cannabis use, and prospectively with shorter duration and lower severity of depression symptoms over follow-up., Conclusion: Results from this preliminary study suggest differences in frontolimbic functional connectivity responses to stress in young adults with bipolar disorder and associations with cannabis use and prospective mood symptoms., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Early life stress (ELS) is a well-established risk factor for many psychiatric and medical disorders, including substance use disorders (SUDs). The relationship between ELS and SUDs is complex and there are likely multiple pathways from ELS to adverse substance use outcomes. The association between ELS and substance use emerges in adolescence. Adolescence is a critical period in development during which substance exposure markedly increases risk for SUDs. Therefore, this review focuses on the literature supporting the hypothesis that ELS increases risk for the development of SUDs through its influence on adolescent substance use. We discuss studies substantiating the role of ELS in adolescent substance use and explore how internalizing and externalizing psychopathology may be antecedents of substance use in adolescence. We examine clinical work suggesting ELS sculpts the Hypothalamic-Pituitary-Adrenal (HPA) Axis and developing brain-particularly subcortical brain regions that underlie stress response, mesocorticolimbic brain systems associated with reward sensitivity, and prefrontal regions that underlie executive control-in a way that increases risk for adolescent substance use and SUDs. We further explore how substance use during adolescence alters structure and function of these same systems, and how brain changes following ELS and adolescent substance use may independently, additively, or interactively contribute to risk for addiction. We conclude by discussing how the current literature can inform interventions aimed at reducing risk for SUDs in individuals with a history of ELS., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Childhood maltreatment increases risk for mood disorders and is associated with earlier onset-and more pernicious disease course following onset-of mood disorders. While the majority of studies to date have been cross-sectional, longitudinal studies are emerging and support the devastating role(s) childhood maltreatment has on development of, and illness course in, mood disorders. This manuscript extends prior reviews to emphasize more recent work, highlighting longitudinal data, and discusses treatment studies that provide clues to mechanisms that mediate disease risk, course, relapse, and treatment response. Evidence suggesting systemic inflammation, alterations in hypothalamic-pituitary-adrenal (HPA) axis function and corticotropin-releasing factor (CRF) neural systems, genetic and other familial factors as mechanisms that mediate risk and onset of, and illness course in, mood disorders following childhood maltreatment is discussed. Risky behaviors following maltreatment, e.g., substance use and unhealthy lifestyles, may further exacerbate alterations in the HPA axis, CRF neural systems, and systematic inflammation to contribute to a more pernicious disease course. More research on sex differences and the impact of maltreatment in vulnerable populations is needed. Future research needs to be aimed at leveraging knowledge on modifiable targets, going beyond childhood maltreatment as a risk factor, to inform prevention and treatment strategies and foster trauma-informed care., (Copyright © 2022 Elsevier Inc. All rights reserved.)

(1) Background: Alcohol use in the course of mood disorders is associated with worse clinical outcomes. The mechanisms by which alcohol use alters the course of illness are unclear but may relate to prefrontal cortical (PFC) sensitivity to alcohol. We investigated associations between alcohol use and PFC structural trajectories in young adults with a mood disorder compared to typically developing peers. (2) Methods: 41 young adults (24 with a mood disorder, agemean = 21 ± 2 years) completed clinical evaluations, assessment of alcohol use, and two structural MRI scans approximately one year apart. Freesurfer was used to segment PFC regions of interest (ROIs) (anterior cingulate, orbitofrontal cortex, and frontal pole). Effects of group, alcohol use, time, and interactions among these variables on PFC ROIs at baseline and follow-up were modeled. Associations were examined between alcohol use and longitudinal changes in PFC ROIs with prospective mood. (3) Results: Greater alcohol use was prospectively associated with decreased frontal pole volume in participants with a mood disorder, but not typically developing comparison participants (time-by-group-by-alcohol interaction; p = 0.007); however, this interaction became a statistical trend in a sensitivity analysis excluding one outlier in terms of alcohol use. Greater alcohol use and a decrease in frontal pole volume related to longer duration of major depression during follow-up (p’s < 0.05). (4) Conclusion: Preliminary findings support more research on alcohol use, PFC trajectories, and depression recurrence in young adults with a mood disorder including individuals with heavier drinking patterns.

Background: Psychosocial stress negatively affects the clinical course of bipolar disorder. Studies primarily focused on adults with bipolar disorder suggest the impact of stress is progressive, i.e., stress response sensitizes with age. Neural mechanisms underlying stress sensitization are unknown. As stress-related mechanisms contribute to alcohol/substance use disorders, variation in stress response in youth with bipolar disorder may contribute to development of co-occurring alcohol/substance use disorders. This study investigated relations between psychosocial stress, amygdala reactivity, and alcohol and cannabis use in youth with bipolar disorder, compared to typically developing youth. Methods: Forty-two adolescents/young adults [19 with bipolar disorder, 23 typically developing, 71% female, age mean ± SD = 21 ± 2 years] completed the Perceived Stress Scale (PSS), Daily Drinking Questionnaire modified for heaviest drinking week, and a modified Montreal Imaging Stress functional MRI Task. Amygdala activation was measured for both the control and stress conditions. Main effects of group, condition, total PSS, and their interactions on amygdala activation were modeled. Relationships between amygdala response to acute stress with recent alcohol/cannabis use were investigated. Results: Greater perceived stress related to increased right amygdala activation in response to the stress, compared to control, condition in bipolar disorder, but not in typically developing youth (group × condition × PSS interaction, p = 0.02). Greater amygdala reactivity to acute stress correlated with greater quantity and frequency of alcohol use and frequency of cannabis use in bipolar disorder. Conclusion: Recent perceived stress is associated with changes in amygdala activation during acute stress with amygdala reactivity related to alcohol/cannabis use in youth with bipolar disorder., Competing Interests: SS and EL received funding for a Janssen-sponsored study through UT. SS serves as DSMB chair for Sunovion, and served recently on a DMC for Otsuka. He is also a contributor to Medscape. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Le, Kirsch, Tretyak, Weber, Strakowski and Lippard.)

Objectives: Altered activity in the ventrolateral prefrontal and anterior cingulate cortices, as well as subcortical and amygdala projection sites, was previously reported during a first manic episode in youth with bipolar disorder and observed to be associated with treatment response. To extend these findings, we investigated functional connectivity among these regions in first-episode manic participants who remitted after 8 weeks of treatment compared to those who did not., Methods: Forty-two participants with bipolar disorder (60% female) during their first manic episode were recruited and received 8 weeks of treatment. Twenty-one remitted following treatment. Participants completed fMRI scans, at baseline and following 8 weeks of treatment, while performing a continuous performance task with emotional and neutral distractors. A healthy comparison group (n = 41) received fMRI evaluations at the same intervals. Differences in functional connectivity of the amygdala and caudate with the rostral anterior cingulate and ventrolateral prefrontal cortices at baseline (and changes in functional connectivity following treatment) were modeled between groups., Results: At baseline, non-remitters showed an increase in positive connectivity between right anterior cingulate and caudate and a loss of negative connectivity between right anterior cingulate and amygdala, compared to healthy participants. Individuals who remitted following treatment showed an increase in negative connectivity between amygdala and left anterior cingulate 8 weeks following treatment., Conclusions: Results provide evidence of alterations in anterior cingulate amygdala and caudate functional connectivity in bipolar disorder non-remitters during a first manic episode and changes in anterior cingulate functional connectivity associated with remission suggesting targets to predict treatment response. Registered at ClinicalTrials.Gov; Functional and Neurochemical Brain Changes in First-episode Bipolar Mania. NCT00609193. URL: https://clinicaltrials.gov/ct2/show/NCT00609193?term=strakowskirank=1., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Alcohol use disorders (AUDs) are highly prevalent in bipolar disorder, however the developmental etiology of this comorbidity remains unknown. Structural differences in the orbitofrontal cortex (OFC) have been linked to problematic drinking in bipolar disorder and typically developing youth, with evidence implicating variations in OFC in differential subjective response to alcohol in typical development., Methods: Subjective response to alcohol, recent alcohol use, impulsivity, and variation in OFC gray matter volume were investigated in 48 emerging adults (24 with bipolar disorder, 24 typically developing). On average 1.5 years later, drinking patterns were reassessed and relations between subjective response and changes in alcohol use were explored., Results: Groups did not differ in baseline alcohol use or subjective response. At baseline, decreased subjective response to alcohol was associated with increased alcohol use in both groups. Lower gray matter volume in medial OFC in bipolar disorder was associated with increased subjective response to alcohol, whereas lower gray matter volume in OFC in typically developing participants was associated with decreased subjective response to alcohol. Increase in alcohol use (baseline to follow-up) was associated with increased baseline subjective response to alcohol in bipolar disorder, and decreased baseline subjective response in the typically developing group., Limitations: Preliminary study with a small sample size., Conclusion: Underlying OFC biology may contribute to differences in alcohol sensitivity in bipolar disorder which may also relate to prospective changes in alcohol use patterns. Future studies are needed to examine how these factors prospectively relate to development of AUDs in bipolar disorder., (Copyright © 2020. Published by Elsevier B.V.)

Childhood maltreatment is associated with adverse effects on the brain, and an increased risk for psychopathology, including mood and substance use disorders. Individuals vary on the degree to which they exhibit neurobiological and clinical differences following maltreatment. Individuals with bipolar disorder exhibit greater magnitude of maltreatment-related prefrontal-paralimbic gray matter volume (GMV) deficits compared to typically developing individuals. It is unclear if greater structural differences stem from greater neural vulnerability to maltreatment in bipolar disorder, or if they relate to presence of other clinical features associated with childhood maltreatment, e.g., elevated prevalence of comorbid substance use disorders. To investigate this, we compared young adults with a family history of bipolar disorder (n = 21), but who did not fulfill diagnostic criteria for bipolar disorder, with typically developing young adults without a family history of bipolar disorder (n = 26). Participants completed structural neuroimaging, clinical and family history interviews, and assessment of childhood maltreatment and recent alcohol and cannabis use patterns. We examined relations between childhood maltreatment and prefrontal-paralimbic GMV by modeling main effects of maltreatment and family history group by maltreatment interactions on prefrontal-paralimbic GMV. We also examined relations between maltreatment and associated GMV changes with recent alcohol and cannabis use. Childhood maltreatment correlated with lower ventral, rostral and dorsolateral prefrontal and insular cortical GMV across all participants regardless of the presence or absence of familial history of bipolar disorder. However, exploratory analyses did reveal greater maltreatment-related GMV differences in individuals with prodromal symptoms of depression. Lower insula GMV was associated with greater frequency of cannabis use across all participants and greater quantity of alcohol use only in those with familial risk for bipolar disorder. Results suggest familial risk for bipolar disorder, and presumably genetic risk, may relate to outcomes following childhood maltreatment and should be considered in prevention/early intervention strategies.

Over 2.3 million people in the United States live with bipolar disorder. Sixty percent of those with a bipolar disorder diagnosis attempt suicide at least once in their lifetime and up to 19% die by suicide. However, the neurobiology of suicide attempts in bipolar disorder remains unclear. We studied the gray matter volume (GMV) of 81 participants with a bipolar-I diagnosis (age-range: 14-34 years old) and 40 healthy participants (age-range 14.7-32 years old) to compare their neuroanatomy and histories of suicide attempt. In the bipolar group, 42 were manic with ages ranging from 14-30.6 years, and 39 were depressed with ages ranging from 14-34.3 years). Twenty three bipolar participants had a suicide attempt history, and 58 had no suicide attempt history. All participants completed behavioral/diagnostic assessments and MRI. We focused on a predefined frontolimbic circuitry in bipolar disorder versus controls to first identify diagnostic GMV correlates and to specifically identify GMV correlates for suicide attempt history. We found reduced GMV in bipolar diagnosis versus controls in the subgenual cingulate and dorsolateral prefrontal cortices. Our observed regional GMV reductions were associated with histories of suicide attempts and measures of individual variations in current suicidal ideation at the time of scanning., (Copyright © 2020. Published by Elsevier B.V.)

Identifying brain alterations that contribute to suicidal thoughts and behaviors (STBs) are important to develop more targeted and effective strategies to prevent suicide. In the last decade, and especially in the last 5 years, there has been exponential growth in the number of neuroimaging studies reporting structural and functional brain circuitry correlates of STBs. Within this narrative review, we conducted a comprehensive review of neuroimaging studies of STBs published to date and summarize the progress achieved on elucidating neurobiological substrates of STBs, with a focus on converging findings across studies. We review neuroimaging evidence across differing mental disorders for structural, functional, and molecular alterations in association with STBs, which converges particularly in regions of brain systems that subserve emotion and impulse regulation including the ventral prefrontal cortex (VPFC) and dorsal PFC (DPFC), insula and their mesial temporal, striatal and posterior connection sites, as well as in the connections between these brain areas. The reviewed literature suggests that impairments in medial and lateral VPFC regions and their connections may be important in the excessive negative and blunted positive internal states that can stimulate suicidal ideation, and that impairments in a DPFC and inferior frontal gyrus (IFG) system may be important in suicide attempt behaviors. A combination of VPFC and DPFC system disturbances may lead to very high risk circumstances in which suicidal ideation is converted to lethal actions via decreased top-down inhibition of behavior and/or maladaptive, inflexible decision-making and planning. The dorsal anterior cingulate cortex and insula may play important roles in switching between these VPFC and DPFC systems, which may contribute to the transition from suicide thoughts to behaviors. Future neuroimaging research of larger sample sizes, including global efforts, longitudinal designs, and careful consideration of developmental stages, and sex and gender, will facilitate more effectively targeted preventions and interventions to reduce loss of life to suicide.

A large body of evidence has demonstrated that exposure to childhood maltreatment at any stage of development can have long-lasting consequences. It is associated with a marked increase in risk for psychiatric and medical disorders. This review summarizes the literature investigating the effects of childhood maltreatment on disease vulnerability for mood disorders, specifically summarizing cross-sectional and more recent longitudinal studies demonstrating that childhood maltreatment is more prevalent and is associated with increased risk for first mood episode, episode recurrence, greater comorbidities, and increased risk for suicidal ideation and attempts in individuals with mood disorders. It summarizes the persistent alterations associated with childhood maltreatment, including alterations in the hypothalamic-pituitary-adrenal axis and inflammatory cytokines, which may contribute to disease vulnerability and a more pernicious disease course. The authors discuss several candidate genes and environmental factors (for example, substance use) that may alter disease vulnerability and illness course and neurobiological associations that may mediate these relationships following childhood maltreatment. Studies provide insight into modifiable mechanisms and provide direction to improve both treatment and prevention strategies.

Background: Mood disorders are major risk factors for suicidal behavior. While cross-sectional studies implicate frontal systems, data to aid prediction of suicide-related behavior in mood disorders are limited. Longitudinal research on neuroanatomical mechanisms underlying suicide risk may assist in developing targeted interventions. Therefore, we conducted a preliminary study investigating baseline gray and white matter structure and longitudinal structural changes associated with future suicide attempts., Methods: High-resolution structural magnetic resonance imaging, diffusion tensor imaging, and suicide-related behavioral assessment data for 46 adolescents and young adults with mood disorders [baseline age mean  = 18 years; 61% female] were collected at baseline and at follow-up (interval mean  = 3 years). Differences in baseline and longitudinal changes in gray matter volume and white matter fractional anisotropy in frontal systems that distinguished the participants who made future attempts from those who did not were investigated., Results: Seventeen (37%) of participants attempted suicide within the follow-up period. Future attempters (those attempting suicide between their baseline and follow-up assessment), compared to those who did not, showed lower baseline ventral and rostral prefrontal gray matter volume and dorsomedial frontal, anterior limb of the internal capsule, and dorsal cingulum fractional anisotropy, as well as greater decreases over time in ventral and dorsal frontal fractional anisotropy (p < 0.005, uncorrected)., Limitations: Sample size was modest., Conclusions: Results suggest abnormalities of gray and white matter in frontal systems and differences in developmental changes of frontal white matter may increase risk of suicide-related behavior in youths with mood disorders. Findings provide potential new leads for early intervention and prevention strategies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Findings regarding brain circuitry abnormalities in suicide attempters (SAs) converge across bipolar disorder (BD) and major depressive disorder (MDD), the most common disorders observed in suicides. These abnormalities appear to be present during adolescence/young adulthood when suicide rates increase steeply, and suicide is a leading cause of death in this age group. Identification of brain circuitry common to adolescent/young adult SAs with BD and MDD is important for generating widely effective early prevention strategies. We examined brain circuitry in SAs in adolescents/young adults across these two disorders., Methods: Eighty-three participants (ages 14-25 years), 46 with BD (21 SAs) and 37 with MDD (19 SAs), underwent structural and diffusion-weighted magnetic resonance scanning. Whole-brain analyses compared gray matter (GM) volume and white matter (WM) fractional anisotropy (FA) between SAs and non-suicide attempters (NSAs) across and within BD and MDD (p < 0.005)., Results: Across and within BD and MDD, SAs showed differences compared to NSAs in ventral prefrontal cortex (PFC) GM volume and fronto-limbic (including uncinate fasciculus (UF)) WM FA. Exploratory analyses showed additional within-disorder differences for BD SAs in dorsolateral PFC (dlPFC) and hippocampus GM volume and UF FA, and for MDD SAs dorsomedial and dlPFC GM and dorsal frontal WM. However, there was no significant interaction between suicide attempt status and diagnosis., Limitations: Modest sample size., Conclusions: Common fronto-limbic gray and white matter alterations in adolescent/young adult SAs are potential targets for suicide prevention strategies across mood disorders. Preliminary findings of disorder-specific regional findings could suggest diagnostic-specific optimal targets may exist., (Copyright © 2018. Published by Elsevier B.V.)

Objective: Longitudinal neuroimaging during adolescence/young adulthood, when bipolar disorder (BD) commonly emerges, can help elucidate the neurodevelopmental pathophysiology of BD. Adults with BD have shown reduced structural integrity in the uncinate fasciculus (UF), a white matter (WM) tract providing major connections between the amygdala and ventral prefrontal cortex (vPFC), important in emotion regulation. In this longitudinal diffusion tensor imaging (DTI) study of adolescents/young adults, we hypothesized differences in age- and time-related changes in UF integrity in BD compared to healthy controls (HC)., Method: Two DTI scans were obtained in 27 adolescents/young adults with BD and 37 HC adolescents/young adults, on average approximately 2.5 years apart. Interactions between diagnosis with age and with time for UF fractional anisotropy (FA) were assessed. Exploratory analyses were performed including euthymic-only participants with BD, and for potential influences of demographic and clinical factors. Whole-brain analyses were performed to explore for interactions in other regions., Results: There were significant interactions between diagnosis with age and with time for UF FA (p < .05). Healthy control adolescents/young adults showed significant UF FA increases with age and over time (p < .05), whereas no significant changes with age or over time were observed in the adolescents/young adults with BD. Significant interactions with age and time were also observed in analyses including euthymic-only participants with BD (p < .05)., Conclusion: These findings provide neuroimaging evidence supporting differences in UF WM structural development during adolescence/young adulthood, suggesting that differences in the development of an amygdala-vPFC system subserving emotion regulation may be a trait feature of BD neurodevelopment., (Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

The single-nucleotide polymorphism rs9804190 in the Ankyrin G (ANK3) gene has been reported in genome-wide association studies to be associated with bipolar disorder (BD). However, the neural system effects of rs9804190 in BD are not known. We investigated associations between rs9804190 and gray and white matter (GM and WM, respectively) structure within a frontotemporal neural system implicated in BD. A total of 187 adolescent and adult European Americans were studied: a group homozygous for the C allele (52 individuals with BD and 56 controls) and a T-carrier group, carrying the high-risk T allele (38 BD and 41 controls). Subjects participated in high-resolution structural magnetic resonance imaging and diffusion tensor imaging (DTI) scanning. Frontotemporal region of interest (ROI) and whole-brain exploratory analyses were conducted. DTI ROI-based analysis revealed a significant diagnosis by genotype interaction within the uncinate fasciculus (P⩽0.05), with BD subjects carrying the T (risk) allele showing decreased fractional anisotropy compared with other subgroups, independent of age. Genotype effects were not observed in frontotemporal GM volume. These findings support effects of rs9804190 on frontotemporal WM in adolescents and adults with BD and suggest a mechanism contributing to WM pathology in BD.