Structural brain alterations associated with suicidal thoughts and behaviors in young people: results from 21 international studies from the ENIGMA Suicidal Thoughts and Behaviours consortium.

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.

Neural functional connectivity changes to psychosocial stress in young adults with bipolar disorder and preliminary associations with clinical trajectories.

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, agemean  ± 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.

Coping drinking motives, neural functional coupling during emotion processing, and alcohol use in young adults with bipolar disorder.

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.

Imaging suicidal thoughts and behaviors: a comprehensive review of 2 decades of neuroimaging studies.

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.

Variation in rostral anterior cingulate functional connectivity with amygdala and caudate during first manic episode distinguish bipolar young adults who do not remit following treatment.

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.

Brain circuitry associated with the development of substance use in bipolar disorder and preliminary evidence for sexual dimorphism in adolescents.

Substance use disorders and mood disorders are highly comorbid and confer a high risk for adverse outcomes. However, data are limited on the neurodevelopmental basis of this comorbidity. Substance use initiation typically occurs during adolescence, and sex-specific developmental mechanisms are implicated. In this preliminary study, we review the literature and investigate regional gray matter volume (GMV) associated with subsequent substance use problems in adolescents with bipolar disorder (BD) and explore these associations for females and males. Thirty adolescents with DSM-IV-diagnosed BD and minimal alcohol/substance exposure completed baseline structural magnetic resonance imaging scans. At follow-up (on average 6 years post baseline), subjects were administered the CRAFFT interview and categorized into those scoring at high ( ≥ 2: CRAFFTHIGH ) vs. low ( < 2: CRAFFTLOW ) risk for alcohol/substance problems. Lower GMV in prefrontal, insular, and temporopolar cortices were observed at baseline among adolescents with BD reporting subsequent alcohol and cannabis use compared to adolescents with BD who did not (P < 0.005, clusters ≥ 20 voxels). Lower dorsolateral prefrontal GMV was associated with future substance use in both females and males. In females, lower orbitofrontal and insula GMV was associated with future substance use, while in males, lower rostral prefrontal GMV was associated with future use. Lower orbitofrontal, insular, and temporopolar GMV was observed in those who transitioned to smoking tobacco. Findings indicate that GMV development is associated with risk for future substance use problems in adolescents with BD, with results implicating GMV development in regions subserving emotional regulation in females and regions subserving executive processes and attention in males. © 2016 Wiley Periodicals, Inc.

The Devastating Clinical Consequences of Child Abuse and Neglect: Increased Disease Vulnerability and Poor Treatment Response in Mood Disorders.

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.

Subjective response to alcohol: Interactive effects of early life stress, parental risk for mood and substance use disorders, and drinking context.

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.

Ventral prefrontal network response to alcohol in young adults with bipolar disorder: a within-subject randomized placebo-controlled alcohol administration study.

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.

Subjective response to alcohol in young adults with bipolar disorder and recent alcohol use: a within-subject randomized placebo-controlled alcohol administration study.

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.

Concerted roles of LRRTM1 and SynCAM 1 in organizing prefrontal cortex synapses and cognitive functions.

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.

Peer victimization and associated alcohol and substance use: Prospective pathways for negative outcomes.

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.

Going beyond risk factor: Childhood maltreatment and associated modifiable targets to improve life-long outcomes in mood disorders.

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.

Early life stress and substance use disorders: The critical role of adolescent substance use.

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.

Alcohol Use and Prefrontal Cortex Volume Trajectories in Young Adults with Mood Disorders and Associated Clinical Outcomes.

(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.

Gender-related association among childhood maltreatment, brain structure and clinical features in bipolar disorder.

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.

Recent Perceived Stress, Amygdala Reactivity to Acute Psychosocial Stress, and Alcohol and Cannabis Use in Adolescents and Young Adults With Bipolar Disorder.

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, agemean ± 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.

Childhood maltreatment, prefrontal-paralimbic gray matter volume, and substance use in young adults and interactions with risk for bipolar disorder.

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.

Subjective response to alcohol: Associated alcohol use and orbitofrontal gray matter volume in bipolar disorder.

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.

The Devastating Clinical Consequences of Child Abuse and Neglect: Increased Disease Vulnerability and Poor Treatment Response in Mood Disorders.

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.