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Background: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects., Methods: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects., Results: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects., Conclusions: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Increased white matter hyperintensities (WMHs) is one of the most consistent imaging findings amongst participants with bipolar disorder (BD). This study investigated WMHs in a young population at high genetic risk for bipolar disorder (HR)., Methods: MRI scans were conducted at baseline in HR individuals (n = 131), patients with BD (n = 47) and controls (CON) (n = 108). Most of the HR (n = 77) and CON (n = 74) group completed scans after two years. Scans were examined for the presence of WMHs., Results: There were significantly more periventricular WMHs in the BD compared to the CON group at baseline (p = .04). Although the prevalence of periventricular WMHs was intermediate in the HR group, there were no significant differences between the HR and CON or BD participants. Deep WMHs did not differ significantly between the groups. Over time, there was a significant increase in the prevalence of periventricular WMHs in both the HR and CON groups (p = .02)., Limitations: The use of a visual rating scale to examine WMHs is subjective. As the gradings were collapsed into 'present' or 'absent', we could not ascertain whether the severity of hyperintensities worsened over time., Conclusions: Periventricular WMHs are more prevalent in young individuals with BD than controls. As these are not more prevalent in HR individuals, it is possible that these are either secondary to the development of bipolar disorder, its treatment, or resulting changes in lifestyle. In a novel finding, there were similar increases in the prevalence of WMHs in controls and HR youth over the 2-year period., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Identifying clinical features that predict conversion to bipolar disorder (BD) in those at high familial risk (HR) would assist in identifying a more focused population for early intervention., Method: In total 287 participants aged 12-30 (163 HR with a first-degree relative with BD and 124 controls (CONs)) were followed annually for a median of 5 years. We used the baseline presence of DSM-IV depressive, anxiety, behavioural and substance use disorders, as well as a constellation of specific depressive symptoms (as identified by the Probabilistic Approach to Bipolar Depression) to predict the subsequent development of hypo/manic episodes., Results: At baseline, HR participants were significantly more likely to report ⩾4 Probabilistic features (40.4%) when depressed than CONs (6.7%; p < .05). Nineteen HR subjects later developed either threshold (n = 8; 4.9%) or subthreshold (n = 11; 6.7%) hypo/mania. The presence of ⩾4 Probabilistic features was associated with a seven-fold increase in the risk of 'conversion' to threshold BD (hazard ratio = 6.9, p < .05) above and beyond the fourteen-fold increase in risk related to major depressive episodes (MDEs) per se (hazard ratio = 13.9, p < .05). Individual depressive features predicting conversion were psychomotor retardation and ⩾5 MDEs. Behavioural disorders only predicted conversion to subthreshold BD (hazard ratio = 5.23, p < .01), while anxiety and substance disorders did not predict either threshold or subthreshold hypo/mania., Conclusions: This study suggests that specific depressive characteristics substantially increase the risk of young people at familial risk of BD going on to develop future hypo/manic episodes and may identify a more targeted HR population for the development of early intervention programs.

This meta-analysis aimed to update existing data on the comparison of prevalence rates of psychopathology primarily among offspring with at least one parent with bipolar disorder (BD) and offspring of parents without psychiatric illness. Seventeen studies were derived from a systematic search of PsychInfo, Medline, Scopus and Embase. Inclusion criteria were use of a control offspring group, standardized diagnostic procedures and reporting of clear frequency data. Risk of psychopathology was estimated by aggregating frequency data from selected studies. Compared to control offspring, high-risk BD offspring are nine times more likely to have a bipolar-type disorder, almost two and a half times more likely to develop a non-BD affective disorder and over two times more likely to develop at least one anxiety disorder. High-risk offspring also showed a significant increased risk of other non-mood psychopathology such as attention deficit hyperactivity disorder (ADHD), any type of behavioral disorder and substance use disorder (SUDs). Risk of developing a broad range of affective and non-affective psychopathology is significantly higher in high-risk BD offspring. Identifying clinical presentations of this genetically high-risk cohort is important in establishing appropriate preventative treatment.

Background: The aim of this study was to examine the relationship between family environment (cohesion and parental bonding), high-risk status, and psychopathology (internalizing and externalizing problems) among offspring of parents with bipolar disorder (BD), from the perspective of both offspring and their parents. We further tested if family environment mediated the relationship between bipolar risk status and internalizing and externalizing problems., Method: High-risk (n = 90) BD offspring and control (n = 56) offspring aged 12-21 years old, and their parents, completed questionnaires on family cohesion and offspring internalizing and externalizing problems. Offspring also completed a parental bonding questionnaire. Group differences were examined, followed by multi-level mediation analysis with maximum likelihood and robust standard errors., Results: Both offspring and parents in the high-risk group reported higher levels of internalizing and externalizing problems than controls. According to offspring reports, high-risk status, lower maternal and paternal care in parental bonding, was independently associated with internalizing problems. Lower maternal care alone predicted externalizing problems. Family environment did not mediate the relationship between bipolar risk status, and offspring problems., Limitations: Due to rates of missing data from parent reports of offspring psychopathology, mediation analysis was completed using offspring reports., Conclusions: The offspring-report data presented indicate that low parental warmth and connection were associated with internalizing and externalizing problems as an independent risk factor, in addition to bipolar risk status. The parent-child relationship therefore warrants attention as a potential target for prevention strategies with such families., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Disruptive mood dysregulation disorder is a newly proposed childhood disorder included in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition to describe children ⩽18 years of age with chronic irritability/temper outbursts. This study aimed to examine the prevalence of disruptive mood dysregulation disorder, severe mood dysregulation and chronic irritability in an Australian study of young people at increased familial risk of developing bipolar disorder ('HR' group) and controls ('CON' group)., Methods: A total of 242 12- to 30-year-old HR or CON subjects were administered the severe mood dysregulation module. Of these, 42 were aged ⩽18 years at the time of assessment, with 29 subjects in the HR group and 13 in the CON group., Results: No subjects ⩽18 years - in either group - fulfilled current or lifetime criteria for disruptive mood dysregulation disorder or severe mood dysregulation, the precursor to disruptive mood dysregulation disorder. Similarly, no subjects in either group endorsed the severe mood dysregulation/disruptive mood dysregulation disorder criteria for irritable mood or marked excessive reactivity. One HR participant endorsed three severe mood dysregulation criteria (distractibility, physical restlessness and intrusiveness), while none of the comparison subjects endorsed any criteria. Exploratory studies of the broader 12- to 30-year-old sample similarly found no subjects with severe mood dysregulation/disruptive mood dysregulation disorder in either the HR or CON group and no increased rates of chronic irritability, although significantly more HR subjects reported at least one severe mood dysregulation/disruptive mood dysregulation disorder criterion (likelihood ratio = 6.17; p = 0.013); most of the reported criteria were severe mood dysregulation 'chronic hyper-arousal' symptoms., Conclusion: This study comprises one of the few non-US reports on the prevalence of disruptive mood dysregulation disorder and severe mood dysregulation and is the first non-US study of the prevalence of these conditions in a high-risk bipolar disorder sample. The failure to replicate the finding of higher rates of disruptive mood dysregulation disorder and chronic irritability in high-risk offspring suggests that these are not robust precursors of bipolar disorder.

Objective: Bipolar disorder (BD) is one of the most heritable psychiatric conditions and is associated with high suicide risk. To explore the reasons for this link, this study examined the interaction between traumatic stress and BD polygenic risk score in relation to suicidal ideation, suicide attempt, and nonsuicidal self-injury (NSSI) in adolescent and young adult offspring and relatives of persons with BD (BD-relatives) compared with adolescent and young adult offspring of individuals without psychiatric disorders (controls)., Method: Data were collected from 4 sites in the United States and 1 site in Australia from 2006 through 2012. Generalized estimating equation models were used to compare rates of ideation, attempts, and NSSI between BD-relatives (n = 307) and controls (n = 166) and to determine the contribution of demographic factors, traumatic stress exposure, lifetime mood or substance (alcohol/drug) use disorders, and BD polygenic risk score., Results: After adjusting for demographic characteristics and mood and substance use disorders, BD-relatives were at increased risk for suicidal ideation and attempts but not for NSSI. Independent of BD-relative versus control status, demographic factors, or mood and substance use disorders, exposure to trauma within the past year (including bullying, sexual abuse, and domestic violence) was associated with suicide attempts (p = .014), and BD polygenic risk score was marginally associated with attempts (p = .061). Importantly, the interaction between BD polygenic risk score and traumatic event exposures was significantly associated with attempts, independent of demographics, relative versus control status, and mood and substance use disorders (p = .041)., Conclusion: BD-relatives are at increased risk for suicide attempts and ideation, especially if they are exposed to trauma and have evidence of increased genetic vulnerability., (Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Bipolar disorder (BD) is characterized by a dysregulation of affect and impaired integration of emotion with cognition. These traits are also expressed in probands at high genetic risk of BD. The inferior frontal gyrus (IFG) is a key cortical hub in the circuits of emotion and cognitive control, and it has been frequently associated with BD. Here, we studied resting-state functional connectivity of the left IFG in participants with BD and in those at increased genetic risk., Methods: Using resting-state functional magnetic resonance imaging we compared 49 young BD participants, 71 individuals with at least one first-degree relative with BD (at-risk), and 80 control subjects. We performed between-group analyses of the functional connectivity of the left IFG and used graph theory to study its local functional network topology. We also used machine learning to study classification based solely on the functional connectivity of the IFG., Results: In BD, the left IFG was functionally dysconnected from a network of regions, including bilateral insulae, ventrolateral prefrontal gyri, superior temporal gyri, and the putamen (p < .001). A small network incorporating neighboring insular regions and the anterior cingulate cortex showed weaker functional connectivity in at-risk than control participants (p < .006). These constellations of regions overlapped with frontolimbic regions that a machine learning classifier selected as predicting group membership with an accuracy significantly greater than chance., Conclusions: Functional dysconnectivity of the IFG from regions involved in emotional regulation may represent a trait abnormality for BD and could potentially aid clinical diagnosis., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Although there is clear evidence that reproductive cycle events are associated with mood episodes for women with bipolar disorder, few studies have examined for relationships between these and specific clinical characteristics of the disorder. This study aimed to explore the relationship between mood symptoms associated with reproductive cycle events and features of the disorder indicative of a more severe lifetime course., Method: Totally, 158 women of at least 18 years of age participated in the study. Subjects were recruited through a specialist clinic at the Black Dog Institute, Sydney, Australia., Results: In total, 77% of women reported increases in mood symptoms during perimenstrual, postnatal or menopausal periods. These women had an earlier age of onset for depressive and hypo/manic episodes and a greater likelihood of comorbid anxiety disorders, rapid cycling and mixed mood compared to those who did not report such reproductive cycle-associated mood changes. Women who experienced postnatal episodes were also more likely to experience worse mood symptoms perimenstrually and menopausally., Conclusion: First, reproductive cycle event-related worsening of mood was associated with a more severe lifetime course of bipolar disorder, and, second, it appears that some women have a greater propensity to mood worsening at each of these reproductive cycle events. If replicated, these findings provide important information for clinicians treating women with reproductive cycle event mood changes and highlight the need for improved therapeutics for such presentations.

The emotional and cognitive vulnerabilities that precede the development of bipolar disorder are poorly understood. The inferior frontal gyrus-a key cortical hub for the integration of cognitive and emotional processes-exhibits both structural and functional changes in bipolar disorder, and is also functionally impaired in unaffected first-degree relatives, showing diminished engagement during inhibition of threat-related emotional stimuli. We hypothesized that this functional impairment of the inferior frontal gyrus in those at genetic risk of bipolar disorder reflects the dysfunction of broader network dynamics underlying the coordination of emotion perception and cognitive control. To test this, we studied effective connectivity in functional magnetic resonance imaging data acquired from 41 first-degree relatives of patients with bipolar disorder, 45 matched healthy controls and 55 participants with established bipolar disorder. Dynamic causal modelling was used to model the neuronal interaction between key regions associated with fear perception (the anterior cingulate), inhibition (the left dorsolateral prefrontal cortex) and the region upon which these influences converge, namely the inferior frontal gyrus. Network models that embodied non-linear, hierarchical relationships were the most strongly supported by data from our healthy control and bipolar participants. We observed a marked difference in the hierarchical influence of the anterior cingulate on the effective connectivity from the dorsolateral prefrontal cortex to the inferior frontal gyrus that is unique to the at-risk cohort. Non-specific, non-hierarchical mechanisms appear to compensate for this network disturbance. We thus establish a specific network disturbance suggesting dysfunction in the processes that support hierarchical relationships between emotion and cognitive control in those at high genetic risk for bipolar disorder., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Recent studies have revealed the polygenic nature of bipolar disorder (BP), and identified common risk variants associated with illness. However, the role of common polygenic risk in multiplex families has not previously been examined. The present study examined 249 European-ancestry families from the NIMH Genetics Initiative sample, comparing subjects with narrowly defined BP (excluding bipolar II and recurrent unipolar depression; n = 601) and their adult relatives without BP (n = 695). Unrelated adult controls (n = 266) were from the NIMH TGEN control dataset. We also examined a prospective cohort of young (12-30 years) offspring and siblings of individuals with BPI and BPII disorder (at risk; n = 367) and psychiatrically screened controls (n = 229), ascertained from five sites in the US and Australia and assessed with standardized clinical protocols. Thirty-two disease-associated SNPs from the PGC-BP Working Group report (2011) were genotyped and additive polygenic risk scores (PRS) derived. We show increased PRS in adult cases compared to unrelated controls (P = 3.4 × 10(-5) , AUC = 0.60). In families with a high-polygenic load (PRS score ≥32 in two or more subjects), PRS distinguished cases with BPI/SAB from other relatives (P = 0.014, RR = 1.32). Secondly, a higher PRS was observed in at-risk youth, regardless of affected status, compared to unrelated controls (GEE-χ(2) = 5.15, P = 0.012). This report is the first to explore common polygenic risk in multiplex families, albeit using only a small number of robustly associated risk variants. We show that individuals with BP have a higher load of common disease-associated variants than unrelated controls and first-degree relatives, and illustrate the potential utility of PRS assessment in a family context., (© 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.)

Despite a growing number of reports, there is still limited knowledge of the clinical features that precede the onset of bipolar disorder (BD). To explore this, we investigated baseline data from a prospectively evaluated longitudinal cohort of subjects aged 12-30 years to compare: first, lifetime rates of clinical features between a) subjects at increased genetic risk for developing BD ('AR'), b) participants from families without mental illness ('controls'), and c) those with established BD; and, second, prior clinical features that predict the later onset of affective disorders in these same three groups. This is the first study to report such comparisons between these three groups (though certainly not the first to compare AR and control samples). 118 AR participants with a parent or sibling with BD (including 102 with a BD parent), 110 controls, and 44 BD subjects were assessed using semi-structured interviews. AR subjects had significantly increased lifetime risks for depressive, anxiety and behavioural disorders compared to controls. Unlike prior reports, preceding anxiety and behavioural disorders were not found to increase risk for later onset of affective disorders in the AR sample, perhaps due to limited sample size. However, preceding behavioural disorders did predict later onset of affective disorders in the BD sample. The findings that i) AR subjects had higher rates of depressive, anxiety and behavioural disorders compared to controls, and ii) prior behavioural disorders increased the risk to later development of affective disorders in the BD group, suggest the possibility of therapeutic targeting for these disorders in those at high genetic risk for BD., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: In a prior study of bipolar disorder pedigrees, we demonstrated distinct clinical differences between depressive episodes in bipolar disorder and major depressive disorder (MDD), including differentiation between these conditions using the Probabilistic Approach to Bipolar Depression. The aim of this retrospective study was to compare the phenomenology of the most severe lifetime depressive episodes between bipolar I (BP-I) and II (BP-II) disorder subtypes and MDD in these pedigrees., Method: Patients with DSM-IV diagnoses of BP-I (n = 202), BP-II (n = 44), and MDD (n = 120) from bipolar disorder pedigrees were assessed using the Diagnostic Interview for Genetic Studies between 1998 and 2012. Multivariate logistic regression was used to identify distinguishing clinical features. The utility of the Probabilistic Approach in distinguishing BP-I and BP-II depression from MDD was assessed., Results: BP-I differed from MDD in terms of greater rates of psychomotor retardation (P < .05) and psychotic features (P < .05). BP-II was distinguished from MDD (P < .01) by the greater likelihood of mixed features. Patients with BP-II had a greater likelihood of mixed features (P < .001) and a lesser likelihood of psychomotor retardation (P < .05) compared to those with BP-I. The Probabilistic Approach significantly differentiated both BP-I and BP-II from MDD (P < .01 to P < .001, depending on cutoff) but did not robustly distinguish between BP-I and BP-II., Conclusions: First, the differentiation of BP-II from both BP-I depression and MDD in terms of the presence of mixed symptoms is of particular interest given the current debate over "mixed specifiers" for these conditions in DSM-5. Second, the Probabilistic Approach to Bipolar Depression was demonstrated for the first time to significantly distinguish both bipolar disorder subtypes from MDD., (© Copyright 2015 Physicians Postgraduate Press, Inc.)

Objectives: In a relatively small number of previous studies, childhood abuse has been found to be associated with more severe symptom course, earlier onset, greater comorbidity, and greater suicidality in those diagnosed with bipolar disorder. There have been no prior reports looking for any association between childhood abuse and cognitive style. This study aimed to examine the relationship between cognitive factors, such as response styles to depressed mood and dysfunctional attitudes, clinical features, and childhood physical and sexual abuse in this population., Methods: A total of 157 adult participants diagnosed with DSM-IV bipolar disorder I or II were assessed on clinical features of this condition and measures of childhood sexual and physical abuse. Participants also completed self-report questionnaires covering areas such as symptom measures of depression, anxiety and stress, dysfunctional attitudes, and response styles to depressed mood., Results: Seventy-four participants (37%) reported having experienced either sexual or physical abuse. Those who reported physical or sexual abuse were significantly more likely to report self-harm or suicidal behaviors and showed higher stress scores. Specifically, those who reported sexual abuse were more likely to have simple phobias, to have attempted suicide, and to have had more hospitalizations for depression. After controlling for current mood severity, there were no significant differences on the self-report cognitive style measures for those who reported childhood sexual or physical abuse compared to those who did not report abuse., Conclusions: Cognitive styles were not found to be associated with childhood sexual or physical abuse in participants with bipolar disorder. Stress may be important to target in psychological interventions, whilst special attention should also be paid to those with a history of sexual abuse given the greater likelihood of suicide attempt., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Recent neuroimaging studies support the contention that depression, pain distress, and rejection distress share the same neurobiological circuits. In two recently published studies we confirmed the hypothesis that the perception of increased pain during both treatment-refractory depression (predominantly unipolar) and difficult-to-treat bipolar depression was related to increased state rejection sensitivity (i.e., rejection sensitivity when depressed). In the present study, we aimed to compare the correlates of pain and rejection sensitivity in individuals with bipolar versus unipolar depression and test the hypothesis that bipolar disorder may be distinguished from unipolar depression both by an increased perception of pain and heightened rejection sensitivity during depression., Methods: We analyzed data from 113 bipolar and 146 unipolar depressed patients presenting to the Black Dog Institute, Sydney, Australia. The patients all met DSM-IV criteria for bipolar disorder or unipolar depression (major depressive disorder)., Results: Bipolar disorder predicted a major increase in state rejection sensitivity when depressed (p = 0.001), whereas trait rejection sensitivity (i.e., a long-standing pattern of rejection sensitivity) was not predicted by polarity. A major increase in the experience of headaches (p = 0.007), chest pain (p < 0.001), and body aches and pains (p = 0.02) during depression was predicted by a major increase in state rejection sensitivity for both bipolar and unipolar depression., Conclusions: State, but not trait, rejection sensitivity is significantly predicted by bipolar depression, suggesting that this might be considered as a state marker for bipolar depression and taken into account in the clinical differentiation of bipolar and unipolar depression.

Background: Previous reports have highlighted perfectionism and related cognitive styles as a psychological risk factor for stress and anxiety symptoms as well as for the development of bipolar disorder symptoms. The anxiety disorders are highly comorbid with bipolar disorder but the mechanisms that underpin this comorbidity are yet to be determined., Method: Measures of depressive, (hypo)manic, anxiety and stress symptoms and perfectionistic cognitive style were completed by a sample of 142 patients with bipolar disorder. Mediation models were used to explore the hypotheses that anxiety and stress symptoms would mediate relationships between perfectionistic cognitive styles, and bipolar disorder symptoms., Results: Stress and anxiety both significantly mediated the relationship between both self-critical perfectionism and goal attainment values and bipolar depressive symptoms. Goal attainment values were not significantly related to hypomanic symptoms. Stress and anxiety symptoms did not significantly mediate the relationship between self-critical perfectionism and (hypo)manic symptoms., Limitations: 1. These data are cross-sectional; hence the causality implied in the mediation models can only be inferred. 2. The clinic patients were less likely to present with (hypo)manic symptoms and therefore the reduced variability in the data may have contributed to the null findings for the mediation models with (hypo) manic symptoms. 3. Those patients who were experiencing current (hypo)manic symptoms may have answered the cognitive styles questionnaires differently than when euthymic., Conclusion: These findings highlight a plausible mechanism to understand the relationship between bipolar disorder and the anxiety disorders. Targeting self-critical perfectionism in the psychological treatment of bipolar disorder when there is anxiety comorbidity may result in more parsimonious treatments., (© 2013 Published by Elsevier B.V.)

Background: Functional brain imaging of young people at increased genetic risk for bipolar disorder provides a means of identifying potential endophenotypes for this condition. Dysfunctional neural mechanisms for the cognitive control of emotion are implicated in the genetic predisposition to bipolar disorder, with aberrant activity in frontocortical, striatal, and limbic brain regions previously reported in subjects with established bipolar disorder during inhibitory and emotion processing tasks., Methods: Functional brain activity during inhibition of emotional material in young people at increased genetic risk for bipolar disorder was investigated using a facial-emotion go/no-go task during functional magnetic resonance imaging. Data from 47 genetically high-risk individuals aged 18 to 30 years with at least one first-degree relative with bipolar disorder were compared with 49 control subjects (within the same age range but without a family history of bipolar disorder or other severe mental illness)., Results: Whole-brain corrected analyses revealed a highly specific and significant lack of recruitment of the inferior frontal gyrus when inhibiting responses to fearful faces in the high-risk participants compared with control subjects (p = .011, family-wise error, peak voxel)., Conclusions: Impaired inhibitory function of the inferior frontal cortex may represent a trait marker of vulnerability to bipolar disorder. That this finding was revealed during inhibition of emotional material further implicates dysregulated frontolimbic brain networks as a potential neurocognitive endophenotype for bipolar disorder and provides evidence for pre-existing functional disturbances in those at high genetic risk for bipolar disorder., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Aim: The detection of early warning signs is a major component of many psychological interventions for assisting in the management of bipolar disorder. The aim of this study was to assess whether the ability to detect early warning signs was associated with clinical and demographic characteristics in a bipolar disorder clinic sample., Method: Two-hundred-and-one participants with DSM-IV bipolar I or II disorder aged over 18 years of age were recruited through a specialized bipolar disorder clinic. Participants were administered a structured interview by psychiatrists asking participants about any early warning signs, and features of the phenomenology, course and treatment of bipolar disorder., Results: Participants were significantly more likely to recognise both hypo/manic and depressive early warning signs rather than only one type of mood episode. The ability to detect signs of both hypo/mania and depression was greater in younger participants. The ability to detect signs of depression was associated with more prior depressive episodes and a lesser likelihood of prior hospitalisations whilst a history of mixed mood was associated with a greater likelihood of detecting depressive symptoms. The ability to recognise signs of hypo/mania was greater in those reporting a history of visual hallucinations (during depressive and/or manic episodes)., Limitations: Cross-sectional design and previous experience with psychotherapy was not assessed., Conclusion: These findings provide useful clinical data pertinent to psychological interventions for bipolar disorder. Longitudinal studies are needed to further examine how the ability to recognise early warning signs may be associated with longer term outcome., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Although genetic epidemiological studies have confirmed increased rates of major depressive disorder among the relatives of people with bipolar affective disorder, no report has compared the clinical characteristics of depression between these two groups., Aims: To compare clinical features of depressive episodes across participants with major depressive disorder and bipolar disorder from within bipolar disorder pedigrees, and assess the utility of a recently proposed probabilistic approach to distinguishing bipolar from unipolar depression. A secondary aim was to identify subgroups within the relatives with major depression potentially indicative of 'genetic' and 'sporadic' subgroups., Method: Patients with bipolar disorder types 1 and 2 (n = 246) and patients with major depressive disorder from bipolar pedigrees (n = 120) were assessed using the Diagnostic Interview for Genetic Studies. Logistic regression was used to identify distinguishing clinical features and assess the utility of the probabilistic approach. Hierarchical cluster analysis was used to identify subgroups within the major depressive disorder sample., Results: Bipolar depression was characterised by significantly higher rates of psychomotor retardation, difficulty thinking, early morning awakening, morning worsening and psychotic features. Depending on the threshold employed, the probabilistic approach yielded a positive predictive value ranging from 74% to 82%. Two clusters within the major depressive disorder sample were found, one of which demonstrated features characteristic of bipolar depression, suggesting a possible 'genetic' subgroup., Conclusions: A number of previously identified clinical differences between unipolar and bipolar depression were confirmed among participants from within bipolar disorder pedigrees. Preliminary validation of the probabilistic approach in differentiating between unipolar and bipolar depression is consistent with dimensional distinctions between the two disorders and offers clinical utility in identifying patients who may warrant further assessment for bipolarity. The major depressive disorder clusters potentially reflect genetic and sporadic subgroups which, if replicated independently, might enable an improved phenotypic definition of underlying bipolarity in genetic analyses.

Objectives: Little is known regarding the correlates of pain in bipolar disorder. Recent neuroimaging studies support the contention that depression, as well as pain distress and rejection distress, share the same neurobiological circuits. In a recently published study, we confirmed the hypothesis that perception of increased pain during treatment-refractory depression, predominantly unipolar, was related to increased rejection sensitivity. In the present study, we aimed to test this same hypothesis for bipolar depression., Methods: The present study analysed data from 67 patients presenting to the Black Dog Institute Bipolar Disorders Clinic in Sydney, Australia. The patients all met DSM-IV criteria for bipolar disorder and had completed a self-report questionnaire regarding perceived pain and rejection sensitivity during depression., Results: A significant increase in the experience of headaches (p=0.003) as well as chest pain (p=0.004) during bipolar depression was predicted by a major increase in rejection sensitivity when depressed, i.e., state rejection sensitivity. Being rejection sensitive in general, i.e., trait rejection sensitivity, did not predict pain during depression., Conclusions: The experience of increased headaches and chest pain during bipolar depression is related to increased rejection sensitivity during depression. Research to further elucidate this relationship is required., (© 2011 John Wiley and Sons A/S.)

The emotional and cognitive vulnerabilities that precede the development of bipolar disorder are poorly understood. The inferior frontal gyrus-a key cortical hub for the integration of cognitive and emotional processes-exhibits both structural and functional changes in bipolar disorder, and is also functionally impaired in unaffected first-degree relatives, showing diminished engagement during inhibition of threat-related emotional stimuli. We hypothesized that this functional impairment of the inferior frontal gyrus in those at genetic risk of bipolar disorder reflects the dysfunction of broader network dynamics underlying the coordination of emotion perception and cognitive control. To test this, we studied effective connectivity in functional magnetic resonance imaging data acquired from 41 first-degree relatives of patients with bipolar disorder, 45 matched healthy controls and 55 participants with established bipolar disorder. Dynamic causal modelling was used to model the neuronal interaction between key regions associated with fear perception (the anterior cingulate), inhibition (the left dorsolateral prefrontal cortex) and the region upon which these influences converge, namely the inferior frontal gyrus. Network models that embodied non-linear, hierarchical relationships were the most strongly supported by data from our healthy control and bipolar participants. We observed a marked difference in the hierarchical influence of the anterior cingulate on the effective connectivity from the dorsolateral prefrontal cortex to the inferior frontal gyrus that is unique to the at-risk cohort. Non-specific, non-hierarchical mechanisms appear to compensate for this network disturbance. We thus establish a specific network disturbance suggesting dysfunction in the processes that support hierarchical relationships between emotion and cognitive control in those at high genetic risk for bipolar disorder. [ABSTRACT FROM AUTHOR]

Objective Our group has previously reported differences in the clinical, genetic and neuroimaging (structural and functional MRI, DTI) profiles of young people at increased genetic risk of bipolar disorder, compared to control subjects from families without mental illness. Identification of clinical, genetic and neuroimaging features that predict later ‘conversion’ to bipolar disorder (BD) in those at high genetic risk (HR) would assist in early intervention. This study aimed to investigate whether clinical features (such as lifetime depressive, anxiety or behavioural disorders) or genetic/neuroimaging findings predict later development of hypo/mania. Method 287 12-30 year-old participants (163 HR with a first-degree relative with DSM-IV BD, and 124 controls) were assessed at baseline and 12-monthly follow-ups for up to six years. Results Nineteen HR subjects later developed either threshold (n=8; 4.9%) or sub-threshold (n=11; 6.7%) hypo/manic episodes. A prior history of MDEs was associated with an increased risk of later conversion to threshold BD (hazard ratio=13.9, p<.05). Anxiety disorders did not predict later occurrence of hypo/mania. Behavioural disorders (including ADHD) predicted sub-threshold but not threshold episodes. After accounting for this risk, the presence of >4 ׳Probabilistic׳ depressive features was associated with a further seven-fold increase in the risk of conversion to threshold BD (hazard ratio=6.9, p<.05). Those features most strongly associated with such conversion were psychomotor retardation and > 5 MDEs. Data on the predictive capacity of genetic (polygenic risk scores) and neuroimaging findings will be presented. Conclusions In one of few prospective studies of predictors of conversion to BD in HR subjects, both a history of MDEs and >4 ׳Probabilistic׳ features predicted later development of threshold episodes of hypo/mania, and hence may constitute ‘targets’ for early intervention. [ABSTRACT FROM AUTHOR]

Highlights from the article: B Background: b "High-risk" (HR) prospective studies of young people at increased risk of Bipolar Disorder (BD) are crucial for identifying risk profiles that underlie the development of psychopathology. The Australian prospective BD HR study has rich phenotyping over 8 years, including annual clinical assessments, neuroimaging and genetic data. Evidence of widespread accelerated thinning of the frontal cortex over time in HR suggests that the frontal cortical thinning observed in established BD appears to be developing early, even before BD manifests.

Bipolar Disorder (BD) is a complex and highly heritable mood disorder associated with a range of cognitive deficits across all illness states. Previous research has demonstrated associations between the dopamine D2 receptor gene (DRD2) and BD diagnosis, structural and functional brain changes, and cognitive dysfunction. Specific SNPs impacting DRD2 function have been identified: rs1800497 (Taq1A1, minor T allele) is associated with reduced striatal D2R dopamine binding; and rs1076560 and rs2283265 (minor A/T alleles) are associated with alternative splicing of DRD2 exon 6, resulting in increased expression of DRD2-short mRNA compared to DRD2-long isoform, and reduced inhibition of glutamate release. The present study adopted a cognitive-neurogenic approach to explore the mediating role of brain structure in the relationship between DRD2 functional haplotypes and cognitive outcomes. Participants comprised 26 BD cases (BD-I or BD-II), 62 at-risk subjects (unaffected first-degree relatives of BD probands), and 55 control subjects with 3 T MRI, genetic and cognitive data. DRD2 haplotypes were defined by three functional SNPs (rs1800497, rs1076560, rs2283265). Cortical thickness, surface area and volume were extracted for three functionally defined regions of interest (ROIs) that were parcellated on the basis of resting state functional connectivity data – Dorsal Attention (DA), Ventral Attention (VA), and Fronto-Parietal (FP). Working memory and attention were assessed using Repeatable Battery for Assessment of Neuropsychological Status (RBANS), and intelligence (IQ) was determined using Wechsler Abbreviated Scale of Intelligence (WASI). A series of simple and multiple mediation models were implemented using SPSS PROCESS macro. These models predicted the effects of the functional DRD2 haplotype on working memory, attention and intelligence, as independently and jointly mediated by cortical area, thickness and volume in the three functionally defined ROIs. The frequency of CCG homozygotes versus TAA carriers was significantly higher in at-risk subjects compared to controls (freq=0.758 vs 0.564, p=0.013) with a trend in BD (freq=0.692, p=0.1). In the control group, CCG homozygotes exhibited an increase in RBANS attention scores as a result of the mediating effects of DA area and volume (of 1.6 and 1.7 standard deviations). Simple mediation effects were also observed in the control group for IQ and RBANS immediate memory in the absence of a significant total effect. In contrast, simple mediation effects were not apparent in the slightly larger at-risk group nor the BD group. While multiple mediation models reinforced many simple mediation effects observed in controls, an additional mediation effect was observed in the BD group – TAT haplotype carriers exhibited a 0.6 SD decrease in RBANS attention scores as a result of the mediating effects of FP volume. The DRD2 mediation effects observed in controls were absent in the at-risk and BD groups, suggesting that the normally ameliorative effect of the CCG haplotype on cognitive outcomes is either negated by other genetic and familial risk factors for BD, or is mediated by alternate brain structures. Additionally, evidence is provided for the reversal of typically observed DRD2 effects on cognitive outcomes by the significant mediation effect for the BD group in the multiple mediation model of attention, where carriers of the TAT haplotype demonstrated improved attention. [ABSTRACT FROM AUTHOR]

B Background: b Bipolar disorder (BD) is a familial psychiatric disorder associated with fronto-limbic brain abnormalities. B Results: b Over time, the HR group, as compared to the control group, showed accelerated cortical thinning and volume reduction in a number of right lateralised frontal regions: inferior frontal gyrus, lateral orbitofrontal cortex, frontal pole, and rostral middle frontal gyrus. Independent of time, the HR group had significantly greater cortical thickness in the left caudal anterior cingulate cortex, and larger volume in the right medial orbitofrontal cortex and right accumbens area compared to controls. [Extracted from the article]

Bipolar Disorder (BP) is a highly heritable mood disorder as demonstrated by a 5 to 10 fold increased risk amongst first degree relatives of BP probands. Structural imaging differences and clinical symptoms have also been observed amongst those with familial risk (At-Risk or AR) prior to any diagnosis of BP. Alternatively, a Polygenic Risk Score (PRS) based on known risk alleles for BD can be used as an index for increased genetic risk, facilitating an examination of the biological mechanism of BP pathogenesis. Within a group of 50 young first-degree relatives of BP probands (mean age 22.6 years, SD 4.2) and 50 gender and age matched controls (22.5 years, SD 4.3) we explored the main and interactive effects of familial and polygenic risk for BP on brain structure. A PRS was derived for each subject from 32 replicated BP associated risk alleles from the first Psychiatric Genomics Consortium genome-wide association study. Using familial risk, PRS, age, and gender as independent factors, a series of general linear models were applied to both vertex-wise cortical thickness data and subcortical regions of interest segmentations extracted from T1-weighted magnetic resonance images. While familial risk was associated with greater cortical thickness in the right inferior frontal gyrus, greater PRS was associated with a thicker cortex in AR, and thinner cortex in controls. Age-dependent effects of PRS were also observed in AR individuals, with the youngest subjects demonstrating the thickest cortex. For all subcortical regions of interest examined, no main or interaction effects were observed for familial or polygenic risk. These findings of differential PRS effects in AR and controls subjects point to the modulating role of other genetic and familial risk factors in the effects of PRS on brain structure. The age dependence of PRS effects in those with familial risk indicates the possibility of a complex developmental trajectory and highlights the need for longitudinal studies. [ABSTRACT FROM AUTHOR]