Incidence and risk factors for anxiety disorders in young adults: A population-based prospective cohort study.

Anxiety disorders are among the most common psychiatric disorders in the general population. Our objective was to describe the cumulative incidence and risk factors of anxiety disorders, including obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD), in a follow-up of young adults over a five-year period. This is a prospective cohort conducted in two waves. The first took place from 2007 to 2009, in which 1,560 young adults aged between 18 and 24 years were evaluated using the Mini-International Neuropsychiatric Interview (MINI). Subjects were invited to participate in the second wave, which wave took place from 2012 to 2014, where 1,244 young adults were evaluated using the MINI-Plus. Our findings showed a cumulative incidence of 10.9% for any anxiety disorder, 6.5% for generalized anxiety disorder, 6.0% for agoraphobia, 2.0% for OCD, 1.6% for panic disorder, 1.1% for social anxiety and 0.7% for PTSD. Being female and having had a depressive episode were risk factors to develop any anxiety disorder. We observed a high cumulative incidence of anxiety disorders in a population-based sample of young adults. Our data highlights the importance of the early identification of these disorders as this could lead to early illness detection, early illness management and a reduced burden of disease.

Early identification of bipolar disorder among young adults - a 22-year community birth cohort.

OBJECTIVE: We set forth to build a prediction model of individuals who would develop bipolar disorder (BD) using machine learning techniques in a large birth cohort. METHODS: A total of 3748 subjects were studied at birth, 11, 15, 18, and 22 years of age in a community birth cohort. We used the elastic net algorithm with 10-fold cross-validation to predict which individuals would develop BD at endpoint (22 years) at each follow-up visit before diagnosis (from birth up to 18 years). Afterward, we used the best model to calculate the subgroups of subjects at higher and lower risk of developing BD and analyzed the clinical differences among them. RESULTS: A total of 107 (2.8%) individuals within the cohort presented with BD type I, 26 (0.6%) with BD type II, and 87 (2.3%) with BD not otherwise specified. Frequency of female individuals was 58.82% (n = 150) in the BD sample and 53.02% (n = 1868) among the unaffected population. The model with variables assessed at the 18-year follow-up visit achieved the best performance: AUC 0.82 (CI 0.75-0.88), balanced accuracy 0.75, sensitivity 0.72, and specificity 0.77. The most important variables to detect BD at the 18-year follow-up visit were suicide risk, generalized anxiety disorder, parental physical abuse, and financial problems. Additionally, the high-risk subgroup of BD showed a high frequency of drug use and depressive symptoms. CONCLUSIONS: We developed a risk calculator for BD incorporating both demographic and clinical variables from a 22-year birth cohort. Our findings support previous studies in high-risk samples showing the significance of suicide risk and generalized anxiety disorder prior to the onset of BD, and highlight the role of social factors and adverse life events.

Risk of dementia in bipolar disorder and the interplay of lithium: a systematic review and meta-analyses.

OBJECTIVES: To assess whether bipolar disorder (BD) increases the rate of dementia and whether lithium is related to a lower risk of dementia in BD. METHODS: A total of 10 studies (6859 BD; 487 966 controls) were included in the meta-analysis to test whether BD is a risk factor for dementia. In addition, five studies (6483 lithium; 43 496 non-lithium) were included in the meta-analysis about the potential protective effect of lithium in BD. RESULTS: BD increases the risk of dementia (odds ratio (OR): 2.96 [95% CI: 2.09-4.18], P < 0.001), and treatment with lithium decreases the risk of dementia in BD (OR: 0.51 [95% CI: 0.36-0.72], P < 0.0001). In addition, secondary findings from our systematic review showed that the risk of progression to dementia is higher in BD than in major depressive disorder (MDD). Moreover, the number of mood episodes predicted the development of dementia in BD. CONCLUSION: Individuals with BD are at higher risk of dementia than both the general population or those with MDD. Lithium appears to reduce the risk of developing dementia in BD.

Emotional hyper-reactivity and cardiometabolic risk in remitted bipolar patients: a machine learning approach.

OBJECTIVE: Remitted bipolar disorder (BD) patients frequently present with chronic mood instability and emotional hyper-reactivity, associated with poor psychosocial functioning and low-grade inflammation. We investigated emotional hyper-reactivity as a dimension for characterization of remitted BD patients, and clinical and biological factors for identifying those with and without emotional hyper-reactivity. METHOD: A total of 635 adult remitted BD patients, evaluated in the French Network of Bipolar Expert Centers from 2010-2015, were assessed for emotional reactivity using the Multidimensional Assessment of Thymic States. Machine learning algorithms were used on clinical and biological variables to enhance characterization of patients. RESULTS: After adjustment, patients with emotional hyper-reactivity (n = 306) had significantly higher levels of systolic and diastolic blood pressure (P < 1.0 × 10-8 ), high-sensitivity C-reactive protein (P < 1.0 × 10-8 ), fasting glucose (P < 2.23 × 10-6 ), glycated hemoglobin (P = 0.0008) and suicide attempts (P = 1.4 × 10-8 ). Using models of combined clinical and biological factors for distinguishing BD patients with and without emotional hyper-reactivity, the strongest predictors were: systolic and diastolic blood pressure, fasting glucose, C-reactive protein and number of suicide attempts. This predictive model identified patients with emotional hyper-reactivity with 84.9% accuracy. CONCLUSION: The assessment of emotional hyper-reactivity in remitted BD patients is clinically relevant, particularly for identifying those at higher risk of cardiometabolic dysfunction, chronic inflammation, and suicide.

Association of intracortical myelin and cognitive function in bipolar I disorder.

OBJECTIVE: Although cognitive dysfunction persists through affective and euthymic states in bipolar disorder (BD), its neurobiological correlates remain undetermined. We explore whole-cortex intracortical myelin (ICM) and cognition in BD-I and controls. METHODS: T1 -weighted images (3T) optimized for ICM measurement were analyzed using a surface-based approach. MRI signal was sampled at cortical mid-depth. Cognitive performance was measured via standardized computerized battery and paper-and-pencil Trails B. RESULTS: ICM was associated with verbal memory (VM) in BD throughout a cortical network identified with pertinence to VM function, with strongest effects in left caudal middle temporal cortex and left dorsolateral prefrontal cortex (Pcorrected  < 0.05). Subanalyses revealed specific association with correct word recognition, without delay. Processing speed, executive function, and reaction time were also predicted by ICM in BD, but not controls, although this did not survive Bonferroni correction. CONCLUSION: This is the first study to show VM association with ICM in BD. ICM has been implicated in the integrity of neural connections and neural synchrony. VM dysfunction is one of the most replicated cognitive abnormalities in BD. Therefore, these results provide a novel mechanism for understanding cognitive dysfunction in BD, which can aid in the development of targeted therapeutics to improve cognitive outcomes in BD.

Mood disorders and prospective suicidality in young adults: a population-based cohort study.

OBJECTIVE: To assess the prospective associations of mood disorders and suicidality in a community sample of young adults from south Brazil. METHOD: Prospective population-based cohort study. Young adults (18-24 years old) were recruited and followed up on 5 years later; people were interviewed at their homes. Suicidality, as well as mood and anxiety disorders, was assessed using the Mini-International Neuropsychiatric Interview. The impact of mood episodes on suicidality was both evaluated when they occurred in the same wave (a current episode) and when suicidality occurred prospectively, with suicidality measured at follow-up (a past episode). RESULTS: The sample included 1560 young adults at baseline, with 1244 reassessed at follow-up (80.6%). Depressive episodes, both current and past, had a significant impact on suicidality in the final multivariable model. Manic episodes, however, were less consistently associated with suicidality. CONCLUSION: Depressive episodes have a strong, independent, and robust association with prospective suicidality. The association between manic episodes and suicidality, on the other hand, was dependent on the analysis and deserves further exploration.

Solar insolation in springtime influences age of onset of bipolar I disorder.

OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density. RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001). CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

Differential expression of transcriptional regulatory units in the prefrontal cortex of patients with bipolar disorder: potential role of early growth response gene 3.

Bipolar disorder (BD) is a severe mental illness with a strong genetic component. Despite its high degree of heritability, current genetic studies have failed to reveal individual loci of large effect size. In lieu of focusing on individual genes, we investigated regulatory units (regulons) in BD to identify candidate transcription factors (TFs) that regulate large groups of differentially expressed genes. Network-based approaches should elucidate the molecular pathways governing the pathophysiology of BD and reveal targets for potential therapeutic intervention. The data from a large-scale microarray study was used to reconstruct the transcriptional associations in the human prefrontal cortex, and results from two independent microarray data sets to obtain BD gene signatures. The regulatory network was derived by mapping the significant interactions between known TFs and all potential targets. Five regulons were identified in both transcriptional network models: early growth response 3 (EGR3), TSC22 domain family, member 4 (TSC22D4), interleukin enhancer-binding factor 2 (ILF2), Y-box binding protein 1 (YBX1) and MAP-kinase-activating death domain (MADD). With a high stringency threshold, the consensus across tests was achieved only for the EGR3 regulon. We identified EGR3 in the prefrontal cortex as a potential key target, robustly repressed in both BD signatures. Considering that EGR3 translates environmental stimuli into long-term changes in the brain, disruption in biological pathways involving EGR3 may induce an impaired response to stress and influence on risk for psychiatric disorders, particularly BD.

BDNF Val66Met polymorphism and peripheral protein levels in pediatric bipolar disorder and attention-deficit/hyperactivity disorder.

OBJECTIVE: Frontiers between pediatric bipolar disorder (PBD) and attention-deficit/hyperactivity disorder (ADHD) are not well defined. Few studies have addressed potentially different neurobiological factors between the two disorders. Brain-derived neurotrophic factor (BDNF) has been increasingly recognized for its etiologic and prognostic role in adult bipolar disorder (BD) studies. This study aimed to examine the BDNF gene polymorphism and potential alterations in BDNF serum levels in the pediatric ADHD patients with or without comorbid BD illness. METHOD: We assessed the non-synonymous single-nucleotide polymorphism in the BDNF gene (rs6265/Val66Met) and its serum levels in children and adolescents with BD comorbid with ADHD (BD + ADHD) and ADHD alone. Children and adolescents were assessed for psychiatric diagnoses using the Kiddie-Sads-Present and Lifetime Version (K-SADS-PL). RESULTS: Using Analysis of covariance (ancova) we detected a significant group effect (patients with BD + ADHD had higher serum levels than those with ADHD - F80,3 = 8.73, P = 0.005). CONCLUSION: Although the Val66Met polymorphism at the BDNF gene does not seem to play a significant role in children and adolescents with BD or ADHD, BDNF serum levels deserve further attention in future research on neurobiological aspects of BD and ADHD.

Areas of controversy in neuroprogression in bipolar disorder.

OBJECTIVE: We aimed to review clinical features and biological underpinnings related to neuroprogression in bipolar disorder (BD). Also, we discussed areas of controversy and future research in the field. METHOD: We systematically reviewed the extant literature pertaining to neuroprogression and BD by searching PubMed and EMBASE for articles published up to March 2016. RESULTS: A total of 114 studies were included. Neuroimaging and clinical evidence from cross-sectional and longitudinal studies show that a subset of patients with BD presents a neuroprogressive course with brain changes and unfavorable outcomes. Risk factors associated with these unfavorable outcomes are number of mood episodes, early trauma, and psychiatric and clinical comorbidity. CONCLUSION: Illness trajectories are largely variable, and illness progression is not a general rule in BD. The number of manic episodes seems to be the clinical marker more robustly associated with neuroprogression in BD. However, the majority of the evidence came from cross-sectional studies that are prone to bias. Longitudinal studies may help to identify signatures of neuroprogression and integrate findings from the field of neuroimaging, neurocognition, and biomarkers.

Childhood trauma, family history, and their association with mood disorders in early adulthood.

OBJECTIVE: To assess the prevalence of childhood trauma and types of trauma on mood disorders among young adults in a population-based sample. We further gathered data on family history of mood disorders to test the hypothesis that childhood trauma is a mediating factor for the association between family history of mood disorder and mood disorder in adulthood. METHOD: This is a cross-sectional study, including young adults with bipolar disorder, major depressive disorder, and matched controls without any mood disorder. Childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). The Hicks and Tingley implementation was employed to assess whether trauma is a mediator of the effect of family history on diagnosis of any mood disorder. RESULTS: All types of trauma were associated with both major depression and bipolar disorder, with the exception of sexual abuse, which was only associated with bipolar disorder. Moreover, family history of psychiatric illness was also associated with mood disorder in adulthood and with childhood trauma. Using the presence of any mood disorder as the outcome, a third of the effect of having any family history of mood disorder was mediated via childhood trauma. CONCLUSION: This investigation provides further support, in a population-based sample of young adults, of the association between childhood trauma and mood disorders, with sexual abuse being specifically linked with bipolar disorder. The hypothesis that childhood trauma would function as a partial mediator of the association between family history of mood disorder and mood disorder in adulthood was also confirmed.

Glucocorticoid Receptors, Brain-Derived Neurotrophic Factor, Serotonin and Dopamine Neurotransmission are Associated with Interferon-Induced Depression.

BACKGROUND: The role of inflammation in mood disorders has received increased attention. There is substantial evidence that cytokine therapies, such as interferon alpha (IFN-alpha), can induce depressive symptoms. Indeed, proinflammatory cytokines change brain function in several ways, such as altering neurotransmitters, the glucocorticoid axis, and apoptotic mechanisms. This study aimed to evaluate the impact on mood of initiating IFN-alpha and ribavirin treatment in a cohort of patients with chronic hepatitis C. We investigated clinical, personality, and functional genetic variants associated with cytokine-induced depression. METHODS: We recruited 344 Caucasian outpatients with chronic hepatitis C, initiating IFN-alpha and ribavirin therapy. All patients were euthymic at baseline according to DSM-IV-R criteria. Patients were assessed at baseline and 4, 12, 24, and 48 weeks after treatment initiation using the Patient Health Questionnaire (PHQ), the Hospital Anxiety and Depression Scale (HADS), and the Temperament and Character Inventory (TCI). We genotyped several functional polymorphisms of interleukin-28 (IL28B), indoleamine 2,3-dioxygenase (IDO-1), serotonin receptor-1A (HTR1A), catechol-O-methyl transferase (COMT), glucocorticoid receptors (GCR1 and GCR2), brain-derived neurotrophic factor (BDNF), and FK506 binding protein 5 (FKBP5) genes. A survival analysis was performed, and the Cox proportional hazards model was used for the multivariate analysis. RESULTS: The cumulative incidence of depression was 0.35 at week 24 and 0.46 at week 48. The genotypic distributions were in Hardy-Weinberg equilibrium. Older age (p = 0.018, hazard ratio [HR] per 5 years = 1.21), presence of depression history (p = 0.0001, HR = 2.38), and subthreshold depressive symptoms at baseline (p = 0.005, HR = 1.13) increased the risk of IFN-induced depression. So too did TCI personality traits, with high scores on fatigability (p = 0.0037, HR = 1.17), impulsiveness (p = 0.0200 HR = 1.14), disorderliness (p = 0.0339, HR = 1.11), and low scores on extravagance (p = 0.0040, HR = 0.85). An interaction between HTR1A and COMT genes was found. Patients carrying the G allele of HTR1A plus the Met substitution of the COMT polymorphism had a greater risk for depression during antiviral treatment (HR = 3.83) than patients with the CC (HTR1A) and Met allele (COMT) genotypes. Patients carrying the HTR1A CC genotype and the COMT Val/Val genotype (HR = 3.25) had a higher risk of depression than patients with the G allele (HTR1A) and the Val/Val genotype. Moreover, functional variants of the GCR1 (GG genotype: p = 0.0436, HR = 1.88) and BDNF genes (Val/Val genotype: p = 0.0453, HR = 0.55) were associated with depression. CONCLUSIONS: The results of the study support the theory that IFN-induced depression is associated with a complex pathophysiological background, including serotonergic and dopaminergic neurotransmission as well as glucocorticoid and neurotrophic factors. These findings may help to improve the management of patients on antiviral treatment and broaden our understanding of the pathogenesis of mood disorders.

The association between biological rhythms, depression, and functioning in bipolar disorder: a large multi-center study.

OBJECTIVE: We examined the relationship between biological rhythms and severity of depressive symptoms in subjects with bipolar disorder and the effects of biological rhythms alterations on functional impairment. METHOD: Bipolar patients (n = 260) and healthy controls (n = 191) were recruited from mood disorders programs in three sites (Spain, Brazil, and Canada). Parameters of biological rhythms were measured using the Biological Rhythms Assessment in Neuropsychiatry (BRIAN), an interviewer administered questionnaire that assesses disruptions in sleep, eating patterns, social rhythms, and general activity. RESULTS: Multivariate analyses of covariance showed significant intergroup differences after controlling for potential confounders (Pillai's F = 49.367; df = 2, P < 0.001). Depressed patients had the greatest biological rhythms disturbance, followed by patients with subsyndromal symptoms, euthymic patients, and healthy controls. Biological rhythms and HAMD scores were independent predictors of poor functioning (F = 12.841, df = 6, P < 0.001, R2  = 0.443). CONCLUSION: Our study shows a dose-dependent association between the severity of depressive symptoms and degree of biological rhythms disturbance. Biological rhythms disturbance was also an independent predictor of functional impairment. Although the directionality of this relationship remains unknown, our results suggest that stability of biological rhythms should be an important target of acute and long-term management of bipolar disorder and may aid in the improvement of functioning.

Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: A CANMAT randomized double-blind trial.

Atypical antipsychotic adjunctive therapy to lithium or valproate is effective in treating acute mania. Although continuation of atypical antipsychotic adjunctive therapy after mania remission reduces relapse of mood episodes, the optimal duration is unknown. As many atypical antipsychotics cause weight gain and metabolic syndrome, they should not be continued unless the benefits outweigh the risks. This 52-week double-blind placebo-controlled trial recruited patients with bipolar I disorder (n=159) who recently remitted from a manic episode during treatment with risperidone or olanzapine adjunctive therapy to lithium or valproate. Patients were randomized to one of three conditions: discontinuation of risperidone or olanzapine and substitution with placebo at (i) entry ('0-weeks' group) or (ii) at 24 weeks after entry ('24-weeks' group) or (iii) continuation of risperidone or olanzapine for the full duration of the study ('52-weeks' group). The primary outcome measure was time to relapse of any mood episode. Compared with the 0-weeks group, the time to any mood episode was significantly longer in the 24-weeks group (hazard ratio (HR) 0.53; 95% confidence interval (CI): 0.33, 0.86) and nearly so in the 52-weeks group (HR: 0.63; 95% CI: 0.39, 1.02). The relapse rate was similar in the 52-weeks group compared with the 24-weeks group (HR: 1.18; 95% CI: 0.71, 1.99); however, sub-group analysis showed discordant results between the two antipsychotics (HR: 0.48, 95% CI: 0.17; 1.32 olanzapine patients; HR: 1.85, 95% CI: 1.00, 3.41 risperidone patients). Average weight gain was 3.2 kg in the 52-weeks group compared with a weight loss of 0.2 kg in the 0-weeks and 0.1 kg in the 24-weeks groups. These findings suggest that risperidone or olanzapine adjunctive therapy for 24 weeks is beneficial but continuation of risperidone beyond this period does not reduce the risk of relapse. Whether continuation of olanzapine beyond this period reduces relapse risk remains unclear but the potential benefit needs to be weighed against an increased risk of weight gain.

Interaction between SLC6A4 promoter variants and childhood trauma on the age at onset of bipolar disorders.

Age at onset (AAO) of bipolar disorders (BD) could be influenced both by a repeat length polymorphism (5HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) and exposure to childhood trauma. We assessed 308 euthymic patients with BD for the AAO of their first mood episode and childhood trauma. Patients were genotyped for the 5HTTLPR (long/short variant) and the rs25531. Genotypes were classified on functional significance (LL, LS, SS). A sample of 126 Brazilian euthymic patients with BD was used for replication. In the French sample, the correlation between AAO and trauma score was observed only among 'SS' homozygotes (p = 0.002) but not among 'L' allele carriers. A history of at least one trauma decreased the AAO only in 'SS' homozygotes (p = 0.001). These results remained significant after correction using FDR. Regression models suggested an interaction between emotional neglect and 'SS' genotype on the AAO (p = 0.009) and no further interaction with other trauma subtypes. Partial replication was obtained in the Brazilian sample, showing an interaction between emotional abuse and 'LS' genotype on the AAO (p = 0.02). In conclusion, an effect of childhood trauma on AAO of BD was observed only in patients who carry a specific stress responsiveness-related SLC6A4 promoter genotype.

The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders.

Psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia, affect a significant percentage of the world population. These disorders are associated with educational difficulties, decreased productivity and reduced quality of life, but their underlying pathophysiological mechanisms are not fully elucidated. Recently, studies have suggested that psychiatric disorders could be considered as inflammatory disorders, even though the exact mechanisms underlying this association are not known. An increase in inflammatory response and oxidative stress may lead to inflammation, which in turn can stimulate microglia in the brain. Microglial activation is roused by the M1 phenotype, which is associated with an increase in interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). On the contrary, M2 phenotype is associated with a release of anti-inflammatory cytokines. Thus, it is possible that the inflammatory response from microglial activation can contribute to brain pathology, as well as influence treatment responses. This review will highlight the role of inflammation in the pathophysiology of psychiatric disorders, such as MDD, BD, schizophrenia, and autism. More specifically, the role of microglial activation and associated molecular cascades will also be discussed as a means by which these neuroinflammatory mechanisms take place, when appropriate.

Damage-associated molecular patterns and immune activation in bipolar disorder.

OBJECTIVE: Immune activation in bipolar disorder (BD) has been frequently reported. Damage-associated molecular patterns (DAMPs) are key players in the immune activation reaction. The aim of this study was to assess DAMP levels in drug-free patients with BD during acute episodes. METHOD: Serum levels of a predetermined set of DAMPs were assessed in drug-free patients with BD (n = 20) during an acute mood episode. We also included two control groups: healthy subjects, used as a negative control (n = 20); and patients with sepsis, used as a positive control for severe immune activation (n = 20). RESULTS: Multivariate analysis using generalized linear mixed model indicated that all DAMPs differed as a function of group membership after controlling for age and addressing multiplicity (P < 0.0006 for all comparisons). Follow-up analyses showed higher levels in BD subjects of circulating cell-free (ccf) nuclear (n)DNA (P = 0.02), HSP70 (P = 0.03) and HSP90α (P = 0.02) as compared to healthy subjects. Also, patients with BD showed lower levels of ccf nDNA (P = 0.04), HSP60 (P = 0.03), HSP70 (P = 0.01), and HSP90α (P = 0.002) as compared to patients with sepsis and higher levels of ccf mitochondrial DNA (P < 0.0001). CONCLUSION: The present findings may be linked to the inflammatory activity previously described among patients with BD and may help in the development of more targeted and personalized treatments for patients under acute episodes of BD.

Changes in the corpus callosum in women with late-stage bipolar disorder.

OBJECTIVE: This study investigated the differences in corpus callosum (CC) volumes between women with early-stage and late-stage bipolar I (BP I) disorder using the criteria previously described in the literature. METHOD: We compared women with early- and late-stage BP I using criteria described in the Staging Systems Task Force Report of the International Society for Bipolar Disorders. We included 20 patients with early stage and 21 patients with late-stage BP I and a group of 25 healthy controls. Patients and controls underwent structural magnetic resonance imaging. Information on the clinical features of bipolar disorder was collected using a standardized questionnaire. Anatomical volumes of five regions of CC were compared between the three groups. RESULTS: Women with late-stage BP I disorder had reduced posterior CC volumes compared with early-stage bipolar I patients and controls (F = 6.05; P = 0.004). The difference was significant after controlling for age, comorbidity with post-traumatic stress disorder, psychotic symptoms during mood episodes, and current use of medication. CONCLUSION: The posterior CC was significantly decreased in volume in women with late-stage bipolar disorder. These findings suggest that CC may be an anatomical target of neuroprogression in the course of bipolar disorder in women.