Structural connectivity associated with familial risk for mental illness: A meta-analysis of diffusion tensor imaging studies in relatives of patients with severe mental disorders.

Schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) are heritable conditions with overlapping genetic liability. Transdiagnostic and disorder-specific brain changes associated with familial risk for developing these disorders remain poorly understood. We carried out a meta-analysis of diffusion tensor imaging (DTI) studies to investigate white matter microstructure abnormalities in relatives that might correspond to shared and discrete biomarkers of familial risk for psychotic or mood disorders. A systematic search of PubMed and Embase was performed to identify DTI studies in relatives of SCZ, BD, and MDD patients. Seed-based d Mapping software was used to investigate global differences in fractional anisotropy (FA) between overall and disorder-specific relatives and healthy controls (HC). Our search identified 25 studies that met full inclusion criteria. A total of 1,144 relatives and 1,238 HC were included in the meta-analysis. The overall relatives exhibited decreased FA in the genu and splenium of corpus callosum (CC) compared with HC. This finding was found highly replicable in jack-knife analysis and subgroup analyses. In disorder-specific analysis, compared to HC, relatives of SCZ patients exhibited the same changes while those of BD showed reduced FA in the left inferior longitudinal fasciculus (ILF). The present study showed decreased FA in the genu and splenium of CC in relatives of SCZ, BD, and MDD patients, which might represent a shared familial vulnerability marker of severe mental illness. The white matter abnormalities in the left ILF might represent a specific familial risk for bipolar disorder.

N-acetylcysteine as an adjunctive treatment for bipolar depression: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: Previous studies and meta-analyses suggested that N-acetylcysteine (NAC) was superior to placebo in improving depression in bipolar disorder. However, more recent data, including two larger trials, found that NAC was no more effective than placebo. We conducted a meta-analysis to appraise the possible efficacy of NAC in treating bipolar depression. METHODS: A systematic review and meta-analysis of double-blind, placebo-controlled trials of NAC as a treatment augmentation strategy for bipolar depression was carried out in PubMed (1966-2020). We utilized random-effect analysis to evaluate improvement in depressive symptoms from baseline to endpoint as the primary efficacy measure. RESULTS: Six trials including 248 patients were included. Treatment augmentation with NAC showed a moderate effect size favoring NAC over placebo (d = 0.45, 95% C.I.: 0.06-0.84). There was substantial heterogeneity (I2  = 49%). Meta-regression analyses did not identify any moderator that might explain variation in heterogeneity, including baseline depressive symptom scores, mean NAC dose, or duration of study. CONCLUSIONS: Results from six clinical trials suggest that treatment augmentation with NAC for bipolar depression appears to be superior to placebo, with a moderate effect size, but a large confidence interval. Larger clinical trials, investigating possible moderating factors, such as NAC dose, treatment duration, baseline depression severity, or chronicity of illness, are warranted.

Individual prediction of symptomatic converters in youth offspring of bipolar parents using proton magnetic resonance spectroscopy.

Children of individuals with bipolar disorder (bipolar offspring) are at increased risk for developing mood disorders, but strategies to predict mood episodes are unavailable. In this study, we used support vector machine (SVM) to characterize the potential of proton magnetic resonance spectroscopy (1H-MRS) in predicting the first mood episode in youth bipolar offspring. From a longitudinal neuroimaging study, 19 at-risk youth who developed their first mood episode (converters), and 19 without mood episodes during follow-up (non-converters) were selected and matched for age, sex and follow-up time. Baseline 1H-MRS data were obtained from anterior cingulate cortex (ACC) and bilateral ventrolateral prefrontal cortex (VLPFC). Glutamate (Glu), myo-inositol (mI), choline (Cho), N-acetyl aspartate (NAA), and phosphocreatine plus creatine (PCr + Cr) levels were calculated. SVM with a linear kernel was adopted to classify converters and non-converters based on their baseline metabolites. SVM allowed the significant classification of converters and non-converters across all regions for Cho (accuracy = 76.0%), but not for other metabolites. Considering all metabolites within each region, SVM allowed the significant classification of converters and non-converters for left VLPFC (accuracy = 76.5%), but not for right VLPFC or ACC. The combined mI, PCr + Cr, and Cho from left VLPFC achieved the highest accuracy differentiating converters from non-converters (79.0%). Our findings from this exploratory study suggested that 1H-MRS levels of mI, Cho, and PCr + Cr from left VLPFC might be useful to predict the development of first mood episode in youth bipolar offspring using machine learning. Future studies that prospectively examine and validate these metabolites as predictors of mood episodes in high-risk individuals are necessary.

Longitudinal proton spectroscopy study of the prefrontal cortex in youth at risk for bipolar disorder before and after their first mood episode.

OBJECTIVES: To investigate neurochemical abnormalities in the left and right ventrolateral prefrontal cortex (VLPFC) and anterior cingulate cortex (ACC) of youth at risk for bipolar disorder using proton magnetic resonance spectroscopy before and after their first mood episode. METHODS: Children and adolescents offspring of parents with bipolar I disorder (at-risk group, n = 117) and matched healthy controls (HC group, n = 61) were recruited at the University of Cincinnati. At-risk subjects had no lifetime major mood and psychotic disorders at baseline, and were followed up every 4 months to monitor for development of a major depressive, manic, hypomanic, or mixed mood episode. Levels of N-acetyl-aspartate (NAA), phosphocreatine plus creatine (PCr + Cr), choline-containing compounds, myo-inositol, and glutamate were determined using LCModel and corrected for partial volume effects. RESULTS: There were no baseline differences in metabolite levels for any of the brain regions between at-risk and HC youth. Nineteen at-risk subjects developed a first mood episode during follow-up. Survival analyses showed that baseline PCr + Cr levels in the left VLPFC significantly predicted a mood episode during follow-up in the at-risk group (HR: 0.47, 95% CI: 0.27-0.82, P = 0.008). There were no longitudinal changes in metabolites levels in the VLPFC and ACC before and after a mood episode in at-risk subjects. CONCLUSIONS: We found no evidence for abnormal proton spectroscopy metabolite levels in the VLPFC and ACC of at-risk youth, prior and after the development of their first mood episode. Preliminary findings of association between baseline PCr + Cr levels in the left VLPFC and risk to develop a mood episode warrant further investigation.

The International Society for Bipolar Disorders Task Force report on pediatric bipolar disorder: Knowledge to date and directions for future research.

OBJECTIVES: Over the past two decades, there has been tremendous growth in research regarding bipolar disorder (BD) among children and adolescents (ie, pediatric BD [PBD]). The primary purpose of this article is to distill the extant literature, dispel myths or exaggerated assertions in the field, and disseminate clinically relevant findings. METHODS: An international group of experts completed a selective review of the literature, emphasizing areas of consensus, identifying limitations and gaps in the literature, and highlighting future directions to mitigate these gaps. RESULTS: Substantial, and increasingly international, research has accumulated regarding the phenomenology, differential diagnosis, course, treatment, and neurobiology of PBD. Prior division around the role of irritability and of screening tools in diagnosis has largely abated. Gold-standard pharmacologic trials inform treatment of manic/mixed episodes, whereas fewer data address bipolar depression and maintenance/continuation treatment. Adjunctive psychosocial treatment provides a forum for psychoeducation and targets primarily depressive symptoms. Numerous neurocognitive and neuroimaging studies, and increasing peripheral biomarker studies, largely converge with prior findings from adults with BD. CONCLUSIONS: As data have accumulated and controversy has dissipated, the field has moved past existential questions about PBD toward defining and pursuing pressing clinical and scientific priorities that remain. The overall body of evidence supports the position that perceptions about marked international (US vs elsewhere) and developmental (pediatric vs adult) differences have been overstated, although additional research on these topics is warranted. Traction toward improved outcomes will be supported by continued emphasis on pathophysiology and novel therapeutics.

Facial emotion recognition in euthymic patients with bipolar disorder and their unaffected first-degree relatives.

BACKGROUND: Facial emotion recognition (FER) is an important task associated with social cognition because facial expression is a significant source of non-verbal information that guides interpersonal relationships. Increasing evidence suggests that bipolar disorder (BD) patients present deficits in FER and these deficits may be present in individuals at high genetic risk for BD. The aim of this study was to evaluate the occurrence of FER deficits in euthymic BD patients, their first-degree relatives, and healthy controls (HC) and to consider if these deficits might be regarded as an endophenotype candidate for BD. METHODS: We studied 23 patients with DSM-IV BD type I, 22 first-degree relatives of these patients, and 27 HC. We used the Penn Emotion Recognition Tests to evaluate tasks of FER, emotion discrimination, and emotional acuity. Patients were recruited from outpatient facilities at the Institute of Psychiatry of the University of Sao Paulo Medical School, or from the community through media advertisements, had to be euthymic, with age above 18years old and a diagnosis of DSM-IV BD type I. RESULTS: Euthymic BD patients presented significantly fewer correct responses for fear, and significantly increased time to response to recognize happy faces when compared with HC, but not when compared with first-degree relatives. First-degree relatives did not significantly differ from HC on any of the emotion recognition tasks. CONCLUSION: Our results suggest that deficits in FER are present in euthymic patients, but not in subjects at high genetic risk for BD. Thus, we have not found evidence to consider FER as an endophenotype candidate for BD.

Prevalence and clinical correlates of alcohol use disorders among bipolar disorder patients: results from the Brazilian Bipolar Research Network.

OBJECTIVES: To investigate prevalence rates and clinical correlates of alcohol use disorders (AUD) among bipolar disorder (BD) patients in a large sample from the Brazilian Bipolar Research Network. METHODS: Four hundred and eighty-three DSM-IV BD patients, divided according to the presence or absence of a lifetime AUD diagnosis (BD-AUD vs. BD-nonAUD), were included. Demographic and clinical characteristics of these two groups were compared. Logistic regression was performed to identify which characteristics were most strongly associated with a lifetime AUD diagnosis. RESULTS: Nearly 23% presented a lifetime AUD diagnosis. BD-AUD patients were more likely to be male, to present rapid cycling, post-traumatic stress disorder (PTSD), anorexia, other substance use disorders (SUD), family history of SUD, any substance misuse during the first mood episode, history of psychosis, suicide attempts, and younger age at onset of illness than BD-nonAUD patients. Logistic regression showed that the variables most strongly associated with a lifetime AUD diagnosis were SUD (non-alcohol), any substance misuse during the first mood episode, PTSD, male gender, suicide attempt, family history of SUD, and younger age at onset of BD. CONCLUSIONS: BD-AUD patients begin their mood disorder earlier and present more suicidal behaviors than BD-nonAUD patients. Personal and family history of SUD may be good predictors of comorbid AUD among BD patients. These variables are easily assessed in the clinical setting and may help to identify a particularly severe subgroup of BD patients.

Editorial: A Roadmap for Advancing the Field in Early-Onset Psychosis.

The number of umbrella reviews, the systematic reviews of all systematic reviews and meta-analyses in a specified subject, have increased exponentially in recent years. In February 2024, a PubMed search with the term "umbrella review" yielded 840 publications in 2023, compared with 77 in 2013, and 16 in 2003. As the number of scientific publications grows, also does the need to synthesize the current state of knowledge to guide research efforts, clinical practice, and health policies.1,2.

A sib-pair analysis of impulsivity in bipolar disorder type I.

OBJECTIVE: The aim of this study was to compare impulsivity among patients with bipolar disorder, their siblings, and healthy controls in order to examine whether impulsivity in bipolar disorder is related to genetic liability for the illness. METHODS: Using the Barratt Impulsiveness Scale, we assessed 204 subjects: 67 euthymic outpatients with bipolar disorder type I, 67 siblings without bipolar disorder, and 70 healthy controls. RESULTS: Impulsivity scores were higher among patients with bipolar disorder than among healthy controls. Siblings showed higher motor impulsivity scores than did healthy controls. CONCLUSIONS: Our results suggest that motor impulsivity may be a vulnerability marker for bipolar disorder. Our data may contribute to further improve preventive strategies in subjects at high risk for bipolar disorder.

Gray matter abnormalities as brain structural vulnerability factors for bipolar disorder: A review of neuroimaging studies of individuals at high genetic risk for bipolar disorder.

OBJECTIVE: Cortical and subcortical gray matter abnormalities have been reported in individuals at high genetic risk for bipolar disorder, but the findings are inconsistent. The aim of this study was to review the available literature to identify common findings that could represent brain structural vulnerability factors for bipolar disorder and to discuss challenges for the advancement of the field. METHOD: A systematic search was conducted using the PubMed database to identify all original articles investigating cortical or subcortical gray matter abnormalities in first-degree relatives of bipolar disorder patients. RESULTS: Very few findings were replicated, with the exception of larger insular cortex volumes in adult first-degree relatives and larger right inferior frontal gyrus in offspring of probands with bipolar disorder, both when compared with healthy controls. Isolated findings included decreased gray matter density in the left thalamus, decreased gray matter volumes in the left hippocampus and parahippocampal gyrus, and thicker right hippocampus in unaffected first-degree relatives. Genetic liability for bipolar disorder was associated with gray matter volumes in regions of the anterior cingulate cortex, ventral striatum, medial frontal gyrus, right precentral gyrus, right insular cortex, and medial orbital gyrus. Some studies found no evidence for gray matter abnormalities in first-degree relatives of bipolar disorder patients. CONCLUSIONS: Possible reasons for the discrepancies of findings across studies include small samples sizes, small effect size of susceptibility genes, the phenotypic heterogeneity of bipolar disorder, and the possible confounding effect of other Axis I psychopathologies among the relatives of patients. Future multisite, prospective, large studies with more homogeneous samples would be a key strategy to advance the field. The ultimate benefit would be an understanding of how to use brain imaging tools to identify individuals at increased risk for bipolar disorder and develop preventive strategies for that population.

Trait impulsivity is increased in bipolar disorder patients with comorbid alcohol use disorders.

BACKGROUND: Up to 60% of bipolar disorder (BD) patients develop alcohol use disorders (AUD) at some point in their lives. The causes of this highly prevalent comorbidity are unknown. High trait impulsivity characterizes both isolated BD and AUD and may be a link to explain the association between BD and AUD. In this study, our aims were to investigate whether BD patients with comorbid AUD would present higher trait impulsivity levels compared to BD patients without comorbid AUD, and whether trait impulsivity levels differ within subgroups of BD according to the subcategory of AUD (abuse vs. dependence, alcoholism alone vs. alcoholism plus drug use disorders). SAMPLING AND METHODS: Forty-seven outpatients with BD with comorbid AUD (alcoholic BD group) were compared to 66 outpatients with BD alone (nonalcoholic BD group) and to 90 healthy controls (HC). BD and AUD diagnoses were obtained using the Structured Clinical Interview for DSM-IV diagnoses. Impulsivity was assessed using the Barratt Impulsiveness Scale (BIS-11), a self-report instrument that measures trait impulsivity in three domains: nonplanning, attentional and motor. RESULTS: Alcoholic BD patients scored significantly higher than nonalcoholic BD and HC on the total and on each subscale BIS scores. Within the alcoholic BD patients, alcohol abusers and alcohol dependents did not statistically differ from each other on the BIS-11 scores. BD patients with AUD plus drug use disorders presented statistically higher nonplanning impulsivity than BD patients with AUD alone. CONCLUSIONS: This was a cross-sectional study and causal inferences about the relationship between impulsivity and the comorbidity phenomenon cannot be made. Increased impulsivity may be a trait marker for the co-occurrence between BD and AUD, and mediate some severe manifestations of this comorbidity.

Brain functional activation and first mood episode in youth at risk for bipolar disorder.

BACKGROUND: In order to identify biomarkers of prodromal mood disorders, we examined functional brain activation in children and adolescent at familial risk for bipolar disorder. METHODS: Offspring of parents with bipolar I disorder (at-risk youth; N = 115, mean ± SD age: 13.6 ± 2.7; 54 % girls) and group-matched offspring of healthy parents (healthy controls; N = 58, mean ± SD age: 14.2 ± 3.0; 53 % girls) underwent functional magnetic resonance imaging while performing a continuous performance task with emotional and neutral distracters. At baseline, at-risk youth had no history of mood episodes or psychotic disorders. Subjects were followed longitudinally until developing their first mood episode or being lost to follow-up. Standard event-related region-of-interest (ROI) analyses were performed to compare brain activation at baseline between groups and in survival analyses. RESULTS: At baseline, at-risk youth exhibited reduced activation to emotional distracters in the right ventrolateral prefrontal cortex (VLPFC) (p = 0.04). Activation was not significantly altered in additional ROIs, including left VLPFC, bilateral amygdala, caudate, or putamen. In those at-risk youth who developed their first mood episode during follow-up (n = 17), baseline increased activation in right VLPFC, right caudate, and right putamen activation predicted the development of a mood episode. LIMITATIONS: Sample size of converters, loss to follow-up, and number of statistical comparisons. CONCLUSIONS: We found preliminary evidence that a reduced activation in right VLPFC might be a marker of risk for or resilience to mood disorders in at-risk youth. Conversely, an increased activation in the right VLPFC, caudate, and putamen might indicate an increased risk for the later development of their first mood episode.

Abnormal resting state corticolimbic blood flow in depressed unmedicated patients with major depression: a (15)O-H(2)O PET study.

We investigated the differences in the resting state corticolimbic blood flow between 20 unmedicated depressed patients and 21 healthy comparisons. Resting state cerebral blood flow (CBF) was measured with H(2)(15)O PET. Anatomical MRI scans were performed on an Elscint 1.9 T Prestige system for PET-MRI coregistration. Significant changes in cerebral blood flow indicating neural activity were detected using an ROI-free image subtraction strategy. In addition, the resting blood flow in patients was correlated with the severity of depression as measured by HAM-D scores. Depressed patients showed decreases in blood flow in right anterior cingulate (Brodmann areas 24 and 32) and increased blood flow in left and right posterior cingulate (Brodmann areas 23, 29, 30), left parahippocampal gyrus (Brodmann area 36), and right caudate compared with healthy volunteers. The severity of depression was inversely correlated with the left middle and inferior frontal gyri (Brodmann areas 9 and 47) and right medial frontal gyrus (Brodmann area 10) and right anterior cingulate (Brodmann areas 24, 32) blood flow, and directly correlated with the right thalamus blood flow. These findings support previous reports of abnormalities in the resting state blood flow in the limbic-frontal structures in depressed patients compared to healthy volunteers.

Impact of sunlight on the age of onset of bipolar disorder.

OBJECTIVE: Although bipolar disorder has high heritability, the onset occurs during several decades of life, suggesting that social and environmental factors may have considerable influence on disease onset. This study examined the association between the age of onset and sunlight at the location of onset. METHOD: Data were obtained from 2414 patients with a diagnosis of bipolar I disorder, according to DSM-IV criteria. Data were collected at 24 sites in 13 countries spanning latitudes 6.3 to 63.4 degrees from the equator, including data from both hemispheres. The age of onset and location of onset were obtained retrospectively, from patient records and/or direct interviews. Solar insolation data, or the amount of electromagnetic energy striking the surface of the earth, were obtained from the NASA Surface Meteorology and Solar Energy (SSE) database for each location of onset. RESULTS: The larger the maximum monthly increase in solar insolation at the location of onset, the younger the age of onset (coefficient= -4.724, 95% CI: -8.124 to -1.323, p=0.006), controlling for each country's median age. The maximum monthly increase in solar insolation occurred in springtime. No relationships were found between the age of onset and latitude, yearly total solar insolation, and the maximum monthly decrease in solar insolation. The largest maximum monthly increases in solar insolation occurred in diverse environments, including Norway, arid areas in California, and Chile. CONCLUSION: The large maximum monthly increase in sunlight in springtime may have an important influence on the onset of bipolar disorder.

Suicide attempts are associated with worse quality of life in patients with bipolar disorder type I.

BACKGROUND: The association between suicidal behavior and quality of life (QoL) in bipolar disorder (BD) is poorly understood. Worse QoL has been associated with suicide attempts and suicidal ideation in schizophrenic patients, but this relationship has not been investigated in BD. This study tested whether a history of suicide attempts was associated with poor QoL in a well-characterized sample of patients with BD, as has been observed in other psychiatric disorders and in the general population. METHODS: One hundred eight patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition BD type I (44 with previous suicide attempts, 64 without previous suicide attempts) were studied. Quality of life was assessed using the World Health Organization's Quality of Life Instrument-Short Version. Depressive and manic symptoms were assessed using the Hamilton Depression Rating Scale-17 items and the Young Mania Rating Scale. RESULTS: Patients with BD and previous suicide attempts had significantly lower scores in all the 4 domains of the World Health Organization's Quality of Life Instrument-Short Version scale than did patients with BD but no previous suicide attempts (physical domain P = .001; psychological domain P < .0001; social domain P = .001, and environmental domain P = .039). In the euthymic subgroup (n = 70), patients with previous suicide attempts had significantly lower scores only in the psychological and social domains (P = .020 and P = .004). LIMITATIONS: This was a cross-sectional study, and no causal associations can be assumed. CONCLUSIONS: Patients with BD and a history of previous suicide attempts seem to have a worse QoL than did patients who never attempted suicide. Poorer QoL might be a marker of poor copying skills and inadequate social support and be a risk factor for suicidal behavior in BD. Alternatively, poorer QoL and suicidal behavior might be different expressions of more severe BD.

Impact of comorbid migraine on the clinical course of bipolar disorder.

BACKGROUND: Recent evidence suggests an association between migraine and bipolar disorder (BD), although the impact of this association in the clinical course of BD is relatively unknown. OBJECTIVE: This study aimed to compare 2 groups of individuals with BD (with vs without comorbid migraine) and evaluate differences in severity of clinical course. METHODS: Three hundred thirty-nine adults with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined bipolar I or II disorder were enrolled and divided into 2 groups: with and without comorbid migraine. Demographic and clinical data were obtained using standardized interviews. RESULTS: Patients with comorbid migraines had more mood episodes, especially those with depressive polarity. In addition, comorbid migraine was associated with a higher prevalence of psychiatric and general medical comorbidities. Differences between the 2 groups in number of lifetime hospitalizations for depression/mania, rates of rapid cycling, and history of suicide attempts were not observed after Bonferroni correction. CONCLUSIONS: Comorbid migraine seems to be associated with poor outcomes in BD. Additional studies should be conducted to investigate shared vulnerabilities and pathophysiologic mechanisms as well as treatment optimization of both illnesses.

N-acetylcysteine for depression and glutamate changes in the left prefrontal cortex in adolescents and young adults at risk for bipolar disorder: A pilot study.

AIMS: To investigate the mechanism of action of N-acetylcysteine (NAC) in depressive symptoms in young individuals at familial risk for bipolar disorder. METHODS: We conducted an 8-week open label clinical trial of NAC 2400 mg/days in 15-24 years old depressed offspring of a bipolar I disorder parent, with baseline and endpoint proton magnetic resonance spectroscopy acquired within the left ventrolateral prefrontal cortex (VLPFC). RESULTS: Nine participants were enrolled and finished the study. NAC significantly improved depressive and anxiety symptom scores, and clinical global impression (all p < .001). There was a non-significant reduction in glutamate levels in the left VLPFC. Reduction in depressive symptom scores was positively associated with reduction in glutamate levels in the left VLPFC (p = .007). CONCLUSIONS: This pilot study suggests that NAC might be efficacious for depressive symptoms in at-risk youth, and that its mechanism of action involves the modulation of glutamate in the left VLPFC.

Changes in the structural brain connectome over the course of a nonrandomized clinical trial for acute mania.

Disrupted topological organization of brain functional networks has been widely reported in bipolar disorder. However, the potential clinical implications of structural connectome abnormalities have not been systematically investigated. The present study included 109 unmedicated subjects with acute mania who were assigned to 8 weeks of treatment with quetiapine or lithium and 60 healthy controls. High resolution 3D-T1 weighted magnetic resonance images (MRI) were collected from both groups at baseline, week 1 and week 8. Brain networks were constructed based on the similarity of morphological features across brain regions and analyzed using graph theory approaches. At baseline, individuals with bipolar disorder illness showed significantly lower clustering coefficient (Cp) (p = 0.012) and normalized characteristic path length (λ) (p = 0.004) compared to healthy individuals, as well as differences in nodal centralities across multiple brain regions. No baseline or post-treatment differences were identified between drug treatment conditions, so change after treatment were considered in the combined treatment groups. Relative to healthy individuals, differences in Cp, λ and cingulate gyrus nodal centrality were significantly reduced with treatment; changes in these parameters correlated with changes in Young Mania Rating Scale scores. Baseline structural connectome matrices significantly differentiated responder and non-responder groups at 8 weeks with 74% accuracy. Global and nodal network alterations evident at baseline were normalized with treatment and these changes associated with symptomatic improvement. Further, baseline structural connectome matrices predicted treatment response. These findings suggest that structural connectome abnormalities are clinically significant and may be useful for predicting clinical outcome of treatment and tracking drug effects on brain anatomy in bipolar disorder. CLINICAL TRIALS REGISTRATION: Name: Functional and Neurochemical Brain Changes in First-episode Bipolar Mania Following Successful Treatment with Lithium or Quetiapine. URL: https://clinicaltrials.gov/ . REGISTRATION NUMBER: NCT00609193. Name: Neurofunctional and Neurochemical Markers of Treatment Response in Bipolar Disorder. URL: https://clinicaltrials.gov/ . REGISTRATION NUMBER: NCT00608075.

Morphometric post-mortem studies in bipolar disorder: possible association with oxidative stress and apoptosis.

Despite extensive research in the last decades, the pathophysiology of bipolar disorder (BD) remains unclear. Access to post-mortem brain tissue of subjects who had BD offers an opportunity to investigate neurobiology and this approach has led to some progress, particularly, due to the availability of more sophisticated molecular and cellular biological methodologies and well characterized brain collections over the past decade. Here we review the findings of morphometric post-mortem studies in BD and interpret them in the context of a potential physiopathological mechanism involving oxidative stress and apoptosis. A review of the literature was conducted to identify post-mortem studies that investigated cellular changes such as number, density and size of neurons and glia, in brains of subjects with BD. We found decreased density of neurons and glia and decreased size of neurons in frontal and subcortical areas of the brain. Based on recent studies that found evidence of increased apoptosis and oxidative stress in BD, we hypothesize that the cell abnormalities described are due to an increase in the apoptotic process that can be triggered, through its intrinsic pathway, by the existence of an exacerbated production of reactive oxygen species and oxidative damage in the disease.

Personality traits in bipolar disorder type I: a sib-pair analysis.

OBJECTIVE: The aim of this study was to compare temperament and character traits among patients with bipolar disorder (BD), their siblings, and healthy controls (HCs) in order to examine whether personality traits are related to the genetic vulnerability to develop BD. METHODS: Using the Temperament and Character Inventory, we assessed 204 subjects: 67 euthymic outpatients with bipolar disorder type I, 67 siblings without BD, and 70 HCs. RESULTS: Scores on harm avoidance, novelty seeking, and self-transcendence were significantly higher among patients with BD than among HCs, whereas those on self-directedness and cooperativeness were significantly lower. Siblings showed higher scores on harm avoidance and lower scores on self-directedness than did HCs. As some of the siblings presented at least one lifetime psychiatric disorder other than BD (n = 35), we examined the subset of siblings who had no lifetime psychiatric disorder (n = 32). This group showed statistically higher harm avoidance scores than HCs. CONCLUSIONS: Our results suggest that the harm avoidance temperament trait and, to a lesser extent, the self-directedness character trait may represent vulnerability factors for BD.