Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative

Context: There is limited information on the prevalence and correlates of bipolar spectrum disorder in international population-based studies using common methods. Objectives: To describe the prevalence, impact, patterns of comorbidity, and patterns of service utilization for bipolar spectrum disorder (BPS) in the World Health Organization World Mental Health Survey Initiative. Design, Setting, and Participants: Crosssectional, face-to-face, household surveys of 61 392 community adults in 11 countries in the Americas, Europe, and Asia assessed with the World Mental Health version of the World Health Organization Composite International Diagnostic Interview, version 3.0, a fully structured, lay-administered psychiatric diagnostic interview. Main Outcome Measures: Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) disorders, severity, and treatment. Results: The aggregate lifetime prevalences were 0.6% for bipolar type I disorder (BP-I), 0.4% for BP-II, 1.4% for subthreshold BP, and 2.4% for BPS. Twelve-month prevalences were 0.4% for BP-I, 0.3% for BP-II, 0.8% for subthreshold BP, and 1.5% for BPS. Severity of both manic and depressive symptoms as well as suicidal behavior increased monotonically from subthreshold BP to BP-I. By contrast, role impairment was similar across BP subtypes. Symptom severity was greater for depressive episodes than manic episodes, with approximately 74.0% of respondents with depression and 50.9% of respondents with mania reporting severe role impairment. Three-quarters of those with BPS met criteria for at least 1 other disorder, with anxiety disorders (particularly panic attacks) being the most common comorbid condition. Less than half of those with lifetime BPS received mental health treatment, particularly in low-income countries, where only 25.2% reported contact with the mental health system. Conclusions: Despite cross-site variation in the prevalence rates of BPS, the severity, impact, and patterns of comorbidity were remarkably similar internationally. The uniform increases in clinical correlates, suicidal behavior, and comorbidity across each diagnostic category provide evidence for the validity of the concept of BPS. Treatment needs for BPS are often unmet, particularly in low-income countries.

AGE DIFFERENCES IN THE PREVALENCE AND CO-MORBIDITY OF DSM-IV MAJOR DEPRESSIVE EPISODES: RESULTS FROM THE WHO WORLD MENTAL HEALTH SURVEY INITIATIVE

Background: Although depression appears to decrease in late life, this could be due to misattribution of depressive symptoms to physical disorders that increase in late we. Methods: We investigated this issue by studying age differences in co-morbidity of DSM-IV major depressive episodes (MDE) with chronic physical conditions in the WHO World Mental Health (WMH) surveys, a series of community epidemiological surveys of respondents in 10 developed countries (n = 52,485) and 8 developing countries (n = 37,265). MDE and other mental disorders were assessed with the Composite International Diagnostic Interview (CIDI). Organic exclusion rules were not used to avoid inappropriate exclusion of cases with physical co-morbidity. Physical conditions were assessed with a standard chronic conditions checklist. Results: Twelve-month DSM-IV/CIDI MDE was significantly less prevalent among respondents ages 65+ than younger respondents in developed but not developing countries. Prevalence of co-morbid mental disorders generally either decreased or remained stable with age, while co-morbidity of MDE with mental disorders generally increased with age. Prevalence of physical conditions, in comparison, generally increased with age, while co-morbidity of MDE with physical conditions generally decreased with age. Depression treatment was lowest among the elderly in developed and developing countries. Conclusions: The weakening associations between MDE and physical conditions with increasing age argue against the suggestion that the low estimated prevalence of MDE among the elderly is due to increased confounding with physical disorders. Future study is needed to investigate processes that might lead to a decreasing impact of physical illness on depression among the elderly. Depression and Anxiety 27:351-364, 2010. (C) 2009 Wiley-Liss, Inc.

Anterior genu corpus callosum and impulsivity in suicidal patients with bipolar disorder

Suicidality is a life-threatening symptom in patients with bipolar disorder (BD). Impulsivity and mood instability are associated with suicidality in mood disorders. Evidence suggests that gray and white matter abnormalities are linked with impulsivity in mood disorders, but little is known about the association between corpus callosum (CC) and impulsivity in BID. We examined the relationship between CC areas, impulsivity and suicidality in BID patients. We studied 10 female BD patients with a history of suicide attempt (mean +/- SD age 36.2 +/- 10.1 years), 10 female BD patients without suicide attempt history (44.2 +/- 12.5 years) and 27 female healthy subjects (36.9 +/- 13.8 years). Impulsivity was evaluated by the Barratt Impulsivity Scale (BIS). We traced MR images to measure the areas of the CC genu, anterior body, posterior body, isthmus and splenium. The genu was divided into anterior, middle and posterior regions. The suicidal and non-suicidal BID patients had significantly higher BIS total, attention and non-planning scores than the healthy subjects (ps < 0.01), and the suicidal BID patients had significantly higher BIS motor scores than the non-suicidal BD and healthy subjects (ps < 0.01). There were no significant differences among the three groups on any regional CC areas, although the suicidal BD patients had the smallest areas. The suicidal BD patients showed a significant inverse correlation between anterior genu area and the BIS total (r = -0.75, p = 0.04), motor (r = -0.79, p = 0.02) and non-planning scores (r = -0.79, p = 0.02). These correlations were not found in the non-suicidal BID patients or healthy subjects. The results suggest that the anterior medial frontal region may be involved in the pathophysiology of impulsive and suicidal behaviors in BD. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Abnormal Amygdala-Prefrontal Effective Connectivity to Happy Faces Differentiates Bipolar from Major Depression

Background: Bipolar disorder is frequently misdiagnosed as major depressive disorder, delaying appropriate treatment and worsening outcome for many bipolar individuals. Emotion dysregulation is a core feature of bipolar disorder. Measures of dysfunction in neural systems supporting emotion regulation might therefore help discriminate bipolar from major depressive disorder. Methods: Thirty-one depressed individuals-15 bipolar depressed (BD) and 16 major depressed (MDD), DSM-IV diagnostic criteria, ages 18-55 years, matched for age, age of illness onset, illness duration, and depression severity-and 16 age- and gender-matched healthy control subjects performed two event-related paradigms: labeling the emotional intensity of happy and sad faces, respectively. We employed dynamic causal modeling to examine significant among-group alterations in effective connectivity (EC) between right- and left-sided neural regions supporting emotion regulation: amygdala and orbitomedial prefrontal cortex (OMPFC). Results: During classification of happy faces, we found profound and asymmetrical differences in EC between the OMPFC and amygdala. Left-sided differences involved top-down connections and discriminated between depressed and control subjects. Furthermore, greater medication load was associated with an amelioration of this abnormal top-down EC. Conversely, on the right side the abnormality was in bottom-up EC that was specific to bipolar disorder. These effects replicated when we considered only female subjects. Conclusions: Abnormal, left-sided, top-down OMPFC-amygdala and right-sided, bottom-up, amygdala-OMPFC EC during happy labeling distinguish BD and MDD, suggesting different pathophysiological mechanisms associated with the two types of depression.

Anterior cingulate volumes associated with trait impulsivity in individuals with bipolar disorder

Objective: Impulsivity is associated with the clinical outcome and likelihood of risky behaviors among bipolar disorder (BD) patients. Our previous study showed an inverse relationship between impulsivity and orbitofrontal cortex (OFC) volume in healthy subjects. We hypothesized that BD patients would show an inverse relationship between impulsivity and volumes of the OFC, anterior cingulate cortex (ACC), medial prefrontal cortex, and amygdala, which have been implicated in the pathophysiology of BD. Methods: Sixty-three BD patients were studied (mean +/- SD age = 38.2 +/- 11.5 years; 79% female). The Barratt Impulsiveness Scale (BIS), version 11A, was used to assess trait impulsivity. Images were processed using SPM2 and an optimized voxel-based morphometry protocol. We examined the correlations between BIS scores and the gray matter (GM) and white matter (WM) volumes of the prespecified regions. Results: Left rostral ACC GM volume was inversely correlated with the BIS total score (t = 3.95, p(corrected) = 0.003) and the BIS motor score (t = 5.22, p(corrected) < 0.001). In contrast to our hypothesis, OFC volumes were not significantly associated with impulsivity in BD. No WM volume of any structure was significantly correlated with impulsivity. No statistical association between any clinical variable and the rostral ACC GM volumes reached significance. Conclusions: Based on our previous findings and the current results, impulsivity may have a different neural representation in BD and healthy subjects, and the ACC may be involved in the pathophysiology of abnormal impulsivity regulation in BD patients.

Reduced gray matter volume in ventral prefrontal cortex but not amygdala in bipolar disorder: Significant effects of gender and trait anxiety

Neuroimaging studies in bipolar disorder report gray matter volume (GMV) abnormalities in neural regions implicated in emotion regulation. This includes a reduction in ventral/orbital medial prefrontal cortex (OMPFC) GMV and, inconsistently, increases in amygdala GMV. We aimed to examine OMPFC and amygdala GMV in bipolar disorder type 1 patients (BPI) versus healthy control participants (HC), and the potential confounding effects of gender, clinical and illness history variables and psychotropic medication upon any group differences that were demonstrated in OMPFC and amygdala GMV Images were acquired from 27 BPI (17 euthymic, 10 depressed) and 28 age- and gender-matched HC in a 3T Siemens scanner. Data were analyzed with SPM5 using voxel-based morphometry (VBM) to assess main effects of diagnostic group and gender upon whole brain (WB) GMV. Post-hoc analyses were subsequently performed using SPSS to examine the extent to which clinical and illness history variables and psychotropic medication contributed to GMV abnormalities in BPI in a priori and non-a priori regions has demonstrated by the above VBM analyses. BPI showed reduced GMV in bilateral posteromedial rectal gyrus (PMRG), but no abnormalities in amygdala GMV. BPI also showed reduced GMV in two non-a priori regions: left parahippocampal gyrus and left putamen. For left PMRG GMV, there was a significant group by gender by trait anxiety interaction. GMV was significantly reduced in male low-trait anxiety BPI versus male low-trait anxiety HC, and in high-versus low-trait anxiety male BPI. Our results show that in BPI there were significant effects of gender and trait-anxiety, with male BPI and those high in trait-anxiety showing reduced left PMRG GMV. PMRG is part of medial prefrontal network implicated in visceromotor and emotion regulation. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Illness duration and total brain gray matter in bipolar disorder: Evidence for neurodegeneration?

Previous studies have suggested that bipolar disorder (BD) is associated with alterations in neuronal plasticity, but the effects of the progression of illness on brain anatomy have been poorly investigated. We studied the correlation between length of illness, age, age at onset, and the number of previous episodes and total brain, total gray, and total white matter volumes in BD, unipolar (UP) and healthy control (HC) subjects. Thirty-six BD, 31 UP and 55 HCs underwent a 1.5 T brain magnetic resonance imaging scan, and gray and white matter volumes were manually traced blinded to the subjects` diagnosis. Partial correlation analysis showed that length of illness was inversely correlated with total gray matter volume after adjusting for total intracranial volume in BD (r(p)=-0.51; p=0.003) but not in UP subjects (r(p)=-0.23; p=0.21). Age at illness onset and the number of previous episodes were not significantly correlated with gray matter volumes in BD or UP subjects. No significant correlation with total white matter volume was observed. These results suggest that the progression of illness may be associated with abnormal cellular plasticity. Prospective longitudinal studies are necessary to elucidate the long-term effects of illness progression on brain structure in major mood disorders. (C) 2008 Published by Elsevier B.V.

Validity and reliability of the Structured Clinical Interview for Mood Spectrum: Brazilian version (SCIMOODS-VB)

OBJECTIVE: The aim of this study was to translate the Structured Clinical Interview for Mood Spectrum into Brazilian Portuguese, measuring its reliability, validity, and defining scores for bipolar disorders. METHOD: Questionnaire was translated (into Brazilian Portuguese) and back-translated into English. Sample consisted of 47 subjects with bipolar disorder, 47 with major depressive disorder, 18 with schizophrenia and 22 controls. Inter-rater reliability was tested in 20 subjects with bipolar disorder and MDD. Internal consistency was measured using the Kuder Richardson formula. Forward stepwise discriminant analysis was performed. Scores were compared between groups; manic (M), depressive (D) and total (T) threshold scores were calculated through receiver operating characteristic (ROC) curves. RESULTS: Kuder Richardson coefficients were between 0.86 and 0.94. Intraclass correlation coefficient was 0.96 (CI 95 % 0.93-0.97). Subjects with bipolar disorder had higher M and T, and similar D scores, when compared to major depressive disorder (ANOVA, p < 0.001). The sub-domains that best discriminated unipolar and bipolar subjects were manic energy and manic mood. M had the best area under the curve (0.909), and values of M equal to or greater than 30 yielded 91.5% sensitivity and 74.5% specificity. CONCLUSION: Structured Clinical Interview for Mood Spectrum has good reliability and validity. Cut-off of 30 best differentiates subjects with bipolar disorder vs. unipolar depression. A cutoff score of 30 or higher in the mania sub-domain is appropriate to help make a distinction between subjects with bipolar disorder and those with unipolar depression.

Sertraline vs. ELectrical Current Therapy for Treating Depression Clinical Trial - SELECT TDCS: Design, rationale and objectives

Background: Despite significant advancements in psychopharmacology, treating major depressive disorder (MDD) is still a challenge considering the efficacy, tolerability, safety, and economical costs of most antidepressant drugs. One approach that has been increasingly investigated is modulation of cortical activity with tools of non-invasive brain stimulation - such as transcranial magnetic stimulation and transcranial direct current stimulation (tDCS). Due to its profile, tDCS seems to be a safe and affordable approach. Methods and design: The SELECT TDCS trial aims to compare sertraline vs. tDCS in a double-blinded, randomized, factorial trial enrolling 120 participants to be allocated to four groups to receive sertraline + tDCS, sertraline, tDCS or placebo. Eligibility criteria are moderate-to-severe unipolar depression (Hamilton Depression Rating Scale >17) not currently on sertraline treatment. Treatment will last 6 weeks and the primary outcome is depression change in the Montgomery-Asberg Depression Rating Score (MADRS). Potential biological markers that mediate response, such as BDNF serum levels, Val66Met BDNF polymorphism, and heart rate variability will also be examined. A neuropsychological battery with a focus on executive functioning will be administered. Discussion: With this design we will be able to investigate whether tDCS is more effective than placebo in a sample of patients free of antidepressants and in addition, we will be able to secondarily compare the effect sizes of sertraline vs. tDCS and also the comparison between tDCS and combination of tDCS and sertraline. (C) 2010 Elsevier Inc. All rights reserved.

Neural activity changes to emotional stimuli in healthy individuals under chronic use of clomipramine

Previous functional magnetic resonance imaging (fMRI) studies examined neural activity responses to emotive stimuli in healthy individuals after acute/subacute administration of antidepressants. We now report the effects of repeated use of the antidepressant clomipramine on fMRI data acquired during presentation of emotion-provoking and neutral stimuli on healthy volunteers. A total of 12 volunteers were evaluated with fMRI after receiving low doses of clomipramine for 4 weeks and again after 4 weeks of washout. Fear-, happiness-, anger-provoking and neutral pictures from the International Affective Picture System (IAPS) were used. Data analysis was performed with statistical parametric mapping (P < 0.05). Paired t-test comparisons for each condition between medicated and unmedicated states showed, to negative valence paradigms, decrease in brain activity in the amygdala when participants were medicated. We also demonstrated, across both positive and negative valence paradigms, consistent decreases in brain activity in the medicated state in the anterior cingulate gyrus and insula. This is the first report of modulatory effects of repeated antidepressant use on the central representation of somatic states in response to emotions of both negative and positive valences in healthy individuals. Also, our results corroborate findings of antidepressant-induced temporolimbic activity changes to emotion-provoking stimuli obtained in studies of subjects treated acutely with such agents.

Increased soluble TNF receptor 2 in antidepressant-free patients with late-life depression

Increased pro-inflammatory state has been implicated in the pathophysiology of major depressive disorder. The aim of this study was to determine serum levels of INF-alpha and soluble TNF-alpha receptors 1 and 2 (sTNFR1 and sTNFR2) in anti-depressant free depressed elderly patients as compared to healthy controls. Sixty-seven older adults (28 with major depression and 39 controls) were enrolled to this study. Participants were assessed by the SCID and diagnosis of major depressive episode was made according to the DSM-IV criteria. Serum INF-alpha, 5TNFR1 and sTNFR2 were determined by ELISA. Anti-depressant free patients with late-life depression showed an increased level of the sTNFR2 as compared to controls (p = 0.03). No significant differences were found in serum INF-alpha and sTNFR1 levels (p = 0.1 and p = 0.4, respectively). There was no correlation between serum levels of these inflammatory markers and the severity of depression. Our findings provide additional evidence of the involvement of abnormal pro-inflammatory state in late-life depression. (c) 2010 Elsevier Ltd. All rights reserved.

Muscle sympathetic nervous activity in depressed patients before and after treatment with sertraline

Background Sympathetic hyperactivity is one of the mechanisms involved in the increased cardiovascular risk associated with depression, and there is evidence that antidepressants decrease sympathetic activity. Objectives We tested the following two hypotheses: patients with major depressive disorder with high scores of depressive symptoms (HMDD) have augmented muscle sympathetic nervous system activity (MSNA) at rest and during mental stress compared with patients with major depressive disorder with low scores of depressive symptoms (LMDD) and controls; sertraline decreases MSNA in depressed patients. Methods Ten HMDD, nine LMDD and 11 body weight-matched controls were studied. MSNA was directly measured from the peroneal nerve using microneurography for 3 min at rest and 4 min during the Stroop color word test. For the LMDD and HMDD groups, the tests were repeated after treatment with sertraline (103.3 +/- 40 mg). Results Resting MSNA was significantly higher in the HMDD [29.1 bursts/min (SE 2.9)] compared with LMDD [19.9 (1.6)] and controls [22.2 (2.0)] groups (P=0.026 and 0.046, respectively). There was a significant positive correlation between resting MSNA and severity of depression. MSNA increased significantly and similarly during stress in all the studied groups. Sertraline significantly decreased resting MSNA in the LMDD group and MSNA during mental stress in LMDD and HMDD groups. Sertraline significantly decreased resting heart rate and heart rate response to mental stress in the HMDD group. Conclusion Moderate-to-severe depression is associated with increased MSNA. Sertraline treatment reduces MSNA at rest and during mental challenge in depressed patients, which may have prognostic implications in this group. J Hypertens 27:2429-2436 (c) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Hypotension caused by therapeutic doses of venlafaxine: case report and proposed pathophysiological mechanisms

Although venlafaxine is usually associated with modest increases in blood pressure and not so often clinical hypertension, there are a few reported cases of hypotension related to overdoses of this specific antidepressant. The case study of a young female patient with a history of Major Depressive Disorder who initiated treatment with venlafaxine 75 mg/day and developed hypotension when the dosage was titrated up to 225 mg/day is described. The patient did not present comorbid diseases nor use other medication. A temporal association and a dose-dependent relationship between the hypotension and the use of venlafaxine is shown. To the best of the knowledge of the authors, this is the first case report that specifically associates regular doses of venlafaxine with the presence of hypotension. A pathophysiological mechanism is proposed, involving the participation of presynaptic alpha2-adrenergic receptors and the presence of a possible genetic polymorphism of cytochrome P4502D6, which is associated with lower drug metabolization, to explain the relationship between venlafaxine in regular dosage and development of hypotension.

Elevated Amygdala Activity to Sad Facial Expressions: A State Marker of Bipolar but Not Unipolar Depression

Background: Difficulties in emotion processing and poor social function are common to bipolar disorder (BD) and major depressive disorder (MDD) depression, resulting in many BID depressed individuals being misdiagnosed with MDD. The amygdala is a key region implicated in processing emotionally salient stimuli, including emotional facial expressions. It is unclear, however, whether abnormal amygdala activity during positive and negative emotion processing represents a persistent marker of BD regardless of illness phase or a state marker of depression common or specific to BID and MDD depression. Methods: Sixty adults were recruited: 15 depressed with BID type 1 (BDd), 15 depressed with recurrent MDD, 15 with BID in remission (BDr), diagnosed with DSM-IV and Structured Clinical Interview for DSM-IV Research Version criteria; and 15 healthy control subjects (HC). Groups were age- and gender ratio-matched; patient groups were matched for age of illness onset and illness duration; depressed groups were matched for depression severity. The BDd were taking more psychotropic medication than other patient groups. All individuals participated in three separate 3T neuroimaging event-related experiments, where they viewed mild and intense emotional and neutral faces of fear, happiness, or sadness from a standardized series. Results: The BDd-relative to HC, BDr, and MDD-showed elevated left amygdala activity to mild and neutral facial expressions in the sad (p < .009) but not other emotion experiments that was not associated with medication. There were no other significant between-group differences in amygdala activity. Conclusions: Abnormally elevated left amygdala activity to mild sad and neutral faces might be a depression-specific marker in BID but not MDD, suggesting different pathophysiologic processes for BD versus MDD depression.

A Voxel-Based Morphometry Study of Frontal Gray Matter Correlates of Impulsivity

Impulsivity is a personality trait exhibited by healthy individuals, but excessive impulsivity is associated with some mental disorders. Lesion and functional, neuroimaging Studies indicate that the ventromedial prefrontal region (VMPFC), including the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC) and medial prefrontal cortex, and the amygdala may modulate impulsivity and aggression. However, no morphometric study has examined the association between VMPFC and impulsivity. We hypothesized that healthy subjects with high impulsivity would have smaller volumes in these brain regions compared with those with low impulsivity. Sixty-two healthy Subjects were Studied (age 35.4 +/- 12.1 years) using a 1.5-T MRI system. The Barratt impulsiveness scale (BIS) was used to assess impulsivity. Images were processed using an optimized voxel-based morphometry (VBM) protocol. We calculated the correlations between BIS scale scores and the gray matter (GM) and white matter (WM) volumes of VMPFC and amygdala. GM volumes of the left and right OFC were inversely correlated with the BIS total score (P = 0.04 and 0.02, respectively). Left ACC GM Volumes had a tendency to be inversely correlated with the BIS total score (P = 0.05. Right OFC GM Volumes were inversely correlated with BIS nonplanning impulsivity, and left OFC GM volumes were inversely correlated with motor impulsivity. There were no significant WM volume correlations with impulsivity. The results Of this morphometry Study indicate that small OFC volume relate to high impulsivity and extend the prior finding that the VMPFC is involved in the circuit modulating impulsivity. HUM Brain Mapp 30:1188-1195, 2009. (C) 2008 Wiley-Liss, Inc.