Right Orbitofrontal Corticolimbic and Left Corticocortical White Matter Connectivity Differentiate Bipolar and Unipolar Depression

Objectives: The absence of pathophysiologically relevant diagnostic markers of bipolar disorder (BD) leads to its frequent misdiagnosis as unipolar depression (UD). We aimed to determine whether whole brain white matter connectivity differentiated BD from UD depression. Methods: We employed a three-way analysis of covariance, covarying for age, to examine whole brain fractional anisotropy (FA), and corresponding longitudinal and radial diffusivity, in currently depressed adults: 15 with BD-type I (mean age 36.3 years, SD 12.0 years), 16 with recurrent UD (mean age 32.3 years, SD 10.0 years), and 24 healthy control adults (HC) (mean age 29.5 years, SD 9.43 years). Depressed groups did not differ in depression severity, age of illness onset, and illness duration. Results: There was a main effect of group in left superior and inferior longitudinal fasciculi (SLF and ILF) (all F >= 9.8; p <= .05, corrected). Whole brain post hoc analyses (all t >= 4.2; p <= .05, corrected) revealed decreased FA in left SLF in BD, versus UD adults in inferior temporal cortex and, versus HC, in primary sensory cortex (associated with increased radial and decreased longitudinal diffusivity, respectively); and decreased FA in left ILF in UD adults versus HC. A main effect of group in right uncinate fasciculus (in orbitofrontal cortex) just failed to meet significance in all participants but was present in women. Post hoc analyses revealed decreased right uncinate fasciculus FA in all and in women, BD versus HC. Conclusions: White matter FA in left occipitotemporal and primary sensory regions supporting visuospatial and sensory processing differentiates BD from UD depression. Abnormally reduced FA in right fronto-temporal regions supporting mood regulation, might underlie. predisposition to depression in BD. These measures might help differentiate pathophysiologic processes of BD versus UD depression.

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.

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.

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.

Orbitofrontal Cortex Volumes in Medication Naive Children with Major Depressive Disorder: A Magnetic Resonance Imaging Study

Objectives: Adults with major depressive disorder (MDD) are reported to have reduced orbitofrontal cortex (OFC) volumes, which could be related to decreased neuronal density. We conducted a study on medication naive children with MDD to determine whether abnormalities of OFC are present early in the illness course. Methods: Twenty seven medication naive pediatric Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition (DSM-IV) MDD patients (mean age +/- SD = 14.4 +/- 2.2 years; 10 males) and 26 healthy controls (mean age +/- SD = 14.4 +/- 2.4 years; 12 males) underwent a 1.5T magnetic resonance imaging (MRI) with 3D spoiled gradient recalled acquisition. The OFC volumes were compared using analysis of covariance with age, gender, and total brain volume as covariates. Results: There was no significant difference in either total OFC volume or total gray matter OFC volume between MDD patients and healthy controls. Exploratory analysis revealed that patients had unexpectedly larger total right lateral (F = 4.2, df = 1, 48, p = 0.05) and right lateral gray matter (F = 4.6, df = 1, 48, p = 0.04) OFC volumes compared to healthy controls, but this finding was not significant following statistical correction for multiple comparisons. No other OFC subregions showed a significant difference. Conclusions: The lack of OFC volume abnormalities in pediatric MDD patients suggests the abnormalities previously reported for adults may develop later in life as a result of neural cell loss.

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.

Family Environment and Pediatric Major Depressive Disorder

Background: The risks for depression broadly include biological and environmental factors. Furthermore, having a family member suffering from major depression is also likely to have consequences for the family environment. Further research aimed at understanding the effects of having a child with major depression on family interaction patterns is warranted. Methods: We studied 31 families with an 8- to 17-year-old child (mean age +/- SD = 12.9 +/- 2.7 years) who met the DSM-IV criteria for major depressive disorder (MDD) and 34 families with no mentally ill children (mean age 8 SD = 12.6 +/- 2.9 years) or parents. Children and their parents were assessed with the K-SADS-PL (Kiddie Schedule for Affective Disorders and Schizophrenia - Present and Lifetime Version) interview. Parents completed the Moos Family Environment Scale (FES) to assess their perceptions of current family functioning. Data were analyzed using the nonparametric Wilcoxon-Mann-Whitney test. Results: Families of MDD children showed significantly different patterns of family functioning on FES subscales representing relationships and personal growth dimensions. The families with MDD children showed higher levels of conflict (p < 0.001) and lower levels of cohesion (p < 0.001), expressiveness (p = 0.003) and active-recreational orientation (p = 0.02) compared to the families without mentally ill children. Conclusion: Families with MDD children show a lower degree of commitment, provide less support to one another, provide less encouragement to express feelings and have more conflicts compared to families with no mentally ill children or parents. Interventions aimed at improving family dynamics may be beneficial to MDD children and their families. Copyright (C) 2010 S. Karger AG, Basel

Normal metabolite levels in the left dorsolateral prefrontal cortex of unmedicated major depressive disorder patients: A single voxel (1)H spectroscopy study

Few proton magnetic resonance spectroscopy ((1)H spectroscopy) studies have investigated the dorsolateral prefrontal cortex (DLPFC), a key region in the pathophysiology of major depressive disorder (MDD). We used (1)H spectroscopy to verify whether MDD patients differ from healthy controls (HQ in metabolite levels in this brain area. Thirty-seven unmedicated DSM-IV MDD patients were compared with 40 HC. Subjects underwent a short echo-time (1)H spectroscopy examination at 1.5 T, with an 8-cm(3) single voxel placed in the left DLPFC. Reliable absolute metabolite levels of N-acetyl aspartate (NAA), phosphocreatine plus creatine (PCr+Cr), choline-containing compounds (GPC+PC), myo-inositol, glutamate plus glutamine (Glu+Gln), and glutamate were obtained using the unsuppressed water signal as an internal reference. Metabolite levels in the left DLPFC did not statistically differ between MDD patients and HC. We found an interaction between gender and diagnosis on PCr+Cr levels. Male MDD patients presented lower levels of PCr+Cr than male HC, and female MDD patients presented higher levels of PCr+Cr than female HC. Moreover, length of illness was inversely correlated with NAA levels. These findings suggest that there is not an effect of diagnosis on the left DLPFC neurochemistry. Possible effects of gender on PCr+Cr levels of MDD patients need to be further investigated. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Amygdala hyperactivation in untreated depressed individuals

The amygdala participates in the detection and control of affective states, and has been proposed to be a site of dysfunction in affective disorders. To assess amygdala processing in individuals with unipolar depression, we applied a functional MRI (fMRI) paradigm previously shown to be sensitive to amygdala function. Fourteen individuals with untreated DSM-IV major depression and 15 healthy subjects were studied using fMRI with a standardized emotion face recognition task. Voxel-level data sets were subjected to a multiple-regression analysis, and functionally defined regions of interest (ROI), including bilateral amygdala, were analyzed with MANOVA. Pearson correlation coefficients between amygdala activation and HAM-D score also were performed. While both depressed and healthy groups showed increased amygdala activity when viewing emotive faces compared to geometric shapes, patients with unipolar depression showed relatively more activity than healthy subjects, particularly on the left. Positive Pearson correlations between amygdala activation and HAM-D score were found for both left and right ROIs in the patient group. This study provides in vivo imaging evidence to support the hypothesis of abnormal amygdala functioning in depressed individuals. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

TEMPERAMENT AND CHARACTER TRAITS IN MAJOR DEPRESSIVE DISORDER: INFLUENCE OF MOOD STATE AND RECURRENCE OF EPISODES

Background: The objective of this study was to compare personality traits between major depressive disorder (MDD) patients and healthy comparison subjects (HC) and examine if personality traits in patients are associated with specific clinical characteristics of the disorder. Methods: Sixty MDD patients (45 depressed, 15 remitted) were compared to 60 HC using the Temperament and Character Inventory. Analysis of covariance, with age and gender as covariates, was used to compare the mean Temperament and Character Inventory scores among the subject groups. Results: Depressed MDD patients scored significantly higher than HC on novelty seeking, harm avoidance, and self-transcendence and lower on reward dependence, self-directedness, and cooperativeness. Remitted MDD patients scored significantly lower than HC only on self-directedness. Comorbidity with anxiety disorder had a main effect only on harm avoidance. Harm avoidance was positively correlated with depression intensity and with number of episodes. Self-directedness bad an inverse correlation with depression intensity. Conclusions: MDD patients present a different personality profile from HC, and these differences are influenced by mood state and comorbid anxiety disorders. When considering patients who have been in remission for some time, the differences pertain to few personality dimensions. Cumulated number of depressive episodes may result in increased harm avoidance. Depression and Anxiety 26.382-388, 2009. (c) 2009 Wiky-Liss, Inc.

Elevated striatal and decreased dorsolateral prefrontal cortical activity in response to emotional stimuli in euthymic bipolar disorder: no associations with psychotropic medication load

To examine abnormal patterns of frontal cortical-subcortical activity in response to emotional stimuli in euthymic individuals with bipolar disorder type I in order to identify trait-like, pathophysiologic mechanisms of the disorder. We examined potential confounding effects of total psychotropic medication load and illness variables upon neural abnormalities. We analyzed neural activity in 19 euthymic bipolar and 24 healthy individuals to mild and intense happy, fearful and neutral faces. Relative to healthy individuals, bipolar subjects had significantly increased left striatal activity in response to mild happy faces (p < 0.05, corrected), decreased right dorsolateral prefrontal cortical (DLPFC) activity in response to neutral, mild and intense happy faces, and decreased left DLPFC activity in response to neutral, mild and intense fearful faces (p < 0.05, corrected). Bipolar and healthy individuals did not differ in amygdala activity in response to either emotion. In bipolar individuals, there was no significant association between medication load and abnormal activity in these regions, but a negative relationship between age of illness onset and amygdala activity in response to mild fearful faces (p = 0.007). Relative to those without comorbidities, bipolar individuals with comorbidities showed a trend increase in left striatal activity in response to mild happy faces. Abnormally increased striatal activity in response to potentially rewarding stimuli and decreased DLPFC activity in response to other emotionally salient stimuli may underlie mood instabilities in euthymic bipolar individuals, and are more apparent in those with comorbid diagnoses. No relationship between medication load and abnormal neural activity in bipolar individuals suggests that our findings may reflect pathophysiologic mechanisms of the illness rather than medication confounds. Future studies should examine whether this pattern of abnormal neural activity could distinguish bipolar from unipolar depression.

Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting

The use of neuromodulation as a treatment for major depressive disorder (MDD) has recently attracted renewed interest due to development of other non-pharmacological therapies besides electroconvulsive therapy (ECT) such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS). METHOD: We convened a working group of researchers to discuss the updates and key challenges of neuromodulation use for the treatment of MDD. RESULTS: The state-of-art of neuromodulation techniques was reviewed and discussed in four sections: [1] epidemiology and pathophysiology of MDD; [2] a comprehensive overview of the neuromodulation techniques; [3] using neuromodulation techniques in MDD associated with non-psychiatric conditions; [4] the main challenges of neuromodulation research and alternatives to overcome them. DISCUSSION: ECT is the first-line treatment for severe depression. TMS and tDCS are strategies with a relative benign profile of side effects; however, while TMS effects are comparable to antidepressant drugs for treating MDD; further research is needed to establish the role of tDCS. DBS and VNS are invasive strategies with a possible role in treatment-resistant depression. In summary, MDD is a chronic and incapacitating condition with a high prevalence; therefore clinicians should consider all the treatment options including invasive and non-invasive neuromodulation approaches.

Factors associated with depression symptoms in high school students in São Paulo, Brazil

OBJECTIVE: To assess factors associated with depression symptoms in high school students. METHODS: A cross-sectional study involving high school students was conducted in the city of São Paulo, Brazil, 2001. A total of 724 students aged 14-18 years answered questionnaires on life and health conditions. Another questionnaire was applied to working (44.8%) and unemployed (22.9%) students to collect information on working conditions. Factors associated to depressive disorders were analyzed using multiple logistic regression controlled for occupational status. RESULTS: Overall prevalence rate of depression was 7.5%. Rates according to gender were 39 (10.3%) in females and 15 (4.3%) in males. The multiple logistic regression analysis showed that factors associated with depressive disorders were: poor self-perception of health (OR=5.78), being female (OR = 2.45), and alcohol consumption (OR=2.35). CONCLUSIONS: The study results showed that sociodemographic, lifestyle and health variables were associated with symptoms of depression in this population. These ndings suggest that it is important to have mental health professionals available in high schools for early detection of mental conditions and student counseling.