Affective Instability, Childhood Trauma and Major Affective Disorders

BACKGROUND: Affective instability (AI), childhood trauma, and mental illness are linked, but evidence in affective disorders is limited, despite both AI and childhood trauma being associated with poorer outcomes. Aims were to compare AI levels in bipolar disorder I (BPI) and II (BPII), and major depressive disorder recurrent (MDDR), and to examine the association of AI and childhood trauma within each diagnostic group. METHODS: AI, measured using the Affective Lability Scale (ALS), was compared between people with DSM-IV BPI (n=923), BPII (n=363) and MDDR (n=207) accounting for confounders and current mood. Regression modelling was used to examine the association between AI and childhood traumas in each diagnostic group. RESULTS: ALS scores in descending order were BPII, BPI, MDDR, and differences between groups were significant (p<0.05). Within the BPI group any childhood abuse (p=0.021), childhood physical abuse (p=0.003) and the death of a close friend in childhood (p=0.002) were significantly associated with higher ALS score but no association was found between childhood trauma and AI in BPII and MDDR. LIMITATIONS: The ALS is a self-report scale and is subject to retrospective recall bias. CONCLUSIONS: AI is an important dimension in bipolar disorder independent of current mood state. There is a strong link between childhood traumatic events and AI levels in BPI and this may be one way in which exposure and disorder are linked. Clinical interventions targeting AI in people who have suffered significant childhood trauma could potentially change the clinical course of bipolar disorder.

Mental health treatment seeking by military members with posttraumatic stress disorder : findings on rates, characteristics, and predictors from a nationally representative Canadian military sample

Objective: The goal of this study was to identify rates, characteristies, and predictors of mental health treatment seeking by military members with posttraumatic stress disorder (PTSD). Method: Our sample was drawn from the 2002 Canadian Community Health Survey-Canadian Forces Supplement (CCHS-CF) dataset. The CCHS-CF is the first epidemiologic survey of PTSD and other mental health conditions in the Canadian military and includes 8441 nationally representative Canadian Forces (CF) members. Of those, 549 who met the criteria for lifetime PTSD were included in our analyses. To identify treatment rates and characteristics, we examined frequency of treatment contact by professional and facility type. To identify predictors of treatment seeking, we conducted a binary logistic regression with lifetime treatment seeking as the outcome variable. Results: About two-thirds of those with PTSD consulted with a professional regarding mental health problems. The most frequently consulted professionals, during both the last year and lifetime, included social workers and counsellors, medical doctors and general practitioners, and psychiatrists. Consultations during the last year most often took place in a CF facility. Treatment seeking was predicted by cumulative lifetime trauma exposure, index traumatic event type, PTSD symptom interference, and comorbid major depressive disorder. Those with comorbid depression were 3.75 times more likely to have sought treatment than those without. Conclusions: Although a significant portion of military members with PTSD sought mental health treatment, 1 in 3 never did. Trauma-related and illness and (or) need factors predicted treatment seeking. Of all the predictors of treatment seeking, comorbid depression most increased the likelihood of seeking treatment.

Failure to regulate: counterproductive recruitment of top-down prefrontal-subcortical circuitry in major depression

Although depressed mood is a normal occurrence in response to adversity in all individuals, what distinguishes those who are vulnerable to major depressive disorder (MDD) is their inability to effectively regulate negative mood when it arises. Investigating the neural underpinnings of adaptive emotion regulation and the extent to which such processes are compromised in MDD may be helpful in understanding the pathophysiology of depression. We report results from a functional magnetic resonance imaging study demonstrating left-lateralized activation in the prefrontal cortex (PFC) when downregulating negative affect in nondepressed individuals, whereas depressed individuals showed bilateral PFC activation. Furthermore, during an effortful affective reappraisal task, nondepressed individuals showed an inverse relationship between activation in left ventrolateral PFC and the amygdala that is mediated by the ventromedial PFC (VMPFC). No such relationship was found for depressed individuals, who instead show a positive association between VMPFC and amygdala. Pupil dilation data suggest that those depressed patients who expend more effort to reappraise negative stimuli are characterized by accentuated activation in the amygdala, insula, and thalamus, whereas nondepressed individuals exhibit the opposite pattern. These findings indicate that a key feature underlying the pathophysiology of major depression is the counterproductive engagement of right prefrontal cortex and the lack of engagement of left lateral-ventromedial prefrontal circuitry important for the downregulation of amygdala responses to negative stimuli.

Expression of the Rap1 guanine nucleotide exchange factor, MR-GEF, is altered in individuals with bipolar disorder

In the rodent forebrain GABAergic neurons are generated from progenitor cells that express the transcription factors Dlx1 and Dlx2. The Rap-1 guanine nucleotide exchange factor, MR-GEF, is turned on by many of these developing GABAergic neurons. Expression of both Dlx1/2 and MR-GEF is retained in both adult mouse and human forebrain where, in human, decreased Dlx1 expression has been associated with psychosis. Using in situ hybridization studies we show that MR-GEF expression is significantly down-regulated in the forebrain of Dlx1/2 double mutant mice suggesting that MR-GEF and Dlx1/2 form part of a common signalling pathway during GABAergic neuronal development. We therefore compared MR-GEF expression by in situ hybridization in individuals with major psychiatric disorders (schizophrenia, bipolar disorder, major depression) and control individuals. We observed a significant positive correlation between layers II and IV of the dorso-lateral prefrontal cortex (DLPFC) in the percentage of MR-GEF expressing neurons in individuals with bipolar disorder, but not in individuals with schizophrenia, major depressive disorder or in controls. Since MR-GEF encodes a Rap1 GEF able to activate G-protein signalling, we suggest that changes in MR-GEF expression could potentially influence neurotransmission.

Suicidality in Obsessive-Compulsive Disorder: Prevalence and Relation to Symptom Dimensions and Comorbid Conditions

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Clinical correlates of social adjustment in patients with obsessive-compulsive disorder

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Long-term sertraline treatment increases expression and decreases phosphorylation of glycogen synthase kinase-3B in platelets of patients with late-life major depression

Background: Abnormal regulation of glycogen synthase kinase 3-beta (GSK3B) activity has been implicated in the pathophysiology of mood disorders. Many pharmacological agents, including antidepressants, can modulate GSK3B. The aim of the present study was to investigate the effect of short-and long-term sertraline treatment on the expression and phosphorylation of GSK3B in platelets of patients with late-life major depression. Methods: Thirty-nine unmedicated elderly adults with major depressive disorder (MOD) were initially included in this study. The comparison group comprised 18 age-matched, healthy individuals. The expression of total and Ser-9 phosphorylated GSK3B (pGSK3B) was determined by Enzyme Immunometric Assay (EIA) in platelets of patients and controls at baseline, and after 3 and 12 months of sertraline treatments for patients only. During this period, patients were continuously treated with therapeutic doses of sertraline. GSK3B activity was indirectly estimated by calculating the proportion of inactive (phosphorylated) forms (pGSK3B) in relation to the total expression of the enzyme (i.e.. GSK3B ratio). Results: Depressed patients had significantly higher levels of pGSK3B as compared to controls (p < 0.001). Within the MDD group, after 3 months of sertraline treatment no significant changes were observed in GSK3B expression and phosphorylation state, as compared to baseline levels. However, after 12 months of treatment we found a significant increase in the expression of total GSK3B (p = 0.05), in the absence of any significant changes in pGSK3B (p = 0.12), leading to a significant reduction in GSK3B ratio (p = 0.001). Conclusions: Our findings indicate that GSK3B expression was upregulated by the continuous treatment with sertraline, along with an increment in the proportion of active forms of the enzyme. This is compatible with an increase in overall GSK3B activity, which may have been induced by the long-term treatment of late-life depression with sertraline. (C) 2012 Elsevier Ltd. All rights reserved.

Reduced serum levels of adiponectin in elderly patients with major depression

Recent studies have implicated adiponectin and other adipocytokines in brain function, particularly in processes related to memory and cognition. Blood levels of adiponectin are reduced in patients with primary cognitive disorders, such as Alzheimer's disease and mild cognitive impairment, and in adult patients with major depression. The aim of the present study is to determine serum levels of adiponectin in a sample of elderly patients with major depressive disorder (MOD) as compared to healthy older adults, and to examine the correlations between adiponectin levels and parameters indicative of mood and cognitive state. We recruited fifty-one unmedicated outpatients with late-life depression (LLD) and 47 age-matched controls in this study. The diagnosis of MDD was made according to the DSM-IV criteria, and the severity of depressive episode was determined with the 21-item Hamilton Depression Scale (HORS). Cognitive state was ascertained with the Cambridge Cognitive Test (CAMCOG) and the Mini-Mental State Examination (MMSE). Serum concentrations of adiponectin were determined using a sandwich ELISA method. Serum levels of adiponectin were significantly reduced in individuals with LLD (F = p < 0.001). Adiponectin level remained significantly reduced in after controlling for BMI index, scores on the CAMCOG, MMSE and HDRS and educational level (p < 0.001). Adiponectin levels showed a negative correlation with HORS scores (r = -0.59, p < 0.001) and BMI index (r = -0.42, p < 0.001); and showed a positive correlation with CAMCOG (r = 0.34, p < 0.01) and MMSE scores (r = 0.20, p = 0.05). The availability of circulating adiponectin is reduced in older adults with major depression, with likely implications on cognitive and mood state. Additional studies are required to determine whether this abnormality pertains to the pathophysiology of geriatric depression per se, or is a consequence of the morbid state. (C) 2012 Elsevier Ltd. All rights reserved.

Abnormal resting state corticolimbic blood flow in depressed unmedicated patients with major depression: A 15O-H2O 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 H215O 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. Hum Brain Mapp, 2012. (C) 2011 Wiley Periodicals, Inc.

Social phobia in obsessive-compulsive disorder: Prevalence and correlates

Background: Social Phobia (SP) is an anxiety disorder that frequently co-occurs with obsessive-compulsive disorder (OCD); however, studies that evaluate clinical factors associated with this specific comorbidity are rare. The aim was to estimate the prevalence of SP in a large multicenter sample of OCD patients and compare the characteristics of individuals with and without SP. Method: A cross-sectional study with 1001 patients of the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders using several assessment instruments, including the Dimensional Yale-Brown Obsessive-Compulsive Scale and the Structured Clinical Interview for DSM-IV Axis I Disorders. Univariate analyses were followed by logistic regression. Results: Lifetime prevalence of SP was 34.6% (N=346). The following variables remained associated with SP comorbidity after logistic regression: male sex, lower socioeconomic status, body dysmorphic disorder, specific phobia, dysthymia, generalized anxiety disorder, agoraphobia, Tourette syndrome and binge eating disorder. Limitations: The cross-sectional design does not permit the inference of causal relationships; some retrospective information may have been subject to recall bias; all patients were being treated in tertiary services, therefore generalization of the results to other samples of OCD sufferers should be cautious. Despite the large sample size, some hypotheses may not have been confirmed due to the small number of cases with these characteristics (type 2 error). Conclusion: SP is frequent among OCD patients and co-occurs with other disorders that have common phenomenological features. These findings have important implications for clinical practice, indicating the need for broader treatment approaches for individuals with this profile. (C) 2012 Elsevier B.V. All rights reserved.

Clinical correlates of social adjustment in patients with obsessive-compulsive disorder

Background: Patients with obsessive-compulsive disorder (OCD) frequently show poor social adjustment, which has been associated with OCD severity. Little is known about the effects that age at symptom onset, specific OCD symptoms, and psychiatric comorbidities have on social adjustment. The objective of this study was to investigate the clinical correlates of social functioning in OCD patients. Methods: Cross-sectional study involving 815 adults with a primary DSM-IV diagnosis of OCD participating in the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders. Patients were assessed with the Social Adjustment Scale, the Medical Outcomes Study 36-item Short-Form Health Survey, the Yale-Brown Obsessive-Compulsive Scale, the Dimensional Yale-Brown Obsessive-Compulsive Scale, and the Structured Clinical Interview for DSM-IV Axis I Disorders. Clinical correlates of social adjustment were assessed with generalized linear models with gamma distribution. Results: Poor overall social functioning was associated with greater OCD severity (p = 0.02); hoarding symptoms (p = 0.004); sexual/religious obsessions (p = 0.005); current major depressive disorder (p = 0.004); current post-traumatic stress disorder (p = 0.002); and current eating disorders (p = 0.02). Poor social adjustment was also associated with impaired quality of life. Conclusions: Patients with OCD have poor social functioning in domains related to personal relationships and professional performance. Hoarding symptoms and sexual/religious obsessions seem to have the strongest negative effects on social functioning. Early age at OCD symptom onset seems to be associated with professional and academic underachievement and impairment within the family unit, whereas current psychiatric comorbidity worsen overall social functioning. In comparison with quality of life, social adjustment measures seem to provide a more comprehensive overview of the OCD-related burden. (C) 2012 Elsevier Ltd. All rights reserved.

Healthy maternal bonding as a resilience factor for depressive disorder

INTRODUCTION: Depressive disorders (DDs) are very prevalent disorders particularly in women, a high-risk gender group. Determining the risk and protective factors associated with the development of DDs is fundamental to planning preventive and therapeutic strategies. In this study, we evaluated the correlations between healthy maternal attachment and the development of DDs in adulthood. METHODS: We evaluated 52 women at 6 months to 1 year after premature childbirth at Maternidade Vila Nova Cachoeirinha. They were evaluated using the following instruments: Brazilian Criteria of Economic Classification,Parental Bonding Inventory (PBI),Center for Epidemiologic Studies Depression Scale (CES-D), and Edinburgh Postnatal Depression Scale (EPDS). Cut-off scores on the CES-D and EPDS were used to classifythe subjects as currently having a DD or having probable postpartum disorder (PPD) after childbirth. Multiple logistic regression was used to evaluate the risk factors associated with DDs. RESULTS: We found that 49.1% of the sample had a current depressive episode, and 73.6% had probable PPD. Based on logistic regression, current depression (odds ratio = 1.092 [confidence interval: 1.005; 1.186]), and a PPD (odds ratio = 1.108 [confidence interval: 1.011; 1.21]) were negatively correlated with affective maternal relationships. CONCLUSIONS: Women who reported healthy attachment with their mothers did not develop DDs when faced with stressful situations such as premature childbirth.

Elevated level of metabotropic glutamate receptor 2/3 in the prefrontal cortex in major depression

Clinical, postmortem and preclinical research strongly implicates dysregulation of glutamatergic neurotransmission in major depressive disorder (MDD). Recently, metabotropic glutamate receptors (mGluRs) have been proposed as attractive targets for the discovery of novel therapeutic approaches against depression. The aim of this study was to examine mGluR2/3 protein levels in the prefrontal cortex (PFC) from depressed subjects. In addition, to test whether antidepressants influence mGluR2/3 expression we also studied levels of mGluR2/3 in fluoxetine-treated monkeys. Postmortem human prefrontal samples containing Brodmann's area 10 (BA10) were obtained from 11 depressed and 11 psychiatrically healthy controls. Male rhesus monkeys were treated chronically with fluoxetine (dose escalated to 3mg/kg, p.o.; n=7) or placebo (n=6) for 39 weeks. The mGluR2/3 immunoreactivity was investigated using Western blot method. There was a robust (+67%) increase in the expression of the mGlu2/3 protein in the PFC of depressed subjects relative to healthy controls. The expression of mGlu2/3 was unchanged in the PFC of monkeys treated with fluoxetine. Our findings provide the first evidence that mGluR2/3 is elevated in the PFC in MDD. This observation is consistent with reports showing that mGluR2/3 antagonists exhibit antidepressant-like activity in animal models and demonstrates that these receptors are promising targets for the discovery of novel antidepressants.

Neural correlates of disbalanced motor control in major depression

Motor retardation is a common symptom of major depressive disorder (MDD). Despite the existence of various assessment methods, little is known on the pathobiology of motor retardation. We aimed to elucidate aspects of motor control investigating the association of objective motor activity and resting state cerebral blood flow (CBF).

Frontal white matter integrity is related to psychomotor retardation in major depression

Altered frontal white matter integrity has been reported in major depression. Still, the behavioral correlates of these alterations are not established. In healthy subjects, motor activity correlated with white matter integrity in the motor system. To explore the relation of white matter integrity and motor activity in major depressive disorder, we investigated 21 medicated patients with major depressive disorder and 21 matched controls using diffusion tensor imaging and wrist actigraphy at the same day. Patients had lower activity levels (AL) compared with controls. Fractional anisotropy (FA) differed between groups in frontal white matter regions and the posterior cingulum. AL was linearly associated with white matter integrity in two clusters within the motor system. Controls had an exclusive positive association of FA and AL in white matter underneath the right dorsal premotor cortex. Only patients had a positive association within the posterior cingulum. Furthermore, patients had negative associations of FA and AL underneath the left primary motor cortex and within the left parahippocampal gyrus white matter. These differences in the associations between structure and behavior may contribute to well-known impaired motor planning or gait disturbances in major depressive disorder. Therefore, signs of psychomotor slowing in major depressive disorder may be linked to changes of the white matter integrity of the motor system.