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.

Discovering imaging endophenotypes for major depression

Psychiatry research lacks an in-depth understanding of mood disorders phenotypes, leading to limited success of genetics studies of major depressive disorder (MDD). The dramatic progress in safe and affordable magnetic resonance-based imaging methods has the potential to identify subtle abnormalities of neural structures, connectivity and function in mood disordered subjects. This review paper presents strategies to improve the phenotypic definition of MDD by proposing imaging endophenotypes derived from magnetic resonance spectroscopy measures, such as cortical gamma-amino butyric acid (GABA) and glutamate/glutamine concentrations, and from measures of resting-state activity and functional connectivity. The proposed endophenotypes are discussed regarding specificity, mood state-independence, heritability, familiarity, clinical relevance and possible associations with candidate genes. By improving phenotypic definitions, the discovery of new imaging endophenotypes will increase the power of candidate gene and genome-wide associations studies. It will also help to develop and evaluate novel therapeutic treatments and enable clinicians to apply individually tailored therapeutic approaches. Finally, improvements of the phenotypic definition of MDD based on neuroimaging measures will contribute to a new classification system of mood disorders based on etiology and pathophysiology.

Reduced metabotropic glutamate receptor 5 density in major depression determined by [(11)C]ABP688 PET and postmortem study

Clinical and preclinical evidence suggests a hyperactive glutamatergic system in clinical depression. Recently, the metabotropic glutamate receptor 5 (mGluR5) has been proposed as an attractive target for novel therapeutic approaches to depression. The goal of this study was to compare mGluR5 binding (in a positron emission tomography [PET] study) and mGluR5 protein expression (in a postmortem study) between individuals with major depressive disorder and psychiatrically healthy comparison subjects.

Reduced Cerebral Blood Flow Within the Default-Mode Network and Within Total Gray Matter in Major Depression

The default-mode network (DMN) was shown to have aberrant blood oxygenation-level-dependent (BOLD) activity in major depressive disorder (MDD). While BOLD is a relative measure of neural activity, cerebral blood flow (CBF) is an absolute measure. Resting-state CBF alterations have been reported in MDD. However, the association of baseline CBF and CBF fluctuations is unclear in MDD. Therefore, the aim was to investigate the CBF within the DMN in MDD, applying a strictly data-driven approach. In 22 MDD patients and 22 matched healthy controls, CBF was acquired using arterial spin labeling (ASL) at rest. A concatenated independent component analysis was performed to identify the DMN within the ASL data. The perfusion of the DMN and its nodes was quantified and compared between groups. The DMN was identified in both groups with high spatial similarity. Absolute CBF values within the DMN were reduced in MDD patients (p<0.001). However, after controlling for whole-brain gray matter CBF and age, the group difference vanished. In patients, depression severity was correlated with reduced perfusion in the DMN in the posterior cingulate cortex and the right inferior parietal lobe. Hypoperfusion within the DMN in MDD is not specific to the DMN. Still, depression severity was linked to DMN node perfusion, supporting a role of the DMN in depression pathobiology. The finding has implications for the interpretation of BOLD functional magnetic resonance imaging data in MDD.

Psychomotor retardation is linked to frontal alpha asymmetry in major depression

BACKGROUND Psychomotor disturbances are a main clinical feature of major depressive disorder (MDD) but little is known about their EEG signature. One of the most replicated EEG findings in MDD is resting frontal asymmetry in the alpha band (FAA), which is thought to be a correlate of withdrawal behavior and reduced approach motivation. The purpose of this study was to assess psychomotor alterations, alpha band power, FAA and investigate the association between them. METHODS 20 MDD patients and 19 healthy subjects were enrolled. Alpha power and FAA scores were calculated from a resting state EEG. Wrist actigraphy was recorded from the non-dominant arm for 24 h and activity level scores (AL) were extrapolated from the wakeful periods. RESULTS MDD patients had a left-lateralized frontal alpha activity and lower AL scores when compared to healthy subjects. A significant correlation was found between mean FAA and AL scores. A negative covariance between power in the lower alpha range and AL scores over the motor cortex bilaterally was detected. LIMITATIONS Relatively small sample size. Patients were pharmacologically treated with antidepressants. CONCLUSIONS This study replicates the finding of left-lateralized FAA and lower AL scores in MDD patients, and establishes the first evidence of significant correlations between alpha power, FAA scores and measures of motor activity, which may be interpreted as an expression of impaired motivational drive in MDD.

EEG marker of inhibitory brain activity correlates with resting-state cerebral blood flow in the reward system in major depression

Frontal alpha band asymmetry (FAA) is a marker of altered reward processing in major depressive disorder (MDD), associated with reduced approach behavior and withdrawal. However, its association with brain metabolism remains unclear. The aim of this study is to investigate FAA and its correlation with resting – state cerebral blood flow (rCBF). We hypothesized an association of FAA with regional rCBF in brain regions relevant for reward processing and motivated behavior, such as the striatum. We enrolled 20 patients and 19 healthy subjects. FAA scores and rCBF were quantified with the use of EEG and arterial spin labeling. Correlations of the two were evaluated, as well as the association with FAA and psychometric assessments of motivated behavior and anhedonia. Patients showed a left – lateralized pattern of frontal alpha activity and a correlation of FAA lateralization with subscores of Hamilton Depression Rating Scale linked to motivated behavior. An association of rCBF and FAA scores was found in clusters in the dorsolateral prefrontal cortex bilaterally (patients) and in the left medial frontal gyrus, in the right caudate head and in the right inferior parietal lobule (whole group). No correlations were found in healthy controls. Higher inhibitory right – lateralized alpha power was associated with lower rCBF values in prefrontal and striatal regions, predominantly in the right hemisphere, which are involved in the processing of motivated behavior and reward. Inhibitory brain activity in the reward system may contribute to some of the motivational problems observed in MDD.

Cognitive-Behavioural Analysis System of Psychotherapy (CBASP), a drug, or their combination: differential therapeutics for persistent depressive disorder: a study protocol of an individual participant data network meta-analysis.

INTRODUCTION Despite important advances in psychological and pharmacological treatments of persistent depressive disorders in the past decades, their responses remain typically slow and poor, and differential responses among different modalities of treatments or their combinations are not well understood. Cognitive-Behavioural Analysis System of Psychotherapy (CBASP) is the only psychotherapy that has been specifically designed for chronic depression and has been examined in an increasing number of trials against medications, alone or in combination. When several treatment alternatives are available for a certain condition, network meta-analysis (NMA) provides a powerful tool to examine their relative efficacy by combining all direct and indirect comparisons. Individual participant data (IPD) meta-analysis enables exploration of impacts of individual characteristics that lead to a differentiated approach matching treatments to specific subgroups of patients. METHODS AND ANALYSIS We will search for all randomised controlled trials that compared CBASP, pharmacotherapy or their combination, in the treatment of patients with persistent depressive disorder, in Cochrane CENTRAL, PUBMED, SCOPUS and PsycINFO, supplemented by personal contacts. Individual participant data will be sought from the principal investigators of all the identified trials. Our primary outcomes are depression severity as measured on a continuous observer-rated scale for depression, and dropouts for any reason as a proxy measure of overall treatment acceptability. We will conduct a one-step IPD-NMA to compare CBASP, medications and their combinations, and also carry out a meta-regression to identify their prognostic factors and effect moderators. The model will be fitted in OpenBUGS, using vague priors for all location parameters. For the heterogeneity we will use a half-normal prior on the SD. ETHICS AND DISSEMINATION This study requires no ethical approval. We will publish the findings in a peer-reviewed journal. The study results will contribute to more finely differentiated therapeutics for patients suffering from this chronically disabling disorder. TRIAL REGISTRATION NUMBER CRD42016035886.