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Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.

BackgroundLithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified.MethodsHere, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis.FindingsA single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0).InterpretationThe response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings.FundingDeutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

Studies of clinical populations that combine MRI data generated at multiple sites are increasingly common. The Canadian Biomarker Integration Network in Depression (CAN-BIND; www.canbind.ca) is a national depression research program that includes multimodal neuroimaging collected at several sites across Canada. The purpose of the current paper is to provide detailed information on the imaging protocols used in a number of CAN-BIND studies. The CAN-BIND program implemented a series of platform-specific MRI protocols, including a suite of prescribed structural and functional MRI sequences supported by real-time monitoring for adherence and quality control. The imaging data are retained in an established informatics and databasing platform. Approximately 1300 participants are being recruited, including almost 1000 with depression. These include participants treated with antidepressant medications, transcranial magnetic stimulation, cognitive behavioural therapy and cognitive remediation therapy. Our ability to analyze the large number of imaging variables available may be limited by the sample size of the substudies. The CAN-BIND program includes a multimodal imaging database supported by extensive clinical, demographic, neuropsychological and biological data from people with major depression. It is a resource for Canadian investigators who are interested in understanding whether aspects of neuroimaging--alone or in combination with other variables--can predict the outcomes of various treatment modalities., Introduction Treatment of major depressive disorder (MDD) is evidence-based, but treatment selection is not personalized to the features of an individual's illness. (1) The discovery of biomarkers --or predictors--of treatment [...]

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Copyright of Canadian Journal of Psychiatry is the property of Sage Publications Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Asthma has long been considered a condition in which psychological factors have a role. As in many illnesses, psychological variables may affect outcome in asthma via their effects on treatment adherence and symptom reporting. Emerging evidence suggests that the relation between asthma and psychological factors may be more complex than that, however. Central cognitive processes may influence not only the interpretation of asthma symptoms but also the manifestation of measurable changes in immune and physiologic markers of asthma. Furthermore, asthma and major depressive disorder share several risk factors and have similar patterns of dysregulation in key biologic systems, including the neuroendocrine stress response, cytokines, and neuropeptides. Despite the evidence that depression is common in people with asthma and exerts a negative impact on outcome, few treatment studies have examined whether improving symptoms of depression do, in fact, result in better control of asthma symptoms or improved quality of life in patients with asthma.

Background: Neuroprotective effects of lithium (Li) have been well documented in tissue cultures and animal models, whereas human data continue to be limited. Previous studies investigating the association between Li treatment and brain N-acetylaspartate (NAA), a putative neuronal marker, showed mixed results because of methodological heterogeneity. Methods: To investigate the effects of Li on prefrontal cortex NAA levels, we compared patients with bipolar disorder from specialized Li clinics in Berlin and Halifax with at least 2 years of ongoing Li treatment (Li group), patients with lifetime Li exposure of less than 3 months more than 2 years ago (non-Li group) and healthy controls. Participants in both patient groups had at least 10 years of illness and 5 episodes. We measured left prefrontal NAA levels using 1.5-T magnetic resonance spectroscopy. Results: We enrolled 27 participants in the Li, 16 in the non-Li and 21 in the healthy control groups. The non-Li group had lower prefrontal NAA levels than the Li group ([t.sub.41] = -3.44, corrected p < 0.01) or control participants ([t.sub.35] = -2.91, corrected p < 0.05), who did not differ from the Li group ([t.sub.46] = -0.14, p = 0.89). The same pattern of prefrontal NAA differences was replicated in both sites. In addition, there was a negative correlation between prefrontal NAA and duration of illness in the non-Li group (r = -0.60, p = 0.019) but not in the Li group (r = 0.07, p = 0.74). Limitations: Study limitations include the cross-sectional design and exposure to other medications. Conclusion: Whereas patients with bipolar disorder, substantial illness burden and limited lifetime Li exposure had significantly lower prefrontal NAA levels than controls, Li-treated patients with similar illness burden showed prefrontal NAA levels comparable to those of healthy controls. These findings provide indirect support for neuroprotective effects of Li and for negative effects of illness burden on prefrontal NAA levels in patients with bipolar disorder., Introduction Neuroprotective effects of lithium (Li) have been well documented in tissue cultures and animal models. (1,2) It has been suggested that Li has neuroprotective effects in humans, but the [...]

Background: This review integrates neuroimaging studies of 2 domains of social cognition--emotion comprehension and theory of mind (ToM)--in patients with major depressive disorder and bipolar disorder. The influence of key clinical and method variables on patterns of neural activation during social cognitive processing is also examined. Methods: Studies were identified using PsycINFO and PubMed (January 1967 to May 2011). The search terms were 'fMRI,' 'emotion comprehension,' 'emotion perception,' 'affect comprehension,' 'affect perception,' 'facial expression,' 'prosody,' 'theory of mind,' 'mentalizing' and 'empathy' in combination with 'major depressive disorder,' 'bipolar disorder,' 'major depression,' 'unipolar depression,' 'clinical depression' and 'mania.' Results: Taken together, neuroimaging studies of social cognition in patients with mood disorders reveal enhanced activation in limbic and emotion-related structures and attenuated activity within frontal regions associated with emotion regulation and higher cognitive functions. These results reveal an overall lack of inhibition by higher-order cognitive structures on limbic and emotion-related structures during social cognitive processing in patients with mood disorders. Critically, key variables, including illness burden, symptom severity, comorbidity, medication status and cognitive load may moderate this pattern of neural activation. Limitations: Studies that did not include control tasks or a comparator group were included in this review. Conclusion: Further work is needed to examine the contribution of key moderator variables and to further elucidate the neural networks underlying altered social cognition in patients with mood disorders. The neural networks underlying higher-order social cognitive processes, including empathy, remain unexplored in patients with mood disorders., Introduction Major depressive disorder (MDD) and bipolar disorder are associated with alterations in multiple domains, including interpersonal and social functioning. (1-4) Recent studies have examined the nature of social impairment [...]

Background: Impairment of recollection memory is consistently reported in patients with major depressive disorder (MDD) and may reflect underlying functional hippocampal changes, particularly in those with extensive histories of illness. We hypothesized that relative to controls, patients with a protracted course of illness would show diminished hippocampal activation on functional magnetic resonance imaging (fMRI) during a recollection memory task. Methods: Patients who experienced 3 or more previously treated depressive episodes were compared with age- and sex-matched controls. We acquired fMRI data while participants performed a recollection memory process dissociation task. Results: Using bilateral regions of interest (ROIs) prescribed for the right and left hippocampal/ parahippocampal complex, we observed increased activation of the right hippocampal and left parahippocampal gyrus in controls compared with patients with MDD during recollection memory trials. Within-group comparisons revealed heightened engagement of the hippocampal head (R/L) for controls during recollection trials, and greater activation of the hippocampal body/tail (R/L) during the learn-list encoding period in both the MDD and control groups. Recollection memory performance was significantly correlated with changes in blood oxygen level-dependent signal during recollection trials in the ROIs of the right hippocampus and right hippocampal head. Limitations: This study was limited by the inclusion of patients taking antidepressant medication, raising the possibility that the reported findings were treatment effects. Conclusion: The findings of decreased recruitment of the right hippocampal and left parahippocampal gyrus in patients with MDD suggest that these regions may be sensitive to the impact of disease burden and repeated episodes of MDD. This attenuated activation may represent stable changes in hippocampal function that occur over the course of illness in patients with MDD. The findings from within-group comparisons show that the group differences in the activation of the right hippocampal head were driven by greater engagement of this region among controls during recollection memory performance. These results also associate recollection performance impairments in patients with MDD with diminished hippocampal engagement., Introduction Major depressive disorder (MDD) is associated with deficits in memory function. Of the discrete memory domains, recollection memory is the most impacted in patients with MDD. Dysfunction of effortful [...]

Whether magnetic resonance imaging studies can provide useful information to clinicians who treat people with major depressive disorder remains to be established. There are, however, several recent findings that suggest that likelihood of response may be predicted by imaging findings. For example, morphometric studies have examined whether hippocampus volume is associated with clinically meaningful outcomes such as response to treatment. In general, patients who remit have larger pretreatment hippocampus volumes bilaterally compared with those who do not remit. There are similar preliminary findings for the anterior cingulate cortex. There are also a number of functional imaging studies that have identified different activity patterns in those who are likely to respond to treatment compared with those who are not. Using positron emission tomography, investigators have reported different patterns of response to treatment in those treated with medication compared with those treated with psychotherapy. Some of the potential barriers to the routine use of imaging in psychiatric practice are reviewed briefly., Introduction Magnetic resonance imaging (MRI) is included in clinical trials investigating a variety of neurologic disorders, including Alzheimer disease, multiple sclerosis and stroke. Ciumas and colleagues (1) recently argued that [...]

Background: Some, although not all, studies report small hippocampal volume in patients with major depressive disorder (MDD) relative to healthy controls. Here, we explore the contribution of key demographic and clinical variables to this difference. Methods: We used meta-analytic techniques to provide an updated analysis of data from 32 magnetic resonance imaging studies of hippocampal volume in patients with MDD. Results: Our analysis confirmed the difference in hippocampal volume, but only among patients with MDD whose duration of illness was longer than 2 years or who had more than 1 disease episode. We found no such effect in studies that included patients who did not fit these criteria. The effect was limited to children and middle-aged or older adults. Analyzed collectively, studies including young adult patients showed equivalent hippocampal volumes across MDD patients and controls, a result that may be attributable to a reduced burden of illness in this population. Age at onset of disease, severity of depression at the time of scanning, sex and slice thickness did not contribute to differences in hippocampal volume between patients with MDD and controls. Limitations: The small size of many of the clinical and demographic subgroups may have limited statistical power to detect between-group differences. Conclusion: Although all studies were cross-sectional, our results suggest that hippocampal volume reductions generally occur after disease onset in patients with MDD. These findings have implications for the timing of clinical interventions aimed at reducing the impact of MDD on neuronal structure and function. Contexte: Certaines etudes, mais pas toutes, signalent que le volume de l&apos;hippocampe est plus petit chez les patients atteints de syndrome depressif majeur (SDM) que chez les temoins en bonne sante. Nous explorons ici la contribution a cette difference de variables demographiques et cliniques cles. Methodes : Nous avons utilise des techniques meta-analytiques pour effectuer une synthese a jour des donnees de 32 etudes ayant mesure le volume de l&apos;hippocampe chez des patients atteints de SDM au moyen de l&apos;imagerie par resonance magnetique. Resultats : Notre analyse a confirme la difference de volume de l&apos;hippocampe, mais uniquement chez les patients qui souffraient de SDM depuis plus de 2 ans, ou qui avaient presente plus d&apos;un episode de la maladie. Nous n&apos;avons pas observe d&apos;effets semblables dans les etudes qui incluaient des patients ne repondant pas a ces criteres. L&apos;effet a semble se limiter aux enfants et aux adultes d&apos;age moyen ou plus avance. Regroupees aux fins de l&apos;analyse, les etudes incluant des patients adultes moins ages ont fait etat de volumes hippocampiques equivalents chez les patients souffrant de SDM et les temoins, un resultat potentiellement attribuable au fardeau moins lourd de la maladie chez cette population. Le sexe du patient, son age lors du declenchement de la maladie, la gravite de la depression au moment de l&apos;epreuve d&apos;imagerie et l&apos;epaisseur des coupes n&apos;ont pas influe sur les differences de volume hippocampique entre les patients atteints de SDM et les temoins. Limites : Le petit echantillon de plusieurs des sous-groupes cliniques et demographiques peut avoir reduit la puissance statistique et empeche la detection des differences entre les groupes. Conclusion : Meme s&apos;il s&apos;agissait dans tous les cas d&apos;etudes transversales, nos resultats indiquent qu&apos;une diminution du volume de l&apos;hippocampe survient generalement apres le declenchement de la maladie chez les patients atteints de SDM. De telles observations ont une incidence sur le moment choisi pour intervenir cliniquement dans le but d&apos;attenuer l&apos;impact du SDM sur la structure et la fonction neuronales., Introduction A number of factors implicate the hippocampus in the pathogenesis of major depressive disorder (MDD), including the fact that the hippocampus is a highly stress-sensitive brain region (1) and [...]

Objective: Bipolar disorders have a strong genetic underpinning. Little is known about biological predispositions that convey vulnerability for the illness. We searched for biological vulnerability markers using proton magnetic resonance [...]