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Antidepressants (ADs) are the most common treatment for major depressive disorder (MDD). However, only ∼30% of patients experience adequate response after a single AD trial, and this variability remains poorly understood. Here, we investigated microRNAs (miRNAs) as biomarkers of AD response using small RNA-sequencing in paired samples from MDD patients enrolled in a large, randomized placebo-controlled trial of duloxetine collected before and 8 weeks after treatment. Our results revealed differential expression of miR-146a-5p, miR-146b-5p, miR-425-3p and miR-24-3p according to treatment response. These results were replicated in two independent clinical trials of MDD, a well-characterized animal model of depression, and post-mortem human brains. Furthermore, using a combination of bioinformatics, mRNA studies and functional in vitro experiments, we showed significant dysregulation of genes involved in MAPK/Wnt signalling pathways. Together, our results indicate that these miRNAs are consistent markers of treatment response and regulators of the MAPK/Wnt systems. Antidepressant drugs are the most common treatment for depressive episodes but only a fraction of patients experience adequate response. Here the authors find dysregulation of miRNAs in peripheral blood samples from depressed patients after antidepressant treatment, and show that the miRNAs are regulators of psychiatrically relevant signalling pathways.

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.

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. 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.” 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. Studies that did not include control tasks or a comparator group were included in this review. 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.

In an effort to optimize patient outcomes, considerable attention is being devoted to identifying patient characteristics associated with major depressive disorder (MDD) and its responsiveness to treatment. In the current study, we extend this work by evaluating whether early change in these sensitivities is associated with response to antidepressant treatment for MDD. Participants included 210 patients with MDD who were treated with 8 weeks of escitalopram and 112 healthy comparison participants. Of the original 210 patients, 90 non-responders received adjunctive aripiprazole for an additional 8 weeks. Symptoms of depression and anhedonia were assessed at the beginning of treatment and 8 weeks later in both samples. Reward and punishment sensitivity were assessed using the BIS/BAS scales measured at the initiation of treatment and 2 weeks later. Individuals with MDD exhibited higher punishment sensitivity and lower reward sensitivity compared with healthy comparison participants. Change in reward sensitivity during the first 2 weeks of treatment was associated with improved depressive symptoms and anhedonia following 8 weeks of treatment with escitalopram. Similarly, improvement in reward responsiveness during the first 2 weeks of adjunctive therapy with aripiprazole was associated with fewer symptoms of depression at post-treatment. Findings highlight the predictive utility of early change in reward sensitivity during antidepressant treatment for major depression. In a clinical setting, a lack of change in early reward processing may signal a need to modify a patient's treatment plan with alternative or augmented treatment approaches.

Subtle changes in hippocampal volumes may occur during both physiological and pathophysiological processes in the human brain. Assessing hippocampal volumes manually is a time-consuming procedure, however, creating a need for automated segmentation methods that are both fast and reliable over time. Segmentation algorithms that employ deep convolutional neural networks (CNN) have emerged as a promising solution for large longitudinal neuroimaging studies. However, for these novel algorithms to be useful in clinical studies, the accuracy and reproducibility should be established on independent datasets. Here, we evaluate the performance of a CNN-based hippocampal segmentation algorithm that was developed by Thyreau and colleagues – Hippodeep. We compared its segmentation outputs to manual segmentation and FreeSurfer 6.0 in a sample of 200 healthy participants scanned repeatedly at seven sites across Canada, as part of the Canadian Biomarker Integration Network in Depression consortium. The algorithm demonstrated high levels of stability and reproducibility of volumetric measures across all time points compared to the other two techniques. Although more rigorous testing in clinical populations is necessary, this approach holds promise as a viable option for tracking volumetric changes in longitudinal neuroimaging studies. •Hippodeep demonstrated high stability of measures across all time-points.•Hippodeep had better agreement with manual segmentations than those of FreeSurfer.•Deep neural network performed better on problematic scans as compared to FreeSurfer.

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.

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.

Studies have examined hippocampal function and volume in depressed subjects, but none have systematically compared never-treated first-episode patients with those who have had multiple episodes. We sought to compare hippocampal function, as assessed by performance on hippocampal-dependent recollection memory tests, and hippocampal volumes, as measured in a 1.5-T magnetic resonance imager, in depressed subjects experiencing a postpubertal onset of depression. Twenty never-treated depressed subjects in a first episode of depression were compared with matched healthy control subjects. Seventeen depressed subjects with multiple past episodes of depression were also compared with matched healthy controls and to the first-episode patients. Both first- and multiple-episode depressed groups had hippocampal dysfunction apparent on several tests of recollection memory; only depressed subjects with multiple depressive episodes had hippocampal volume reductions. Curve-fitting analysis revealed a significant logarithmic association between illness duration and hippocampal volume. Reductions in hippocampal volume may not antedate illness onset, but volume may decrease at the greatest rate in the early years after illness onset.

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. 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. 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. This study was limited by the inclusion of patients taking antidepressant medication, raising the possibility that the reported findings were treatment effects. 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.

Background: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. Methods: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. “Neurostimulation Treatments” is the fourth of six sections of the 2016 guidelines. Results: Evidence-informed responses were developed for 31 questions for 6 neurostimulation modalities: 1) transcranial direct current stimulation (tDCS), 2) repetitive transcranial magnetic stimulation (rTMS), 3) electroconvulsive therapy (ECT), 4) magnetic seizure therapy (MST), 5) vagus nerve stimulation (VNS), and 6) deep brain stimulation (DBS). Most of the neurostimulation treatments have been investigated in patients with varying degrees of treatment resistance. Conclusions: There is increasing evidence for efficacy, tolerability, and safety of neurostimulation treatments. rTMS is now a first-line recommendation for patients with MDD who have failed at least 1 antidepressant. ECT remains a second-line treatment for patients with treatment-resistant depression, although in some situations, it may be considered first line. Third-line recommendations include tDCS and VNS. MST and DBS are still considered investigational treatments.