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BackgroundFour ablative neurosurgical procedures are used in the treatment of refractory psychiatric illness. The long-term effects of these procedures on psychiatric symptoms across disorders has never been synthesised and meta-analysed.MethodsA preregistered systematic review was performed on studies reporting clinical results following ablative psychiatric neurosurgery. Four possible outcome measures were extracted for each study: depression, obsessive–compulsive symptoms, anxiety and clinical global impression. Effect sizes were calculated using Hedge’s g. Equipercentile linking was used to convert symptom scores to a common metric. The main outcome measures were the magnitude of improvement in depression, obsessive compulsive symptoms, anxiety and clinical global impression. The secondary outcome was a subgroup analysis comparing the magnitude of symptom changes between the four procedures.ResultsOf 943 articles, 43 studies reporting data from 1414 unique patients, were included for pooled effects estimates with a random-effects meta-analysis. Results showed that there was a large effect size for improvements in depression (g=1.27; pConclusionsContemporary ablative neurosurgical procedures were significantly associated with improvements in depression, obsessive–compulsive symptoms, anxiety and clinical global impression.PROSPERO registration numberCRD42020164784.

BACKGROUND Post-concussive symptoms (PCSs) are common, disabling, and challenging to manage. Evolving models of concussion pathophysiology suggest evidence of brain network dysfunction that may be amenable to neuromodulation. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a potential novel treatment option for PCSs. OBJECTIVES To systematically review rTMS trials for the treatment of symptoms following concussion/mild traumatic brain injury (mTBI). MATERIALS AND METHODS We conducted a systematic review of Pubmed/Medline, Embase, and PsychINFO databases were searched up to May 19, 2020. Studies were included if they were prospective rTMS treatment studies of patients with mTBI/concussion. Variables including patient demographics, study design, rTMS protocol parameters, primary outcome measures, and efficacy data were extracted and qualitatively synthesized. rTMS methodology and study quality were also evaluated. RESULTS Of the 342 studies identified, 11 met eligibility criteria and were included for synthesis. Forty-one percent of patients were female and age ranged from 18 to 65 (average age = 38.5 years). Post-concussive depression (seven studies) and headache (four studies) were the most commonly investigated symptoms. The majority of trials were sham-controlled with randomized control trial (RCT) designs, but all were small pilot samples (n

Non-response to first-line treatment for major depressive disorder (MDD) is common; for such individuals, quality of life (QoL) impairments can be severe. Identifying predictors of QoL changes may support the management of cases with persistent depressive symptoms despite adequate initial pharmacological/psychological treatment. The present study aimed to explore predictors of domain-specific QoL improvement following adjunctive aripiprazole treatment for inadequate response to initial antidepressant therapy. We evaluated secondary QoL outcomes from a CAN-BIND (Canadian Biomarker Integration Network in Depression) study in patients with MDD who did not respond to an initial 8 weeks of escitalopram and received a further 8 weeks of adjunctive aripiprazole (n = 96). Physical, psychological, social, and environmental QoL domains were assessed using the World Health Organization QoL Scale Brief Version (WHOQOL-BREF). Clinician-rated depressive symptoms were assessed using the Montgomery–Asberg Depression Rating Scale (MADRS). Functioning was measured with the Sheehan Disability Scale (SDS). Satisfaction with medication was assessed with a single item from the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF). Exploratory t-tests were used to describe domain score changes. A hierarchical linear regression was used to explore demographic, clinical, and treatment-related predictors of improvement. Across domains, QoL improved with adjunctive aripiprazole treatment. Satisfaction with medication and MADRS and SDS scores similarly improved. Symptom reduction was a predictor for positive change to physical and psychological QoL; functioning improvements were predictive of increases to all QoL domains. Satisfaction with medication predicted improvements to physical and psychological domains, whereas number of medication trials was a predictor of worsening QoL in the physical domain. The final model explained the most variance in psychological (68%) and physical (67%) QoL. Less variance was explained for environmental (43%) and social QoL (33%), highlighting a need for further exploration of predictors in these domains. Strategies such as functional remediation may have potential to support QoL for individuals with persistent depressive symptoms. ClinicalTrials.gov identifier: NCT016557.

Introduction Many individuals with major depressive disorder (MDD) do not respond to initial antidepressant monotherapy. Adjunctive aripiprazole is recommended for treatment non-response; however, the impacts on quality of life (QoL) for individuals who receive this second-line treatment strategy have not been described. Methods We evaluated secondary QoL outcomes in patients with MDD (n=179). After 8 weeks of escitalopram, non-responders ( Results Escitalopram responders experienced the most QoL improvements in the first treatment phase. For non-responders, QoL improved with a large effect during adjunctive aripiprazole treatment. At the endpoint, 47% of patients achieving symptomatic remission still had impaired QoL. Discussion Individuals who were treated with adjunctive aripiprazole after non-response to escitalopram experienced improved QoL, but a substantial degree of QoL impairment persisted. Since QoL deficits may predict MDD recurrence, attention to ways to support this outcome is required.

Background Treatment‐resistant depression (TRD) is a debilitating chronic mental illness that confers increased morbidity and mortality, decreases the quality of life, impairs occupational, social, and offspring development, and translates into increased costs on the healthcare system. The goal of this study is to reach an agreement on the concept, definition, staging model, and assessment of TRD. Methods This study involved a review of the literature and a modified Delphi process for consensus agreement. The Appraisal of Guidelines for Research & Evaluation II guidelines were followed for the literature appraisal. Literature was assessed for quality and strength of evidence using the grading, assessment, development, and evaluations system. Canadian national experts in depression were invited for the modified Delphi process based on their prior clinical and research expertize. Survey items were considered to have reached a consensus if 80% or more of the experts supported the statement. Results Fourteen Canadian experts were recruited for three rounds of surveys to reach a consensus on a total of 27 items. Experts agreed that a dimensional definition for treatment resistance was a useful concept to describe the heterogeneity of this illness. The use of staging models and clinical scales was recommended in evaluating depression. Risk factors and comorbidities were identified as potential predictors for treatment resistance. Conclusions TRD is a meaningful concept both for clinical practice and research. An operational definition for TRD will allow for opportunities to improve the validity of predictors and therapeutic options for these patients.

Major depressive disorder is a common and debilitating disorder. Although most patients with this disorder benefit from established treatments, a subset of patients have symptoms that remain treatment resistant. Novel treatment approaches, such as deep brain stimulation, are urgently needed for patients with treatment-resistant major depressive disorder. These novel treatments are currently being tested in clinical trials in which success hinges on how accurately and comprehensively the primary outcome measure captures the treatment effect. In this Personal View, we argue that current measures used to assess outcomes in neurosurgical trials of major depressive disorder might be missing clinically important treatment effects. A crucial problem of continuing to use suboptimal outcome measures is that true signals of efficacy might be missed, thereby disqualifying potentially effective treatments. We argue that a re-evaluation of how outcomes are measured in these trials is much overdue and describe several novel approaches that attempt to better capture meaningful change.

Background Psychiatric surgery is an important domain of functional neurosurgery and involves deep brain stimulation (DBS) or lesional procedures performed for treatment-resistant psychiatric illness. It has recently become possible to use magnetic-guided focused ultrasound (MRgFUS) to perform bilateral capsulotomy, a lesional technique commonly carried out with surgical radiofrequency ablation or stereotactic radiosurgery. MRgFUS offers several advantages, including improved safety and real-time imaging of the lesions. Objective To describe the clinical and technical aspects of performing bilateral MRgFUS capsulotomy in patients with severe refractory depression and obsessive-compulsive disorder. Methods We describe the clinical and technical considerations of performing MRgFUS capsulotomy. Topics discussed include patient selection, headframe application, targeting, sonication strategies, and follow-up procedures. Results MRgFUS capsulotomy was performed in 16 patients without serious clinical or radiographic adverse events. Conclusion MRgFUS allows for a safe, less invasive technique for performing a well-studied psychiatric surgery procedure-the anterior capsulotomy.

Post-traumatic stress disorder (PTSD) is a prevalent and debilitating illness. While standard treatment with pharmacotherapy and psychotherapy may be effective, approximately 20 to 30% of patients remain symptomatic. These individuals experience depression, anxiety, and elevated rates of suicide. For treatment-resistant patients, there is a growing interest in the use of neuromodulation therapies, including transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS). We conducted a systematic review on the use of neuromodulation strategies for PTSD and pooled 13 randomized clinical trials (RCTs), 11 case series, and 6 case reports for analysis. Overall, most studies reported favorable outcomes in alleviating both PTSD and depressive symptoms. Although several RCTs described significant differences when active and sham stimulations were compared, others found marginal or nonsignificant differences between groups. Also positive were studies comparing PTSD symptoms before and after treatment. The side effect profile with all 3 modalities was found to be low, with mostly mild adverse events being reported. Despite these encouraging data, several aspects remain unknown. Given that PTSD is a highly heterogeneous condition that can be accompanied by distinct psychiatric diagnoses, defining a unique treatment for this patient population can be quite challenging. There has also been considerable variation across trials regarding stimulation parameters, symptomatic response, and the role of adjunctive psychotherapy. Future studies are needed to address these issues. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-020-00871-0) contains supplementary material, which is available to authorized users.

Obsessive compulsive disorder (OCD) and major depressive disorder (MDD) are common, often refractory, neuropsychiatric conditions for which new treatment approaches are urgently needed. Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel surgical technique permitting incisionless ablative neurosurgery. We examined the safety profile, clinical response, and imaging correlates of MRgFUS bilateral anterior capsulotomy in patients with refractory obsessive compulsive disorder (OCD, N = 6) and major depressive disorder (MDD, n = 6). There were no serious adverse events. Nonserious adverse events included headaches and pin-site swelling in 7/12 patients. The response rate was 4/6 and 2/6 in the OCD and MDD cohorts respectively. To delineate the white-matter tracts impacted by capsulotomy, a normative diffusion MRI-based structural connectome was used, revealing tracts terminating primarily in the frontal pole, medial thalamus, striatum, and medial-temporal lobe. Positron emission tomography (PET) analysis (nine subjects) revealed widespread decreases in metabolism bilaterally in the cerebral hemispheres at 6 months post treatment, as well as in the right hippocampus, amygdala, and putamen. A pretreatment seed-to-voxel resting-state functional magnetic resonance imaging (rs-fMRI) analysis (12 subjects) revealed three voxel clusters significantly associated with eventual clinical response. MRgFUS capsulotomy appears to be safe, well tolerated, and according to these initial results, may be an important treatment option for patients with refractory OCD and MDD. MRgFUS capsulotomy results in both targeted and widespread changes in neural activity, and neuroimaging may hold potential for the prediction of outcome.

Introduction Although the antidepressant efficacy of rTMS is well documented, patient reported outcomes (PROs) with rTMS are poorly characterized. The aim of the current study is to assess short and long-term changes in self-reported quality of life and disability following a 6-week course of rTMS. Methods We performed a secondary analysis of data from the multi-centre THREE-D trial of 10 Hz high-frequency (HF) rTMS (n = 192) vs. intermittent theta-burst stimulation (iTBS) (n = 193) of the left dorsolateral prefrontal cortex (DLPFC). We assessed changes in the Quality of Life Enjoyment and Satisfaction Questionnaire and Sheehan Disability Scale pre-treatment, at 1-week post-rTMS treatment (Acute Follow-up), and at 12-weeks post-treatment (Long-Term Follow-Up). Results PROs significantly improved with rTMS. There were no differences in PROs between iTBS and HF left DLPFC rTMS at either the Acute or Long-Term Follow-Up. The magnitude of the change in effect sizes seen for the PROs were significantly greater in those who achieved greater resolution their depressive symptoms, with remitters demonstrating very large effect size improvements in PROs compared to small-to-medium effect sizes in non-remitters. Conclusions This study is the largest in the literature exploring at the effect of rTMS on PROs. rTMS yielded acute and sustained improvements in PROs. The improvements in PROs were strongly associated with the degree of resolution of depressive symptoms. The magnitude of the change in remitters was comparable to those reported with ECT. The goal of a course of rTMS should be for full remission of depressive symptoms in order to achieve optimal functional outcomes.

The global prevalence of obesity increases yearly along with a rising demand for efficacious, safe, and accessible treatments. Neuromodulation interventions (i.e., deep brain stimulation [DBS], transcranial magnetic stimulation [TMS], transcranial direct current stimulation [tDCS], percutaneous neurostimulation [PENS], vagus nerve stimulation [VNS], and gastric electrical stimulation [GES]) have been proposed as novel therapies. This systematic review sought to examine the safety and efficacy of neuromodulation therapies in reducing body weight in patients with obesity. Using PRISMA guidelines, we performed a systematic review for studies on neuromodulation for the treatment of obesity, resulting in 60 trials included (7 DBS, 5 TMS, 7 tDCS, 17 PENS and VNS, and 24 GES; a total of 3,042 participants). While promising results have been reported in open label studies, double-blinded randomized clinical trials often did not reach their primary endpoints, with no technique inducing a striking reduction in body weight. Bearing in mind the complexity and multifactorial nature of obesity, it is possible that a single treatment may not be enough for patients to lose or maintain the weight lost at long term.

Major depressive disorder (MDD) is one of the leading causes of disability worldwide. Conventional treatment consists of psychotherapy and pharmacotherapy. Severity, improvement, and remission of d...

Background: Deep brain stimulation targeting the subcallosal cingulate gyrus (SCG DBS) improves the symptoms of treatment-resistant depression in some patients, but not in others. We hypothesized that there are pre-existing structural brain differences between responders and nonresponders to SCG DBS, detectable using structural MRI. Methods: We studied preoperative, T1-weighted MRI scans of 27 patients treated with SCG DBS from 2003 to 2011. Responders (n = 15) were patients with a > 50% improvement in Hamilton Rating Scale for Depression score following 12 months of SCG DBS. Preoperative subcallosal cingulate gyrus grey matter volume was obtained using manual segmentation by a trained observer blinded to patient identity. Volumes of hippocampus, thalamus, amygdala, whole-brain cortical grey matter and white matter volume were obtained using automated techniques. Results: Preoperative subcallosal cingulate gyrus, thalamic and amygdalar volumes were significantly larger in patients who went on to respond to SCG-DBS. Hippocampal volume did not differ between groups. Cortical grey matter volume was significantly smaller in responders, and cortical grey matter:white matter ratio distinguished between responders and nonresponders with high sensitivity and specificity. Limitations: Normalization by intracranial volume nullified some between-group differences in volumetric measures. Conclusion: There are structural brain differences between patients with treatment-resistant depression who respond to SCG DBS and those who do not. Specifically, the structural integrity of the subcallosal cingulate gyrus target region and its connected subcortical areas, and variations in cortical volume across the entire brain, appear to be important determinants of response. Structural MRI shows promise as a biomarker in deep brain stimulation for depression, and may play a role in refining patient selection for future trials.

Background Panic attacks affect a sizeable proportion of the population. The neurocircuitry of panic remains incompletely understood. Objective To investigate the neuroanatomical underpinnings of panic attacks induced by deep brain stimulation (DBS) through (1) connectomic analysis of an obsessive-compulsive disorder patient who experienced panic attacks during inferior thalamic peduncle DBS; (2) appraisal of existing clinical reports on DBS-induced panic attacks. Methods Panicogenic, ventral contact stimulation was compared with benign stimulation at other contacts using volume of tissue activated (VTA) modelling. Networks associated with the panicogenic zone were investigated using state-of-the-art normative connectivity mapping. In addition, a literature search for prior reports of DBS-induced panic attacks was conducted. Results Panicogenic VTAs impinged primarily on the tuberal hypothalamus. Compared to non-panicogenic VTAs, panicogenic loci were significantly functionally coupled to limbic and brainstem structures, including periaqueductal grey and amygdala. Previous studies found stimulation of these areas can also provoke panic attacks. Conclusions DBS in the region of the tuberal hypothalamus elicited panic attacks in a single obsessive-compulsive disorder patient and recruited a network of structures previously implicated in panic pathophysiology, reinforcing the importance of the hypothalamus as a hub of panicogenic circuitry.

Background Whereas transient, self-limiting seizures are an infrequent but known complication of deep brain stimulation (DBS) implantation surgery, stimulation itself has occasionally been reported to result in seizure activity at delayed time points. The neural circuitry implicated in stimulation-induced seizures is unknown. Case Description A 47-year-old woman underwent chronic subcallosal cingulate DBS for treatment of refractory anorexia nervosa and experienced seizure with stimulation onset. Supratherapeutic voltage caused a generalized seizure. The patient subsequently experienced a full recovery. We reviewed the literature for other cases of delayed postoperative DBS seizures associated with stimulation. We also investigated whether the higher voltage may have recruited networks implicated in epilepsy. The supratherapeutic voltage stimulated a larger area and engaged vulnerable networks, including bilateral hippocampi, cingulate gyrus, and temporal lobes. Literature review identified 20 studies reporting delayed seizure after DBS surgery, 13 of which demonstrated a robust association with mostly nonmotor DBS stimulation. Conclusions Nonmotor DBS targets, particularly in patients with epilepsy, may be more vulnerable to stimulation-induced seizures; as such, extra caution should be used when programming stimulation parameters at these DBS targets.

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for refractory major depressive disorder, yet no studies have characterized trajectories of rTMS response. The aim of this study was to characterize response trajectories for patients with major depression undergoing left dorsolateral prefrontal cortex rTMS and to determine associated baseline clinical characteristics.This was a secondary analysis of a randomized noninferiority trial (N=388) comparing conventional 10-Hz rTMS and intermittent theta burst stimulation (iTBS) rTMS. Participants were adult outpatients who had a primary diagnosis of major depressive disorder, had a score ≥18 on the 17-item Hamilton Depression Rating Scale (HAM-D), and did not respond to one to three adequate antidepressant trials. Treatment was either conventional 10-Hz rTMS or iTBS rTMS applied to the dorsolateral prefrontal cortex, 5 days/week over 4-6 weeks (20-30 sessions). Group-based trajectory modeling was applied to identify HAM-D response trajectories, and regression techniques were used to identify associated characteristics.Four trajectories were identified: nonresponse (N=43, 11%); rapid response (N=73, 19%); higher baseline symptoms, linear response (N=118, 30%); and lower baseline symptoms, linear response (N=154, 40%). Significant differences in response and remission rates between trajectories were detectable by week 1. There was no association between treatment protocol and response trajectory. Higher baseline scores on the HAM-D and the Quick Inventory of Depression Symptomatology-Self-Report (QIDS-SR) were associated with the nonresponse trajectory, and older age, lower QIDS-SR score, and lack of benzodiazepine use were associated with the rapid response trajectory.Major depression shows distinct response trajectories to rTMS, which are associated with baseline clinical characteristics but not treatment protocol. These response trajectories with differential response to rTMS raise the possibility of developing individualized treatment protocols.

Background: Several different surgical procedures targeting the limbic circuit have been utilized for severe, treatment resistant obsessive-compulsive disorder; however, there has only been limited exploration of the inferior thalamic peduncle (ITP). The aim of this study was to determine the safety and initial efficacy of ITP deep brain stimulation (DBS) in patients with severe obsessive-compulsive disorder. Methods: Patients with severe, treatment-refractory obsessive-compulsive disorder were enrolled into this open-label phase 1 DBS pilot study. Bilateral ITP DBS devices were implanted between November 2010 and December 2015. The primary outcome was safety. The initial efficacy was determined by Yale-Brown Obsessive-Compulsive scale (YBOCs) scores. Component Y-BOCs scores, Hamilton Depression Severity Scale, Quality of Life Assessment (SF-36), Oxford Happiness Questionnaire, Warwick-Edinburgh Mental Well-Being Scale, and Sheehan Disability Scale were also analyzed for a minimum of 2 years after surgery. Additionally, preoperative and three-month postoperative FDG-PET studies were performed on two patients. Results: Five patients (2 males, 3 females; age range 25–48 years) received ITP DBS. All five patients were considered responders at one year (52% improvement in YBOCs scores compared to baseline (range 39–73%, p

Background Major Depressive Disorder (MDD) is characterized by objective and subjective cognitive deficits. Discrepancies between objective and subjective cognitive performance can reflect under- to over-estimations of cognitive abilities, and these discrepancies are referred to as cognitive self-appraisals. Despite evidence that low self-appraisals are associated with depression, the modifiability of self-appraisals and their association with treatment outcome remains unclear. The current study examined whether self-appraisals change following antidepressant treatment. Furthermore, we investigated the association of self-appraisals with treatment outcome. Methods As part of the CAN-BIND-1 clinical trial, 154 patients with MDD completed measures of objective and subjective cognitive abilities, depressive symptoms, and functional outcomes (work productivity, psychosocial functioning, and quality of life) at baseline and post-escitalopram treatment. Self-appraisals were calculated based on discrepancies between objective and subjective cognitive abilities, with higher scores indicating overestimation of cognitive abilities. Results Baseline self-appraisals were not predictive of treatment outcomes. However, self-appraisals increased from pre- to post-treatment. Moreover, pre-post treatment increases in self-appraisals were associated with positive treatment response and remission, decreases in depressive symptoms, and improvements in work productivity, psychosocial functioning, and quality of life. Limitations The pre-post intervention design precluded examining the temporal precedence of change in self-appraisals versus depressive symptoms and functional outcomes. Conclusions Findings are the first to demonstrate that self-appraisals are treatment-sensitive and are associated with treatment outcomes and recovery from MDD. Cognitive self-appraisals may represent a key marker of treatment response and a valuable target for assessment and intervention, as well as a potential mechanism underlying risk and recovery.

Subcallosal cingulate deep brain stimulation produces long-term clinical improvement in approximately half of patients with severe treatment-resistant depression. We hypothesized that both structural and functional brain attributes may be important in determining responsiveness to this therapy.In a treatment-resistant depression subcallosal cingulate deep brain stimulation cohort, we retrospectively examined baseline and longitudinal differences in MRI-derived brain volume (n = 65) and 18F-fluorodeoxyglucose-PET glucose metabolism (n = 21) between responders and non-responders. Support vector machines were subsequently trained to classify patients’ response status based on extracted baseline imaging features. A machine learning model incorporating preoperative frontopolar, precentral/frontal opercular and orbitofrontal local volume values classified binary response status (12 months) with 83% accuracy [leave-one-out cross-validation (LOOCV): 80% accuracy] and explained 32% of the variance in continuous clinical improvement. It was also predictive in an out-of-sample subcallosal cingulate deep brain stimulation cohort (n = 21) with differing primary indications (bipolar disorder/anorexia nervosa; 76% accuracy). Adding preoperative glucose metabolism information from rostral anterior cingulate cortex and temporal pole improved model performance, enabling it to predict response status in the treatment-resistant depression cohort with 86% accuracy (LOOCV: 81% accuracy) and explain 67% of clinical variance. Response-related patterns of metabolic and structural post-deep brain stimulation change were also observed, especially in anterior cingulate cortex and neighbouring white matter. Areas where responders differed from non-responders—both at baseline and longitudinally—largely overlapped with depression-implicated white matter tracts, namely uncinate fasciculus, cingulum bundle and forceps minor/rostrum of corpus callosum. The extent of patient-specific engagement of these same tracts (according to electrode location and stimulation parameters) also served as an independent predictor of treatment-resistant depression response status (72% accuracy; LOOCV: 70% accuracy) and augmented performance of the volume-based (88% accuracy; LOOCV: 82% accuracy) and combined volume/metabolism-based support vector machines (100% accuracy; LOOCV: 94% accuracy).Taken together, these results indicate that responders and non-responders to subcallosal cingulate deep brain stimulation exhibit differences in brain volume and metabolism, both pre- and post-surgery. Moreover, baseline imaging features predict response to treatment (particularly when combined with information about local tract engagement) and could inform future patient selection and other clinical decisions.

This chapter explores the complex neuroethical aspects of neurosurgery and neuromodulation in the context of Canadian healthcare and innovation, as seen through the lens of the Pan Canadian Neurotechnology Ethics Consortium (PCNEC). Highlighted are key areas of ethical focus, each with its own unique challenges: technical advances, readiness and risk, vulnerable populations, medico-legal issues, training, and research. Through an exploration of Canadian neurotechnological practice from these various clusters, we provide a critical review of progress, describe opportunities to address areas of debate, and seek to foster ethical innovation. Underpinning this comprehensive review are the fundamental principles of solution-oriented, practical neuroethics, with beneficence and justice at the core. In our view, it is a moral imperative that neurotechnological advancements include a delineation of ethical priorities for future guidelines, oversight, and interactions.

Obsessive-compulsive disorder is a debilitating and often refractory psychiatric disorder. Magnetic resonance-guided focused ultrasound is a novel, minimally invasive neuromodulatory technique that has shown promise in treating this condition. We investigated the relationship between lesion location and long-term outcome in patients with obsessive-compulsive disorder treated with focused ultrasound to discern the optimal lesion location and elucidate the efficacious network underlying symptom alleviation. Postoperative images of 11 patients who underwent focused ultrasound capsulotomy were used to correlate lesion characteristics with symptom improvement at 1-year follow-up. Normative resting-state functional MRI and normative diffusion MRI-based tractography analyses were used to determine the networks associated with successful lesions. Patients with obsessive-compulsive disorder treated with inferior thalamic peduncle deep brain stimulation (n = 5) and lesions from the literature implicated in obsessive-compulsive disorder (n = 18) were used for external validation. Successful long-term relief of obsessive-compulsive disorder was associated with lesions that included a specific area in the dorsal anterior limb of the internal capsule. Normative resting-state functional MRI analysis showed that lesion engagement of areas 24 and 46 was significantly associated with clinical outcomes (R = 0.79, P = 0.004). The key role of areas 24 and 46 was confirmed by (i) normative diffusion MRI-based tractography analysis, showing that streamlines associated with better outcome projected to these areas; (ii) association of these areas with outcomes in patients receiving inferior thalamic peduncle deep brain stimulation (R = 0.83, P = 0.003); and (iii) the connectedness of these areas to obsessive-compulsive disorder-causing lesions, as identified using literature-based lesion network mapping. These results provide considerations for target improvement, outlining the specific area of the internal capsule critical for successful magnetic resonance-guided focused ultrasound outcome and demonstrating that discrete frontal areas are involved in symptom relief. This could help refine focused ultrasound treatment for obsessive-compulsive disorder and provide a network-based rationale for potential alternative targets.

Anorexia nervosa (AN) is an eating disorder characterised by pervasive preoccupations with body weight, shape and size. This translates into caloric restriction and/or excessive physical exercise to obtain and maintain a low body mass index (BMI). Pharmacotherapy has no sustained impact on weight or AN psychometrics. Conventional psychiatric treatment fails in about half, and 30%–50% of weight-restored patients relapse within a year.1 2 Since 2011, we have investigated deep brain stimulation (DBS) targeting the subcallosal cingulate (SCC) in patients with chronic, severe and highly refractory AN.3 4 We previously published 9-month outcomes in six patients3 and 1-year outcomes in 16 patients.4 We demonstrated short-term safety and acceptability of SCC–DBS and observed affective symptom improvements and cerebral glucose metabolism changes in key AN-related structures. Moreover, average BMI increased by 3.5 kg/m2 from baseline after 1-year of SCC–DBS.3 4 Given the invasive and experimental nature of SCC–DBS and the characteristic waxing and waning course of AN, we wished to report our long-term observations. This was a prospective long-term extension of a previously published open-label trial (ClinicalTrials.gov NCT01476540) conducted at the University of Toronto.3 4 Research Ethics Board approval (#10-0991-A) and informed consent were obtained. Inclusion and exclusion criteria, surgical details, adverse event classification and DBS programming algorithms have been described previously.3 4 In the current study, we exclusively analysed patients who had been stimulated for ≥3 years as of 1 October 2018. The primary outcome was procedure safety and acceptability. Secondary outcomes were long-term changes in BMI, eating behaviour, psychometrics (Hamilton Depression Rating Scale (HAMD), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Yale-Brown Obsessive Compulsive Scale (YBOCS), Yale-Brown-Cornell Eating Disorder Scale rituals …

Magnetic resonance-guided focused ultrasound (MRgFUS) anterior capsulotomy is a novel treatment option for patients with refractory obsessive compulsive disorder (OCD) or major depressive disorder (MDD). However, there is concern that lesional psychiatric surgery procedures may have adverse effects on cognition. In this study, we examined whether MRgFUS capsulotomy causes cognitive decline in patients with psychiatric illness. Ten patients with refractory OCD (n = 5) or MDD (n = 5) underwent MRgFUS capsulotomy. Cognitive functioning was measured at baseline as well as 6 months and 12 months postoperatively, with a battery of neuropsychological tests assessing domains of executive function, memory, and processing speed. Scores were analyzed at the individual-level, and changes ≥2 standard deviations were considered clinically significant. We also examined whether changes in clinical symptoms were associated with changes in cognitive performance. At baseline intellectual functioning was in the average to high-average range for the group. Following MRgFUS capsulotomy, there were no deteriorations in cognition that reached ≥2 standard deviations at 6 or 12 months. Eight out of ten patients demonstrated a ≥2 standard deviation improvement in at least one cognitive score at 6 or 12 months postoperatively. Improvements in clinical symptoms correlated significantly with self-reported improvements in frontal lobe function (p

Deep Brain Stimulation (DBS) has been investigated as a treatment option for patients with refractory psychiatric illness. Over the past two decades, neuroimaging developments have helped to advance the field, particularly the use of diffusion tensor imaging (DTI) and tractographic reconstruction of white-matter pathways. In this article, we review translational considerations and how DTI and tractography have been used to improve targeting during DBS surgery for depression, obsessive compulsive disorder (OCD) and post-traumatic stress disorder (PTSD).

The last two decades have seen a re-emergence of surgery for intractable psychiatric disease, in large part due to increased use of deep brain stimulation. The development of more precise, image-guided, less invasive interventions has improved the safety of these procedures, even though the relative merits of modulation at various targets remain under investigation. With an increase in the number and type of interventions for modulating mood/anxiety circuits, the need for biomarkers to guide surgeries and predict treatment response is as critical as ever. Electroencephalography (EEG) has a long history in clinical neurology, cognitive neuroscience, and functional neurosurgery, but has limited prior usage in psychiatric surgery. MEDLINE, Embase, and Psyc-INFO searches on the use of EEG in guiding psychiatric surgery yielded 611 articles, which were screened for relevance and quality. We synthesized three important themes. First, considerable evidence supports EEG as a biomarker for response to various surgical and non-surgical therapies, but large-scale investigations are lacking. Second, intraoperative EEG is likely more valuable than surface EEG for guiding target selection, but comes at the cost of greater invasiveness. Finally, EEG may be a promising tool for objective functional feedback in developing “closed-loop” psychosurgeries, but more systematic investigations are required.

Purpose of review This article provides a synopsis of the current understanding of the pathophysiology of anxiety disorders, the biological and environmental risk factors that contribute to their development and maintenance, a review of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria, and a practical approach to the treatment of anxiety disorders in adults. Recent findings Despite the ubiquity of anxiety, the evidence is that most individuals with an anxiety disorder are not identified and do not receive guideline-level care. In part, this may be because of the manifold clinical presentations of anxiety disorders and clinicians' lack of confidence in accurately diagnosing and treating these conditions, especially in nonpsychiatric settings. Anxiety disorders represent the complex interplay between biological, psychological, temperamental, and environmental factors. Converging lines of evidence point to dysfunction in regulating activity in the "threat circuit" in the brain as a putative common pathophysiology underlying anxiety disorders. Evidence-based treatments for anxiety disorders, such as cognitive-behavioral therapy and antidepressant medications, have been shown to regulate activity in this circuit, which consists of reciprocal connections between the dorsomedial prefrontal cortex, insula, and amygdala. Summary Anxiety disorders are the most common class of emotional disorders and a leading cause of disability worldwide. A variety of effective treatment strategies are available, which may exert their therapeutic benefits from top-down or bottom-up modulation of the dysfunctional brain activity associated with anxiety disorders.

Although the antidepressant efficacy of ECT is well documented, patient-reported outcomes after this treatment are less well characterized. The aims of the current meta-analysis are to quantify the impact of an acute course of ECT on health-related quality of life (HRQoL) and to identify related moderators, specifically post-ECT depressive symptom remission and patient age.We searched PubMed, PsycINFO, and Web of Science databases for randomized and nonrandomized studies that report on changes in HRQoL measures after an acute course of ECT. Only studies that used the Medical Outcomes Study Short Form 36 (SF-36) instrument were included. A random effects model using the Hedges' g effect size was used in calculating the pre-post ECT outcomes on all 8 SF-36 subscales and the SF-36 total scores including the physical and mental composite scores. Subgroup analyses were conducted using remission status and age as moderators.Four studies contributed to this analysis. Significant improvements across all subscales of the SF-36 were observed. Large and very large effect sizes were present for both the SF-36 physical component score (PCS) and mental health component score (MCS), with the change in MCS being statistically superior to the PCS (MCS, Hedges' g = 1.28; 95% confidence interval, 1.15-1.42; PCS, Hedges' g = 0.97; 95% confidence interval, 0.86-1.07). Medium, large, and very large effect sizes were observed for SF-36 subscales scores. Post-ECT depression remission status was related to HRQoL improvement, with statistically significant differences present between remitters and nonremitters for PCS, MCS, and most SF-36 subscale scores. No significant differences were observed in improvement in HRQoL with ECT based on patient age.An acute course of ECT for depressive symptoms produces medium to very large effect size improvements in HRQoL across multiple components and subscales measured by the SF-36. The magnitude of the effects reported by ECT patients is greater than those that have been reported in other open-label studies of brain stimulation techniques. This study confirms that ECT plays a vital role in the treatment of the most severely ill patients with depressive disorders.

Summary Background Treatment-resistant major depressive disorder is common; repetitive transcranial magnetic stimulation (rTMS) by use of high-frequency (10 Hz) left-side dorsolateral prefrontal cortex stimulation is an evidence-based treatment for this disorder. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS that can be delivered in 3 min, versus 37·5 min for a standard 10 Hz treatment session. We aimed to establish the clinical effectiveness, safety, and tolerability of iTBS compared with standard 10 Hz rTMS in adults with treatment-resistant depression. Methods In this randomised, multicentre, non-inferiority clinical trial, we recruited patients who were referred to specialty neurostimulation centres based at three Canadian university hospitals (Centre for Addiction and Mental Health and Toronto Western Hospital, Toronto, ON, and University of British Columbia Hospital, Vancouver, BC). Participants were aged 18–65 years, were diagnosed with a current treatment-resistant major depressive episode or could not tolerate at least two antidepressants in the current episode, were receiving stable antidepressant medication doses for at least 4 weeks before baseline, and had an HRSD-17 score of at least 18. Participants were randomly allocated (1:1) to treatment groups (10 Hz rTMS or iTBS) by use of a random permuted block method, with stratification by site and number of adequate trials in which the antidepressants were unsuccessful. Treatment was delivered open-label but investigators and outcome assessors were masked to treatment groups. Participants were treated with 10 Hz rTMS or iTBS to the left dorsolateral prefrontal cortex, administered on 5 days a week for 4–6 weeks. The primary outcome measure was change in 17-item Hamilton Rating Scale for Depression (HRSD-17) score, with a non-inferiority margin of 2·25 points. For the primary outcome measure, we did a per-protocol analysis of all participants who were randomly allocated to groups and who attained the primary completion point of 4 weeks. This trial is registered with ClinicalTrials.gov, number NCT01887782. Findings Between Sept 3, 2013, and Oct 3, 2016, we randomly allocated 205 participants to receive 10 Hz rTMS and 209 participants to receive iTBS. 192 (94%) participants in the 10 Hz rTMS group and 193 (92%) in the iTBS group were assessed for the primary outcome after 4–6 weeks of treatment. HRSD-17 scores improved from 23·5 (SD 4·4) to 13·4 (7·8) in the 10 Hz rTMS group and from 23·6 (4·3) to 13·4 (7·9) in the iTBS group (adjusted difference 0·01, lower 95% CI −1·16; p=0·0011), which indicated non-inferiority of iTBS. Self-rated intensity of pain associated with treatment was greater in the iTBS group than in the 10 Hz rTMS group (mean score on verbal analogue scale 3·8 [SD 2·0] vs 3·4 [2·0] out of 10; p=0·011). Dropout rates did not differ between groups (10 Hz rTMS: 13 [6%] of 205 participants; iTBS: 16 [8%] of 209 participants); p=0·6004). The most common treatment-related adverse event was headache in both groups (10 Hz rTMS: 131 [64%] of 204; iTBS: 136 [65%] of 208). Interpretation In patients with treatment-resistant depression, iTBS was non-inferior to 10 Hz rTMS for the treatment of depression. Both treatments had low numbers of dropouts and similar side-effects, safety, and tolerability profiles. By use of iTBS, the number of patients treated per day with current rTMS devices can be increased several times without compromising clinical effectiveness. Funding Canadian Institutes of Health Research.

Objective Explore how previous work during the 2003 Severe Acute Respiratory Syndrome (SARS) outbreak affects the psychological response of clinical and non-clinical healthcare workers (HCWs) to the current COVID-19 pandemic. Methods A cross-sectional, multi-centered hospital online survey of HCWs in the Greater Toronto Area, Canada. Mental health outcomes of HCWs who worked during the COVID-19 pandemic and the SARS outbreak were assessed using Impact of Events—Revised scale (IES-R), Generalized Anxiety Disorder scale (GAD-7), and Patient Health Questionnaire (PHQ-9). Results Among 3852 participants, moderate/severe scores for symptoms of post- traumatic stress disorder (PTSD) (50.2%), anxiety (24.6%), and depression (31.5%) were observed among HCWs. Work during the 2003 SARS outbreak was reported by 1116 respondents (29.1%), who had lower scores for symptoms of PTSD (P = .002), anxiety (P < .001), and depression (P < .001) compared to those who had not worked during the SARS outbreak. Multivariable logistic regression analysis showed non-clinical HCWs during this pandemic were at higher risk of anxiety (OR, 1.68; 95% CI, 1.19–2.15, P = .01) and depressive symptoms (OR, 2.03; 95% CI, 1.34–3.07, P < .001). HCWs using sedatives (OR, 2.55; 95% CI, 1.61–4.03, P < .001), those who cared for only 2–5 patients with COVID-19 (OR, 1.59; 95% CI, 1.06–2.38, P = .01), and those who had been in isolation for COVID-19 (OR, 1.36; 95% CI, 0.96–1.93, P = .05), were at higher risk of moderate/severe symptoms of PTSD. In addition, deterioration in sleep was associated with symptoms of PTSD (OR, 4.68, 95% CI, 3.74–6.30, P < .001), anxiety (OR, 3.09, 95% CI, 2.11–4.53, P < .001), and depression (OR 5.07, 95% CI, 3.48–7.39, P < .001). Conclusion Psychological distress was observed in both clinical and non-clinical HCWs, with no impact from previous SARS work experience. As the pandemic continues, increasing psychological and team support may decrease the mental health impacts.

Psychostimulants have been used in the treatment of depression, with mixed results. This meta-analysis examines the efficacy and tolerability of the stimulant Lisdexamfetamine (LDX) as an add-on strategy in those with MDD who have failed to respond to an antidepressant.Randomized control trials were identified and extracted from Pubmed; Web of Science; PsychINFO; and Cochrane Library. The efficacy of LDX was evaluated using Hedges' g and Odds Ratio, whereas Risk Difference was used to assess the safety and tolerability of LDX.Four studies met inclusion criteria. LDX did not demonstrate superiority in efficacy relative to placebo as indicated by a Hedges' g score of 0.126 (95% CI -0.040-0.291; p = 0.136) for mean change in Montgomery-Asberg Depression Rating Scale. Odds ratios of 1.206 (95% CI 0.745-1.954; p = 0.446) and 1.244 (95% CI 0.959-1.614; p = 0.1) were found for remission and response rates respectively. Risk differences of -0.1 (95% CI -0.155-(-0.045); p0.001) indicated a 10% increase chance of developing treatment-emergent adverse events (TEAE) in the LDX group. There was no significant difference in risk for developing serious or severe TEAE and discontinuing treatment due to TEAE.The number of included studies was small and only one metric was available for analysis of antidepressant efficacy of LDX.LDX when used as antidepressant augmentation produced a small effect in improving depressive symptoms that approached trend-level significance and demonstrated comparable tolerability to placebo. Further studies are needed to determine the optimal clinical subset of depressive symptoms responsive to LDX augmentation.

This prognostic study of patients with major depressive disorder estimates how accurately an outcome of escitalopram treatment can be predicted from electroencephalographic data., Key Points Question Is it possible to predict whether the condition of a patient with depression will improve after escitalopram treatment by analyzing their resting-state electroencephalographic signals? Findings In this prognostic study of data from 122 patients diagnosed with major depressive disorder, support vector machine classifiers demonstrated an accuracy of 82.4% for predicting escitalopram treatment outcome. Meaning When complemented by appropriate analysis methods, resting-state electroencephalographic recordings may be instrumental in improving treatment of patients with depression., Importance Social and economic costs of depression are exacerbated by prolonged periods spent identifying treatments that would be effective for a particular patient. Thus, a tool that reliably predicts an individual patient’s response to treatment could significantly reduce the burden of depression. Objective To estimate how accurately an outcome of escitalopram treatment can be predicted from electroencephalographic (EEG) data on patients with depression. Design, Setting, and Participants This prognostic study used a support vector machine classifier to predict treatment outcome using data from the first Canadian Biomarker Integration Network in Depression (CAN-BIND-1) study. The CAN-BIND-1 study comprised 180 patients (aged 18-60 years) diagnosed with major depressive disorder who had completed 8 weeks of treatment. Of this group, 122 patients had EEG data recorded before the treatment; 115 also had EEG data recorded after the first 2 weeks of treatment. Interventions All participants completed 8 weeks of open-label escitalopram (10-20 mg) treatment. Main Outcomes and Measures The ability of EEG data to predict treatment outcome, measured as accuracy, specificity, and sensitivity of the classifier at baseline and after the first 2 weeks of treatment. The treatment outcome was defined in terms of change in symptom severity, measured by the Montgomery-Åsberg Depression Rating Scale, before and after 8 weeks of treatment. A patient was designated as a responder if the Montgomery-Åsberg Depression Rating Scale score decreased by at least 50% during the 8 weeks and as a nonresponder if the score decrease was less than 50%. Results Of the 122 participants who completed a baseline EEG recording (mean [SD] age, 36.3 [12.7] years; 76 [62.3%] female), the classifier was able to identify responders with an estimated accuracy of 79.2% (sensitivity, 67.3%; specificity, 91.0%) when using only the baseline EEG data. For a subset of 115 participants who had additional EEG data recorded after the first 2 weeks of treatment, use of these data increased the accuracy to 82.4% (sensitivity, 79.2%; specificity, 85.5%). Conclusions and Relevance These findings demonstrate the potential utility of EEG as a treatment planning tool for escitalopram therapy. Further development of the classification tools presented in this study holds the promise of expediting the search for optimal treatment for each patient.

In recent years, there has been a renaissance in the interest in brain stimulation as a treatment for refractory psychiatric illness. In the last 2 decades, there has been continued development of neurocircuitry models of the brain, leading to hypothesis-driven direct-to-brain interventional approaches for the treatment of Major Depressive Disorder. Multiple neuromodulation techniques are available, including non-invasive approaches, such as repetitive transcranial magnetic stimulation (rTMS), convulsive therapies in the form of electroconvulsive therapy (ECT) and magnetic seizure therapy (MST), and surgical interventions including, deep brain stimulation (DBS), vagus nerve stimulation (VNS), and magnetic resonance imaging (MRI)-guided focused ultrasound (FUS). Each of these techniques appear to possess distinct neurophysiological mechanisms and kinetics of response. Noninvasive stimulation in the form of rTMS has been recommended as a first-line choice for those that have failed to respond to at least one adequate antidepressant medication. ECT has the quickest onset of antidepressant effects, while implantable device-related stimulation (VNS and DBS) appear to have delayed but sustained effects. Positive results from sham-controlled trials are needed to evaluate the safety and efficacy of the novel techniques of MST and FUS in the treatment of MDD. Future research should prioritize the identification of biomarkers of response and the exploration of when is the optimal point in the disease course for each neuromodulation technique to be provided. This would allow more precise patient selection to maximize clinical and functional outcomes.

Major depressive disorder (MDD) is primarily treated with antidepressants, yet many patients fail to respond adequately, and identifying antidepressant response biomarkers is thus of clinical significance. Some hypothesis-driven investigations of epigenetic markers for treatment response have been previously made, but genome-wide approaches remain unexplored. Healthy participants (n = 112) and MDD patients (n = 211) between 18–60 years old were recruited for an 8-week trial of escitalopram treatment. Responders and non-responders were identified using differential Montgomery-Åsberg Depression Rating Scale scores before and after treatment. Genome-wide DNA methylation and gene expression analyses were assessed using the Infinium MethylationEPIC Beadchip and HumanHT-12 v4 Expression Beadchip, respectively, on pre-treatment peripheral blood DNA and RNA samples. Differentially methylated positions (DMPs) located in regions of differentially expressed genes between responders (n = 82) and non-responders (n = 95) were identified, and technically validated using a targeted sequencing approach. Three DMPs located in the genes CHN2 (cg23687322, p = 0.00043 and cg06926818, p = 0.0014) and JAK2 (cg08339825, p = 0.00021) were the most significantly associated with mRNA expression changes and subsequently validated. Replication was then conducted with non-responders (n = 76) and responders (n = 71) in an external cohort that underwent a similar antidepressant trial. One CHN2 site (cg06926818; p = 0.03) was successfully replicated. Our findings indicate that differential methylation at CpG sites upstream of the CHN2 and JAK2 TSS regions are possible peripheral predictors of antidepressant treatment response. Future studies can provide further insight on robustness of our candidate biomarkers, and greater characterization of functional components.

Background Reverse translating putative biomarkers of depression from patients to animals is complex because Major Depressive Disorder (MDD) is a highly heterogenous condition. This review proposes an approach to reverse translation based on relating relevant bio-behavioural functions in laboratory rodents to MDD symptoms. Methods This systematic review outlines symptom clusters assessed by psychometric tests of MDD and antidepressant treatment response including the Montgomery–Asberg Depression Rating Scale, the Hamilton Depression Rating Scale, and the Beck Depression Inventory. Symptoms were related to relevant behavioural assays in laboratory rodents. Results The resulting battery of tests includes passive coping, anxiety-like behaviours, sleep, caloric intake, cognition, psychomotor functions, hedonic reactivity and aversive learning. These assays are discussed alongside relevant clinical symptoms of MDD, providing a framework through which reverse translation of a biomarker can be interpreted. Limitations Certain aspects of MDD may not be quantified by tests in laboratory rodents, and their biological significance may not always be of clinical relevance. Conclusions Using this reverse translation approach, it is possible to clarify the functional significance of a putative biomarker in rodents and hence translate its contribution to specific clinical symptoms, or clusters of symptoms.

OBJECTIVE To report the symptomatic and functional outcomes in patients with major depressive disorder (MDD) during a 2-phase treatment trial and to estimate the value of early improvement after 2 weeks in predicting clinical response to escitalopram and subsequently to adjunctive treatment with aripiprazole. METHODS Participants with MDD (N = 211) identified with the Montgomery-Asberg Depression Rating Scale (MADRS) and confirmed with the Mini-International Neuropsychiatric Interview were recruited from 6 outpatient centers across Canada (August 2013 through December 2016) and treated with open-label escitalopram (10-20 mg) for 8 weeks (Phase 1). Clinical and functional outcomes were evaluated using the MADRS, Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), Sheehan Disability Scale (SDS), and Lam Employment Absence and Productivity Scale (LEAPS). Participants were evaluated at 8 and 16 weeks for clinical and functional response and remission. Phase 1 responders continued escitalopram while nonresponders received adjunctive aripiprazole (2-10 mg) for a further 8 weeks (Phase 2). RESULTS After Phase 1, MADRS response (≥ 50% decrease from baseline) and remission (score ≤ 10) were, respectively, 47% and 31%, and SDS response (score ≤ 12) and remission (score ≤ 6) were, respectively, 53% and 24%. Response to escitalopram was maintained in 91% of participants at week 16, while 61% of the adjunctive aripiprazole group achieved MADRS response during Phase 2. Response and remission rates with the QIDS-SR were lower than with the MADRS. The LEAPS demonstrated significant occupational improvement (P < .05). Early symptomatic improvement predicted outcomes with modest accuracy. CONCLUSIONS This study demonstrates comparable symptomatic and functional outcomes to those of other large practical-design studies. There was a high response rate with the adjunctive use of aripiprazole in escitalopram nonresponders. Given the limited value of early clinical improvement to predict outcome, integration of clinical and biological markers deserves further exploration. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01655706.

Background: There is an urgent need to develop safe and effective treatments for patients with treatment-resistant depression (TRD). Several neurosurgical procedures have been developed to treat the dysfunctional brain circuits implicated in major depression. Objectives: This review describes the most common ablative procedures used to treat major depressive disorder: anterior cingulotomy, subcaudate tractotomy, limbic leucotomy, and anterior capsulotomy. The efficacy and safety of each are discussed and compared with other current and emerging modalities, including deep brain stimulation (DBS) and MR-guided focused ultrasound (MRgFUS). Methods: The PubMed and MEDLINE electronic databases were used in this study, through July 2016. Keywords, including “treatment resistant depression,” and “ablative neurosurgery,” etc. were used to generate reference hits. Results: Approximately a third to half of patients who underwent ablative procedures achieved a treatment response and/or remission. The efficacy and safety profiles corresponding to both ablative procedures and DBS were very similar. Conclusions: The longitudinal experience with ablative procedures shows that there remains an important role for accurate, discrete lesions in disrupting affective circuitry in the treatment of TRD. New modalities, such as MRgFUS, have the potential to further improve the accuracy of ablative procedures, while enhancing safety by obviating the need for open brain surgery.

The endocannabinoid (eCB) system is a potential target for the treatment of symptoms of post-traumatic stress disorder (PTSD). Similar to clinical PTSD, approximately 25–30% of rats that undergo cued fear conditioning exhibit impaired extinction learning. In addition to extinction-resistant fear, these “weak extinction” (WE) rats show persistent anxiety-like behaviors. The goal of the present study was to test the hypothesis that behavioural differences between WE animals and those presenting normal extinction patterns (strong extinction; SE) could be mediated by the eCB system. Rats undergoing fear conditioning/extinction and fear recall sessions were initially segregated in weak and strong-extinction groups. Two weeks later, animals underwent a fear recall session followed by a novelty-suppressed feeding (NSF) test. In acute experiments, WE rats were injected with either the fatty acid amide hydrolase (FAAH) inhibitor URB597 or the CB1 agonist WIN55,212-2 1 h prior to long-term recall and NSF testing. SE animals were injected with the inverse CB1 receptor agonist AM251. In chronic experiments, WE and SE rats were given daily injections of URB597 or AM251 between short and long-term recall sessions. We found that acute administration of WIN55,212-2 but not URB597 reduced anxiety-like behaviour in WE rats. In contrast, AM251 was anxiogenic in SE animals. Neither treatment was effective in altering freezing expression during fear recall. The chronic administration of AM251 to SE or URB597 to WE did not alter fear or anxiety-like behaviour or changed the expression of FAAH and CB1. Together, these results suggest that systemic manipulations of the eCB system may alter anxiety-like behaviour but not the behavioural expression of an extinction-resistant associative fear memory.

Electroconvulsive therapy (ECT) has been around since the 1930’s, yet it is still associated with passionate controversy. A large contributing factor to the current perception of ECT include the negative and grossly inaccurate portrayals in various forms of media. Through a literature review, the mechanisms, safety, efficacy, and side effects of the therapy are presented in a graphic narrative. Using both words and art to present a more accurate and holistic depiction of ECT, it was decided to use this visual medium so that the information could be accessed by a wide range of readers and counter incorrect depictions. In particular, this narrative could be read by individuals who are interested in learning more about ECT or are considering the treatment, allowing this comic to be a tool to help others make informed decisions. The findings from the review suggest that while the mechanism of action has still yet to be elucidated for ECT, it is an effective treatment in certain severe psychiatric illnesses. Specifically, it can improve symptoms and the quality of life of patients, especially for those who may be resistant to pharmacotherapy.

OBJECTIVE To investigate how the combination of clinical and molecular biomarkers can predict worsening of suicidal ideation during antidepressant treatment. METHODS Samples were obtained from 237 patients with major depressive disorder (DSM-IV criteria) treated with either duloxetine or placebo in an 8-week randomized controlled trial. Data were collected between 2007 and 2011. The relationship between treatment-worsening suicidal ideation (TWSI) and a number of clinical variables, as well as peripheral expression of messenger RNA (mRNA) and microRNA (miRNA), was assessed at baseline. We generated 4 predictive models for TWSI: clinical, mRNA, miRNA, and a combined model comprising the best predictive variables from clinical, mRNA, and miRNA data. RESULTS Eleven patients (9.8%) presented with TWSI in the duloxetine group. Among the clinical variables, only baseline depressive severity was found to be mildly predictive of TWSI. Two mRNAs (stathmin 1 [STMN1] and protein phosphatase 1 regulatory subunit 9B [PPP1R9B]) and 2 miRNAs (miR-3688 and miR-5695) were identified that were significantly predictive of TWSI when mRNA and miRNA were assessed separately (P = .002, .044, .004, and .005, respectively). The best model included baseline depression severity and expression of STMN1 and miR-5695 and predicted TWSI with area under the curve = 0.94 (P < .001). Additionally, the combined model did not significantly predict TWSI in the placebo group. CONCLUSIONS This study generated a predictive tool for TWSI that combines both biological and clinical variables. These biological variables can be easily quantified in peripheral tissues, thus rendering them viable targets to be used in both clinical practice and future studies of suicidal behaviors. TRIAL REGISTRATION ClinicalTrials.gov identifiers: NCT00635219, NCT00599911, and NCT01140906.

Background: Major depressive disorder (MDD) is primarily treated with antidepressants, yet many patients fail to respond to adequate trials. Understanding who is likely to respond to antidepressant treatment and/or what mediates this response is of considerable clinical importance. As part of the Canadian Biomarker Integration Network in Depression (CAN-BIND-1) initiative, we aimed to identify differential DNA methylation marks as epigenetic predictors of antidepressant response (ADR) in MDD patients. Methods: Healthy participants (n=112) and depressed participants (n=211) between 18-60 years of age were recruited across six Canadian clinical centers. Eligible depressed patients with MDD by DSM-IV-TR criteria and a Montgomery-Asberg Depression Rating Scale (MADRS) score of ≥24 were enrolled. Genome-wide DNA methylation analysis was conducted using the Infinium MethylationEPIC Beadchipb with DNA extracted from baseline peripheral blood samples prior to beginning an eight-week trial of escitalopram. Genome-wide mRNA expression analysis was conducted on the HumanHT-12 v4 Expression Beadchip in RNA extracted from leukocytes at baseline. Depressed patients were classified as non-responders (NRES) and responders (RES) according to changes in MADRS scores following eight weeks of treatment. Differentially methylated positions (DMPs) were identified in regions of differentially expressed genes and validated using a targeted sequencing approach. Replication was conducted with patients participating in a similar trial, the Douglas Biomarker Study. CAN-BIND-1 clinical trial was registered with the ClinicalTrials.gov identification #: NCT101655706. Findings: After depressed participants concluded the 8-week trial, 82 RES and 95 NRES were included in this study. Genome-wide differential DNA methylation revealed 2,572 DMPs (p

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.