Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023 : Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes.

BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) last published clinical guidelines for the management of major depressive disorder (MDD) in 2016. Owing to advances in the field, an update was needed to incorporate new evidence and provide new and revised recommendations for the assessment and management of MDD in adults. METHODS: CANMAT convened a guidelines editorial group comprised of academic clinicians and patient partners. A systematic literature review was conducted, focusing on systematic reviews and meta-analyses published since the 2016 guidelines. Recommendations were organized by lines of treatment, which were informed by CANMAT-defined levels of evidence and supplemented by clinical support (consisting of expert consensus on safety, tolerability, and feasibility). Drafts were revised based on review by patient partners, expert peer review, and a defined expert consensus process. RESULTS: The updated guidelines comprise eight primary topics, in a question-and-answer format, that map a patient care journey from assessment to selection of evidence-based treatments, prevention of recurrence, and strategies for inadequate response. The guidelines adopt a personalized care approach that emphasizes shared decision-making that reflects the values, preferences, and treatment history of the patient with MDD. Tables provide new and updated recommendations for psychological, pharmacological, lifestyle, complementary and alternative medicine, digital health, and neuromodulation treatments. Caveats and limitations of the evidence are highlighted. CONCLUSIONS: The CANMAT 2023 updated guidelines provide evidence-informed recommendations for the management of MDD, in a clinician-friendly format. These updated guidelines emphasize a collaborative, personalized, and systematic management approach that will help optimize outcomes for adults with MDD.

Reduction of aggressive behaviour following hypothalamic deep brain stimulation: Involvement of 5-HT1A and testosterone.

BACKGROUND: Aggressive behaviour (AB) may occur in patients with different neuropsychiatric disorders. Although most patients respond to conventional treatments, a small percentage continue to experience AB despite optimized pharmacological management and are considered to be treatment-refractory. For these patients, hypothalamic deep brain stimulation (pHyp-DBS) has been investigated. The hypothalamus is a key structure in the neurocircuitry of AB. An imbalance between serotonin (5-HT) and steroid hormones seems to exacerbate AB. OBJECTIVES: To test whether pHyp-DBS reduces aggressive behaviour in mice through mechanisms involving testosterone and 5-HT. METHODS: Male mice were housed with females for two weeks. These resident animals become territorial and aggressive towards intruder mice placed in their cages. Residents had electrodes implanted in the pHyp. DBS was administered for 5 h/day for 8 consecutive encounters prior to the interaction with the intruder. After testing, blood and brains were recovered for measuring testosterone and 5-HT receptor density, respectively. In a second experiment, residents received WAY-100635 (5-HT1A antagonist) or saline injections prior to pHyp-DBS. After the first 4 encounters, the injection allocation was crossed, and animals received the alternative treatment during the next 4 encounters. RESULTS: DBS-treated mice showed reduced AB that was correlated with testosterone levels and an increase in 5-HT1A receptor density in the orbitofrontal cortex and amygdala. Pre-treatment with WAY-100635 blocked the anti-aggressive effect of pHyp-DBS. CONCLUSIONS: This study shows that pHyp-DBS reduces AB in mice via changes in testosterone and 5-HT1A mechanisms.

Deep brain stimulation of the nucleus accumbens in the treatment of severe alcohol use disorder: a phase I pilot trial.

Alcohol use disorder (AUD) is a highly prevalent, often refractory, medical illness. The symptoms of AUD are driven by dysfunction in several neurocircuits centered on the nucleus accumbens (NAc). Case reports and animal studies suggest NAc-DBS may be an effective harm-reduction treatment in severe AUD. Six patients with severe, refractory AUD underwent NAc-DBS. Safety metrics and clinical outcomes were recorded. Positron emission tomography (FDG-PET) was used to measure glucose metabolism in the NAc at baseline and 6 months. Functional magnetic resonance imaging (fMRI) was used to characterize postoperative changes in NAc functional connectivity to the rest of the brain, as well as NAc and dorsal striatal reactivity to alcoholic visual cues. This study was registered with ClinicalTrials.gov, NCT03660124. All patients experienced a reduction in craving. There was a significant reduction in alcohol consumption, alcohol-related compulsivity, and anxiety at 12 months. There was no significant change in depression. FDG-PET analysis demonstrated reduced NAc metabolism by 6 months, which correlated with improvements in compulsive drinking behaviors. Clinical improvement correlated with reduced functional connectivity between the NAc and the visual association cortex. Active DBS was associated with reduced activation of the dorsal striatum during passive viewing of alcohol-containing pictures. NAc-DBS is feasible and safe in patients with severe, otherwise refractory AUD. It is associated with a reduction in cravings and addictive behavior. A potential mechanism underlying this process is a down-regulation of the NAc, a disruption of its functional connectivity to the visual association cortex, and interference of cue-elicited dorsal striatum reactivity. Trial Registration NCT03660124 ( www.clinicaltrials.gov ).

Structuro-functional surrogates of response to subcallosal cingulate deep brain stimulation for depression.

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.

3T MRI of rapid brain activity changes driven by subcallosal cingulate deep brain stimulation.

Deep brain stimulation targeting the subcallosal cingulate area, a hub with multiple axonal projections, has shown therapeutic potential for treatment-resistant mood disorders. While subcallosal cingulate deep brain stimulation drives long-term metabolic changes in corticolimbic circuits, the brain areas that are directly modulated by electrical stimulation of this region are not known. We used 3.0 T functional MRI to map the topography of acute brain changes produced by stimulation in an initial cohort of 12 patients with fully implanted deep brain stimulation devices targeting the subcallosal cingulate area. Four additional subcallosal cingulate deep brain stimulation patients were also scanned and employed as a validation cohort. Participants underwent resting state scans (n = 78 acquisitions overall) during (i) inactive deep brain stimulation; (ii) clinically optimal active deep brain stimulation; and (iii) suboptimal active deep brain stimulation. All scans were acquired within a single MRI session, each separated by a 5-min washout period. Analysis of the amplitude of low-frequency fluctuations in each sequence indicated that clinically optimal deep brain stimulation reduced spontaneous brain activity in several areas, including the bilateral dorsal anterior cingulate cortex, the bilateral posterior cingulate cortex, the bilateral precuneus and the left inferior parietal lobule (PBonferroni < 0.0001). Stimulation-induced dorsal anterior cingulate cortex signal reduction correlated with immediate within-session mood fluctuations, was greater at optimal versus suboptimal settings and was related to local cingulum bundle engagement. Moreover, linear modelling showed that immediate changes in dorsal anterior cingulate cortex, posterior cingulate cortex and precuneus activity could predict individual long-term antidepressant improvement. A model derived from the primary cohort that incorporated amplitude of low-frequency fluctuations changes in these three areas (along with preoperative symptom severity) explained 55% of the variance in clinical improvement in that cohort. The same model also explained 93% of the variance in the out-of-sample validation cohort. Additionally, all three brain areas exhibited significant changes in functional connectivity between active and inactive deep brain stimulation states (PBonferroni < 0.01). These results provide insight into the network-level mechanisms of subcallosal cingulate deep brain stimulation and point towards potential acute biomarkers of clinical response that could help to optimize and personalize this therapy.

Interventional Psychiatry and Neurotechnologies: Education and Ethics Training.

The last two decades have seen dramatic growth in the application of procedurally based interventions for treating refractory psychiatric conditions, leading to interest in developing the foundations for the subspecialty of "Interventional Psychiatry." However, there is cause for concern that the rate of expansion of clinical advances in this field may be outpacing the ability of postgraduate curricula to provide sufficient exposure to and teaching and supervision of these treatments. The paucity of adequately trained practitioners in Interventional Psychiatry further exacerbates inequities in the ability of eligible patients to access and benefit from these approaches. This paper explores the rates of utilization of Interventional Psychiatry treatments, the current state of education in these treatments, and the role that training can play in translating scientific advances in this area to ensure equitable access and maximum impact at a population level. The majority of the discussion is centered on electroconvulsive therapy (ECT), the most established and available of these treatments, highlighting how enhancing education and training in ECT can reduce barriers to its utilization. It is argued that innovations in pedagogical approaches for disseminating the learning of these procedures are needed to increase the current low rates of competency in these treatments and can facilitate the more rapid dissemination of other Interventional Psychiatry approaches and neurotechnologies, such as repetitive transcranial magnetic stimulation, ketamine, deep brain stimulation, and focused ultrasound.

Competencies for Repetitive Transcranial Magnetic Stimulation in Postgraduate Medical Education: Expert Consensus Using a Modified Delphi Process.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is recommended in Canadian guidelines as a first-line treatment for major depressive disorder. With the shift towards competency-based medical education, it remains unclear how to determine when a resident is considered competent in applying knowledge of rTMS to patient care. Given inconsistencies between postgraduate training programmes with regards to training requirements, defining competencies will improve the standard of care in rTMS delivery. OBJECTIVE: The goal of this study was to develop competencies for rTMS that can be implemented into a competency-based training curriculum in postgraduate training programmes. METHODS: A working group drafted competencies for postgraduate psychiatry trainees. Fourteen rTMS experts from across Canada were invited to participate in the modified Delphi process. RESULTS: Ten experts participated in all three rounds of the modified Delphi process. A total of 20 items reached a consensus. There was improvement in the Cronbach's alpha over the rounds of modified Delphi process (Cronbach's alpha increased from 0.554 to 0.824) suggesting improvement in internal consistency. The intraclass correlation coefficient (ICC) increased from 0.543 to 0.805 suggesting improved interrater agreement. CONCLUSIONS: This modified Delphi process resulted in expert consensus on competencies to be acquired during postgraduate medical education programmes where a learner is training to become competent as a consultant and/or practitioner in rTMS treatment. This is a field that still requires development, and it is expected that as more evidence emerges the competencies will be further refined. These results will help the development of other curricula in interventional psychiatry.

Probabilistic Mapping of Deep Brain Stimulation: Insights from 15 Years of Therapy.

Deep brain stimulation (DBS) depends on precise delivery of electrical current to target tissues. However, the specific brain structures responsible for best outcome are still debated. We applied probabilistic stimulation mapping to a retrospective, multidisorder DBS dataset assembled over 15 years at our institution (ntotal = 482 patients; nParkinson disease = 303; ndystonia = 64; ntremor = 39; ntreatment-resistant depression/anorexia nervosa = 76) to identify the neuroanatomical substrates of optimal clinical response. Using high-resolution structural magnetic resonance imaging and activation volume modeling, probabilistic stimulation maps (PSMs) that delineated areas of above-mean and below-mean response for each patient cohort were generated and defined in terms of their relationships with surrounding anatomical structures. Our results show that overlap between PSMs and individual patients' activation volumes can serve as a guide to predict clinical outcomes, but that this is not the sole determinant of response. In the future, individualized models that incorporate advancements in mapping techniques with patient-specific clinical variables will likely contribute to the optimization of DBS target selection and improved outcomes for patients. ANN NEUROL 2021;89:426-443.

Neuromodulation for the treatment of functional neurological disorder and somatic symptom disorder: a systematic review.

Functional neurological disorder and somatic symptom disorder are complex neuropsychiatric conditions that have been linked to circuit-based dysfunction of brain networks. Neuromodulation is a novel therapeutic strategy capable of modulating relevant brain networks, making it a promising potential candidate for the treatment of these patient populations. We conducted a systematic review of Medline, Embase and PsycINFO up to 4 March 2021. Trials investigating neuromodulation devices for the treatment of functional neurological disorder or somatic symptom disorder were selected. Extracted variables included study design, demographic and clinical characteristics, psychiatric comorbidity, neurostimulation protocols, clinical outcome measures and results. 404 studies were identified with 12 meeting inclusion criteria. 221 patients were treated in the included studies with mean study sample size of 18 (4-70). Five studies were randomised clinical trials. Functional motor symptoms (six weakness, four movement disorders) were the most studied subpopulations. Transcranial magnetic stimulation (TMS) was the most frequently used device (10 studies), followed by electroconvulsive therapy (one study) and direct-current stimulation (one study). Treatment protocols varied in intended therapeutic mechanism(s): eight studies aimed to modulate underlying network dysfunction, five aimed to demonstrate movement (one also leveraged the former) and three boosted their primary mechanism with enhanced suggestion/expectation. All but one study reported positive results; however, methodological/outcome heterogeneity, mixed study quality and small sample sizes precluded quantitative meta-analysis. Neuromodulation, particularly TMS for the treatment of functional motor symptoms, shows preliminary promise in a growing line of research. Larger, sham-controlled studies are needed to further establish efficacy and better understand therapeutic mechanisms.

Lesional psychiatric neurosurgery: meta-analysis of clinical outcomes using a transdiagnostic approach.

BACKGROUND: Four 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. METHODS: A 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. RESULTS: Of 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; p<0.0001), obsessive-compulsive symptoms (g=2.25; p<0.0001) and anxiety (g=1.76; p<0.0001). The pooled clinical global impression improvement score was 2.36 (p<0.0001). On subgroup analysis, there was only a significant degree of heterogeneity in effect sizes between procedure types for anxiety symptoms, with capsulotomy resulting in a greater reduction in anxiety than cingulotomy. CONCLUSIONS: Contemporary ablative neurosurgical procedures were significantly associated with improvements in depression, obsessive-compulsive symptoms, anxiety and clinical global impression. PROSPERO REGISTRATION NUMBER: CRD42020164784.

Potential optimization of focused ultrasound capsulotomy for obsessive compulsive disorder.

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.

Brain Structures and Networks Underlying Treatment Response to Deep Brain Stimulation Targeting the Inferior Thalamic Peduncle in Obsessive-Compulsive Disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a debilitating disease with a lifetime prevalence of 2-3%. Neuromodulatory treatments have been successfully used in severe cases. Deep brain stimulation (DBS) targeting the inferior thalamic peduncle (ITP) has been shown to successfully alleviate symptoms in OCD patients; however, the brain circuits implicated remain unclear. Here, we investigate the efficacious neural substrates following ITP-DBS for OCD. METHODS: High-quality normative structural and functional connectomics and voxel-wise probabilistic mapping techniques were applied to assess the neural substrates of OCD symptom alleviation in a cohort of 5 ITP-DBS patients. RESULTS: The region of most efficacious stimulation was located in the regions of the ITP and bed nucleus of the stria terminalis. Both functional and structural connectomics analyses demonstrated that successful symptom alleviation involved a brain network encompassing the bilateral amygdala and prefrontal regions. LIMITATIONS: The main limitation is the small size of the ITP-DBS cohort. While the findings are highly consistent and significant, these should be validated in larger studies. CONCLUSIONS: These results identify a tripartite brain network - composed of the bilateral amygdala and prefrontal regions 24 and 46 - whose engagement is associated with greater symptom improvement. They also provide information for optimizing targeting and identifying network components critically involved in ITP-DBS treatment response. Amygdala engagement in particular seems to be a key component for clinical benefits and could constitute a biomarker for treatment optimization.

Senior Residents' Perceived Competence in Evidence-Based Treatments for Major Depressive Disorder.

OBJECTIVE: The current study aims to assess the self-reported competence of graduating psychiatry residents in Canada to provide pharmacotherapy and psychotherapy for major depressive disorder as recommended in national practice guidelines. METHODS: Canadian psychiatry residents who participated in an optional national review course to prepare for licensing were anonymously surveyed regarding their experience and competence in providing treatments recommended by the 2016 Canadian Network for Mood and Anxiety Treatments guidelines. RESULTS: The majority (89%, 130/146) reported competence in ≥ 5 medication monotherapies (e.g., selective serotonin/norepinephrine reuptake inhibitors, bupropion, mirtazapine) and ≥ 3 adjuncts (e.g., mirtazapine, second-generation antipsychotics). While 76% expressed interest in practicing multiple psychotherapeutic modalities, only 47% reported self-assessed competence in delivering multiple modalities. Only 42% reported pharmacological competence (≥ 5 monotherapies, ≥ 3 adjuncts) and competence in ≥ 2 psychotherapies. Only 9% reported competence in offering medication, psychotherapy, and electroconvulsive therapy. Less than two-thirds endorsed sufficient didactic teaching (58%) or supervision in pharmacotherapy (50%) for treatment-resistant depression. CONCLUSIONS: Canadian psychiatry residents report competence in prescribing many first-line medications. However, only a minority report competence in prescribing medications and competence in psychotherapies and/or electroconvulsive therapy. Given known biases in assessments by self-report, real-world competence may be even lower. This study identifies gaps between national practice guidelines and the comfort of the emerging psychiatric workforce in delivering recommended treatments. These gaps in resident competence may lead to under-use of effective treatments for depression. Residency programs should consider how to improve resident competence in providing the full range of evidence-based treatments for depression.

Magnetic resonance-guided focused ultrasound capsulotomy for refractory obsessive compulsive disorder and major depressive disorder: clinical and imaging results from two phase I trials.

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.

Treatment-resistant major depressive disorder: Canadian expert consensus on definition and assessment.

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.

Impacts on Quality of Life with Escitalopram Monotherapy and Aripiprazole Augmentation in Patients with Major Depressive Disorder: A CAN-BIND Report.

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 (<50% decrease in clinician-rated depression) were treated with adjunctive aripiprazole for 8 weeks (n=97); responders continued escitalopram (n=82). A repeated-measures ANOVA evaluated change in Quality of Life Enjoyment and Satisfaction Short Form scores. QoL was described relative to normative benchmarks. 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.

Transcranial Magnetic Stimulation for the Treatment of Concussion: A Systematic Review.

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 < 30). Methodological heterogeneity and a low number of identified trials precluded quantitative meta-analysis. Regarding rTMS for post-concussive depression, positive results were found in two out of four studies with depression as a primary outcome, and all three studies that assessed depression as a secondary outcome. All four rTMS studies for post-concussive headache reported positive results. CONCLUSIONS: rTMS for the treatment of concussion/mTBI shows promising preliminary results for post-concussive depression and headache, symptoms that otherwise have limited effective treatment options. More studies with larger sample sizes are needed to further establish potential efficacy.

Predicting response to psychiatric surgery: a systematic review of neuroimaging findings.

Background: Psychiatric surgery, including deep brain stimulation and stereotactic ablation, is an important treatment option in severe refractory psychiatric illness. Several large trials have demonstrated response rates of approximately 50%, underscoring the need to identify and select responders preoperatively. Recent advances in neuroimaging have brought this possibility into focus. We systematically reviewed the psychiatric surgery neuroimaging literature to assess the current state of evidence for preoperative imaging predictors of response. Methods: We performed this study in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) frameworks, and preregistered it using PROSPERO. We systematically searched the Medline, Embase and Cochrane databases for studies reporting preoperative neuroimaging analyses correlated with clinical outcomes in patients who underwent psychiatric surgery. We recorded and synthesized the methodological details, imaging results and clinical correlations from these studies. Results: After removing duplicates, the search yielded 8388 unique articles, of which 7 met the inclusion criteria. The included articles were published between 2001 and 2018 and reported on the outcomes of 101 unique patients. Of the 6 studies that reported significant findings, all identified clusters of hypermetabolism, hyperconnectivity or increased size in the frontostriatal limbic circuitry. Limitations: The included studies were few and highly varied, spanning 2 decades. Conclusion: Although few studies have analyzed preoperative imaging for predictors of response to psychiatric surgery, we found consistency among the reported results: most studies implicated overactivity in the frontostriatal limbic network as being correlated with clinical response. Larger prospective studies are needed. Registration: www.crd.york.ac.uk/prospero/display_record.php?RecordID=131151.

Neuroanatomical predictors of response to subcallosal cingulate deep brain stimulation for treatment-resistant depression

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.

Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial.

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 0·103 [corrected], 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.