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Importance: There is an unmet need for effective treatments for suicidality in mental disorders. Magnetic seizure therapy (MST) has been investigated as an alternative to electroconvulsive therapy, a known effective treatment for suicidality, in the management of treatment-resistant major depressive disorder, with promising findings. Yet, there are very limited data on the association of MST with suicidality directly. It is important to explore the potential of MST as a viable treatment alternative to electroconvulsive therapy for suicidality., Objective: To determine the association of MST with suicidality in patients with treatment-resistant major depressive disorder., Design, Setting, and Participants: This nonrandomized controlled trial took place at a single tertiary care psychiatric facility in Canada. It followed an open-label study design with consecutive treatment cohorts. Consecutive groupings of 67 patients with treatment-resistant major depressive disorder and with baseline suicidality present were treated for up to 24 treatments. The study was run from February 2012 through June 2019. Patients were followed up for 6 months at the end of the treatment period. This post hoc secondary analysis of the trial was performed from January to November 2019., Interventions: MST was delivered at 100% stimulator output over the prefrontal cortex with low (25 Hz), moderate (50 or 60 Hz), or high (100 Hz) frequency, for a maximum of 24 sessions., Main Outcomes and Measures: Remission from suicidality was measured as an end point score of 0 on the Beck Scale for Suicidal Ideation. A linear mixed model was used to assess the trajectory of Beck Scale for Suicidal Ideation scores., Results: A total of 67 patients (mean [SD] age, 46.3 [13.6] years; 40 women [60.0%]) received a mean (SD) of 19.5 (5.1) MST treatments. The overall number of patients achieving remission was 32 (47.8%). Sixteen patients (55.2%) receiving low-frequency MST achieved remission, as well as 12 patients (54.5%) in the moderate-frequency group, and 4 patients (25.0%) in the high-frequency group. The linear mixed model revealed an association of time with Beck Scale for Suicidal Ideation scores (F8,293.95 = 5.73; P < .001)., Conclusions and Relevance: These findings suggest that MST may be an effective treatment for suicidality, and sensitivity analysis shows this may be particularly so at low and moderate frequencies. Future studies should directly compare MST with electroconvulsive therapy for treating suicidality and should evaluate MST as a treatment for suicidality across mental disorders., Trial Registration: ClinicalTrials.gov Identifier: NCT01596608.

Background/objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes high morbidity and mortality in older adults with chronic illnesses. Several trials are currently underway evaluating the antimalarial drug hydroxychloroquine as a potential treatment for acute infection. However, polypharmacy predisposes patients to increased risk of drug-drug interactions with hydroxychloroquine and may render many in this population ineligible to participate in trials. We aimed to quantify the degree of polypharmacy and burden of potentially inappropriate medications (PIMs) that older hospitalized adults are taking that would interact with hydroxychloroquine., Methods: We reanalyzed data from the cohort of patients 65 years and older enrolled in the MedSafer pilot study. We first identified patients taking medications with potentially harmful drug-drug interactions with hydroxychloroquine that might exclude them from participation in a typical 2019 coronavirus disease (COVID-19) therapeutic trial. Next, we identified medications that were flagged by MedSafer as potentially inappropriate and crafted guidance around medication management if contemplating the use of hydroxychloroquine., Results: The cohort contained a total of 1,001 unique patients with complete data on their home medications at admission. Of these 1,001 patients, 590 (58.9%) were receiving one or more home medications that could potentially interact with hydroxychloroquine, and of these, 255 (43.2%) were flagged as potentially inappropriate by the MedSafer tool. Common classes of PIMs observed were antipsychotics, cardiac medications, and antidiabetic agents., Conclusion: The COVID-19 pandemic highlights the importance of medication optimization and deprescribing PIMs in older adults. By acting now to reduce polypharmacy and use of PIMs, we can better prepare this vulnerable population for inclusion in trials and, if substantiated, pharmacologic treatment or prevention of COVID-19. J Am Geriatr Soc 68:1636-1646, 2020., (© 2020 The American Geriatrics Society.)

Objective: Our objective was to describe interventions that aim to improve communication of prognosis to adult patients and to summarize the effect of interventions., Methods: We included randomized controlled trials of interventions that included prognosis delivery. We excluded studies of decision aids. Our analysis was a narrative synthesis of interventions and outcomes., Results: Our search identified 1151 unique records. After screening, and full text review we included 21 reports from 17 RCTs. Only 2 studies used a prediction model to generate prognostic estimates. Four studies used education, ten used patient mediated interventions, and 2 used coordination of care. In some studies education that includes prognosis improves patient reported outcomes, communication and treatment decisions, patient mediated interventions can increase the number of questions patients ask about prognosis. Coordination of care may improve satisfaction., Conclusions: Education for clinicians that includes teaching about how to communicate prognosis may improve patient reported outcomes. Patient mediated interventions can increase the number of prognosis related questions asked by patients., Practice Implications: Communication skills training that includes training on delivering prognosis may improve communication and patient reported outcomes, but the evidence is uncertain. Giving patients question prompt lists can help them ask more prognosis related questions., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Current first-line treatments for major depressive disorder (MDD) include pharmacotherapy and cognitive-behavioral therapy. However, one-third of depressed patients do not achieve remission after multiple medication trials, and psychotherapy can be costly and time-consuming. Although non-implantable neuromodulation (NIN) techniques such as transcranial magnetic stimulation, transcranial direct current stimulation, electroconvulsive therapy, and magnetic seizure therapy are gaining momentum for treating MDD, the efficacy of non-convulsive techniques is still modest, whereas use of convulsive modalities is limited by their cognitive side effects. In this context, we propose that NIN techniques could benefit from a precision-oriented approach. In this review, we discuss the challenges and opportunities in implementing such a framework, focusing on enhancing NIN effects via a combination of individualized cognitive interventions, using closed-loop approaches, identifying multimodal biomarkers, using computer electric field modeling to guide targeting and quantify dosage, and using machine learning algorithms to integrate data collected at multiple biological levels and identify clinical responders. Though promising, this framework is currently limited, as previous studies have employed small samples and did not sufficiently explore pathophysiological mechanisms associated with NIN response and side effects. Moreover, cost-effectiveness analyses have not been performed. Nevertheless, further advancements in clinical trials of NIN could shift the field toward a more "precision-oriented" practice.

Anhedonia is thought to reflect deficits in reward processing that are associated with abnormal activity in mesocorticolimbic brain regions. It is expressed clinically as a deficit in the interest or pleasure in daily activities. More severe anhedonia in major depressive disorder (MDD) is a negative predictor of antidepressant response. It is unknown, however, whether the pathophysiology of anhedonia represents a viable avenue for identifying biological markers of antidepressant treatment response. Therefore, this study aimed to examine the relationships between reward processing and response to antidepressant treatment using clinical, behavioral, and functional neuroimaging measures. Eighty-seven participants in the first Canadian Biomarker Integration Network in Depression (CAN-BIND-1) protocol received 8 weeks of open-label escitalopram. Clinical correlates of reward processing were assessed at baseline using validated scales to measure anhedonia, and a monetary incentive delay (MID) task during functional neuroimaging was completed at baseline and after 2 weeks of treatment. Response to escitalopram was associated with significantly lower self-reported deficits in reward processing at baseline. Activity during the reward anticipation, but not the reward consumption, phase of the MID task was correlated with clinical response to escitalopram at week 8. Early (baseline to week 2) increases in frontostriatal connectivity during reward anticipation significantly correlated with reduction in depressive symptoms after 8 weeks of treatment. Escitalopram response is associated with clinical and neuroimaging correlates of reward processing. These results represent an important contribution towards identifying and integrating biological, behavioral, and clinical correlates of treatment response. ClinicalTrials.gov: NCT01655706.

Public health emergencies have the potential to place enormous strain on health systems. The current pandemic of the novel 2019 coronavirus disease has required hospitals in numerous countries to expand their surge capacity to meet the needs of patients with critical illness. When even surge capacity is exceeded, however, principles of critical care triage may be needed as a means to allocate scarce resources, such as mechanical ventilators or key medications. The goal of a triage system is to direct limited resources towards patients most likely to benefit from them. Implementing a triage system requires careful coordination between clinicians, health systems, local and regional governments, and the public, with a goal of transparency to maintain trust. We discuss the principles of tertiary triage and methods for implementing such a system, emphasizing that these systems should serve only as a last resort. Even under triage, we must uphold our obligation to care for all patients as best possible under difficult circumstances., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: When people die in intensive care units (ICUs), as many as half of their family members may experience a severe grief reaction. While families report a need for bereavement support, most ICUs do not routinely follow-up with family members. Clinicians are typically involved in supporting families during death and dying, yet little is known about how they work with families in bereavement. Our goal was to explore how clinicians support bereaved families, identify factors that facilitate and hinder support, and understand their interest and needs for follow-up., Methods: Mixed-methods study of nurses and physicians working in one of nine adult medical-surgical ICUs in academic hospitals across Canada. Qualitative interviews followed quantitative surveys to reflect, expand, and explain the quantitative results., Results: Both physicians and nurses perceived that they provided empathetic support to bereaved families. Emotional engagement was a crucial element of support, but clinicians were not always able to engage with families because of their roles, responsibilities, experiences, or unit resources. Another important factor that could facilitate or challenge engagement was the degree to which families accepted death. Clinicians were interested in participating in a follow-up bereavement program, but their participation was contingent on time, training, and the ability to manage their own emotions related to death and bereavement in the ICU., Conclusions: Multiple opportunities were identified to enhance current bereavement support for families, including the desire of ICU clinicians for formal follow-up programs. Many psychological, sociocultural, and structural factors would need to be considered in program design.

Purpose: Grief is a normal reaction, and most family members (FMs) experience grief following a death. Typically, grief subsides without any major psychological or medical impairment. Nevertheless, some FMs may experience complicated grief (CG) reactions, with symptoms lasting months or years, and CG is particularly prominent among FMs of those who die in the intensive care unit (ICU). The purpose of this study was to examine how FMs experience grief, particularly CG, to inform future early screening and support programs in the ICU., Methods: This was a multicentre qualitative study focusing on semi-structured interviews with FMs who displayed symptoms of CG. Family members of patients who died in the ICU and who had a six-month inventory of CG score > 25 were included. Semi-structured interviews were conducted with FMs post-loss, with follow-up interviews three months after the initial interviews., Results: Major themes identified following thematic analysis from eight participants with CG included 1) ante-mortem experience: the impact of the ICU experience prior to death of a loved on subsequent grief; 2) post-mortem experience: unpredictable post death reactions; 3) coping strategies: techniques used to reduce the severity of grief reactions; 4) sources of support: focusing on resources that the FM draws from for emotional support; and 5) perspectives on future ICU bereavement screening and support programs: advice that FM participants provided for future bereavement support., Conclusion: Bereaved FMs with CG described their experiences with grief, how ICU events influenced their bereavement, their coping strategies and sources of support, and their advice for future bereavement support programs for FMs of deceased ICU patients.

Purpose of Review: An increasing number of patients are turning to cannabis and cannabinoids for management of their palliative and nonpalliative cancer pain and other cancer-related symptoms. Canadians have a legal framework for access to medical cannabis, which provides a unique perspective in a setting lacking robust clinical evidence. This review seeks to delineate the role of cannabis and cannabinoids in cancer pain management and offers insight into the Canadian practice., Recent Findings: A cohort study using nabiximols on advanced cancer pain in patients already optimized on opioids, over 3 weeks, demonstrated improved average pain score. A large observational study of cancer patients using cannabis over 6 months demonstrated a decreased number of patients with severe pain and decreased opioid use, whereas the number of patients reporting good quality of life increased., Summary: Good preclinical animal data and a large body of observational evidence point to the potential efficacy of cannabinoids for cancer pain management. However, there are relatively weak data pointing to clinical efficacy from clinical trial data to date. In Canada, the burgeoning cannabis industry has driven the population to embrace a medicine before clinical evidence. There remains a need for high-quality randomized controlled trials to properly assess the effectiveness and safety of medical cannabis, compared with placebo and standard treatments for cancer-related symptoms.

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., Competing Interests: Declaration of Competing Interest Dr. Giacobbe has received research support from the CIHR, NIH and Veteran's Affairs Canada and has been an unpaid consultant for St. Jude Medical and has served on an advisory board for Janssen and Bristol Myers Squibb., (Copyright © 2020. Published by Elsevier B.V.)

Background: Although repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depressive disorder (MDD), treatment selection is still mainly a process of trial-and-error. The present study aimed to identify clinical predictors of remission after a course of rTMS delivered to the left DLPFC to improve patient selection., Methods: Data from a large randomised non-inferiority trial comparing standard 10 Hz and intermittent theta burst stimulation (iTBS) for the treatment of MDD were used for the exploratory analyses. Individual variables were assessed for their association with remission and then included in a logistic regression model to determine odds ratios (OR) and corresponding 95% confidence intervals. Model discrimination (internal validation) was carried out to assess model optimism using the c-index. ClinicalTrials.gov identifier: NCT01887782., Findings: 388 subjects were included in the analysis (199-iTBS and 189-10 Hz, respectively). Higher baseline severity of both depressive and anxiety symptoms were associated with a lower chance of achieving remission (OR=0.64, 95% CI 0.46-0.88; and 0.78, 95% CI 0·60-0.98, respectively). Current employment was a positive predictor for remission (OR=1.69, 95% CI 1.06-2.7), while greater number of treatment failures was associated with lower odds of achieving remission (OR=0.51, 95% CI 0.27-0.98). A non-linear effect of age and remission was observed. An analysis to allow an estimate of the probability of remission using all variables was assessed. The c-index for the fitted model was 0.687., Interpretation: Our results suggest that measuring depression symptom severity, employment status, and refractoriness are important in prognosticating outcome to a course of rTMS in MDD., Funding: Canadian Institutes of Health Research MOP-136801., Competing Interests: Dr. Downar reports non-financial support from Brainsway Inc., non-financial support from Magventure Inc., grants from Arrell Family Foundation, grants from Buchan Family Foundation, grants from Canadian Biomarker Integration Network in Depression, grants from Canadian Institutes of Health Research (CIHR), grants from Klarman Family Foundation, grants from National Institute of Mental Health, grants from Ontario Brain Institute, grants from Weston Family Foundation, personal fees from Lundbeck, personal fees from ANT Neuro, personal fees from BrainCheck, personal fees from Restorative Brain Clinics, personal fees from TMS Neuro Solutions, during the conduct of the study. Dr. Vila-Rodriguez reports grants from Canadian Institutes of Health Research, grants from Brain Canada, grants from Vancouver Coastal Health Research Institute, grants from Michael Smith Foundation for Health Research, personal fees from Janssen Pharmaceuticals, non-financial support from Magventure, during the conduct of the study. Dr. Daskalakis reports non-financial support from Brainsway Inc., non-financial support from Magventure Inc., grants from Ontario Mental Health Foundation (OMHF), grants from Canadian Institutes of Health Research (CIHR), grants from National Institutes of Mental Health (NIMH), grants from Temerty Family, grants from Grant Family, grants from Centre for Addiction and Mental Health (CAMH) Foundation, grants from Campbell Institute, during the conduct of the study. Dr. Blumberger reports grants from Brain Canada, grants from Canadian Institutes of Health Research, grants from Weston Brain Institute, grants from Centre for Addiction and Mental Health (CAMH) Foundation, grants from Campbell Institute, non-financial support from Brainsway, non-financial support from Indivior, other from Janssen, grants from National Institute of Health, during the conduct of the study. All the other authors do not have any conflicts of interest to declare., (© 2020 The Author(s).)

Background: The number of medical undergraduate and postgraduate students completing palliative care clinical rotations in Canadian medical schools is currently unknown. The aim of this study was to assess the proportion of Canadian medical trainees completing clinical rotations in palliative care and to determine whether changes took place between 2008 and 2018., Methods: In this descriptive study, all Canadian medical schools ( n = 17) were invited to provide data at the undergraduate and postgraduate levels (2007/08-2015/16 and 2007/08-2017/18, respectively). Information collected included the number, type and length of palliative care clinical rotations offered and the total number of medical trainees or residents enrolled at each school., Results: All 17 Canadian medical schools responded to the request for information. At the undergraduate level, palliative care clinical rotations were not offered in 2 schools, mandatory in 2 and optional in 13. Three schools that offered optional rotations were unable to provide complete data and were therefore excluded from further analyses. In 2015/16, only 29.7% of undergraduate medical students completed palliative care clinical rotations, yet this was a significant improvement compared to 2011/12 (13.6%, p = 0.02). At the postgraduate level, on average, 57.9% of family medicine trainees completed such rotations between 2007/08 and 2016/17. During the same period, palliative care clinical rotations were completed by trainees in specialty or subspecialty programs in anesthesiology (34.2%), geriatric medicine (64.4%), internal medicine (30.9%), neurology (28.2%) and psychiatry (64.5%)., Interpretation: Between 2008 and 2018, a large proportion of Canadian medical trainees graduated without the benefit of a clinical rotation in palliative care. Without dedicated clinical exposure to palliative care, many physicians will enter practice without vital palliative care competencies., Competing Interests: Competing interests: None declared., (Copyright 2020, Joule Inc. or its licensors.)

Competing Interests: Competing interests: Sandy Buchman is the president and a member of the Board of Directors of the Canadian Medical Association. He has received speaker fees from the University of Toronto and Cancer Care Ontario, and nonfinancial support from the Israel National Institute for Health Policy Research. James Downar has received consultant fees from Joule and honoraria from Boehringer Ingelheim (Canada). Amit Arya has received honoraria from Pallium Canada for peer review activities for LEAP course materials. No other competing interests were declared.

Background: Identifying objective biomarkers can assist in predicting remission/non-remission to treatment, improving remission rates, and reducing illness burden in major depressive disorder (MDD)., Methods: Sixteen MDD 8-week remitters (MDD-8), twelve 16-week remitters (MDD-16), 14 non-remitters (MDD-NR) and 30 healthy comparison participants (HC) completed a functional magnetic resonance imaging emotional conflict task at baseline, prior to treatment with escitalopram, and 8 weeks after treatment initiation. Patients were followed 16 weeks to assess remitter status., Results: All groups demonstrated emotional Stroop in reaction time (RT) at baseline and Week 8. There were no baseline differences between HC and MDD-8, MDD-16, or MDD-NR in RT or accuracy. By Week 8, MDD-8 demonstrated poorer accuracy compared to HC. Compared to HC, the baseline blood-oxygen level dependent (BOLD) signal was decreased in MDD-8 in brain-stem and thalamus; in MDD-16 in lateral occipital cortex, middle temporal gyrus, and cuneal cortex; in MDD-NR in lingual and occipital fusiform gyri, thalamus, putamen, caudate, cingulate gyrus, insula, cuneal cortex, and middle temporal gyrus. By Week 8, there were no BOLD activity differences between MDD groups and HC., Limitations: The Emotional Conflict Task lacks a neutral (non-emotional) condition, restricting interpretation of how mood may influence perception of non-emotionally valenced stimuli., Conclusions: The Emotional Conflict Task is not an objective biomarker for remission trajectory in patients with MDD receiving escitalopram treatment. Escitalopram may have influenced emotion recognition in MDD groups in terms of augmented accuracy and BOLD signal in response to an Emotional Conflict Task, following 8 weeks of escitalopram treatment., Competing Interests: Declaration of Competing Interest All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2019. Published by Elsevier B.V.)

Objectives: On 19 June 2019, assisted dying became lawful in Victoria, the second most populous state in Australia. Section 8 of the Voluntary Assisted Dying Act is a legislative safeguard that is designed to ensure a patient's request for assistance to die is voluntary. This section prohibits health practitioners from initiating a conversation about assisted dying with the patient. This article explores the potential implications of this prohibition for effective communication between doctors and their patients, and the ability of doctors to provide high quality end-of-life (EOL) care in some cases., Method: The authors reviewed and analysed literature on the importance of communication at the EOL including the need to understand and appropriately respond to Desire to Die or Desire to Hasten Death statements. A legal critique of section 8 of the Victorian Voluntary Assisted Dying Act was also undertaken to determine the scope of this new duty and how it aligns with existing legal obligations that would otherwise require doctors to provide information about EOL options requested by a patient., Results: Contemporary literature suggests that open and honest communication between doctor and patient including the provision of information about all EOL options when sought by the patient represents good clinical practice and will lead to optimal EOL care. The provision of such information also reflects professional, ethical and legal norms., Conclusion: Despite (arguably) promoting an appropriate policy objective, the legislative prohibition on health professionals initiating conversations about voluntary assisted dying may, in cases where patients seek information about all EOL options, lead to less optimal patient outcomes., Competing Interests: Competing interests: LW has been engaged by the Victorian Government to design and provide the legislatively mandated training for doctors involved in voluntary assisted dying. LW is also a member of the board of Palliative Care Australia (but this article only represents her views not those of Palliative Care Australia). BW has been engaged by the Victorian Government to design and provide the legislatively mandated training for doctors involved in voluntary assisted dying. DK is on the Voluntary Assisted Dying Review Board (but this article represents her views only). JD is a former member of the Physicians’ Advisory Committee for Dying with Dignity Canada, a group that advocated for the legalisation of voluntary assisted dying in Canada. He currently works at Bruyere Continuing Care, a Catholic healthcare facility. This article does not represent the views of either Dying with Dignity Canada or Bruyere Continuing Care. LD has no competing interests., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Medical assistance in dying (MAiD) was legalized across Canada in June 2016. Some have expressed concern that patient requests for MAiD might be driven by poor access to palliative care and that social and economic vulnerability of patients may influence access to or receipt of MAiD. To examine these concerns, we describe Ontario's early experience with MAiD and compare MAiD decedents with the general population of decedents in Ontario., Methods: We conducted a retrospective cohort study comparing all MAiD-related deaths with all deaths in Ontario, Canada, between June 7, 2016, and Oct. 31, 2018. Clinical and demographic characteristics were collected for all MAiD decedents and compared with those of all Ontario decedents when possible. We used logistic regression analyses to describe the association of demographic and clinical factors with receipt of MAiD., Results: A total of 2241 patients (50.2% women) were included in the MAiD cohort, and 186 814 in the general Ontario decedent cohort. Recipients of MAiD reported both physical (99.5%) and psychologic suffering (96.4%) before the procedure. In 74.4% of cases, palliative care providers were involved in the patient's care at the time of the MAiD request. The statutory 10-day reflection period was shortened for 26.6% of people. Compared with all Ontario decedents, MAiD recipients were younger (mean 74.4 v. 77.0 yr, standardized difference 0.18);, more likely to be from a higher income quintile (24.9% v. 15.6%, standardized difference across quintiles 0.31); less likely to reside in an institution (6.3% v. 28.0%, standardized difference 0.6); more likely to be married (48.5% v. 40.6%) and less likely to be widowed (25.7% v. 35.8%, standardized difference 0.34); and more likely to have a cancer diagnosis (64.4% v. 27.6%, standardized difference 0.88 for diagnoses comparisons)., Interpretation: Recipients of MAiD were younger, had higher income, were substantially less likely to reside in an institution and were more likely to be married than decedents from the general population, suggesting that MAiD is unlikely to be driven by social or economic vulnerability. Given the high prevalence of physical and psychologic suffering, despite involvement of palliative care providers in caring for patients who request MAiD, future studies should aim to improve our understanding and treatment of the specific types of suffering that lead to a MAiD request., Competing Interests: Competing interests: James Downar is currently employed by Bruyère Continuing Care, a Catholic faith–based health care facility; he is a former unpaid member of the Clinicians Advisory Council of Dying with Dignity Canada, a group that advocated for legalization of medical assistance in dying (MAiD) in Canada; and he previously received consultation fees for curriculum development for a MAiD course offered by Joule, Inc. The work presented here does not represent the views of Bruyère Continuing Care, Dying with Dignity Canada, or Joule, Inc. Jennifer Gibson was co-chair of the Provincial–Territorial Expert Advisory Group on Physician-Assisted Dying (2015), which was commissioned by provincial and territorial governments to develop recommendations for the implementation of MAiD in Canada; she was also chair of the Advance Requests Working Group of the Council of Canadian Academies Expert Panel on Medical Assistance in Dying. No other competing interests were declared., (© 2020 Joule Inc. or its licensors.)

Finding a clinically useful neuroimaging biomarker that can predict treatment response in patients with major depressive disorder (MDD) is challenging, in part because of poor reproducibility and generalizability of findings across studies. Previous work has suggested that posterior hippocampal volumes in depressed patients may be associated with antidepressant treatment outcomes. The primary purpose of this investigation was to examine further whether posterior hippocampal volumes predict remission following antidepressant treatment. Magnetic resonance imaging (MRI) scans from 196 patients with MDD and 110 healthy participants were obtained as part of the first study in the Canadian Biomarker Integration Network in Depression program (CAN-BIND 1) in which patients were treated for 16 weeks with open-label medication. Hippocampal volumes were measured using both a manual segmentation protocol and FreeSurfer 6.0. Baseline hippocampal tail (Ht) volumes were significantly smaller in patients with depression compared to healthy participants. Larger baseline Ht volumes were positively associated with remission status at weeks 8 and 16. Participants who achieved early sustained remission had significantly greater Ht volumes compared to those who did not achieve remission by week 16. Ht volume is a prognostic biomarker for antidepressant treatment outcomes in patients with MDD.

Electroconvulsive therapy (ECT) is effective for major depressive disorder (MDD) but its effects on memory limit its widespread use. Magnetic seizure therapy (MST) is a potential alternative to ECT that may not adversely affect memory. In the current trial, consecutive patients with MDD consented to receive MST applied over the prefrontal cortex according to an open-label protocol. Depressive symptoms and cognition were assessed prior to, during and at the end of treatment. Patients were treated two to three times per week with high-frequency MST (i.e., 100 Hz) (N = 24), medium frequency MST (i.e., 60 or 50 Hz) (N = 26), or low-frequency MST (i.e., 25 Hz MST) (N = 36) using 100% stimulator output. One hundred and forty patients were screened; 86 patients with MDD received a minimum of eight treatments and were deemed to have an adequate course of MST; and 47 completed the trial per protocol, either achieving remission (i.e., 24-item Hamilton Rating Scale for Depression score <10 and a relative reduction of >60% at two consecutive assessments; n = 17) or received a maximum of 24 sessions (n = 30). High-frequency (100 Hz) MST produced the highest remission rate (33.3%). Performance on most cognitive measures remained stable, with the exception of significantly worsened recall consistency of autobiographical information and significantly improved brief visuospatial memory task performance. Under open conditions, MST led to clinically meaningful reduction in depressive symptoms in patients with MDD and produced minimal cognitive impairment. Future studies should compare MST and ECT under double-blind randomized condition.

Background: Heart rate in MDD is often dysregulated, expressed in overall higher heart rates (HR) and lower heart rate variability (HRV). Interestingly, HR decelerations have been reported after stimulation of the DLPFC using rTMS, suggesting connectivity between the DLPFC and the heart. Recently, a new form of rTMS called theta burst stimulation (TBS) has been developed. One form of TBS, intermittent TBS (iTBS), delivers 600 pulses in just 3 min., Objective: To determine whether iTBS aimed at the DLPFC also affects HR, blood pressure and HRV, and whether these cardiac responses at baseline are associated with treatment response., Methods: ECG and blood pressure were recorded during both sham and active iTBS in 15 MDD patients, over 30 sessions., Results: We found a significantly larger HR deceleration for active iTBS, compared to sham, within the first minute of stimulation. Also, a trend towards an association between HR deceleration and treatment response was found, explaining 26% of the variance. Furthermore, several measures of heart rate variability were significantly higher during iTBS stimulation over sessions, compared to sham. Both systolic and diastolic blood pressure, were lower during active iTBS., Conclusion: Active iTBS applied to the DLPFC is able to transsynaptically modulate the autonomic nervous system, in particular the parasympathetic branch, similar to what has been found for conventional rTMS methods. Furthermore, data suggest that the larger the autonomic changes induced at baseline, the better the clinical response after 30 sessions of iTBS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Objective: Repetitive transcranial magnetic stimulation (rTMS) is a first-line treatment for treatment-resistant depression (TRD). The mechanisms of action of rTMS are not fully understood, and no biomarkers are available to assist in clinical practice to predict response to rTMS. This study aimed to demonstrate that after-rTMS clinical improvement is associated with functional connectivity (FC) changes of the subgenual cingulate cortex (sgACC) and rostral anterior cingulate (rACC), and FC of sgACC and rACC might serve as potential predictors for treatment response., Methods: Resting-state functional magnetic resonance imaging (rs-fMRI) data were collected within 1 week before rTMS initiation in 50 TRD patients to predict subsequent response to rTMS on the left dorsolateral prefrontal cortex (DLPFC). Follow-up rs-fMRI was obtained 12 weeks after completion of rTMS and neural correlates of rTMS in sgACC- and rACC-related FC patterns were compared to before rTMS data and with rs-fMRI from healthy participants., Results: Treatment response was associated with lower FC of sgACC to right DLPFC and higher FC of rACC to left lateral parietal cortex (IPL) measured at baseline. Using sgACC-DLPFC and rACC-IPL connectivity as features, responder-nonresponder classification accuracies of 84% and 76% (end-of-treatment), 88% and 81% (3-month follow-up), respectively were achieved. Longitudinal rs-fMRI data analyses revealed that the hyperconnectivity between sgACC and visual cortex was normalized to a level which was comparable to that of healthy participants., Conclusions: Brain activity patterns in depression are predictive of treatment response to rTMS, and longitudinal change of brain activity in relevant brain circuits after rTMS is associated with treatment response in depression. Target engagement paradigms may offer opportunities to increase the efficacy of rTMS in TRD by optimal selection of patients for treatment., Trial Registration: ClinicalTrials.gov Identifiers: NCT01887782 and NCT02800226., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: In-hospital cardiac arrest (IHCA) is common and associated with high mortality. Frailty is increasingly recognized as a predictor of worse prognosis among critically ill patients, but its association with outcomes and resource utilization following IHCA is unknown., Methods: We performed a retrospective analysis (2013-2016) of a prospectively collected registry from two hospitals of consecutive hospitalized adult patients with IHCA occurring on the hospital wards. We defined frailty using the Clinical Frailty Scale (CFS) score ≥5. CFS scores were based on validated medical review criteria. The primary outcome is hospital mortality. Secondary outcomes include return of spontaneous circulation (ROSC), discharge to long-term care, and hospital costs. We used multivariable logistic regression to adjust for known confounders., Results: We included 477 patients, and 124 (26.0%) had frailty. Frailty was associated with increased odds of hospital death (adjusted odds ratio [aOR]: 2.91 [95% confidence interval [CI]: 2.37-3.48) and discharge to long-term care (aOR 1.94 [95% CI: 1.57-2.32]). Compared with patients without frailty, patients with frailty had decreased odds of ROSC following IHCA (aOR 0.63 [95% CI: 0.41-0.93]). No difference in mean total costs was demonstrated between patients with and without frailty ($50,799 vs. $45,849). Frail patients did have higher cost-per-survivor ($947,546 vs. $161,550)., Conclusions: Frail individuals who experience an IHCA are more likely to die in hospital or be discharged to long-term care, and less likely to achieve ROSC in comparison with individuals who are not frail. The hospital costs per-survivor of IHCA are increased when frailty is present., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Repetitive transcranial magnetic stimulation (rTMS) has become increasingly popular during the last decades mainly driven by the antidepressant effects of dorsolateral prefrontal cortex stimulation with "butterfly" coils. Only recently, alternative targets such as the dorsomedial prefrontal cortex (dmPFC) have been brought into focus and innovative coil designs such as the angled geometry of the double cone coil (DCC) have raised hope to reach even deeper located targets., Objective: To provide a systematic and comprehensive review on the application of rTMS stimulation of the dmPFC using the DCC in neuropathological and healthy samples., Methods: We systematically searched the MEDLINE® database (http://www.ncbi.nlm.nih.gov/pubmed/). Due to the heterogeneous naming of DCC stimulation over the dmPFC a variety of search terms was applied resulting in a numeral quantity of 340 hits., Results: DCC stimulation over the dmPFC has been proven to be safe and feasible in various neuropsychiatric disorders and in healthy subjects. Clinical results are encouraging, but have to be considered as preliminary as data from sham-controlled clinical trials and knowledge about the neurobiological underpinnings are still scarce., Conclusion: DCC stimulation over the dmPFC represents a promising approach in the fast evolving noninvasive brain stimulation techniques aiming at the functional modulation of brain areas vitally involved in affect, sensory autonomic, cognitive, and salience regulation. This may hold potential for both neuroscientific research and clinical applications in the treatment of psychiatric disorders., (© 2018 International Neuromodulation Society.)

Objective: The need for clinical staff to reliably identify patients with a shortened life expectancy is an obstacle to improving palliative and end-of-life care. We developed and evaluated the feasibility of an automated tool to identify patients with a high risk of death in the next year to prompt treating physicians to consider a palliative approach and reduce the identification burden faced by clinical staff., Methods: Two-phase feasibility study conducted at two quaternary healthcare facilities in Toronto, Canada. We modified the Hospitalised-patient One-year Mortality Risk (HOMR) score, which identifies patients having an elevated 1-year mortality risk, to use only data available at the time of admission. An application prompted the admitting team when patients had an elevated mortality risk and suggested a palliative approach. The incidences of goals of care discussions and/or palliative care consultation were abstracted from medical records., Results: Our model (C-statistic=0.89) was found to be similarly accurate to the original HOMR score and identified 15.8% and 12.2% of admitted patients at Sites 1 and 2, respectively. Of 400 patients included, the most common indications for admission included a frailty condition (219, 55%), chronic organ failure (91, 23%) and cancer (78, 20%). At Site 1 (integrated notification), patients with the notification were significantly more likely to have a discussion about goals of care and/or palliative care consultation (35% vs 20%, p = 0.016). At Site 2 (electronic mail), there was no significant difference (45% vs 53%, p = 0.322)., Conclusions: Our application is an accurate, feasible and timely identification tool for patients at elevated risk of death in the next year and may be effective for improving palliative and end-of-life care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: Eliana Close has received PhD funding from the National Health and Medical Research Council (Australia) and Postgraduate Research Training Program funding from the Government of Australia, outside the submitted work. No other competing interests were declared.

Non-invasive brain stimulation (NIBS) is emerging as a robust treatment alternative for major depressive disorder, with a potential for achieving higher remission rates by providing targeted stimulation to underlying brain networks, such as the salience network (SN). Growing evidence suggests that these therapeutic effects are dependent on the frequency and phase synchrony between SN oscillations and stimulation as well as the task-specific state of the SN during stimulation. However, the development of phase-synchronized non-invasive stimulation has proved challenging until recently. Here, we use a phase-locked pulsed brain stimulation approach to study the effects of two NIBS methods: transcranial alternating current stimulation (tACS) versus phase-locked transcranial pulsed current stimulation (tPCS), on the SN during an SN activating task. 20 healthy volunteers participated in the study. Each volunteer partook in four sessions, receiving one stimulation type at random (theta-tACS, peak tPCS, trough tPCS or sham) while undergoing a learning game, followed by an unstimulated test based on learned material. Each session lasted approximately 1.5 h, with an interval of at least 2 days to allow for washout and to avoid cross-over effects. Our results showed no statistically significant effect of stimulation on the event related potential (ERP) recordings, resting electroencephalogram (EEG), and the performance of the volunteers. While stimulation effects were not apparent in this study, the nominal performance of the phase-locking algorithm offers a technical foundation for further research in determining effective stimulation paradigms and conditions. Specifically, future work should investigate stronger stimulation and true task-specific stimulation of SN nodes responsible for the task as well as their recording. If refined, NIBS could offer an effective, homebased treatment option., (Copyright © 2019 Mansouri, Shanbour, Mazza, Fettes, Zariffa and Downar.)

Background: Currently, the mainstay of treatment in patients diagnosed with major depressive disorder (MDD) requiring medical attention is second generation anti-depressants. However, about 40% of patients treated with second-generation anti-depressants do not respond to initial treatment and approximately 70% do not achieve remission during the first-step treatment. There are a few non-pharmacological options available, but none have shown consistently positive results. There is a need for an intervention that is relatively easy to administer, produces consistently positive results and is associated with minimal side effects. In the current study, we assessed the feasibility of using transcutaneous Functional Electrical Stimulation Therapy (FEST) of the facial muscles, as a tool for improving depressive symptoms in individuals with MDD., Results: Ten (10) individuals with moderate to severe MDD received three FEST sessions/week for a minimum of 10 to a maximum of 40 sessions. All study participants completed the required 10 therapy sessions, and 5 of the 10 participants completed additional 30 (totalling 40) FEST sessions. There were no adverse events or concerns regarding compliance to therapy. We found statistically significant improvements on Hamilton Rating Scale for Depression (HDS) and Inventory of Depressive Symptomatology (IDS) measures. However, no significant improvements were found on Positive and Negative Affect Scale and 10-point Visual Analogue Scale scales. Participants reported improvements in sleeping patterns, and this correlated with statistically significant improvements on sleep parameters of HDS and IDS measures., Conclusion: This study indicates that facial FEST is an acceptable, practical, and safe treatment in individuals with MDD. We provide preliminary evidence to show improvements in depressive symptoms following a minimum of 10 FEST sessions.

Background: Multiple prior treatment failures are associated with reduced rates of remission to subsequent antidepressant treatment, including rTMS. The degree of treatment resistance that is especially predictive of inferior outcome is uncertain. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS where less is known regarding clinical predictors of remission. The THREE-D study demonstrated that iTBS is non-inferior to 10 Hz rTMS for the treatment of depression., Objective: Determine if the number and type of prior pharmacotherapy trials affect the rate of remission with two types of rTMS., Method: Compare remission rates based on prior pharmacotherapy using data from the THREE-D trial (NCT01887782)., Results: No differences in remission rates were noted between the three levels of treatment resistance, however, participants with 3 compared to <3 treatment failures had lower rates of remission: 17.3% versus 29.4% (χ 2 4.87; df = 1; p = 0.03)., Conclusions: Three or more treatment failures may be associated with lower remission rates with rTMS., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Methods: We studied 48 MDD and 30 HC who performed an emotional conflict task in a functional magnetic resonance imaging (fMRI) scanner., Results: On the emotional conflict task, MDD and HC demonstrated a robust emotional Stroop effect in reaction time and accuracy. Overall, accuracy was lower in MDD compared to HC with no significant reaction time differences. The fMRI data indicated lower BOLD activation in MDD compared to HC on comparisons of all trials, congruent, incongruent, and incongruent > congruent trials in regions including right inferior temporal gyrus, lateral occipital cortex, and occipital fusiform gyrus. Behavioural and neuroimaging data indicated no group differences in fearful versus happy face processing., Limitations: Inclusion of a neutral condition may have provided a valuable contrast to how MDD and HC process stimuli without emotional valence compared to stimuli with a strong emotional valence., Conclusions: MDD and HC demonstrated a robust emotional Stroop effect. Compared to HC, MDD demonstrated an overall reduced accuracy on the emotional conflict task and reduced BOLD activity in regions important for face perception and emotion information processing, with no differences in responding to fearful versus happy faces. These findings provide support for the theory of emotion context insensitivity in individuals with depression., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Repetitive transcranial magnetic stimulation (rTMS) is an evidence-based treatment for depression that is increasingly implemented in healthcare systems across the world. A new form of rTMS called intermittent theta burst stimulation (iTBS) can be delivered in 3 min and has demonstrated comparable effectiveness to the conventional 37.5 min 10Hz rTMS protocol in patients with depression., Objectives: To compare the direct treatment costs per course and per remission for iTBS compared to 10Hz rTMS treatment in depression., Methods: We conducted a cost analysis from a healthcare system perspective using patient-level data from a large randomized non-inferiority trial (THREE-D). Depressed adults 18 to 65 received either 10Hz rTMS or iTBS treatment. Treatment costs were calculated using direct healthcare costs associated with equipment, coils, physician assessments and technician time over the course of treatment. Cost per remission was estimated using the proportion of patients achieving remission following treatment. Deterministic sensitivity analyses and non-parametric bootstrapping was used to estimate uncertainty., Results: From a healthcare system perspective, the average cost per patient was USD$1,108 (SD 166) for a course of iTBS and $1,844 (SD 304) for 10Hz rTMS, with an incremental net savings of $735 (95% CI 688 to 783). The average cost per remission was $3,695 (SD 552) for iTBS and $6,146 (SD 1,015) for 10Hz rTMS, with an average incremental net savings of $2,451 (95% CI 2,293 to 2,610)., Conclusions: The shorter session durations and treatment capacity increase associated with 3 min iTBS translate into significant cost-savings per patient and per remission when compared to 10Hz rTMS., Competing Interests: We have read the journal's policy and the authors of this manuscript have the following competing interests: JD has received research support from the Canadian Institutes of Health Research (CIHR), NIMH, Brain Canada, the Canadian Biomarker Integration Network in Depression, the Ontario Brain Institute, the Klarman Family Foundation, the Arrell Family Foundation, the Edgestone Foundation, a travel stipend from Lundbeck and from ANT Neuro, an advisor to BrainCheck and in-kind equipment support for this investigator-initiated trial from MagVenture. FVR receives research support from CIHR, Brain Canada, Michael Smith Foundation for Health Research, Vancouver Coastal Health Research Institute, and in-kind equipment support for this investigator-initiated trial from MagVenture. He has participated in an advisory board for Janssen. ZJD has received within the last 3 years both research and equipment in-kind support for an investigator-initiated study through Brainsway Ltd. and Magventure. DMB receives research support from CIHR, National Institutes of Health – US (NIH), Weston Brain Institute, Brain Canada and the Temerty Family through the CAMH Foundation and the Campbell Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. and he is the site principal investigator for three sponsor-initiated studies for Brainsway Ltd. He received in-kind equipment support from Magventure for this investigator-initiated study. He received medication supplies for an investigator-initiated trial from Indivior. He has participated in an advisory board for Janssen. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: Polypharmacy is common, costly, and harmful for hospitalized older adults. Scalable strategies to reduce the burden of potentially inappropriate medications (PIMs) are needed. We sought to leverage medication reconciliation in hospitalized older adults by pairing with MedSafer, an electronic decision support tool for deprescribing., Design: This was a nonrandomized controlled before-and-after study., Setting: The study took place on four internal medicine clinical teaching units., Participants: Subjects were aged 65 years and older, had an expected prognosis of 3 or more months, and were taking five or more usual home medications., Intervention: In the baseline phase, patients received usual care that was medication reconciliation. Patients in the intervention arm also had a "deprescribing opportunity report" generated by MedSafer and provided to their in-hospital treating team., Measurements: The primary outcome was ascertained at the time of hospital discharge and was the proportion of patients who had one or more PIMs deprescribed., Results: A total of 1066 patients were enrolled, and deprescribing opportunities were present for 873 (82%; 418 during the control and 455 during the intervention phases, respectively). The proportion of patients with one or more PIMs deprescribed at discharge increased from 46.9% in the control period to 54.7% in the intervention period with an adjusted absolute risk difference of 8.3% (2.9%-13.9%). Not all classes of drugs in the intervention arm were associated with an increase in deprescribing, and new PIM starts were equally common in both arms of the study., Conclusion: Using an electronic decision support tool for deprescribing, we increased the proportion of patients with one or more PIMs deprescribed at hospital discharge as compared with usual care. Although this type of intervention may help address medication overload in hospitalized patients, it also underscores the importance of powering future trials for a reduction in adverse drug events., Trial Registration: NCT02918058. J Am Geriatr Soc 67:1843-1850, 2019., (© 2019 The American Geriatrics Society.)

Background: Red blood cell transfusion is one therapeutic option for the treatment of anemia. Current transfusion practices and factors influencing the decision to prescribe this therapy are not well understood. Objective: To explore current transfusion practices, attitudes, and factors that influence the decision to transfuse among palliative care physicians. Design: Self-administered questionnaire addressing clinical experiences and decision making pertaining to blood transfusion. Setting/Subjects: Specialist palliative care physicians at two Canadian academic centers. Measurements: Descriptive, presented as the number/proportion of respondents indicating a specific answer. Results: Of 62 physicians surveyed, 29 (47%) responded to the study questionnaire. For patients with solid tumors and hematologic malignancies, respectively, 79% and 82% of respondents reported prescribing blood transfusion; 59% and 46% reported that they would seldom recommend its discontinuation. Factors influential in the decision to transfuse included symptoms of anemia (97%), bleeding (62%), low hemoglobin (52%, of whom 87% indicated a hemoglobin threshold <70 g/L), and pressure from patients/families (48%). Physicians routinely reassessed patients for symptomatic improvement following transfusion, but 72% did not use an objective symptom scale. Twenty-six (90%) respondents believed that transfusion provided symptomatic benefit; the majority had observed adverse reactions to transfusion. Most perceived a lack of evidence to guide transfusion therapy in palliative care, and 79% indicated willingness to enroll their patients in a trial aiming to address this question. Conclusions: Most palliative care specialists consider red blood cell transfusion to have a role in symptom management, but many clinical and nonclinical factors influence their decisions to provide or discontinue transfusions. Prospective clinical trials will likely be needed to inform transfusion practices in this population.

Studies of clinical populations that combine MRI data generated at multiple sites are increasingly common. The Canadian Biomarker Integration Network in Depression (CAN-BIND; www.canbind.ca) is a national depression research program that includes multimodal neuroimaging collected at several sites across Canada. The purpose of the current paper is to provide detailed information on the imaging protocols used in a number of CAN-BIND studies. The CAN-BIND program implemented a series of platform-specific MRI protocols, including a suite of prescribed structural and functional MRI sequences supported by real-time monitoring for adherence and quality control. The imaging data are retained in an established informatics and databasing platform. Approximately 1300 participants are being recruited, including almost 1000 with depression. These include participants treated with antidepressant medications, transcranial magnetic stimulation, cognitive behavioural therapy and cognitive remediation therapy. Our ability to analyze the large number of imaging variables available may be limited by the sample size of the substudies. The CAN-BIND program includes a multimodal imaging database supported by extensive clinical, demographic, neuropsychological and biological data from people with major depression. It is a resource for Canadian investigators who are interested in understanding whether aspects of neuroimaging — alone or in combination with other variables — can predict the outcomes of various treatment modalities., Competing Interests: G. MacQueen reports consultancy/speaker fees from Lundbeck, Pfizer, Johnson & Johnson and Janssen, outside the submitted work. B. Frey reports grants and personal fees from Pfizer and personal fees from Sunovion, outside the submitted work. R. Milev reports grants, nonfinancial support and honoraria from Lundbeck, Janssen and Pfizer; personal fees and honoraria from Sunovion, Shire, Allergan and Otsuka; grants from Boehringer Ingelheim; and grants from the Ontario Brain Institute, the Canadian Institutes for Health Research and CAN-BIND, outside the submitted work. F. Vila-Rodriguez reports nonfinancial support from Magventure during the conduct of the study; grants from the Canadian Institutes for Health Research, Brain Canada, the Michael Smith Foundation for Health Research, and the Vancouver Coastal Health Research Institute; and personal fees from Janssen, outside the submitted work. S. Rizvi reports grants from Pfizer Canada, outside the submitted work. S. Strother reports grants from Canadian Biomarker Integration Network in Depression during the conduct of the study and grants from Ontario Brain Institute, outside the submitted work. He is also the chief scientific officer of the neuroimaging data analysis company ADMdx, Inc (www. admdx.com), which specializes in brain image analysis to enable diagnosis, prognosis and drug effect detection for Alzheimer disease and various other forms of dementia. R. Lam reports grants from Canadian Institutes of Health Research during the conduct of the study; grants from Asia-Pacific Economic Cooperation, VGH-UBCH Foundation, BC LEading Edge Endowment Fund, Janssen, Lundbeck, Pfizer and St. Jude Medical, outside the submitted work; personal fees from Allergan, Akili, CME Institute, Canadian Network for Mood and Anxiety Treatments, Janssen, Lundbeck, Lundbeck Institute, Pfizer, Otsuka, Medscape and Hansoh, outside the submitted work; travel expenses from Asia-Pacific Economic Cooperation outside the submitted work; and stock options from Mind Mental Health Technologies., (© 2019 Joule Inc. or its licensors)

Repetitive transcranial magnetic stimulation (rTMS) is a first-line option for treatment-resistant depression (TRD), but prediction of treatment outcome remains a clinical challenge. The present study aimed to compare structural and functional covariance networks (SCNs and FCNs) between remitters and nonremitters. We determined the predictive capacities of SCNs and FCNs to discriminate the two groups. Fifty TRD patients underwent a course of rTMS to the left dorsolateral prefrontal cortex. They were categorized into remitters (n = 22) and nonremitters (n = 28) based on HDRS≤7 at the end of treatment. Baseline structural and functional magnetic imaging (sMRI and fMRI) of the patients and 42 healthy controls were collected. SCNs and FCNs were defined based on structural and functional covariance of gray mater volume (GMV) and fractional amplitude of low-frequency fluctuations (fALFF) from sMRI and fMRI, respectively. Structural/functional network integrity of these networks (default mode network [DMN], central executive network [CEN] and salience network [SN]) were compared between the three groups. In patients, associations between SCNs and FCNs with clinical improvements were studied using linear correlation analysis. Receiver-operating characteristic (ROC) analysis was conducted to confirm the utility of the SCNs and FCNs in classifying clinical sub-groups. Nonremitters exhibited lower structural integrity in CEN than remitters and controls. Higher structural integrity of CEN was related to clinical improvement (r = 0.423, p = .002), and structural integrity distinguished remitters and nonremitters with a fairly high accuracy (AUC = 0.71, p = .008). No group differences or correlation with clinical changes were found in FCNs. Results suggest the CEN may play a role mediating clinical improvement in rTMS for depression. Structural covariance networks may be features to consider in prediction of clinical improvement., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Importance: Hyperactivity in the subgenual cingulate cortex (SGC) is associated with major depressive disorder (MDD) and anticorrelated with activity in the dorsolateral prefrontal cortex (DLPFC). This association was found to be predictive of responsiveness to repetitive transcranial magnetic stimulation (rTMS) treatment. Such findings suggest that DLPFC-SGC connectivity is important for understanding both the therapeutic mechanism of rTMS in patients with MDD and the underlying pathophysiology of MDD., Objective: To evaluate SGC hyperactivity in patients with MDD before and after rTMS treatment., Design, Setting, and Participants: In this diagnostic study, among participants recruited from the adult and geriatric mood and anxiety services at the Centre for Addiction and Mental Health, Toronto, Ontario, Canada, who had participated in a randomized clinical trial, baseline SGC activity of patients with MDD was compared with healthy controls. In patients with MDD, SGC activity was compared before and after active or sham high-frequency rTMS treatment. Data collection started in July 2008 and concluded in March 2012. Neurophysiological data analysis started in January 2017 and ended in May 2018., Main Outcomes and Measures: Hyperactivity in the SGC before and after rTMS treatment was measured. Subgenual cingulate cortex hyperactivity activity was quantified using significant current density (SCD), and effective connectivity between the left DLPFC and SGC was computed using significant current scattering (SCS). Both measures were computed around TMS evoked potentials standard peak latencies prior to rTMS and after rTMS treatment, comparing patients with MMD treated with active and sham rTMS. Patients with MDD were assessed with the 17-item Hamilton Rating Scale for Depression., Results: Of 121 patients with MDD in the initial trial, 30 (15 [50.0%] women) were compared with 30 healthy controls (15 [50.0%] women) at rTMS treatment baseline. The mean (SD) age of the cohort with MDD was 39.1 (10.9) years, and the mean (SD) age of healthy controls was 37.0 (11.0) years. Following rTMS treatment, 26 patients with MDD who had active rTMS treatment (21.5%) were compared with 17 patients with MDD who had sham treatment (14.0%). At baseline, the SGC mean (SD) SCD and mean (SD) SCS at 200 milliseconds after TMS pulse were higher in participants with MDD compared with healthy controls (SCD: 1.04 × 10-6 [1.41 × 10-6] μA/mm2 vs 3.8 × 10-7 [7.8 × 10-7] μA/mm2; z = -2.95; P = .004; SCS: 0.87 [0.86] mm vs 0.54 [0.87] mm; z = -2.27; P = .02). Baseline source current density was able to classify MDD with 77% accuracy. Scores on the 17-item Hamilton Rating Scale for Depression were correlated with current density at the SGC (ρ = 0.41; P = .03). After rTMS treatment, SGC mean (SD) SCD and mean (SD) SCS at 200 milliseconds after rTMS pulse were attenuated to approximately the standard TMS-evoked potential latencies in the active rTMS group compared with the sham rTMS group (SCD: 1.57 × 10-7 [3.67 × 10-7] μA/mm2 vs 7.00 × 10-7 [7.51 × 10-7] μA/mm2; z = -2.91; P = .004; SCS: 0.20 [0.44] mm vs 0.74 [0.73] mm; z = -2.78; P = .006). Additionally, the SGC SCS change was correlated with symptom improvement on the 17-item Hamilton Rating Scale for Depression in the active rTMS group (ρ = 0.58; P = .047)., Conclusions and Relevance: The findings of this study further implicate left DLPFC-SGC effective connectivity and SGC excitability in the pathophysiology of MDD and treatment with rTMS. These findings suggest that DLPFC-SGC connectivity may be a marker of rTMS treatment responsiveness., Trial Registration: ClinicalTrials.gov identifier: NCT01515215.

Competing Interests: Competing interests: Canadian Blood Services reports receiving grants from Health Canada and all provincial and territorial governments, during the conduct of the study. James Downar reports receiving personal fees from Boehringer-Ingelheim (Canada), Novartis and the Ontario College of Family Physicians, outside the submitted work. Dr. Downar is also the previous co-chair of the Physicians’ Advisory Committee for Dying with Dignity Canada, an advocacy group for the legalization of medical assistance in dying in Canada. Sam Shemie reports receiving personal fees from Canadian Blood Services, during the conduct of the study. Vanessa Gruben reports receiving a grant from Canadian Blood Services, during the conduct of the study. Aviva Goldberg reports that as a nephrologist, she is primarily involved in the care of transplant recipients. No other competing interests were declared.