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Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression

Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression Key Points Question Is magnetic seizure therapy IMPORTANCE There is an unmet need for effective treatments for suicidality in mental disorders. associated with decreased suicidality in Magnetic seizure therapy (MST) has been investigated as an alternative to electroconvulsive therapy, patients with treatment-resistant a known effective treatment for suicidality, in the management of treatment-resistant major depression? depressive disorder, with promising findings. Yet, there are very limited data on the association of Findings This nonrandomized MST with suicidality directly. It is important to explore the potential of MST as a viable treatment controlled trial of 67 patients in alternative to electroconvulsive therapy for suicidality. consecutive cohorts treated with magnetic seizure therapy found an OBJECTIVE To determine the association of MST with suicidality in patients with treatment- overall remission rate from suicidality of resistant major depressive disorder. 47.8%. Remission rates were higher in the low- and moderate-frequency DESIGN, SETTING, AND PARTICIPANTS This nonrandomized controlled trial took place at a single treatment groups compared with the tertiary care psychiatric facility in Canada. It followed an open-label study design with consecutive high-frequency group. 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 Meaning These findings suggest that run from February 2012 through June 2019. Patients were followed up for 6 months at the end of the magnetic seizure therapy holds early treatment period. This post hoc secondary analysis of the trial was performed from January to promise as a treatment for suicidality in November 2019. patients with treatment-resistant depression. 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. Supplemental content MAIN OUTCOMES AND MEASURES Remission from suicidality was measured as an end point score Author affiliations and article information are listed at the end of this article. 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 (F = 5.73; P < .001). 8,293.95 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 JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 1/11 JAMA Network Open | Psychiatry Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression Introduction Suicidality, a term that encompasses the spectrum of suicidal thoughts and behaviors, is a major public health problem. Worldwide, at least 800 000 people die by suicide each year. Approximately 90% of these individuals who die by suicide have a primary psychiatric illness. For patients with unipolar and bipolar depression, the lifetime rate of suicide is 15% to 20%. As such, there is a considerable need for new, effective, and better-tolerated treatments for suicidality in patients with both subacute and emergent suicidality. Evidence-based pharmacological treatments for both subacute and emergent suicidality are limited. Clozapine has known antisuicidal effects but is indicated only for patients with treatment- resistant schizophrenia. Lithium has robust protective effects against suicide, but its use is typically 5 6 limited to patients with bipolar disorder. Ketamine is a promising antisuicidal treatment, but it appears to have transient effects and is still experimental. In addition, ketamine may have addiction 6,7 8 potential, possibly through intrinsic opioid agonism activity. Commonly used antidepressant medications are not consistently protective against suicide and may even increase suicidality in youths. Electroconvulsive therapy (ECT) is a very effective treatment for suicidality in mood 11-13 disorders, with various forms of evidence supporting this claim dating back more than 80 years. In the landmark Consortium for Research in ECT Study, ECT led to rapid remission of high expressed suicidality in 250 patients with major depressive disorder and bipolar depression, with a suicidality remission rate of 63.2%. Although ECT is highly effective at treating suicidality, it is an underused treatment: fewer than 1% of patients with treatment-resistant depression (TRD) receive ECT. This 15,16 is because of a combination of stigma and perceived risk of cognitive adverse effects. Effective and tolerable treatments for suicidality are needed. New lines of research are being created to explore alternative forms of brain stimulation for treating suicidality. Recent evidence 17-19 suggests a potential role for repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation as treatments for subacute suicidal ideation through targeting of the brain region the dorsolateral prefrontal cortex. Magnetic seizure therapy (MST) is another emerging brain stimulation therapy in which magnetic pulses, similar to rTMS, induce focal seizures, similar to ECT, in patients under general anesthesia. The hope for MST is to match the treatment efficacy of ECT with fewer adverse effects, because its effect is mediated by a different mechanism of action and 21,22 a more focal treatment target in the brain structures. There is evidence for this with regard to 22-24 MST as a treatment for major depressive disorder. However, it has not yet been established whether MST has the same antisuicidal effects as ECT. Thus, we explored the association of MST with suicidality in a secondary analysis of a recently published open-label study on MST for TRD. We hypothesized that MST would be associated with clinically meaningful rates of remission from suicidality as measured by the Beck Scale for Suicidal Ideation (SSI). We also explored whether the association of MST with suicidality differed among different MST stimulation frequencies in a sensitivity analysis. Methods Overall Design This study is a secondary analysis of data from an open-label, nonrandomized, controlled trial of MST as a treatment for TRD, which is described in detail in the original report (see the eAppendix in the Supplement for the full clinical trial protocol). This study follows the Transparent Reporting of Evaluations With Nonrandomized Designs (TREND) guideline for reporting of nonrandomized evaluations. Participants As described previously, all participants were aged 18 to 85 years, presented with TRD, and were initially referred for a course of ECT. The research protocol was approved by the Centre for Addiction JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 2/11 JAMA Network Open | Psychiatry Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression and Mental Health Research ethics board in accordance with the Declaration of Helsinki, and all patients provided written informed consent. The study was run from February 2012 through June 2019. All patients had a baseline score on the 24-item Hamilton Rating Scale for Depression (HRSD-24) of 21 or higher. Women of child-bearing potential had to be using an accepted form of contraception. Exclusion criteria were as follows: unstable physical or neurological illness or other significant neuropsychiatric comorbidity; currently pregnant or lactating; not stable enough to undergo general anesthesia; having a cardiac pacemaker, cochlear implant, implanted electronic device, or nonelectric metallic implant; use of any anticonvulsant or a benzodiazepine at a dosage equivalent to lorazepam 2 mg per day or higher; active substance misuse during the preceding 3 months; a diagnosis of delirium, dementia, or cognitive disorder secondary to general medical condition; and history of an eating disorder, borderline personality disorder, or antisocial personality disorder. Patients with a suicide attempt during the previous 6 months were also excluded from the study. In the original study, a total of 86 participants with a Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) major depressive episode with or without psychotic features completed an adequate MST trial. Nineteen of these 86 participants (22.1%) did not have baseline suicidality, as defined by a score greater than 0 at the initial study visit on the Beck SSI, a validated 19-item scale used to quantify suicidality with a range from 0 to 38. The main analyses in the present report focus on the 67 participants with baseline suicidality who were defined as adequate trial completers in that they completed at least 8 MST sessions. In addition, we analyzed outcomes in a subgroup of 36 participants defined as protocol completers: either they attained remission from depression or they completed the maximum number of MST sessions selected a priori, 24. Please refer to Figure 1 for the modified CONSORT diagram. MST Procedures Participants completed MST sessions 2 to 3 times per week until they achieved remission from their depressive episode or until they reached a maximum of 24 sessions. Participants received MST using the MagPro MST device with Twin Coil-XS (both from MagVenture) applied over the frontal cortex at 100% machine output with low (25 Hz), moderate (50 or 60 Hz), or high (100 Hz) frequency. These frequencies were chosen for participants in an open-label fashion in consecutive treatment cohorts (ie, there was no randomization for treatment groupings). Please refer to the original report for further details of treatment procedures. Outcome Measures Participants were assessed every 3 weeks and at the end of the study with the Beck SSI and HRSD-24. Participants were also followed for 6 months at the end of the treatment period. The primary outcome for this study was remission from suicidality as measured by an end point score of 0 on the Beck SSI. To cross-validate our results with the Beck SSI, we also report outcomes with the suicide item (item 3) of the HRSD-24, which has also been used in previous studies of suicidality. Statistical Analysis Statistical analysis was completed using SPSS statistical software version 24 (IBM Corp). All analyses were 2-tailed with the significance level set as P < .05 for all outcomes. Post hoc t tests were completed when significant results were found with analysis of variance or χ analyses. We calculated Pearson correlation coefficients for change in the HRSD-24 suicide item and change in the Beck SSI score. Linear mixed models were used with Beck SSI scores as dependent continuous measures. These analyses were conducted using the MIXED command in SPSS. The basic model included treatment frequency group, time, and the interaction between group and time. Model fit was compared with and without the following covariates, reflecting the degree of treatment resistance: mean cumulative Antidepressant Treatment History Form (ATHF) score (derived by adding the ATHF ratings of all antidepressant trials during the current episode), number of adequate JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 3/11 JAMA Network Open | Psychiatry Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression antidepressant trials in the current episode (ie, trials rated3 on the ATHF), and the total number of 28,29 psychotropic medication trials. As a subgroup type sensitivity analysis, we analyzed differences between groupings by treatment frequency. We compared baseline characteristics between these groups and calculated effect size (Cohen d) for the primary outcome for each treatment frequency grouping. Data analysis was performed from January to November 2019. Results Patient Flow, Demographic Characteristics, and Follow-up A total of 67 patients (mean [SD] age 46.3, [13.6] years; 40 women [60.0%]) received an mean (SD) of 19.5 (5.1) MST treatments. Table 1 presents the demographic and clinical characteristics of the 67 adequate trial completers divided into treatment frequency groups. Of the 67 participants who had baseline suicidality present and completed a minimally adequate MST trial, 36 (53.7%) completed the protocol. None of the participants attempted or completed suicide during the study or the 6-month follow-up period. One participant with no baseline suicidality experienced the emergence of suicidality during the course of MST, with a change in Beck SSI score from 0 to 4 of a maximum possible score of 38. The 3 treatment frequency groups did not differ in terms of baseline suicidality (Beck SSI scores) (F = 0.68; P = .52) or in other variables, except for their baseline cumulative 2,64 ATHF score (F = 3.53; P = .02): the scores of the high-frequency group were significantly lower 3,72 than the scores of both the low-frequency group (t =2.02; P < .001) and the moderate-frequency group (t = 2.06; P = .003). Figure 1. Patient Flow Diagram 140 Patients assessed for eligibility 32 Excluded 24 Did not meet inclusion or exclusion criteria 6 Declined to participate or withdrew before first treatment 2 Device malfunction 108 Enrolled 22 Excluded: Not adequate trial completers 86 Adequate trial completers 19 Excluded: No baseline suicidality 67 Baseline suicidality present 16 Received high-frequency 22 Received moderate-frequency 29 Received low-frequency 100-Hz MST 50- to 60-Hz MST 25-Hz MST a a a 10 Completed trial 12 Completed trial 15 Completed trial 6 Withdrew 9 Withdrew 9 Withdrew 0 Discontinued 1 Discontinued 5 Discontinued Reason for withdrawal Reason for withdrawal Reason for withdrawal or discontinuation or discontinuation or discontinuation Adapted from Daskalakis et al, 2020. MST indicates 1 Could not tolerate 2 Anxiety 9 No benefit perceived magnetic seizure therapy. 4 No benefit perceived 6 No benefit perceived 2 Device malfunction 1 Other 1 Noncompliance 2 Health concerns Patients completed trial as per primary 1 Health concerns 1 Other depression outcome. JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 4/11 JAMA Network Open | Psychiatry Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression Adequate Trial Completers The overall number of patients achieving remission from suicidality was 32 of 67 (47.8%) among the adequate trial completers. The mean (SD) Beck SSI score decreased from 10.9 (4.9) at baseline to 6.0 (6.6) at the end of the trial (paired t =2.0; P < .001). Analysis with the suicide item of the HRSD-24 validated these results with qualitatively similar outcomes (eTable in the Supplement). The change in Beck SSI scores and HRSD-24 suicide item scores were moderately correlated for the 67 patients (r = 0.47; P < .001). For the subgroup sensitivity analysis, participants treated with low-frequency and moderate- frequency MST had numerically higher rates of remission from suicidality (16 participants [55.2%] and 12 participants [54.5%], respectively) than those treated with high-frequency MST (4 participants [25.0%]) (Figure 2); however, the differences between these rates did not reach statistical significance (low vs high frequency, χ = 3.802; P = .05). The effect size for change in Beck SSI scores were large and statistically significant in the 2 groups treated with low-frequency (Cohen d = 1.43; 95% CI, 0.59 to 1.88) and moderate-frequency (Cohen d = 0.87; 95% CI, 0.28 to 1.35) MST. In the high-frequency MST treatment group, the effect size was not significant (Cohen d = 0.42; 95% CI, −0.35 to 1.04) (Table 2). The linear mixed model revealed a main association of time (F = 5.73; P < .001) with SSI 8,293.95 scores. In the sensitivity analysis, the group-by-time interaction was not statistically significant (Figure 3). The goodness-of-fit of the model improved when we included the following covariates: mean cumulative ATHF score, number of adequate antidepressant trials, and number of psychotropic medication trials. However, the group-by-time interaction remained nonsignificant. Table 1. Demographic and Clinical Variables by Treatment Frequency in Adequate Trial Completers Group Mean (SD) Treatment frequency Total Low Moderate High Variable (N = 67) (n = 29) (n = 22) (n = 16) Female, No. (%) 40 (60.0) 15 (52.0) 15 (68.0) 10 (63.0) Education, y 15 (3.10) 15.28 (2.75) 14.81 (3.08) 16 (3.79) Age, y 46.3 (13.6) 46.2 (13.1) 47.2 (14.0) 45.4 (14.8) Adequate trial completers are defined as participants Age at onset of major depressive disorder, y 23.7 (11.6) 23.8 (12.1) 25.6 (13.5) 20.8 (7.5) completing 8 or more magnetic seizure therapy Length of current major depressive episode, wk 175.3 (185.6) 178.7 (193.5) 203.4 (186.2) 130.6 (172.8) sessions. Recurrent major depressive episodes, No. (%) 52 (78.0) 23 (79.0) 15 (68.0) 14 (88.0) b Magnetic seizure therapy frequencies are defined as c c c Antidepressant treatment history form 13.1 (9.1) 15.3 (10.3) 14.5 (8.3) 7.1 (4.0) low (25 Hz), moderate (50 or 60 Hz), and high cumulative score (100 Hz). Magnetic seizure therapy sessions, No. 19.5 (5.1) 19.5 (5.2) 19.8 (4.8) 19.31 (5.4) Denotes statistically significant differences (P < .05). Figure 2. Rates of Remission From Suicidality Indexed by Beck Scale for Suicidal Ideation (SSI) Scores in the Adequate Trial Completers and Protocol Completer Groups Adequate trial completers Protocol completers There were 67 patients in adequate trial completer group (ie, participants who completed8 magnetic seizure therapy [MST] sessions) and 36 patients in the protocol completer group (ie, those who attained 10 remission from depression or completed 24 MST sessions, which is the maximum). MST frequencies are High Moderate Low defined as low (25 Hz), moderate (50 or 60 Hz), and MST treatment frequency high (100 Hz). Vertical lines and error bars indicate SEs. JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 5/11 Remitters from suicidality as indexed by the Beck SSI, % JAMA Network Open | Psychiatry Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression Protocol Completers The overall number of patients achieving remission from suicidality, as indexed by the Beck SSI score, was 21 of 36 protocol completers (58.3%). The overall mean (SD) Beck SSI score decreased from 10.6 (4.6) at baseline to 4.8 (6.4) at the end of the trial (paired t =2.03; P < .001) (Figure 3). An analysis similar to the aforementioned analysis with the suicide item of the HRSD-24 validated these results with qualitatively similar outcomes (data not shown). The odds of remission from suicidality were lower in the adequate trial completer group compared with the protocol completers group, although the difference was not significant (odds ratio, 0.65; 95% CI, 0.29-1.48). For the subgroup sensitivity analysis, the participants treated with low- and moderate-frequency MST had numerically higher rates of remission from suicidality (11 participants [73.3%] and 7 participants [58.3%], respectively) than those treated with high-frequency MST (3 participants [33.3%]) (Figure 2); however, the differences between these rates were not statistically significant (low vs high frequency, χ =3.70; P = .05). Discussion In this secondary analysis of an open-label trial of MST for TRD, we explored the association of MST with suicidality. Overall, MST treatment was associated with reductions in suicidality that were both statistically significant and clinically meaningful in both the adequate trial group and per protocol treatment subgroup. The findings with our primary outcome measure (the Beck SSI score) were confirmed by additional analyses with the HRSD-24 suicide item, even though these 2 measures were only moderately correlated in our study. Our sensitivity analysis revealed that all MST treatment frequencies were associated with a reduction of suicidality, and that low- and moderate-frequency MST were associated with the highest rates of remission clinically from suicidality in both the group of participants who completed an adequate MST trial (55.2% for low-frequency MST and 54.5% for moderate-frequency MST) and in the subgroup who completed the protocol (73.3% for Table 2. Suicidality Scores by Treatment Frequency for Adequate Trial Completers Treatment frequency Adequate trial completers are defined as participants Variable Low (n = 29) Moderate (n = 22) High (n = 16) completing 8 or more magnetic seizure therapy Beck Scale for Suicidal Ideation score, mean (SD) sessions. At baseline 10.3 (5.5) 11.0 (4.8) 12.1 (3.9) Magnetic seizure therapy frequencies are defined as low (25 Hz), moderate (50 or 60 Hz), and high At end point 4.7 (6.2) 5.0 (6.8) 9.0 (6.5) (100 Hz). Relative reduction, % 53.4 64.4 18.8 Remission from suicidality is defined as a final score Rate of remission from suicidality % 55.2 54.5 25.0 of 0. Figure 3. General Linear Mixed Model of Beck Scale for Suicidal Ideation (SSI) Total Scores by Treatment Frequency With Group-by-Time Interaction Treatment frequency All Low Moderate High Baseline Treatment 3 Treatment 6 Treatment 9 Treatment 12 Treatment 15 Treatment 18 Treatment 21 Treatment 24 Magnetic seizure therapy frequencies are defined as low (25 Hz), moderate (50 or 60 Hz), and high (100 Hz). JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 6/11 SSI estimated marginal means JAMA Network Open | Psychiatry Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression low-frequency MST and 58.3% for moderate-frequency MST). However, the differences between these rates of remission from suicidality were not significant, possibly because of the small sample sizes of the 3 groups. Our results are exploratory and represent a post hoc analysis, so comparison with established treatments is limited. Nonetheless, we attempt to give some sense of comparative efficacy to other brain stimulation treatments used for suicidality in TRD. In the largest study of ECT and suicidality in depression, Fink et al. measured suicidality with the HRSD-24 suicide item, pooling data from 2 ECT 13,30 trials ; they reported a rate of remission from suicidality of 63.2%. This is comparable to the rate of remission from suicidality of 47.8% that we observed in our primary analysis for MST. The differences in the methods in that ECT study and our MST study demand a direct comparison in a randomized study, which is currently under way (ClinicalTrials.gov Identifier: NCT03191058). Considering that early evidence suggests that MST can be delivered with far less stigma and fewer cognitive adverse effects than ECT, MST may be a preferred treatment for suicidality in many patients. The rate of remission from suicidality we observed with MST also suggests potential superiority of MST over rTMS. We previously described the association of bilateral rTMS with remission from suicidality as measured with the HRSD-24 suicide item at 40.4% with bilateral rTMS (compared with 47.8% in the current study). Again, differences in study methods here greatly limit this interpretation, and direct comparisons should be performed in future studies. Some of our own and others’ recent work sheds light on potential mechanisms of action of MST in treating suicidality, and why low and moderate frequencies could be the most effective treatment frequencies. Backhouse et al reported that seizure adequacy (a composite measure of several seizure characteristics) was better in patients with TRD receiving 25-Hz and 50-Hz MST than in those receiving 100-Hz MST. This may be, in part, due to 100-Hz treatment not entraining pyramidal cells optimally, because this frequency is too high given the duration of the refractory period of cortical neurons, thereby inhibiting optimal recurrence of neuron depolarization (ie, seizure activity). This hypothesis should be evaluated in future MST trials, because it is still uncertain how to optimize treatment parameters for each individual patient receiving MST. In 2 earlier, overlapping 33,34 studies, we found that transcranial magnetic stimulation–electroencephalographic measures, such as long-interval cortical inhibition and N100, could be used to estimate improvement in suicidality in patients with TRD treated with MST. In the earlier of the 2 analyses, improvement in suicidality appeared to be mediated by dorsolateral prefrontal cortex plasticity through changes of GABAergic activity. It is possible that GABA-mediated plasticity in the dorsolateral prefrontal cortex was associated with the antisuicidal association of MST in our participants. MST may also be associated with reductions in suicidality through its action on other prefrontal brain areas, potentially medially located regions such as the dorsomedial prefrontal or ventromedial prefrontal cortices, or possibly the frontopolar cortex. These regions are not targeted with traditional rTMS, which could account for potential differences between the associations of MST and rTMS with suicidality. Although these mechanisms are possible, other studies have emphasized the role of alternative neurobiological mechanisms involving the hypothalamic-pituitary-adrenal axis, serotonin system, or glutamate and opioid signaling in suicidality, which could be targeted by MST. Overall, changes in depressive symptoms were only moderately correlated with changes in suicidality in our adequate trial completers (data not shown). Also, in an unpublished analysis of the factors associated with depression remission from MST in the larger sample of 86 suicidal and nonsuicidal participants, higher baseline suicidality was associated with lower odds of depression remission (D.M.B., J.D., Z.J.D., unpublished data, 2019). Taken together, these results support the clinical wisdom that change in suicidality is not necessarily congruent with change in overall depression. This furthers the notion of suicidality being its own neuro-endophenotype and symptom 36-38 construct independent of, yet highly comorbid with, other psychiatric illness, which should be explored further in future clinical trials. JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 7/11 JAMA Network Open | Psychiatry Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression Limitations There are multiple limitations to this study. Although, to our knowledge, this is the largest trial to date to evaluate the association of MST with suicidality in TRD, it is open label, and participants were assigned sequentially to different treatment frequencies. As such, there is the potential for bias, with treaters and participants being aware of the experimental nature of the treatment and of the frequency of MST received. Also, a non-MST comparator group (eg, placebo or another active treatment) was not used. There is also the risk of false-positive results with the multiple statistical tests in this report. Patients with a suicide attempt during the preceding 6 months or those at risk for an imminent suicide attempt were excluded, thus limiting application of our findings to these types of patients. Similarly, given our exclusion criteria, our results may not be directly applicable to patients with borderline personality disorder, bipolar illness, substance use disorders, or other disorders with high rates of suicidality. In addition, although we did find clinically meaningful differences in response by treatment frequency, we highlight that these differences were not statistically significant, likely because of the small sample sizes. Conclusions MST appears to be a promising intervention to target suicidality. Its efficacy will need to be confirmed in future MST trials exploring its use, potentially at low-to-moderate frequencies to start, in patients experiencing suicidality. A direct comparison is also needed to determine the relative associations of MST and ECT with suicidality. Such a comparison is currently under way. ARTICLE INFORMATION Accepted for Publication: April 1, 2020. Published: August 18, 2020. doi:10.1001/jamanetworkopen.2020.7434 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Weissman CR et al. JAMA Network Open. Corresponding Author: Zafiris J. Daskalakis, MD, PhD, Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, 1001 Queen St W, Toronto, ON M6H1H4, Canada (jeff.daskalakis@camh.ca). Author Affiliations: Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada (Weissman, Blumberger, Dimitrova, Throop, Voineskos, Daskalakis); Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada (Downar); Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada (Downar); Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada (Mulsant, Rajji); Epworth Centre for Innovation in Mental Health, Epworth Healthcare and Monash University Department of Psychiatry, Camberwell, Victoria, Australia (Fitzgerald). Author Contributions: Drs Weissman and Daskalakis had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Weissman, Blumberger, Downar, Mulsant, Rajji, Fitzgerald, Daskalakis. Acquisition, analysis, or interpretation of data: Weissman, Blumberger, Dimitrova, Throop, Voineskos, Downar, Mulsant. Drafting of the manuscript: Weissman, Throop, Daskalakis. Critical revision of the manuscript for important intellectual content: Weissman, Blumberger, Dimitrova, Voineskos, Downar, Mulsant, Rajji, Fitzgerald. Statistical analysis: Weissman, Dimitrova, Daskalakis. Obtained funding: Rajji, Daskalakis. Administrative, technical, or material support: Weissman, Blumberger, Dimitrova, Throop, Voineskos, Daskalakis. Supervision: Voineskos, Mulsant, Fitzgerald, Daskalakis. JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 8/11 JAMA Network Open | Psychiatry Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression Conflict of Interest Disclosures: Dr Blumberger reported receiving grants from Brain Canada, Canadian Institutes of Health Research (CIHR), National Institutes of Health (NIH), and the Temerty Family Foundation through the Centre for Addiction and Mental Health (CAMH) Foundation and the Campbell Family Research Institute; in-kind equipment support from MagVenture; research support and in-kind equipment support from Brainsway; and medication supplies for an investigator-initiated trial from Indivior outside the submitted work. Dr Voineskos reported receiving research training fellowship funding from the Ontario Mental Health Foundation, an American Psychiatric Association/Eli Lilly research fellowship, a CAMH postdoctoral fellowship, and support from the Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario. Dr Downar reported being a medical advisor for TMS Neuro Solutions and NeuroStim Health; receiving grants from NIH, CIHR, Brain Canada, Ontario Brain Institute, Arrell Family Foundation, and Buchan Family Foundation; and receiving nonfinancial support from MagVenture outside the submitted work. Dr Mulsant reported receiving research support from Brain Canada, CIHR, the CAMH Foundation, the Patient-Centered Outcomes Research Institute, NIH, Capital Solution Design (software used in a study founded by CAMH Foundation), HAPPYneuron (software used in a study founded by Brain Canada), Eli Lilly (medications for a NIH-funded clinical trial), and Pfizer (medications for a NIH-funded clinical trial) outside the submitted work and reported owning stock in General Electric (<$5000). Dr Rajji reported receiving research support from Brain Canada, Brain and Behavior Research Foundation, BrightFocus Foundation, Canada Foundation for Innovation, Canada Research Chair, CIHR, Centre for Aging and Brain Health Innovation, NIH, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, and the Weston Brain Institute; in-kind equipment support for an investigator-initiated study from Magstim; and in-kind research accounts from Scientific Brain Training Pro. Dr Fitzgerald reported receiving a Practitioner Fellowship grant from National Health and Medical Research Council (1078567); receiving equipment for research from MagVenture, Medtronic, Neurosoft, and Brainsway; serving on scientific advisory boards for Bionomics and LivaNova; and acting as a founder for TMS Australia. Dr Daskalakis reported receiving research grants and in-kind equipment support for an investigator-initiated study through Brainsway and MagVenture and receiving support from the Ontario Mental Health Foundation, CIHR, the National Institutes of Mental Health, and the Temerty Family and Grant Family through the CAMH Foundation and the Campbell Institute. No other disclosures were reported. REFERENCES 1. World Health Organization. Preventing suicide: a global imperative. Published 2014. Accessed July 23, 2020. https://www.who.int/mental_health/suicide-prevention/world_report_2014/en/ 2. Beautrais AL, Joyce PR, Mulder RT, Fergusson DM, Deavoll BJ, Nightingale SK. 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Psychiatr Serv. 2018;69(5):542-548. doi:10.1176/appi.ps.201700364 15. Rose D, Fleischmann P, Wykes T, Leese M, Bindman J. Patients’ perspectives on electroconvulsive therapy: systematic review. BMJ. 2003;326(7403):1363. doi:10.1136/bmj.326.7403.1363 16. Lisanby SH, Maddox JH, Prudic J, Devanand DP, Sackeim HA. The effects of electroconvulsive therapy on memory of autobiographical and public events. Arch Gen Psychiatry. 2000;57(6):581-590. doi:10.1001/archpsyc. 57.6.581 17. Weissman CR, Blumberger DM, Brown PE, et al. Bilateral repetitive transcranial magnetic stimulation decreases suicidal ideation in depression. J Clin Psychiatry. 2018;79(3):17m11692. doi:10.4088/JCP.17m11692 18. Keshtkar M, Ghanizadeh A, Firoozabadi A. Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for the treatment of major depressive disorder, a randomized controlled clinical trial. JECT. 2011;27(4):310-314. doi:10.1097/YCT.0b013e318221b31c 19. George MS, Raman R, Benedek DM, et al. A two-site pilot randomized 3 day trial of high dose left prefrontal repetitive transcranial magnetic stimulation (rTMS) for suicidal inpatients. Brain Stimul. 2014;7(3):421-431. doi:10. 1016/j.brs.2014.03.006 20. Brunoni AR, Júnior RF, Kemp AH, Lotufo PA, Benseñor IM, Fregni F; Electrical Current Therapy for Treating Depression Clinical Study. Differential improvement in depressive symptoms for tDCS alone and combined with pharmacotherapy: an exploratory analysis from the Sertraline vs. Electrical Current Therapy for Treating Depression clinical study. Int J Neuropsychopharmacol. 2014;17(1):53-61. doi:10.1017/S1461145713001065 21. Kayser S, Bewernick BH, Grubert C, Hadrysiewicz BL, Axmacher N, Schlaepfer TE. Antidepressant effects, of magnetic seizure therapy and electroconvulsive therapy, in treatment-resistant depression. J Psychiatr Res. 2011; 45(5):569-576. doi:10.1016/j.jpsychires.2010.09.008 22. Daskalakis ZJ, Dimitrova J, McClintock SM, et al. Magnetic seizure therapy (MST) for major depressive disorder. Neuropsychopharmacology. 2020;45(2):276-282. doi:10.1038/s41386-019-0515-4 23. Kayser S, Bewernick BH, Matusch A, Hurlemann R, Soehle M, Schlaepfer TE. Magnetic seizure therapy in treatment-resistant depression: clinical, neuropsychological and metabolic effects. Psychol Med. 2015;45(5): 1073-1092. doi:10.1017/S0033291714002244 24. Fitzgerald PB, Hoy KE, Herring SE, Clinton AM, Downey G, Daskalakis ZJ. Pilot study of the clinical and cognitive effects of high-frequency magnetic seizure therapy in major depressive disorder. Depress Anxiety. 2013; 30(2):129-136. doi:10.1002/da.22005 25. Des Jarlais DC, Lyles C, Crepaz N; TREND Group. Improving the reporting quality of nonrandomized evaluations of behavioral and public health interventions: the TREND statement. Am J Public Health. 2004;94(3): 361-366. doi:10.2105/AJPH.94.3.361 26. Beck AT, Kovacs M, Weissman A. Assessment of suicidal intention: the Scale for Suicide Ideation. J Consult Clin Psychol. 1979;47(2):343-352. doi:10.1037/0022-006X.47.2.343 27. Desseilles M, Perroud N, Guillaume S, et al. Is it valid to measure suicidal ideation by depression rating scales? J Affect Disord. 2012;136(3):398-404. doi:10.1016/j.jad.2011.11.013 28. Thabane L, Mbuagbaw L, Zhang S, et al. A tutorial on sensitivity analyses in clinical trials: the what, why, when and how. BMC Med Res Methodol. 2013;13:92. doi:10.1186/1471-2288-13-92 29. Yusuf S, Wittes J, Probstfield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA. 1991;266(1):93-98. doi:10.1001/jama.1991.03470010097038 30. Kellner CH, Knapp R, Husain MM, et al. Bifrontal, bitemporal and right unilateral electrode placement in ECT: randomised trial. Br J Psychiatry. 2010;196(3):226-234. doi:10.1192/bjp.bp.109.066183 31. Backhouse FA, Noda Y, Knyahnytska Y, et al. Characteristics of ictal EEG in magnetic seizure therapy at various stimulation frequencies. Clin Neurophysiol. 2018;129(8):1770-1779. doi:10.1016/j.clinph.2018.03.025 32. Kallioniemi E, McClintock SM, Deng Z-D, Husain MM, Lisanby SH. Magnetic seizure therapy: towards personalized seizure therapy for major depression. Pers Med Psychiatry. 2019;17-18:37-42. doi:10.1016/j.pmip. 2019.04.003 33. Sun Y, Blumberger DM, Mulsant BH, et al. Magnetic seizure therapy reduces suicidal ideation and produces neuroplasticity in treatment-resistant depression. Transl Psychiatry. 2018;8(1):253. doi:10.1038/s41398-018- 0302-8 JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 10/11 JAMA Network Open | Psychiatry Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression 34. Sun Y, Farzan F, Mulsant BH, et al. Indicators for remission of suicidal ideation following magnetic seizure therapy in patients with treatment-resistant depression. JAMA Psychiatry. 2016;73(4):337-345. doi:10.1001/ jamapsychiatry.2015.3097 35. Downar J, Daskalakis ZJ. New targets for rTMS in depression: a review of convergent evidence. Brain Stimul. 2013;6(3):231-240. doi:10.1016/j.brs.2012.08.006 36. Oquendo MA, Sullivan GM, Sudol K, et al. Toward a biosignature for suicide. Am J Psychiatry. 2014;171(12): 1259-1277. doi:10.1176/appi.ajp.2014.14020194 37. Oquendo MA, Baca-Garcia E. Suicidal behavior disorder as a diagnostic entity in the DSM-5 classification system: advantages outweigh limitations. World Psychiatry. 2014;13(2):128-130. doi:10.1002/wps.20116 38. Kaschka WP, Rujescu D. Biological Aspects of Suicidal Behavior. Karger; 2016. SUPPLEMENT. eTable. Suicidality Scores by Treatment Frequency for Adequate Trial Completers eAppendix. MST Detailed Project Protocol eReferences JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 11/11 Supplementary Online Content Weissman CR, Blumberger DM, Dimitrova J, et al. Magnetic seizure therapy for suicidality in treatment-resistant depression. JAMA Netw Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 eTable. Suicidality Scores by Treatment Frequency for Adequate Trial Completers eAppendix. MST Detailed Project Protocol eReferences This supplementary material has been provided by the authors to give readers additional information about their work. © 2020 Weissman CR et al. JAMA Network Open. a eTable. Suicidality Scores by Treatment Frequency for Adequate Trial Completers Treatment Frequency Low frequency Moderate High n=29 n=22 n=16 HRSD suicide item at 1.6 (0.8) 1.4 (0.6) 2.6 (0.8) baseline HRSD suicide item at 0.9 (1.0) 1.0 (0.9) 1.5 (1.3) endpoint HRSD relative reduction 43.6 33.3 41.7 (%) Rate of remission from 40.0 36.8 28.6 suicidality (%) All results are presented as mean (SD) unless indicated otherwise. HRSD: Hamilton Rating Scale for Depression a Adequate trial completers: participants completing eight or more MST sessions b Remission from suicidality defined as a final score of 0 eAppendix. MST Detailed Project Protocol Background Treatment Resistant Depression and Electroconvulsive Therapy Depression is a common (~15-20% life prevalence) and important clinical problem with high morbidity and mortality. A significant subset of depressed patients continue to experience highly distressing and disabling symptoms despite standard treatments . This subset has been estimated to be in the range of between 10 and 20% of patients with the disorder . Electroconvulsive therapy (ECT) is the most effective treatment for major depressive disorder . However, many patients are reluctant to engage in a trial due to stigma and the risk of cognitive side effects The development of cognitive impairment, particularly memory impairment, is a particularly troubling side effect of ECT and often leads to treatment non acceptance. Anecdotally, many patients who have had successful ECT will not return for follow-up treatment upon the relapse of the depression because of such side effects. Modifications to the ECT treatment procedure that could substantially reduce or minimize these side-effects would, therefore, be of substantial benefit. Importantly, both the efficacy and side effects produced by ECT may be affected by a variety of treatment parameters such as electrode placement, electrical dose and also potentially the pattern of seizure initiation and spread . However, the degree to which these factors can be varied is limited in ECT, particularly with regard to the way in which the seizure is initiated . Treatment-Resistant Schizophrenia and Electroconvulsive Therapy Schizophrenia (SCZ) is a debilitating disorder that exacts enormous personal, social and economic costs. Despite recent advances in psychopharmacological treatments nearly 40% of patients achieve only a partial response and 10% experience no response at all . To date, only a few alternatives have been available: these generally include clozapine and ECT. Both, however, are associated with significant side effects. For example, clozapine has been associated with hyperlipidemia, blood dyscrasias, diabetes, seizures and 6,7 cardiomyopathy . Furthermore, some patients will not tolerate the rigorous monitoring associated with clozapine treatment. Similarly, ECT is associated with significant cognitive impairment and the stigma associated with ECT limits its broader use as a refractory treatment. Together, these limitations highlight the need for additional treatments aimed at ameliorating the sequelae of SCZ. To date, no studies have reported the use of magnetic seizure therapy (MST) in a population of patients with refractory SCZ. Treatment Resistant Obsessive Compulsive Disorder and Electroconvulsive Therapy © 2020 Weissman CR et al. JAMA Network Open. Obsessive compulsive disorder (OCD) is a prevalent and highly debilitating illness. Estimates suggest that close to 3% of the general population have this illness . Despite advances in psychotherapeutic and psychopharmacological treatments, approximately 50% of patients with OCD remain refractory to 9 10 treatment . ECT is indicated for refractory OCD, yet the data is mainly from case series . Other non- pharmacologic treatments include implantable deep brain stimulation and neurosurgical ablation which carry significant risk of morbidity and side effects. Due to the high rates of treatment resistance and the severe morbidity of the illness, treatment alternatives are required. MST holds the potential to be another potential treatment for treatment refractory OCD. To date, no studies of MST in OCD have been conducted Magnetic seizure therapy Like ECT, MST involves the intentional induction of a seizure for therapeutic purposes. However, the induction of a seizure occurs through the use of high frequency repetitive transcranial magnetic stimulation (rTMS) rather than through stimulation of the brain with a direct electrical current, such as that which occurs with ECT. In this context, MST should be differentiated from rTMS, which uses the same or similar equipment but is non convulsive. rTMS involves the application of magnetic pulses at a considerably lower intensity and frequency. It is likely that rTMS and MST have substantially differing mechanisms of action. As has been practised to date, MST is administered under general anesthesia in much the same way as ECT. MST, like rTMS, does not involve the direct application of electricity. Instead, electrical current is produced indirectly in the brain via electromagnetic induction. The rTMS stimulator induces a high field magnetic pulse, which passes into the brain, inducing an electrical current in brain cells. This capacity to indirectly stimulate the brain overcomes one of the major problems with ECT: its inability to provide focal or directed stimulation. Although a number approaches have tried to apply ECT in focused ways (e.g frontal, temporal), the substantial electrical impedance of the scalp and skull means that the bulk of the electrical stimulus is shunted away from the brain, resulting in stimulation of widespread cortical and subcortical regions . However, as there is no resistance to the passage of the magnetic field produced by an rTMS device into the brain, magnetic stimulation may be focused quite precisely. Therefore, it is possible that seizures may be produced with less spread to medial temporal lobe structures, reducing memory related side-effects . There is another substantial difference in regards to the mechanism of seizure induction between MST and ECT related to pulse width. Basic physiological studies have suggested that the best pulse width for stimulating cortical neurons may be briefer than that used in ECT. Briefer pulses excite neurons more efficiently at lower charge densities and have a larger safety margin because of their lower charge per phase . Recent ECT studies have investigated briefer pulse width stimulation to try and reduce cognitive side 13,14 effects . The pulse width of an rTMS stimulator (typically 0.2ms) is in the ultra brief range, which might be expected to enhance its efficacy of seizure induction, although the waveform itself differs between magnetic stimulation and ECT. Due to differences in pulse wave form, a lengthening of the MST pulse to 0.5 ms has been found to be more effective . Animal Studies The initial research with MST was conducted in nonhuman primates with the first MST- induced seizure reported in 1998 . Custom modified rTMS devices capable of stimulating at higher intensities and frequencies were developed for this purpose. Several important outcomes of this research have emerged. First, MST has been shown to not produce identifiable histological lesions in the brain in primates . Second, information with regard to optimal stimulation parameters for seizure induction has been gathered . Third, there appears to be fewer cognitive side effects with MST, as opposed to ECT, in this animal model . Human Studies © 2020 Weissman CR et al. JAMA Network Open. In parallel, a number of initial human studies have been undertaken. The first patient received MST 15 18 stimulation over 4 sessions and a second successfully received a full treatment course . Both patients were treated with stimulation at 40 Hz, tolerated the treatment well and responded clinically. In a subsequent study, 10 patients received two MST sessions within a course of ECT . The MST sessions were better tolerated and resulted in fewer acute side-effects compared to the ECT. Notably, in 3 of the 10 patients, the MST seizure threshold was at the maximum output of the device. 20 patients were 19,20 subsequently treated with a full course of MST using the same 50 Hz device . Mood improvement was again seen in the MST group with fewer side effects and dramatically more rapid reorientation post- stimulation than in ECT group. However, the magnitude of improvement did not seem as great as that of ECT. The authors have speculated that, as the stimulation dose was, on average, only 1.3 times the magnetic seizure threshold, substantially greater responses may have been achieved with higher stimulation intensity, especially given that ECT response rates are highly sensitive to dose relative to seizure threshold Since these initial studies, the technology used to produce MST has advanced considerably. Two companies have developed MST devices capable of stimulating continuously at 100Hz for sufficient durations to induce seizures. This type of stimulation has been shown in primate experiments to induce seizures and still demonstrates fewer cognitive side-effects than conventional ECT . This type of stimulation has now been tested in human subjects, with 11 patients being stimulated with 100 Hz MST in a single session during a regular course of ECT. Seizures were elicited in 10 of the 11 patients. All patients had a highly rapid recovery of orientation (on average 15 minutes shorter than recovery time after ECT) and reported less confusion . In addition to the published reports, we are aware of studies underway utilizing in MST in a number of centres around the world. Four centres (Columbia University, the University of Texas Southwestern Medical Centre (US), Cardiff University and the University of Oxford (UK)) are currently using an MST device produced by Magstim (Whitland, UK). Two centres in Germany (Bonn and Berlin), as well as the centre at Columbia University have commenced studies with the device relevant to this application, the Magventure A/S MST Magpro MST device. Summary Treatment resistant depression, schizophrenia and OCD remain substantial clinical problems for which there are limited alternatives. MST is a novel modification of ECT with the potential for similar effectiveness, fewer side-effects and a more rapid return of orientation / shorter duration of post-ictal confusion. Furthermore, MST is not associated with the same cognitive burden and media-related stigma as ECT, which may lead to broader acceptance if it is found to be effective. However, experience with this technique has been limited to date and considerable further research is required. In this application we propose to conduct an initial Canadian pilot study of MST using a stimulator capable of 100 Hz. Within this pilot study, patients will be treated in an open label manner to observe response rates, cognitive implications of MST treatment as well as several neurobiological variables that may enhance our understanding of treatment response. The results of the study should allow us to proceed to a double -blind randomized comparison of MST with ECT. Methods Objectives and hypotheses Objective 1: To evaluate the efficacy of MST in with severe depression, schizophrenia, and OCD. Hypothesis 1: MST will demonstrate substantial efficacy (i.e., substantial rates of response and remission) on objective measures of mood, schizophrenia, and OCD symptoms. Objective 2: To evaluate the effects of MST on autobiographical memory and other cognitive functions in patients with severe depression, schizophrenia, and OCD. Hypothesis 2: MST will have limited adverse effects on objective measures of autobiographical memory and other cognitive functions in patients with severe depression, schizophrenia, and OCD. Objective 3: To compare the changes in brain function that result from MST. © 2020 Weissman CR et al. JAMA Network Open. Hypothesis 3: MST will produce changes in functional brain activity consistent with antidepressant response, antipsychotic response, and antiobsessive response, along with a sparing of cognitive functions. Design The core study will involve an open label design with before-, during- and after- treatment assessments of depression severity, subjective side-effects and cognitive performance. We will assess baseline treatment resistance using the antidepressant treatment history form (ATHF) . Baseline medical comorbidity will be assessed using the Cumulative Illness Rating Scale(CIRS) . Cognition will be monitored at baseline, at every 6 treatments, and at the end of the treatment course. In addition, we will engage patients in pre- and post- treatment neuroimaging and cortical inhibition measures to study the biological effects of MST treatment. Subjects A total of 250 patients will be included in the study, including at least 20 schizophrenia and 20 OCD patients, 20 with major depressive episode with psychotic features in the context of Major Depressive Disorder or Bipolar Disorder, 150 major depressive episode without psychotic features in the context of Major Depressive Disorder, 40 major depressive episode without psychotic features in the context of Bipolar Disorder. With a 10 point difference in mean pre post 24-item HDRS scores and a standard deviation of 8, the smallest group (n=11) in this sample should still have a power approaching 1 (>0.99) (alpha =0.05, 2 tailed). Inclusion Criteria: Patients will be included if they: 1. have a DSM-IV diagnosis of a major depressive episode with or without psychotic features in the context of major depressive disorder or bipolar disorder, obsessive compulsive disorder, or schizophrenia/schizoaffective based on SCID-IV criteria 2. are within the age range from 18-85 3. have a 24-item HDRS score of > 21 (depression patients, moderate severe) 4. have an 18-item BPRS score of > 37 (schizophrenia/schizoaffective patients, moderate severe) 5. have a Y-BOCS score of > 16 (OCD patients, moderate severe) 6. demonstrates capacity to consent according to study and treating psychiatrist or MacCAT for subjects with schizophrenia/schizoaffective 7. are on a medically acceptable form of birth control, if a woman of child-bearing potential Exclusion Criteria: Patients are excluded if they: 1. have an unstable medical and/or neurological condition 2. are currently pregnant or lactating 3. are not considered sufficiently well to undergo general anesthesia for any reason 4. have a cardiac pacemaker, cochlear implant, implanted electronic device or non-electric ferrometallic implant in the head only 5. are taking a benzodiazepine at a dose greater than lorazepam 2mg or equivalent 6. are taking any non-benzodiazepine anticonvulsant 7. have active substance misuse or dependence within the past 3 months 8. have a current diagnosis of delirium, dementia or another cognitive disorder secondary to a general medical condition 9. have other significant Axis I co-morbidity 10. have a co-morbid borderline personality disorder and/or antisocial personality disorder as confirmed by the Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II) 11. have had a history of any suicide attempts in the past 6 months Clinical Measures Demographic variables and potential co-variates will be recorded at baseline following a clinical interview. These will include the duration of the current episode, years from first diagnosis, number of previous episodes, type and dose of current and previous treatment and family history of mood disorder. Diagnosis will be assessed with the SCID (DSM IV). Clinical rating measures will include the 24-item Hamilton © 2020 Weissman CR et al. JAMA Network Open. Depression Rating scale (HDRS) for consistency with most prior ECT studies, as well as the Quick Inventory of Depressive Symptomatology (QIDS) and Brief Psychiatric Rating Scale (BPRS) and YBOCS (Yale-Brown Obsessive-Compulsive Scale), as appropriate. For those patients with Major Depressive Disorder and Bipolar Disorder we will use the Young Mania Rating Scale (YMARS) to monitor for emergence of hypomania. Given the significant toll of these illnesses on quality of life, all patients will answer the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q)[50] prior to and at the end of the acute treatment phase. The Beck Scale for Suicide Ideation (BSS)[27] will be used to evaluate suicidal ideation, which is a common symptom in depression. A systematic evaluation of suicidal ideation is needed in any depression treatment study for safety reasons and because clinicians need to know the effects of treatment on suicidality to understand risks vs. benefits. At each clinical assessment if score on suicidal ideation. The Snaith-Hamilton Pleasure Scale (SHAPS) will be used to evaluate and monitor anhedonia in participants with depression and the effects of treatment on this core feature of depression [55]. The entire clinical battery will be repeated after every three treatments, at the end of acute treatment phase, and at 1, 2, 3, and 6 months after the acute treatment phase. The battery will again be repeated 6 months after the maintenance MST treatment phase, if applicable. The QIDS will be administered prior to every treatment visit for those subjects with depression in order to check for symptom improvement between clinical assessments. If the score falls within the euthymic range (0-5), the entire clinical battery will be administered to assess possible remission. For depression, remission will be defined as a 24-item HDRS 10, and a greater than 60% decrease in scores from baseline on two consecutive ratings with a change no greater than 3 points. Response -item HDRS score from baseline on two consecutive ratings. For schizophrenia, response will be defined as an 18-item BPRS < 25, for consistency of criterion with recent large studies of ECT in treatment-resistant schizophrenia . For OCD, remission will be defined as a Y-BOCS score 8, and a greater than 60% decrease in scores from baseline on two consecutive ratings with a change no greater than 3 points. Cognitive assessment All patients will be assessed with the entire cognitive battery prior to and at the end of the acute treatment phase, and at 6 months post-treatment. The MOCA will be administered at baseline and every 6 treatments during acute treatment. The MOCA will also be administered before the last treatment if the patient will not be receiving maintenance treatment, and will be done before their first maintenance treatment if continuing onto the maintenance phase. It will then be administered once a month during maintenance treatment. The cognitive battery will include assessments of anterograde and retrograde memory, specifically looking at learning, retention and retrieval in both the verbal and non verbal domains. This will include assessments such as the Autobiographical Memory Interview Short Form , MATRICS Consensus Cognitive Battery (MCCB), Stroop and Verbal Fluency using the COWAT . Finally we will look at general intellectual functioning with the WTAR (Wechsler Test of Adult Reading) prior to treatment start. Cognitive function during the treatment phase of the study will be assessed with the Montreal Cognitive Assessment (MoCA). This test has three different English versions which allow us to avoid practice effects. Additionally, time to reorientation will also be measured after each MST session using previously published standardized methods [30,31] that evaluate orientation to name, date of birth, age, place and day of the week. This will be accomplished by repeatedly asking orientation questions from the time of resumed respiration post-MST and noting the recovery time required to recall 4 of the 5 items listed above [32]. MST treatment procedure The range of frequency stimulation used to treat patients will be between 20 Hz and 100Hz, with a duration range between 2 and 20 seconds depending on the frequency used. Furthermore, we would also like to specify that the anatomical location of stimulation will be either the frontal or vertex region of the brain. These are the two sites at which stimulation is most commonly applied [32, 56, 57]. The MST determination of seizure threshold will be done at 100% stimulator output applied at the selected treatment frequency with progressively escalating train durations until an adequate seizure is produced. During an © 2020 Weissman CR et al. JAMA Network Open. ECT treatment an adequate seizure is described as generalized tonic-clonic activity > 20 seconds on the EMG recording or > 25 seconds of EEG seizure activity. However, little data is available on the characteristics of MST induced seizures therefore the adequacy of the seizure will be determined at each session by the treating MST psychiatrist. During titration a maximum of three stimulations will be given at the same session, provided the coil temperature allows for a third stimulation. If an adequate seizure is not produced by the third stimulation, titration will continue at the next treatment session until threshold is reached. Subsequent treatments will then be delivered according to the established conventions for delivering MST. Acute Treatment Phase Six treatment sessions, at a frequency of two or three times per week will be administered. Patients will not have treatments on consecutive days. As previously stated, remission will be assessed at every 3 treatments, and if the pre-defined remission rate is not met 3 additional treatments will be provided. This will be repeated a total of 5 times (i.e., maximum treatment number is 24). 24 treatments is typically longer that a conventional ECT treatment course. However, evidence does suggest that longer treatment courses may be needed with MST, particularly in more treatment resistant psychiatric conditions such as OCD and Schizophrenia [51-52]. Furthermore, response during the acute treatment course will also be monitored and the dose adjusted accordingly. In the study the dose was originally adjusted at every 6 sessions. However, response during the acute treatment course will also be monitored and the dose adjusted accordingly every three sessions rather than every 6 sessions. That is, if the patient fails to achieve an equal or greater than th 30% decrease from baseline following treatment 3, the dose will be increased on their 4 treatment. After treatment 6, if the patient fails to achieve further response, that is an equal or greater than 30% decrease th from the score after treatment 3, the dose will be increased on their 7 treatment. Treatment continues in this manner up to a maximum of 24 total treatments. If at any point the patient is already at maximum stimulation (20 seconds or 1000 pulses) the treatment continues with the dose unchanged. Patients will be withdrawn from the study and offered to switch to ECT if, despite MST treatment, they experience a significant clinical decline or an acute worsening of symptoms that creates concerns over their safety. Specific criteria for withdrawal from MST treatment would include 1) the emergence of suicidal intent or plan; 2) suicide attempt; 3) serious attempt to harm others; 4) emergence of catatonia; 5) emergence of severe inanition (e.g., failure to consume food or fluids). Any incidents of safety concerns requiring a switch to ECT will be monitored as one of the MST efficacy measures in the study. Non- responding subjects can be withdrawn from the study prematurely if the investigator deems this to be in the patient's best interest. Additionally, subjects will be discontinued from the study if more than 3 consecutive treatments are missed. Maintenance Treatment Phase Rates of depressive relapse after a successful course of ECT can be as high as 50% within the first 6 months [53]. Similarly, psychotic exacerbation can occur at high rates after patients with schizophrenia improve with ECT [51]. Evidence based strategies to prevent depressive relapse within the first 6 months after a successful course of ECT include the combination of an antidepressant and lithium or maintenance ECT [53, 54]. Maintenance ECT is often used after patients with schizophrenia improve with ECT [51]. There is very little data on rates of relapse after a successful course of ECT in patients with OCD; nevertheless, there is no reason to believe that it would not have a similarly beneficial effect at reducing relapse. To date, there have not been any reports on the use of maintenance MST. Therefore, all patients who attain the a-priori defined remission and/or response criteria in the acute treatment phase of MST will be offered participation in maintenance MST as means of preventing relapse. Subjects will also be provided with psycho-education and recommendations will be made to their attending physicians regarding alternative evidence based treatments to prevent relapse. Those subjects that elect to receive maintenance MST will receive treatment according to the standard maintenance schedule used for ECT: one treatment per week for 4 weeks, then one treatment every two weeks for 2 months, then one treatment every 3 weeks for 2 months and then one treatment 4 weeks later. Subjects will be assessed at regularly scheduled intervals throughout the maintenance phase and as needed, to determine if they are maintaining response or remission. If subjects have two consecutive scores above the a-priori defined remission or response score they will be offered two weeks of booster treatments (2 treatments per week). If they do not respond after two weeks they will exit from the study and alternative treatment will be discussed clinically. If the subject © 2020 Weissman CR et al. JAMA Network Open. does not wish to receive booster treatments they will exit from the study and alternative treatment will be discussed clinically. Safety Considerations MST is an involved treatment, with many congruencies to ECT in regards to the short-term side effects experienced following treatment session(s). As mentioned, MST has been shown to result in less cognitive burden than treatment with ECT. However, there are other potential side effects that we anticipate over the course of the trial. This section discusses anticipated adverse events based on a careful review of existing research literature regarding ECT and MST treatment. This review has been further supplemented by subject reports received to date. The following adverse events are anticipated in a sub-sample of the participant population: reversible cardiac ectopy, transient hypertension, uncomplicated asystole, fatigue, headache, aching/stiffness in muscles, nausea and vomiting, acute post-treatment delirium, post-ictal agitation, disorientation, memory impairment (e.g., anterograde and retrograde memory loss), prolonged seizures (i.e., seizures > 120 seconds in duration), treatment emergent mania, treatment emergent anxiety and fear, laryngospasm, peripheral nerve palsies, and aspiration. Several steps are taken to mitigate the risk of side effects. Prior to treatment all MST patients at CAMH receive an in-depth consultation from an ECT psychiatrist. The purpose of the consultation is to assess illness type and severity, previous treatments and outcomes, relative contraindications, discuss risks and benefits, and capacity to consent to ECT/MST. In addition to the psychiatric consult, all potential subjects receive a pre-MST consultation from the anesthesia service to assess suitability for general anesthesia, medical comorbidities that may impact anesthesia, discuss the risks of general anesthesia, and finally, conduct the informed consent for general anesthesia. During all treatment sessions, vital signs (heart rate, BP, O2 saturation, ECG, EEG) are monitored continuously. Patients undergo preoxygenation, anesthesia and muscle relaxation with accepted medications used in ECT practice, bite guard placement, and immmoblization prior to seizure induction. After EEG-confirmed seizure termination and recovery from anesthesia, patients are transferred to a recovery room once vital signs are stable and breathing. In the event a subject experiences a side effect, several steps are taken to minimize discomfort. Additional medications for symptomatic relief of side effects will be used based on accepted medications used in ECT practice For example, participants reporting moderate to severe headaches during previous treatments may receive an anti-inflammatory medication prior to their next treatment as a means of preventing headaches. Similarly, a participant that experienced nausea or vomiting will be given an intravenous anti-nausea medication to ease symptoms at the next treatment. Participants are also encouraged to take Tylenol for any muscle soreness. Risks of wakening paralysis and post-ictal agitation are mitigated by giving midazolam post-treatment. This is done on a case-by- first treatment. Analysis of Clinical Outcomes Depression scores and cognitive performance will be compared pre- and post-treatment using paired t-tests, with significance thresholds Bonferroni-corrected for multiple comparisons. Biomarkers of Treatment Response Participation in this component of the protocol is voluntary does not preclude participation in the treatment component of the trial. Changes in Cortical Inhibition Dysfunctional cortical inhibition (CI) has been postulated as a mechanism through which the symptoms of MDD, SCZ and OCD are mediated [33-36]. Cortical inhibition refers to the neurophysiological process in -aminobutyric acid (GABA) inhibitory interneurons selectively attenuate the activity of pyramidal neurons in the cortex. TMS capitalizes on the ability of time-varying magnetic fields to induce eddy currents in biological tissue via the principle of electromagnetic induction. TMS can provide an index of © 2020 Weissman CR et al. JAMA Network Open. GABA receptor-mediated inhibition in the cortex because it differentially stimulates inhibitory interneurons and pyramidal neurons. There are several TMS paradigms which provide a measure of GABA receptor- mediated inhibitory neurotransmission long interval cortical inhibition (LICI) [37-41], the cortical silent period (CSP) and short-interval cortical inhibition (SICI). Single or paired-pulse transcranial magnetic stimulation (TMS) represents a unique experimental modality that has been used to directly index CI. With single and paired-pulse TMS we have recently demonstrated that MDD is associated with deficits in CI that are more pronounced in patients with SCZ, OCD and MDD. It has also been shown that treatment with electroconvulsive therapy (ECT) is associated with enhanced CI [35,42-44]. Collectively, these studies suggest that potentiation of CI may represent a unique neurophysiological mechanism through which brain stimulation treatments (i.e., ECT and MST) exert their therapeutic effects in the above mentioned psychiatric disorders. TMS shall be used to examine GABAB receptor mediated inhibitory neurotransmission, through LICI, in both the DLPFC and motor cortex. Further, we will also evaluate the CSP in the motor cortex as a second index of GABAB receptor mediated inhibitory neurotransmission in the motor cortex. Evaluation of the DLPFC and motor cortex will be conducted in counterbalanced order and each region will be assessed immediately after completion of the other. To evaluate LICI from the DLPFC, EEG recordings will be acquired through a 64-channel Synamps 2 EEG system. Electrodes of interest will include those which optimally represent the overlap of Brodmann areas (BA) 9 and 46 of the DLPFC that has been shown to be most closely associated with electrode AF3. All neurophysiological data will be coded and analysed by an experienced rater. Measures of cortical inhibition will be administered twice, prior to and at the end of the acute treatment phase within 48hrs of the first and last MST treatment. Measurement of Working Memory As one of the main objectives of this study is to evaluate the effects of MST on autobiographical memory and other cognitive functions, we will also administer a working memory task prior to and at the end of the acute treatment phase. Working memory will be examined with the verbal N-back task (1- and 3-Back task) while EEG is recorded at the same session as TMS-EEG analysis at baseline and following an acute course of MST treatment. This test will allow us to further explore the cognitive affect of MST as well as examine the relationship between working memory and cortical inhibition. Neuroimaging In addition to measures of cortical inhibition, all patients will also undergo three sessions of neuroimaging: one prior to treatment, one within 48 hours of the end of treatment, and one at 6 months after treatment. Each session will include 3 types of neuroimaging studies in order to assess changes in brain structure and brain function, as follows: 1. A T1-weighted MRI sequence to provide high-resolution anatomical images of the cerebral gray and white matter. These images will be used for anatomical co-registration of the functional neuroimaging data, and for voxel-based morphometry (VBM) to assess regional changes in cortical and hippocampal gray matter thickness before and after treatment. Pre- and post-treatment scans will be compared using standard SPM8 and FSL software for identifying statistically significant regional changes in whole-brain VBM data. 2. A diffusion tensor imaging (DTI) MRI sequence to provide detailed information on the structural integrity of white matter tracts in the prefrontal lobes, hippocampus, and other cortical region s before and after treatment. Pre- and post-treatment scans will be compared using standard FSL software for reconstruction and statistical comparison of white matter tract structure, trajectory, and integrity. 3. A T2*-weighted, functional MRI (fMRI) sequence to assess blood oxygenation level dependent (BOLD) signal changes marking increases and decreases in regional functional connectivity to the amygdala and ventral striatum during the resting state, before and after treatment. Pre- and post treatment scans will be analysed using standard SPM8 and FSL software for identifying statistically significant regional changes in whole-brain BOLD signal data. © 2020 Weissman CR et al. JAMA Network Open. The first aim of the neuroimaging measures is to determine whether MST results in changes in brain structure and activity that are consistent with antidepressant response to other treatments, including ECT, DBS, and antidepressant medications. Based on previous studies, we propose that this will include increases in resting brain metabolism on PET in dorsal prefrontal and dorsal anterior cingulate cortex and 29-31 decreases in orbitofrontal prefrontal cortex and ventral striatum . The second aim of the neuroimaging measures is to determine whether MST also has milder effects on the brain structures most closely linked to episodic memory and other related cognitive functions. We also propose that there will be a more pronounced recovery of functional activity in the hippocampal and retrosplenial regions on PET and fMRI 31 32 measures , as well as volumetric expansion in the hippocampus on VBM , and improved hippocampal- prefrontal and hippocampal-retrosplenial white matter tract integrity on DTI measures . © 2020 Weissman CR et al. JAMA Network Open. eReferences 1. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53(8):649-659. 2. Ebmeier KP, Donaghey C, Steele JD. Recent developments and current controversies in depression. Lancet. 2006;367(9505):153-167. 3. Lisanby SH. Electroconvulsive therapy for depression. N Engl J Med. 2007;357(19):1939-1945. 4. Lisanby SH. 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Anesthetic considerations for magnetic seizure therapy: a novel therapy for severe depression. Anesth Analg. 2006;103(1):76-80, table of contents. 21. Sackeim HA, Prudic J, Devanand DP, et al. A prospective, randomized, double- blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Arch Gen Psychiatry. 2000;57(5):425-434. 22. Peterchev AV, Jalinous R, Lisanby SH. A transcranial magnetic stimulator inducing near-rectangular pulses with controllable pulse width (cTMS). IEEE Trans Biomed Eng. 2008;55(1):257-266. 23. Kirov G, Ebmeier KP, Scott AI, et al. Quick recovery of orientation after magnetic seizure therapy for major depressive disorder. Br J Psychiatry. 2008;193(2):152-155. 24. Oquendo MA, Malone KM, Ellis SP, Sackeim HA, Mann JJ. Inadequacy of antidepressant treatment for patients with major depression who are at risk for suicidal behavior. Am J Psychiatry. 1999;156(2):190-194. 25. Miller MD, Paradis CF, Houck PR, et al. Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale. Psychiatry Res. 1992;41(3):237-248. 26. Beck AT, Kovacs M, Weissman A. Assessment of suicidal intention: the Scale for Suicide Ideation. J Consult Clin Psychol. 1979;47(2):343-352. 27. Chanpattana W, Sackeim HA. Electroconvulsive Therapy in Treatment-Resistant Schizophrenia: Prediction of Response and the Nature of Symptomatic Improvement. J ECT. 2010. 28. King MJ, Macdougall AG, Ferris SM, Levine B, Macqueen GM, McKinnon MC. A review of factors that moderate autobiographical memory performance in patients with major depressive disorder. J Clin Exp Neuropsychol. 2010:1-23. 29. Kennedy SH, Konarski JZ, Segal ZV, et al. Differences in brain glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. Am J Psychiatry. 2007;164(5):778-788. 30. Lozano AM, Mayberg HS, Giacobbe P, Hamani C, Craddock RC, Kennedy SH. 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Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression

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Copyright 2020 Weissman CR et al. JAMA Network Open.
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10.1001/jamanetworkopen.2020.7434
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Abstract

Key Points Question Is magnetic seizure therapy IMPORTANCE There is an unmet need for effective treatments for suicidality in mental disorders. associated with decreased suicidality in Magnetic seizure therapy (MST) has been investigated as an alternative to electroconvulsive therapy, patients with treatment-resistant a known effective treatment for suicidality, in the management of treatment-resistant major depression? depressive disorder, with promising findings. Yet, there are very limited data on the association of Findings This nonrandomized MST with suicidality directly. It is important to explore the potential of MST as a viable treatment controlled trial of 67 patients in alternative to electroconvulsive therapy for suicidality. consecutive cohorts treated with magnetic seizure therapy found an OBJECTIVE To determine the association of MST with suicidality in patients with treatment- overall remission rate from suicidality of resistant major depressive disorder. 47.8%. Remission rates were higher in the low- and moderate-frequency DESIGN, SETTING, AND PARTICIPANTS This nonrandomized controlled trial took place at a single treatment groups compared with the tertiary care psychiatric facility in Canada. It followed an open-label study design with consecutive high-frequency group. 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 Meaning These findings suggest that run from February 2012 through June 2019. Patients were followed up for 6 months at the end of the magnetic seizure therapy holds early treatment period. This post hoc secondary analysis of the trial was performed from January to promise as a treatment for suicidality in November 2019. patients with treatment-resistant depression. 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. Supplemental content MAIN OUTCOMES AND MEASURES Remission from suicidality was measured as an end point score Author affiliations and article information are listed at the end of this article. 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 (F = 5.73; P < .001). 8,293.95 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 JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 1/11 JAMA Network Open | Psychiatry Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression Introduction Suicidality, a term that encompasses the spectrum of suicidal thoughts and behaviors, is a major public health problem. Worldwide, at least 800 000 people die by suicide each year. Approximately 90% of these individuals who die by suicide have a primary psychiatric illness. For patients with unipolar and bipolar depression, the lifetime rate of suicide is 15% to 20%. As such, there is a considerable need for new, effective, and better-tolerated treatments for suicidality in patients with both subacute and emergent suicidality. Evidence-based pharmacological treatments for both subacute and emergent suicidality are limited. Clozapine has known antisuicidal effects but is indicated only for patients with treatment- resistant schizophrenia. Lithium has robust protective effects against suicide, but its use is typically 5 6 limited to patients with bipolar disorder. Ketamine is a promising antisuicidal treatment, but it appears to have transient effects and is still experimental. In addition, ketamine may have addiction 6,7 8 potential, possibly through intrinsic opioid agonism activity. Commonly used antidepressant medications are not consistently protective against suicide and may even increase suicidality in youths. Electroconvulsive therapy (ECT) is a very effective treatment for suicidality in mood 11-13 disorders, with various forms of evidence supporting this claim dating back more than 80 years. In the landmark Consortium for Research in ECT Study, ECT led to rapid remission of high expressed suicidality in 250 patients with major depressive disorder and bipolar depression, with a suicidality remission rate of 63.2%. Although ECT is highly effective at treating suicidality, it is an underused treatment: fewer than 1% of patients with treatment-resistant depression (TRD) receive ECT. This 15,16 is because of a combination of stigma and perceived risk of cognitive adverse effects. Effective and tolerable treatments for suicidality are needed. New lines of research are being created to explore alternative forms of brain stimulation for treating suicidality. Recent evidence 17-19 suggests a potential role for repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation as treatments for subacute suicidal ideation through targeting of the brain region the dorsolateral prefrontal cortex. Magnetic seizure therapy (MST) is another emerging brain stimulation therapy in which magnetic pulses, similar to rTMS, induce focal seizures, similar to ECT, in patients under general anesthesia. The hope for MST is to match the treatment efficacy of ECT with fewer adverse effects, because its effect is mediated by a different mechanism of action and 21,22 a more focal treatment target in the brain structures. There is evidence for this with regard to 22-24 MST as a treatment for major depressive disorder. However, it has not yet been established whether MST has the same antisuicidal effects as ECT. Thus, we explored the association of MST with suicidality in a secondary analysis of a recently published open-label study on MST for TRD. We hypothesized that MST would be associated with clinically meaningful rates of remission from suicidality as measured by the Beck Scale for Suicidal Ideation (SSI). We also explored whether the association of MST with suicidality differed among different MST stimulation frequencies in a sensitivity analysis. Methods Overall Design This study is a secondary analysis of data from an open-label, nonrandomized, controlled trial of MST as a treatment for TRD, which is described in detail in the original report (see the eAppendix in the Supplement for the full clinical trial protocol). This study follows the Transparent Reporting of Evaluations With Nonrandomized Designs (TREND) guideline for reporting of nonrandomized evaluations. Participants As described previously, all participants were aged 18 to 85 years, presented with TRD, and were initially referred for a course of ECT. The research protocol was approved by the Centre for Addiction JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 2/11 JAMA Network Open | Psychiatry Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression and Mental Health Research ethics board in accordance with the Declaration of Helsinki, and all patients provided written informed consent. The study was run from February 2012 through June 2019. All patients had a baseline score on the 24-item Hamilton Rating Scale for Depression (HRSD-24) of 21 or higher. Women of child-bearing potential had to be using an accepted form of contraception. Exclusion criteria were as follows: unstable physical or neurological illness or other significant neuropsychiatric comorbidity; currently pregnant or lactating; not stable enough to undergo general anesthesia; having a cardiac pacemaker, cochlear implant, implanted electronic device, or nonelectric metallic implant; use of any anticonvulsant or a benzodiazepine at a dosage equivalent to lorazepam 2 mg per day or higher; active substance misuse during the preceding 3 months; a diagnosis of delirium, dementia, or cognitive disorder secondary to general medical condition; and history of an eating disorder, borderline personality disorder, or antisocial personality disorder. Patients with a suicide attempt during the previous 6 months were also excluded from the study. In the original study, a total of 86 participants with a Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) major depressive episode with or without psychotic features completed an adequate MST trial. Nineteen of these 86 participants (22.1%) did not have baseline suicidality, as defined by a score greater than 0 at the initial study visit on the Beck SSI, a validated 19-item scale used to quantify suicidality with a range from 0 to 38. The main analyses in the present report focus on the 67 participants with baseline suicidality who were defined as adequate trial completers in that they completed at least 8 MST sessions. In addition, we analyzed outcomes in a subgroup of 36 participants defined as protocol completers: either they attained remission from depression or they completed the maximum number of MST sessions selected a priori, 24. Please refer to Figure 1 for the modified CONSORT diagram. MST Procedures Participants completed MST sessions 2 to 3 times per week until they achieved remission from their depressive episode or until they reached a maximum of 24 sessions. Participants received MST using the MagPro MST device with Twin Coil-XS (both from MagVenture) applied over the frontal cortex at 100% machine output with low (25 Hz), moderate (50 or 60 Hz), or high (100 Hz) frequency. These frequencies were chosen for participants in an open-label fashion in consecutive treatment cohorts (ie, there was no randomization for treatment groupings). Please refer to the original report for further details of treatment procedures. Outcome Measures Participants were assessed every 3 weeks and at the end of the study with the Beck SSI and HRSD-24. Participants were also followed for 6 months at the end of the treatment period. The primary outcome for this study was remission from suicidality as measured by an end point score of 0 on the Beck SSI. To cross-validate our results with the Beck SSI, we also report outcomes with the suicide item (item 3) of the HRSD-24, which has also been used in previous studies of suicidality. Statistical Analysis Statistical analysis was completed using SPSS statistical software version 24 (IBM Corp). All analyses were 2-tailed with the significance level set as P < .05 for all outcomes. Post hoc t tests were completed when significant results were found with analysis of variance or χ analyses. We calculated Pearson correlation coefficients for change in the HRSD-24 suicide item and change in the Beck SSI score. Linear mixed models were used with Beck SSI scores as dependent continuous measures. These analyses were conducted using the MIXED command in SPSS. The basic model included treatment frequency group, time, and the interaction between group and time. Model fit was compared with and without the following covariates, reflecting the degree of treatment resistance: mean cumulative Antidepressant Treatment History Form (ATHF) score (derived by adding the ATHF ratings of all antidepressant trials during the current episode), number of adequate JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 3/11 JAMA Network Open | Psychiatry Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression antidepressant trials in the current episode (ie, trials rated3 on the ATHF), and the total number of 28,29 psychotropic medication trials. As a subgroup type sensitivity analysis, we analyzed differences between groupings by treatment frequency. We compared baseline characteristics between these groups and calculated effect size (Cohen d) for the primary outcome for each treatment frequency grouping. Data analysis was performed from January to November 2019. Results Patient Flow, Demographic Characteristics, and Follow-up A total of 67 patients (mean [SD] age 46.3, [13.6] years; 40 women [60.0%]) received an mean (SD) of 19.5 (5.1) MST treatments. Table 1 presents the demographic and clinical characteristics of the 67 adequate trial completers divided into treatment frequency groups. Of the 67 participants who had baseline suicidality present and completed a minimally adequate MST trial, 36 (53.7%) completed the protocol. None of the participants attempted or completed suicide during the study or the 6-month follow-up period. One participant with no baseline suicidality experienced the emergence of suicidality during the course of MST, with a change in Beck SSI score from 0 to 4 of a maximum possible score of 38. The 3 treatment frequency groups did not differ in terms of baseline suicidality (Beck SSI scores) (F = 0.68; P = .52) or in other variables, except for their baseline cumulative 2,64 ATHF score (F = 3.53; P = .02): the scores of the high-frequency group were significantly lower 3,72 than the scores of both the low-frequency group (t =2.02; P < .001) and the moderate-frequency group (t = 2.06; P = .003). Figure 1. Patient Flow Diagram 140 Patients assessed for eligibility 32 Excluded 24 Did not meet inclusion or exclusion criteria 6 Declined to participate or withdrew before first treatment 2 Device malfunction 108 Enrolled 22 Excluded: Not adequate trial completers 86 Adequate trial completers 19 Excluded: No baseline suicidality 67 Baseline suicidality present 16 Received high-frequency 22 Received moderate-frequency 29 Received low-frequency 100-Hz MST 50- to 60-Hz MST 25-Hz MST a a a 10 Completed trial 12 Completed trial 15 Completed trial 6 Withdrew 9 Withdrew 9 Withdrew 0 Discontinued 1 Discontinued 5 Discontinued Reason for withdrawal Reason for withdrawal Reason for withdrawal or discontinuation or discontinuation or discontinuation Adapted from Daskalakis et al, 2020. MST indicates 1 Could not tolerate 2 Anxiety 9 No benefit perceived magnetic seizure therapy. 4 No benefit perceived 6 No benefit perceived 2 Device malfunction 1 Other 1 Noncompliance 2 Health concerns Patients completed trial as per primary 1 Health concerns 1 Other depression outcome. JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 4/11 JAMA Network Open | Psychiatry Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression Adequate Trial Completers The overall number of patients achieving remission from suicidality was 32 of 67 (47.8%) among the adequate trial completers. The mean (SD) Beck SSI score decreased from 10.9 (4.9) at baseline to 6.0 (6.6) at the end of the trial (paired t =2.0; P < .001). Analysis with the suicide item of the HRSD-24 validated these results with qualitatively similar outcomes (eTable in the Supplement). The change in Beck SSI scores and HRSD-24 suicide item scores were moderately correlated for the 67 patients (r = 0.47; P < .001). For the subgroup sensitivity analysis, participants treated with low-frequency and moderate- frequency MST had numerically higher rates of remission from suicidality (16 participants [55.2%] and 12 participants [54.5%], respectively) than those treated with high-frequency MST (4 participants [25.0%]) (Figure 2); however, the differences between these rates did not reach statistical significance (low vs high frequency, χ = 3.802; P = .05). The effect size for change in Beck SSI scores were large and statistically significant in the 2 groups treated with low-frequency (Cohen d = 1.43; 95% CI, 0.59 to 1.88) and moderate-frequency (Cohen d = 0.87; 95% CI, 0.28 to 1.35) MST. In the high-frequency MST treatment group, the effect size was not significant (Cohen d = 0.42; 95% CI, −0.35 to 1.04) (Table 2). The linear mixed model revealed a main association of time (F = 5.73; P < .001) with SSI 8,293.95 scores. In the sensitivity analysis, the group-by-time interaction was not statistically significant (Figure 3). The goodness-of-fit of the model improved when we included the following covariates: mean cumulative ATHF score, number of adequate antidepressant trials, and number of psychotropic medication trials. However, the group-by-time interaction remained nonsignificant. Table 1. Demographic and Clinical Variables by Treatment Frequency in Adequate Trial Completers Group Mean (SD) Treatment frequency Total Low Moderate High Variable (N = 67) (n = 29) (n = 22) (n = 16) Female, No. (%) 40 (60.0) 15 (52.0) 15 (68.0) 10 (63.0) Education, y 15 (3.10) 15.28 (2.75) 14.81 (3.08) 16 (3.79) Age, y 46.3 (13.6) 46.2 (13.1) 47.2 (14.0) 45.4 (14.8) Adequate trial completers are defined as participants Age at onset of major depressive disorder, y 23.7 (11.6) 23.8 (12.1) 25.6 (13.5) 20.8 (7.5) completing 8 or more magnetic seizure therapy Length of current major depressive episode, wk 175.3 (185.6) 178.7 (193.5) 203.4 (186.2) 130.6 (172.8) sessions. Recurrent major depressive episodes, No. (%) 52 (78.0) 23 (79.0) 15 (68.0) 14 (88.0) b Magnetic seizure therapy frequencies are defined as c c c Antidepressant treatment history form 13.1 (9.1) 15.3 (10.3) 14.5 (8.3) 7.1 (4.0) low (25 Hz), moderate (50 or 60 Hz), and high cumulative score (100 Hz). Magnetic seizure therapy sessions, No. 19.5 (5.1) 19.5 (5.2) 19.8 (4.8) 19.31 (5.4) Denotes statistically significant differences (P < .05). Figure 2. Rates of Remission From Suicidality Indexed by Beck Scale for Suicidal Ideation (SSI) Scores in the Adequate Trial Completers and Protocol Completer Groups Adequate trial completers Protocol completers There were 67 patients in adequate trial completer group (ie, participants who completed8 magnetic seizure therapy [MST] sessions) and 36 patients in the protocol completer group (ie, those who attained 10 remission from depression or completed 24 MST sessions, which is the maximum). MST frequencies are High Moderate Low defined as low (25 Hz), moderate (50 or 60 Hz), and MST treatment frequency high (100 Hz). Vertical lines and error bars indicate SEs. JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 5/11 Remitters from suicidality as indexed by the Beck SSI, % JAMA Network Open | Psychiatry Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression Protocol Completers The overall number of patients achieving remission from suicidality, as indexed by the Beck SSI score, was 21 of 36 protocol completers (58.3%). The overall mean (SD) Beck SSI score decreased from 10.6 (4.6) at baseline to 4.8 (6.4) at the end of the trial (paired t =2.03; P < .001) (Figure 3). An analysis similar to the aforementioned analysis with the suicide item of the HRSD-24 validated these results with qualitatively similar outcomes (data not shown). The odds of remission from suicidality were lower in the adequate trial completer group compared with the protocol completers group, although the difference was not significant (odds ratio, 0.65; 95% CI, 0.29-1.48). For the subgroup sensitivity analysis, the participants treated with low- and moderate-frequency MST had numerically higher rates of remission from suicidality (11 participants [73.3%] and 7 participants [58.3%], respectively) than those treated with high-frequency MST (3 participants [33.3%]) (Figure 2); however, the differences between these rates were not statistically significant (low vs high frequency, χ =3.70; P = .05). Discussion In this secondary analysis of an open-label trial of MST for TRD, we explored the association of MST with suicidality. Overall, MST treatment was associated with reductions in suicidality that were both statistically significant and clinically meaningful in both the adequate trial group and per protocol treatment subgroup. The findings with our primary outcome measure (the Beck SSI score) were confirmed by additional analyses with the HRSD-24 suicide item, even though these 2 measures were only moderately correlated in our study. Our sensitivity analysis revealed that all MST treatment frequencies were associated with a reduction of suicidality, and that low- and moderate-frequency MST were associated with the highest rates of remission clinically from suicidality in both the group of participants who completed an adequate MST trial (55.2% for low-frequency MST and 54.5% for moderate-frequency MST) and in the subgroup who completed the protocol (73.3% for Table 2. Suicidality Scores by Treatment Frequency for Adequate Trial Completers Treatment frequency Adequate trial completers are defined as participants Variable Low (n = 29) Moderate (n = 22) High (n = 16) completing 8 or more magnetic seizure therapy Beck Scale for Suicidal Ideation score, mean (SD) sessions. At baseline 10.3 (5.5) 11.0 (4.8) 12.1 (3.9) Magnetic seizure therapy frequencies are defined as low (25 Hz), moderate (50 or 60 Hz), and high At end point 4.7 (6.2) 5.0 (6.8) 9.0 (6.5) (100 Hz). Relative reduction, % 53.4 64.4 18.8 Remission from suicidality is defined as a final score Rate of remission from suicidality % 55.2 54.5 25.0 of 0. Figure 3. General Linear Mixed Model of Beck Scale for Suicidal Ideation (SSI) Total Scores by Treatment Frequency With Group-by-Time Interaction Treatment frequency All Low Moderate High Baseline Treatment 3 Treatment 6 Treatment 9 Treatment 12 Treatment 15 Treatment 18 Treatment 21 Treatment 24 Magnetic seizure therapy frequencies are defined as low (25 Hz), moderate (50 or 60 Hz), and high (100 Hz). JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 6/11 SSI estimated marginal means JAMA Network Open | Psychiatry Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression low-frequency MST and 58.3% for moderate-frequency MST). However, the differences between these rates of remission from suicidality were not significant, possibly because of the small sample sizes of the 3 groups. Our results are exploratory and represent a post hoc analysis, so comparison with established treatments is limited. Nonetheless, we attempt to give some sense of comparative efficacy to other brain stimulation treatments used for suicidality in TRD. In the largest study of ECT and suicidality in depression, Fink et al. measured suicidality with the HRSD-24 suicide item, pooling data from 2 ECT 13,30 trials ; they reported a rate of remission from suicidality of 63.2%. This is comparable to the rate of remission from suicidality of 47.8% that we observed in our primary analysis for MST. The differences in the methods in that ECT study and our MST study demand a direct comparison in a randomized study, which is currently under way (ClinicalTrials.gov Identifier: NCT03191058). Considering that early evidence suggests that MST can be delivered with far less stigma and fewer cognitive adverse effects than ECT, MST may be a preferred treatment for suicidality in many patients. The rate of remission from suicidality we observed with MST also suggests potential superiority of MST over rTMS. We previously described the association of bilateral rTMS with remission from suicidality as measured with the HRSD-24 suicide item at 40.4% with bilateral rTMS (compared with 47.8% in the current study). Again, differences in study methods here greatly limit this interpretation, and direct comparisons should be performed in future studies. Some of our own and others’ recent work sheds light on potential mechanisms of action of MST in treating suicidality, and why low and moderate frequencies could be the most effective treatment frequencies. Backhouse et al reported that seizure adequacy (a composite measure of several seizure characteristics) was better in patients with TRD receiving 25-Hz and 50-Hz MST than in those receiving 100-Hz MST. This may be, in part, due to 100-Hz treatment not entraining pyramidal cells optimally, because this frequency is too high given the duration of the refractory period of cortical neurons, thereby inhibiting optimal recurrence of neuron depolarization (ie, seizure activity). This hypothesis should be evaluated in future MST trials, because it is still uncertain how to optimize treatment parameters for each individual patient receiving MST. In 2 earlier, overlapping 33,34 studies, we found that transcranial magnetic stimulation–electroencephalographic measures, such as long-interval cortical inhibition and N100, could be used to estimate improvement in suicidality in patients with TRD treated with MST. In the earlier of the 2 analyses, improvement in suicidality appeared to be mediated by dorsolateral prefrontal cortex plasticity through changes of GABAergic activity. It is possible that GABA-mediated plasticity in the dorsolateral prefrontal cortex was associated with the antisuicidal association of MST in our participants. MST may also be associated with reductions in suicidality through its action on other prefrontal brain areas, potentially medially located regions such as the dorsomedial prefrontal or ventromedial prefrontal cortices, or possibly the frontopolar cortex. These regions are not targeted with traditional rTMS, which could account for potential differences between the associations of MST and rTMS with suicidality. Although these mechanisms are possible, other studies have emphasized the role of alternative neurobiological mechanisms involving the hypothalamic-pituitary-adrenal axis, serotonin system, or glutamate and opioid signaling in suicidality, which could be targeted by MST. Overall, changes in depressive symptoms were only moderately correlated with changes in suicidality in our adequate trial completers (data not shown). Also, in an unpublished analysis of the factors associated with depression remission from MST in the larger sample of 86 suicidal and nonsuicidal participants, higher baseline suicidality was associated with lower odds of depression remission (D.M.B., J.D., Z.J.D., unpublished data, 2019). Taken together, these results support the clinical wisdom that change in suicidality is not necessarily congruent with change in overall depression. This furthers the notion of suicidality being its own neuro-endophenotype and symptom 36-38 construct independent of, yet highly comorbid with, other psychiatric illness, which should be explored further in future clinical trials. JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 7/11 JAMA Network Open | Psychiatry Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression Limitations There are multiple limitations to this study. Although, to our knowledge, this is the largest trial to date to evaluate the association of MST with suicidality in TRD, it is open label, and participants were assigned sequentially to different treatment frequencies. As such, there is the potential for bias, with treaters and participants being aware of the experimental nature of the treatment and of the frequency of MST received. Also, a non-MST comparator group (eg, placebo or another active treatment) was not used. There is also the risk of false-positive results with the multiple statistical tests in this report. Patients with a suicide attempt during the preceding 6 months or those at risk for an imminent suicide attempt were excluded, thus limiting application of our findings to these types of patients. Similarly, given our exclusion criteria, our results may not be directly applicable to patients with borderline personality disorder, bipolar illness, substance use disorders, or other disorders with high rates of suicidality. In addition, although we did find clinically meaningful differences in response by treatment frequency, we highlight that these differences were not statistically significant, likely because of the small sample sizes. Conclusions MST appears to be a promising intervention to target suicidality. Its efficacy will need to be confirmed in future MST trials exploring its use, potentially at low-to-moderate frequencies to start, in patients experiencing suicidality. A direct comparison is also needed to determine the relative associations of MST and ECT with suicidality. Such a comparison is currently under way. ARTICLE INFORMATION Accepted for Publication: April 1, 2020. Published: August 18, 2020. doi:10.1001/jamanetworkopen.2020.7434 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Weissman CR et al. JAMA Network Open. Corresponding Author: Zafiris J. Daskalakis, MD, PhD, Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, 1001 Queen St W, Toronto, ON M6H1H4, Canada (jeff.daskalakis@camh.ca). Author Affiliations: Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada (Weissman, Blumberger, Dimitrova, Throop, Voineskos, Daskalakis); Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada (Downar); Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada (Downar); Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada (Mulsant, Rajji); Epworth Centre for Innovation in Mental Health, Epworth Healthcare and Monash University Department of Psychiatry, Camberwell, Victoria, Australia (Fitzgerald). Author Contributions: Drs Weissman and Daskalakis had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Weissman, Blumberger, Downar, Mulsant, Rajji, Fitzgerald, Daskalakis. Acquisition, analysis, or interpretation of data: Weissman, Blumberger, Dimitrova, Throop, Voineskos, Downar, Mulsant. Drafting of the manuscript: Weissman, Throop, Daskalakis. Critical revision of the manuscript for important intellectual content: Weissman, Blumberger, Dimitrova, Voineskos, Downar, Mulsant, Rajji, Fitzgerald. Statistical analysis: Weissman, Dimitrova, Daskalakis. Obtained funding: Rajji, Daskalakis. Administrative, technical, or material support: Weissman, Blumberger, Dimitrova, Throop, Voineskos, Daskalakis. Supervision: Voineskos, Mulsant, Fitzgerald, Daskalakis. JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 8/11 JAMA Network Open | Psychiatry Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression Conflict of Interest Disclosures: Dr Blumberger reported receiving grants from Brain Canada, Canadian Institutes of Health Research (CIHR), National Institutes of Health (NIH), and the Temerty Family Foundation through the Centre for Addiction and Mental Health (CAMH) Foundation and the Campbell Family Research Institute; in-kind equipment support from MagVenture; research support and in-kind equipment support from Brainsway; and medication supplies for an investigator-initiated trial from Indivior outside the submitted work. Dr Voineskos reported receiving research training fellowship funding from the Ontario Mental Health Foundation, an American Psychiatric Association/Eli Lilly research fellowship, a CAMH postdoctoral fellowship, and support from the Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario. Dr Downar reported being a medical advisor for TMS Neuro Solutions and NeuroStim Health; receiving grants from NIH, CIHR, Brain Canada, Ontario Brain Institute, Arrell Family Foundation, and Buchan Family Foundation; and receiving nonfinancial support from MagVenture outside the submitted work. Dr Mulsant reported receiving research support from Brain Canada, CIHR, the CAMH Foundation, the Patient-Centered Outcomes Research Institute, NIH, Capital Solution Design (software used in a study founded by CAMH Foundation), HAPPYneuron (software used in a study founded by Brain Canada), Eli Lilly (medications for a NIH-funded clinical trial), and Pfizer (medications for a NIH-funded clinical trial) outside the submitted work and reported owning stock in General Electric (<$5000). Dr Rajji reported receiving research support from Brain Canada, Brain and Behavior Research Foundation, BrightFocus Foundation, Canada Foundation for Innovation, Canada Research Chair, CIHR, Centre for Aging and Brain Health Innovation, NIH, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, and the Weston Brain Institute; in-kind equipment support for an investigator-initiated study from Magstim; and in-kind research accounts from Scientific Brain Training Pro. Dr Fitzgerald reported receiving a Practitioner Fellowship grant from National Health and Medical Research Council (1078567); receiving equipment for research from MagVenture, Medtronic, Neurosoft, and Brainsway; serving on scientific advisory boards for Bionomics and LivaNova; and acting as a founder for TMS Australia. Dr Daskalakis reported receiving research grants and in-kind equipment support for an investigator-initiated study through Brainsway and MagVenture and receiving support from the Ontario Mental Health Foundation, CIHR, the National Institutes of Mental Health, and the Temerty Family and Grant Family through the CAMH Foundation and the Campbell Institute. No other disclosures were reported. REFERENCES 1. World Health Organization. Preventing suicide: a global imperative. Published 2014. Accessed July 23, 2020. https://www.who.int/mental_health/suicide-prevention/world_report_2014/en/ 2. Beautrais AL, Joyce PR, Mulder RT, Fergusson DM, Deavoll BJ, Nightingale SK. 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Indicators for remission of suicidal ideation following magnetic seizure therapy in patients with treatment-resistant depression. JAMA Psychiatry. 2016;73(4):337-345. doi:10.1001/ jamapsychiatry.2015.3097 35. Downar J, Daskalakis ZJ. New targets for rTMS in depression: a review of convergent evidence. Brain Stimul. 2013;6(3):231-240. doi:10.1016/j.brs.2012.08.006 36. Oquendo MA, Sullivan GM, Sudol K, et al. Toward a biosignature for suicide. Am J Psychiatry. 2014;171(12): 1259-1277. doi:10.1176/appi.ajp.2014.14020194 37. Oquendo MA, Baca-Garcia E. Suicidal behavior disorder as a diagnostic entity in the DSM-5 classification system: advantages outweigh limitations. World Psychiatry. 2014;13(2):128-130. doi:10.1002/wps.20116 38. Kaschka WP, Rujescu D. Biological Aspects of Suicidal Behavior. Karger; 2016. SUPPLEMENT. eTable. Suicidality Scores by Treatment Frequency for Adequate Trial Completers eAppendix. MST Detailed Project Protocol eReferences JAMA Network Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 (Reprinted) August 18, 2020 11/11 Supplementary Online Content Weissman CR, Blumberger DM, Dimitrova J, et al. Magnetic seizure therapy for suicidality in treatment-resistant depression. JAMA Netw Open. 2020;3(8):e207434. doi:10.1001/jamanetworkopen.2020.7434 eTable. Suicidality Scores by Treatment Frequency for Adequate Trial Completers eAppendix. MST Detailed Project Protocol eReferences This supplementary material has been provided by the authors to give readers additional information about their work. © 2020 Weissman CR et al. JAMA Network Open. a eTable. Suicidality Scores by Treatment Frequency for Adequate Trial Completers Treatment Frequency Low frequency Moderate High n=29 n=22 n=16 HRSD suicide item at 1.6 (0.8) 1.4 (0.6) 2.6 (0.8) baseline HRSD suicide item at 0.9 (1.0) 1.0 (0.9) 1.5 (1.3) endpoint HRSD relative reduction 43.6 33.3 41.7 (%) Rate of remission from 40.0 36.8 28.6 suicidality (%) All results are presented as mean (SD) unless indicated otherwise. HRSD: Hamilton Rating Scale for Depression a Adequate trial completers: participants completing eight or more MST sessions b Remission from suicidality defined as a final score of 0 eAppendix. MST Detailed Project Protocol Background Treatment Resistant Depression and Electroconvulsive Therapy Depression is a common (~15-20% life prevalence) and important clinical problem with high morbidity and mortality. A significant subset of depressed patients continue to experience highly distressing and disabling symptoms despite standard treatments . This subset has been estimated to be in the range of between 10 and 20% of patients with the disorder . Electroconvulsive therapy (ECT) is the most effective treatment for major depressive disorder . However, many patients are reluctant to engage in a trial due to stigma and the risk of cognitive side effects The development of cognitive impairment, particularly memory impairment, is a particularly troubling side effect of ECT and often leads to treatment non acceptance. Anecdotally, many patients who have had successful ECT will not return for follow-up treatment upon the relapse of the depression because of such side effects. Modifications to the ECT treatment procedure that could substantially reduce or minimize these side-effects would, therefore, be of substantial benefit. Importantly, both the efficacy and side effects produced by ECT may be affected by a variety of treatment parameters such as electrode placement, electrical dose and also potentially the pattern of seizure initiation and spread . However, the degree to which these factors can be varied is limited in ECT, particularly with regard to the way in which the seizure is initiated . Treatment-Resistant Schizophrenia and Electroconvulsive Therapy Schizophrenia (SCZ) is a debilitating disorder that exacts enormous personal, social and economic costs. Despite recent advances in psychopharmacological treatments nearly 40% of patients achieve only a partial response and 10% experience no response at all . To date, only a few alternatives have been available: these generally include clozapine and ECT. Both, however, are associated with significant side effects. For example, clozapine has been associated with hyperlipidemia, blood dyscrasias, diabetes, seizures and 6,7 cardiomyopathy . Furthermore, some patients will not tolerate the rigorous monitoring associated with clozapine treatment. Similarly, ECT is associated with significant cognitive impairment and the stigma associated with ECT limits its broader use as a refractory treatment. Together, these limitations highlight the need for additional treatments aimed at ameliorating the sequelae of SCZ. To date, no studies have reported the use of magnetic seizure therapy (MST) in a population of patients with refractory SCZ. Treatment Resistant Obsessive Compulsive Disorder and Electroconvulsive Therapy © 2020 Weissman CR et al. JAMA Network Open. Obsessive compulsive disorder (OCD) is a prevalent and highly debilitating illness. Estimates suggest that close to 3% of the general population have this illness . Despite advances in psychotherapeutic and psychopharmacological treatments, approximately 50% of patients with OCD remain refractory to 9 10 treatment . ECT is indicated for refractory OCD, yet the data is mainly from case series . Other non- pharmacologic treatments include implantable deep brain stimulation and neurosurgical ablation which carry significant risk of morbidity and side effects. Due to the high rates of treatment resistance and the severe morbidity of the illness, treatment alternatives are required. MST holds the potential to be another potential treatment for treatment refractory OCD. To date, no studies of MST in OCD have been conducted Magnetic seizure therapy Like ECT, MST involves the intentional induction of a seizure for therapeutic purposes. However, the induction of a seizure occurs through the use of high frequency repetitive transcranial magnetic stimulation (rTMS) rather than through stimulation of the brain with a direct electrical current, such as that which occurs with ECT. In this context, MST should be differentiated from rTMS, which uses the same or similar equipment but is non convulsive. rTMS involves the application of magnetic pulses at a considerably lower intensity and frequency. It is likely that rTMS and MST have substantially differing mechanisms of action. As has been practised to date, MST is administered under general anesthesia in much the same way as ECT. MST, like rTMS, does not involve the direct application of electricity. Instead, electrical current is produced indirectly in the brain via electromagnetic induction. The rTMS stimulator induces a high field magnetic pulse, which passes into the brain, inducing an electrical current in brain cells. This capacity to indirectly stimulate the brain overcomes one of the major problems with ECT: its inability to provide focal or directed stimulation. Although a number approaches have tried to apply ECT in focused ways (e.g frontal, temporal), the substantial electrical impedance of the scalp and skull means that the bulk of the electrical stimulus is shunted away from the brain, resulting in stimulation of widespread cortical and subcortical regions . However, as there is no resistance to the passage of the magnetic field produced by an rTMS device into the brain, magnetic stimulation may be focused quite precisely. Therefore, it is possible that seizures may be produced with less spread to medial temporal lobe structures, reducing memory related side-effects . There is another substantial difference in regards to the mechanism of seizure induction between MST and ECT related to pulse width. Basic physiological studies have suggested that the best pulse width for stimulating cortical neurons may be briefer than that used in ECT. Briefer pulses excite neurons more efficiently at lower charge densities and have a larger safety margin because of their lower charge per phase . Recent ECT studies have investigated briefer pulse width stimulation to try and reduce cognitive side 13,14 effects . The pulse width of an rTMS stimulator (typically 0.2ms) is in the ultra brief range, which might be expected to enhance its efficacy of seizure induction, although the waveform itself differs between magnetic stimulation and ECT. Due to differences in pulse wave form, a lengthening of the MST pulse to 0.5 ms has been found to be more effective . Animal Studies The initial research with MST was conducted in nonhuman primates with the first MST- induced seizure reported in 1998 . Custom modified rTMS devices capable of stimulating at higher intensities and frequencies were developed for this purpose. Several important outcomes of this research have emerged. First, MST has been shown to not produce identifiable histological lesions in the brain in primates . Second, information with regard to optimal stimulation parameters for seizure induction has been gathered . Third, there appears to be fewer cognitive side effects with MST, as opposed to ECT, in this animal model . Human Studies © 2020 Weissman CR et al. JAMA Network Open. In parallel, a number of initial human studies have been undertaken. The first patient received MST 15 18 stimulation over 4 sessions and a second successfully received a full treatment course . Both patients were treated with stimulation at 40 Hz, tolerated the treatment well and responded clinically. In a subsequent study, 10 patients received two MST sessions within a course of ECT . The MST sessions were better tolerated and resulted in fewer acute side-effects compared to the ECT. Notably, in 3 of the 10 patients, the MST seizure threshold was at the maximum output of the device. 20 patients were 19,20 subsequently treated with a full course of MST using the same 50 Hz device . Mood improvement was again seen in the MST group with fewer side effects and dramatically more rapid reorientation post- stimulation than in ECT group. However, the magnitude of improvement did not seem as great as that of ECT. The authors have speculated that, as the stimulation dose was, on average, only 1.3 times the magnetic seizure threshold, substantially greater responses may have been achieved with higher stimulation intensity, especially given that ECT response rates are highly sensitive to dose relative to seizure threshold Since these initial studies, the technology used to produce MST has advanced considerably. Two companies have developed MST devices capable of stimulating continuously at 100Hz for sufficient durations to induce seizures. This type of stimulation has been shown in primate experiments to induce seizures and still demonstrates fewer cognitive side-effects than conventional ECT . This type of stimulation has now been tested in human subjects, with 11 patients being stimulated with 100 Hz MST in a single session during a regular course of ECT. Seizures were elicited in 10 of the 11 patients. All patients had a highly rapid recovery of orientation (on average 15 minutes shorter than recovery time after ECT) and reported less confusion . In addition to the published reports, we are aware of studies underway utilizing in MST in a number of centres around the world. Four centres (Columbia University, the University of Texas Southwestern Medical Centre (US), Cardiff University and the University of Oxford (UK)) are currently using an MST device produced by Magstim (Whitland, UK). Two centres in Germany (Bonn and Berlin), as well as the centre at Columbia University have commenced studies with the device relevant to this application, the Magventure A/S MST Magpro MST device. Summary Treatment resistant depression, schizophrenia and OCD remain substantial clinical problems for which there are limited alternatives. MST is a novel modification of ECT with the potential for similar effectiveness, fewer side-effects and a more rapid return of orientation / shorter duration of post-ictal confusion. Furthermore, MST is not associated with the same cognitive burden and media-related stigma as ECT, which may lead to broader acceptance if it is found to be effective. However, experience with this technique has been limited to date and considerable further research is required. In this application we propose to conduct an initial Canadian pilot study of MST using a stimulator capable of 100 Hz. Within this pilot study, patients will be treated in an open label manner to observe response rates, cognitive implications of MST treatment as well as several neurobiological variables that may enhance our understanding of treatment response. The results of the study should allow us to proceed to a double -blind randomized comparison of MST with ECT. Methods Objectives and hypotheses Objective 1: To evaluate the efficacy of MST in with severe depression, schizophrenia, and OCD. Hypothesis 1: MST will demonstrate substantial efficacy (i.e., substantial rates of response and remission) on objective measures of mood, schizophrenia, and OCD symptoms. Objective 2: To evaluate the effects of MST on autobiographical memory and other cognitive functions in patients with severe depression, schizophrenia, and OCD. Hypothesis 2: MST will have limited adverse effects on objective measures of autobiographical memory and other cognitive functions in patients with severe depression, schizophrenia, and OCD. Objective 3: To compare the changes in brain function that result from MST. © 2020 Weissman CR et al. JAMA Network Open. Hypothesis 3: MST will produce changes in functional brain activity consistent with antidepressant response, antipsychotic response, and antiobsessive response, along with a sparing of cognitive functions. Design The core study will involve an open label design with before-, during- and after- treatment assessments of depression severity, subjective side-effects and cognitive performance. We will assess baseline treatment resistance using the antidepressant treatment history form (ATHF) . Baseline medical comorbidity will be assessed using the Cumulative Illness Rating Scale(CIRS) . Cognition will be monitored at baseline, at every 6 treatments, and at the end of the treatment course. In addition, we will engage patients in pre- and post- treatment neuroimaging and cortical inhibition measures to study the biological effects of MST treatment. Subjects A total of 250 patients will be included in the study, including at least 20 schizophrenia and 20 OCD patients, 20 with major depressive episode with psychotic features in the context of Major Depressive Disorder or Bipolar Disorder, 150 major depressive episode without psychotic features in the context of Major Depressive Disorder, 40 major depressive episode without psychotic features in the context of Bipolar Disorder. With a 10 point difference in mean pre post 24-item HDRS scores and a standard deviation of 8, the smallest group (n=11) in this sample should still have a power approaching 1 (>0.99) (alpha =0.05, 2 tailed). Inclusion Criteria: Patients will be included if they: 1. have a DSM-IV diagnosis of a major depressive episode with or without psychotic features in the context of major depressive disorder or bipolar disorder, obsessive compulsive disorder, or schizophrenia/schizoaffective based on SCID-IV criteria 2. are within the age range from 18-85 3. have a 24-item HDRS score of > 21 (depression patients, moderate severe) 4. have an 18-item BPRS score of > 37 (schizophrenia/schizoaffective patients, moderate severe) 5. have a Y-BOCS score of > 16 (OCD patients, moderate severe) 6. demonstrates capacity to consent according to study and treating psychiatrist or MacCAT for subjects with schizophrenia/schizoaffective 7. are on a medically acceptable form of birth control, if a woman of child-bearing potential Exclusion Criteria: Patients are excluded if they: 1. have an unstable medical and/or neurological condition 2. are currently pregnant or lactating 3. are not considered sufficiently well to undergo general anesthesia for any reason 4. have a cardiac pacemaker, cochlear implant, implanted electronic device or non-electric ferrometallic implant in the head only 5. are taking a benzodiazepine at a dose greater than lorazepam 2mg or equivalent 6. are taking any non-benzodiazepine anticonvulsant 7. have active substance misuse or dependence within the past 3 months 8. have a current diagnosis of delirium, dementia or another cognitive disorder secondary to a general medical condition 9. have other significant Axis I co-morbidity 10. have a co-morbid borderline personality disorder and/or antisocial personality disorder as confirmed by the Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II) 11. have had a history of any suicide attempts in the past 6 months Clinical Measures Demographic variables and potential co-variates will be recorded at baseline following a clinical interview. These will include the duration of the current episode, years from first diagnosis, number of previous episodes, type and dose of current and previous treatment and family history of mood disorder. Diagnosis will be assessed with the SCID (DSM IV). Clinical rating measures will include the 24-item Hamilton © 2020 Weissman CR et al. JAMA Network Open. Depression Rating scale (HDRS) for consistency with most prior ECT studies, as well as the Quick Inventory of Depressive Symptomatology (QIDS) and Brief Psychiatric Rating Scale (BPRS) and YBOCS (Yale-Brown Obsessive-Compulsive Scale), as appropriate. For those patients with Major Depressive Disorder and Bipolar Disorder we will use the Young Mania Rating Scale (YMARS) to monitor for emergence of hypomania. Given the significant toll of these illnesses on quality of life, all patients will answer the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q)[50] prior to and at the end of the acute treatment phase. The Beck Scale for Suicide Ideation (BSS)[27] will be used to evaluate suicidal ideation, which is a common symptom in depression. A systematic evaluation of suicidal ideation is needed in any depression treatment study for safety reasons and because clinicians need to know the effects of treatment on suicidality to understand risks vs. benefits. At each clinical assessment if score on suicidal ideation. The Snaith-Hamilton Pleasure Scale (SHAPS) will be used to evaluate and monitor anhedonia in participants with depression and the effects of treatment on this core feature of depression [55]. The entire clinical battery will be repeated after every three treatments, at the end of acute treatment phase, and at 1, 2, 3, and 6 months after the acute treatment phase. The battery will again be repeated 6 months after the maintenance MST treatment phase, if applicable. The QIDS will be administered prior to every treatment visit for those subjects with depression in order to check for symptom improvement between clinical assessments. If the score falls within the euthymic range (0-5), the entire clinical battery will be administered to assess possible remission. For depression, remission will be defined as a 24-item HDRS 10, and a greater than 60% decrease in scores from baseline on two consecutive ratings with a change no greater than 3 points. Response -item HDRS score from baseline on two consecutive ratings. For schizophrenia, response will be defined as an 18-item BPRS < 25, for consistency of criterion with recent large studies of ECT in treatment-resistant schizophrenia . For OCD, remission will be defined as a Y-BOCS score 8, and a greater than 60% decrease in scores from baseline on two consecutive ratings with a change no greater than 3 points. Cognitive assessment All patients will be assessed with the entire cognitive battery prior to and at the end of the acute treatment phase, and at 6 months post-treatment. The MOCA will be administered at baseline and every 6 treatments during acute treatment. The MOCA will also be administered before the last treatment if the patient will not be receiving maintenance treatment, and will be done before their first maintenance treatment if continuing onto the maintenance phase. It will then be administered once a month during maintenance treatment. The cognitive battery will include assessments of anterograde and retrograde memory, specifically looking at learning, retention and retrieval in both the verbal and non verbal domains. This will include assessments such as the Autobiographical Memory Interview Short Form , MATRICS Consensus Cognitive Battery (MCCB), Stroop and Verbal Fluency using the COWAT . Finally we will look at general intellectual functioning with the WTAR (Wechsler Test of Adult Reading) prior to treatment start. Cognitive function during the treatment phase of the study will be assessed with the Montreal Cognitive Assessment (MoCA). This test has three different English versions which allow us to avoid practice effects. Additionally, time to reorientation will also be measured after each MST session using previously published standardized methods [30,31] that evaluate orientation to name, date of birth, age, place and day of the week. This will be accomplished by repeatedly asking orientation questions from the time of resumed respiration post-MST and noting the recovery time required to recall 4 of the 5 items listed above [32]. MST treatment procedure The range of frequency stimulation used to treat patients will be between 20 Hz and 100Hz, with a duration range between 2 and 20 seconds depending on the frequency used. Furthermore, we would also like to specify that the anatomical location of stimulation will be either the frontal or vertex region of the brain. These are the two sites at which stimulation is most commonly applied [32, 56, 57]. The MST determination of seizure threshold will be done at 100% stimulator output applied at the selected treatment frequency with progressively escalating train durations until an adequate seizure is produced. During an © 2020 Weissman CR et al. JAMA Network Open. ECT treatment an adequate seizure is described as generalized tonic-clonic activity > 20 seconds on the EMG recording or > 25 seconds of EEG seizure activity. However, little data is available on the characteristics of MST induced seizures therefore the adequacy of the seizure will be determined at each session by the treating MST psychiatrist. During titration a maximum of three stimulations will be given at the same session, provided the coil temperature allows for a third stimulation. If an adequate seizure is not produced by the third stimulation, titration will continue at the next treatment session until threshold is reached. Subsequent treatments will then be delivered according to the established conventions for delivering MST. Acute Treatment Phase Six treatment sessions, at a frequency of two or three times per week will be administered. Patients will not have treatments on consecutive days. As previously stated, remission will be assessed at every 3 treatments, and if the pre-defined remission rate is not met 3 additional treatments will be provided. This will be repeated a total of 5 times (i.e., maximum treatment number is 24). 24 treatments is typically longer that a conventional ECT treatment course. However, evidence does suggest that longer treatment courses may be needed with MST, particularly in more treatment resistant psychiatric conditions such as OCD and Schizophrenia [51-52]. Furthermore, response during the acute treatment course will also be monitored and the dose adjusted accordingly. In the study the dose was originally adjusted at every 6 sessions. However, response during the acute treatment course will also be monitored and the dose adjusted accordingly every three sessions rather than every 6 sessions. That is, if the patient fails to achieve an equal or greater than th 30% decrease from baseline following treatment 3, the dose will be increased on their 4 treatment. After treatment 6, if the patient fails to achieve further response, that is an equal or greater than 30% decrease th from the score after treatment 3, the dose will be increased on their 7 treatment. Treatment continues in this manner up to a maximum of 24 total treatments. If at any point the patient is already at maximum stimulation (20 seconds or 1000 pulses) the treatment continues with the dose unchanged. Patients will be withdrawn from the study and offered to switch to ECT if, despite MST treatment, they experience a significant clinical decline or an acute worsening of symptoms that creates concerns over their safety. Specific criteria for withdrawal from MST treatment would include 1) the emergence of suicidal intent or plan; 2) suicide attempt; 3) serious attempt to harm others; 4) emergence of catatonia; 5) emergence of severe inanition (e.g., failure to consume food or fluids). Any incidents of safety concerns requiring a switch to ECT will be monitored as one of the MST efficacy measures in the study. Non- responding subjects can be withdrawn from the study prematurely if the investigator deems this to be in the patient's best interest. Additionally, subjects will be discontinued from the study if more than 3 consecutive treatments are missed. Maintenance Treatment Phase Rates of depressive relapse after a successful course of ECT can be as high as 50% within the first 6 months [53]. Similarly, psychotic exacerbation can occur at high rates after patients with schizophrenia improve with ECT [51]. Evidence based strategies to prevent depressive relapse within the first 6 months after a successful course of ECT include the combination of an antidepressant and lithium or maintenance ECT [53, 54]. Maintenance ECT is often used after patients with schizophrenia improve with ECT [51]. There is very little data on rates of relapse after a successful course of ECT in patients with OCD; nevertheless, there is no reason to believe that it would not have a similarly beneficial effect at reducing relapse. To date, there have not been any reports on the use of maintenance MST. Therefore, all patients who attain the a-priori defined remission and/or response criteria in the acute treatment phase of MST will be offered participation in maintenance MST as means of preventing relapse. Subjects will also be provided with psycho-education and recommendations will be made to their attending physicians regarding alternative evidence based treatments to prevent relapse. Those subjects that elect to receive maintenance MST will receive treatment according to the standard maintenance schedule used for ECT: one treatment per week for 4 weeks, then one treatment every two weeks for 2 months, then one treatment every 3 weeks for 2 months and then one treatment 4 weeks later. Subjects will be assessed at regularly scheduled intervals throughout the maintenance phase and as needed, to determine if they are maintaining response or remission. If subjects have two consecutive scores above the a-priori defined remission or response score they will be offered two weeks of booster treatments (2 treatments per week). If they do not respond after two weeks they will exit from the study and alternative treatment will be discussed clinically. If the subject © 2020 Weissman CR et al. JAMA Network Open. does not wish to receive booster treatments they will exit from the study and alternative treatment will be discussed clinically. Safety Considerations MST is an involved treatment, with many congruencies to ECT in regards to the short-term side effects experienced following treatment session(s). As mentioned, MST has been shown to result in less cognitive burden than treatment with ECT. However, there are other potential side effects that we anticipate over the course of the trial. This section discusses anticipated adverse events based on a careful review of existing research literature regarding ECT and MST treatment. This review has been further supplemented by subject reports received to date. The following adverse events are anticipated in a sub-sample of the participant population: reversible cardiac ectopy, transient hypertension, uncomplicated asystole, fatigue, headache, aching/stiffness in muscles, nausea and vomiting, acute post-treatment delirium, post-ictal agitation, disorientation, memory impairment (e.g., anterograde and retrograde memory loss), prolonged seizures (i.e., seizures > 120 seconds in duration), treatment emergent mania, treatment emergent anxiety and fear, laryngospasm, peripheral nerve palsies, and aspiration. Several steps are taken to mitigate the risk of side effects. Prior to treatment all MST patients at CAMH receive an in-depth consultation from an ECT psychiatrist. The purpose of the consultation is to assess illness type and severity, previous treatments and outcomes, relative contraindications, discuss risks and benefits, and capacity to consent to ECT/MST. In addition to the psychiatric consult, all potential subjects receive a pre-MST consultation from the anesthesia service to assess suitability for general anesthesia, medical comorbidities that may impact anesthesia, discuss the risks of general anesthesia, and finally, conduct the informed consent for general anesthesia. During all treatment sessions, vital signs (heart rate, BP, O2 saturation, ECG, EEG) are monitored continuously. Patients undergo preoxygenation, anesthesia and muscle relaxation with accepted medications used in ECT practice, bite guard placement, and immmoblization prior to seizure induction. After EEG-confirmed seizure termination and recovery from anesthesia, patients are transferred to a recovery room once vital signs are stable and breathing. In the event a subject experiences a side effect, several steps are taken to minimize discomfort. Additional medications for symptomatic relief of side effects will be used based on accepted medications used in ECT practice For example, participants reporting moderate to severe headaches during previous treatments may receive an anti-inflammatory medication prior to their next treatment as a means of preventing headaches. Similarly, a participant that experienced nausea or vomiting will be given an intravenous anti-nausea medication to ease symptoms at the next treatment. Participants are also encouraged to take Tylenol for any muscle soreness. Risks of wakening paralysis and post-ictal agitation are mitigated by giving midazolam post-treatment. This is done on a case-by- first treatment. Analysis of Clinical Outcomes Depression scores and cognitive performance will be compared pre- and post-treatment using paired t-tests, with significance thresholds Bonferroni-corrected for multiple comparisons. Biomarkers of Treatment Response Participation in this component of the protocol is voluntary does not preclude participation in the treatment component of the trial. Changes in Cortical Inhibition Dysfunctional cortical inhibition (CI) has been postulated as a mechanism through which the symptoms of MDD, SCZ and OCD are mediated [33-36]. Cortical inhibition refers to the neurophysiological process in -aminobutyric acid (GABA) inhibitory interneurons selectively attenuate the activity of pyramidal neurons in the cortex. TMS capitalizes on the ability of time-varying magnetic fields to induce eddy currents in biological tissue via the principle of electromagnetic induction. TMS can provide an index of © 2020 Weissman CR et al. JAMA Network Open. GABA receptor-mediated inhibition in the cortex because it differentially stimulates inhibitory interneurons and pyramidal neurons. There are several TMS paradigms which provide a measure of GABA receptor- mediated inhibitory neurotransmission long interval cortical inhibition (LICI) [37-41], the cortical silent period (CSP) and short-interval cortical inhibition (SICI). Single or paired-pulse transcranial magnetic stimulation (TMS) represents a unique experimental modality that has been used to directly index CI. With single and paired-pulse TMS we have recently demonstrated that MDD is associated with deficits in CI that are more pronounced in patients with SCZ, OCD and MDD. It has also been shown that treatment with electroconvulsive therapy (ECT) is associated with enhanced CI [35,42-44]. Collectively, these studies suggest that potentiation of CI may represent a unique neurophysiological mechanism through which brain stimulation treatments (i.e., ECT and MST) exert their therapeutic effects in the above mentioned psychiatric disorders. TMS shall be used to examine GABAB receptor mediated inhibitory neurotransmission, through LICI, in both the DLPFC and motor cortex. Further, we will also evaluate the CSP in the motor cortex as a second index of GABAB receptor mediated inhibitory neurotransmission in the motor cortex. Evaluation of the DLPFC and motor cortex will be conducted in counterbalanced order and each region will be assessed immediately after completion of the other. To evaluate LICI from the DLPFC, EEG recordings will be acquired through a 64-channel Synamps 2 EEG system. Electrodes of interest will include those which optimally represent the overlap of Brodmann areas (BA) 9 and 46 of the DLPFC that has been shown to be most closely associated with electrode AF3. All neurophysiological data will be coded and analysed by an experienced rater. Measures of cortical inhibition will be administered twice, prior to and at the end of the acute treatment phase within 48hrs of the first and last MST treatment. Measurement of Working Memory As one of the main objectives of this study is to evaluate the effects of MST on autobiographical memory and other cognitive functions, we will also administer a working memory task prior to and at the end of the acute treatment phase. Working memory will be examined with the verbal N-back task (1- and 3-Back task) while EEG is recorded at the same session as TMS-EEG analysis at baseline and following an acute course of MST treatment. This test will allow us to further explore the cognitive affect of MST as well as examine the relationship between working memory and cortical inhibition. Neuroimaging In addition to measures of cortical inhibition, all patients will also undergo three sessions of neuroimaging: one prior to treatment, one within 48 hours of the end of treatment, and one at 6 months after treatment. Each session will include 3 types of neuroimaging studies in order to assess changes in brain structure and brain function, as follows: 1. A T1-weighted MRI sequence to provide high-resolution anatomical images of the cerebral gray and white matter. These images will be used for anatomical co-registration of the functional neuroimaging data, and for voxel-based morphometry (VBM) to assess regional changes in cortical and hippocampal gray matter thickness before and after treatment. Pre- and post-treatment scans will be compared using standard SPM8 and FSL software for identifying statistically significant regional changes in whole-brain VBM data. 2. A diffusion tensor imaging (DTI) MRI sequence to provide detailed information on the structural integrity of white matter tracts in the prefrontal lobes, hippocampus, and other cortical region s before and after treatment. Pre- and post-treatment scans will be compared using standard FSL software for reconstruction and statistical comparison of white matter tract structure, trajectory, and integrity. 3. A T2*-weighted, functional MRI (fMRI) sequence to assess blood oxygenation level dependent (BOLD) signal changes marking increases and decreases in regional functional connectivity to the amygdala and ventral striatum during the resting state, before and after treatment. Pre- and post treatment scans will be analysed using standard SPM8 and FSL software for identifying statistically significant regional changes in whole-brain BOLD signal data. © 2020 Weissman CR et al. JAMA Network Open. The first aim of the neuroimaging measures is to determine whether MST results in changes in brain structure and activity that are consistent with antidepressant response to other treatments, including ECT, DBS, and antidepressant medications. Based on previous studies, we propose that this will include increases in resting brain metabolism on PET in dorsal prefrontal and dorsal anterior cingulate cortex and 29-31 decreases in orbitofrontal prefrontal cortex and ventral striatum . The second aim of the neuroimaging measures is to determine whether MST also has milder effects on the brain structures most closely linked to episodic memory and other related cognitive functions. We also propose that there will be a more pronounced recovery of functional activity in the hippocampal and retrosplenial regions on PET and fMRI 31 32 measures , as well as volumetric expansion in the hippocampus on VBM , and improved hippocampal- prefrontal and hippocampal-retrosplenial white matter tract integrity on DTI measures . © 2020 Weissman CR et al. JAMA Network Open. eReferences 1. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53(8):649-659. 2. Ebmeier KP, Donaghey C, Steele JD. Recent developments and current controversies in depression. Lancet. 2006;367(9505):153-167. 3. Lisanby SH. Electroconvulsive therapy for depression. N Engl J Med. 2007;357(19):1939-1945. 4. Lisanby SH. 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Published: Aug 18, 2020

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