A randomized sham-controlled trial of high-dosage accelerated intermittent theta burst rTMS in major depression: study protocol.

BACKGROUND: Intermittent theta burst stimulation (iTBS), a novel form of repetitive transcranial magnetic stimulation (rTMS), can be administered in 1/10th of the time of standard rTMS (~ 3 min vs. 37.5 min) yet achieves similar outcomes in depression. The brief nature of the iTBS protocol allows for the administration of multiple iTBS sessions per day, thus reducing the overall course length to days rather than weeks. This study aims to compare the efficacy and tolerability of active versus sham iTBS using an accelerated regimen in patients with treatment-resistant depression (TRD). As a secondary objective, we aim to assess the safety, tolerability, and treatment response to open-label low-frequency right-sided (1 Hz) stimulation using an accelerated regimen in those who do not respond to the initial week of treatment. METHODS: Over three years, approximately 230 outpatients at the Centre for Addiction and Mental Health and University of British Columbia Hospital, meeting diagnostic criteria for unipolar MDD, will be recruited and randomized to a triple blind sham-controlled trial. Patients will receive five consecutive days of active or sham iTBS, administered eight times daily at 1-hour intervals, with each session delivering 600 pulses of iTBS. Those who have not achieved response by the week four follow-up visit will be offered a second course of treatment, regardless of whether they initially received active or sham stimulation. DISCUSSION: Broader implementation of conventional iTBS is limited by the logistical demands of the current standard course consisting of 4-6 weeks of daily treatment. If our proposed accelerated iTBS protocol enables patients to achieve remission more rapidly, this would offer major benefits in terms of cost and capacity as well as the time required to achieve clinical response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04255784.

Perceptions, Experiences, and Patterns of Cannabis Use in Individuals with Mood and Anxiety Disorders in the Context of Cannabis Legalization and Medical Cannabis Program in Canada - A Qualitative Study.

INTRODUCTION: Perceptions of cannabis as a potential medical treatment for mood and anxiety disorders have been increasing in the context of legalizations, availability, and medical cannabis programs, though current evidence predominately indicates risks and negative effects of cannabis use (CU) on mental health outcomes. This study aims to understand motivations, perceptions, effects, and patterns of CU in individuals with mood and anxiety disorders. METHODS: Thirty-six adult patients diagnosed with mood or anxiety disorders, obsessive-compulsive disorder, or posttraumatic stress disorder who were currently using cannabis completed an in-depth qualitative interview on individual motivations, perceptions, experiences, effects, and patterns of their CU. The thematic analysis focused on phases of CU and sources of cannabis products and information. RESULTS: Reported motivations for initiation of CU included curiosity, peer pressure, and dissatisfaction with conventional treatments. Factors such as psychotropic effects and coping with mental health symptoms and insomnia contributed to the continuation of CU. More negative effects, including cognitive dysfunction, worsening of mood, and anxiety symptoms, were acknowledged with ongoing CU. Concerning findings included common initiation of CU before age 18, combined medical and recreational CU, rare consultation of medical professionals on CU, and potential effects and harms. DISCUSSION: Findings indicate individual complexity of motivations, perceptions, and patterns of CU in the study population. The reported potential beneficial effects of specific cannabis products should be further investigated. Findings emphasize patient-provider dialogue on both CU and conventional treatments. Information from this study can contribute to and inform the development of education, prevention, and intervention strategies.

Vagally Mediated Heart Rate Variability Is Associated With Executive Function Changes in Patients With Treatment-Resistant Depression Following Magnetic Seizure Therapy.

OBJECTIVES: Magnetic seizure therapy (MST) is a novel investigational brain stimulation modality for patients with treatment-resistant depression (TRD). MST is a potential alternative seizure-based treatment to electroconvulsive therapy (ECT), given that it may offer equivalent antidepressant efficacy, yet with a relative sparing of cognitive functioning. Heart rate variability (HRV) is a marker of central autonomic functioning. We aimed to explore the relationships among baseline HRV, age, clinical outcome, and executive function following MST, in patients with TRD. MATERIALS AND METHODS: Eighty-eight TRD patients (55 females; 18-70 years) were enrolled and 48 patients completed a course of MST in an open-label study. Patients received MST treatments two to three times per week, using one of three stimulation frequencies (ie, 100 Hz, 50 Hz, or 25 Hz) at 100% stimulator output. Root mean square of the successive R-R differences (RMSSD), an index of HRV, was computed from a baseline electrocardiogram (ECG) recording. Clinical symptoms were assessed using the Hamilton Depression Rating Scale (HAM-D24) and the Quick Inventory of Depressive Symptomatology (QIDS16). Executive function was assessed using the Trail Making Test and the Mazes Test from the MATRICS battery. RESULTS: Baseline RMSSD was correlated with baseline HAM-D24 (r = -0.340, p = 0.001) and baseline Mazes Test (r = 0.417, p = 0.0007) but not with baseline Trail Making Test. Furthermore, baseline RMSSD was not correlated with changes on the HAM-D24, QIDS16, or total scores on the Trail Making Test. However, there was a significant correlation between baseline RMSSD and improvement on the Mazes Test following MST (r = 0.502, p = 0.0004). CONCLUSIONS: Since this is an open-label trial, the influence of the placebo effect cannot be excluded. However, our results suggest that baseline RMSSD may be a state-biomarker of depression and executive function impairment. Additionally, while baseline vagally mediated resting cardiac activity did not predict the outcome of depression, it may mediate executive function improvements following MST.

Neurophysiological markers of response to theta burst stimulation in youth depression.

BACKGROUND: Theta burst stimulation (TBS) has recently been proposed as a novel treatment for youth depression. However, the impact of TBS on the youth brain and neurophysiological predictors of response to TBS in this population have not been investigated. METHODS: Cortical reactivity was assessed at baseline and following 2 weeks of bilateral dorsolateral prefrontal cortex (DLPFC) TBS treatment in 16 youth with depression (aged 16-24 years old). In 16 age-matched health youths, cortical reactivity was assessed twice, 2 weeks apart. Transcranial magnetic stimulation (TMS) combined with electroencephalography was used to assess TMS-evoked potentials in bilateral DLPFC, motor cortices, and intraparietal lobules (IPL). Resting-state functional magnetic resonance imaging (fMRI) data was also collected at baseline. RESULTS: Left DLPFC pretreatment cortical reactivity, specifically the negativity at 45 ms (i.e., N45), which is related to GABAA neurotransmission, was associated with changes in depressive symptoms. Furthermore, TBS treatment was found to alter the N45 in the right IPL, a site distal to the treatment sites. The magnitude of the right IPL N45 modulation was correlated with the baseline fMRI connectivity between the right IPL and right DLPFC. CONCLUSIONS: TMS-probed cortical inhibition at the site of TBS application may have potential as a predictor of treatment response in youth depression. Furthermore, pre-treatment functional connectivity may predict the impact of TBS on the neurophysiology of regions distal to the stimulation site. Collectively, these results offer novel neurophysiological insights into the application of TBS for youth depression, which may facilitate its wider use in the youth population.

A pilot study of magnetic seizure therapy for treatment-resistant obsessive-compulsive disorder.

BACKGROUND: There is growing interest in the potential of neuromodulation options in treatment-resistant obsessive-compulsive disorder (OCD). Magnetic seizure therapy (MST), is a new treatment intervention in which generalized seizures are induced with transcranial magnetic stimulation. We conducted a pilot study to assess the efficacy and cognitive effects of MST in patients with treatment-resistant OCD. METHODS: In an open-label pilot study, participants with treatment-resistant OCD and a baseline Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores of ≥16 were treated with up to 24 acute treatments. The primary clinical outcomes were clinical response (Y-BOCS score reduction ≥30%) and remission (final Y-BOCS score ≤8). A neurocognitive battery, the Quick Inventory for Depressive Symptoms-Self Report (QIDS-SR), the Beck Scale for Suicidal Ideation (SSI), and the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) were also completed as secondary measures. RESULTS: Ten participants with OCD who had not responded to medications or psychotherapy enrolled in the study and seven completed an adequate trial (defined as ≥8 treatments). MST was associated with minimal cognitive effects except for some decrease in autobiographical memory and no serious adverse effects. Only one participant met the predefined criteria for response, and none for remission. The baseline and endpoint Y-BOCS scores were not statistically different. CONCLUSION: Overall, MST was not beneficial in a small group of patients with treatment-resistant OCD. At this time, other studies of MST for OCD are not warranted until different coil placements targeting other brain circuits can be proposed.

Prefrontal Cortical Reactivity and Connectivity Markers Distinguish Youth Depression from Healthy Youth.

Up to 50% of youth with depression do not respond to conventional first-line treatments. However, little research has been conducted on the pathophysiology of youth depression, hindering the identification of more effective treatments. Our goal was to identify neurophysiological markers that differentiate youth with depression from healthy youth and could serve as targets of novel treatments. We hypothesized that youth with depression would exhibit network-specific cortical reactivity and connectivity abnormalities compared with healthy youth. Transcranial magnetic stimulation combined with electroencephalography and magnetic resonance imaging was employed in combination with clinical and behavioral assessments to study cortical reactivity and connectivity in bilateral dorsolateral prefrontal cortex (DLPFC), motor cortex, and inferior parietal lobule, sites linked to the frontoparietal network, sensorimotor network, and default mode network, respectively. In youth depression, greater cortical reactivity was observed specific to the left and right DLPFC stimulation only, which correlated with anhedonia scores. Additionally, the connectivity of the right DLPFC was significantly higher in youth depression. Source reconstruction attributed the observed connectivity dysregulation to regions belonging to the default mode network. The neurophysiological signatures identified in this study have high potential to inform the development of more effective and targeted interventions for the youth depression population.

Online Mindfulness-Based Cognitive Behavioral Therapy Intervention for Youth With Major Depressive Disorders: Randomized Controlled Trial.

BACKGROUND: Approximately 70% of mental health disorders appear prior to 25 years of age and can become chronic when ineffectively treated. Individuals between 18 and 25 years old are significantly more likely to experience mental health disorders, substance dependencies, and suicidality. Treatment progress, capitalizing on the tendencies of youth to communicate online, can strategically address depressive disorders. OBJECTIVE: We performed a randomized controlled trial (RCT) that compared online mindfulness-based cognitive behavioral therapy (CBT-M) combined with standard psychiatric care to standard psychiatric care alone in youth (18-30 years old) diagnosed with major depressive disorder. METHODS: Forty-five participants were randomly assigned to CBT-M and standard care (n=22) or to standard psychiatric care alone (n=23). All participants were provided standard psychiatric care (ie, 1 session per month), while participants in the experimental group received an additional intervention consisting of the CBT-M online software program. Interaction with online workbooks was combined with navigation coaching delivered by phone and secure text messaging. RESULTS: In a two-level linear mixed-effects model intention-to-treat analysis, significant between-group differences were found for the Beck Depression Inventory-II score (difference -8.54, P=.01), Quick Inventory of Depressive Symptoms score (difference -4.94, P=.001), Beck Anxiety Inventory score (difference -11.29, P<.001), and Brief Pain Inventory score (difference -1.99, P=.03), while marginal differences were found for the Five Facet Mindfulness Questionnaire-Nonjudging subscale (difference -2.68, P=.05). CONCLUSIONS: These results confirm that youth depression can be effectively treated with online CBT-M that can be delivered with less geographic restriction. TRIAL REGISTRATION: Clinical Trials.gov NCT03406052; https://www.clinicaltrials.gov/ct2/show/NCT03406052.

Magnetic seizure therapy is efficacious and well tolerated for treatment-resistant bipolar depression: an open-label clinical trial

Background: Treatment-resistant bipolar depression can be treated effectively using electroconvulsive therapy, but its use is limited because of stigma and cognitive adverse effects. Magnetic seizure therapy is a new convulsive therapy with promising early evidence of antidepressant effects and minimal cognitive adverse effects. However, there are no clinical trials of the efficacy and safety of magnetic seizure therapy for treatment-resistant bipolar depression. Methods: Participants with treatment-resistant bipolar depression were treated with magnetic seizure therapy for up to 24 sessions or until remission. Magnetic seizure therapy was applied over the prefrontal cortex at high (100 Hz; n = 8), medium (50 or 60 Hz; n = 9) or low (25 Hz; n = 3) frequency, or over the vertex at high frequency (n = 6). The primary outcome measure was the 24-item Hamilton Rating Scale for Depression. Participants completed a comprehensive battery of neurocognitive tests. Results: Twenty-six participants completed a minimally adequate trial of magnetic seizure therapy (i.e., ≥ 8 sessions), and 20 completed full treatment per protocol. Participants showed a significant reduction in scores on the Hamilton Rating Scale for Depression. Adequate trial completers had a remission rate of 23.1% and a response rate of 38.5%. Per-protocol completers had a remission rate of 30% and a response rate of 50%. Almost all cognitive measures remained stable, except for significantly worsened recall consistency on the autobiographical memory inventory. Limitations: The open-label study design and modest sample size did not allow for comparisons between stimulation parameters. Conclusion: In treatment-resistant bipolar depression, magnetic seizure therapy produced significant improvements in depression symptoms with minimal effects on cognitive performance. These promising results warrant further investigation with larger randomized clinical trials comparing magnetic seizure therapy to electroconvulsive therapy. Clinical trial registration: NCT01596608; clinicaltrials.gov

Minocycline as adjunctive treatment for treatment-resistant depression: study protocol for a double blind, placebo-controlled, randomized trial (MINDEP2).

BACKGROUND: Available evidence suggests that adjunctive treatment with immunomodulatory medications may be effective in the treatment of major depressive disorder (MDD). A pilot trial of the tetracycline minocycline as adjunctive treatment in treatment-resistant depression (TRD), produced promising results, however, a larger scale trial is needed to confirm the antidepressant actions of this drug. METHODS: This is a 12-week double blind, placebo-controlled, randomized trial of minocycline as an add-on to standard antidepressants for adults (age > 18) with DSM-5 major depressive episode, who have failed to respond to at least two adequate trials of antidepressant treatment. It is a parallel-arm study with 50 participants in each group. The primary outcome measure is change in 17-item Hamilton Depression Rating Scale (HRSD-17) total scores from baseline to week 12. Secondary measures include the Clinical Global Impression (CGI) scale, World Health Organization Quality of Life Short Version (WHOQOL-BREF) and the Generalized Anxiety Disorder scale (GAD-7). Peripheral inflammatory biomarkers will be collected at baseline, week 6 and 12. DISCUSSION: If minocycline is well tolerated and effective in reducing depressive symptoms in patients with TRD, it would warrant genuine consideration as a treatment option for TRD. Additionally, if results demonstrate that minocycline has antidepressant properties, and that changes in inflammatory status are associated with its antidepressant action, it will inform the development of individualized treatment for a subset of patients with MDD. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03947827. Registered 13th May, 2019.

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

BACKGROUND: Treatment-resistant major depressive disorder is common; repetitive transcranial magnetic stimulation (rTMS) by use of high-frequency (10 Hz) left-side dorsolateral prefrontal cortex stimulation is an evidence-based treatment for this disorder. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS that can be delivered in 3 min, versus 37·5 min for a standard 10 Hz treatment session. We aimed to establish the clinical effectiveness, safety, and tolerability of iTBS compared with standard 10 Hz rTMS in adults with treatment-resistant depression. METHODS: In this randomised, multicentre, non-inferiority clinical trial, we recruited patients who were referred to specialty neurostimulation centres based at three Canadian university hospitals (Centre for Addiction and Mental Health and Toronto Western Hospital, Toronto, ON, and University of British Columbia Hospital, Vancouver, BC). Participants were aged 18-65 years, were diagnosed with a current treatment-resistant major depressive episode or could not tolerate at least two antidepressants in the current episode, were receiving stable antidepressant medication doses for at least 4 weeks before baseline, and had an HRSD-17 score of at least 18. Participants were randomly allocated (1:1) to treatment groups (10 Hz rTMS or iTBS) by use of a random permuted block method, with stratification by site and number of adequate trials in which the antidepressants were unsuccessful. Treatment was delivered open-label but investigators and outcome assessors were masked to treatment groups. Participants were treated with 10 Hz rTMS or iTBS to the left dorsolateral prefrontal cortex, administered on 5 days a week for 4-6 weeks. The primary outcome measure was change in 17-item Hamilton Rating Scale for Depression (HRSD-17) score, with a non-inferiority margin of 2·25 points. For the primary outcome measure, we did a per-protocol analysis of all participants who were randomly allocated to groups and who attained the primary completion point of 4 weeks. This trial is registered with ClinicalTrials.gov, number NCT01887782. FINDINGS: Between Sept 3, 2013, and Oct 3, 2016, we randomly allocated 205 participants to receive 10 Hz rTMS and 209 participants to receive iTBS. 192 (94%) participants in the 10 Hz rTMS group and 193 (92%) in the iTBS group were assessed for the primary outcome after 4-6 weeks of treatment. HRSD-17 scores improved from 23·5 (SD 4·4) to 13·4 (7·8) in the 10 Hz rTMS group and from 23·6 (4·3) to 13·4 (7·9) in the iTBS group (adjusted difference 0·103 [corrected], lower 95% CI -1·16; p=0·0011), which indicated non-inferiority of iTBS. Self-rated intensity of pain associated with treatment was greater in the iTBS group than in the 10 Hz rTMS group (mean score on verbal analogue scale 3·8 [SD 2·0] vs 3·4 [2·0] out of 10; p=0·011). Dropout rates did not differ between groups (10 Hz rTMS: 13 [6%] of 205 participants; iTBS: 16 [8%] of 209 participants); p=0·6004). The most common treatment-related adverse event was headache in both groups (10 Hz rTMS: 131 [64%] of 204; iTBS: 136 [65%] of 208). INTERPRETATION: In patients with treatment-resistant depression, iTBS was non-inferior to 10 Hz rTMS for the treatment of depression. Both treatments had low numbers of dropouts and similar side-effects, safety, and tolerability profiles. By use of iTBS, the number of patients treated per day with current rTMS devices can be increased several times without compromising clinical effectiveness. FUNDING: Canadian Institutes of Health Research.

Extended course accelerated intermittent theta burst stimulation as a substitute for depressed patients needing electroconvulsive therapy.

In response to restrictions on electroconvulsive therapy (ECT) access during COVID-19, we designed a trial to assess the clinical outcomes service impacts, employing an extended course of accelerated intermittent theta burst stimulation (aiTBS), in patients with moderate to severe depression in need of ECT. This open label clinical trial was comprised of 3 phases: (i) an acute phase, where iTBS treatments were administered 8 times daily, for up to 10 days; (ii) a tapering phase of 2 treatment days per week for 2 weeks, followed by 1 treatment day per week for 2 weeks; and (iii) a symptom-based relapse prevention phase, whereby treatments were scheduled based on symptom re-emergence, for up to 6 months. Of the 155 patients who completed the acute phase of the study, the remission rate was 16.1%. The mean reduction from baseline on the HRSD-24 was 29.4% (p < 0.001) and the response rate was 25.2%. Of the 110 patients who completed the tapering phase, the mean reduction from baseline was 42.6% (p < 0.001) and response and remission rates were 49.6% and 34.8%, respectively. Of the 61 patients who were eligible for the relapse prevention phase, 43 completed, with a mean reduction from baseline of 60.1% (p < 0.001); 7 patients relapsed during this phase. This study demonstrated that an extended aiTBS protocol safely led to meaningful clinical outcomes in patients with severe depression, who otherwise would have received ECT, and thus reduced pressure on ECT services during the pandemic. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04384965 ( https://clinicaltrials.gov/study/NCT04384965?term=NCT04384965&rank=1 ).

The Use of Text Messaging as an Adjunct to Internet-Based Cognitive Behavioral Therapy for Major Depressive Disorder in Youth: Secondary Analysis.

BACKGROUND: As an established treatment for major depressive disorder (MDD), cognitive behavioral therapy (CBT) is now implemented and assessed in internet-based formats that, when combined with smartphone apps, enable secure text messaging. As an adjunct to such internet-based CBT (ICBT) approaches, text messaging has been associated with increased adherence and therapeutic alliance. OBJECTIVE: This study analyzed data from the intervention arm of a randomized control trial evaluating 24-week ICBT for MDD (intervention arm) against standard-care psychiatry (waitlist control). The aim of this secondary analysis was to assess MDD symptom improvement in relation to the frequency and content of text messages sent by ICBT participants to Navigator-Coaches during randomized control trial participation. Higher text frequency in general and in 3 conceptual categories (appreciating alliance, alliance building disclosures, and agreement confirmation) was hypothesized to predict larger MDD symptom improvement. METHODS: Participants were young adults (18-30 years) from the Centre for Addiction and Mental Health. The frequencies of categorized texts from 20 ICBT completers were analyzed with respect to MDD symptom improvement using linear regression models. Texts were coded by 2 independent coders and categorized using content analysis. MDD symptoms were measured using the Beck Depression Inventory-II (BDI-II). RESULTS: Participants sent an average of 136 text messages. Analyses indicated that BDI-II improvement was negatively associated with text messaging frequency in general (ß=-0.029, 95% CI -0.11 to 0.048) and in each of the 3 categories: appreciating alliance (ß=-0.096, 95% CI -0.80 to 0.61), alliance building disclosures (ß=-0.098, 95% CI -0.28 to 0.084), and agreement confirmation (ß=-0.076, 95% CI -0.40 to 0.25). Altogether, the effect of text messaging on BDI-II improvement was uniformly negative across statistical models. More text messaging appeared associated with less MDD symptom improvement. CONCLUSIONS: The hypothesized positive associations between conceptually categorized text messages and MDD symptom improvement were not supported in this study. Instead, more text messaging appeared to indicate less treatment benefit. Future studies with larger samples are needed to discern the optimal use of text messaging in ICBT approaches using adjunctive modes of communication. TRIAL REGISTRATION: Clinical Trials.gov NCT03406052; https://www.clinicaltrials.gov/ct2/show/NCT03406052.

Neural Correlates of the DEEPP (Anti-suicidal Response to Ketamine in Treatment-Resistant Bipolar Depression) Study: Protocol for a Pilot, Open-Label Clinical Trial.

BACKGROUND: Suicide is among the top 10 leading causes of death worldwide. Of people who died by suicide, the majority are diagnosed with depression. It is estimated that 25%-60% of people with bipolar depression (BD) will attempt suicide at least once, and 10%-15% will die by suicide. Several treatments, such as lithium, clozapine, electroconvulsive therapy, and cognitive behavioral therapy, have been shown to be effective in treating suicidality. However, these treatments can be difficult to tolerate or may take months to take effect. Ketamine, a glutamate N-methyl-D-aspartate antagonist, has been shown to have rapid antisuicidal effect and antidepressant qualities, and is thus a promising intervention to target acute suicidality in patients with BD. However, the biological mechanism underlying its therapeutic action remains poorly understood. Enhancing our understanding of underlying mechanisms of action for ketamine's effectiveness in reducing suicidality is critical to establishing biological markers of treatment response and developing tailored, personalized interventions for patients with BD. OBJECTIVE: This is an open-label clinical trial to test the safety and feasibility of repeated ketamine infusions to treat acute suicidality. The primary objective is to test the safety and feasibility of ketamine intervention. The secondary objective is to examine ketamine's potential neurophysiological mechanisms of action by assessing cortical excitation and inhibition to determine potential biomarkers of clinical response. Other objectives are to evaluate the effect of ketamine on acute suicidality and other clinical outcomes, such as depressive symptoms and quality of life, to inform a future larger trial. METHODS: This open-label clinical trial aims to test the safety and feasibility of repeated ketamine infusions in patients with BD for suicidality and to assess ketamine's neurophysiological effects. A sterile form of racemic ketamine hydrochloride will be administered over a 40-minute intravenous infusion 2 times per week on nonconsecutive days for 4 weeks (8 sessions). We will recruit 30 adults (24-65 year olds) over 2 years from an academic psychiatric hospital in Toronto, Canada. RESULTS: This study is currently ongoing and actively recruiting participants. So far, 5 participants have completed the trial, 1 is currently in active treatment, and 8 participants are on the waitlist to be screened. We anticipate initial results being available in the fall of 2023. This proposal was presented as a poster presentation at the Research to Reality Global Summit on Psychedelic-Assisted Therapies and Medicine, held in May 2022 in Toronto, Canada. CONCLUSIONS: Developing effective interventions for acute suicidality in high-risk populations such as those with BD remains a major therapeutic challenge. Ketamine is a promising treatment due to its rapid antidepressant and antisuicidal effects, but its underlying neurophysiological mechanisms of action remain unknown. TRIAL REGISTRATION: ClinicalTrials.gov NCT05177146; https://clinicaltrials.gov/ct2/show/NCT05177146. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/41013.

The Role of Daily Steps in the Treatment of Major Depressive Disorder: Secondary Analysis of a Randomized Controlled Trial of a 6-Month Internet-Based, Mindfulness-Based Cognitive Behavioral Therapy Intervention for Youth.

BACKGROUND: Current evidence supports physical activity (PA) as an adjunctive treatment for major depressive disorder (MDD). Few studies, however, have examined the relationship between objectively measured PA and MDD treatment outcomes using prospective data. OBJECTIVE: This study is a secondary analysis of data from a 24-week internet-based, mindfulness-based cognitive behavioral therapy program for MDD. The purpose of this analysis was twofold: (1) to examine average daily step counts in relation to MDD symptom improvement, and whether pain moderated this relationship; and (2) to examine whether changes in step activity (ie, step trajectories) during treatment were associated with baseline symptoms and symptom improvement. METHODS: Patients from the Centre for Addiction and Mental Health were part of a randomized controlled trial evaluating the effects of internet-based, mindfulness-based cognitive behavioral therapy for young adults (aged 18-30 years old) with MDD. Data from 20 participants who had completed the intervention were analyzed. PA, in the form of objectively measured steps, was measured using the Fitbit-HR Charge 2 (Fitbit Inc), and self-reported depression severity was measured with the Beck Depression Inventory-II (BDI-II). Linear regression analysis was used to test PA's relationship with depression improvement and the moderating effect of pain severity and pain interference. Growth curve and multivariable regression models were used to test longitudinal associations. RESULTS: Participants walked an average of 8269 steps per day, and each additional +1000-step difference between participants was significantly associated with a 2.66-point greater improvement (reduction) in BDI-II, controlling for anxiety, pain interference, and adherence to Fitbit monitoring (P=.02). Pain severity appeared to moderate (reduce) the positive effect of average daily steps on BDI-II improvement (P=.03). Higher baseline depression and anxiety symptoms predicted less positive step trajectories throughout treatment (Ps≤.001), and more positive step trajectories early in the trial predicted greater MDD improvement at the end of the trial (Ps<.04). However, step trajectories across the full duration of the trial did not significantly predict MDD improvement (Ps=.40). CONCLUSIONS: This study used objective measurements to demonstrate positive associations between PA and depression improvement in the context of cognitive behavioral treatment. Pain appeared to moderate this relationship, and baseline symptoms of anxiety and depression predicted PA trajectories. The findings inform future interventions for major depression. Future research with larger samples should consider additional moderators of PA-related treatment success and the extent to which outcomes are related to PA change in multimodal interventions. TRIAL REGISTRATION: Clinical Trials.gov NCT03406052; https://www.clinicaltrials.gov/ct2/show/NCT03406052. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/11591.

Exploring women's experiences of treatment for binge eating disorder: Methylphenidate vs. cognitive behavioural therapy.

OBJECTIVE: The current qualitative study explored the personal experiences of a sample of women with binge eating disorder (BED). The women were previously enrolled in a 12-week randomized controlled trial comparing pharmacotherapy (methylphenidate [MP]) and cognitive behavioural therapy (CBT). METHODS: Semi-structured interviews were conducted with 15 women who completed the trial (8 MP, 7 CBT) to obtain their narrative accounts. Key themes were then identified from transcribed tape recordings, using thematic analysis. RESULTS: Participants described self-awareness as bringing greater attention to their binge eating, and to their thoughts and emotions. Furthermore, both groups valued the interpersonal relationships with the clinicians and their ability to create a safe and comforting environment. In the MP group, many participants described the medication as reducing their preoccupation with food, and hence, binge frequency. In CBT, there was a focus on psychoeducation and obtaining a "toolbox" of long-term binge-management skills that could also be used following treatment. In both groups, stress was described as a primary trigger for a binge and/or a cause of relapse. DISCUSSION: Although patients reported having a positive experience in the therapies, it is suggested that broader stress regulation skills training would be useful to evaluate further, to bolster relapse prevention skills. These qualitative findings add a much-needed lived-experience perspective on clinical treatments for binge eating. This is especially significant considering that a psychostimulant similar to MP is the only approved pharmacotherapy for BED, and to date, little is known about the patient's subjective experiences when taking this medication.

The Safety, Clinical, and Neurophysiological Effects of Intranasal Ketamine in Patients Who Do Not Respond to Electroconvulsive Therapy: Protocol for a Pilot, Open-Label Clinical Trial.

BACKGROUND: Major depressive disorder is among the most disabling illnesses worldwide, with a lifetime prevalence of 16.2%. Research suggests that 20% to 40% of patients with depression do not respond to pharmacotherapy, developing treatment-resistant depression. Electroconvulsive therapy is the gold standard for treating individuals with treatment-resistant depression, with remission rates of approximately 75% to 90%. However, 10% to 25% of patients do not respond to electroconvulsive therapy, and many are unable to tolerate it due to the side effects. Both groups are considered to be patients who do not respond to electroconvulsive therapy, because both groups continue to exhibit symptoms of severe depression, have a limited number of treatment options available, and are in need of rapid treatment. Ketamine, an N-methyl-D-aspartate receptor antagonist, has been shown to exert rapid antidepressant effects in patients with treatment-resistant depression when administered in subanesthetic doses through 40-minute intravenous infusions. Recently, a ketamine compound, esketamine (Spravato), that is administered through the intranasal route received regulatory approval by the US Food and Drug Administration and Health Canada to treat depression. However, esketamine is challenging to access due to high costs and limited availability. Racemic ketamine (rketamine) is cheap and easy to access; however, the effects in patients who have not responded to electroconvulsive therapy have yet to be understood or tested. This study will use transcranial magnetic stimulation to study mechanisms of human brain cortical physiology at the systemic level to identify neurobiomarkers of response. OBJECTIVE: The objective of this open-label pilot clinical trial is to test the feasibility and safety of intranasal ketamine in patients who have not responded to electroconvulsive therapy. The primary outcome is to determine the feasibility of a larger randomized controlled trial to test the efficacy of intranasal ketamine for patients who have not responded to electroconvulsive therapy for clinical indicators in unipolar depression. The secondary outcome is to determine the preliminary effects of an intervention on clinical outcomes, such as depressive symptoms, suicidal ideation, and quality of living. The third outcome is to explore neurophysiological changes as measured by transcranial magnetic stimulation electromyography and electroencephalography to measure changes in cortical excitability as potential predictors of clinical response. METHODS: A sterile solution of racemic ketamine hydrochloride will be administered twice per week for 4 weeks (8 sessions) intranasally to patients with treatment-resistant depression who did not respond to or could not tolerate an acute course of electroconvulsive therapy. We will recruit 25 adults (24-65 years old) over the course of 2 years from an academic psychiatric hospital in Toronto, Canada. RESULTS: This study has received ethics approval, and funding has been secured. The study is currently active. CONCLUSIONS: This is the first study to test repeated doses of intranasal rketamine in patients who have not responded to electroconvulsive therapy for depression. Results from this study will (1) inform the development of a larger adequately powered randomized controlled trial to test the efficacy of intranasal ketamine for depression and (2) determine potential neurophysiological markers of clinical response. TRIAL REGISTRATION: Clinical Trials.gov NCT05137938; http://clinicaltrials.gov/ct2/show/NCT05137938. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/30163.

Benefits of Digital Mental Health Care Interventions for Correctional Workers and Other Public Safety Personnel: A Narrative Review.

Chronic exposure to stressors and potentially psychologically traumatic events contributes to the high prevalence of mental health disorders in correctional workers (CWs) and other public safety personnel (PSP). Digital mental health interventions are an accessible and scalable method of improving and maintaining the mental health of this population. The current review explores the benefits of digital mental health interventions for PSP-with a focus on CWs-and how these innovations can address the limitations in in-person mental health care. A systematic literature search of five databases (Medline, PsycInfo, Embase, CINAHL, Google Scholar) was conducted until March 2022. The search yielded 16 publications that focused on digital mental health interventions or care available to CWs and other PSP. The benefits of digital innovations were summarized into five categories which discussed (1) their ability to enhance accessibility and reduce stigma; (2) the provision of evidence-based and structured psychotherapy programs; (3) variability in the degree of therapist engagement; (4) the integration of proactive interventions; and (5) enhancing engagement by acknowledging unique experiences and interpersonal relationships. Although digital mental health technologies for CWs are still in their infancy, there is strong evidence to support their effectiveness in ameliorating symptoms of mental distress. Future research should consider how ethnicity, gender, culture, sexual orientation, and socioeconomic status can be integrated into these therapies and how the interplay between different stakeholders and organizations can impact the effectiveness of online therapies and programs.

A qualitative exploration of the mental health challenges and therapeutic needs of Canadian correctional workers.

Purpose: Correctional work is described as a high-stress environment associated with increased prevalence of mental health disorders in employees. Identifying appropriate healthcare services necessitates investigating the mental health challenges and needs of correctional workers (CWs). Methods: Individual interviews (n = 9; 5 M and 4 W) and a mixed gender focus group (n = 6; 3 M and 3 W) were conducted to gather a general sense of the mental health landscape. Data were analyzed to develop a targeted and comprehensive question guide for gender-specific focus groups (n = 14 unique participants; 6 M and 8 W). Results: Eight themes emerged from the gender-specific focus groups. Themes focusing on work culture described the negative repercussions of job stress and the inability to discuss challenges openly due to confidentiality concerns and feelings of seclusion associated with the CW profession. Men were more likely to be subjected to physical violence and women to emotional and sexual harassment from staff and inmates. Themes related to mental health care described the benefits and limitations of the current services and digital mental healthcare. Stigma and accessibility were notable treatment barriers. Lastly, sector-specific therapy was seen as an important component in enhancing engagement and therapist interaction. Conclusion: The study demonstrates the interconnection between work culture and CW mental health that needs to be acknowledged when addressing mental health care.

Correction: Comparing Online and On-Site Cognitive Behavior Therapy in Major Depressive Disorder: Protocol for a Noninferiority Randomized Controlled Trial.

[This corrects the article DOI: 10.2196/29726.].

Comparing Online and On-Site Cognitive Behavior Therapy in Major Depressive Disorder: Protocol for a Noninferiority Randomized Controlled Trial.

BACKGROUND: The incidence of mental health disorders in Canada is increasing with costs of CAD $51 billion (US $40 billion) per year. Depression is the most prevalent cause of disability while cognitive behavioral therapy (CBT) is the best validated behavioral depression treatment. CBT, when combined with mindfulness meditation (CBT-M), has strong evidence for increased efficacy. While randomized controlled trials (RCTs) have demonstrated online CBT-M efficacy, comparisons with in-office delivery are lacking. OBJECTIVE: The aim of this research is to assess whether online group CBT-M (with standard psychiatric care) is non-inferior in efficacy and more cost-effective than office-based, on-site group CBT-M at post-intervention and 6-months follow-up in major depressive disorder. The study will also assess whether digitally recorded data (ie, online workbooks completed, Fitbit step count, and online text messages) predict depression symptom reduction in online participants. METHODS: This single-center, two-arm, noninferiority RCT employs assessor-blinded and self-report outcomes and economic evaluation. The research site is the Centre for Addiction and Mental Health (Toronto), a research-based psychiatry institution where participants will be identified from service wait lists and through contacts with other Toronto clinics. Inclusion criteria are as follows: (1) aged 18-60 years, any ethnicity; (2) Beck Depression Inventory-II (BDI-II) of mild severity (score ≥14) with no upper severity limit; (3) Mini-International Neuropsychiatric Interview-confirmed, psychiatric major depressive disorder diagnosis; (4) fluent in English. All patients are diagnosed by staff psychiatrists. Exclusion criteria are as follows: (1) receipt of weekly structured psychotherapy; (2) observation of Diagnostic and Statistical Manual of Mental Disorders (5th Edition) criteria for severe alcohol or substance use disorder (in past 3 months), borderline personality disorder, schizophrenia (or other primary psychotic disorder), bipolar disorder, or obsessive-compulsive disorder; (3) clinically significant suicidal ideation (imminent intent or attempted suicide in the past 6 months); and (4) treatment-resistant depression. All participants receive standard psychiatric care, experimental participants receive online group CBT-M, and controls receive standard care in-office group CBT-M. The online group program (in collaboration with NexJ Health, Inc) combines smartphone and computer-accessed workbooks with mental health phone counselling (16 hours in 16 weeks) that coordinates software interactions (eg, secure text messaging and Fitbit-tracked walking). The primary outcome is BDI-II, and secondary outcomes are anxiety (Beck Anxiety Inventory), depression (ie, Quick Inventory of Depressive Symptomatology and 17-item Hamilton Depression Rating Scale), mindfulness (Five-Facet Mindfulness Questionnaire), quality of life (European Quality of Life Five Dimension), and pain (Brief Pain Inventory). RESULTS: Based on prior studies with the BDI-II and 80% power to reject an inferiority hypothesis with a 1-sided type I error rate of 5%, a sample of 78 per group is adequate to detect small-to-medium-effect sizes. CONCLUSIONS: This study assesses online CBT-M efficacy and noninferiority in relation to in-person CBT, and the cost-effectiveness of both interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT04825535; https://www.clinicaltrials.gov/ct2/show/NCT04825535. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/29726.