Predictors of remission after repetitive transcranial magnetic stimulation for the treatment of late-life depression.

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment in patients with depression, yet treatment response remains variable. While previous work has identified predictors of remission in younger adults, relatively little data exists in late-life depression (LLD). To address this gap, data from 164 participants with LLD from a randomized non-inferiority treatment trial comparing standard bilateral rTMS to bilateral theta burst stimulation (TBS) (ClinicalTrials.gov identifier: NCT02998580) were analyzed using binary logistic regression and conditional inference tree (CIT) modeling. Lower baseline depression symptom severity, fewer prior antidepressant treatment failures, and higher global cognition predicted remission following rTMS treatment. The CIT predicted a higher likelihood of achieving remission for patients with a total score of 19 or lower on the Montgomery-Åsberg Depression Rating Scale, 1 or fewer prior antidepressant treatment failures, and a total score of 23 or higher on the Montreal Cognitive Assessment. Our results indicate that older adults with lower severity of depression, fewer antidepressant treatment failures, and higher global cognition benefit more from current forms of rTMS. The results suggest that there is potentially higher value in using rTMS earlier in the treatment pathway for depression in older adults.

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.

Efficacy of insula deep repetitive transcranial magnetic stimulation combined with varenicline for smoking cessation: A randomized, double-blind, sham controlled trial.

BACKGROUND: Current smoking cessation treatments are limited in terms of efficacy, particularly with regards to long term abstinence. There is a large amount of evidence implicating the insula in nicotine addiction. OBJECTIVE: To examine the efficacy of bilateral repetitive transcranial magnetic stimulation (rTMS) directed to the insular cortex with the H11 coil, relative to sham stimulation, on smoking abstinence and smoking outcomes in smokers who are receiving standard varenicline treatment. METHODS: This randomized, double-blind, sham controlled trial recruited 42 participants who were randomized to receive either active (n = 24) or sham (n = 18) high frequency rTMS directed to the insula (4 weeks), while receiving varenicline treatment (12 weeks). The primary outcome was 7-day point prevalence abstinence at the end of 12 weeks. RESULTS: Smokers in the active group had significantly higher abstinence rates than those in the sham group (82.4% vs. 30.7%, p = 0.013) at the end of treatment (Week 12). Secondary outcome measures of abstinence rate at the end of rTMS treatment (Week 4), abstinence rate at 6 months, and smoking outcomes (e.g., craving, withdrawal) showed no significant differences between groups. No differences were found in adverse events reported between the groups. CONCLUSION: This study provides evidence of the potential benefit of having a combined treatment for smoking cessation using insula rTMS with the H11 coil and varenicline. Maintenance rTMS sessions and continuation of varenicline for those in abstinence may induce longer-term effects and should be considered in future studies.

Effect of prior pharmacotherapy on remission with sequential bilateral theta-burst versus standard bilateral repetitive transcranial magnetic stimulation in treatment-resistant late-life depression.

Repetitive transcranial magnetic stimulation (rTMS) is used for treatment of late-life depression. In the FOUR-D study, sequential bilateral theta-burst stimulation (TBS) had comparable remission rates to standard bilateral rTMS. Data were analysed from the FOUR-D trial to compare remission rates between two types of rTMS based on the number and class of prior medication trials. The remission rate was higher in participants with ≤1 previous trial (43.9%) than in participants with 2 previous trials (26.5%) or ≥3 previous trials (24.6%; χ² = 6.36, d.f. = 2, P = 0.04). Utilising rTMS earlier in late-life depression may lead to better outcomes.

Effectiveness of Standard Sequential Bilateral Repetitive Transcranial Magnetic Stimulation vs Bilateral Theta Burst Stimulation in Older Adults With Depression: The FOUR-D Randomized Noninferiority Clinical Trial.

Importance: Treatment-resistant depression (TRD) is common in older adults. Bilateral repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex for 48 minutes has demonstrated efficacy in TRD. Theta burst stimulation (TBS), a newer form of rTMS, can also be delivered bilaterally using left intermittent TBS and right continuous TBS for only 4 minutes. Objective: To establish the effectiveness and tolerability of TBS compared with standard rTMS in older adults with TRD. Design, Setting, and Participants: In this randomized noninferiority trial with open treatment and blinded assessors, recruitment occurred between December 2016 and March 2020. The trial was conducted at the Centre for Addiction and Mental Health in Toronto, Ontario, Canada and included outpatients 60 years and older with a diagnosis of depression, moderate severity, and nonresponse to 1 or more antidepressant trial of adequate dosage and duration or intolerance of 2 or more trials. Interventions: Participants were randomized to receive a course of 4 to 6 weeks of either bilateral standard rTMS or TBS. Main Outcomes and Measures: The primary outcome measure was change in Montgomery-Åsberg Depression Rating Scale; secondary outcome measures included the 17-item Hamilton Rating Scale for Depression, Quick Inventory of Depressive Symptomatology (16-item) (self-report), and dropout rates. A noninferiority margin of 2.75 points was used for the primary outcome. All participants who attained the primary completion point of 4 weeks were analyzed. Results: A total of 87 participants (mean [SD] age, 67.1 [6.7] years; 47 [54.0%] female) were randomized to standard bilateral rTMS and 85 (mean [SD] age, 66.3 [5.3] years; 45 [52.9%] female) to TBS, of whom 85 (98%) and 79 (93%) were assessed for the primary outcome, respectively, whereas tolerability was assessed in all randomized participants. In the rTMS group, 4 (4.6%) were American Indian, reported other, or preferred not to answer; 5 (5.8%) were Asian; and 78 (89.7%) were White. In the TBS group, 6 (7.1%) were Asian, 2 (2.4%) were Black or reported other, and 77 (90.3%) were White. Mean (SD) Montgomery-Åsberg Depression Rating Scale total scores improved from 25.6 (4.0) to 17.3 (8.9) for rTMS and 25.7 (4.7) to 15.8 (9.1) for TBS (adjusted difference, 1.55; lower 95% CI -0.67), establishing noninferiority for TBS. The all-cause dropout rates were relatively similar between groups (rTMS: 2 of 87 [2.3%]; TBS: 6 of 85 [7.1%]; P = .14; χ2 = 2.2). Conclusions and Relevance: In older adults with TRD, bilateral TBS compared with standard bilateral rTMS achieved noninferior reduction in depression symptoms. Both treatments had low and similar dropout rates. Using TBS rather than rTMS could increase access to treatment several-fold for older adults with TRD. Trial Registration: ClinicalTrials.gov Identifier: NCT02998580.

Repetitive transcranial magnetic stimulation in patients with borderline personality disorder: A systematic review.

The literature on the application of repetitive transcranial magnetic stimulation (rTMS) in Borderline Personality Disorder (BPD) is unclear, even though its neuromodulatory effects on underlying neural circuitry involved in BPD symptoms suggest that it could be a potential treatment option. We sought to review the evidence on rTMS as a treatment option in BPD. PubMed (for Medline database), Google Scholar, and Scopus were systematically searched following the PRISMA guidelines for studies of any design examining the application of the rTMS treatment in adult patients with precise and primary diagnosis of BPD written in the English language. The systematic review has been registered on PROSPERO (CRD42020215927). Forty one records were screened, and eight fulfilled inclusion criteria (total of 63 patients). The existing studies suggest that rTMS is a well-tolerated treatment in patients with BPD. Double-blind randomized controlled studies are necessary to help elucidate the effects of rTMS in the different symptoms in BPD and establish efficacy and the best cortical targets and stimulation protocols. Longitudinal studies that combine evidenced based psychotherapy with rTMS may be a future line of investigation that could potentially improve outcomes for this population.

Is Obesity A Determinant Of Success With Pharmacological Treatment For Depression? A Systematic Review, Meta-Analysis And Meta-Regression.

BACKGROUND: The bidirectional association between Major Depressive Disorder (MDD) and obesity suggests that body mass index (BMI) at the baseline could influence remission rates (RR) with pharmacological treatment. We evaluated the influence of baseline BMI on the chances of remission among patients with MDD administered antidepressants. METHODS: Based on the guidelines of the PRISMA statement, we conducted a systematic review on PubMed, Cochrane and Embase databases with subsequent meta-analysis and meta-regression. We included only randomized controlled trials evaluating the efficacy of antidepressants of different classes (monotherapy and combined therapies) that evidenced baseline BMI assessment. We created a model to describe the linear relationship between baseline BMI and RR. RESULTS: Our systematic review yielded 70 studies with a total of 9,779 patients in the active group and 7,136 patients in the placebo group. In placebo controlled studies, BMI influenced the RR of patients randomized to active treatment. The RR for antidepressants in monotherapy was higher in normal weight to overweight patients rather than obese patients (33% vs 12%, respectively). Also in monotherapy, the RR is higher when the study is conducted on patients with a lower baseline BMI (p=0.029). For combined therapies, the pooled RR was higher in obese patients rather than in normal weight to overweight patients (75% vs 17%, respectively). LIMITATIONS: BMI provides no information about body composition and obesity can be related to several potential confounders that potentially influence RR. CONCLUSION: The RR with antidepressant therapy seems to be associated with baseline BMI in patients with MDD, although this simple variable was insufficiently explored so far.

Effect of repetitive transcranial magnetic stimulation on anxiety symptoms in patients with major depression: An analysis from the THREE-D trial.

BACKGROUND: Despite the advances in the use of repetitive transcranial magnetic stimulation (rTMS) for the treatment of major depressive disorder (MDD), there is relatively little information about its effect on comorbid anxiety symptoms. METHODS: Data from a large randomized noninferiority trial comparing intermittent theta-burst stimulation (iTBS) and high-frequency (10 Hz) rTMS delivered to the left dorsolateral prefrontal cortex (HFL) were analyzed. The primary aim was assessing changes in anxiety/somatization items from the 17-item Hamilton Depression Rating Scale (HAM-D) and the Brief Symptom Inventory (BSI-A), using baseline-adjusted change with an analysis of covariance (ANCOVA), with the final scores as the outcome and baseline scores as the adjustment covariates. RESULTS: The analytical cohort comprised 388 participants (189 in HFL and 199 in iTBS groups). From baseline to the end of the rTMS course, the combined score from the anxiety items from the HAM-D dropped from 7.43 (SD = 2.15) to 4.24 (SD = 2.33) in the HFL group, and 7.33 (SD = 2.13) to 3.76 (SD = 2.23) in the iTBS group. The ANCOVA resulted in an effect from time (p < .0001), but not from group allocation (p = .793) or time × group interaction (p = .976). We observed mean changes in the BSI-A of -3.5 (SD = 5.4) and -3.2 (SD = 4.8), with significant effect of time (p < .0001) in the ANCOVA, but not group allocation (p = .793) or group × time interaction (.664). CONCLUSIONS: Our findings suggest that both 10 Hz and iTBS may yield potential reductions in anxiety symptoms when used for the treatment of MDD. Our findings warrant future research into the effects of left-sided rTMS on depressed patients struggling with concurrent anxiety symptoms.

Predictors of remission after repetitive transcranial magnetic stimulation for the treatment of major depressive disorder: An analysis from the randomised non-inferiority THREE-D trial.

BACKGROUND: Although repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depressive disorder (MDD), treatment selection is still mainly a process of trial-and-error. The present study aimed to identify clinical predictors of remission after a course of rTMS delivered to the left DLPFC to improve patient selection. METHODS: Data from a large randomised non-inferiority trial comparing standard 10 Hz and intermittent theta burst stimulation (iTBS) for the treatment of MDD were used for the exploratory analyses. Individual variables were assessed for their association with remission and then included in a logistic regression model to determine odds ratios (OR) and corresponding 95% confidence intervals. Model discrimination (internal validation) was carried out to assess model optimism using the c-index. ClinicalTrials.gov identifier: NCT01887782. FINDINGS: 388 subjects were included in the analysis (199-iTBS and 189-10 Hz, respectively). Higher baseline severity of both depressive and anxiety symptoms were associated with a lower chance of achieving remission (OR=0.64, 95% CI 0.46-0.88; and 0.78, 95% CI 0·60-0.98, respectively). Current employment was a positive predictor for remission (OR=1.69, 95% CI 1.06-2.7), while greater number of treatment failures was associated with lower odds of achieving remission (OR=0.51, 95% CI 0.27-0.98). A non-linear effect of age and remission was observed. An analysis to allow an estimate of the probability of remission using all variables was assessed. The c-index for the fitted model was 0.687. INTERPRETATION: Our results suggest that measuring depression symptom severity, employment status, and refractoriness are important in prognosticating outcome to a course of rTMS in MDD. FUNDING: Canadian Institutes of Health Research MOP-136801.

An Update on Repetitive Transcranial Magnetic Stimulation for the Treatment of Major Depressive Disorder.

Repetitive transcranial magnetic stimulation (rTMS) has emerged as an evidenced-based treatment for major depression that does not respond to standard first-line therapies. The majority of data support the use of high-frequency (10 Hz) treatment delivered to the left dorsolateral prefrontal cortex. Intermittent theta burst stimulation is a new emerging treatment that reduces the time required to deliver treatment and can increase capacity and access to this treatment. This review will comprehensively cover recent advancements in the field of rTMS for depression, including stimulation parameters and targets aimed at enhancing outcomes. In addition, efforts to use modern neuroscience tools to personalize this treatment and optimize outcomes will be reviewed.

Editorial: Transcutaneous Trigeminal Nerve Stimulation for Children With Attention-Deficit/Hyperactivity Disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a prevalence of 9.5% of school-aged children and 4.4% of adults in the United States. ADHD is defined by clinically significant and developmentally inappropriate levels of inattention and hyperactivity/impulsivity. Executive functioning and control and attention regulation are the neuropsychological deficits commonly associated with ADHD.1.

Hypersomnia and Bipolar Disorder: A systematic review and meta-analysis of proportion.

BACKGROUND: Hypersomnia is a common problem amongst individuals with Bipolar Disorder (BD). The objective of this meta-analysis is to estimate the frequency of hypersomnia in individuals with BD, and identify associated factors METHODS: Our search focused on articles documenting the frequency of hypersomnia among individuals with BD indexed in PubMed database and in the Cochrane Library, following the recommendations from the Meta-Analysis Of Observational Studies in Epidemiology (MOOSE) Group. A meta-analysis of proportion was conducted; funnel plot and Egger's test were used for the assessment of publication bias. Subgroups analyses were performed in order to evaluate possible confounders and associated factors. RESULTS: We identified 10 studies, which included 1824 patients with BD. The overall estimate of the proportion of BD cases that reported hypersomnia was 29.9% [95% confidence interval (CI): 25.8 - 34.1%, I2 = 59.2%; p < .05]. The funnel plot and the Egger's test suggest a low risk of publication bias (p = .527). The polarity of mood state, Bipolar Disorder type, use of medication, age, diagnostic criteria and hypersomnia criteria were not significantly related to hypersomnia. LIMITATIONS: There is a possibility that smaller cross-sectional studies were not included. The high heterogeneity between studies is frequent in meta-analysis of both interventional and observational studies. Hypersomnia was not the primary outcome in some of the included studies. CONCLUSIONS: To our knowledge, this is the first systematic review and meta-analysis of hypersomnia prevalence in patients with BD. Further studies focused on clinical correlates and implications for health outcomes in BD are warranted.

Peripheral interleukin-6 levels and working memory in non-obese adults: A post-hoc analysis from the CALERIE study.

OBJECTIVES: This analysis aimed to investigate the association among interleukin 6 (IL-6) levels, caloric intake, and working memory and to explore the potential mediators of these associations using the public dataset from the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) clinical trial. METHODS: The CALERIE study was designed to evaluate the effects of 2 y of prolonged caloric restriction in humans. Individuals were randomized to caloric restriction (CR; n = 145) or an ad libitum diet (AL; n = 75) for 2 y. The outcome measures used herein were spatial working memory tests (i.e., total number of errors and strategy). Generalized estimating equations were used to assess the effects of treatment, time, and potential moderators (e.g., sleep and physical activities). RESULTS: At baseline, there was an effect of hours of sleep, alcohol intake, and physical activities (i.e., mean total metabolic equivalent of task hours per day [MET-hours/day]) on IL-6 levels. The association between IL-6 and energy intake was moderated by MET-hours/day. The longitudinal analysis indicated that there was an effect of time, but not of treatment, on IL-6 levels, with decreasing values in both the CR and AL groups. Changes in IL-6 levels were associated with changes in working memory performance, but there were no between-group (i.e., CR vs. AL) differences. CONCLUSIONS: We observed an association between changes in IL-6 levels and improvement in spatial working memory tests. IL-6 was associated with higher caloric consumption, poorer sleep quality, and lower levels of physical activity.

The effect of body mass index on glucagon-like peptide receptor gene expression in the post mortem brain from individuals with mood and psychotic disorders.

There is an increasing interest in the putative role of glucagon-like peptide 1 receptor (GLP-1R) agonists as novel therapeutic agents for mental disorders. Herein, we investigated the expressions of GLP-1R and GLP-2R genes, and its relationship with body mass index (BMI), in the post-mortem brain tissue of patients with mood (MD) and psychotic disorders. Brain samples were localized to the dorsolateral prefrontal cortex (dlPFC) (n = 459) and hippocampus (n = 378). After adjustment for age, sex, ethnicity, post-mortem interval (PMI) and BMI, we observed significant differences, between healthy controls and MD subjects, in GLP-1R and GLP-2R gene expression in the dlPFC (ß = 1.504, p = 0.004; and ß = 1.305, p = 0.011, respectively); whereas in the hippocampus, only GLP-1R expression was significantly associated with MD (ß = -1.28, p = 0.029). No significant differences were found in relation to schizophrenia. In addition, we observed a moderating effect of MD diagnosis on the associations between BMI, GLP-1R and GLP-2R expression values in the dlPFC (ß = -0.05, p = 0.003; and ß = -0.04, p = 0.004, respectively). There was a similar moderating effect for GLP-1R in the hippocampus (ß = 0.043, 95% CI 0.003; 0.08 p = 0.03), but in an opposite direction than observed in the dlPFC. This is the first evidence of abnormal gene expression of GLP-1R and GLP-2R in postmortem brain of individuals with MD, providing a rationale for further inquiry and proof of principle interventional studies.

The impact of body mass index in gene expression of reelin pathway mediators in individuals with schizophrenia and mood disorders: A post-mortem study.

The objective of this study was to compare the expression of genes involved in the reelin pathway, in the post-mortem brain of individuals with schizophrenia (SZ) and mood disorders (MD) with a healthy control (HC) group; and to investigate the role f body mass index (BMI) as a potential mediator. The "Gene Expression in Postmortem dlPFC and Hippocampus from Schizophrenia and Mood Disorders" study holds microarray data on individuals with SZ, MD and HCs (from whom 849 specimens are from the dlPFC and 579 from the hippocampus). mRNA data was obtained using HumanHT-12 v4 BeadChip arrays (Illumina). Multivariate analysis of covariance were used to investigate the main effects of group and relevant covariates on RELNm, NOTCH1, GRIN1m, GRIN3A, CAMK2Gm, CAMK2A, CAMK2Bm, CAMK2N2, GRIN2Bm, GRIN2A, CREBBPm, APOE, LDLR and DAB1 gene expression. In the dlPFC, individuals with SZ had higher expression, relative to HCs, of APOE. Individuals with MD had higher expression, relative to HCs, of CAMK2A, CAMK2N2, and GRIN2Bm. Moreover, individuals with MD had higher expression, relative to SZ patients, of CAMK2N2. There were significant group by BMI effects for expression of RELN, CAMK2A, CAMK2N2, and GRIN2A. In the hippocampus, individuals with MD had lower expression, relative to HCs, of APOE. The results of this study suggest that the expression of genes related to the reelin pathway could be different between individuals with SZ and MD and healthy controls, with a greater vulnerability associated with greater BMI.