Euthanasia requests in a Canadian psychiatric emergency room: A case series: Part 1 of the McGill University euthanasia in psychiatry case series.

Euthanasia was decriminalized in Quebec in December 2015, and Canada-wide in June 2016. Both the Provincial and Federal legislation have limited the right to medical assistance in dying (MAID) to end-of-life cases; which makes MAID inaccessible to most patients solely suffering from psychiatric illness. While some end-stage anorexia nervosa or elderly patients may meet the end-of-life criterion because of their medical comorbidities or their age (Kelly et al., 2003), repeated suicide attempts or psychotic disorganization would not qualify since they would not be seen as elements of an illness leading to a foreseeable "natural death" (Canada, 2016). This is in contradiction to other jurisdictions, such as Belgium and the Netherlands as well as the eligibility criteria stated in the Supreme Court of Canada's decision in Carter v. Canada (Supreme Court of Canada, 2015). Here we analyze three cases of patients who presented to a psychiatric emergency department and requested MAID for psychiatric reasons. While none of the patients were eligible for MAID under Canadian law, we find that their demographics match closely that of patients granted MAID for psychiatric reasons in jurisdictions where that practice is allowed. Based on these cases, we comment on potentially negative consequences that may come from decriminalizing MAID for psychiatric reasons (such as an increased assessment burden on ED staff) and potentially positive consequences (such as encouraging suffering patients who had not consulted to seek care). While it is by no means our intention to take a political or moral stand on this important issue, or to conclusively weigh the negatives and positives of allowing MAID for psychiatric reasons, we do stress the importance of an active voice for psychiatry in this ongoing public debate.

High frequency repetitive transcranial magnetic stimulation treatment for major depression: Dissociated effects on psychopathology and neurocognition.

OBJECTIVES: This open-label pilot study explored the effects of a course of accelerated high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) on two neurocognitive domains (decision-making and impulse control) in patients with major depressive disorder (MDD). METHODS: Participants with MDD and a treatment resistant major depressive episode (n=24) underwent twice-daily HF-rTMS targeted at the left dorsolateral prefrontal cortex (lDLPFC) over two weeks. Psychopathology was assessed by clinician-administered and self-reported measures of depression and anxiety; decision-making was assessed by the Iowa Gambling Task, the Balloon Analog Risk Task and the Game of Dice Task; impulse control was assessed by the Stroop Color-Word Task, the Continuous Performance Task and the Stop-Signal Task. RESULTS: Depression and anxiety scores significantly improved from pre-post HF-rTMS treatment. However, none of the decision-making or impulse control variables of interest changed significantly from pre-post HF-rTMS. Moreover, there was no correlation between changes in psychopathological symptoms and in neurocognition. LIMITATIONS: This is a moderately sized open label trial, and the confounds of ongoing psychotropics and illness chronicity can not be excluded in this treatment resistant sample. CONCLUSIONS: There is dissociation between acute symptomatic benefit after a course of accelerated HF-rTMS applied to the lDLPFC in treatment resistant MDD and performance on tests of decision making and impulse control. Though rTMS appears cognitively safe, additional research is warranted to understand this potential dissociation and its putative clinical implications.

A Lack of Clinical Effect of High-frequency rTMS to Dorsolateral Prefrontal Cortex on Bulimic Symptoms: A Randomised, Double-blind Trial.

Studies suggest that stimulation of the left dorsolateral prefrontal cortex (DLPFC) reduces food craving in bulimic patients, but evidence supporting repetitive transcranial magnetic stimulation (rTMS) as a therapeutic tool is lacking. We investigated the safety and therapeutic efficacy of an adjunct high-frequency rTMS programme targeting the left DLPFC. Forty-seven women with bulimia nervosa were randomised to a real or sham stimulation group. The real group underwent 10 rTMS sessions, each consisting of 20 trains of 5 seconds with 55-second intervals between trains, at a frequency of 10 Hz. The main outcome was the number of binge episodes in the 15 days following the end of stimulation. Overall, no significant improvement in bingeing and purging symptoms was noted after the programme. rTMS was well tolerated. This suggests that 10 sessions of high-frequency rTMS to the left DLPFC provide no greater benefit than placebo. Future studies should consider methodological issues as well as alternative targets. Copyright © 2016 John Wiley & Sons, Ltd and Eating Disorders Association.

A Randomised Controlled Trial of Neuronavigated Repetitive Transcranial Magnetic Stimulation (rTMS) in Anorexia Nervosa.

BACKGROUND: Anorexia nervosa (AN) is associated with morbid fear of fatness, extreme food restriction and altered self-regulation. Neuroimaging data implicate fronto-striatal circuitry, including the dorsolateral prefrontal cortex (DLPFC). METHODS: In this double-blind parallel group study, we investigated the effects of one session of sham-controlled high-frequency repetitive transcranial magnetic stimulation (rTMS) to the left DLPFC (l-DLPFC) in 60 individuals with AN. A food exposure task was administered before and after the procedure to elicit AN-related symptoms. OUTCOMES: The primary outcome measure was 'core AN symptoms', a variable which combined several subjective AN-related experiences. The effects of rTMS on other measures of psychopathology (e.g. mood), temporal discounting (TD; intertemporal choice behaviour) and on salivary cortisol concentrations were also investigated. Safety, tolerability and acceptability were assessed. RESULTS: Fourty-nine participants completed the study. Whilst there were no interaction effects of rTMS on core AN symptoms, there was a trend for group differences (p = 0.056): after controlling for pre-rTMS scores, individuals who received real rTMS had reduced symptoms post-rTMS and at 24-hour follow-up, relative to those who received sham stimulation. Other psychopathology was not altered differentially following real/sham rTMS. In relation to TD, there was an interaction trend (p = 0.060): real versus sham rTMS resulted in reduced rates of TD (more reflective choice behaviour). Salivary cortisol concentrations were unchanged by stimulation. rTMS was safe, well-tolerated and was considered an acceptable intervention. CONCLUSIONS: This study provides modest evidence that rTMS to the l-DLPFC transiently reduces core symptoms of AN and encourages prudent decision making. Importantly, individuals with AN considered rTMS to be a viable treatment option. These findings require replication in multiple-session studies to evaluate therapeutic efficacy. TRIAL REGISTRATION: www.Controlled-Trials.com ISRCTN22851337.

Enhancing decision-making and cognitive impulse control with transcranial direct current stimulation (tDCS) applied over the orbitofrontal cortex (OFC): A randomized and sham-controlled exploratory study.

BACKGROUND: Decision-making and impulse control (both cognitive and motor) are complex interrelated processes which rely on a distributed neural network that includes multiple cortical and subcortical regions. Among them, the orbitofrontal cortex (OFC) seems to be particularly relevant as demonstrated by several neuropsychological and neuroimaging investigations. METHODS: In the present study we assessed whether transcranial direct current stimulation (tDCS) applied bilaterally over the OFC is able to modulate decision-making and cognitive impulse control. More specifically, 45 healthy subjects were randomized to receive a single 30-min session of active or sham anodal tDCS (1.5 mA) applied over either the left or the right OFC (coupled with contralateral cathodal tDCS). They were also assessed pre- and post-tDCS with a battery of computerized tasks. RESULTS: Our results show that participants who received active anodal tDCS (irrespective of laterality), vs. those who received sham tDCS, displayed more advantageous decision-making (i.e., increased Iowa Gambling Task "net scores" [p = 0.04]), as well as improved cognitive impulse control (i.e., decreased "interference" in the Stroop Word-Colour Task [p = 0.007]). However, we did not observe tDCS-related effects on mood (assessed by visual analogue scales), attentional levels (assessed by the Continuous Performance Task) or motor impulse control (assessed by the Stop-Signal Task). CONCLUSIONS: Our study potentially serves as a key translational step towards the development of novel non-invasive neuromodulation-based therapeutic interventions directly targeting vulnerability factors for psychiatric conditions such as suicidal behaviour and addiction.

n-back task performance and corresponding brain-activation patterns in women with restrictive and bulimic eating-disorder variants: preliminary findings.

Eating disorder (ED) variants characterized by "binge-eating/purging" symptoms differ from "restricting-only" variants along diverse clinical dimensions, but few studies have compared people with these different eating-disorder phenotypes on measures of neurocognitive function and brain activation. We tested the performances of 19 women with "restricting-only" eating syndromes and 27 with "binge-eating/purging" variants on a modified n-back task, and used functional magnetic resonance imaging (fMRI) to examine task-induced brain activations in frontal regions of interest. When compared with "binge-eating/purging" participants, "restricting-only" participants showed superior performance. Furthermore, in an intermediate-demand condition, "binge-eating/purging" participants showed significantly less event-related activation than did "restricting-only" participants in a right posterior prefrontal region spanning Brodmann areas 6-8-a region that has been linked to planning of motor responses, working memory for sequential information, and management of uncertainty. Our findings suggest that working memory is poorer in eating-disordered individuals with binge-eating/purging behaviors than in those who solely restrict food intake, and that observed performance differences coincide with interpretable group-based activation differences in a frontal region thought to subserve planning and decision making.

Neural correlates of clinical improvement after deep transcranial magnetic stimulation (DTMS) for treatment-resistant depression: a case report using functional magnetic resonance imaging.

We report the effects of a 4-week trial of deep transcranial magnetic stimulation (DTMS) on depressive and anxious symptoms and brain activity in a patient (Mrs A) with treatment-resistant depression (TRD). The protocol involved a pre- and a post-functional magnetic resonance imaging (fMRI) scan during which Mrs A had to perform a working memory task (i.e., n-back). Her baseline score on the 21-item Hamilton Depression Rating Scale (HAM-D21) was 24, indicating severe depressive symptoms. Immediately after 4 weeks of daily DTMS treatment applied over the left dorsolateral prefrontal cortex (DLPFC), her HAM-D21 score decreased to 13 (a 46% reduction), and 1 month later, it was 12 (a 50% reduction). Moreover, Mrs A's accuracy scores on the n-back task (i.e., 2-back condition) improved from 79% (baseline) to 96% (after DTMS treatment). At the neural level, Mrs A showed significantly increased brain activity in the working memory network (e.g., DLPFC, parietal cortex) during the execution of the 2-back condition after DTMS treatment compared to baseline.

Effectiveness and acceptability of accelerated repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depressive disorder: an open label trial.

BACKGROUND: Major depressive disorder (MDD) is a significant cause of worldwide disability and treatment resistance is common. High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has emerged as a treatment for MDD, and while efficacious, the daily commitment for typical 4-6 weeks of treatment poses a significant challenge. We aimed to determine the effectiveness and acceptability of an accelerated rTMS protocol for MDD. METHODS: In this naturalistic trial, 27 patients with moderate to severe chronic and treatment-resistant MDD were treated with twice-daily HF-rTMS (10 Hz) applied over the left dorsolateral prefrontal cortex for 2 consecutive weeks (60,000 pulses). The primary outcomes were rates of clinical remission and response (16-item Quick Inventory of Depressive Symptomatology post-treatment score ≤ 6, and ≥ 50% reduction, respectively). Secondary outcomes were self-reported anxious symptoms, depressive symptoms and quality of life, and dropout rates as a proxy for acceptability. RESULTS: Ten (37.0%) patients met criteria for clinical remission and 15 (55.6%) were classified as responders, with comparable outcomes for both moderate and severe MDD. Clinician-rated improvements in depressive symptoms were paralleled in self-reported depressive and anxious symptoms, as well as quality of life. No patient discontinued treatment. LIMITATIONS: This study is limited by short treatment duration that might be lengthened with corresponding improvements in effectiveness, limited duration of follow-up, small sample size, and an open-label design requiring randomized controlled replication. CONCLUSION: An accelerated protocol involving twice-daily sessions of HF-rTMS over the left DLPFC for 2 weeks was effective in treatment-resistant MDD, and had excellent acceptability. Additional research is required to optimize accelerated rTMS treatment protocols and determine efficacy using sham-controlled trials.

Augmenting antidepressants with deep transcranial magnetic stimulation (DTMS) in treatment-resistant major depression.

OBJECTIVES: Deep transcranial magnetic stimulation (DTMS) has been shown to be efficacious and relatively safe for major depressive disorder (MDD). However, its clinical utility as an augmenting strategy for treatment-resistant depression (TRD) remains unexplored. METHODS: In an open label trial, 17 outpatients with severe TRD received 4 weeks of daily high frequency DTMS over the left dorsolateral prefrontal cortex. Depressive and anxious symptoms, suicidality and quality of life (QOL) were measured at baseline (i.e., in the week prior to the start of the DTMS treatment) and at week 5 (i.e., in the week following the end of the DTMS treatment). Primary outcome measures were rates of response and remission at week 5 using an intention-to-treat approach. RESULTS: Response and remission rates at week 5 were 70.6 and 41.2%, respectively. Also, depression, anxiety, and suicidality ratings were significantly improved by week 5 (with Hedges' g estimates ranging from 0.6 to 1.72), as well as four of the five QOL domain scores (i.e., global, psychological, environmental and social). Finally, two patients dropped out of the study at week 1 because of significant scalp discomfort during stimulation. CONCLUSIONS: Our study suggests that DTMS, when used as an augmenting strategy for antidepressants in severe TRD, is efficacious, safe and relatively well tolerated. However, controlled studies with larger samples are needed to confirm and expand our preliminary findings.

Effectiveness and acceptability of deep brain stimulation (DBS) of the subgenual cingulate cortex for treatment-resistant depression: a systematic review and exploratory meta-analysis.

BACKGROUND: Deep brain stimulation (DBS) applied to the subgenual cingulate cortex (SCC) has been recently investigated as a potential treatment for severe and chronic treatment-resistant depression (TRD). Given its invasive and experimental nature, a comprehensive evaluation of its effectiveness and acceptability is of paramount importance. Therefore, we conducted the present systematic review and exploratory meta-analysis. METHODS: We searched the literature for English language prospective clinical trials on DBS of the SCC for TRD from 1999 through December 2012 using MEDLINE, EMBASE, PsycINFO, CENTRAL and SCOPUS, and performed a random effects exploratory meta-analysis using Event Rates and Hedges׳ g effect sizes. RESULTS: Data from 4 observational studies were included, totaling 66 subjects with severe and chronic TRD. Twelve-month response and remission rates following DBS treatment were 39.9% (95% CI=28.4% to 52.8%) and 26.3% (95% CI=13% to 45.9%), respectively. Also, depression scores at 12 months post-DBS were significantly reduced (i.e., pooled Hedges׳ g effect size=-1.89 [95% CI=-2.64 to -1.15, p<0.0001]). Also, there was a significant decrease in depression scores between 3 and 6 months (Hedges׳ g=-0.27, p=0.003), but no significant changes from months 6 to 12. Finally, dropout rates at 12 months were 10.8% (95% CI=4.3% to 24.4%). LIMITATIONS: Small number of included studies (most of which were open label), and limited long-term effectiveness data. CONCLUSIONS: DBS applied to the SCC seems to be associated with relatively large response and remission rates in the short- and medium- to long-term in patients with severe TRD. Also, its maximal antidepressant effects are mostly observed within the first 6 months after device implantation. Nevertheless, these findings are clearly preliminary and future controlled trials should include larger and more representative samples, and focus on the identification of optimal neuroanatomical sites and stimulation parameters.

Personality dimensions and deep repetitive transcranial magnetic stimulation (DTMS) for treatment-resistant depression: a pilot trial on five-factor prediction of antidepressant response.

BACKGROUND: Prognostication is poor in repetitive transcranial magnetic stimulation (rTMS) treatment for major depressive disorder (MDD). Personality traits, particularly extraversion and neuroticism, have attracted increasing attention for both trait- and state-dependent characteristics in predicting response to pharmacotherapy, psychotherapy, and more recently to therapeutic neuromodulation for MDD. The advent of deep rTMS (DTMS) allows stimulation of deeper cortical regions, and we aimed to prospectively characterize personality dimensions and antidepressant response to DTMS in treatment-resistant MDD. METHODS: A convenience sample of 15 patients with treatment-resistant MDD received four weeks of daily sessions of DTMS (20 Hz, 3000 pulses/session) of the left dorsolateral prefrontal cortex (DLFPC). At baseline and at the conclusion of treatment, patients completed the Big Five Inventory, a five-factor assessment of major personality dimensions. Clinical response was measured using the 21-item Hamilton Depression Rating Scale. RESULTS: Four weeks of DTMS treatment were not associated with changes in personality measures. Clinical remission was associated with higher baseline levels of agreeableness (score ≥ 29:100% sensitive and 72.7% specific) and conscientiousness (score ≥ 30:75% sensitive and 81.8% specific). Levels of agreeableness and extraversion were linearly associated with antidepressant response. Neuroticism was not associated with the antidepressant effects of DTMS in this cohort. CONCLUSIONS: Five-factor personality assessment may have prognostic value in DTMS for resistant MDD. Agreeableness, extraversion, and conscientiousness are associated with decreases in depressive symptoms during treatment with DTMS.

Testing a neurobiological model of depersonalization disorder using repetitive transcranial magnetic stimulation.

BACKGROUND: Depersonalization disorder (DPD) includes changes in subjective experiencing of self, encompassing emotional numbing. Functional magnetic resonance imaging (fMRI) has pointed to ventrolateral prefrontal cortex (VLPFC) inhibition of insula as a neurocognitive correlate of the disorder. OBJECTIVE: We hypothesized that inhibition to right VLPFC using repetitive transcranial magnetic stimulation (rTMS) would lead to increased arousal and reduced symptoms. METHODS: Patients with medication-resistant DSM-IV DPD (N = 17) and controls (N = 20) were randomized to receive one session of right-sided rTMS to VLPFC or temporo-parietal junction (TPJ). 1 Hz rTMS was guided using neuronavigation and delivered for 15 min. Co-primary outcomes were: (a) maximum skin conductance capacity, and (b) reduction in depersonalization symptoms (Cambridge Depersonalisation Scale (CDS) [state version]). Secondary outcomes included spontaneous fluctuations (SFs) and event-related skin conductance responses. RESULTS: In patients with DPD, rTMS to VLPFC led to increased electrodermal capacity, namely maximum skin conductance deflections. Patients but not controls also showed increased SFs post rTMS. Patients who had either VLPFC or TPJ rTMS showed a similar significant reduction in symptoms. Event-related electrodermal activity did not change. CONCLUSIONS: A single session of right-sided rTMS to VLPFC (but not TPJ) significantly increased physiological arousal capacity supporting our model regarding the relevance of increased VLPFC activity to emotional numbing in DPD. rTMS to both sites led to reduced depersonalization scores but since this was independent of physiological arousal, this may be a non-specific effect. TMS is a potential therapeutic option for DPD; modulation of VLPFC, if replicated, is a plausible mechanism.

Repetitive transcranial magnetic stimulation over the dorsolateral prefrontal cortex for treating posttraumatic stress disorder: an exploratory meta-analysis of randomized, double-blind and sham-controlled trials.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) applied to the dorsolateral prefrontal cortex (DLPFC) has yielded promising results as a treatment for posttraumatic stress disorder (PTSD). However, to date, no quantitative review of its clinical utility has been published. METHOD: We searched for randomized and sham-controlled trials from 1995 to March 2013 using MEDLINE, Embase, PsycINFO, CENTRAL, and SCOPUS. We then performed an exploratory random effects meta-analysis. RESULTS: Studies on rTMS applied to the right DLPFC included 64 adults with PTSD. The pooled Hedges g effect size for pre and post changes in clinician-rated and self-reported PTSD symptoms were, respectively, 1.65 (P < 0.001) and 1.91 (P < 0.001), indicating significant and large-sized differences in outcome favouring active rTMS. Also, there were significant pre and post decreases with active rTMS in overall anxiety (Hedges g = 1.24; P = 0.02) and depressive (Hedges g = 0.85; P < 0.001) symptoms. Dropout rates at study end did not differ between active and sham rTMS groups. Regarding rTMS applied to the left DLPFC, there is only one study published to date (using a high frequency protocol), and its results showed that active rTMS seems to be superior overall to sham rTMS. CONCLUSIONS: Our exploratory meta-analysis shows that active rTMS applied to the DLPFC seems to be effective and acceptable for treating PTSD. However, the small number of subjects included in the analyses limits the generalizability of these findings. Future studies should include larger samples and deliver optimized stimulation parameters.

Brain responses to body image stimuli but not food are altered in women with bulimia nervosa.

BACKGROUND: Research into the neural correlates of bulimia nervosa (BN) psychopathology remains limited. METHODS: In this functional magnetic resonance imaging study, 21 BN patients and 23 healthy controls (HCs) completed two paradigms: (1) processing of visual food stimuli and (2) comparing their own appearance with that of slim women. Participants also rated food craving and anxiety levels. RESULTS: Brain activation patterns in response to food cues did not differ between women with and without BN. However, when evaluating themselves against images of slim women, BN patients engaged the insula more and the fusiform gyrus less, compared to HCs, suggesting increased self-focus among women with BN whilst comparing themselves to a 'slim ideal'. In these BN patients, exposure to food and body image stimuli increased self-reported levels of anxiety, but not craving. CONCLUSIONS: Our findings suggest that women with BN differ from HCs in the way they process body image, but not in the way they process food stimuli.

Evaluation of enhanced attention to local detail in anorexia nervosa using the embedded figures test; an FMRI study.

The behavioural literature in anorexia nervosa and autism spectrum disorders has indicated an overlap in cognitive profiles. One such domain is the enhancement of local processing over global processing. While functional imaging studies of autism spectrum disorder have revealed differential neural patterns compared to controls in response to tests of local versus global processing, no studies have explored such effects in anorexia nervosa. This study uses functional magnetic resonance imaging in conjunction with the embedded figures test, to explore the neural correlates of this enhanced attention to detail in the largest anorexia nervosa cohort to date. On the embedded figures tests participants are required to indicate which of two complex figures contains a simple geometrical shape. The findings indicate that whilst healthy controls showed greater accuracy on the task than people with anorexia nervosa, different brain regions were recruited. Healthy controls showed greater activation in the precuneus whilst people with anorexia nervosa showed greater activation in the fusiform gyrus. This suggests that different cognitive strategies were used to perform the task, i.e. healthy controls demonstrated greater emphasis on visuospatial searching and people with anorexia nervosa employed a more object recognition-based approach. This is in accordance with previous findings in autism spectrum disorder using a similar methodology and has implications for therapies addressing the appropriate adjustment of cognitive strategies in anorexia nervosa.

Repetitive transcranial magnetic stimulation (rTMS) for obsessive-compulsive disorder (OCD): an exploratory meta-analysis of randomized and sham-controlled trials.

OBJECTIVE: Randomized and sham-controlled trials (RCTs) on repetitive transcranial magnetic stimulation (rTMS) for treating obsessive-compulsive disorder (OCD) have yielded conflicting results that may be due to limited statistical power among individual studies. We pursued the present systematic review and meta-analysis to assess the efficacy of rTMS for OCD and to generate hypotheses for more robustly powered RCTs. METHOD: We searched the literature for RCTs on rTMS for OCD from 1995 through December 2012 using MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, and SCOPUS. We then performed an exploratory random-effects meta-analysis with the main outcome measures as pre-post changes in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores, response to treatment and overall dropout rates at study end. RESULTS: Data were obtained from 10 RCTs, totaling 282 subjects with OCD. The pooled Hedges' g for pre-post Y-BOCS scores was 0.59 (z = 2.73, p = 0.006), indicating a significant and medium-sized difference in outcome favoring active rTMS. Furthermore, response rates were 35% and 13% for patients receiving active and sham rTMS, respectively (OR = 3.4, p = 0.002). Sub-group analyses indicated that LF-rTMS and rTMS protocols targeting non-DLPFC regions (i.e., orbitofrontal cortex or supplementary motor area) seem to be the most promising for reducing OCD-related symptoms. No differences on baseline depression scores or dropout rates at study end were observed between active and sham rTMS groups, although OCD severity at baseline was higher in the active group. CONCLUSIONS: Our exploratory analyses show that active rTMS seems to be efficacious for treating OCD. Moreover, LF-rTMS and protocols targeting the orbitofrontal cortex or the supplementary motor area seem to be the most promising. Nevertheless, future RCTs on rTMS for OCD should include larger sample sizes and be more homogeneous in terms of demographic/clinical variables as well as stimulation parameters and brain targets.

High-frequency repetitive transcranial magnetic stimulation accelerates and enhances the clinical response to antidepressants in major depression: a meta-analysis of randomized, double-blind, and sham-controlled trials.

OBJECTIVE: High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) is a safe and effective treatment for major depression. However, its utility as a strategy to accelerate and improve clinical response to antidepressants is still unclear. DATA SOURCES: We searched the literature from 1995 through May 2012 using EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, Scopus, and ProQuest Dissertations and Theses, and, from October 2008 until May 2012, by using MEDLINE. We included only studies written in the English language. STUDY SELECTION: We selected all randomized, double-blind, and sham-controlled trials on HF-rTMS used as an accelerating (add-on) strategy to antidepressants for major depression. DATA EXTRACTION: We performed a random effects meta-analysis using odds ratios (ORs) for response and remission rates following HF-rTMS and sham rTMS. Two time points were considered: the end of the add-on HF-rTMS stimulation period (T1) and the end of the study (T2). RESULTS: Data were obtained from 6 randomized controlled trials (RCTs), totaling 392 subjects with major depression. For T1 (at mean ± SD 2.67 ± 0.82 weeks following start of combined rTMS + antidepressant treatment), 6 studies reported on response and 4 on remission rates. We found significantly higher response rates for active HF-rTMS (43.3%; 84/194) compared to sham rTMS (26.8%; 53/198) (OR = 2.5; 95% CI, 1.12-5.56; P = .025); however, remission rates did not differ between groups (P = .33). Heterogeneity between the included RCTs reporting data on response and remission rates at T1 was significant (response: Q5 = 11.4, P = .044, I2 = 56.12; remission: Q3 = 12.24, P = .007, I2 = 75.45). For study end (T2; at mean ± SD 6.80 ± 3.11 weeks following start of combined rTMS + antidepressant treatment), 5 studies reported on response and 4 on remission rates; overall, response rates at T2 were significantly higher for subjects receiving HF-rTMS in comparison to those receiving sham rTMS (62% [104/168] and 46% [79/172], respectively; OR = 1.9; 95% CI, 1.003-3.56; P = .049). Also, 53.8% (57/106) and 38.64% (36/107) of subjects receiving active HF-rTMS and sham rTMS, respectively, were in remission at T2 (OR = 2.42; 95% CI, 1.27-4.61; P = .007). Heterogeneity between the included RCTs reporting data on remission rates at T2 was not significant, although RCTs reporting on response rates at T2 were heterogeneous. The baseline depression scores for active and sham rTMS groups were similar. Finally, HF-rTMS was comparable to sham rTMS in terms of dropout rates. CONCLUSIONS: HF-rTMS is a promising strategy for accelerating clinical response to antidepressants in major depression, providing clinically meaningful benefits that are comparable to those of other agents such as triiodothyronine and pindolol. Furthermore, HF-rTMS seems to be an acceptable treatment for depressed subjects.

Blinding integrity in randomized sham-controlled trials of repetitive transcranial magnetic stimulation for major depression: a systematic review and meta-analysis.

Repetitive transcranial magnetic stimulation (rTMS) is a safe and effective treatment for major depression (MD). However, the perceived lack of a suitable sham rTMS condition might have compromised the success of blinding procedures in clinical trials. Thus, we conducted a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials (RCTs) on high frequency (HF-), low frequency (LF-) and bilateral rTMS for MD. We searched the literature from January 1995 to July 2012 using Medline, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials and Scopus. The main outcome measure was participants' ability to correctly guess their treatment allocation at study end. We used a random-effects model and risk difference (RD). Overall, data were obtained from seven and two RCTs on HF- and bilateral rTMS, respectively. No RCT on LF-rTMS reporting on blinding success was found. HF- and bilateral rTMS trials enrolled 396 and 93 depressed subjects and offered an average of approximately 13 sessions. At study end, 52 and 59% of subjects receiving HF-rTMS and sham rTMS were able to correctly guess their treatment allocation, a non-significant difference (RD = -0.04; z = -0.51; p = 0.61). Furthermore, 63.3 and 57.5% of subjects receiving bilateral and sham rTMS were able to correctly guess their treatment allocation, also a non-significant difference (RD = 0.05; z = 0.49; p = 0.62). In addition, the use of angulation and sham coil in HF-rTMS trials produced similar results. In summary, existing sham rTMS interventions appear to result in acceptable levels of blinding regarding treatment allocation.

Are neuroticism and extraversion associated with the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS)? An exploratory 4-week trial.

Several randomized, controlled trials have found high frequency repetitive transcranial magnetic stimulation (HF-rTMS) to be effective for treating major depressive disorder (MDD), but its antidepressant mechanisms have yet to be firmly understood. In this context, pre-treatment personality traits and subsequent changes in personality concomitant to treatment may be relevant for our understanding of these mechanisms. To investigate this issue we conducted a naturalistic trial in which 14 subjects with moderate to severe depression were treated with daily HF-rTMS over the left dorsolateral prefrontal cortex for 4 weeks. Objective depressive symptoms (as assessed by the HAM-D(21)) and the major personality dimensions of neuroticism and extraversion were measured pre-post HF-rTMS. Pre-rTMS levels of extraversion predicted subsequent decrease in depressive symptoms. Also, HF-rTMS treatment resulted in a decrease in neuroticism scores, and this relative decrease was associated with the relative decrease in depression. Our results suggest that HF-rTMS may positively affect the personality dimension of neuroticism. Also, pre-treatment levels of extraversion may predict the subsequent antidepressant response to HF-rTMS. However, further studies with larger samples and controlled designs are needed to better clarify these preliminary findings.