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Daphne Voineskos, 1, 2 Zafiris J Daskalakis, 1, 2 Daniel M Blumberger 1, 2 1Centre for Addiction and Mental Health, Toronto, Ontario, Canada; 2Department of Psychiatry, University of Toronto, Toronto, Ontario, CanadaCorrespondence: Daniel M BlumbergerCentre for Addiction and Mental Health, 1001 Queen Street West, Unit 4-1, Toronto, Ontario M6J1H4, CanadaTel +1 416 535-8501Fax +1 416 583-1358Email daniel.blumberger@camh.caAbstract: Treatment-resistant depression (TRD) is a subset of Major Depressive Disorder which does not respond to traditional and first-line therapeutic options. There are several definitions and staging models of TRD and a consensus for each has not yet been established. However, in common for each model is the inadequate response to at least 2 trials of antidepressant pharmacotherapy. In this review, a comprehensive analysis of existing literature regarding the challenges and management of TRD has been compiled. A PubMed search was performed to assemble meta-analyses, trials and reviews on the topic of TRD. First, we address the confounds in the definitions and staging models of TRD, and subsequently the difficulties inherent in assessing the illness. Pharmacological augmentation strategies including lithium, triiodothyronine and second-generation antipsychotics are reviewed, as is switching of antidepressant class. Somatic therapies, including several modalities of brain stimulation (electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy and deep brain stimulation) are detailed, psychotherapeutic strategies and subsequently novel therapeutics including ketamine, psilocybin, anti-inflammatories and new directions are reviewed in this manuscript. Our review of the evidence suggests that further large-scale work is necessary to understand the appropriate treatment pathways for TRD and to prescribe effective therapeutic options for patients suffering from TRD.Keywords: treatment resistant depression, major depressive disorder, pharmacotherapy, psychotherapy, brain stimulation, novel therapies

Yuliya O Knyahnytska,1,2 Daniel M Blumberger,1–3 Zafiris J Daskalakis,1,2 Reza Zomorrodi,1 Allan S Kaplan1,2 1Temerty Centre for Therapeutic- Brain Intervention, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; 2Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; 3Geriatric Division, Department of Psychiatry, University of Toronto, Toronto, Ontario, CanadaIntroduction: Anorexia nervosa (AN) is a complex disorder of unknown etiology, characterized by obsessions and compulsions around body shape, weight, and calorie intake. In the course of AN, 10%–30% will recover, while the rest will develop a treatment-resistant course with a high mortality rate due to AN-related complications. The insula is a region in the brain of considerable interest to its role in gustatory modulation, feeding behavior, and processing of interoceptive stimuli.Objective: Recent advances in the neurophysiology of AN suggest insula dysfunction as a potential biomarker for people with severe and enduring AN (SE-AN). Deep transcranial magnetic stimulation (dTMS) is of particular interest in SE-AN because of its ability to target deep areas of the brain.Design: We conducted a pilot study to investigate the feasibility and safety of insula dTMS in subjects with SE-AN.Results: We found that dTMS is a safe and well-tolerated treatment. We also found a reduction in AN-related obsessions and compulsions, as well as depression and anxiety scores from baseline to the end of the trial. Due to small sample size, the results of this study should be interpreted with great caution.Discussion: The results suggest that dTMS is safe and well tolerated and may be of some clinical interest in patients with SE-AN. However, to determine the true efficacy of dTMS for SE-AN, there is a need to conduct a randomized controlled trial comparing real versus sham dTMS in a larger number of AN subjects.Keywords: severe and enduring anorexia nervosa, deep transcranial magnetic stimulation, repetitive transcranial magnetic stimulation, insula

Christine E Dobek,1 Daniel M Blumberger,2 Jonathan Downar,3 Zafiris J Daskalakis,2 Fidel Vila-Rodriguez11Department of Psychiatry, Faculty of Medicine, Non-Invasive Neurostimulation Therapies (NINET) Laboratory, University of British Columbia, Vancouver, BC, 2Department of Psychiatry, Centre for Addiction and Mental Health, 3Department of Psychiatry, University Health Network, University of Toronto, Toronto, ON, CanadaObjective: When considering repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder, clinicians often face a lack of detailed information on potential interactions between rTMS and pharmacotherapy. This is particularly relevant to patients receiving bupropion, a commonly prescribed antidepressant with lower risk of sexual side effects or weight increase, which has been associated with increased risk of seizure in particular populations. Our aim was to systematically review the information on seizures occurred with rTMS to identify the potential risk factors with attention to concurrent medications, particularly bupropion.Data sources: We conducted a systematic review through the databases PubMed, PsycINFO, and EMBASE between 1980 and June 2015. Additional articles were found using reference lists of relevant articles. Reporting of data follows Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.Study selection: Two reviewers independently screened articles reporting the occurrence of seizures during rTMS. Articles reporting seizures in epilepsy during rTMS were excluded. A total of 25 rTMS-induced seizures were included in the final review.Data extraction: Data were systematically extracted, and the authors of the applicable studies were contacted when appropriate to provide more detail about the seizure incidents.Results: Twenty-five seizures were identified. Potential risk factors emerged such as sleep deprivation, polypharmacy, and neurological insult. High-frequency-rTMS was involved in a percentage of the seizures. None of these seizures reported had patients taking bupropion in the literature review. One rTMS-induced seizure was reported from the Food and Drug Administration in a sleep-deprived patient who was concurrently taking bupropion, sertraline, and amphetamine.Conclusion: During the consent process, potential risk factors for an rTMS-induced seizure should be carefully screened for and discussed. Data do not support considering concurrent bupropion treatment as contraindication to undergo rTMS.Keywords: repetitive transcranial magnetic stimulation, seizures, bupropion, consent process, interaction

Yoshihiro Noda,1,2 Zafiris J Daskalakis,1–3 Jonathan Downar,4 Paul E Croarkin,5 Paul B Fitzgerald,6 Daniel M Blumberger1–3 1Department of Psychiatry, Faculty of Medicine, University of Toronto, 2Temerty Centre for Therapeutic Brain Intervention, 3Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 4MRI-Guided rTMS Clinic, University Health Network, Toronto, ON, Canada; 5Division of Child and Adolescent Psychiatry, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA; 6Monash Alfred Psychiatry Research Centre, The Alfred and Monash University Central Clinical School, Melbourne, Australia Abstract: Magnetic seizure therapy (MST) has shown efficacy in adult patients with treatment-resistant depression with limited impairment in memory. To date, the use of MST in adolescent depression has not been reported. Here we describe the first successful use of MST in the treatment of an adolescent patient with refractory bipolar depression. This patient received MST in an ongoing open-label study for treatment-resistant major depression. Treatments employed a twin-coil MST apparatus, with the center of each coil placed over the frontal cortex (ie, each coil centered over F3 and F4). MST was applied at 100 Hz and 100% machine output at progressively increasing train durations. Depressive symptoms were assessed using the 24-item Hamilton Depression Rating Scale and cognitive function was assessed with a comprehensive neuropsychological battery. This adolescent patient achieved full remission of clinical symptoms after an acute course of 18 MST treatments and had no apparent cognitive decline, other than some autobiographical memory impairment that may or may not be related to the MST treatment. This case report suggests that MST may be a safe and well tolerated intervention for adolescents with treatment-resistant bipolar depression. Pilot studies to further evaluate the effectiveness and safety of MST in adolescents warrant consideration. Keywords: brain stimulation, treatment-resistant depression, adolescent depression, cognitive effects