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Long-term potentiation (LTP)-like activity can be induced by stimulation protocols such as paired associative stimulation (PAS). We aimed to determine whether PAS-induced LTP-like activity (PAS-LTP) of the dorsolateral prefrontal cortex (DLPFC) is associated with cortical thickness and other structural measures impaired in Alzheimer's dementia (AD). We also explored longitudinal relationships between these brain structures and PAS-LTP response after a repetitive PAS (rPAS) intervention. Mediation and regression analyses were conducted using data from randomized controlled trials with AD and healthy control participants. PAS-electroencephalography assessed DLPFC PAS-LTP. DLPFC thickness and surface area were acquired from T1-weighted magnetic resonance imaging. Fractional anisotropy and mean diffusivity (MD) of the superior longitudinal fasciculus (SLF)—a tract important to induce PAS-LTP—were measured with diffusion-weighted imaging. AD participants exhibited reduced DLPFC thickness and increased SLF MD. There was also some evidence that reduction in DLPFC thickness mediates DLPFC PAS-LTP impairment. Longitudinal analyses showed preliminary evidence that SLF MD, and to a lesser extent DLPFC thickness, is associated with DLPFC PAS-LTP response to active rPAS. This study expands our understanding of the relationships between brain structural changes and neuroplasticity. It provides promising evidence for a structural predictor to improving neuroplasticity in AD with neurostimulation. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'. [ABSTRACT FROM AUTHOR]

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

BACKGROUND The benefits and risks of augmenting or switching antidepressants in older adults with treatment-resistant depression have not been extensively studied. METHODS We conducted a two-step, open-label trial involving adults 60 years of age or older with treatment-resistant depression. In step 1, patients were randomly assigned in a 1:1:1 ratio to augmentation of existing antidepressant medication with aripiprazole, augmentation with bupropion, or a switch from existing antidepressant medication to bupropion. Patients who did not benefit from or were ineligible for step 1 were randomly assigned in step 2 in a 1:1 ratio to augmentation with lithium or a switch to nortriptyline. Each step lasted approximately 10 weeks. The primary outcome was the change from baseline in psychological well-being, assessed with the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales (population mean, 50; higher scores indicate greater well-being). A secondary outcome was remission of depression. RESULTS In step 1, a total of 619 patients were enrolled; 211 were assigned to aripiprazole augmentation, 206 to bupropion augmentation, and 202 to a switch to bupropion. Well-being scores improved by 4.83 points, 4.33 points, and 2.04 points, respectively. The difference between the aripiprazole-augmentation group and the switch-to-bupropion group was 2.79 points (95% CI, 0.56 to 5.02; P=0.014, with a prespecified threshold P value of 0.017); the between-group differences were not significant for aripiprazole augmentation versus bupropion augmentation or for bupropion augmentation versus a switch to bupropion. Remission occurred in 28.9% of patients in the aripiprazole-augmentation group, 28.2% in the bupropion-augmentation group, and 19.3°6 in the switch-to-bupropion group. The rate of falls was highest with bupropion augmentation. In step 2, a total of 248 patients were enrolled; 127 were assigned to lithium augmentation and 121 to a switch to nortriptyline. Well-being scores improved by 3.17 points and 2.18 points, respectively (difference, 0.99; 95% CI, -1.92 to 3.91). Remission occurred in 18.9% of patients in the lithium-augmentation group and 21.5% in the switch-to-nortriptyline group; rates of falling were similar in the two groups. CONCLUSIONS In older adults with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole improved well-being significantly more over 10 weeks than a switch to bupropion and was associated with a numerically higher incidence of remission. Among patients in whom augmentation or a switch to bupropion failed, changes in well-being and the occurrence of remission with lithium augmentation or a switch to nortriptyline were similar. (Funded by the Patient-Centered Outcomes Research Institute; OPTIMUM ClinicalTrials.gov number, NCT02960763.) [ABSTRACT FROM AUTHOR]

Exposure to stress is known to affect biological aging as well as individuals' susceptibility to a wide variety of mental illnesses, such as schizophrenia. There is an established relationship between the onset of schizophrenia spectrum disorders (SSD) and biological aging. On the other hand, epigenetic modifications, such as DNA methylation (DNAm), are used as biomarkers for biological aging and were previously proven to be altered in schizophrenia. However, previous research did not consider the effect of psychosocial resilience to stress and its effect on aging in schizophrenia, which is what our study aims to address. For our pilot study, 65 schizophrenia patients were recruited and stress exposure and perception levels were assessed using the Social Readjustment Rating Scale (SRRS) and Perceived Stress Scale (PSS), respectively. Moreover, DNA was extracted from venous blood samples and 850,000 CpG loci were assessed for DNA methylation analysis. Average age of participants was 43.15 ± 13.32 years (55.4% male, 44.6% female). Linear regression plots showed significant correlation between SRRS and PSS scores as well as between biological and chronological ages (p < 0.05). The residuals from the two regression models were defined as the psychosocial resilience and DNAm age acceleration, respectively. Interestingly, DNAm age acceleration was inversely correlated with resilience to stress (p < 0.05). In conclusion, it appears that epigenetic age acceleration is associated with reduced resilience to stress in schizophrenia patients. Future studies should focus on establishing resilience effect on disease prognosis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

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., (©Yuliya Knyahnytska, Reza Zomorrodi, Tyler Kaster, Daphne Voineskos, Alisson Trevizol, Daniel Blumberger. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 27.01.2023.)

Introduction: Executive function deficits (EFD) in late life depression (LLD) are associated with poor outcomes. Dysfunction of the cognitive control network (CCN) has been posited in the pathophysiology of LLD with EFD., Methods: Seventeen older adults with depression and EFD were randomized to iTBS or sham for 6 weeks. Intervention was delivered bilaterally using a recognized connectivity target., Results: A total of 89% (17/19) participants completed all study procedures. No serious adverse events occurred. Pre to post-intervention change in mean Montgomery-Asberg-depression scores was not different between iTBS or sham, p = 0.33. No significant group-by-time interaction for Montgomery-Asberg Depression rating scale scores (F 3, 44  = 0.51; p = 0.67) was found. No significant differences were seen in the effects of time between the two groups on executive measures: Flanker scores (F 1, 14  = 0.02, p = 0.88), Dimensional-change-card-sort scores F 1, 14  = 0.25, p = 0.63, and working memory scores (F 1, 14  = 0.98, p = 0.34). The Group-by-time interaction effect for functional connectivity (FC) within the Fronto-parietal-network was not significant (F 1, 14  = 0.36, p = 0.56). No significant difference in the effect-of-time between the two groups was found on FC within the Cingulo-opercular-network (F 1, 14  = 0, p = 0.98)., Conclusion: Bilateral iTBS is feasible in LLD. Preliminary results are unsupportive of efficacy on depression, executive function or target engagement of the CCN. A future Randomized clinical trial requires a larger sample size with stratification of cognitive and executive variables and refinement in the target engagement., (© 2022 John Wiley & Sons Ltd.)

Background: Late-life depression (LLD) affects up to 18% of older adults and has been linked to elevated dementia risk. Mindfulness-based cognitive therapy (MBCT) holds promise for treating symptoms of depression and ameliorating cognitive deficits in older adults. While preliminary findings are promising, a definitive RCT investigating its effects on late life depression and cognition have not yet been conducted. We present a protocol describing a multi-site blinded randomized controlled trial, comparing the effects of MBCT and of an active control, a Health Enhancement Program (HEP), on depressive symptoms, executive functioning, and brain biomarkers of LLD, among several other exploratory outcomes., Methods: Two-hundred and thirteen ( n = 213) patients with LLD will be recruited at various centers in Montreal, QC, Canada. Participants will undergo stratified randomization to either MBCT or HEP intervention groups. We will assess changes in (1) depression severity using the Hamilton Depression Rating Scale (HAM-D17), (2) processing speed and executive functioning, (3) brain biomarkers of LLD (hippocampal volume, default network resting-state functional connectivity and executive network resting-state functional connectivity), and (4) other exploratory physiological and mood-based measures, at baseline (0 weeks), post intervention (8 weeks), and 26 weeks after baseline., Discussion: The proposed study will assess the clinical potential of MBCT to improve symptoms of depression, as well as examine its impact on cognitive impairments and neurobiological markers, and thus inform its use as a promising adjunct in the treatment of LLD., Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT05366088., Competing Interests: SR receives a salary award from the Fonds de Recherche de Québec Santé FRQS, is a consultant for AbbVie, and is a shareholder of Aifred Health. HS has a CIHR fellowship award, MITACS fellowship award, and AGE-WELL award. ZS is a cofounder of Mindful Noggin and receives royalties from Guilford Press. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bein, Lesage, Dikaios, Chakravarty, Segal, Royal, Speechley, Schiavetto, Blumberger, Sacchet, Therriault, Gruber, Tourjman, Richard-Devantoy, Nair, Bruneau, Rej, Lifshitz and Sekhon.)

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., (©Yuliya Knyahnytska, Reza Zomorrodi, Tyler Kaster, Daphne Voineskos, Alisson Trevizol, Daniel Blumberger. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 17.01.2022.)