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Background: A few studies have examined the durability of transcranial magnetic stimulation (TMS) antidepressant benefit once patients remitted. This study examined the long-term durability of clinical benefit from TMS using a protocol-specified TMS taper and either continuation pharmacotherapy or naturalistic follow-up.Methods: Patients were remitters from an acute double-blind sham-controlled trial of TMS (n = 18), or from an open-label extension in patients who did not respond to the acute trial (n = 43). Long-term durability of TMS acute effect was examined in remitters over a 12-week follow-up. Relapse, defined as 24-item Hamilton Depression Rating Scale (HDRS-24) ≥20, was the primary outcome.Results: Of 61 remitters in the acute trial, five entered naturalistic follow-up and 50 entered the TMS taper. Thirty-two patients completed TMS taper and 1-, 2-, and 3-month follow-up. At 3-month visit, 29 of 50 (58%) were classified as in remission (HDRS-24 ≤10), two of 50 (4%) as partial responders (30%≤ HDRS-24 reduction <50% from baseline), and one of 50 (2%) met criteria for relapse. During the entire 3-month follow-up, five of the 37 patients relapsed (relapse rate = 13.5%), but four of them regained remission by the end of the study. The average time to relapse in these five patients was 7.2 ± 3.3 weeks. Patients who relapsed had higher depression scores at 1 month.Conclusions: While one third of the sample was lost to follow-up, our results demonstrate that most patients contributing to observations experienced persistence of benefit from TMS followed by pharmacotherapy or no medication. Longer follow-up and more rigorous studies are needed to explore the true long-term durability of remission produced by TMS. [ABSTRACT FROM AUTHOR]

Posttraumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder that can become chronic and debilitating when left untreated. The most commonly recommended first-line treatments for PTSD among adults are individual trauma-focused psychotherapies. Other evidence-based treatments include specific antidepressant medications and non-trauma-focused psychotherapies. Despite the effectiveness of these available treatments, many patients' symptoms do not remit. This has led to the search for novel treatments for PTSD. In this review, the authors critically evaluate the data supporting several emerging pharmacological and other somatic interventions in the categories of medication-assisted psychotherapy, novel medication monotherapy strategies, and neuromodulation, selected because of the salience of their mechanisms of action to the pathophysiology of PTSD (e.g., MDMA-assisted psychotherapy, ketamine, cannabidiol, transcranial magnetic stimulation). The authors also evaluate the evidence for treatments that are the focus of increasing scientific or public interest (i.e., hyperbaric oxygen therapy, stellate ganglion block, neurofeedback). To date, the evidence supporting most novel pharmacological and somatic treatments for PTSD is preliminary and highly variable; however, the data for several specific treatments, such as transcranial magnetic stimulation, are encouraging., Competing Interests: Dr. Kelmendi is a Co-founder, consultant, and has equity in Transcend Therapeutics, and is also a consultant for Ceruvia Lifesciences. Dr. Alpert reports royalties from Cambridge University Press, Honoraria from Belvoir Publishing and MGH Psychiatry Academy. Dr. Carpenter discloses consulting income in the past three years from Neuronetics, Neurolief, Magnus Medical, Motif Neurotech, Sage Therapeutics, Otsuka, MAPS Public Benefit Corporation, and Change Healthcare. She has clinical trials contracts with Neuronetics, Neurolief, and Janssen and research device loans from Neuronetics and Nexstim. Her effort was supported in part by the National Institute of General Medical Sciences (P20GM130452) funded COBRE Center for Neuromodulation at Butler Hospital. Dr. Grzenda discloses income from consulting to the American Psychiatric Association. Dr. Kraguljac has served on an advisory board for Neurocrine Biosciences Inc. and is a member of the American Board of Psychiatry and Neurology Article Based Continuing Certification committee. Dr. McDonald is compensated as the chair of the DSMB for an NIA sponsored multicenter study. He is on the Board of Skyland Trail and 3Keys. He is a paid consultant for Signant and Sage Therapeutics. He receives a stipend as a deputy editor of the American Journal of Psychiatry. Dr. Rodriguez has, in the last three years, been a consultant for Biohaven Inc., Osmind, and Biogen; received research grant support from Biohaven Inc.; received royalties from American Psychiatric Association Publishing; and received a stipend from APA Publishing for her role as Deputy Editor at The American Journal of Psychiatry. Dr. Rodriguez’s effort was supported in part by the VA Office of Research and Development Clinical Science Research & Development Service, US, Department of Veterans Affairs (1I01CX001789-01A2). Dr. Widge discloses device donations from Medtronic, consulting income from Dandelion Science, and multiple unlicensed patents in the area of brain stimulation for psychiatric illness. Dr. Nemeroff serves as a paid consultant to AbbVie, ANeuroTech (division of Anima BV), Signant Health, Magstim, Inc., Intra-Cellular Therapies, Inc., EMA Wellness, Sage, Silo Pharma, Engrail Therapeutics, Pasithea Therapeutic Corp., EcoR1, GoodCap Pharmaceuticals, Inc., Senseye, Clexio, Ninnion Therapeutics, AncoraBio, and SynapseBio. Dr. Nemeroff is a stockholder with the following: Seattle Genetics, Antares, Inc., Corcept Therapeutics Pharmaceuticals Company, EMA Wellness, and Naki Health. He serves on the scientific advisory boards of ANeuroTech (division of Anima BV), Brain and Behavior Research Foundation (BBRF), Anxiety and Depression Association of America (ADAA), Skyland Trail, Signant Health, Laureate Institute for Brain Research (LIBR), Inc., Heading Health, Pasithea Therapeutic Corp., and Sage and on the board of directors for Gratitude America, ADAA, Lucy Scientific Discovery, Inc. His patents are as follows: “Method and devices for transdermal delivery of lithium (US 6,375,990B1)” and “Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2).” Dr. Holtzheimer receives royalties from Oxford University Press and UpToDate. Drs. Sippel, Hamblen, and Schnurr report no financial relationships with commercial interests.

Genome-wide association studies (GWASs) of major depressive disorder (MDD) have recently achieved extremely large sample sizes and yielded substantial numbers of genome-wide significant loci. Because of the approach to ascertainment and assessment in many of these studies, some of these loci appear to be associated with dysphoria rather than with MDD, potentially decreasing the clinical relevance of the findings. An alternative approach to MDD GWAS is to focus on the most severe forms of MDD, with the hope that this will enrich for loci of larger effect, rendering their identification plausible, and providing potentially more clinically actionable findings. Here we review the genetics of severe depression by using clinical markers of severity including: age of onset, recurrence, degree of impairment, and treatment with ECT. There is evidence for increased family-based and Single Nucleotide Polymorphism (SNP)-based estimates of heritability in recurrent and early-onset illness as well as severe functional impariment. GWAS have been performed looking at severe forms of MDD and a few genome-wide loci have been identified. Several whole exome sequencing studies have also been performed, identifying associated rare variants. Although these findings have not yet been rigorously replicated, the elevated heritability seen in severe MDD phenotypes suggests the value of pursuing additional genome-wide interrogation of samples from this population. The challenge now is generating a cohort of adequate size with consistent phenotyping that will allow for careful and robust classifications and distinctions to be made. We are currently pursuing such a strategy in our 50-site worldwide Gen-ECT-ics consortium., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

In recent history, the world has witnessed a trend towards liberalization of abortion laws driven by an increasing understanding of the negative personal and public health consequences of criminalizing abortion. By contrast, several countries have recently implemented restrictive reproductive laws, joining the 112 countries where access to abortion care is banned completely or with narrow exceptions. On June 24, 2022, the US Supreme Court ruling in Dobbs v Jackson Women's Health Organization overturned its landmark decisions in Roe v Wade that established abortion until the point of viability of the fetus as a constitutional right. After Roe v Wade having been overturned, it is projected that many women in the USA will be prevented from accessing safe abortion care. Importantly, abortion bans not only impose constraints on patient autonomy, they also restrict physicians' ability to practice evidence-based medicine, which will negatively impact psychiatric care. It is therefore crucial for the practicing psychiatrist to be familiar with this new legal landscape. In this Personal View, we aim to provide a topical overview to help clinicians gain a clear understanding of legal, clinical, and ethical responsibilities, focusing on the USA. We also discuss the reality that psychiatrists might be called upon to determine medical necessity for an abortion on psychiatric grounds, which is new for most US psychiatrists. We predict that psychiatrists will be confronted with very difficult situations in which lawful and ethical conduct might be incongruent, and that abortion bans will result in greater numbers of patients needing psychiatric care from a system that is ill-prepared for additional demands., Competing Interests: Declaration of interests ASW acknowledges financial support from the Minnesota Medical Discovery Team on Addictions and the MnDRIVE Brain Conditions Initiative. LLC reports clinical trials contracts with Brown University, Janssen, Neuronetics, and Neurolief; consulting income from Janssen, Neuronetics, Neurolief, Sage Therapeutics, Otsuka, and Magnus Medical; and a research equipment loan from Nexstim. JEA receives income from Cambridge University Press, Belvoir Media Group, and Massachusetts General Hospital Psychiatry Academy. JHK reports individual consultant agreements worth less than US$5000 per year with Aptinyx, Biogen, Idec, the state of Massachusetts, Bionomics (Australia), Boehringer Ingelheim International, Epiodyne, EpiVario, Janssen Research & Development, Jazz Pharmaceuticals, Otsuka America Pharmaceutical, Spring Care, and Sunovion Pharmaceuticals; is cofounder of Freedom Biosciences; serves on scientific advisory boards for Biohaven Pharmaceuticals, BioXcel Therapeutics (Clinical Advisory Board), Cerevel Therapeutics, Delix Therapeutics, Eisai, EpiVario, Jazz Pharmaceuticals, Neumora Therapeutics, Neurocrine Biosciences, Novartis Pharmaceuticals Corporation, PsychoGenics, Takeda Pharmaceuticals, Tempero Bio, and Terran Biosciences; owns stock in Biohaven Pharmaceuticals, Freedom Biosciences, and Spring Health; has stock options in Biohaven Pharmaceuticals Medical Sciences, Cartego Therapeutics, Damona Pharmaceuticals, Delix Therapeutics, EpiVario, Neumora Therapeutics, Rest Therapeutics, Tempero Bio, Terran Biosciences, and Tetricus; receives income as the editor of Biological Psychiatry; and holds the following patents and interventions: dopamine and noradrenergic reuptake inhibitors in treatment of schizophrenia (US patent 5447948), glutamate modulating agents in the treatment of mental disorders (US patent 8778979B2, US patent application 15/695164), intranasal administration of ketamine to treat depression (US patent 9592207, licensed to Janssen Research & Development), methods for treating suicidal ideation (US patent application 15/379013), composition and methods to treat addiction (US provisional use patent application 61/973/961), treatment selection for major depressive disorder (US Patent and Trademark Office docket number Y0087.70116US00), compounds, compositions and methods for treating or preventing depression and other diseases (US provisional patent application 62/444552), combination therapy for treating or preventing depression or other mood diseases (US provisional patent application 62/719,935), and mavoglurant in treating gambling and gaming disorders (US provisional patent application 63/125,181); and has the following non-federal research support: AstraZeneca Pharmaceuticals provides Saracatinib for research related to a National Institute on Alcohol Abuse and Alcoholism (NIAAA) grant to the Center for Translational Neuroscience of Alcoholism, Novartis provides mavoglurant for research related to a NIAAA grant to the Center for Translational Neuroscience of Alcoholism, Cerevel provides the drug PF-06412562 for A Translational and Neurocomputational Evaluation of a D1R Partial Agonist for Schizophrenia (project number 1U01MH121766-01). CBN reports consulting income from AbbVie, ANeuroTech (division of Anima BV), Signant Health, Magstim, Intra-Cellular Therapies, EMA Wellness, Sage, Silo Pharma, Engrail Therapeutics, Pasithea Therapeutic, GoodCap Pharmaceuticals, Senseye, Clexio, Ninnion Therapeutics, EmbarkNeuro, SynapseBio, BioXcel Therapeutics, and Relmada Therapeutics; holds stocks in Seattle Genetics, Antares, Corcept Therapeutics Pharmaceuticals, EMA Wellness, Naki Health, and Relmada Therapeutics; serves on the scientific advisory boards of ANeuroTech (division of Anima BV), the Brain and Behavior Research Foundation, the Anxiety and Depression Association of America, Skyland Trail, Signant Health, Laureate Institute for Brain Research, Heading Health, Pasithea Therapeutic, and Sage; is on the board of directors for Gratitude America, the Anxiety and Depression Association of America, and Lucy Scientific Discovery; and holds patents for method and devices for transdermal delivery of lithium (US patent 6375990B1) and method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US patent 7148027B2). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Objectives: Electroconvulsive therapy (ECT) is an effective somatic treatment, but it may be limited by cognitive adverse effects. The existing cognitive screening instruments often lack specificity to ECT-associated cognitive deficits. The ElectroConvulsive Therapy Cognitive Assessment was developed and validated in a clinical setting, but the reliability and validity of the Chinese version of ElectroConvulsive Therapy Cognitive Assessment (ECCA-C) have not been studied in a large clinical sample., Methods: The ECCA-C and the Montreal Cognitive Assessment (MoCA) were administered to patients with major depressive disorder (MDD) undergoing ECT at 3 time points: pretreatment (baseline), before the fifth treatment, and 1 week posttreatment. The instruments were also administered to a sample of healthy subjects., Results: Sixty-five patients with MDD and 50 age- and sex-matched healthy controls were recruited in this study. Overall, the patient group had statistically significantly lower MoCA and ECCA-C scores than the control group (both P values <0.001). The Cronbach α of the ECCA-C was 0.88 at baseline. Statistically significant decreases over time were observed in ECCA-C: pre-ECT (23.9 ± 4.0) > mid-ECT (21.3 ± 3.4) > post-ECT (18.7 ± 4.8) (all P values <0.001), whereas no statistically significant changes in MoCA scores were found at these 3 time points ( F = 1.86, P = 0.165). A cutoff score of 26.5 on the ECCA-C was found to best differentiate between MDD patients and healthy controls., Conclusions: The ECCA-C showed satisfactory psychometric properties and may be a more sensitive instrument than the MoCA to assess cognitive impairment associated with ECT., Competing Interests: The 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. This study was supported by the Beijing Anding Hospital, Capital Medical University (YJ2021-05)., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: In this review, the authors update the 2018 position statement of the American Psychiatric Association Council of Research Workgroup on Biomarkers and Novel Treatments on pharmacogenomic (PGx) tools for treatment selection in depression., Methods: The literature was reviewed for new clinical trials and meta-analyses, published from 2017 to 2022, of studies using PGx tools for treatment selection in depression. The blinding and control conditions, as well as primary and secondary outcomes and post hoc analyses, were summarized., Results: Eleven new clinical trials and five meta-analyses were identified; all studies had primary outcome measures related to speed or efficacy of treatment response. Three trials (27%) demonstrated efficacy on the primary outcome measure with statistical significance; the three studies used different PGx tools; one study was open-label and the other two were small single-blind trials. Five trials (45%) did not detect efficacy with statistical significance on either primary or secondary outcome measures. Only one trial (9%) used adverse events as a primary outcome measure. All studies had significant limitations; for example, none adopted a fully blinded study design, only two studies attempted to blind the treating clinician, and none incorporated measures to estimate the effectiveness of the blinds or the influence of lack of blinding on the study results., Conclusions: The addition of these new data do not alter the recommendations of the 2018 report, or the advice of the U.S. Food and Drug Administration, that the evidence does not support the use of currently available combinatorial PGx tools for treatment selection in major depressive disorder. Priority efforts for future studies and the development and testing of effective tools include fully blinded study designs, inclusion of promising genetic variants not currently included in any commercially available tests, and investigation of other uses of pharmacogenomics, such as estimating the likelihood of rare adverse drug effects, rather than increasing the speed or magnitude of drug response., Competing Interests: Dr. Baum receives royalties from Oxford University Press. Dr. Widge has received donations of deep brain stimulation devices from Medtronic and consulting fees from Abbott, and he holds multiple granted and pending patents related to deep brain stimulation. Dr. Carpenter has received research support from Affect Neuro, Janssen Pharmaceuticals, Neuronetics, Neurolief, Nexstim, and SynapseBio, and she has served as a scientific adviser or consultant for Affect Neuro, Janssen Pharmaceuticals, Neuronetics, Neurolief, Nexstim, Otsuka, Sage Therapeutics, and Sunovion. Dr. McDonald is a Deputy Editor of the American Journal of Psychiatry; disclosures of Editors’ financial relationships appear in the April 2024 issue of the Journal. Dr. Nemeroff has served as a consultant for AbbVie, ANeuroTech, Autobahn Therapeutics, BioXcel Therapeutics, Clexio, EMA Wellness, EmbarkNeuro, Engrail Therapeutics, GoodCap Pharmaceuticals, Guidepoint, Intra-Cellular Therapies, Magstim, Ninnion Therapeutics, Pasithea Therapeutics Corp., Relmada Therapeutics, Sage, Senseye, Signant Health, Silo Pharma, and SynapseBio; he is a stockholder in Antares, Corcept Therapeutics, EMA Wellness, Naki Health, PreciseMent Health, Relmada Therapeutics, and Seattle Genetics; he has served on scientific advisory boards for ANeuroTech, the Anxiety and Depression Association of America (ADAA), the Brain and Behavior Research Foundation, Galen Health, Heading Health, the Laureate Institute for Brain Research, Pasithea Therapeutics Corp., Sage, Signant Health, and Skyland Trail and on the boards of directors for ADAA, Gratitude America, and Lucy Scientific Discovery; and he is named on patents on a method and devices for transdermal delivery of lithium and a method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay. Dr. Cohen reports no financial relationships with commercial interests.

Objective: For nursing home residents with severe dementia, high-intensity medical treatment offers little possibility of benefit but has the potential to cause significant distress. Nevertheless, mechanical ventilation and intensive care unit (ICU) transfers have increased in this population. We sought to understand how and why such care is occurring., Design: Mixed methods study, with retrospective collection of qualitative and quantitative data., Setting: Department of Veterans Affairs (VA) hospitals., Methods: Using the Minimum Data Set, we identified veterans aged ≥65 years who had severe dementia, lived in nursing homes, and died in 2013. We selected those who underwent mechanical ventilation or ICU transfer in the last 30 days of life. We restricted our sample to patients receiving care at VA hospitals because these hospitals share an electronic medical record, from which we collected structured information and constructed detailed narratives of how medical decisions were made. We used qualitative content analysis to identify distinct paths to high-intensity treatment in these narratives., Results: Among 163 veterans, 41 (25.2%) underwent mechanical ventilation or ICU transfer. Their median age was 85 (IQR, 80-94), 97.6% were male, and 67.5% were non-Hispanic white. More than a quarter had living wills declining some or all treatment. There were 5 paths to high-intensity care. The most common (18 of 41 patients) involved families who struggled with decisions. Other patients (15 of 41) received high-intensity care reflexively, before discussion with a surrogate. Four patients had families who advocated repeatedly for aggressive treatment, against clinical recommendations. In 2 cases, information about the patient's preferences was erroneous or unavailable. In 2 cases, there was difficulty identifying a surrogate., Conclusions and Implications: Our findings highlight the role of surrogates' difficulty with decision making and of health system-level factors in end-of-life ICU transfers and mechanical ventilation among nursing home residents with severe dementia., Competing Interests: Disclosure The authors declare no conflicts of interest., (Published by Elsevier Inc.)

Accelerated TMS is an emerging application of Transcranial Magnetic Stimulation (TMS) aimed to reduce treatment length and improve response time. Extant literature generally shows similar efficacy and safety profiles compared to the FDA-cleared protocols for TMS to treat major depressive disorder (MDD), yet accelerated TMS research remains at a very early stage in development. The few applied protocols have not been standardized and vary significantly across a set of core elements. In this review, we consider nine elements that include treatment parameters (i.e., frequency and inter-stimulation interval), cumulative exposure (i.e., number of treatment days, sessions per day, and pulses per session), individualized parameters (i.e., treatment target and dose), and brain state (i.e., context and concurrent treatments). Precisely which of these elements is critical and what parameters are most optimal for the treatment of MDD remains unclear. Other important considerations for accelerated TMS include durability of effect, safety profiles as doses increase over time, the possibility and advantage of individualized functional neuronavigation, use of biological readouts, and accessibility for patients most in need of the treatment. Overall, accelerated TMS appears to hold promise to reduce treatment time and achieve rapid reduction in depressive symptoms, but at this time significant work remains to be done. Rigorous clinical trials combining clinical outcomes and neuroscientific measures such as electroencephalogram, magnetic resonance imaging and e-field modeling are needed to define the future of accelerated TMS for MDD., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed., Aims: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au., Method: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4., Results: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v . 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v . 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h., Conclusions: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.

Background: Sexual and/or gender minority (SGM) individuals experience higher rates and greater severity of depressive disorders than non-SGM persons. SGM individuals are more likely than non-SGM individuals to seek mental health treatment and to present to treatment with unique characteristics that should be accounted for when considering treatment recommendations. Patients seeking care for treatment-resistant depression (TRD) are offered a variety of evidence-based interventions ranging in modality and invasiveness (eg, psychotherapy and neuromodulation)., Methods: The current study used data from a TRD clinical research program to examine whether SGM (N = 52) and non-SGM (N = 202) patients differed in their clinical presentations and the treatment recommendations offered to them., Results: We found that SGM patients were younger, had a more severe history of childhood trauma, and reported greater current suicidality than non-SGM patients. There were no significant differences in treatment recommendations between groups., Conclusions: This study adds to nascent literature investigating clinical characteristics of SGM populations seeking mental health care and provides foundational evidence for the unique treatment considerations necessary for SGM individuals seeking treatment for TRD. Research into whether treatment outcomes differ for SGM and non-SGM individuals with TRD is encouraged, given clinical differences in trauma history and suicidality.