Comparison of rTMS and esketamine for treatment-resistant depression: A target trial emulation.

The Neglected Role of Psychotherapy for Treatment-Resistant Depression.

Changes in Regional Cerebral Blood Flow After Repetitive Transcranial Magnetic Stimulation of the Left Dorsolateral Prefrontal Cortex in Treatment-Resistant Depression

A retrospective 'target trial emulation' comparing amiodarone and lidocaine for adult out-of-hospital cardiac arrest resuscitation.

Type 2 diabetes mellitus (T2DM) paradoxically increases fracture risk despite normal or elevated bone mineral density. While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) show promise in bone health, evidence remains controversial. This large-scale real-world study evaluated the primary outcome of femur fracture risk associated with GLP-1 RAs versus dipeptidyl peptidase-4 inhibitors (DPP-4is) in T2DM patients using a rigorous target trial emulation approach. This retrospective cohort study adopted a large-scale target trial emulation framework with a new-user, active-comparator design using data from the TriNetX US Collaborative Network. Adults (≥18years) with T2DM identified between 2018 and 2022 (n=3,620,983) were classified as GLP-1 RA (n=491,936) or DPP-4i (n=345,484) users at treatment initiation. Propensity score matching (PSM) was performed to emulate random assignment and balance baseline characteristics. Cox proportional-hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for bone fractures during a maximum 5-year follow-up. After 1:1 PSM, each cohort included 172,381 patients (mean age 59years; 51% male) with a mean follow-up of 40months. GLP-1 RA users demonstrated significantly lower femoral fracture risk compared to DPP-4i users (HR 0.91, 95% CI 0.85-0.98), with consistent protective effects across all sensitivity analyses. Similar associations were observed when comparing GLP-1 RAs with most other antidiabetic medications. GLP-1 RA use was associated with a modest reduction in femur fracture risk. However, given the observational design, possible residual confounding, and multiple testing, these findings are exploratory and require prospective confirmation before clinical application.

Back to table of contents Previous article Next article Clinical & ResearchFull AccessIs Magnetic Seizure Therapy Ready to Round the Corner?Nick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:25 May 2021https://doi.org/10.1176/appi.pn.2021.5.44AbstractAn ongoing phase 3 trial comparing magnetic seizure therapy with electroconvulsive therapy may finally provide the proof needed to get this promising intervention into clinical use.In May of 2000, Sarah Lisanby, M.D., then an assistant professor of psychiatry at Columbia University, was flying over to Bern, Switzerland, to test out a new tool in the fight against depression. She had spent the previous five years building and testing a device that used strong magnetic waves to stimulate controlled seizures in the brain. The hope was that this new approach to neuromodulation might provide severely depressed patients welcome relief from their symptoms without some of the risks associated with electroconvulsive therapy (ECT), which uses electricity to stimulate controlled seizures.Sarah Lisanby, M.D., prepares to administer magnetic seizure therapy to the first human volunteer in 2000.Courtesy of Sarah Lisanby, M.D.Lisanby’s colleague Thomas Schlaepfer, M.D., had identified a young woman with treatment-resistant depression who lived in Switzerland and was willing to undergo the experimental procedure. So, with a suitcase full of spare machine parts, Lisanby set out to conduct the first in-human trial of magnetic seizure therapy (MST).The results of that trial, which were published 20 years ago this spring, were promising, setting magnetic seizure therapy on a long clinical journey that may soon reach fruition.Magnetic Pulses Have AdvantagesThe research by Lisanby, now the director of the Noninvasive Neuromodulation Unit at the NIH Clinical Center, followed decades of work by others to increase options for patients with treatment-resistant depression. Lisanby is also the director of the Division of Translational Research at the National Institute of Mental Health (NIMH).“Attempts to modify how ECT is given are nearly as old as ECT itself,” she explained. By adjusting the amount of current delivered and changing where the electrodes are placed on the scalp, researchers looked for ways to increase the efficacy and reduce the side effects of ECT, including short-term memory loss. One of the most significant safety advances in ECT practice was shifting the placement of electrodes from bilateral (one on each side of the scalp) to unilateral (one on the right side and one on the center top of the head), she noted.“But physics limits how far we can advance with electric stimulation,” Lisanby said. Electrical currents meet heavy resistance and diffuse as they pass through skin and skull, thus making it difficult to target a specific region of the brain. Additionally, excess electrical energy spills out to surrounding brain regions, which leads to side effects.In contrast, magnetic waves can pass through biological tissue unimpeded.The idea of triggering brain seizures via magnetism was conceptualized in the early 1990s by Columbia’s Harold Sackeim, Ph.D., one of Lisanby’s mentors and a leading authority on ECT. At that time, a novel approach known as transcranial magnetic stimulation (TMS) was making headlines as a potential depression treatment. Though TMS relied on low-level magnetic energy to “gently” modulate brain activity, these pulses were found to induce seizures in rare instances. Sackeim reasoned that stronger magnetic pulses could induce more focalized seizures and mimic ECT’s antidepressant effects with fewer unwanted side effects.MST is not without risks, as patients who receive the procedure report transient scalp pain and headaches, said Shawn McClintock, Ph.D., an associate professor of psychiatry at the University of Texas Southwestern Medical Center (UTSW) who studies neurostimulation therapies. “But the risk of short-term amnesia and other cognitive problems that have contributed to ECT’s stigma is far less.”MST Hurdles Left to ClearIn the 21 years since Lisanby successfully treated her first patient with MST, the technology has undergone a steady if plodding progression toward clinical use. Numerous small studies, including a couple of head-to-head comparisons, have shown MST is about as effective as ECT at reducing depressive symptoms with fewer cognitive side effects. Some research centers, notably the Temerty Centre for Therapeutic Brain Intervention in Toronto, have also begun testing whether MST might be effective in patients with treatment-resistant bipolar depression or schizophrenia.Researchers at the University of Texas Southwest Medical Center demonstrate a contemporary MST device, which is believed to provide the antidepressant efficacy of electroconvulsive therapy with reduced cognitive side effects.UTSWDespite more than 20 years of positive data and the approval of TMS for treatment-resistant depression in 2008, experts say it will likely be years before MST machines appear in clinics.“MST requires a different device and uses different frequencies than TMS, so it is essentially a brand-new therapy and not a modified form of TMS,” said McLintock. “Seizure therapy is also an intensive treatment, so you want to proceed with the highest rigor, especially when it comes to safety, even if it takes more time.”Another factor contributing to delays in moving MST to the clinic is that the medical device industry has not invested in this new technology as they did with TMS, Lisanby acknowledged. Currently, only MagVenture (based in Denmark) builds MST devices, and the company does not have the capital to sponsor large, multicenter studies (though they have donated machines for clinical research).“NIMH recently stepped up to the plate and agreed to support a phase 3 trial” evaluating MST for treatment-resistant depression—a pivotal step for clinical approval, Lisanby explained. The trial is known as CREST-MST (for Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy for Depression). The multicenter trial will be led by Daniel Blumberger, M.D., the director of Toronto’s Temerty Centre, and Carol Tamminga, M.D., the Lou and Ellen McGinley Distinguished Chair and the McKenzie Chair in Psychiatry at UTSW.Comparison Trial UnderwayAs the director of the largest ECT service in Canada, Blumberger knows firsthand that ECT is the most effective treatment for severe treatment-resistant depression. He also knows it is the treatment option most refused when suggested to patients.“If we could offer patients an alternative, we could help so many more,” he said. The same belief was held by the Centre’s prior director, Jeff Daskalakis, M.D., Ph.D., who in 2011 led the effort to obtain an MST device and funding to start clinical trials in Canada.A decade later, the Temerty Centre has become a leader in clinical neuromodulation research and is a fitting choice to lead CREST-MST. Blumberger recently oversaw a head-to-head study that ultimately led to the FDA clearance of a new, rapid form of TMS known as theta-burst stimulation.The CREST-MST trial is enrolling 260 adults with treatment-resistant depression at both the Temerty Centre and UTSW and providing them with either ECT or MST in a random and blinded fashion. (Both procedures are done under anesthesia so patients are not aware of their treatment; the clinicians assessing patient recovery will also be unaware of the treatment patients are receiving.) Blumberger told Psychiatric News that the trial has two primary goals. “The intent is to see whether MST is as clinically effective as ECT in terms of depression improvement and whether it has a better cognitive side-effect profile,” he said.The trial had enrolled about 25% of participants when the COVID-19 pandemic hit last spring. Enrollment had to be put on hold as research activities and patient volumes were limited at both participating centers. Both sites have since reopened, and Blumberger is hopeful that the study can get back to full speed. He is also looking to re-launch another trial with his colleagues in Vancouver and London, Ontario, which is comparing MST and ECT for bipolar depression.“When all the data are in, I am hopeful MST will meet the bar for regulatory approval and within a few years become a new option for treatment-resistant depression and potentially other refractory psychiatric disorders,” he said.‘One Size Does Not Fit All’If MST does emerge as a safer alternative to ECT, will that spell the end for the original neuromodulation therapy?Lisanby won’t rule anything out but thinks it’s most likely that MST will become another option for patients with treatment-resistant depression rather than a replacement for ECT. She noted that despite the consensus that unilateral ECT was a tremendous advance over bilateral ECT, some patients still receive the latter procedure. “Patients who qualify for ECT have severe and treatment-resistant depression, so we want as broad a range of options as possible.”“One size does not fit all,” agreed McClintock, who will also be working on CREST-MST. “As the field advances, we may find that ECT might be better in certain cases, such as patients with psychotic symptoms or suicidal ideation. That’s why we need to find biomarkers that may suggest which treatment would work best for a given patient.”A key element of personalizing these brain stimulation procedures is to understand how they exert their effects—the mechanisms of ECT and MST are still somewhat of a black box. One of the focuses of McClintock’s research is using neurocognitive and neuroimaging tools to measure the changes in the brain after therapeutic seizures are induced. “We need to know why these treatments are doing what they are doing,” he said. ■The details of the first MST trial, “Magnetic Seizure Therapy of Major Depression,” is posted here.More information on CREST-MST is posted here. ISSUES NewArchived

Background and Aims The concept of target trial emulation has recently been introduced and implemented in nephrology as a complement to when randomized trials may not be feasible. Thereby critical questions in the comparative effectiveness and safety of interventions during kidney failure can be addressed. This methodological systematic review aims to evaluate the scope, validity and robustness of the target trial approach for studying outcomes in patients with kidney disease. Method MEDLINE, Embase, and reference lists were searched up until 1st June 2023 to identify studies on kidney disease patients that use target trial emulation. Dual study selection (AA, PK) was undertaken, with a third reviewer settling disagreements (JP). Interventional observational studies were eligible that used target trial emulation to mimic a hypothetical trial where the conduct of a randomized trial was unfeasible, unethical, or untimely. We included studies across the range of chronic kidney diseases, i.e., predialysis, dialysis and transplantation; studies assessing acute disease states (including acute kidney injury) were excluded as well as non-primary research (i.e., case series/editorials/reports/narrative reviews). The quality of reporting and risk of bias was assessed independently by three reviewers and differences resolved through consensus with a fourth reviewer. The critical appraisal was piloted using a previously published reporting checklist and refined throughout the process. Results The systematic search yielded 2883 studies, of which 649 duplicates were removed. From 2232 studies, 367 full-text studies were assessed for eligibility according to target trial emulation criteria and 74 studies were included. A large number of studies (47) focused on patients with kidney failure undergoing renal replacement therapy, mainly haemodialysis. 30 studies were reported before 2019. Of the 74 studies, 46 focused on pharmacological interventions, six on surgical interventions, four on transplantation and 18 on other interventions. Studies used either registries (41), health administration data (4), insurance data (5), electronic health records (15), study databases (8) or other (1). It should be noted that in multiple instances more than one data source was used. The majority (66) of studies did not explicitly mention target trial emulation in the title or abstract. Only a minority (8) of studies explicitly prespecified a target trial protocol. To mitigate confounding, studies mainly focused on exact matching of the groups by using inverse probability weighting and propensity score matching. Conclusion In the past decade the use of the target trial emulation framework in nephrology has substantially increased. However, reporting and quality of study conduct is variable and shows the clear need for a reporting framework to increase clarity and reliability, and to understand to what extent study findings are generalisable into clinical practice to improve health outcomes

Association of SGLT2 inhibitors with hematologic malignancies in type 2 diabetes: a target trial emulation study.

Accelerated Intermittent Theta Burst Stimulation: Expediting and Enhancing Treatment Outcomes in Treatment-Resistant Depression.

IntroductionPerinatal depression is a serious and highly prevalent medical condition in the USA. Nearly 85% of individuals with perinatal depression go untreated, leading to significant morbidity and mortality. There is an urgent need to develop and advance safe and effective treatments for perinatal depression. Transcranial magnetic stimulation is an established intervention for depression in non-pregnant individuals yet is not well studied in perinatal depression.Case presentationA 33-year-old pregnant Latina female presented with severe, recurrent, treatment-resistant depression and suicidal ideation. The patient had previously trialed psychotherapy, multiple antidepressants, and mood stabilizers and had achieved remission with lithium prior to pregnancy. Due to pregnancy and fetal safety concerns, the patient discontinued lithium and consequently suffered progressive worsening of perinatal depression. At 24 weeks gestation and after additional failed medication trials, a prolonged course of transcranial magnetic stimulation was initiated. Following 46 transcranial magnetic stimulation treatments over 9 weeks using two protocol types (repetitive transcranial magnetic stimulation and intermittent theta burst stimulation), she achieved near-remission of perinatal depression and resolution of suicidal ideation. There were no identified maternal or fetal adverse events at 6 weeks post-delivery.ConclusionTo our knowledge, this is the first published case of a pregnant individual with perinatal depression who received and tolerated a prolonged transcranial magnetic stimulation course with two distinct protocols (repetitive transcranial magnetic stimulation and intermittent theta burst stimulation) with clinically significant response. Transcranial magnetic stimulation is a well-tolerated and effective intervention that warrants further investigation for use in treatment-resistant perinatal depression.

Back to table of contents Previous article Next article Interventional PsychiatryFull Access2021 Educational Opportunities to Learn More About Interventional Treatments, ResearchRichard A. Bermudes, M.D.Richard A. BermudesSearch for more papers by this author, M.D.Published Online:27 Jul 2021https://doi.org/10.1176/appi.pn.2021.8.38The 2021 Clinical TMS Society Meeting and Pulses Course were held in West Palm Beach, Fla., in June. This was the first in-person interventional psychiatry meeting since the start of the pandemic. The majority of attendees had completed vaccination, and overall, they expressed a sense of gratitude and relief in being able to socialize and network in person while attending excellent lectures and workshops on current and evolving clinical applications of transcranial magnetic stimulation (TMS).The meeting had two two-day components: The Pulses Course and the Annual Meeting. About 100 participants attended the Pulses Course. The course consisted of a series of lectures and demonstrations on the clinical administration of TMS and offered practical recommendations for implementing TMS in a clinical practice. Lecture topics ranged from a review of TMS for treatment-resistant depression (TRD) to how to negotiate the increasing complexity of insurance coverage for TMS. Attendees also had the opportunity to participate in a virtual lecture by Prof. Anthony Barker, designer of the first TMS machine in 1985. He reviewed the history and basic scientific principles of TMS.More than 500 TMS researchers, clinicians, and thought leaders attended the Annual Meeting. The meeting featured a number of workshops and invited lecturers on a range of TMS topics. General themes included new research on clinical applications for TMS for neuropsychiatric conditions other than TRD (see box “Expanding Indications for TMS”), as well as evolving TMS applications to optimize outcomes for patients with TRD (see box “Optimizing Outcomes in Patients With Treatment-Resistant Depression”).How can TMS be more rapid and effective in severe TRD patients? With evolving applications, can we raise remission rates to the equivalent of electroconvulsive therapy and intravenous ketamine? During the Annual Meeting, Nolan Williams, M.D., presented two open-label studies of patients who had very severe TRD (that is, would qualify for deep brain stimulation) utilizing the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT TMS) protocol. These datasets showed rapid reductions in depression and suicidality within three days of treatment. Remission rates at the end of the five-day protocol were > 90%.There are a number of in-person meetings for psychiatrists who want to learn more about new developments in interventional treatments:The Clinical TMS Society will hold another Pulses Course in Nashville, Tenn., September 11 and 12.The American Society of Ketamine Physicians, Psychotherapists, and Practitioners (ASKP) will hold its 2021 Annual Conference (virtual/in person) in Detroit, Mich., November 4 to 6. This conference features education and research on ketamine, esketamine, and ketamine/esketamine-assisted psychotherapy.The Fourth International Brain Stimulation Meeting will be held in Charleston, S.C., December 4 to 6. This will feature reports on ECT, VNS, TMS, DBS, and tDCS. ■Expanding Indications for TMSBipolar depression: Prospective open-label data from two academic centers suggest that conventional TMS (10 hz to the L-DLPFC) may be effective in patients with treatment-resistant bipolar depression.Addiction: Multisite sham-controlled data indicate that deep TMS with a unique coil design increases the rate of smoking cessation. Future studies are planned on other substance use disorders.Adolescent depression: Studies are planned that combine psychotherapy with bilateral sequential TMS in adolescents with treatment- resistant depression.Posttraumatic stress disorder: Studies are evolving to optimize improved brain network targeting and stimulation protocols.Neuropathic pain: A consensus review by a 30-person multinational expert panel supports the finding that TMS reduces neuropathic pain.Headaches associated with traumatic brain injury (TBI): The multinational expert panel supports the finding that TMS reduces headache associated with TBI.Optimizing Outcomes in Patients With Treatment-Resistant DepressionIncreasing the dose of intermittent theta burst TMS, acceleration, and optimizing targeting:Prospective open-label data of the SAINT protocol (AJP) suggest dramatically improved remission rates after just one week of treatment.The study design for a pivotal multisite randomized, controlled study is evolving.Adding pulses and brain targets: Data comparing bilateral sequential TMS and conventional TMS show equivalent outcomes.Optimizing patient selection with potential biomarkers: Emerging biomarkers and stratification of biomarkers to predict response to TMS are evolving, but definitive trials are needed.Extending the duration of conventional TMS and developing protocols for continuation and maintenance TMS: Recent data from a literature review indicate that reintroducing TMS prior to full relapse improves patient outcomes and durability.Richard A. Bermudes, M.D., is the chief medical officer at Mindful Health Solutions in San Francisco and an assistant clinical professor of psychiatry at the University of California, San Francisco. He is also the co-editor of Transcranial Magnetic Stimulation: Clinical Applications for Psychiatric Practice from APA Publishing. APA members may purchase the book at a discount here. ISSUES NewArchived

Over the past two decades, the number of somatic treatments for psychiatric disorders has expanded, leading to new insights into the complex relationship between chemical and electric transmission of signals in the brain. In this article, the authors discuss the different device-based treatments currently available in psychiatry. They review clinical indications; putative mechanism of action; efficacy and adverse effects; the results and limitations of salient clinical trials; and active areas of research into the neurobiology of device-based stimuli.

Background:Both the ACR[1] and EULAR[2] guidelines endorse the use of colchicine or NSAIDs for gout flare prophylaxis when initiating urate-lowering therapy for gout care; however, a recent UK study[3] found...

Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = −17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = −14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = −13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = −37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = −42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = −34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.Trial registration: ClinicalTrials.gov, NCT02977299

Treatments for major depression – Authors' reply

Treating depression in adolescents is a significant challenge, and major depressive disorder (MDD) with suicidal ideation and treatment-resistant depression (TRD) are common and potentially devastating to optimal psychological and physical development in this age group. Suicide is among the leading causes of youth mortality, and TRD occurs in up to 40% of adolescents with MDD. TRD involves severe, persistent symptoms that are hard to treat, significantly reducing functioning and quality of life. We conducted a literature search focusing on key terms related to ketamine and esketamine for MDD with suicidal ideation and TRD in adolescents, aiming to review the potential utility of these molecules in adolescents for these conditions. Ketamine has shown efficacy in reducing depressive symptoms in adolescents with TRD. Esketamine has shown efficacy in reducing depressive symptoms and treating suicidal ideation in adolescents. Both ketamine and esketamine have demonstrated favorable safety and tolerability profiles. Using these drugs for serious conditions like adolescent MDD with suicidal thoughts and TRD can effectively treat symptoms, reduce self-harm and suicide risks, and provide a window for longer-term therapeutic interventions. The prompt and effective treatment of TRD could improve adolescents' quality of life. However, more research is needed to optimize treatment protocols and evaluate long-term effects.