Case Report: Personalizing Transcranial Magnetic Stimulation Therapy for Treatment-Resistant Depression for a Patient with Complex Medical History

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

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

High frequency repetitive transcranial magnetic stimulation as an augmenting strategy in severe treatment-resistant major depression: A prospective 4-week naturalistic trial

Brian did reasonably well for about 3 years, with occasional worsening of depressive symptoms but generally with good functioning, when he developed his current major depressive episode. This was his most severe episode to date, with active suicidal ideation with a plan (but no immediate intent) to shoot himself. Over the next year, he had a number of treatments, among them multiple antidepressant medications, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, mirtazapine, tricyclic antidepressants, and tranylcypromine, as well as augmentation with lithium, thyroid hormone, buspirone, atypical antipsychotics, anticonvulsants, stimulants, light therapy, and ongoing psychotherapy. No treatment was able to achieve remission or a persistent clinically signifi cant reduction in symptoms. Given his degree of treatment resistance and continued overall deterioration, including increased suicidal ideation, he was referred for ECT. He achieved a good response (50%‐60% symptom reduction) with eight highdose right unilateral ECT treatments. ECT was delivered concurrently with ongoing medications, and attempts were made to optimize medications during and after ECT. However, Brian relapsed in about 6 weeks, and repeat ECT (including four right unilateral and eight bitemporal treatments delivered concurrently with ongoing medications) was unsuccessful in achieving signifi cant symptom reduction but was associated with notable cognitive impairment.

Brain stimulation therapies have demonstrated efficacy in the treatment of depression and treatment-resistant depression (TRD). Non-invasive brain stimulation in the treatment of depression has grown substantially due to their favorable adverse effect profiles. The role of transcranial direct current stimulation in TRD is unclear, but emerging data suggests that it may be an effective add-on treatment. Repetitive transcranial magnetic stimulation has demonstrated efficacy in TRD that is supported by several multicenter randomized controlled trials. Though, vagus nerve stimulation has been found to be effective in some studies, sham controlled studies were equivocal. Electroconvulsive therapy (ECT) is a well-established brain stimulation treatment for severe depression and TRD, yet stigma and cognitive adverse effects limit its wider use. Magnetic seizure therapy has a more favorable cognitive adverse effect profile; however, equivalent efficacy to ECT needs to be established. Deep brain stimulation may play a role in severe TRD and controlled trials are now underway.

Magnetic seizure therapy: development of a novel intervention for treatment resistant 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.

Pacemaker and Transcranial Magnetic Stimulation (TMS) use in H-1, figure-8, and single-pulse coils

The field of non-pharmacological therapies for treatment resistant depression (TRD) is rapidly evolving and new somatic therapies are valuable options for patients who have failed numerous other treatments. A major challenge for clinicians (and patients alike) is how to integrate the results from published clinical trials in the clinical decision-making process.We reviewed the literature for articles reporting results for clinical trials in particular efficacy data, contraindications and side effects of somatic therapies including electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), vagal nerve stimulation (VNS) and deep brain stimulation (DBS). Each of these devices has an indication for patients with different level of treatment resistance, based on acuteness of illness, likelihood of response, costs and associated risks. ECT is widely available and its effects are relatively rapid in severe TRD, but its cognitive adverse effects may be cumbersome. TMS is safe and well tolerated, and it has been approved by FDA for adults who have failed to respond to one antidepressant, but its use in TRD is still controversial as it is not supported by rigorous double-blind randomized clinical trials. The options requiring surgical approach are VNS and DBS. VNS has been FDA-approved for TRD, however it is not indicated for management of acute illness. DBS for TRD is still an experimental area of investigation and double-blind clinical trials are underway.

Treatment-resistant depression (TRD) is a major clinical challenge, with limited augmentation strategies beyond conventional antidepressants. Lamotrigine, an anticonvulsant licensed for bipolar depression, has been trialled in unipolar TRD, though evidence remains inconsistent, and its use is currently off-license. We describe a 45-year-old gentleman with severe TRD who failed multiple trials of antidepressants, including citalopram and mirtazapine in the community, and subsequently fluoxetine during admission following a suicide attempt. Given his lack of response, lamotrigine augmentation was initiated. Within three weeks, he demonstrated substantial improvement in mood, engagement, and self-care, alongside near-complete resolution of suicidal ideation. Depression severity, measured by the Patient Health Questionnaire-9 (PHQ-9), decreased from 23/27 (severe) to 3/27 (minimal) three weeks post lamotrigine. This rapid response occurred earlier than typically reported in clinical studies. The case highlights lamotrigine as a potentially valuable augmentation option in TRD and emphasises the need for further research to clarify its efficacy and predictors of early response.

Major depressive disorder is one of the most common psychiatric disorders, with a worldwide lifetime prevalence rate of 10%-20% in women and a slightly lower rate in men. While many patients are successfully treated using established therapeutic strategies, a significant percentage of patients fail to respond. This report describes the successful recovery of a previously treatment-resistant patient following right unilateral deep brain stimulation of Brodmann's area 25. Current therapeutic approaches to treatment-resistant patients are reviewed in the context of this case with an emphasis on the role of the right and left hemispheres in mediating disease pathogenesis and clinical recovery.

Why is depression comorbid with chronic myofascial face pain?: A family study test of alternative hypotheses

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.

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