Q&A: Neuromodulation in Major Depressive Disorder

Heidi Moawad, MDHeidi Moawad, MD, is a neurologist, medical educator, and medical editor. In this interview, she reviews the published evidence on the use of neuromodulation in major depressive disorder (MDD), including treatment selection, safety, accelerated protocols, maintenance, and prescription home-use technologies.What is neuromodulation treatment for MDD?There are several types of neuromodulation techniques and devices used for treating MDD. Evidence and regulatory status differ by modality: Some are established treatments, while many remain investigational. An understanding of the brain circuitry involved continues to develop alongside evidence of efficacy.[1,2]The oldest, electroconvulsive therapy (ECT), is a noninvasive method that requires general anesthesia and muscle relaxants. An electrical pulse is used to induce a therapeutic seizure. The treatment process involves several sessions over the course of weeks, and some patients continue to receive continuation or maintenance ECT.[1,3]Invasive therapies require a surgical procedure for implantation, do not intentionally induce seizures, and provide ongoing treatment. Deep brain stimulation (DBS) uses electrodes implanted into the brain, and vagus nerve stimulation (VNS) uses an implanted pulse generator connected to an electrode on the cervical vagus nerve. The electrical stimulation is programmed and delivered between visits, and ongoing clinical follow-up is required after implantation. Implanted VNS has a specific FDA indication for depression; DBS remains investigational for depression.[3,4]Noninvasive transcranial magnetic stimulation (TMS), typically delivered as repetitive TMS (rTMS), uses magnetic pulses to induce electrical currents in targeted cortical regions, commonly the left dorsolateral prefrontal cortex. It does not require anesthesia and does not intentionally induce seizures. The treatments are delivered by trained specialists over a course of sessions spanning several weeks.[2]Home-use electrical stimulation now includes transcranial direct current stimulation (tDCS) and external combined occipital and trigeminal afferent stimulation. These are distinct technologies with different approved indications. These medical devices require a prescription and medical supervision.[5,6]Where does neuromodulation now enter the MDD treatment pathway?Neuromodulation is becoming more accepted, and its place in treatment depends on the modality and clinical presentation. Generally, rTMS is considered when antidepressant treatment has not produced adequate improvement or has been poorly tolerated. It does not need to be reserved until every medication option has been exhausted. Treatment history, patient preference, urgency, and feasibility are points for consideration.[1,2]ECT remains an important option for severe depression when a rapid response is needed, particularly in patients with severe suicidality, catatonia, psychotic features, or physical deterioration. The Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines permit first-choice ECT in selected severe presentations. National Institute for Health and Care Excellence (NICE) guidance similarly recommends considering ECT for severe depression when a rapid response is needed, other treatments have failed, or an informed patient prefers it based on previous experience.[1,7]Implanted VNS occupies a different position; its FDA indication is adjunctive long-term treatment of chronic or recurrent depression in adults who have not responded adequately to four or more adequate antidepressant treatments. Benefits may take months to emerge, so it is not an acute rescue treatment.[3,4]The newer home-use approaches should not be treated as interchangeable with rTMS or implanted VNS. One approved tDCS system is indicated for adults with moderate-to-severe MDD that is not considered refractory to medication treatment, whereas combined occipital and trigeminal stimulation is approved as adjunctive treatment after inadequate improvement with at least one antidepressant.[5,6]Which patients with MDD are the best candidates for neuromodulation?Before concluding that a patient with depression is treatment-resistant, clinicians should reassess the diagnosis, adequacy of prior treatment, adherence, and contributing psychiatric or medical conditions. A history of mania or hypomania is consequential because evidence and management for bipolar depression differ from those for unipolar MDD. Insurance requirements and the clinical threshold for offering treatment are not necessarily identical.[1,2]Patients should receive a clear explanation of the treatment, its duration, and realistic expectations. For ECT, informed consent, decision-making capacity, and applicable legal requirements should be addressed and documented.[7] Management may involve monitoring the patient’s response to treatment, including depressive symptoms and functioning. For outpatient and home treatment, transportation, work or caregiving responsibilities, and the ability to follow the prescribed course are practical considerations.[2]Clinical suitability also requires modality-specific safety screening. An implant or neurologic history should prompt a device-specific assessment rather than automatic exclusion from every form of neuromodulation.[2]What are the safety concerns of neuromodulation?Safety concerns differ substantially by modality. Surgical implantation can cause complications such as infection. Intracranial bleeding is a risk of DBS implantation, whereas cervical VNS does not involve intracranial surgery. VNS may cause voice changes, cough, swallowing difficulty, or breathing symptoms and requires ongoing device management.[3]ECT can cause memory loss or confusion, in addition to risks associated with general anesthesia. Cognitive effects vary. Informed consent should address both the potential benefits and cognitive risks.[1,7]rTMS may cause head or jaw discomfort or pain, muscle twitching, headache, or disrupted sleep. These devices make a loud sound during treatment, and the sound may be unpleasant for patients. Appropriate hearing protection is needed. There is also a risk for seizures, but the risk with standard clinical protocols is low.[2]Pretreatment assessment should review seizure history, neurologic disease, medications, substance use or withdrawal, sleep deprivation, and metallic or electronic implants. Implant compatibility depends on the device, location, and stimulation system. During treatment, changes in medication or clinical status may require reassessment of stimulation settings or motor threshold; mood worsening and treatment-emergent activation also warrant attention.[2]Home-use electrical stimulation has its own precautions, including electrode-site irritation or burns and system-specific implant restrictions.[5,6,8]How strong is the evidence for accelerated TMS?Accelerated TMS uses a compressed timeframe, with treatments delivered multiple times per day. It is not one standardized intervention; pulse dose, session spacing, targeting, and total treatment duration vary. A short individual theta-burst session is not the definition of an accelerated course; acceleration refers to the schedule of multiple sessions.[2,9]Positive results from randomized clinical trials are available. In a 2025 single-center, sham-controlled trial of 100 adults with treatment-resistant depression, three intermittent theta-burst stimulation (iTBS) sessions per weekday for 15 weekdays produced greater improvement on the 17-item Hamilton Depression Rating Scale (HDRS-17) than sham at week 5. This protocol used scalp measurements rather than individualized imaging-based targeting.[10]A separate 2026 randomized trial of 48 participants evaluated high-dose, functional-connectivity MRI-guided iTBS delivered over 5 days. At 1 month, remission occurred in 50% with active treatment vs 20.8% with sham, although some participants received additional treatment before that assessment.[11]These findings support efficacy for specific protocols and cannot be used to conclude that every accelerated schedule is equally effective or superior to standard rTMS. A systematic review found mixed results across protocols and highlighted differences in dose, spacing, targeting, and patient populations. Larger comparative trials and longer follow-up could help clarify durability, retreatment, and the best balance between faster delivery and treatment burden.[9]How do you maintain improvement after neuromodulation?Many patients who are treated with neuromodulation for MDD are also prescribed antidepressants. Psychotherapy, especially cognitive-behavioral therapy (CBT), may also be part of the treatment plan. Some patients who are unable to tolerate antidepressant medication may benefit from other therapeutic interventions, such as CBT and counseling. Additionally, neuromodulation is not universally restricted to adjunctive use; monotherapy is permitted for some indications.[1,5]Maintenance planning should begin early in treatment planning. Follow-up should assess depressive symptoms, functioning, adverse effects, and suicide risk, with a clear plan for recurrence. Sustained benefit cannot be assumed simply because the initial treatment was beneficial.[1,2]Following successful ECT, continuation pharmacotherapy and, for selected patients, continuation or maintenance ECT are options. A 2026 systematic review that included heterogeneous studies found the strongest evidence for lithium-based pharmacotherapy and, separately, continuation ECT combined with medication. Evidence for CBT specifically as post-ECT relapse prevention was limited.[12]Scheduled maintenance and symptom-triggered re-treatment are both used for rTMS, but an optimal schedule has not been established. A meta-analysis of 14 studies involving 705 participants suggested benefit, with substantial heterogeneity that limits definitive conclusions about the preferred approach.[2,13]Implanted VNS involves continued stimulation rather than a finite acute course. The 493-patient RECOVER randomized trial did not meet its primary efficacy outcome, although several secondary outcomes favored active treatment. A subsequent uncontrolled extension found that most participants with meaningful benefit at 12 months retained it during the following year, with the exact proportion depending on the outcome measure and definition. That durability finding applies to selected continuing participants and is not a controlled estimate of benefit for every patient starting treatment.[14,15]Could magnetic seizure therapy (MST) change the role of convulsive treatment?MST remains investigational for depression. Like ECT, it intentionally induces a seizure and requires general anesthesia with muscle relaxation, but it uses magnetic stimulation rather than directly applied electrical stimulation. The goal is to retain antidepressant efficacy while reducing adverse cognitive effects.[3]The 2026 Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy (CREST-MST) randomized 239 adults with nonpsychotic MDD to MST or right unilateral ultrabrief-pulse ECT; 236 received treatment. In the prespecified modified completer analysis (219 participants), remission occurred in 22.5% with MST vs 27.8% with ECT, meeting the noninferiority criterion. Findings were consistent in the modified intention-to-treat analysis: 21.4% vs 25.2%, respectively. The cognitive outcome was analyzed in the modified intention-to-treat sample; among participants with evaluable memory outcomes, prespecified worsening on the Autobiographical Memory Test, defined as a decline of at least 25%, occurred in 2.7% with MST vs 17.3% with ECT.[16]These results are promising. The trial excluded psychotic depression and tested only one ECT technique. Further research may help clarify long-term outcomes and the role of MST.[16]How do the new home-use devices differ for MDD?Two distinct prescription home-use electrical-stimulation approaches have received FDA approval for specific systems. These medical devices require a prescription and medical supervision; neither is home-use TMS. Approval is system specific, not class-wide.[5,6]tDCS delivers a low-intensity current through scalp electrodes. The approved system is indicated for adults with moderate-to-severe MDD that is not refractory to medication treatment, either alone or adjunctively. Treatment starts with five 30-minute sessions weekly for 3 weeks, followed by up to three sessions weekly.[5]In the pivotal 174-participant trial, the adjusted HDRS-17 improvement favored active treatment by approximately 2.3 points over sham at 10 weeks.[5,17] It judged the probable benefit to be modest but sufficient to outweigh probable risks, while noting uncertainty about clinical significance and conflicting evidence.[5]A 2026 meta-analysis found a small benefit across home-use tDCS systems, but inconsistent results limited confidence in routine use. The findings were not specific to the approved system.[18]External combined occipital and trigeminal afferent stimulation delivers electrical pulses through forehead and occipital electrodes to stimulate peripheral nerve branches. The approved system is adjunctive treatment for adults whose MDD has not improved satisfactorily with at least one antidepressant.[6]The pivotal 8-week trial found greater symptom improvement than sham in a restricted analysis, but response and remission outcomes were not statistically significant after adjustment for multiple comparisons. Uncertainty remained about blinding, clinical significance, and longer-term benefit.[6]At-home self-administered noninvasive treatment can be an appealing concept for patients with transportation difficulties or who live far from a treatment center. Some important considerations involve whether a patient can maintain a consistent schedule and follow the treatment plan, position electrodes correctly, and communicate with the supervising clinician. Monitoring should address skin reactions, worsening depression, and suicidal thoughts; the need for care is urgent and must not be delayed. Nonprescription products should not be assumed equivalent to these prescription systems.[5,6,7,8]Editor's Note: This article was created using several editorial tools, including generative AI models, as part of the process. Human review and editing of this content were performed prior to publication.