Treatment-resistant depression (TRD) represents a subtype of major depressive disorder (MDD) characterized by an inadequate response to standard antidepressant treatments. While various definitions and staging models exist, a commonly accepted criterion proposed by the U.S. Food and Drug Administration (FDA) is the failure to achieve a satisfactory response after at least two adequate trials of different antidepressant medications (1). This lack of consensus on a precise definition reflects the complexity of TRD and underscores the need for individualized treatment approaches. TRD remains a significant clinical challenge, affecting approximately 30-40% of individuals with MDD. These patients experience extended periods of illness while struggling with disabling symptoms such as hopelessness, anhedonia, and cognitive dysfunction. Additionally, the chronic nature of their condition increases their risk for a wide range of psychiatric and somatic comorbidities, such as chronic suicidality, anxiety disorders, substance abuse, and cardiovascular disease (2).

Introduced in the 1930s, ECT emerged as a groundbreaking intervention for severe psychiatric conditions. Its application in treating depression, particularly in cases resistant to other treatments, has been well-documented. A study from the 1940s reported that 80% of patients receiving ECT experienced symptomatic improvement, compared to 50% in the control group. Additionally, the average length of hospitalization for the ECT group was significantly shorter, underscoring its efficacy in managing severe depression (3). In modern clinical practice, ECT remains a highly effective treatment for TRD and is considered a first-line treatment for severely depressed patients who require a fast response because of a high suicide or homicide risk, extreme agitation, life-threatening inanition, psychosis, or stupor (4). Beyond its established use for severe TRD, bipolar disorder, schizophrenia, and catatonia, electroconvulsive therapy (ECT) is also being investigated for a broader range of psychiatric and neuropsychiatric conditions. These include post-traumatic stress disorder (PTSD), Parkinson’s disease with psychiatric symptoms, neuropsychiatric complications associated with COVID-19, and perinatal psychiatric disorders, where pharmacologic treatments may pose risks (5). Additionally, ECT is increasingly being applied in acute medical scenarios where a rapid therapeutic response is essential. For medically unstable patients suffering from severe somatic comorbidities, such as dehydration, malnutrition, or profound weight loss, ECT can facilitate urgent clinical stabilization. Emerging evidence also supports its efficacy in managing intractable delirium, particularly in intensive care settings, and in select cases of refractory or super-refractory status epilepticus, where standard treatments have proven ineffective and ECT has been associated with clinical improvement (6, 7).

Although ECT is highly effective in the rapid treatment of various psychiatric disorders and symptoms, it continues to be an underutilized and stigmatized intervention (8), mainly due to its cognitive side effects, such as anterograde and retrograde amnesia. However, ongoing research continues to shed light on its mechanisms of action and develop strategies to mitigate adverse effects, reinforcing its role as a vital option in treating TRD (9). Moreover, recent advancements in ECT techniques have significantly enhanced both its safety and therapeutic efficacy. Innovations in dosing parameters, electrode placement strategies, and the integration of augmenting agents have been meticulously designed to optimize clinical outcomes while minimizing adverse effects. These refinements emphasize the evolving role of ECT in contemporary psychiatric practice, broadening its applicability while ensuring greater precision and safety in treatment delivery.

This review aims to synthesize recent findings on the effectiveness and biological mechanisms of ECT in treating TRD. It includes a discussion of studies that compare ECT with ketamine and repetitive transcranial magnetic stimulation (rTMS), focusing on differences in clinical outcomes. Furthermore, we highlight emerging insights into the neurobiological mechanisms underlying ECT's antidepressant effects, emphasizing pathways implicated in its therapeutic action. By integrating these findings, this review offers a comprehensive overview of the current state of ECT research and outlines promising directions for optimizing its clinical utility in TRD.

This narrative review was conducted using a targeted literature search conducted across multiple databases, including PubMed, PsycINFO, and Scopus. The strategy utilized combinations of terms such as “electroconvulsive therapy,” “ECT,” treatment-resistant depression,” “mechanisms,” “efficacy,” “neuroplasticity,” “cognitive effects,” “biomarkers,”, “rTMS,” and “ketamine,” In addition to database searches, we performed manual screening of relevant articles from ECT-specific and interventional psychiatry journals, including The Journal of ECT, Brain Stimulation, and Neuropsychopharmacology.

We prioritized peer-reviewed English language publications, including systematic reviews, meta-analyses, randomized controlled trials (RCTs), mechanistic studies, and high-impact narrative reviews. Studies were included if they addressed the clinical efficacy, biological mechanisms, or safety profile of ECT in TRD or related neuropsychiatric conditions.

Exclusion criteria included non-peer-reviewed content, case reports with unclear methodology, or studies focused exclusively on other disorders without relevance to TRD or ECT. This methodology aimed to synthesize foundational and emerging findings while capturing the comparative landscape between ECT, rTMS, and ketamine. The final selection includes over 80 references, representing a balance of clinical and mechanistic perspectives to guide future research and practice.

Electroconvulsive therapy (ECT), ketamine, and rTMS are among the most effective treatments for individuals with TRD, each offering distinct clinical advantages ( Table 1 ). ECT remains the gold standard, particularly for patients with severe symptoms, suicidality, or psychotic features, or late-life depression, where its efficacy is consistently supported by meta-analyses and geriatric trials. Moreover, older adults often respond more robustly to ECT than younger populations, likely reflecting age-related neurobiological differences and the distinct clinical characteristics of late-life depression (10, 11). However, its broader use is limited by the need for anesthesia and the risk of cognitive side effects, as well as associated costs. Moreover, ECT’s requirement for general anesthesia and muscle relaxation imposes procedural constraints and hospital burdens. In particular, it affects patients with complex medical conditions. Individuals with cardiovascular conditions, such as recent myocardial infarction, unstable coronary artery disease, congestive heart failure, or arrhythmias, as well as those with pulmonary comorbidities (e.g., COPD or OSA). These patients require extensive pre-anesthetic evaluation, which may lead to delays or disqualification from treatment (12). rTMS, on the other hand, offers a non-invasive alternative that targets specific brain regions through magnetic pulses, without the need for anesthesia and with generally good tolerability. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has gained recognition for its rapid antidepressant effects, more favorable cognitive profile, and ease of administration. This section examines current evidence comparing ECT, ketamine, and rTMS in the treatment of TRD, focusing on onset of therapeutic effects, cognitive outcomes, and durability of response.

A growing body of literature comparing ECT and ketamine for TRD underscores the effectiveness of both interventions. However, they exhibit notable differences in the speed of onset, cognitive effects, and patient outcomes preference. Basso et al. (13), conducted an open-label clinical trial demonstrating that, while both treatments were equally effective, ketamine exerted a more rapid antidepressant effect and improved neurocognitive functions. In contrast, ECT was associated with a mild decline in cognitive performance. In line with this, Ghasemi et al. (14), found that ketamine led to a significantly faster reduction in depressive symptoms within 24 hours compared to ECT. However, its efficacy became comparable to ECT after multiple treatments. A study by Kheirabadi et al. (15), further supported these findings, showing no statistically significant difference in antidepressant efficacy between ECT and ketamine. However, cognitive performance was slightly better in the ketamine group. The KetECT, a multicenter randomized controlled study, added another layer to this evolving comparison, showing that ECT had superior remission rates (62.6% vs. 46.3% for ketamine) (16). The ELEKT-D trial, a multicenter randomized controlled study, found that ketamine was noninferior to ECT in reducing depressive symptoms, with response rates of 55.4% for ketamine and 41.2% for ECT (17). In a post hoc secondary analysis, the authors found that patients with the highest severity appeared to benefit more quickly from ECT, potentially due to its robust neurobiological impact. However, ketamine demonstrated higher overall response rates and was especially effective among outpatients with nonpsychotic depression who experienced moderate to severe symptoms of depression (18). A recent meta-analysis encompassing six randomized controlled trials found that both treatments significantly reduced depressive symptoms, with no substantial difference in overall efficacy between the two modalities. Ketamine demonstrated superior memory function improvement compared to ECT. In terms of adverse events, ketamine was associated with significantly higher rates of dissociative symptoms, blurred vision, and dizziness, while demonstrating a lower incidence of muscle pain (19).

Comparative studies have also shown differences in efficacy between rTMS and ECT. In a meta-analysis by Ren et al. (2014), ECT had a higher response rate than high-frequency rTMS (HF-rTMS) for major depression, with response rates of 52.9% for ECT versus 38.3% for HF-rTMS. Similarly, Micallef-Trigona (20) found that ECT was more effective than rTMS, with a significant reduction in HDRS scores in the ECT group. However, rTMS still showed a notable antidepressant effect, suggesting its potential as a viable alternative, especially for patients who may not tolerate ECT. On the other hand, Cano et al. (21), showed that both right unilateral (RUL) ECT versus left dorsolateral prefrontal cortex (lDLPFC) rTMS significantly reduced depressive symptoms in patients with TRD, with QIDS scores decreasing by 30.40% and 36.13%, respectively. Despite higher baseline severity in the ECT group, there was no significant difference in clinical response between the two treatment modalities. A retrospective cohort study showed that ECT exerted a significantly stronger antidepressant effect than rTMS in terms of MADRS-S score reduction, response rate, remission rate, and clinically meaningful change (22). Kaster and Blumberger (23) emphasized the role of rTMS in sequential treatment models, noting that while less effective than ECT, it remains a viable step before ECT for patients seeking non-invasive options. A recent meta-analysis comparing ECT, rTMS, and ketamine in adolescents with TRD confirmed that while ECT remains the most effective, it is often avoided due to stigma and accessibility issues (24). Similarly, a systematic review of RCTs found that ECT is superior to both ketamine and rTMS in overall efficacy. However, ketamine offers faster symptom relief, making it useful in acute interventions (25). Despite these findings, more research is needed to better characterize patient-level predictors of treatment response, which could help guide the selection of optimal treatment modalities based on individual clinical profiles.

ECT, ketamine, and rTMS are three principal interventions for TRD, each characterized by distinct advantages and limitations. ECT has historically been regarded as the most efficacious treatment, particularly for individuals with severe depression, psychotic symptoms, suicidality, or late-life depression. Its well-established effectiveness in older adults should be especially noted, as this population often shows greater clinical response and tolerability (10, 11). However, concerns regarding its associated cognitive impairment, societal stigma, and restricted accessibility have contributed to a decline in its utilization. Ketamine has emerged as a promising alternative due to its rapid antidepressant effects, a more favorable cognitive side effect profile, and its comparatively less invasive administration. rTMS, a non-invasive neuromodulation technique, represents another viable therapeutic option, offering a favorable safety profile but exhibiting more variable efficacy across patient populations ( Table 2 ).

Concerns about cognitive side effects are a significant barrier to the wider acceptance of ECT, despite its effectiveness in treating TRD (26). While early reports highlighted cognitive risks, accumulating evidence indicates that many of these effects are time-limited and, in some cases, reversible. Studies indicate that impairments in attention, executive function, and processing speed typically persist for a brief duration. Most studies find a return to baseline or improvement within weeks to three months after treatment, suggesting that these improvements likely result from both the effects of ECT on the brain and the relief of depressive symptoms (27–29). A large-scale longitudinal study utilizing data from 1,498 patients in the Swedish National Quality Register for ECT found that 25.2% of individuals reported subjective memory worsening six months after treatment. Notably, the strongest predictor of long-term cognitive complaints was residual depressive symptoms, as measured by MADRS-S scores, rather than ECT technical variables such as electrode placement, pulse width, or number of sessions. These findings suggest that patients’ perception of cognitive impairment may reflect unresolved mood symptoms more than the direct neurobiological effects of ECT and highlight the importance of achieving and maintaining full remission (30). Xu et al. (31), demonstrated that ECT is effective in treating young adults with TRD and highlighted the heterogeneous nature of cognitive outcomes during treatment. While global cognition, verbal fluency, and working memory generally remained stable or showed improvement, delayed verbal recall exhibited a transient decline that typically resolved after treatment. Importantly, cognitive impairments were more pronounced among individuals with older age, lower educational attainment, and pre-existing cognitive deficits. A quasi-experimental study examining the timing of autobiographical memory retrieval relative to ECT initiation found that patients who completed the Autobiographical Memory Interview within 24 hours before their first session showed a decline in memory performance post-treatment, whereas those who completed it more than 24 hours in advance demonstrated improvement. These results support the hypothesis that ECT can interfere with the reconsolidation of reactivated memories, a process during which recalled memories become temporarily labile and susceptible to disruption (32).

A recent consensus guideline, developed by a committee of clinical and academic experts from Australia and New Zealand, emphasizes that while most cognitive domains return to baseline or improve shortly after treatment, autobiographical memory loss may endure in a subset of individuals and can be distressing and functionally impairing. Factors influencing cognitive risk include older age, pre-existing brain vulnerability, concurrent lithium use, and extended or bilateral treatment protocols. Although the mean group data suggest recovery, individual-level analyses reveal that some patients may experience significant impairments that are masked by group averages (33).

Collectively, these findings suggest that while most cognitive effects of ECT are transient and may even improve over time, persistent autobiographical memory loss remains a significant concern for a subset of patients. Importantly, perceived cognitive deficits appear to be shaped by both neurobiological and psychological factors, including symptom resolution and timing of memory activation. Future work should focus on refining cognitive monitoring strategies, elucidating individual risk profiles, and exploring behavioral or procedural adjustments to minimize adverse cognitive outcomes without compromising therapeutic efficacy.

Preclinical and clinical studies indicate that ECT treatment leads to an increase in the count of hippocampal granule cells. Madsen et al. (57), found that ECT induces a more pronounced neurogenic effect compared to traditional pharmacological antidepressants, exhibiting a faster onset of action. Nordanskog et al. (58), showed an increase in hippocampal volumes following ECT using a 3-Tesla MRI scanner. Subsequent longitudinal MRI studies and meta-analyses confirmed increases in hippocampal and amygdala volumes after ECT (59–61).

In a study using longitudinal MRI and neuropsychological testing in two distinct clinical populations (MDD and schizophrenia-spectrum disorders), greater hippocampal volume increases were consistently associated with poorer post-ECT cognitive performance, despite differences in diagnostic profile, electrode placement, and treatment parameters. Notably, the study investigated 42 cortical and subcortical regions and demonstrated that the cognitive outcomes were specifically related to the hippocampus (62). Another study focusing on subjective memory outcomes found that increases in the volume of hippocampal subregions (the right and left dentate gyrus) were associated with greater self-reported memory impairment, particularly in autobiographical recall. Conversely, by the 6-month follow-up, reductions in dentate gyrus volume compared to pre-ECT assessments were observed, and these reductions correlated with improvements in objective cognitive performance (63). These findings highlight a potential paradox: while hippocampal enlargement may reflect a form of treatment-induced neuroplasticity, it may also contribute to cognitive side effects.

Mechanistically, ECT is known to upregulate neurotrophic factors and stimulate neurogenesis within the dentate gyrus, contributing to synaptic remodeling and circuit reorganization. However, the rapid onset and magnitude of observed volume changes suggest that neurogenesis alone cannot fully account for these effects. Corroborating this hypothesis, a study using high-field MRI in mice found that electroconvulsive stimulation induced dose-dependent increases in hippocampal volume. Notably, these volumetric changes persisted even in mice where neurogenesis was ablated through X-ray irradiation, implying that other neuroplastic processes, such as increased synaptic density, contribute to the observed structural alterations (64). While some studies hypothesized that the volumetric changes are a result of the hemodynamic and metabolic shifts that occur during seizures, potentially leading to vasogenic or cytotoxic edema, several studies have found no evidence of increased T2 signal intensity or alterations in diffusivity after ECT, suggesting that edema may not play a central role in the observed structural changes (58, 65, 66). Seizure-induced neuroinflammation remains a plausible contributor, potentially facilitating aberrant neurogenesis and transient blood-brain barrier disruption, which may further explain associated cognitive side effects.

Beyond hippocampal changes, large-scale analyses, such as those from the Global ECT-MRI Research Collaboration (GEMRIC), demonstrated that ECT-induced brain volume changes extend beyond the hippocampus, affecting multiple brain regions, with the most significant changes occurring in the hippocampus and amygdala (67, 68). The magnitude of these volumetric changes was found to be dose-dependent and influenced by the electrical field and induced seizures (69). Moreover, several studies have shown that volume increase was most pronounced in the dentate gyrus, a region associated with neurogenesis, aligning with the neuroplasticity hypothesis (70–72). A recent neuroimaging study by Cano et al. (21),, using structural MRI, found that only ECT caused notable increases in gray matter volume, in the right striatum, pallidum, medial temporal lobe (including the amygdala and hippocampus), anterior insula, anterior midbrain (substantia nigra/ventral tegmental area), and subgenual anterior cingulate cortex. In contrast, no significant structural changes occurred after rTMS, even though both groups showed similar improvements in depressive symptoms. Importantly, these volume changes did not relate to the level of symptom reduction. The findings support the idea that ECT leads to large-scale structural changes in the brain through neuroinflammatory or cellular remodeling processes.

Diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) studies provide valuable insights into the microstructural effects of ECT on brain tissue, complementing volumetric findings. In white matter, early reports suggested that ECT enhances fiber integrity, as reflected by increased fractional anisotropy (FA) in regions such as the anterior cingulum and frontal tracts; however, more recent findings have revealed increases in mean diffusivity (MD) and radial diffusivity (RD), which may indicate transient extracellular fluid shifts or blood–brain barrier permeability rather than lasting improvements in white matter organization. Gray matter DWI studies have more consistently reported reductions in MD within the hippocampus and amygdala following ECT, potentially reflecting increased cellular complexity (73). Multisite studies further clarify these effects. Repple et al. (74), found ECT-specific increases in MD in right-hemispheric white matter tracts, with baseline white matter integrity (higher FA, lower MD/RD) predicting greater clinical response. Similarly, Belge et al. (75), reported increases in FA, MD, and axial diffusivity (AD) across several white matter pathways post-ECT, notably in cortico-spinal and fronto-occipital tracts. Although diffusion changes were not directly associated with symptom improvement, both studies suggest that baseline microstructural differences may help identify individuals more likely to benefit from ECT, reinforcing the role of ECT in modulating neural circuits implicated in emotion regulation and neuroplasticity.

Besides these structural modifications, ECT also causes functional changes in the connectivity of the brain network. An overactive default mode network (DMN), especially in the medial prefrontal cortex, is closely associated with ruminative thinking, which is a prevalent disorder associated with depression (76). According to fMRI studies, ECT decreases DMN hyperconnectivity, which is linked to symptom alleviation (77). Additionally, ECT improves stress management and emotional processing by increasing connections between the prefrontal cortex and limbic regions like the hippocampus and amygdala (78). Pang et al. (79), showed that clinical improvement was associated with improved connections within the DMN and between the DMN and the central executive network following ECT. Furthermore, Sun et al. (80), revealed that ECT changed the brain's local and global information-processing processes, and the increase in network metrics was associated with clinical remission. A study using resting-state electroencephalography (RS-EEG) showed that ECT significantly changed the network's topology, indicating a restructuring of functional connections that might be the basis for its antidepressant effects (81). Thus, it is believed that these modifications in functional connectivity contribute to the strong and rapid antidepressant effects of ETC (82, 83).

In summary, ECT causes significant structural and functional changes in the brain, especially in hippocampal circuits, through a complex interplay of neurogenesis, synaptic plasticity, and inflammatory signaling. While these changes contribute to its therapeutic efficacy, they may also explain the temporary cognitive side effects observed in some patients, as they may transiently disrupt pre-existing memory circuits (84). Such effects are commonly observed in the early post-treatment phase, and are typically time-limited, with most patients recovering cognitive function over the weeks to months following treatment (27). These findings underscore the importance of balancing therapeutic efficacy with individualized cognitive risk assessment, particularly in patients with baseline memory vulnerabilities.