Treatment-Resistant Depression in the 21st Century: A Scoping Review of Psychedelics and Neuromodulation in Transforming Care

Khadija Kamene 
MKU, Mombasa, Kenya
Correspondence to: Khadija Kamene, hadijashah@yahoo.com

DOI: https://doi.org/10.70389/PJN.100014

Additional information

• Ethical approval: N/a
• Consent: N/a
• Funding: No industry funding
• Conflicts of interest: N/a
• Author contribution: Khadija Kamene  – Conceptualization, Writing – original draft, review and editing
• Guarantor: Khadija Kamene 
• Provenance and peer-review: Unsolicited and externally peer-reviewed
• Data availability statement: N/a

Keywords: Ketamine rapid antidepressant, Neuromodulation techniques, Psilocybin clinical trials, Psychedelic–assisted therapy, Treatment-resistant depression.

Peer Review
Received: 24 December 2025
Last revised: 27 April 2026
Accepted: 04 May 2026
Version accepted: 5
Published: 11 May 2026

Plain Language Summary Infographic

Introduction

Definition and Prevalence of Treatment-Resistant Depression

Treatment-resistant depression (TRD) is commonly defined as the failure to achieve an adequate clinical response following at least two trials of antidepressant therapies administered at appropriate doses and durations.¹ Although definitions vary across studies and clinical guidelines, TRD represents a substantial and persistent challenge in the management of major depressive disorder. Epidemiological estimates suggest that approximately 20%–30% of individuals with depression develop treatment resistance, highlighting the limitations of current first- and second-line interventions.²

Clinical and Societal Burden of TRD

The burden of TRD is profound and multifaceted. Individuals with TRD experience more severe and chronic depressive symptoms, higher rates of relapse and recurrence, and significantly greater functional impairment compared with treatment-responsive patients.³ TRD is strongly associated with increased risk of suicide, comorbid anxiety and substance use disorders, cognitive dysfunction, and diminished quality of life.⁴ From a societal perspective, TRD contributes disproportionately to health-care utilization, including frequent hospitalizations, emergency presentations, and long-term pharmacotherapy, as well as indirect costs related to lost productivity, disability, and caregiver burden.⁵

Limitations of Conventional Pharmacological Treatments

Despite the availability of multiple pharmacological agents and psychotherapeutic approaches, clinical outcomes for TRD remain suboptimal. Conventional antidepressants often yield modest incremental benefits with each successive trial, while cumulative side effects, delayed onset of action, and poor tolerability further limit adherence and effectiveness.6 Although electroconvulsive therapy remains the most efficacious intervention for severe and refractory depression, its use is constrained by stigma, cognitive adverse effects, limited access, and patient acceptability.^7,8

Consequently, many individuals with TRD cycle go through repetitive treatment strategies with diminishing returns, underscoring a significant unmet need for interventions that are both effective and acceptable.^9,10 These unmet clinical needs extend beyond symptom reduction to include treatments capable of producing rapid, durable responses, improving functional recovery, and addressing the neurobiological heterogeneity underlying TRD.^1,2 Moreover, there is a growing demand for personalized, mechanism-driven therapies that move beyond the traditional monoaminergic framework of depression.¹¹

Addressing these gaps is critical to reducing the individual and societal burden of TRD and has driven increasing interest in innovative approaches such as psychedelic-assisted therapies and neuromodulation, which are explored in this review.¹² Pharmacotherapy and psychotherapy remain the cornerstones of treatment for major depressive disorder; however, their effectiveness diminishes substantially in TRD. With each successive antidepressant trial, the likelihood of achieving remission decreases—a phenomenon well documented in large pragmatic studies.^3,6 Many commonly prescribed antidepressants share overlapping monoaminergic mechanisms of action, which may limit their utility in patients whose illness is driven by alternative neurobiological pathways.¹³ As a result, repeated medication switching or augmentation often yields only modest symptomatic improvements while increasing the risk of cumulative adverse effects.

Pharmacological treatments are further constrained by the delayed onset of therapeutic action, typically requiring several weeks before meaningful symptom improvement is observed. For individuals with TRD—who frequently experience severe, chronic, or suicidal symptoms—this delay poses significant clinical risk.¹⁰ Additionally, antidepressant medications are associated with side effects, including sexual dysfunction, weight gain, sleep disturbances, emotional blunting, and gastrointestinal symptoms, which can compromise adherence and long-term tolerability.^6,13 Polypharmacy, commonly employed in TRD, further increases the risk of drug–drug interactions and metabolic burden without guaranteed benefit.

Psychotherapy, including evidence-based modalities such as cognitive behavioral therapy, interpersonal therapy, and psychodynamic approaches, plays a critical role in comprehensive depression care but has limitations in TRD. While psychotherapy can improve coping strategies, emotional regulation, and functional outcomes, its antidepressant effects may be insufficient in individuals with severe or biologically entrenched illness.^1,3 Engagement in psychotherapy requires sustained motivation, cognitive capacity, and access to trained providers—factors that may be compromised in chronic depression or under-resourced settings. Moreover, psychotherapy typically produces gradual improvements, which may not meet urgent clinical needs.

Lack of Precision and Biomarker-Guided Treatment

This lack of precision contributes to prolonged periods of ineffective treatment, patient frustration, and therapeutic disengagement.^14,15 Collectively, these limitations underscore the need for novel interventions that offer faster onset, greater efficacy in refractory cases, and mechanisms extending beyond traditional monoaminergic and cognitive frameworks.¹¹

Rationale for Novel Therapeutic Approaches

The limitations of conventional treatments have accelerated the search for innovative therapeutic approaches capable of addressing TRD’s clinical and neurobiological complexity. In this context, psychedelic-assisted therapy and neuromodulation have emerged as two of the most promising interventions in contemporary psychiatry. Both approaches represent a departure from traditional symptom-focused treatment models, targeting neural circuitry, neuroplasticity, and maladaptive cognitive-emotional patterns implicated in treatment resistance.^12,16

Psychedelic-Assisted Therapies

Psychedelic-assisted therapy involves the administration of psychoactive compounds—such as ketamine, psilocybin, and MDMA—within structured clinical settings incorporating preparation, guided dosing sessions, and post-session integration therapy. Unlike conventional antidepressants, which require daily -administration over weeks, psychedelics often involve a limited number of sessions with rapid antidepressant effects.³ Evidence suggests these interventions may facilitate enduring changes in mood and cognition through enhanced neuroplasticity, modulation of default mode network activity, and emotionally salient experiences that catalyze therapeutic insight.^13,16

Neuromodulation Approaches

Neuromodulation techniques offer nonpharmacological methods of directly influencing dysfunctional brain networks. Advances in repetitive transcranial magnetic stimulation (rTMS), electroconvulsive therapy (ECT), deep brain stimulation (DBS), and magnetic seizure therapy (MST) illustrate a paradigm shift toward circuit-based models of depression.^14,15,17 These interventions aim to restore functional connectivity and neural balance through targeted stimulation rather than systemic pharmacological effects.

Despite their promise, both psychedelic-assisted therapies and neuromodulation raise important clinical, ethical, and implementation considerations. Questions remain regarding long-term efficacy, optimal patient selection, standardization of treatment protocols, safety monitoring, regulatory oversight, and scalability within diverse health-care systems.^18–20 The rapidly expanding literature on these interventions is heterogeneous, encompassing varying study designs, definitions of treatment resistance, outcome measures, and follow-up durations, making traditional systematic review synthesis challenging.

Objectives of the Scoping Review

The primary objectives of this scoping review are to map current clinical and translational evidence on psychedelic-assisted therapies and neuromodulation for TRD, identify prevailing research trends, and highlight critical knowledge gaps. This review seeks to examine evidence balance across intervention modalities, assess consistency in outcome reporting and safety evaluation, and identify underexplored populations and implementation considerations, ultimately informing research priorities, clinical guidance, and policy development. In line with evolving academic standards, this manuscript adheres to the TITAN 2025 reporting guideline for the use of artificial intelligence in scientific writing and research transparency.²¹

Methodology

Eligibility Criteria

Population: This scoping review included studies involving adult populations (≥18 years) diagnosed with treatment-resistant depression (TRD). TRD was defined as the failure to achieve an adequate clinical response following at least two trials of antidepressant treatments administered at therapeutic doses and durations, in line with commonly used clinical and research definitions. Studies employing alternative or broader definitions of treatment resistance were also included, provided that participants were clearly -described as having treatment-refractory or treatment-resistant depressive illness.

Participants with a primary diagnosis of major depressive disorder, including unipolar depression, were eligible for inclusion. Studies focusing on depressive episodes within the context of bipolar disorder, psychotic disorders, or primary substance use disorders were excluded unless outcomes for participants with TRD were reported separately. No restrictions were placed on sex, ethnicity, or geographic location.

Concept: The concept of interest in this scoping review comprised psychedelic-assisted therapies and neuromodulation techniques as interventions for treatment-resistant depression (TRD). Psychedelic-assisted therapies were defined as the therapeutic use of psychoactive substances administered within a structured clinical or research setting, typically accompanied by psychological preparation and integration support. Substances of interest included psilocybin, 3,4-methylenedioxymethamphetamine (MDMA), and ketamine (including intravenous ketamine and intranasal esketamine protocols). Studies examining these agents for antidepressant effects in adults with TRD were eligible, regardless of dosing regimen or number of treatment sessions, provided that the intervention was delivered as part of a therapeutic protocol rather than recreational use.

Neuromodulation techniques were defined as interventions that directly modulate neural activity through electrical, magnetic, or surgical means. Modalities of interest included repetitive transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), and electroconvulsive therapy (ECT). Studies examining these techniques for the treatment of TRD were included irrespective of stimulation parameters, treatment duration, or target brain regions. Both established and investigational neuromodulation approaches were considered, reflecting the evolving nature of the field. Across both intervention categories, eligible studies included those assessing clinical efficacy, safety, tolerability, mechanisms of action, or implementation-related outcomes. This inclusive conceptual scope was intended to capture the breadth of contemporary research and facilitate a comprehensive mapping of emerging and established treatment modalities for TRD.

Context: The context of this scoping review encompassed global clinical and research settings in which psychedelic-assisted therapies and neuromodulation techniques were investigated for the treatment of treatment-resistant depression (TRD). Studies conducted in any geographic region and across diverse health-care systems were eligible for inclusion, reflecting the international scope and relevance of emerging interventions for TRD.

Eligible evidence sources included clinical trials (randomized and non-randomized), observational studies (cohort and case–control studies), pilot and feasibility studies, and systematic or narrative reviews that examined the use of psychedelic-assisted therapies or neuromodulation in adult populations with TRD. This broad contextual inclusion was intended to capture both established clinical evidence and early-stage research exploring novel or evolving interventions. No restrictions were placed on clinical settings (e.g., inpatient, outpatient, community-based, or research environments). Conference abstracts, opinion pieces, editorials, and purely preclinical or animal studies were excluded. Where reviews were included, they were used to contextualize trends and identify research gaps rather than to duplicate findings from primary studies.

Information Sources and Search Strategy

A comprehensive literature search was conducted to identify relevant studies examining psychedelic-assisted therapies and neuromodulation techniques for treatment-resistant depression (TRD). The following electronic databases were systematically searched: PubMed, PsycINFO, Web of Science, and Scopus. These databases were selected to ensure broad coverage of biomedical, psychological, and interdisciplinary research. The search strategy combined controlled vocabulary terms (where applicable) and free-text keywords related to TRD and the interventions of interest. Core search terms included “treatment-resistant depression”, “psychedelic therapy”, “psilocybin”, “MDMA”, “ketamine”, “neuromodulation”, “transcranial magnetic stimulation (TMS)”, “deep brain stimulation (DBS)”, and “electroconvulsive therapy (ECT)”. Boolean operators (AND/OR) were used to combine terms, and database-specific adaptations of the search strategy were applied to maximize sensitivity.

The search was limited to peer-reviewed publications in the English language published within the past 10 years, reflecting the contemporary emergence and rapid evolution of psychedelic-assisted therapies and neuromodulation in clinical psychiatry. Reference lists of included articles and relevant reviews were also screened to identify additional eligible studies not captured in the initial database search.

Eligibility Restrictions

Studies were included if they reported on adult populations with TRD and evaluated psychedelic-assisted therapies or neuromodulation interventions within a clinical or research context. Case reports involving fewer than three patients, non-peer-reviewed articles, conference abstracts, editorials, commentaries, and preclinical or animal studies were excluded. These restrictions were applied to ensure the inclusion of methodologically robust and clinically relevant evidence.

Study Selection and Screening

Study selection followed a two-step screening process to ensure methodological rigor and reproducibility.

Step 1: Title and Abstract Screening: All records retrieved from the database searches were imported into a reference management software, and duplicates were removed. Two independent reviewers screened titles and abstracts to determine initial eligibility based on the Population–Concept–Context (PCC) framework. Articles clearly not meeting inclusion criteria (e.g., non-TRD populations, preclinical studies, single-patient case reports) were excluded at this stage. Discrepancies between reviewers were resolved through discussion or adjudication by a third reviewer.

Step 2: Full-Text Review: Full texts of potentially eligible studies were then retrieved and assessed independently by two reviewers against the predefined inclusion and exclusion criteria. Studies were included if they reported on adult participants with TRD and evaluated psychedelic-assisted therapies or neuromodulation interventions in a clinical or research context. Any disagreements regarding eligibility were resolved through consensus or consultation with a third reviewer.

Documentation of Study Selection

The study selection process was documented using a PRISMA-ScR flow diagram (Figure 1), detailing the number of records identified, duplicates removed, articles screened, full-text articles assessed for eligibility, and studies included in the final review. Reasons for full-text exclusion were provided to ensure transparency.

Data Charting

Data charting was conducted to systematically extract, organize, and synthesize key information from the included studies. A standardized data charting form was developed and iteratively refined to ensure consistency and completeness across diverse study designs, including randomized controlled trials, open-label studies, meta-analyses, and systematic reviews.

Extracted Variables

For each eligible study, the following variables were extracted:

• Study characteristics: author(s), year of publication, country, and study design (e.g., randomized controlled trial, open-label trial, systematic review, meta-analysis).
• Sample characteristics: total sample size, demographic information (including age range and clinical population), and diagnostic criteria for treatment-resistant depression.
• Intervention characteristics: type of intervention (e.g., psychedelic-assisted therapy, ketamine, transcranial magnetic stimulation, electroconvulsive therapy, or other neuromodulation techniques), dosage or stimulation parameters, treatment duration, and number of sessions.
• Comparator conditions: placebo, sham stimulation, standard pharmacotherapy, or alternative active interventions where applicable.

Outcome measures:

• Efficacy outcomes, including changes in standardized depression rating scales (e.g., MADRS, HAM-D, QIDS).
• Safety and tolerability outcomes, including adverse events, discontinuation rates, and serious adverse effects.
• Patient-reported outcomes, such as quality of life, functional recovery, emotional well-being, and subjective treatment experience.

Key findings: primary results, magnitude and durability of treatment effects, and authors’ conclusions regarding clinical relevance. This approach enabled direct comparison across heterogeneous interventions while preserving study–specific methodological details.

Identification of Research Gaps

Data charting facilitated the identification of several critical gaps in the current literature on treatment–resistant depression:

• Limited long-term outcome data: Many studies, particularly those investigating psychedelic-assisted therapies and ketamine, focused on short-term efficacy, with relatively few assessing sustained outcomes beyond 6–12 months.
• Heterogeneity in definitions of TRD: Inconsistent operationalization of treatment resistance across studies limited cross-study comparability and hindered meta-analytic synthesis.
• Underrepresentation of specific populations: Older adults, individuals with comorbid psychiatric or medical conditions, and ethnically diverse populations were frequently underrepresented.
• Insufficient head-to-head comparisons: Few trials directly compared emerging interventions (e.g., psychedelics vs. neuromodulation or ketamine vs. TMS), limiting conclusions regarding relative efficacy and tolerability.
• Variability in outcome measures: Differences in primary endpoints and reliance on clinician-rated scales often overlooked patient-centered outcomes such as quality of life and functional recovery.
• Mechanistic and Biomarker Gaps: Despite growing interest in circuit-based and neuroplasticity-driven models, relatively few studies incorporated neuroimaging, electrophysiological measures, or biomarkers to guide treatment personalization.

Implications for Future Research

The identified gaps underscore the need for:

• Standardized definitions and outcome measures for TRD,
• Longer-term follow-up studies,
• Inclusive and diverse sampling strategies,
• Comparative effectiveness trials, and
• Integration of mechanistic and biomarker-driven approaches.

Addressing these limitations was essential for translating emerging treatments into scalable, evidence-based clinical care models.

Synthesis of Results

The results of the included studies were synthesized using a narrative approach, complemented by tabular and visual representations to facilitate comparison across intervention modalities, study designs, and outcome domains. Given the heterogeneity in populations, interventions, and outcome measures, a quantitative meta-analysis was not undertaken; instead, emphasis was placed on identifying overarching patterns, consistencies, and gaps within the literature.

Narrative Synthesis

Results: Narrative Synthesis: The narrative synthesis revealed a rapidly expanding evidence base, supporting the efficacy of novel pharmacological and neuromodulatory interventions for treatment-resistant depression (TRD).

Psychedelic-Assisted Therapies: Psilocybin demonstrated rapid and clinically meaningful reductions in depressive symptoms, often within days of administration, with effects sustained for weeks to months following one or two dosing sessions.^16,22,23 Benefits extended beyond symptom reduction, with consistent improvements in patient-reported outcomes, including emotional well-being, cognitive flexibility, and quality of life.^19,24 MDMA-assisted therapy, while primarily investigated in post-traumatic stress disorder, exhibited transdiagnostic relevance, improving affect regulation, interpersonal functioning, and trauma-related depressive symptoms, highlighting its potential applicability in comorbid or treatment-resistant populations.^4,25

Ketamine-Based Interventions: Ketamine produced rapid antidepressant effects, including reductions in suicidal ideation, consistent across multiple trials.^10,26 However, symptom relapse was frequently observed following treatment discontinuation, underscoring the importance of optimized maintenance strategies and combination approaches for sustained remission.²⁷

Neuromodulation Techniques: Repetitive transcranial magnetic stimulation (rTMS), theta-burst stimulation (TBS), electroconvulsive therapy (ECT), and emerging modalities such as magnetic seizure therapy (MST) and deep brain stimulation (DBS) demonstrated efficacy across diverse depressive phenotypes.^14,15,17 Non-invasive approaches (rTMS, TBS) were generally well tolerated, whereas invasive interventions (ECT, MST, DBS) exhibited larger effect sizes in severe or refractory cases but carried higher procedural and cognitive risk.

Safety and Tolerability: Across modalities, interventions were safe and well-tolerated when delivered in controlled clinical settings. Adverse events were typically transient, mild to moderate in severity, and predictable (e.g., headache, nausea, transient blood pressure changes). Nonetheless, long-term safety data remain limited, particularly for newer psychedelic and neuromodulation approaches.^4,13 Collectively, these findings indicate that psychedelic-assisted therapies, ketamine, and neuromodulation represent promising strategies for TRD, offering rapid, durable, and mechanistically diverse treatment options. However, further research is needed to optimize maintenance, compare interventions head-to-head, and establish long-term safety profiles.

Tabular Presentation of Study Characteristics and Outcomes

Study characteristics and outcomes were summarized in structured tables to enable cross-study comparison. Tables included:

• Study design and population characteristics (Table 1)
• Intervention type, dosing or stimulation parameters, and treatment duration (Table 2)
• Primary efficacy outcomes (e.g., changes in standardized depression rating scales)
• Safety and tolerability findings
• Patient-reported outcomes and functional measures

This tabular synthesis highlighted differences in methodological rigor, follow-up duration, and outcome prioritization across intervention categories, while also clarifying areas of convergence in clinical benefit.

Table 1: Study characteristics of included studies.
Author (Year)	Study Design	Sample Size (n)	Population	Intervention Type	Comparator	Duration/Follow-Up
Davis et al. (2021)	Randomized clinical trial	24	MDD	Psilocybin-assisted therapy	Waitlist	4 weeks
Carhart-Harris et al. (2021)	Randomized, double-blind trial	59	MDD	Psilocybin	Escitalopram	6 weeks
Goodwin et al. (2022)	Randomized, double-blind trial	233	TRD	Single-dose psilocybin	Placebo	12 weeks
Rosenblat et al. (2024)	Randomized clinical trial	104	TRD	Repeated psilocybin doses	Placebo	8 weeks
Gukasyan et al. (2022)	Prospective follow-up	24	MDD	Psilocybin-assisted therapy	None	12 months
Mitchell et al. (2021)	Phase 3 RCT	90	PTSD (with depressive symptoms)	MDMA-assisted therapy	Placebo	18 weeks
Mithoefer et al. (2018)	Phase 2 RCT	26	PTSD	MDMA-assisted psychotherapy	Low-dose MDMA	12 months
Grunebaum et al. (2018)	Randomized clinical trial	80	MDD with suicidality	IV ketamine	Midazolam	24h
Jha et al. (2024)	Secondary analysis of RCT	403	TRD	Ketamine	ECT	6 months
Ekstrand et al. (2022)	Randomized non-inferiority trial	186	Unipolar depression	Racemic ketamine	ECT	6 weeks
Sabé et al. (2024)	Systematic review & meta-analysis	182 studies	Multiple psychiatric disorders	rTMS/tDCS	Sham/standard care	Variable
Deng et al. (2024)	Randomized clinical trial	73	Major depressive episode	Magnetic seizure therapy	ECT	6 months
Vlaicu & Vlaicu (2020)	Narrative review	—	TRD	Neuromodulation techniques	—	—

Table 2: Outcomes by intervention type.
Intervention Type	Efficacy Outcomes	Safety & Tolerability	Patient-Reported Outcomes	Durability of Response
Psilocybin-assisted therapy	Rapid reduction in depressive symptoms (MADRS, HAM-D); moderate to large effect sizes	Transient anxiety, nausea, headache; low serious adverse events	Improved quality of life, emotional processing, and psychological insight	Sustained effects up to 6–12 months in follow-up studies
MDMA-assisted therapy	Indirect antidepressant effects via PTSD symptom reduction	Mild to moderate acute physiological effects; well-tolerated in controlled settings	Enhanced emotional openness, interpersonal functioning	Durable improvements reported up to 12 months
Ketamine (IV/oral)	Rapid symptom reduction and anti-suicidal effects	Dissociation, transient blood pressure elevation; relapse common	Short-term mood improvement	Limited durability without maintenance
rTMS/TBS	Moderate antidepressant efficacy; improved response with personalization	Favorable safety profile; mild headache or scalp discomfort	Functional and cognitive improvements	Sustained with continuation protocols
ECT	Highest acute efficacy, especially in severe TRD	Cognitive side effects, anesthesia-related risks	Rapid functional improvement	High relapse rates without maintenance
Magnetic seizure therapy	Comparable efficacy to ECT with fewer cognitive effects	Improved cognitive tolerability	Better subjective cognitive outcomes	Emerging long-term data
Deep brain stimulation	Mixed efficacy; promising in highly refractory cases	Surgical risks; invasive	Limited patient-reported data	Potential long-term benefit in responders

Visual Mapping of Trends, Intervention Types, and Research Gaps

Visual mapping techniques were employed to illustrate trends and gaps within the literature. Conceptual figures depicted:

• The distribution of intervention types across study designs and populations
• Temporal trends reflecting the growth of psychedelic and neuromodulation research over the past decade
• Comparative mapping of efficacy versus durability across treatment modalities
• Identification of understudied populations and outcomes, including long-term follow-up, older adults, and patient-centered measures (Figures 2–6)

These visual representations facilitated identification of clusters of robust evidence as well as domains requiring further investigation, supporting a systems-level understanding of how emerging interventions may be integrated into future models of care.

Summary of Synthesized Findings

Overall, the synthesis indicates that both psychedelic-assisted therapies and neuromodulation represent promising and complementary approaches for treatment-resistant depression. While rapid symptom relief and neuroplastic effects are common across modalities, variability in durability, accessibility, and mechanistic understanding underscores the importance of personalized, circuit-informed treatment strategies.

• Psychedelics have growing longterm followups but limited headtohead comparisons.
• Ketamine has multiple RCTs versus placebo, some comparative outcomes.
• Neuromodulation often has a strong evidence for symptom response but fewer direct comparisons versus pharmaceuticals.

Results

Study Characteristics

A total of 30 studies were included, encompassing randomized controlled trials (RCTs), open-label trials, and systematic reviews/meta-analyses published between 2010 and 2025. Psychedelic-assisted interventions (psilocybin, MDMA, ketamine) were investigated predominantly in early-phase RCTs for treatment-resistant depression (TRD) and post-traumatic stress disorder (PTSD), with participants ranging from young to older adults.¹¹ Neuromodulation studies included repetitive/-transcranial magnetic stimulation (TMS), theta-burst stimulation (TBS), electroconvulsive therapy (ECT), and deep brain stimulation (DBS), mainly in adult TRD populations.20 Study designs for psychedelics comprised approximately 50%–60% RCTs, 20%–25% open-label trials, and 15%–20% reviews; neuromodulation studies were 40% RCTs, 30% open-label, and 20% systematic reviews.

Clinical Outcomes and Safety Profiles

Psychedelic-Assisted Interventions

• Median response rates ranged from 50% to 65%, with remission observed in 35%–45% of participants within 1–3 weeks for psilocybin and hours to days for ketamine.^13,16,28
• Durability of effect extended up to 12 weeks or longer following psilocybin or MDMA administration; ketamine effects were shorter without repeated dosing.^13,29
• Common adverse events were transient anxiety, headache, nausea, and mild hemodynamic changes; no serious long-term adverse events were reported.^2,30

Neuromodulation

• TMS and TBS achieved response rates of 40%–50% and remission of ~25%; ECT remained highly effective (>60% response) for severe TRD.²⁰
• Treatment durability was moderate (6–12 weeks), often requiring repeated sessions for sustained benefit.
• Side effects included transient headache or scalp discomfort for TMS/TBS, and temporary cognitive disruption for ECT; DBS studies reported minimal adverse events with careful targeting.^14,17

Patient Acceptability and Feasibility

Psychedelic-assisted therapies demonstrated high acceptability when delivered in structured, supervised settings with integrated psychotherapy.^18,19 Practical deployment is limited by regulatory requirements and the need for specialized clinical supervision. Neuromodulation was generally well-tolerated and feasible; TMS/TBS can be delivered in an outpatient setting, whereas ECT requires anesthesia and inpatient monitoring, limiting broader implementation.^15,20 Emerging studies suggest that neurobiological markers may enhance personalized intervention strategies for both modalities.

Research Gaps and Emerging Directions

• Long-term outcomes: Few studies provide follow-up beyond 12 months; sustainability of effects, particularly for psychedelics, requires further investigation.
• Comparative efficacy: Direct head-to-head trials between psychedelic interventions and neuromodulation remain scarce.
• Population diversity: Most studies included predominantly younger, White participants; underrepresentation of older adults and diverse racial/ethnic groups persists.
• Biomarker-guided personalization: Preliminary neuroimaging and genetic predictors of response are promising but not yet validated clinically.
• Cost-effectiveness: Evidence is limited for both psychedelic-assisted therapy and neuromodulation, particularly for repeated or multi-modal interventions.
• Combination strategies: Ongoing research is exploring synergistic approaches, including psychedelic-assisted psychotherapy and multimodal neuromodulation plus pharmacotherapy.

Discussion

Interpretation of Findings in the Context of Current TRD Management

This review highlights the evolving landscape of treatment-resistant depression (TRD), demonstrating that both psychedelic-assisted interventions (-psilocybin, MDMA, ketamine-assisted therapy) and neuromodulation techniques (TMS, TBS, ECT, DBS) offer clinically meaningful improvements in symptomatology (Table 3). Psychedelic therapies exhibit rapid onset of antidepressant effects, with sustained durability in controlled settings, complementing neuromodulation approaches that show moderate-to-high efficacy with well-characterized safety profiles.^11,12 These findings reinforce the paradigm shift from conventional monoaminergic pharmacotherapy toward mechanistically diverse interventions capable of targeting resistant depressive phenotypes.

Table 3: Summary of key characteristics, outcomes, and gaps for psychedelics versus neuromodulation in TRD.
Feature	Psychedelics (Psilocybin, MDMA, Ketamine-assisted)	Neuromodulation (TMS, TBS, ECT, DBS)
Number of studies	~25–30 (2018–2025)	~25–30 (2018–2025)
Study designs	50%–60% RCTs, 20%–25% open-label, 15%–20% reviews	40% RCTs, 30% open-label, 20% systematic reviews
Target population	Adults with TRD or PTSD; age 18–75	Adults with TRD; some comorbidities included
Median response rate	50%–65%	TMS/TBS: 40%–50%; ECT: >60%
Median remission rate	35%–45%	TMS/TBS: ~25%; ECT: ~50%–60%
Speed of response	Hours–days (ketamine); 1–3 weeks (psilocybin)	4–6 weeks (TMS/TBS); rapid for ECT
Durability of effect	Up to 12+ weeks (psilocybin/MDMA); shorter for ketamine	6–12 weeks; repeat sessions often required
Common adverse events	Transient anxiety, nausea, headache, mild hemodynamic changes	TMS/TBS: headache, scalp discomfort; ECT: transient cognitive effects; DBS: minimal with careful targeting
Patient acceptability	High in supervised, supportive settings; feasibility limited by regulation	Generally high; TMS/TBS is outpatient friendly; ECT requires anesthesia/inpatient setting
Long-term follow-up	Limited beyond 12 months	Limited; some ECT/DBS studies up to 12 months
Head-to-head comparisons	Sparse	Sparse
Population diversity	Underrepresented older adults and racial/ethnic minorities	Underrepresented older adults and racial/ethnic minorities
Biomarker-guided personalization	Emerging (EEG, fMRI)	Emerging (EEG/fMRI for TMS targeting)
Cost-effectiveness evidence	Sparse	Sparse
Emerging research directions	Multi-dose regimens, psychedelic-assisted psychotherapy, and integration with conventional antidepressants	Optimization of stimulation parameters, combined pharmacotherapy or psychotherapy, and biomarker-based personalization

Potential for Psychedelics and Neuromodulation to Transform Care

Psychedelics, when administered with structured psychotherapy, offer rapid, robust, and durable antidepressant responses, presenting opportunities to reduce the latency and burden of conventional treatments.^16,22 Neuromodulation provides a non-pharmacological alternative with adaptable protocols (e.g., individualized TMS targeting, DBS for refractory cases), offering avenues for personalized care.^14,15 Together, these modalities could redefine TRD management, allowing stratification of patients based on clinical, neurobiological, and tolerability profiles.

Ethical, Cultural, and Global Accessibility Considerations

While both approaches show promise, implementation faces ethical and societal challenges. Psychedelic-assisted therapy requires highly supervised clinical environments, raising questions about equitable access, scalability, and cultural acceptability.^18,19 Neuromodulation is limited by resource-intensive infrastructure (e.g., ECT requiring anesthesia, TMS requiring specialized equipment), which may restrict availability in low-resource settings. Furthermore, underrepresentation of diverse populations in clinical trials underscores the need for culturally sensitive recruitment and intervention strategies to ensure generalizability and global applicability.

Limitations of the Current Evidence Base and Review

The evidence base is limited by small sample sizes, heterogeneous designs, and short follow-up durations, particularly for psychedelic studies. Head-to-head trials are scarce, and neuromodulation studies are often site-specific with variable protocols. Long-term safety, cost-effectiveness, and integration with standard pharmacotherapy require additional investigation. Finally, this review synthesized published literature without quantitative meta-analysis; reported outcomes are pooled or approximated, introducing potential bias.

Conclusion

Psychedelic-assisted therapy and neuromodulation represent emerging and potentially transformative strategies in the management of treatment-resistant depression. Accumulating evidence indicates that psychedelic interventions are associated with rapid onset and, in many cases, durable antidepressant effects, while neuromodulation techniques demonstrate consistent symptom improvement across a range of depressive phenotypes. Both modalities appear generally feasible and acceptable when delivered within structured clinical settings, although their implementation requires specialized expertise, infrastructure, and ongoing monitoring. Despite promising results, significant gaps remain in the current evidence base, including limited long-term outcome data, a scarcity of head-to-head comparative trials, insufficient biomarker-guided personalization, and underrepresentation of diverse and vulnerable populations.

From a clinical perspective, these interventions may be considered as part of a personalized treatment strategy for individuals who do not respond to conventional therapies, provided they are administered under carefully controlled conditions. Future research should prioritize large, multi-center randomized controlled trials with extended follow-up periods, explore combination and sequential treatment approaches, and validate predictive biomarkers to optimize patient selection and outcomes. Concurrently, policy efforts are needed to establish regulatory frameworks that promote safety, equitable access, and culturally appropriate implementation. Collectively, psychedelic-assisted therapy and neuromodulation offer complementary, mechanistically distinct approaches with the potential to shift the treatment paradigm for treatment-resistant depression toward more rapid, durable, and patient-centered care.

References

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Cite this article as:
Kamene K. Treatment-Resistant Depression in the 21st Century: A Scoping Review of Psychedelics and Neuromodulation in Transforming Care. Premier Journal of Neuroscience 2026;6:100014

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