2026 ECNP Congress

PS04-4125

Effectiveness of esketamine/ketamine and non-invasive neuromodulation techniques on severity and cognitive-emotional regulation in treatment-resistant depression: systematic review and meta-analysis

Firaol Ayele — E. De Filippi, M. Ruiz Ortiz, D. J Palao, M. Fradera, V. Galvez, V. Soria · Institut d’Investigació i Innovació Parc Taulí I3PT-CERCA- Parc Taulí Hospital Universitari, Mental Health and Neuroscience Area, Sabadell, Spain

2026 ECNP Congress

Introduction

Cognitive emotional regulation strategies refer to the conscious or unconscious mental processes people use following emotional-eliciting events to cope with that event or influence the experience, intensity, and duration of their emotional response [1–3]. Maladaptive cognitive-emotional regulation strategies are critical in treatment-resistant depression (TRD) because they determine the ability of patients to process emotional information, control negative thinking patterns, and use cognitive resources effectively [4,5]. Therefore, this review aims to synthesize the effectiveness of esketamine/ketamine, tDCS/TMS/VNS, and neurofeedback in managing maladaptive cognitive-emotional regulation and depressive severity outcomes among adult TRD patients.

Methods

This review was conducted in accordance with the JBI methodology for systematic reviews of the effectiveness of evidence. A comprehensive search was carried out on PubMed, Embase, PsycINFO, CINAHL, Web of Science, Scopus, ScienceDirect, Cochrane, and Google Scholar from inception to August 8, 2025, then updated on April 15, 2026. Studies published in the English language were included. Articles with the effect of esketamine/ketamine or non-invasive brain stimulation or neurofeedback on the outcome of maladaptive cognitive-emotional regulation and depression outcomes among adult TRD patients were included in the review. Two independent reviewers screened the articles, extracted the data, and conducted the methodological quality assessment of eligible studies. Bias was assessed using the standardized critical appraisal instruments of the Cochrane Risk of Bias tool (RoB 2) and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I). The results of the review were reported according to PRISMA guidelines. This review is registered on PROSPERO with protocol number CRD420251157949.

Results

A total of eight studies included, with 403 participants. Due to a limited head-to-head comparative study, the result is presented narratively, followed by a hierarchical meta-analysis based on evidence quality in tiers. Ketamine/esketamine, non-invasive brain stimulation (NIBS), and neurofeedback consistently demonstrated significant therapeutic effectiveness in reducing both depressive severity and maladaptive cognitive emotional regulations (MCER). The evidence for neurofeedback intervention was very sparse, with only a single-arm study. The largest effect size for the reduction of depression severity was observed in the intervention group receiving ketamine/esketamine (intravenous ketamine and intranasal esketamine), while the neurofeedback intervention was associated with the largest effect size for MCER. The NIBS intervention group has the strongest evidence base because it is the only intervention group with direct RCT evidence. NIBS interventions (rTMS, tDCS) were highly efficacious for depression but had the lowest relative effect sizes for MCER.

Conclusions

This meta-analysis shows that esketamine/ketamine, NIBS, and neurofeedback are associated with a significant overall reduction in depression severity and address maladaptive cognitive emotional regulation (i.e., rumination, repetitive negative thinking, and cognitive rigidity) in TRD patients. The lack of head-to-head evidence of ketamine, esketamine, and neurofeedback interventions worldwide means that initiating large-scale RCTs should be a primary research priority. Clinicians should tailor the treatment of patients’ primary symptom profile with prioritization of esketamine/ketamine for patients who require rapid and deep reduction in depressive symptom severity and consider neurofeedback as a primary option for patients with significant maladaptive cognitive-emotional regulation.

References

  1. Campbell-Sills L, Barlow DH. Incorporating emotion regulation into conceptualizations and treatments of anxiety and mood disorders. Published online 2007.
  2. Williams LE, Bargh JA, Nocera CC, Gray JR. The unconscious regulation of emotion: nonconscious reappraisal goals modulate emotional reactivity. Emotion. 2009;9(6):847.
  3. LeMoult J, Gotlib IH. Depression: A cognitive perspective. Clinical psychology review. 2019;69:51-66.
  4. Solem S, Hagen R, Hoksnes JJ, Hjemdal O. The metacognitive model of depression: An empirical test in a large Norwegian sample. Psychiatry Research. 2016;242:171-173.
  5. Nordahl H, Nordahl HM, Vogel PA, Wells A. Explaining depression symptoms in patients with social anxiety disorder: Do maladaptive metacognitive beliefs play a role? Clinical psychology & psychotherapy. 2018;25(3):457-464.