Ketamine, TMS Show Promise in Treatment-Resistant Depression in Older Adults

Ketamine and transcranial magnetic stimulation (TMS) show potential for treating treatment-resistant depression (TRD) in older adults, according to a March 2025 study. The systematic review accounted for various pharmacological and nonpharmacological interventions for TRD, analyzing 14 randomized controlled trials involving 1196 participants, evaluating remission rates and treatment efficiency.¹

The mean age of all study participants was 65, ranging from 55.2 to 75.9. Women made up 55.5% of the participant population with 648 participants, and 458 being male.¹ Investigators researched the likelihood of achieving remission across all the studies, finding that over study periods of 1 to 12 weeks, the overall odds of remission was 37% (95% CI = 0.26 to 0.45). In analyzing active intervention compared with placebo, active intervention was found to have an odds ratio (OR) of 2.42 (95% CI = 1.49 to 3.92).¹

Ketamine demonstrated the most promise among the pharmacological treatments, with 3 studies showing an OR of 2.91 (95% CI = 1.11 to 7.65) for remission compared with placebo. TMS showed a trend toward effectiveness, with an OR of 1.99 (95% CI = 0.71 to 5.61).¹ However, investigators classified the evidence quality for both ketamine and TMS as weak or very weak, necessitating further research. Additionally, ketamine’s long-term safety and cost effectiveness remains unceratain. A February 2025 systematic review supports the efficacy of ketamine and found that TMS treatments were effective compared with placebo or no treatment, showing statistically significant changes in depressive symptoms at 4 weeks.² While the study findings showed promise, the authors advocate for larger scale studies with longer follow up periods for a better understanding.

Aripiprazole augmentation showed potential in improving remission rates, with an OR of 1.93 (95% CI = 1.04 – 3.58).¹ In the February 2025 study, aripiprazole augmentation appeared to be an effective treatment with an acceptable adverse effect profile.² A single study found that prescription guided by pharmacogenetic testing significantly improved outcomes (OR 3.20, 95% CI = 1.26 – 8.14). Over 24 weeks, clinicians had access to test results for intervention, and assessors were blinded until week 8.¹ High dose selegiline showed to significantly improve depressive symptoms in patients, with a 37.4% in Hamilton Depression Rating Scale (HAM-D) scores. Lithium showed a greater rate of remission than phenelzine, with a 33% reduction to phenelzine’s 0%.¹

Cognitive and psychological interventions were also examined, including neuroplasticity-based computerized cognitive remediation (NCCR). This intervention significantly improved remission rates in 1 trial lasting 4 weeks (OR 21.25, 95% CI = 2.31 – 195.64).¹ Participants took part in activities that target the cognitive control deficits thought to influence depression and its poor outcomes in older populations. Investigators offered online activities targeting the processing of sensory stimuli as a depression treatment.¹

Investigators recommend large-scale studies to determine the long-term safety and efficacy of newer interventions, like ketamine and TMS. A recent article discussed a Yale-led study comparing the effectiveness of intravenous ketamine with Spravato (esketamine) nasal spray. Expanding research on augmentation strategies and cognitive therapies can help to refine treatment approaches. As depression is the leading global cause of disability and affects around 13% of older individuals, with roughly 33% experiencing TRD, this study affirms the need for more targeted and evidence based treatments to address TRD effectively.⁴ “There is an urgent need for TRD therapies for older adults that preserve cognition and are effective in polypharmacy and physical frailty contexts,” the study authors conclude.¹

References

1. Larsen AJ, Teobaldi G, Espinoza Jeraldo RI, et al. Effectiveness of pharmacological and non-pharmacological interventions for treatment-resistant depression in older patients: a systematic review and meta-analysis. BMJ Ment Health. 2025;28(1):e301324.

2. Moyano BP, Bautista DG, Porras Ibarra KJ, et al. Systematic review of clinical effectiveness of interventions for treatment resistant late-life depression. Ageing Res Rev. Published online February 28, 2025.

3. Gardner C. Yale-led study will compare effectiveness of iv ketamine and esketamine nasal spray. Psychiatric Times. January 30, 2025. https://www.psychiatrictimes.com/view/yale-led-study-will-compare-effectiveness-of-iv-ketamine-and-esketamine-nasal-spray

4. Abdoli N, Salari N, Darvishi N, et al. The global prevalence of major depressive disorder (MDD) among the elderly: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2022;132:1067-1073.