Article link: https://pmc.ncbi.nlm.nih.gov/articles/PMC11877238/

Citation: Larsen AJ, Teobaldi G, Espinoza Jeraldo RI, Falkai P, Cooper C. Effectiveness of pharmacological and non-pharmacological interventions for treatment-resistant depression in older patients: a systematic review and meta-analysis. BMJ Ment Health. 2025 Mar 3;28(1):e301324. doi: 10.1136/bmjment-2024-301324. PMID: 40032553; PMCID: PMC11877238.

Title: Effectiveness of pharmacological and non-pharmacological interventions for treatment-resistant depression in older patients: a systematic review and meta-analysis

This systematic review and meta-analysis of 14 randomized controlled trials (RCTs) provides a long-overdue update on treating treatment-resistant depression (TRD) in patients aged 55 and older, offering several critical insights for the practicing psychiatrist.

  1. The Scope of Success in Late-Life TRD
  • Encouraging Remission Rates: Despite the challenge of treatment resistance, the pooled proportion of older adults achieving remission across all active interventions was 35%.
  • Superiority Over Placebo: Patients receiving active interventions were 2.42 times more likely to remit than those in placebo control groups.
  • The Clinical Gap: Most currently used antidepressants and psychosocial treatments lack an age-specific RCT evidence base for TRD, forcing psychiatrists to extrapolate data from younger populations.
  1. Pharmacological Take-Home Messages
  • Ketamine and Esketamine: These agents showed the strongest odds of remission (OR 2.91). However, the evidence is graded as weak due to high risk of bias in some studies and limited long-term safety data in older populations. Clinicians must remain vigilant regarding side effects such as drowsiness, derealisation, and hypertension.
  • Aripiprazole Augmentation: There is weak-quality evidence supporting aripiprazole augmentation. Notably, in one study, aripiprazole significantly resolved suicidal ideation (73.3% in the active group vs. 44% in placebo), which is a critical finding given that 27.2% of global suicides occur in those aged 60+.
  • Imipramine vs. Mirtazapine: In a direct comparison for venlafaxine-resistant patients, switching to imipramine (with plasma level monitoring) resulted in a significantly higher remission rate (71.4%) than adding mirtazapine (39.3%).
  1. Neurostimulation and Cognitive Interventions
  • TMS (rTMS, TBS, and tDCS): While there was a trend toward benefit (OR 1.99), the evidence for transcranial magnetic stimulation is currently very weak due to small sample sizes and high heterogeneity.
  • Cognitive Remediation: Very weak evidence supports neuroplasticity-based computerized cognitive remediation (NCCR) for targeting cognitive control deficits, but it remains a promising non-pharmacological area for further exploration.
  1. Precision Psychiatry: Pharmacogenetics
  • Guided Prescribing: There is very weak evidence that pharmacogenetic-guided prescribing (PGP) can improve outcomes in older adults (OR 3.20 at 8 weeks). This suggests that identifying individual metabolic variants may eventually help mitigate the risks associated with polypharmacy and age-related pharmacokinetic changes.
  1. Clinical Application for the Psychiatrist
  • Differentiating TRD Definitions: This study uses a broad definition of TRD (failure of ≥1 trial), which is more inclusive than the FDA’s standard of ≥2 failed trials. Psychiatrists may consider shifting strategies earlier in older patients to prevent the disability and increased dementia risk associated with prolonged depression.
  • Managing Vulnerable Populations: Be aware that many TRD trials exclude the very patients seen in daily practice: those with dementia, active suicidality, or psychosis. Clinical judgment remains paramount when treating these high-risk subgroups.
  • Routine Monitoring: Given the higher prevalence of physical frailty and medical comorbidities in this demographic, pharmacological interventions (especially ketamine or antipsychotic augmentation) require aggressive monitoring of vital signs and cognitive status.

 

Summary Table

Intervention Evidence Quality Odds of Remission (OR) Key Clinical Note
Ketamine Weak 2.91 Monitor for hypertension/sedation.
Aripiprazole Weak 1.93 Effective for suicidal ideation resolution.
TMS Very Weak 1.99 Trend toward benefit; safe but underdosed.
PGP Testing Very Weak 3.20 Potential to reduce polypharmacy risks.