REVIEW OF: Larsen AJ et al, BMJ Ment Health 2025;28(1):e301324

STUDY TYPE: Systematic review and meta-analysis

Most treatment algorithms for treatment-resistant depression (TRD) were built on trials in younger adults. This updated meta-analysis asked what the evidence says for patients age 55 or older who have failed at least one adequate treatment trial.

Fourteen RCTs involving 1,196 older adults tested ketamine, transcranial magnetic stimulation (TMS), aripiprazole augmentation, and pharmacogenetic-guided prescribing over 1–12 weeks, with remission on standardized scales as the primary outcome.

About one-third of participants remitted, and active treatment roughly doubled the odds versus control (odds ratio [OR] 2.4). Aripiprazole augmentation had the strongest data, outperforming placebo added to venlafaxine (OR 1.9), with an even greater benefit in patients with suicidal ideation (73% vs 44%). Ketamine showed the largest signal (pooled OR 2.9 across three trials) but the evidence quality was rated weak. TMS trended positive but fell short of significance. Pharmacogenetic testing had almost no supporting data.

CARLAT TAKE
Evidence for TRD in older adults is thin but actionable. Start with aripiprazole augmentation (low dose, slow titration) and move it to the top of the list if suicidality is in the picture. Esketamine is a reasonable next step, as two of the three ketamine trials actually used the intranasal formulation, so you’re not extrapolating from IV data. But the largest trial didn’t hit its primary endpoint, so plan for maintenance dosing and set expectations early. TMS is worth offering to patients who can’t tolerate or don’t want medications, but set honest expectations about its very weak evidence in this age group.