TMS is ideal for this difficult-to-treat depression
STUDY: Flôr-Rodrigues B et al, Int Psychogeriatr 2026
STUDY TYPE: Systematic review of randomized controlled trials
FUNDING: Academic and institutional grants
Background
Small ischemic injuries build up as we age, causing cognitive problems and depression. The clinical signs are apathy, cognitive problems, cardiovascular risk factors, and it can be confirmed by white matter hyperintensities on an MRI as seen above.
Nearly 100% of patients with depression have a vascular contribution after age 75, and these patients are around 35% less responsive to antidepressants.
This review looked at eight randomized trials to find effective treatments.
Results
Nimodipine, a calcium channel blocker, was effective in two small trials. It lowered relapse over the following months, in one trial dropping recurrence from 36% to 4% (NNT=3). Tandospirone, available in Asia for anxiety and depression, sped up early relief in three of four trials but didn’t reliably improve outcomes by week 8.
Brain stimulation showed the clearest effect: higher-dose rTMS beat sham on response (39% vs 7%) and remission (27% vs 4%), and twice-daily tDCS beat once-daily and sham, with remission rates of 58%, 29%, and 0%. Both improved executive function independent of mood.
Missed Medications
A few promising candidates didn’t match the inclusion criteria for this analysis, but that does not diminish their clinical relevance:
- Pentoxifylline is a phosphodiesterase inhibitor that decreases blood viscosity, increases red blood cell flexibility, and reduces inflammation. It is FDA approved for disease of vascular perfusion, and has five controlled trials in depression, including a trial in depression after cardiac surgery. Why was it missed? None of these trials enrolled patients with verified microvascular brain disease.
- Ginkgo improves cerebral blood flow and modulates modulates acetylcholine, dopamine, and serotonin. In a small-vessel disease, ginkgo reduced white-matter lesions, hippocampal neuronal loss, and cognitive deficits by inhibiting mitochondrial oxidative stress and cellular death. It is well established for vascular dementia, and has multiple trials for depression with vascular disease (4 large, 10 small randomized trials; 86% positive). Why was it missed? Although the trials looked at depression with vascular disease, they did not confirm the small vessel ischemic disease of vascular depression, and most were small and Chinese-language (dose 120–240 mg BID of the EGB/Tebonin standardized extract).
- Lithium is effective in late-life depression, and its robust neuroprotective and antiinflammatory properties make it appealing, including repair of white-matter integrity and post-stroke gray-matter. New studies suggest it may protect against atherosclerosis. However, it lacks specific trials in vascular depression.
Side Effects
Adverse events were generally mild, with no serious events. Nimodipine caused more hypotension, and active tDCS caused more local skin irritation than sham. Ginkgo is well-tolerated but can cause nausea, headache, dizziness, and palpitations.
Limitations
All eight trials were small, mostly single-center, with inconsistent definitions of vascular depression, since no consensus diagnostic criteria exist. Follow-up was short, several lacked blinding, and heterogeneity precluded a meta-analysis.
What About Psychotherapy?
This wasn’t addressed in the paper, as psychotherapy is untested in vascular depression, but trials do support its benefits in related conditions like post-stroke depression and depression in older adults with executive dysfunction. There is an outdated notion that psychotherapy is more effective in the young; older adults had one of the largest benefits in Pim Cuijpers et al’s analysis of 366 therapy trials.
Here’s how I’d modify psychotherapy for vascular depression:
- Lifestyle to improve vascular health (Mediterranean diet, brisk walking, medical care)
- Cognitive rehabilitation
- While brain games may be beneficial, dexterity games have better evidence. Studies tested these for 20-45 minutes a day, including exergames like Nintendo (Switch Ring Fit Adventure, Wii Sports, Wii Fit, or Wii skiing) and Xbox 360 Kinect. If non-digital is preferred, try table tennis, pool, or crafts like pottery and woodworking.
Practice Implications
- Look for vascular causes in older adults with depression. White matter hyperintensities confirm the diagnosis, even if they are reported as normal age-related changes.
- Consider TMS or tDCS, nimodipine and ginkgo. Learn more in the vascular chapter in Difficult to Treat Depression.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
