REVIEW OF: Carpenter LL et al, Brain Stimulation 2025;18:1695–1704
STUDY TYPE: Randomized, double-blind, sham-controlled trial
EVIDENCE GRADE: High (10/10)
Background
Neuromodulation treats depression by activating neurons with magnetic or electrical energy. To simplify, it exercises brain cells so they build new connections (neuroplasticity). So far, these devices — which include transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) — activate neurons in the brain. Today’s study is the first to treat depression by activating sensory nerves that feed into the brain.
The industry-sponsored trial tested a wearable home-based device that goes by the lengthy name “external Combined Occipital and Trigeminal Afferent Stimulation” (eCOT-AS) and is branded as ProLivRx. eCOT-AS (ProLivRx) is based on a similar device, Relivion, that is FDA-cleared for migraines. Both devices stimulate the occipital and trigeminal nerves, two cranial nerves that affect brainstem pathways involved in mood regulation.
The trial lead to the FDA approval of ProLivRx in depression in January 2026. Earlier psychiatric devices were only cleared by the FDA, but approval requires a higher bar of evidence, so let’s look at that evidence.
The Trial
124 adults with moderate-to-severe major depressive disorder who had failed one to four antidepressant trials (average 1.8) were randomized to active or sham (ie, placebo) eCOT-AS, self-administered at home for 40 minutes twice daily, five to seven days a week for eight weeks, while continuing their current antidepressants. Blinding was well-maintained, with nearly 90% of participants unable to tell if they got the sham or the real thing.
After eight weeks, active treatment produced an 8.62-point drop in HDRS17 scores versus 6.01 for sham — a 2.61-point therapeutic gain with an effect size of 0.7-0.9. That’s a large effect, suggesting it is among the more potent treatments in psychiatry, but we’ll need more trials to confirm that. Remission rates told a more striking story: 21% for active versus 6% for sham.
As you see in the graph above, the benefits continued to build over 16 weeks, where remission reached 32%, although the final 8 weeks were uncontrolled, so the improvements there could be due to the natural course rather than the treatment.
Adverse events were mostly mild headaches and scalp discomfort. Many found the treatment pleasant, a bit like a mild head massage.
Practice Implications
- eCOT-AS (ProLivRx) brings a tolerable, effective solution for depressions that have not recovered on an antidepressant
- Though not as well established as TMS, the at-home delivery is a plus for patients
- It appears more effective and better tolerated than another at-home device, tDCS, which does not work when antidepressants fail
- Expect ProLivRx out by summer 2026.
- It will be a prescription model, as the app that runs it will require activation by a clinician
- Learn more in our podcast interview with the lead investigator, Linda Carpenter, parts I and II
Share Your Input in Comments
- What role do you see for ProLivRx in depression?
- It only has one study. What other limitations concern you about it?
