Vagus nerve stimulation in RECOVER: a negative primary outcome, but durable benefit in responders

Design

12-month triple-blind randomised sham-controlled trial, with second-year follow-up

Population

493 adults with depression unresponsive to at least four treatments in the current episode

Primary outcome

Percent time in MADRS response

Effect

No difference on primary; QIDS-C response 39.6% vs 30.7%, CGI improvement 53.8% vs 39.8%

RECOVER was a 12-month, triple-blind trial in 493 adults with markedly treatment-resistant depression, at least four failed treatments in the current episode, an average of 13 lifetime antidepressant treatments and an episode lasting nearly 18 years. Participants were randomised to adjunctive active or sham vagus nerve stimulation. The review here is written by trial investigators.

The prespecified primary outcome, the proportion of time in response on the Montgomery-Åsberg scale, did not separate the groups. Several other measures favoured active stimulation: clinician-rated symptom response (39.6% vs 30.7%), global improvement (53.8% vs 39.8%), function (43.3% vs 37.5%) and quality of life (45.4% vs 37.1%).

More than 80% of those who had a meaningful benefit at 12 months still had it at 18 and 24 months, and about 30% of non-responders improved during the second year. That durability is notable in a group expected to relapse often, but the second-year data are uncontrolled.

For practice, vagus nerve stimulation stays a niche option for people who have exhausted standard treatments, including ECT where appropriate. A failed primary outcome means the trial does not establish efficacy, however favourable the secondary measures look.

• Keep vagus nerve stimulation for depression that has failed multiple adequate treatments, including ECT where suitable.
• Tell patients the trial's main measure was negative; benefit was seen on secondary measures.
• Expect any benefit to take months: some improved only in the second year.
• Interpret the review knowing it was written by the trial's investigators.

Why it matters

These results will be cited when the device is discussed, and the distinction between the failed primary and the positive secondaries is what a patient needs explained.

Don't overread it

The primary outcome did not differ from sham; the secondary and durability findings do not establish efficacy.

The statistics, in plain English

When a trial misses its primary outcome, positive secondary results are hypothesis-generating: with several measures tested, some may favour treatment by chance. Durability in responders comes from continued open treatment without a sham comparison, so it cannot separate device effect from natural course.

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