Vagus nerve stimulation in resistant depression: a negative primary outcome, durable secondary gains

Design

Review of a 12-month triple-blind sham-controlled randomised trial with open continuation

Population

493 adults with markedly treatment-resistant major depression

Primary outcome

Percentage of time in MADRS response over 12 months

Effect

Primary outcome not different; QIDS-C response 39.6% vs 30.7%, CGI improvement 53.8% vs 39.8%

A review in the American Journal of Psychiatry, published on 26 August, summarises the RECOVER trial: 493 adults with markedly treatment-resistant depression — at least four failed treatments in the current episode, an average of 13 lifetime treatments and an episode lasting about 18 years — randomised to active or sham adjunctive vagus nerve stimulation for 12 months.

The prespecified primary outcome, percentage of time in response on the Montgomery–Åsberg scale, did not separate the groups. Several secondary measures favoured active stimulation: clinician-rated symptom response 39.6% vs 30.7%, global improvement 53.8% vs 39.8%, and quality-of-life response 45.4% vs 37.1%. Over 80% of those with meaningful benefit at 12 months kept it at 18 and 24 months, and about 30% of non-responders improved in the second year.

The honest reading is that the trial missed its primary endpoint and the positive findings are secondary, in a group with very high expected relapse. For patients who have exhausted medication, ECT and other options, it is a reason to discuss referral, not evidence that the device works for resistant depression generally.

• Count failed adequate treatments in the current episode — this trial enrolled patients with four or more.
• Raise neuromodulation options with patients who have not responded to several medicines and psychotherapy.
• Explain that benefit, where it came, built over months rather than weeks.
• Check that ECT has been considered before discussing an implanted device.

Why it matters

It is one of the few controlled data sets in patients this resistant, and it shows slow, durable gains rather than a quick response.

Don't overread it

The primary endpoint was negative; the benefits are on secondary measures, and the review is written by trial investigators.

The statistics, in plain English

When a trial misses its primary outcome, positive secondary results are hypothesis-generating: the more outcomes tested, the more likely some cross the significance line by chance. The 24-month durability data come from responders continuing active stimulation, without a sham comparison in year two.

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