VNS in markedly treatment-resistant depression: negative primary, durable secondary gains

Design

12-month triple-blind randomised trial of adjunctive active vs sham VNS

Population

493 adults with markedly treatment-resistant major depression

Primary outcome

Percent of time in response on the Montgomery-Asberg Depression Rating Scale

Effect

Primary endpoint not met; secondary CGI improvement 53.8% vs 39.8%, benefit durable to 24 months in over 80% of responders

RECOVER enrolled 493 adults with markedly treatment-resistant major depression, averaging 13.3 lifetime antidepressant trials and a current episode of nearly 18 years, and randomised them to adjunctive active or sham vagus nerve stimulation (VNS) for 12 months under triple-blind conditions. This is about the most refractory population a trial can assemble.

The prespecified primary outcome, percent of time in response on the Montgomery-Asberg scale, did not separate active from sham. Secondary measures did: clinician-rated symptom response 39.6% vs 30.7%, Clinical Global Impressions improvement 53.8% vs 39.8%, with similar gaps in work function and quality of life, and a combined metric favouring active stimulation. Among those who benefited at 12 months, more than 80% still had that benefit at 18 and 24 months, and about 30% of initial non-responders improved in the second year.

The honest reading is mixed but useful. In a group expected to relapse relentlessly, durable benefit on how patients feel and function is meaningful even though the primary endpoint was not met. VNS stays a late-line option for the most refractory illness, and the durability data strengthen the case for persisting once a response appears.

• RECOVER studied adjunctive VNS in 493 adults with profoundly treatment-resistant depression (mean 13.3 prior antidepressant trials).
• The primary endpoint (time in MADRS response) did not separate active from sham stimulation.
• Secondary symptom, function and quality-of-life measures favoured active VNS (for example CGI improvement 53.8% vs 39.8%).
• Over 80% of 12-month responders retained benefit at 18 and 24 months; about 30% of non-responders improved in year two.
• Keep VNS as a late-line option for the most refractory illness, and persist once a response emerges.

Why it matters

It reframes a device for the most treatment-resistant patients: the gain to watch is durable function and quality of life, not a single rating-scale primary.

Don't overread it

The prespecified primary endpoint was not met, so the benefit rests on secondary measures and should be presented to patients as such.

The statistics, in plain English

A negative primary endpoint means the trial did not prove its main hypothesis, so the positive secondary outcomes are supportive rather than confirmatory; the durability figures are within-responder observations, not a randomised comparison.

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