Matthews & Elijamel (Reference Matthews and Eljamel2003) lucidly describe the origin, mechanism and role of vagus nerve stimulation (VNS) in the treatment of refractory depression.

Lack of evidence for strategies to treat refractory depression and lack of perceived options necessitate a fresh look into research on the efficacy of existing treatments and development of new ones. Vagus nerve stimulation may prove to be an effective option and a major advancement, but it is too early even to speculate on recommending it for general use.

The authors state, “If any treatment for chronic, refractory depressive disorder were to offer the prospect of sustained, clinically significant changes in 20-30% of patients, this would represent a major therapeutic advancement”. However, our systematic review of treatment of refractory depression (Reference Stimpson, Agrawal and LewisStimpson et al, 2002) showed an overall placebo response rate of 15% with 95% CI of 7.9-23.4%. This rate is even higher in relatively less chronic depression, reaching up to 30-40% in some trials. Hence, the response rate of 31% in open trials for VNS may largely be due to placebo response and may not result in a satisfactory ‘number needed to treat’ in randomised trials.

The need for further research in this area cannot be overemphasised. Authors have highlighted the difficulty of finding an appropriate control condition. Even if we can satisfy the need for an appropriate placebo control, these trials should not be considered sufficient. For evidence to be robust, any new treatment for refractory depression should at least be compared with the existing active treatments, such as augmentation strategies, in addition to placebo control. Non-inferiority trials without active treatment comparison are not only unethical, they do not help clarify the question of what is the next best strategy in a particular patient with refractory depression. The second half of the past century saw a number of commonly used treatment strategies based only on preliminary evidence. Let us not perpetuate the same mistake in the 21st century.