Neuromodulation for treatment-refractory major depressive disorder.

ajor depressive disorder is among the most prevalent psychiatric disorders and is a leading cause of morbidity and lost productivity. 1 The 1-year prevalence of major depressive disorder in the Canadian population is 3.2%–4.6%. 2 A large, multisite prospective trial showed that only 28% of patients ex-peri ence remission following monotherapy with a serotonin reuptake inhibitor. 3 Further, remission rates following antidepressant use decrease with each successive treatment failure, such that after 12 months of follow-up and up to 4 attempts at symptom control with different medications , only 60% of patients experience remission. 4,5 The remaining patients can be classified as having treatment-refractory depression. The failure of monoamine-modulating medi-cat ions to successfully treat a significant percentage of cases of major depressive disorder challenges the traditional conception of this condition as a monoamine deficiency state. 5 Accordingly, and in light of neurocircuitry models of the brain (Appendix 1, available at www .cmaj .ca /lookup /suppl /doi :10 .1503 /cmaj .121317 /-/DC1) and advances in technology allowing various means of modulating activity in key structures of the brain, interest in the therapeutic potential of neuromodulation for difficult-to-treat mood disorders has increased in recent years. In this review, we outline the mechanisms, safety and clinical evidence for neuromodulation in treatment-refractory major depression. The quality of evidence for the different neuromodulation strategies varies substantially, ranging from small, open-label case series to blinded, random-ized controlled trials and meta-analyses (Box 1). Neuromodulation is either noninvasive or inva-sive, based on the extent to which the technology interacts directly with the brain (Figure 1). Non-invasive options include electroconvulsive therapy , transcranial magnetic stimulation and trans-cranial direct current stimulation. 6 Invasive options include vagal nerve stimulation 7 and deep brain stimulation. Here we focus on the 3 modalities for which the most evidence is currently available: electroconvulsive therapy, transcranial magnetic stimulation and deep brain stimulation. Electroconvulsive therapy Electroconvulsive therapy is the oldest neuro-modulatory modality still used to treat major depressive disorder. It arguably remains the gold-standard to which other antidepressant treatments are compared, yet it is underused. 8 Electroconvulsive therapy involves the administration of an electrical current to the brain via the scalp to induce a seizure while the patient is in a state of general anesthesia. Although its mech an-isms are unknown, 9 the superiority of real elec-troconvulsive therapy over sham electroconvul-sive therapy (anesthesia, with or without a subconvulsive dose of electrical current) suggests that the induction …