This proof-of-concept trial demonstrated that nitrous oxide has rapid and marked antidepressant effects in patients with TRD.

To the Editor: Approximately one-third of patients with major depressive disorder (MDD) are treatment resistant. 1,2 Despite high prevalence, the clinical characteristics and management of treatment-resistant depression (TRD) are not well described. We present a comprehensive clinical description of a case series of 79 well-characterized patients with TRD referred to a university-based TRD specialty clinic.Method. Of 104 patients referred to our TRD clinic from 2009 to 2014, 79 met clinic inclusion criteria: DSM-IV-TR-defined MDD with resistance to ≥ 3 antidepressant trials of adequate dose and duration and no diagnoses of bipolar I or II disorder, personality disorder, psychotic disorder, or alcohol or drug abuse/dependence. Medical records for psychiatric treatments within at least 5 years were obtained. Psychiatric history, including symptom, clinical, family, and treatment information, was obtained at the initial visit. Patients completed the Montgomery-Asberg Depression Rating Scale (MADRS). 3 Institutional review board approval and patient consent were obtained for research use of data.Results. Of the 79 patients, 67% (n = 53) were women; the mean age was 49.3 years (SD = 14.2). One-third (n = 26) were receiving disability support. The mean age at MDD onset was 24.3 years (SD = 13.8), with 50% of patients reporting MDD onset after age 18. The mean number of lifetime MDD episodes was 2.6 (SD = 1.7), with 70% (n = 55) of patients reporting ≥ 2 episodes; 30% (n = 24) reported 1 sustained MDD episode. The mean number of lifetime MDD years was 18.6 (SD = 10.0), with 51% (n = 40) of patients reporting ≥ 18 years. Most patients, 63% (n = 50), reported at least 1 psychiatric hospitalization; 21% (n = 17) reported ≥ 4 hospitalizations (maximum = 20). Of those hospitalized at least once, the mean number of hospitalizations was 3.8 (SD = 4.3); 43% (n = 34) of all patients reported ≥ 2 hospitalizations. At least 1

These cases suggest that some patients with treatment-resistant depression may have a previously unrecognized bipolar disorder, triggered only by VNS. This report also provides evidence that VNS-induced manic switches, however serious and troubling to patients, can be managed safely, and that VNS maintenance can be continued for an extended period of time without manic relapses. Although the mechanism of action of VNS is not known, emerging evidence supports central nervous system dopaminergic and possibly cholinergic system involvement.