Introduction

Although antidepressant medications are effective for many patients with depression, the rate of response to the first agent administered can be as low as 50%. For nonresponders to the first agent, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial showed that the remission rate decreased from 37% to 13% as successive medication alternatives were tried [1] . Electroconvulsive therapy (ECT) is generally acknowledged to be the most effective treatment for severe and medication-refractory depression [2]. Its remission rates are between 55–90%, even in patients whose depression fails to remit with multiple trials of medications [3], [4], [5]. Significant reduction in symptoms also occurs more rapidly with ECT than medications, typically in 2–4 weeks consisting of 8–14 treatment sessions. Though effective, ECT is associated with significant adverse cognitive effects such as retrograde amnesia, problems with concentration and attention, and other cognitive sequelae. With the notable exception of autobiographical memory problems, most adverse cognitive effects of ECT are reported to resolve within 2 weeks [6]. Bifrontal ECT is equally effective to the more traditional bitemporal ECT and has less memory disruption [7]. There is also a widespread public misunderstanding that the seizure induced by ECT may be painful and traumatic, and carries high risk of brain damage and personality change, making patients and family members reluctant to approve this treatment option [8]. For these reasons, this effective therapy has become a treatment of last resort (relegated to 5th, 6th or 7th step after the failure of other therapies per American Psychiatric Association guidelines) and ECT is administered to only about 100,000 patients a year [8]. Thus, millions of patients suffering from major depression do not receive effective therapy, and others receive relief only after many months of medication trials.

It would be highly desirable to establish an alternative therapy that has similar benefits to ECT while minimizing any adverse neurocognitive effects and having wider social acceptability. One alternative meeting these criteria that has some prior data supporting its potential effectiveness in depression is deep inhalation anesthesia with isoflurane (ISO). Like ECT, deep anesthesia with ISO induces a brief state of electrocortical quiescence (burst suppression on electroencephalogram (EEG)), but does so without inducing convulsions or other seizure symptoms. Based on two preliminary studies directed by Langer, et al in Europe [9],[10], a series of 6 treatments with ISO had similar efficacy to 6 ECT sessions in reducing depressive symptoms without causing memory loss. The first study was a pilot study showing reduction of depressive symptoms in 11 patients exposed to variable numbers of ISO treatments, and the second was a small double-blind study comparing 10 depressed women treated with ISO vs. 10 treated with ECT for 6 sessions. Assessments indicated cognitive improvement in the ISO group vs. declines in ECT group after treatment. Subsequent work by Engelhardt [11] demonstrated similar antidepressant effect with a combined series of ISO treatments followed by ECT. A small open-label report by Carl, et al. [12] also suggested similar antidepressant efficacy of deep ISO anesthesia compared to ECT. In contrast, however, Greenberg, et al. [13] showed relatively little improvement with ISO treatments in a pilot study involving 6 elderly depressed patients (including 5 aged 74–82 years). In another pilot study, Garcia-Toro, et al. [14] treated 10 patients with 4 treatments of low dose sevoflurane (approximately 2.5%). While a 24% reduction in depressive symptoms was noted on average, the clinical effect was not deemed sufficient after 4 treatments and patients were switched to ECT. In these negative studies, methodological concerns were that the number of treatments were fewer than are typically effective for ECT, treatment effects that initially seemed promising nevertheless were stopped, and in the latter study, a low concentration of sevoflurane was used instead of a high concentration of isoflurane. There was essentially a cessation of interest in this potential treatment until recently, when studies in animal models also indicated antidepressant effects of ISO anesthesia. In a pilot study in our lab, mice treated with a single dose of either high dose ISO or desipramine and assessed 24 hours later using the forced swim test showed reduced immobility times as compared to the control group, suggesting antidepressant efficacy [15]. To assess more enduring antidepressant effects, Wang, et al [16] administered isoflurane (2%) or halothane (1.5%) to adult male Sprague Dawley rats continuously for two hours. Two weeks later, in a learned helplessness paradigm, isoflurane-treated rats had fewer failure trials and faster mean escape latency than naïve controls in the shuttle box avoidance task. Halothane-treated rats showed no antidepressant effects, suggesting that the reduced expression of learned helplessness is specific to isoflurane rather than a general effect associated with exposure to volatile anesthetics.

Given the large number of patients with medication-refractory depression (including many who are under age 70, relatively healthy, and would be deemed good candidates for ISO anesthesia), and improvements in medical monitoring and management of patients during deep anesthesia, a renewed effort to evaluate ISO anesthesia as an effective alternative therapy to ECT is warranted. As a small open-label comparability study, the present study's primary objective was to examine whether deep ISO anesthesia shows similar efficacy to ECT in alleviating moderate to severe depression in medication-refractory patients. The secondary objective was to evaluate whether a series of 10 treatments with deep ISO anesthesia over a 3 week period results better neurocognitive function at 24–48 hours after the last treatment and 4 weeks later than treatments with bifrontal ECT, a form of ECT previously shown to have lesser effects on memory on cognition than bitemporal ECT [7].