Propofol for Treatment-Resistant Depression: A Pilot Study

Abstract

Background: We hypothesized that propofol, a unique general anesthetic that engages N-methyl-D-aspartate and gamma-aminobutyric acid receptors, has antidepressant properties. This open-label trial was designed to collect preliminary data regarding the feasibility, tolerability, and efficacy of deep propofol anesthesia for treatment-resistant depression.

Methods: Ten participants with moderate-to-severe medication-resistant depression (age 18-45 years and otherwise healthy) each received a series of 10 propofol infusions. Propofol was dosed to strongly suppress electroencephalographic activity for 15 minutes. The primary depression outcome was the 24-item Hamilton Depression Rating Scale. Self-rated depression scores were compared with a group of 20 patients who received electroconvulsive therapy.

Results: Propofol treatments were well tolerated by all subjects. No serious adverse events occurred. Montreal Cognitive Assessment scores remained stable. Hamilton scores decreased by a mean of 20 points (range 0-45 points), corresponding to a mean 58% improvement from baseline (range 0-100%). Six of the 10 subjects met the criteria for response (>50% improvement). Self-rated depression improved similarly in the propofol group and electroconvulsive therapy group. Five of the 6 propofol responders remained well for at least 3 months. In posthoc analyses, electroencephalographic measures predicted clinical response to propofol.

Conclusions: These findings demonstrate that high-dose propofol treatment is feasible and well tolerated by individuals with treatment-resistant depression who are otherwise healthy. Propofol may trigger rapid, durable antidepressant effects similar to electroconvulsive therapy but with fewer side effects. Controlled studies are warranted to further evaluate propofol's antidepressant efficacy and mechanisms of action. ClinicalTrials.gov: NCT02935647.

Figure 1.

Electroencephalographic (EEG) effects of propofol treatments. (A) Representative EEG traces are shown under light and deep propofol anesthesia. During the burst-suppression state of deep anesthesia, isoelectric periods are occasionally interrupted by stereotypical bursting activity. (B) Suppression ratio (SR) is plotted vs time for a typical participant (10 treatments shown). SR reflects the fraction of time the EEG is isoelectric and free of bursting activity during each 1-minute epoch. The burst-suppression period was defined as the time interval during which SR >50% (double dotted line). Curves are aligned on the time axis such that the first time point at which the target was reached (SR ≥80%, single dotted line) corresponds to 0 minutes. For each treatment session, 3 summary measures were calculated from the SR curve, as shown in histograms to the right. (C) The duration of the burst-suppression state (number of 1-minute epochs during which SR >50%) characterized the “width” of the SR curve. (D) The “height” of the curve was quantified by the SR intensity (median SR value during the burst-suppression period). (E) The integral of the SR curve (sum of SR values across all 1-minute epochs during the treatment session) summarized EEG suppression with a single number that represented total time in the isoelectric state. Histograms show the distributions of these summary measures across all participants and treatments.

Figure 2.

Change in depressive symptoms during a series of 10 deep propofol treatments. (A) Total score on the 24-item Hamilton Depression Rating Scale (HDRS-24) is shown at 3 time points during the trial. Each color represents an individual subject. The mid-series assessment was performed 48 to 72 hours after the 5th treatment and the postseries assessment was performed 48 to 72 hours after the final treatment. Scores below the dotted line represent remission of symptoms (HDRS-24<10). (B) HDRS-24 scores in A are re-plotted relative to the individual’s baseline score. Scores below the dotted line represent response (>50% improvement).

Figure 3.

Change in self-reported depressive symptoms with propofol vs electroconvulsive therapy (ECT). (A) Total score on the self-rated 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR) is shown during a series of 10 propofol treatments (mean±SD, n=10). Subjects completed the QIDS-SR just before each treatment session. (B) QIDS-SR total score is shown for a comparison group of patients who received a series of 10 ECT treatments (mean±SD, n=20).

Figure 4.

Electroencephalographic (EEG) suppression was associated with depression improvement. (A) Improvement in 24-item Hamilton Depression Rating Scale (HDRS-24) is plotted vs suppression ratio (SR) integral for responders (circles) and nonresponders (triangles). SR integral is an EEG measure representing the total time spent in the isoelectric state (explained in Figure 1). Each symbol represents a propofol treatment session. (B) Data from A are re-plotted to show subject-level measures (median values across treatment sessions). (C) As described in Figure 1, SR integral is dependent on both the “height” of the SR curve (SR intensity) and the “width” of the SR curve (duration of burst-suppression state). Here, SR intensity is plotted against duration of burst-suppression for each treatment session and each subject (circles, responders; triangles, nonresponders). (D) Data from C are re-plotted to show subject-level measures (median values across treatments). The treatments of subsequent responders were characterized by duration of burst-suppression <20 minutes and SR intensity <95%.