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.
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.
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.
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.
Treatment-resistant depression afflicts tens of millions of individuals worldwide, causing enormous suffering, economic costs, and mortality. Novel interventions are needed. This study provides the first evidence suggesting that propofol, a widely available anesthetic agent, has rapid and long-lasting antidepressant effects. Future studies are warranted to further evaluate propofol’s antidepressant efficacy and mechanisms of action.
Depression is among the most common and debilitating of mental disorders. Although many patients respond to currently available treatments, about one-third have a form of the illness that is not responsive to optimized treatment with antidepressant medications (Rush et al., 2006). Many individuals with severe, treatment-resistant depression pursue electroconvulsive therapy (ECT)—still considered the most effective treatment for depression—but the cognitive side effects of ECT cause many patients to avoid this treatment (Lisanby, 2007). Consequently, each year millions of individuals in the United States alone are debilitated by treatment-resistant depression and left with limited treatment options, at enormous societal costs (Mrazek et al., 2014).
The urgency of this problem has encouraged investigations of novel antidepressant interventions. Agents that target N-methyl-D-aspartate (NMDA) glutamate receptors and gamma-aminobutyric acid (GABA) receptors have appeared particularly promising. Substantial clinical evidence now supports the efficacy of ketamine for treatment-resistant depression (Berman et al., 2000; Zarate et al., 2006; McGirr et al., 2015), and a recent randomized controlled trial demonstrated antidepressant effects of nitrous oxide (Nagele et al., 2015). Several studies have suggested efficacy of another inhaled anesthetic, isoflurane, at high doses in humans (Langer et al., 1985, 1995; Weeks et al., 2013) and rodent models (Antila et al., 2017; Brown et al., 2018). Furthermore, positive GABA-A receptor modulators have shown promising antidepressant effects (Kanes et al., 2017; McMurray et al., 2018). These agents may share pharmacodynamic mechanisms, including inhibition of NMDA receptors and activation of GABAergic neurotransmission, as reviewed recently (Zanos et al., 2018). Indeed, ECT has been reported to reduce NMDA receptor expression and function (Fumagalli et al., 2010; Park et al., 2014), alter glutamatergic synaptic function (Stewart and Reid, 2000; Li et al., 2012), and increase cortical GABA levels in humans (Sanacora et al., 2003). The convergent observations among these diverse interventions suggest a new class of antidepressant agents that rapidly trigger plasticity within glutamate and GABAergic circuitry to induce antidepressant effects (Tadler and Mickey, 2018).
Propofol is a unique, intravenous, general anesthetic that potentiates the function of GABA-A and glycine receptors (Hales and Lambert, 1991) and inhibits the function of NMDA receptors (Orser et al., 1995; Yamakura et al., 1995; Kingston et al., 2006). It has been widely used for over 25 years for procedural sedation and general anesthesia. Propofol is known for its rapid onset and offset of action, tolerability, and safety (Lamperti, 2015). Similar to isoflurane, at high doses propofol induces burst-suppression, a state of intrinsic cortical hyperexcitability that is quantifiable using electroencephalography (EEG) and that is disrupted by blockade of GABA, NMDA, or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (Steriade et al., 1994; Lukatch et al., 2005; Kroeger and Amzica, 2007; Ferron et al., 2009). Taken together, these properties of propofol led us to hypothesize that high-dose propofol would have antidepressant effects and a favorable side-effect profile. To collect preliminary evidence of feasibility, tolerability, and efficacy among individuals with treatment-resistant depression, we performed an open-label trial of deep propofol anesthesia.
Design and Participants
This open-label study was approved by the University of Utah Institutional Review Board and preregistered at ClinicalTrials.gov (NCT02935647). All participants provided written informed consent. We recruited outpatients who were seen for consultation in a referral clinic for treatment-resistant mood disorders. Assessment included a comprehensive psychiatric evaluation, full medical history, physical examination, screening blood tests (complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone), 12-lead electrocardiogram, and urine pregnancy test as indicated. Inclusion and exclusion criteria (Table 1) were confirmed by a psychiatrist and an anesthesiologist. Importantly, we excluded many individuals with medications or conditions that increased risk of experiencing adverse effects during propofol treatments (e.g., advanced age, severe obesity, hypertension, heart disease). Bipolar depression was not excluded because previous studies of ECT and ketamine have shown similar response rates for bipolar and unipolar depression (Dierckx et al., 2012; Coyle and Laws, 2015; Haq et al., 2015). Of 249 patients screened, 36 met criteria for the study, 11 consented to participate in the study, and 10 received at least 1 treatment. Baseline assessments incorporated the Structured Interview Guide for the Hamilton Depression Rating Scale (HDRS) with Atypical Depression Supplement (Williams et al., 1988) and the Montreal Cognitive Assessment (MoCA) (Nasreddine et al., 2005; Srisurapanont et al., 2017). See supplementary Information for further details about participants.
Inclusion and Exclusion Criteria
Age 18–55 y, inclusive
Primary diagnosis of DSM-5 major depressive disorder or bipolar disorder
Current moderate-to-severe depressive episode
Minimum of 2 failed antidepressant medication trials of adequate dose and duration
(at least one trial within the current depressive episode)a
Quick Inventory of Depressive Symptomatology, Self-Rated, total score >10 at baseline
24-item Hamilton Depression Rating Scale total score >18b
Other current DSM-5 disorders, with the exception of anxiety disorders and attention deficit disorder
Electroconvulsive therapy within the past 6 months
Lifetime history of DSM-5 cognitive disorder
Body mass index >40
Daily use of angiotensin converting enzyme inhibitor or angiotensin receptor blocker **
Symptomatic coronary artery disease or congestive heart failureb
History of transient ischemic attack or neurologic signs during the past yearb
History of or susceptibility to malignant hyperthermiab
Any contraindication to propofolb
Diabetes requiring insulinb
Abnormal kidney functionb
Daily use of opioid medicationb
Daily use of benzodiazepine medication
Pregnant or breastfeeding
Psychiatric instability requiring a higher level of care
Incompetent to provide consent
Anesthesiologists administered a series of 10 propofol infusions at a frequency of 3 times per week (1 subject received only 9 treatments due to a holiday schedule conflict). The decision to deliver a series of treatments rather than a single treatment was based on prior experience with ECT, ketamine, and isoflurane, all of which appear to produce higher response rates with 6 to 12 administrations (Langer et al., 1995; Lisanby, 2007; Weeks et al., 2013; Coyle and Laws, 2015). Monitoring included continuous EKG, pulse oximetry, blood pressure by noninvasive cuff, respiratory rate, and end-tidal carbon dioxide. A BIS Monitor (BIS VISTA Monitoring System, Aspect Medical Systems) was applied with a 4-electrode sensor (BIS Quatro, Covidien) to measure the left frontal EEG throughout the procedure. After preoxygenation, the anesthesiologist administered an induction dose of propofol (2,6-diisopropylphenol; Diprivan injectable emulsion; Fresenius Kabi) i.v., started a continuous infusion, and gave additional small boluses as needed. (Propofol dosing is described below.) A laryngeal mask airway and mechanical ventilation were employed. Trendelenburg positioning, IV fluids, and small boluses of pressors were used as needed for hypotension. During the recovery phase, a nurse monitored the participant in a postanesthesia care unit until discharge criteria were met. Further details about treatments are provided in supplementary Information.
Because brain concentrations and pharmacodynamic effects of a given dose of propofol vary substantially between individuals (Ludbrook et al., 2002), propofol dosing was guided by real-time EEG feedback via the BIS Monitor. This approach enabled us to produce relatively consistent pharmacodynamic effects across participants and across treatment sessions. Propofol induction (200–600 mg) was followed by a continuous infusion (300–650 µg/kg/min) and augmented with repeated small boluses (50–100 mg) as needed. Lower induction doses of 200 to 400 mg were used during each subject’s initial treatment to assure hemodynamic stability, and higher induction doses were introduced during later treatments as tolerated. After induction, the infusion rate was adjusted, and additional boluses were given with the goal of maintaining a burst-suppression state with a suppression ratio (SR) of 80% to 100% for 15 minutes. The SR is a metric calculated by the BIS Monitor that indicates the fraction of time the EEG is completely suppressed (isoelectric) during each 1-minute epoch. The rationale for suppressing EEG activity for 15 minutes was that previous studies of burst suppression using isoflurane anesthesia reported antidepressant effects using a similar protocol (Langer et al., 1995; Weeks et al., 2013).
After the procedure, EEG parameters calculated by the BIS Monitor were exported for off-line analysis. As shown in Figure 1, we defined the burst-suppression period of each treatment session as the interval during which SR was >50%. The duration at SR target was defined as the time during which SR was ≥80%. SR intensity was defined as the median SR value during the burst-suppression period. The integral of the SR curve (sum of SR values across all 1-minute epochs during the session) represented the cumulative time spent in the isoelectric state. The average signal quality index calculated by the BIS Monitor exceeded 95% throughout the burst-suppression period of all recording sessions.