Major depressive disorder (MDD) is a common mental illness with significant morbidity, mortality, and public health impact.1 About 40% to 50% of MDD patients do not respond to traditional pharmacologic treatment; such patients are described as having treatment-resistant depression (TRD).2 In these treatment-resistant cases, electroconvulsive therapy (ECT) is considered the gold standard treatment.3 However, even with symptom improvement rates of up to 90% initially following treatment,4 the majority of patients relapse within 6 months of index course completion; hence, prolonged maintenance courses of ECT are generally indicated following the initial index courses.5 This challenge presents an opportunity for anesthesiologists to improve patient psychiatric outcomes.
Subanesthetic doses of ketamine have been shown to be effective in TRD therapy,6 relieving depression symptoms within hours of administration7 and persisting for up to a week following initial administration of one dose.8 However, relapse rates of TRD after a single ketamine infusion may be as high as 70% at one month requiring repeat dosing.9 There is uncertainty with regard to the safety of repeat subanesthetic doses of ketamine (given its abuse potential), and studies are ongoing to determine the optimal redosing intervals to prevent symptom relapse.10
Ketamine anesthesia for ECT poses theoretical advantages in treatment of TRD over either ECT or ketamine alone.11 Unlike methohexital, propofol, or etomidate, ketamine does not increase the seizure threshold.12 Some reports have suggested that ketamine may improve depressive symptoms when compared with a standard anesthetic regimen, whereas others have shown no difference in outcomes12–20; however, many of these prior clinical investigations have heterogeneity in methodology.4 Many studies do not use consistent patient assessment criteria for improvement, adequately blind subjects21 or achieve significant sample size.12 Therefore, the antidepressive effect of repeat consistent doses of ketamine in ECT, the mechanism of ketamine’s action22 and a clear therapeutic strategy necessary to provide lasting antidepressant benefit23 remain unclear.
Brain-derived neurotrophic factor (BDNF), a neuronal growth factor involved in neuron maturation, neurogenesis, and synaptic plasticity, has been linked to the mechanism of action of antidepressants,24 particularly the rapid antidepressant effect of ketamine.25 BDNF has been suggested as a marker of both ECT seizure quality26 as well as general effects of anesthetics.27 To date, there are no studies that have investigated the effect of anesthetic selection on BDNF changes in ECT.
The primary aim of this dual-arm, double-blinded, prospective, randomized clinical trial was to determine if patients receiving ketamine as the sole general anesthetic during ECT would have meaningful improvement in depressive symptoms when compared with patients receiving methohexital. We also evaluated to measure effects on cognition, seizure quality, hemodynamic parameters, and changes in plasma BDNF. We hypothesized that patients receiving ketamine anesthesia during ECT would experience greater improvements in depressive symptoms when compared with patients receiving methohexital.
MATERIALS AND METHODS
We conducted a randomized clinical trial at the Seattle VA Puget Sound Medical Center following approval of the Institutional Review Board (IRB 00850). Inclusion criteria were all veterans 18 years of age and older scheduled for an index course of ECT for treatment of a major depressive episode associated with treatment-resistant MDD as defined by the diagnostic and statistical manual fifth edition (DSM-V). Exclusion criteria for this study included uncontrolled hypertension (defined as blood pressure >180/90 mm Hg at the preanesthesia clinic visit), renal failure, neurological disorders (epilepsy, space occupying lesions, traumatic brain injuries in the past 6 mo), myocardial infarction in the past 6 months, known allergies or adverse reactions to ketamine, prior ECT treatment in the past 12 months, comorbid psychosis, schizophrenia and current abuse of drugs/alcohol, and pregnancy.
All subjects gave written informed consent before enrollment. Patient randomization was performed using permuted block randomization to ensure number of subjects assigned to each treatment arm was balanced.
Outpatient benzodiazepines were discontinued 48 hours before ECT, whereas all other psychiatric medications were continued during the study. Once enrolled, subjects were randomized to receive either intravenous racemic ketamine (1 to 2 mg/kg) or methohexital (1 to 2 mg/kg) for induction of general anesthesia for every seizure in their index course (protocol available in Supplemental Table 1, Supplemental Digital Content 1, http://links.lww.com/JNA/A61). Subjects and depression score raters were blinded to study drug intervention. Because of feasibility issues, anesthesiologists and psychiatrists were not blinded during ECT sessions. All the subjects received ketorolac 30 mg intravenously before induction of general anesthesia. Standard ASA monitoring was used during ECT and general anesthesia. At the end of the seizure, subjects in the ketamine arm received 1 to 2 mg of IV midazolam to mitigate postprocedural psychedelic effects. Periprocedural management of hemodynamics and management in the postanesthesia care unit (PACU) was under discretion of an attending anesthesiologist.
Electroconvulsive treatment was performed by 1 of 2 psychiatrists (A.B., J.B.) with a Mecta Spectrum 5000Q device (Portland, OR) using an ultrabrief pulse width of 0.3 ms for all patients. Patients were treated using right unilateral electrode placement, and initial seizure threshold was set by using an age-based method rather than by titration, as previously described.28 If seizures were insufficient or patients did not respond clinically, the stimulation dose was increased to improve seizure quality. If an increase of stimulation failed to improve seizure quality or provide clinical improvement, bilateral stimulus was applied. Patients were switched to bilateral stimulus only if right unilateral stimulus proved ineffective at the highest possible stimulus. If bilateral stimulation did not improve quality of seizure, psychiatrist could request a switch of the anesthetic. An index ECT course was scheduled with consecutive sessions 3 times a week with length determined by clinical response per the treating psychiatrist.
Severity of depression was scored using 2 validated depression questionnaires: the Patient Health Questionnaire-9 (PHQ-9),29 a patient self-assessment, and the Hamilton Depression Scale (HAM-D, 21-item version30), a clinician-performed assessment. Both PHQ-9 and HAM-D were performed before ECT and at the final ECT session. At 72 hours after the final ECT treatment, PHQ-9 was assessed during a telephone interview (HAM-D scores must be performed in person by a clinician).
To assess cognitive effects of the study intervention, the Montreal Cognitive Assessment (MOCA31) was administered before the first and at the final ECT session. All patients were followed-up by the treating psychiatrist (A.B.), 2 to 4 weeks after index course completion, for assessment of symptoms and for determination of maintenance ECT requirements, based on the clinical judgment of the treating psychiatrist.3 Ongoing psychiatric medication management, after ECT, was the responsibility of the patient’s primary outpatient mental health provider.
Samples of venous blood were taken after at least 8 hours of fasting (NPO) on the morning before starting ECT treatment (baseline) and before the last ECT session. Blood was drawn into heparinized blood collection tubes and was immediately processed. Lysed blood samples were assessed for BDNF concentrations using a commonly used, commercially available 2-site sandwich enzyme-linked immunosorbent assay (ELISA) kit (CYT306; Chemicon, Temecula), as previously described and validated.32 The concentration of the samples was calculated from a standard curve. All plasma BDNF levels are expressed as nanograms per milliliters and are within published plasma ranges.26
Statistical Analysis and Sample Size Calculation
All statistical analyses were performed using STATA (version 14; StataCorp, TX 77845) or Graphpad Prism (version 7; Graphpad, La Jolla, CA) at a significance level of 0.05 and a confidence interval of 95% on an intention to treat basis. Sample size calculations were made a priori based on prior data33 for a sample size of at least 46 patients where measurable reductions in HAM-D depression scores were reached.18 Analysis of trial data was planned once sample size (plus 4 to account for patients who were switched to ketamine from methohexital) was achieved, and the trial was stopped for outcome review. Where appropriate Mann-Whitney U Test, paired 2-tailed t test (with the Welch correction as appropriate) and Fisher exact test were used for comparison of parametrically or nonparametrically distributed continuous or dichotomous variables. Depressive and cognitive rating measures were analyzed using analysis of covariance (ANCOVA) comparing pre-post-ECT scores with anesthetic and time as covariates. Data were analyzed if patients completed any follow-up assessment.
In total, 52 subjects were enrolled in this parallel-arm prospective clinical trial between March 2016 and April 2017 (Fig. 1). No patients were withdrawn due to agitation as observed by staff or due to patient-reported symptoms of dissociation. Demographic data were similar in the 2 groups (Table 1). All patients met the criteria for TRD (failing 2 different therapeutic antidepressant drugs), with most patients having duration of depressive symptoms >1 year and having comorbid posttraumatic stress disorder (PTSD). Data from 50 subjects were included in primary and secondary endpoint analysis (2 were withdrawn), and data from a total of 297 ECT seizures were recorded (Table 2).
Quality of Seizures
In the methohexital group, more patients were switched to bilateral stimulus (P=0.03, Table 2) and 4 were switched to the ketamine arm after failure to achieve successful seizures at maximum ECT stimulus as defined by the treating psychiatrist. Each patient had at least 3 methohexital ECTs before conversion to ketamine ECT. One patient was unable to experience a seizure with methohexital, 2 had poor quality seizures and 1 experienced myoclonus with methohexital. These 4 patients are included in the methohexital arm as part of the intention to treat analysis under original trial randomization.
Depression Questionnaires (Primary Endpoint)
Severity of baseline depression scores before ECT was not different between trial arms (Fig. 2).
Patients in both groups had depression score improvement (decreased) after completing the ECT index course. For HAM-D scores, ANCOVA found no main effect of anesthetic selection (F 1,45=0.43, mean square error [MSE]=18.4, P=0.51, ηp 2=0.01) rather a main effect of treatment intervention (time) (F 1,45=7.8, MSE=333.6, P=0.008, ηp 2=0.16) where pre-ECT scores were higher than post-ECT scores. Similarly for PHQ-9 scores measured at the final ECT, ANCOVA also showed no main effect of anesthetic (F 1,47=0.96, MSE=21, P=0.331, ηp 2=0.02) rather a main effect of treatment intervention (time) (F 1,47=6.45, MSE=140.4, P=0.01, ηp 2=0.13) where pre-ECT scores again are higher (worse) than post-ECT scores. PHQ-9 measured at 72 hours after final ECT session showed no main effect of anesthetic drug (F 1,45=0.23, MSE=7.8, P=0.63, ηp 2=0.005) and was different from pre-ECT PHQ-9 but not post-ECT PHQ-9 in both treatment interventions. Age, number of seizures completed in index course and sex were considered as covariates in depressive scores but had no significant impact on acute effect analysis. Averages were also compared using 2-tailed t tests shown in Supplemental Table 1 (Supplemental Digital Content 1, http://links.lww.com/JNA/A61).
Effect of Anesthesia on Periprocedural Clinical Outcomes
There were no significant differences in the mean seizure length, PACU stay, number of seizures in index course, or increase in ECT stimulus in either treatment group (Table 2) or when compared individually at each index course timepoint. There were no between-group differences in blood pressure or heart rate, either at baseline or at maximum blood pressure and heart rate recorded during ECT (Fig. 3). There were no between-group differences in cognition, as assessed by MOCA administered before and after ECT with no effect of anesthetic selection (F 1,45=0.2, MSE=2.2, P=0.66, ηp 2=0.005) (Fig. 2C).
In the PACU, in the methohexital group, there were more agitation events (P=0.02) and more postoperative doses of propofol given than in the ketamine group (P<0.001). Two patients in the ketamine arm experienced transient memorable dissociative symptoms, as defined by patient-reported subjective out-of-body or otherness experience. The self-reported dissociative symptoms were reported to the psychiatrist and no recurrences were reported during outpatient follow-up visits with the psychiatrist at 2 to 4 weeks. There were no differences in patients shortening index course duration due to perceived disturbances in short-term memory and reasoning ability, although these disturbances were not reflected in MOCA scoring. At their 2 to 4 week follow-up appointments, all patients reported resolution of cognitive symptoms.
Anesthetic Selection and Plasma BDNF Concentration
Plasma concentrations of BDNF levels measured before ECT initiation did not differ between trial groups (P=0.79, Fig. 4). BDNF levels measured at the final ECT session increased only in the ketamine group but not in the methohexital group (Fig. 4). There were no significant relationships/correlations between change in BDNF and degree of depression score change.
The primary outcome of this study, depression severity as measured by self-reported and clinician-assessed depression questionnaire scores, showed no additional benefit of ketamine over methohexital during index course ECT. In addition, results of this study suggest that: (1) ketamine is well-tolerated as a single induction agent throughout an index course of ECT and is not superior to methohexital with regard to depression outcomes; (2) patients receiving ketamine when compared with methohexital were less likely to require bilateral seizure stimulus and more likely to achieve successful seizures as defined by a clinical psychiatrist; (3) ketamine anesthesia in combination with midazolam given after seizure completion causes less PACU agitation compared with methohexital anesthesia; (4) BDNF increases at the end of index course ECT with ketamine anesthesia.
Our study’s methodology differs from the previous reports in several domains: design, protocol, evaluation of biomarkers, and duration of follow-up after ECT termination. Since the most important parameters of ECT efficacy are seizure duration and stimulus quality,34 our protocol used consistent right unilateral seizure-stimulus titration, seizure-length monitoring, and careful selection of only index course ECT patients in a US veteran population. Unlike many trials which used ketamine as an adjuvant with a barbiturate or propofol,12 our trial compares ketamine with methohexital as the sole induction agents throughout the index course. Mixing ketamine with other induction agents may blunt ketamine’s antidepressant effects.35 We however, administered small sedative dose of midazolam after the seizure was completed in the ketamine group to attenuate possible psychedelic effect of ketamine after awakening. Although theoretically benzodiazepines might affect both antidepressant and cognitive effects of ketamine, the trajectory of antidepressant effect of GABA-ergic stimulation is largely unknown.4 Moreover, prior work investigating the antidepressant effect of ketamine compared with midazolam failed to demonstrate worsening of depression36 or meaningful change in cognitive ability with midazolam doses larger than the doses administered in this trial.37 We also used blinded clinician-assessed and self-reported scores and had no cases of wrong study anesthetic administration as in one trial.33
Depression symptoms improved in both arms from severe depression to mild/moderate depression on average which was likely attributable to ECT but not induction agent choice consistent with one meta-analysis of ketamine ECT studies.38 Contrary to our hypothesis, ketamine did not improve depressive symptoms more than methohexital at post-ECT or 72-hour endpoints; however, it is important to note that patients were less likely to require bilateral ECT stimulus, a risk factor for retrograde amnesia when used instead of unilateral stimulus.39 It has been suggested that the effect of ketamine may be canceled by ECT or that an ECT treatment ceiling effect exists that might blunt additional ketamine benefit40 making the timing of depression assessment essential in future studies. There also remains clinical equipoise that might justify ketamine’s use in patients for whom adequate seizures cannot be achieved with other anesthetics. Further, use of ketamine as an add-on treatment in ECT has shown some benefit in the short to moderate treatment course.41
Because prior ketamine infusion data suggest the antidepressant effects of ketamine peak at 72 hours,42 we chose to assess patients at this timepoint. Moreover, ketamine’s antidepressant effects peak 72 hours after IV infusion at 0.5 mg/kg and generally persist for 1 to 2 weeks23; therefore, we chose routine outpatient 2 to 4 week follow-up at psychiatry visit to see if there were differences in treatment response per the psychiatrist (which ultimately dictates maintenance ECT or other interventions). Consistent with a recently published trial,43 we did not observe increased ECT response in ketamine patients during outpatient follow-up or greater incidence of short-term cognitive dysfunction after index course of ECT in either group.
Contrary to widespread perception that ketamine has prominent hypertensive and tachycardia effects in ECT, we did not observe differences in hemodynamics between groups in our study. Most likely, the sympathetic stimulation of ECT overrides the hemodynamic side effects of the anesthetic; therefore, if hemodynamics are carefully managed during the procedure, the primary choice of anesthetic is likely secondary in maintaining hemodynamic stability.21 Most patients did not have hypertension, and those who did were well managed on medications. Agitation events were attributed generally to increased seizure duration, and none of the events led to discontinuation of index course therapy.
Administration of midazolam at seizure termination in ketamine subjects did not meaningfully change any outcomes with regard to delirium, orientation, or time to discharge. Adverse behavioral events were minor overall and similar in the 2 groups. This is important since the dissociative properties of ketamine are often used to justify excluding ketamine from ECT anesthesia, despite evidence that transient dissociative properties may mediate ketamine’s antidepressant effects.44
To date, we are the first to report evidence that ketamine increases a plasma biomarker for depression and neuroplasticity in ECT. BDNF changes did not significantly correlate with primary depression score (PHQ-9, HAM-D 21) endpoints but decreased primarily in the ECT-nonresponders. This suggests that while ketamine-induced BDNF changes may be important to ECT responsiveness, an increase in BDNF may not be sufficient to enhance ECT treatment response. As a growth factor downstream of NMDA receptor antagonism, this finding may reinforce work that suggests ketamine’s antidepressant effects are non-NMDA receptor mediated45 particularly since antidepressant effects have not been shown with other NMDA antagonists (such as memantine46 or dextromethorphan47). Although some studies have demonstrated a small increase in BDNF after ECT,48,49 others have not.50,51 No study to date except ours reports BDNF changes by anesthetic type which may be underappreciated in understanding the mechanism of ECT effect. Our finding that BDNF did not increase after ECT in the methohexital group is consistent with findings in patients undergoing ECT with a barbiturate.50,52 It is possible that larger sample size might provide the basis for a statistical model of treatment response based on BDNF data to identify nonresponders.
This study has several limitations. Despite efforts to recruit a diverse patient population, the patients in this trial are predominantly white male individuals in a US veteran population, and our data are from a single institution. Studies in animals53 and preliminary data from human subjects54 have suggested a difference in response to ketamine by sex, which requires further investigation. ECT patients are difficult to recruit and obtain follow-up data from due to their complex psychosocial and behavior comorbidities. Although depression scores reported here are quantitative, outcome measurements in psychiatric trials are prone to bias and to reporting inconsistencies despite validated questionnaire utilization.
In summary, results of this study suggest that patients undergoing ECT for TRD with ketamine anesthesia had similar improvement of depression when compared with patients undergoing ECT with methohexital anesthesia and with less treatment failure in a small number of patients. Ketamine anesthesia was not worse that a barbiturate and may be beneficial for the quality of the ECT when compared with methohexital anesthesia for those patients unable to achieve seizures. This trial provides a one-to-one comparison of anesthetic medications in ECT and suggests that BDNF may serve as a biomarker in distinguishing patients treated with ketamine for future work. Our findings demonstrate depression outcomes in a US veteran population with TRD and underscore the importance of anesthetic selection for ECT in improving periprocedural psychiatric outcomes.
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