Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression.

BACKGROUND: Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain. METHODS: We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was -10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period. RESULTS: A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, -0.9±1.1 in the ketamine group vs. -9.7±1.2 in the ECT group; scores range from -300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation. CONCLUSIONS: Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968.).

Catatonia After COVID-19: A Case Series.

ABSTRACT: Coronavirus disease 2019 (COVID-19) has affected more than a hundred million people worldwide. In addition to the devastating number of deaths caused by this disease, it can cause significant morbidity in some survivors. The understanding of the morbidity associated with COVID-19 is rapidly evolving. This report describes 3 cases of catatonia associated with COVID-19. Catatonia is easily confused with other forms of delirium but if recognized can be effectively treated. We hope that awareness gained from these cases would help clinicians better recognize and diagnose catatonia following COVID-19 infection.

Advanced training in interventional psychiatry.

Interventional Psychiatry is an emerging subspecialty that treats patients with disorders resistant to routine measures by employing advanced treatment modalities and procedures that require expertise beyond the training provided in a general psychiatric residency. Interventional psychiatrists thus require advanced technical, psychiatric, and general medical training and expertise to be able to provide these treatments in a safe and effective manner. In this article, we will discuss our take on the definition of interventional psychiatry, review the modalities included in this field, and suggest training requirements for an interventional psychiatrist. We will also share our experience in providing advanced interventional psychiatry training as a chief residency or fellowship at the Yale New Haven Psychiatric Hospital.

ELEctroconvulsive therapy (ECT) vs. Ketamine in patients with Treatment-resistant Depression: The ELEKT-D study protocol.

Major depressive disorder (MDD) is the most common mental illness and the leading cause of disability worldwide. Electroconvulsive therapy (ECT) is the most effective treatment for MDD and the gold-standard therapy for treatment-resistant depression (TRD), yet it remains underutilized due to factors such as limited availability, stigma, and concerns about cognitive side effects. Ketamine has emerged as the first rapid-acting antidepressant and shows robust short-term efficacy in clinical trials, but there are concerns about its long-term safety and efficacy. While response rates are similar between ECT and ketamine in clinical trials, these treatments have never been compared head-to-head in a sufficiently large, well-powered randomized study. Here we describe the study protocol for ELEctroconvulsive therapy (ECT) vs. Ketamine in patients with Treatment-resistant Depression (ELEKT-D), a non-inferiority, comparative effectiveness trial. Patients with TRD seeking clinical treatment are randomized (1:1) to receive ECT (thrice weekly) or intravenous ketamine (twice weekly) for 3-5 weeks. The primary outcome is the proportion of responders in each group at the end of study visit, as measured by a patient-reported outcome measure (Quick Inventory of Depressive Symptomatology-Self Report). The study is powered such that the non-inferiority margin allows for ketamine to retain 90% of the ECT treatment effect, with a projected sample size of 400 patients (200 per group). Secondary outcomes include remission rates, depression severity, cognitive functioning, quality of life, adverse events, and tolerability. The results of the ELEKT-D study will have important implications for patient choice, clinical practice, and health insurance policies.

Acute and Longer-Term Outcomes Using Ketamine as a Clinical Treatment at the Yale Psychiatric Hospital.

OBJECTIVE: Ketamine has emerged as a rapid-acting antidepressant, though controversy remains whether sufficient data exist to justify its use outside of research protocols. In October 2014, the authors' institution began providing ketamine as an off-label therapy on a case-by-case basis for patients unable to participate in research protocols. Here, the participant experience during 29 months of providing ketamine as a clinical treatment for severe and treatment-resistant mood disorders through February 2017 is described. METHODS: Patients were initially treated with a single- or double-infusion protocol (0.5 mg/kg for 40 minutes intravenously) and were later transitioned to a 4-infusion protocol over 2 weeks. RESULTS: Fifty-four patients received ketamine, with 518 total infusions performed. A subset of 44 patients with mood disorders initiated the 4-infusion protocol, of whom 45.5% responded and 27.3% remitted by the fourth infusion. A subsample (n = 14) received ketamine on a long-term basis, ranging from 12 to 45 total treatments, over a course of 14 to 126 weeks. No evidence was found of cognitive decline, increased proclivity to delusions, or emergence of symptoms consistent with cystitis in this subsample. CONCLUSIONS: In general, ketamine infusions were tolerated well. The response and remission rates in this clinical sample were lower than those observed in some research protocols. The small number of patients who were treated on a maintenance schedule limits the conclusions that can be drawn regarding the long-term safety of ketamine; however, no long-term adverse effects were observed in this sample.

Cognitive Behavior Therapy May Sustain Antidepressant Effects of Intravenous Ketamine in Treatment-Resistant Depression.

INTRODUCTION: Ketamine has shown rapid though short-lived antidepressant effects. The possibility of concerning neurobiological changes following repeated exposure to the drug motivates the development of strategies that obviate or minimize the need for longer-term treatment with ketamine. In this open-label trial, we investigated whether cognitive behavioral therapy (CBT) can sustain or extend ketamine's antidepressant effects. METHODS: Patients who were pursuing ketamine infusion therapy for treatment-resistant depression were invited to participate in the study. If enrolled, the subjects initiated a 12-session, 10-week course of CBT concurrently with a short 4-treatment, 2-week course of intravenous ketamine (0.5 mg/kg infused over 40 min) provided under a standardized clinical protocol. RESULTS: Sixteen participants initiated the protocol, with 8 (50%) attaining a response to the ketamine and 7 (43.8%) achieving remission during the first 2 weeks of protocol. Among ketamine responders, the relapse rate at the end of the CBT course (8 weeks following the last ketamine exposure) was 25% (2/8). On longer-term follow-up, 5 of 8 subjects eventually relapsed, the median time to relapse being 12 weeks following ketamine exposure. Among ketamine remitters, 3 of 7 retained remission until at least 4 weeks following the last ketamine exposure, with 2 retaining remission through 8 weeks following ketamine exposure. Ketamine nonresponders did not appear to benefit from CBT. CONCLUSIONS: CBT may sustain the antidepressant effects of ketamine in treatment-resistant depression. Well-powered randomized controlled trials are warranted to further investigate this treatment combination as a way to sustain ketamine's antidepressant effects.

Computer-Assisted Cognitive Behavior Therapy to Prevent Relapse Following Electroconvulsive Therapy.

OBJECTIVE: The goal of this study was to explore the feasibility and potential efficacy of providing computer-assisted cognitive behavior therapy (CCBT) after an index course of electroconvulsive therapy (ECT) to prevent relapse. METHODS: In an open-label trial, subjects with major depressive episode who achieved response or remission after an acute treatment with ECT were recruited to enroll in a 9-module CCBT course. Subjects completed the CCBT modules in their own home at their own pace, but were asked to do at least 1 lesson per week, such that all 9 lessons would be completed in the first 2 months. Depression severity and relapse were monitored during the 6 months after ECT. RESULTS: Fifteen subjects (10 responders and 5 remitters) enrolled in the study and logged onto the CCBT course. The mean (SD) number of online lessons completed was 7.6 (1.7) or 84% of the total lessons and the mean (SD) time spent working online was 8.4 (3.9) hours. During the first 2 months (the prescribed time period), the mean (SD) number of lessons completed was 6.5 (1.8), or 72% and the mean (SD) time spent working online was 6.8 (3.2) hours. Of the entire sample of responders and remitters (n = 15), 5 (33%) relapsed at 6 months. Of the 5 remitters, none relapsed during this time period. CONCLUSIONS: Our results provide preliminary evidence that CCBT is feasible following ECT. Large controlled trials are needed to definitively assess whether this strategy is efficacious in preventing relapse.

Perphenazine suspension: a new, old treatment, side effects and continuous use.

A number of innovative delivery systems for acute antipsychotic pharmacotherapy have been developed over the years which include oral suspensions, rapidly dissolving wafers and acute intramuscular preparations. Currently, the availability of first generation antipsychotic (FGA) formulations is limited to two high potency agents: haloperidol and fluphenazine. At Yale New-Haven Psychiatric Hospital, the hospital pharmacy was able to create perphenazine suspension, a mid-potency FGA, with a record of effectiveness and tolerability that was no worse than that of second generation antipsychotics (SGAs) in the CATIE trial. In this study we compare perphenazine suspension to other first and SGAs in the risk of extrapyramidal reactions and whether or not patients were continued on the same antipsychotic they were started with at the time of discharge. Medical records of patients who received acute pharmacotherapy in a unique form while hospitalized at Yale New Haven Psychiatric Hospital from July 2009 to December 2009 were examined. All data were collected thru a chart review using a form that was created to systematically document experiences. A total of 229 patients were included in the study. There were no significant differences between treatment groups on gender, age, race or diagnosis. In the entire samples 1.75% had pseudo-parkonisnism, 1.31% had acute dystonia, 0.04% had tardive dyskinesia, 1.31% akithesia, and 4.8% any neurological side effects. There were no significant differences between agents in the likelihood of any of these side effects or of having any side effect. Higher use of anticholinergics was found in patients treated with FGAs. We also found that 77% were discharged on the same antipsychotic agent they received when they were initially hospitalized. A wide range of acute oral pharmacoptherapy in non-tablet formulations of first and SGAs should be available in psychiatric hospital formularies. FGAs seems to be as well tolerated as SGAs.

The use of electroconvulsive therapy in postpartum affective disorders.

Postpartum affective disorders continue to be a major health issue for women. There is a general belief that electroconvulsive therapy (ECT) is effective in treating severe or treatment-refractory postpartum affective illnesses, but evidence to support this assertion is lacking. In this case series, we present 5 cases of women with postpartum depression and psychosis, all of whom had failed prior pharmacological therapy. All 5 women had a significant response within 3 to 6 treatments with ECT. Our findings suggest that ECT is overall an effective treatment of postpartum illnesses. In addition to being an excellent choice for women who have failed prior medication trials, ECT may also be considered for women whose severity of illness necessitates rapid symptom resolution.

Imaging onset and propagation of ECT-induced seizures.

PURPOSE: Regions of seizure onset and propagation in human generalized tonic-clonic seizures are not well understood. Cerebral blood flow (CBF) measurements with single photon emission computed tomography (SPECT) during electroconvulsive therapy (ECT)-induced seizures provide a unique opportunity to investigate seizure onset and propagation under controlled conditions. METHODS: ECT stimulation induces a typical generalized tonic-clonic seizure, resembling spontaneous generalized seizures in both clinical and electroencephalogram (EEG) manifestations. Patients were divided into two groups based on timing of ictal (during seizure) SPECT tracer injections: 0 s after ECT stimulation (early group), and 30 s after ECT (late group). Statistical parametric mapping (SPM) was used to determine regions of significant CBF changes between ictal and interictal scans on a voxel-by-voxel basis. RESULTS: In the early injection group, we saw increases near the regions of the bitemporal stimulating electrodes as well as some thalamic and basal ganglia activation. With late injections, we observed increases mainly in the parietal and occipital lobes, regions that were quiescent 30 s prior. Significant decreases occurred only at the later injection time, and these were localized to the bilateral cingulate gyrus and left dorsolateral frontal cortex. CONCLUSIONS: Activations in distinct regions at the two time points, as well as sparing of intermediary brain structures, suggest that ECT-induced seizures propagate from the site of initiation to other specific brain regions. Further work will be needed to determine if this propagation occurs through cortical-cortical or cortico-thalamo-cortical networks. A better understanding of seizure propagation mechanisms may lead to improved treatments aimed at preventing seizure generalization.

Combined use of lamotrigine and electroconvulsive therapy in bipolar depression: a case series.

OBJECTIVE: Lamotrigine and electroconvulsive therapy (ECT) are both safe and effective treatments for bipolar depression. Concerns exist that anticonvulsants may interfere with seizure expression during ECT or may exacerbate cognitive side effects, potentially affecting clinical response. This report examines the clinical use of concurrent ECT and lamotrigine for acute bipolar depression and the transition to maintenance therapy. METHODS: Nine patients with acute bipolar depression were simultaneously treated with a course of ECT while titrating lamotrigine for maintenance therapy. We compared mean stimulus intensity, mean seizure duration, and mean time to orientation after treatment for each patient during treatment with their highest and lowest lamotrigine dose. RESULTS: All 9 patients were treated to remission. From the lowest daily dose to the highest daily dose, mean increase in lamotrigine was 102.8 mg. Clinically adequate seizures were obtained in each patient. Lamotrigine had minimal effect on each measured ECT parameter. The interval between ECT treatments was spaced to a mean of 15.2 days. The treatment combination was well tolerated, with no serious adverse events, no rashes, and no worsening of cognitive side effects. CONCLUSIONS: Concurrent use of lamotrigine with ECT in bipolar depression seems safe, did not interfere with routine ECT practice, and allowed for transition to maintenance pharmacotherapy.

Selective frontal, parietal, and temporal networks in generalized seizures.

Are "generalized" seizures truly generalized? Generalized tonic-clonic seizures are classified as either secondarily generalized with local onset or primarily generalized, without known focal onset. In both types of generalized seizures widespread regions of the nervous system engage in abnormally synchronous and high-frequency neuronal firing. However, emerging evidence suggests that all neurons are not homogeneously involved; specific nodes within the network may be crucial for the propagation and behavioral manifestations of generalized tonic-clonic seizures. Study of human tonic-clonic seizures has been limited by problems with patient movement and variable seizure types. To circumvent these problems, we imaged generalized tonic-clonic seizures during electroconvulsive therapy, in which seizure type and timing are well controlled. (99m)Tc-hexamethylpropylene amine oxime injections during seizures provide a "snapshot" of cerebral blood flow that can be imaged by single photon emission computed tomography (SPECT) after seizure termination. Here we show that focal regions of frontal and parietal association cortex show the greatest relative signal increases. Involvement of the higher-order association cortex may explain the profound impairment of consciousness seen in generalized seizures. In addition, focal involvement of the dominant temporal lobe was associated with impaired retrograde verbal memory. Similar focal increases were also seen in imaging of spontaneous secondarily generalized tonic-clonic seizures. Relative sparing of many brain regions during both spontaneous and induced seizures suggests that specific networks may be more important than others in so-called generalized seizures.

Targeted prefrontal cortical activation with bifrontal ECT.

The anatomical brain regions involved in the therapeutic and adverse actions of electroconvulsive therapy (ECT) are unknown. Previous studies suggest that bifrontal vs. bitemporal ECT differ in therapeutic efficacy and cognitive side effects. We therefore performed cerebral blood flow (CBF) imaging during bitemporal vs. bifrontal ECT-induced seizures to identify regions crucial for the differences between these treatments. Patients with major depression, undergoing bitemporal or bifrontal ECT, were studied. Ictal-interictal SPECT images were analyzed with statistical parametric mapping for bitemporal (n=11 image pairs in 8 patients) and bifrontal (n=4 image pairs in 2 patients) ECT-induced seizures to identify regions of ictal CBF changes. Bifrontal ECT was found to cause increases in CBF in prefrontal and anterior cingulate regions. Bitemporal ECT, however, caused CBF increases in the lateral frontal cortex and in the anterior temporal lobes. In bifrontal ECT, a greater increase in prefrontal activation, while sparing the temporal lobes, may result in a better therapeutic response and fewer adverse effects on memory than bitemporal ECT.

Increased cortical GABA concentrations in depressed patients receiving ECT.

OBJECTIVE: Reduced gamma-aminobutyric acid (GABA) concentrations have been reported in the plasma, CSF, and cortex of depressed subjects. Of interest is that ECT, one of the most effective treatments for severe refractory depression, produces considerable anticonvulsant effects that may be related to increased GABAergic transmission. The purpose of this study was to determine if cortical GABA concentrations increase following a course of ECT. METHOD: Occipital cortex GABA concentrations in eight depressed patients were measured by using proton magnetic resonance spectroscopy before and after a course of ECT. RESULTS: A significant increase in occipital cortex GABA concentrations was seen following ECT treatment of depression. CONCLUSIONS: Occipital cortex GABA concentrations increase two-fold following ECT. This suggests possible GABAergic involvement in ECT's mechanism of anticonvulsant and antidepressant actions.