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 After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients.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.).

The genetics of severe depression.

Genome-wide association studies (GWASs) of major depressive disorder (MDD) have recently achieved extremely large sample sizes and yielded substantial numbers of genome-wide significant loci. Because of the approach to ascertainment and assessment in many of these studies, some of these loci appear to be associated with dysphoria rather than with MDD, potentially decreasing the clinical relevance of the findings. An alternative approach to MDD GWAS is to focus on the most severe forms of MDD, with the hope that this will enrich for loci of larger effect, rendering their identification plausible, and providing potentially more clinically actionable findings. Here we review the genetics of severe depression by using clinical markers of severity including: age of onset, recurrence, degree of impairment, and treatment with ECT. There is evidence for increased family-based and Single Nucleotide Polymorphism (SNP)-based estimates of heritability in recurrent and early-onset illness as well as severe functional impariment. GWAS have been performed looking at severe forms of MDD and a few genome-wide loci have been identified. Several whole exome sequencing studies have also been performed, identifying associated rare variants. Although these findings have not yet been rigorously replicated, the elevated heritability seen in severe MDD phenotypes suggests the value of pursuing additional genome-wide interrogation of samples from this population. The challenge now is generating a cohort of adequate size with consistent phenotyping that will allow for careful and robust classifications and distinctions to be made. We are currently pursuing such a strategy in our 50-site worldwide Gen-ECT-ics consortium.

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.

Factors associated with health-related quality of life in patients with cirrhosis: a systematic review.

BACKGROUND: Patients with cirrhosis have a poor health-related quality of life (HRQoL). Recognizing factors that affect HRQoL is key in delivering patient-centred care. AIM: To identify factors most commonly associated with a poor HRQoL in adults with cirrhosis in a systematic review of the literature. METHODS: Four databases (MEDLINE, EMBASE, CENTRAL and PsycINFO) were searched from inception to March 2020, using terms related to patient-reported outcomes plus cirrhosis. Studies that analysed an association between at least one factor and HRQoL in adult patients with cirrhosis were included. Abstract and full-text screening was performed by two reviewers. Data were collected on factors evaluated in each study and the significance of their association with HRQoL. RESULTS: A total of 10647 citations were reviewed, of which 109 met eligibility criteria. 76% of the studies used a generic instrument while only 45% used liver-specific instruments. Among identified factors, demographic factors and cirrhosis aetiology were not generally associated with poor HRQoL except for poor social support. Depression, poor sleep and muscle cramps affected HRQoL in all the studies that evaluated them. Among comorbidities, frailty, falls, malnutrition and cognitive impairment were also associated with poor HRQoL in the majority of studies. Among cirrhosis-specific decompensating events, only hepatic encephalopathy (HE) was consistently associated with impairment in HRQoL (75% of studies). CONCLUSION: Many factors impact poor HRQoL in patients with cirrhosis such as depression, muscle cramps, poor sleep, falls, frailty and malnutrition. Among cirrhosis decompensating events, HE was the complication most commonly associated with a poor HRQoL.

Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU.

OBJECTIVE: To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU. DESIGN: Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups gathered face-to-face at annual Society of Critical Care Medicine congresses; virtual connections included those unable to attend. A formal conflict of interest policy was developed a priori and enforced throughout the process. Teleconferences and electronic discussions among subgroups and whole panel were part of the guidelines' development. A general content review was completed face-to-face by all panel members in January 2017. METHODS: Content experts, methodologists, and ICU survivors were represented in each of the five sections of the guidelines: Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption). Each section created Population, Intervention, Comparison, and Outcome, and nonactionable, descriptive questions based on perceived clinical relevance. The guideline group then voted their ranking, and patients prioritized their importance. For each Population, Intervention, Comparison, and Outcome question, sections searched the best available evidence, determined its quality, and formulated recommendations as "strong," "conditional," or "good" practice statements based on Grading of Recommendations Assessment, Development and Evaluation principles. In addition, evidence gaps and clinical caveats were explicitly identified. RESULTS: The Pain, Agitation/Sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) panel issued 37 recommendations (three strong and 34 conditional), two good practice statements, and 32 ungraded, nonactionable statements. Three questions from the patient-centered prioritized question list remained without recommendation. CONCLUSIONS: We found substantial agreement among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults. Highlighting this evidence and the research needs will improve Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) management and provide the foundation for improved outcomes and science in this vulnerable population.

Depressive Symptoms After Critical Illness: A Systematic Review and Meta-Analysis.

OBJECTIVES: To synthesize data on prevalence, natural history, risk factors, and post-ICU interventions for depressive symptoms in ICU survivors. DATA SOURCES: PubMed, EMBASE, Cumulative Index of Nursing and Allied Health Literature, PsycINFO, and Cochrane Controlled Trials Registry (1970-2015). STUDY SELECTION: Studies measuring depression after hospital discharge using a validated instrument in more than 20 adults from non-specialty ICUs. DATA EXTRACTION: Duplicate independent review and data abstraction. DATA SYNTHESIS: The search identified 27,334 titles, with 42 eligible articles on 38 unique studies (n = 4,113). The Hospital Anxiety and Depression Scale-Depression subscale was used most commonly (58%). The pooled Hospital Anxiety and Depression Scale-Depression subscale prevalence (95% CI) of depressive symptoms at a threshold score greater than or equal to 8 was 29% (22-36%) at 2-3 months (12 studies; n = 1,078), 34% (24-43%) at 6 months (seven studies; n = 760), and 29% (23-34%) at 12-14 months (six studies; n = 1,041). The prevalence of suprathreshold depressive symptoms (compatible with Hospital Anxiety and Depression Scale-Depression subscale, ≥ 8) across all studies, using all instruments, was between 29% and 30% at all three time points. The pooled change in prevalence (95% CI) from 2-3 to 6 months (four studies; n = 387) was 5% (-1% to +12%), and from 6 to 12 months (three studies; n = 412) was 1% (-6% to +7%). Risk factors included pre-ICU psychologic morbidity and presence of in-ICU psychologic distress symptoms. We did not identify any post-ICU intervention with strong evidence of improvement in depressive symptoms. CONCLUSIONS: Clinically important depressive symptoms occurred in approximately one-third of ICU survivors and were persistent through 12-month follow-up. Greater research into treatment is needed for this common and persistent post-ICU morbidity.

Blood pressure changes during ketamine infusion for the treatment of depression.

OBJECTIVE: This study aimed to examine blood pressure changes during ketamine infusion for depression and exploring the factors associated with these changes. METHOD: This study is a retrospective chart-review of patients with depression undergoing ketamine infusion at Yale Psychiatry Hospital during a 7-year period. Blood pressure (BP) was recorded every 10 min during the infusion. Surges in systolic and diastolic blood pressure (SBP, DBP), along with severe hypertension events, were analyzed in relation to patient demographics. RESULTS: A total of 138 patients received a total of 2342 infusions. SBP and DBP peaked at 40 min after the start of the infusion with a mean change of 16.0 (SD: 11.2) and 11.0 mmHg (SD: 8.45) respectively. Severe hypertension was observed in 17 patients (12.5%) and 23 infusion sessions (0.98%), occuring more frequently during the first three infusions (43.4%). Age (OR = 1.04 [1.02,1.05], p-value <0.001) was significantly associated with a surge in SBP and all patients with a past medical history of hypertension experienced a BP surge during their infusions. CONCLUSION: Ketamine infusions can cause significant blood pressure increases, particularly in older and hypertensive patients, highlighting the need for careful cardiovascular monitoring to mitigate risks during treatment.

Efficacy and Safety of Ketamine/Esketamine in Bipolar Depression in a Clinical Setting.

Background: Bipolar disorder represents a significant source of morbidity and elevated mortality risk. Ketamine has emerged as a powerful antidepressant; however, there have been few trials of ketamine in bipolar depression and no trials with esketamine in bipolar depression, and few data exist from real-world settings. Here, we report outcomes from a cohort of patients with bipolar depression treated with ketamine/ esketamine in a real-world setting.Methods: Patients with treatment refractory bipolar depression were referred to Yale Psychiatric Hospital Interventional Services for treatment from October 2014 to November 2023. Appropriate patients were treated with intravenous (IV) ketamine (0.5 mg/kg over 40 minutes) or intranasal esketamine (56 or 84 mg). Diagnosis of bipolar depression was done by clinical evaluation by an attending psychiatrist, based on DSM criteria. Clinical outcomes were tabulated from medical records.Results: Overall, 45 patients with bipolar depression were treated with IV ketamine or intranasal (IN) esketamine during the time period specified. Depression severity outcomes were available for 38 patients that completed an acute series, defined as treatment twice weekly for up to 4 weeks. Overall, 15/38 (39%) achieved clinical response (≥50% improvement on the Montgomery-Asberg Depression Rating Scale [MADRS]) and 5/38 (13.2%) achieved remission (≤10 on MADRS) following the acute series. Mean MADRS scores decreased from 31.1 to 19.2 (38.3% mean improvement). Safety data (hypomania/manic symptoms) were available for all 45 patients (518 patient-months of follow-up). No patients experienced any mania/hypomania during the acute series phase (when treatments are given twice weekly). However, 13/45 (28.9%) patients experienced symptoms consistent with a hypomanic or manic episode at some point following the acute phase while continuing to receive ketamine or esketamine during a maintenance phase. There were 16 manic/hypomanic events, indicating 1 event for every 2.7 patient-years. Only 1 event was severe and resulted in hospitalization.Conclusion: In a small sample of patients with bipolar depression treated with ketamine/esketamine, no evidence of mania/hypomania was seen during the acute phase of treatment. Further research is needed to evaluate whether ketamine or esketamine confers heightened risk of affective switch during maintenance treatment.

Ketamine vs Electroconvulsive Therapy for Treatment-Resistant Depression: A Secondary Analysis of a Randomized Clinical Trial.

Importance: The ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous ketamine vs ECT for nonpsychotic TRD. Clinical features that can guide selection of ketamine vs ECT may inform shared decision-making for patients with TRD. Objective: To evaluate whether selected clinical features were associated with differential improvement with ketamine vs ECT. Design, Setting, and Participants: This secondary analysis of an open-label noninferiority randomized clinical trial was a multicenter study conducted at 5 US academic medical centers from April 7, 2017, to November 11, 2022. Analyses for this study, which were not prespecified in the trial protocol, were conducted from May 10 to Oct 31, 2023. The study cohort included patients with TRD, aged 21 to 75 years, who were in a current nonpsychotic depressive episode of at least moderate severity and were referred for ECT by their clinicians. Exposures: Eligible participants were randomized 1:1 to receive either 6 infusions of ketamine or 9 treatments with ECT over 3 weeks. Main Outcomes and Measures: Association between baseline factors (including 16-item Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR16], Montgomery-Asberg Depression Rating Scale [MADRS], premorbid intelligence, cognitive function, history of attempted suicide, and inpatient vs outpatient status) and treatment response were assessed with repeated measures mixed-effects model analyses. Results: Among the 365 participants included in this study (mean [SD] age, 46.0 [14.5] years; 191 [52.3%] female), 195 were randomized to the ketamine group and 170 to the ECT group. In repeated measures mixed-effects models using depression levels over 3 weeks and after false discovery rate adjustment, participants with a baseline QIDS-SR16 score of 20 or less (-7.7 vs -5.6 points) and those starting treatment as outpatients (-8.4 vs -6.2 points) reported greater reduction in the QIDS-SR16 with ketamine vs ECT. Conversely, those with a baseline QIDS-SR16 score of more than 20 (ie, very severe depression) and starting treatment as inpatients reported greater reduction in the QIDS-SR16 earlier in course of treatment (-8.4 vs -6.7 points) with ECT, but scores were similar in both groups at the end-of-treatment visit (-9.0 vs -9.9 points). In the ECT group only, participants with higher scores on measures of premorbid intelligence (-14.0 vs -11.2 points) and with a comorbid posttraumatic stress disorder diagnosis (-16.6 vs -12.0 points) reported greater reduction in the MADRS score. Those with impaired memory recall had greater reduction in MADRS during the second week of treatment (-13.4 vs -9.6 points), but the levels of MADRS were similar to those with unimpaired recall at the end-of-treatment visit (-14.3 vs -12.2 points). Other results were not significant after false discovery rate adjustment. Conclusions and Relevance: In this secondary analysis of the ELEKT-D randomized clinical trial of ECT vs ketamine, greater improvement in depression was observed with intravenous ketamine among outpatients with nonpsychotic TRD who had moderately severe or severe depression, suggesting that these patients may consider ketamine over ECT for TRD.

Cognitive behavioral therapy following esketamine for major depression and suicidal ideation for relapse prevention: The CBT-ENDURE randomized clinical trial study protocol.

In 2020, esketamine received a supplemental indication as a therapy for major depression with suicidal ideation (MDSI), based on protocols enrolling hospitalized patients. Given the high risk of suicide following hospital discharge and the high relapse rates following discontinuation of esketamine, the optimal long-term treatment approach remains unclear. Cognitive behavioral therapy (CBT) is highly effective in relapse prevention and has been shown to prevent suicide attempts in high-risk populations. Here we describe the study protocol for the CBT-ENDURE trial: Cognitive Behavioral Therapy Following Esketamine for Major Depression and SUicidal Ideation for RElapse Prevention. Patients with depression (N = 100) who are admitted to hospital or are outpatients with clinically significant suicidal ideation will be enrolled in the study. All patients will receive esketamine (twice weekly for four weeks) and will be randomly assigned (1:1 ratio) to receive a 16-week course of CBT plus treatment as usual (CBT group) or treatment as usual only (TAU only group). Patients are followed for a total of 6 months. Supported under a funding announcement from NIMH to conduct safety and feasibility trials for patients at high risk for suicide, the primary outcome of the CBT-ENDURE study is feasibility (as measured by recruitment and retention), with a key secondary outcome being relapse among those who experience substantial benefit following two weeks of esketamine.

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.

Long-term safety of ketamine and esketamine in treatment of depression.

INTRODUCTION: Ketamine can produce rapid-acting antidepressant effects. Esketamine (Spravato), the S-enantiomer of racemic ketamine, was approved by the FDA for treatment-resistant depression in 2019. Here we review what is known about the long-term safety of both racemic ketamine and esketamine as therapies for psychiatric disorders. AREAS COVERED: In this article, we conducted a safety review of ketamine and esketamine. In looking at ketamine and esketamine long-term safety effects, we considered data available from experimental studies and several phase-three clinical trials. EXPERT OPINION: Based on available data, the most common side effects of ketamine/esketamine are generally transient, mild, and self-limited. These include dissociation, nausea, headache, elevated heart rate, and blood pressure. Treatment with esketamine may lead to an increased risk of lower urinary tract symptoms, such as dysuria or urgency. However, severe bladder pathology has not been reported among patients receiving doses of esketamine/ketamine in line with prescribing guidelines for depression. There is considerable data that ketamine at high doses can lead to long-term impairments in cognition. However, the esketamine clinical trials found that cognition generally remains stable or improves over time, suggesting that when used appropriately, there is no increased risk of cognitive impairment.

Evaluating the Role of Ketamine/Esketamine in the Management of Major Depressive Disorder with Suicide Risk.

Nearly 5% of individuals in the USA had serious thoughts of suicide in 2019 and over 30% of individuals suffering with major depressive disorder reported suicidal ideation with 2 million of those reporting suicidal ideation with some level of intent. However, options to treat depressed individuals considered at imminent risk of suicide remain limited. Until the recent approval of esketamine in the treatment of patients with major depressive disorder with serious suicidal thoughts or actions, no medications had been specifically evaluated for use in this population in the acute setting. This review discusses the history and the current understanding of the role of ketamine and esketamine in depression and suicidal ideation and behavior. It covers some of the pivotal studies in this field and provides a summary of their major findings. The trials of esketamine in patients with major depressive disorder with active suicidal ideation or behavior are the first large-scale trials in patients considered at imminent risk of suicide. As such, the design of these studies is by definition novel, a fact that complicates the interpretation of the data and assessment of the true clinical meaningfulness of the findings. Despite this, the findings in toto draw a consistent picture of benefits that appears to outweigh the potential risks of the treatment. The studies also serve to highlight the complexities and limitations associated with clinical trials aiming to test the ability of novel therapeutics to reduce the burden and risks in patients with suicide ideation and behavior.

The Intricate Interaction Between Expectations and Therapeutic Outcomes of Psychedelic Agents.

This Viewpoint explores how expectations influence outcomes of psychedelic drug therapy.

Anxiety symptoms in survivors of critical illness: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the epidemiology of and postintensive care unit (ICU) interventions for anxiety symptoms after critical illness. METHODS: We searched five databases (1970-2015) to identify studies assessing anxiety symptoms in adult ICU survivors. Data from studies using the most common assessment instrument were meta-analyzed. RESULTS: We identified 27 studies (2880 patients) among 27,334 citations. The Hospital Anxiety and Depression Scale-Anxiety (HADS-A) subscale was the most common instrument (81% of studies). We pooled data at 2-3, 6 and 12-14month time-points, with anxiety symptom prevalences [HADS-A≥8, 95% confidence interval (CI)] of 32%(27-38%), 40%(33-46%) and 34%(25-42%), respectively. In a subset of studies with repeated assessments in the exact same patients, there was no significant change in anxiety score or prevalence over time. Age, gender, severity of illness, diagnosis and length of stay were not associated with anxiety symptoms. Psychiatric symptoms during admission and memories of in-ICU delusional experiences were potential risk factors. Physical rehabilitation and ICU diaries had potential benefit. CONCLUSIONS: One third of ICU survivors experience anxiety symptoms that are persistent during their first year of recovery. Psychiatric symptoms during admission and memories of in-ICU delusional experiences were associated with post-ICU anxiety. Physical rehabilitation and ICU diaries merit further investigation as possible interventions.

Seroprevalence of Hepatitis A among Students Enrolled in Tehran University of Medical Sciences during 2011.

BACKGROUND: Hepatitis A is often asymptomatic in children, however it can become a serious disease in adults. For countries that do not have a universal vaccination strategy targeted vaccination for high risk groups is recommended. Health workers could be at a higher risk of infection with hepatitis A virus (HAV) compared to the general population. The aim of this study is to investigate the seroprevalence of hepatitis A among enrolled students in Tehran University of Medical Sciences in 2011. METHODS: This study included all students enrolled in Tehran University of Medical Sciences during 2011. We checked serum samples for anti-HAV antibody and participants completed a simple questionnaire. RESULTS: SFrom 1864 health sciences students enrolled in Tehran University of Medical Sciences, 1813 samples were analyzed for anti-HAV IgG antibody. The results showed that 970 (53.5%) were seronegative, 722 (39.8%) were seropositive, and 121 (6.7%) were equivocal. There were significantly higher seropositive results for males (54%) compared to females (37%; RR = 1.46; 95% CI: 1.31-1.62). CONCLUSION: The seroprevalence of HAV among enrolled medical science students is considerably lower than previous reports from Iran. Targeted vaccination for health sciences students prior to exposure should be seriously considered.