Low-dose ketamine does not improve the speed of recovery from depression in electroconvulsive therapy: a randomized controlled trial

Objective: Electroconvulsive therapy (ECT) is a well-established therapeutic intervention for major depressive disorder. Recent literature has shown that the anesthetic agent ketamine has some antidepressant properties at low doses and may be an alternative therapy for treatment-resistant major depressive disorder. We hypothesized that the use of low-dose ketamine as an anesthetic adjunct in ECT would more rapidly improve depression while maintaining hemodynamic stability than ECT with propofol alone. Methods: Institutional ethics approval was obtained, and the use of ketamine in this study was approved by Health Canada. This is a randomized, double-blinded, placebo-controlled trial that involved ketamine administration at 0.5 mg/kg IV in addition to propofol anesthesia for ECT. The primary outcome was the number of ECT treatments required to achieve a 50% reduction in the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included the number of ECT treatments required to achieve a 25% reduction in MADRS score, as well as any differences in the Clinical Global Impression Scale for Severity, hemodynamic variables, and seizure duration. Adverse events were recorded for safety assessment. Results: A total of 45 patients completed the study. No difference was found between groups with respect to the primary or secondary outcomes. The ketamine group showed a trend towards a decreased dose of propofol required to achieve adequate anesthesia. No adverse events were reported. Conclusion: Low-dose ketamine does not improve psychiatric outcomes in the setting of propofol-based anesthesia for ECT. Specifically, ketamine did not reduce the number of ECT sessions necessary to achieve a 50 or 25% reduction in MADRS scores. Reassuringly, the fact that no differences in hemodynamic variables or unexpected adverse events occurred suggests that low-dose ketamine may be safely used in this setting should clinical indications warrant its use. Clinical trial registration: ClinicalTrials.gov, NCT02579642

Low-dose ketamine does not improve the speed of recovery from depression in electroconvulsive therapy: a randomized controlled trial.

OBJECTIVE: Electroconvulsive therapy (ECT) is a well-established therapeutic intervention for major depressive disorder. Recent literature has shown that the anesthetic agent ketamine has some antidepressant properties at low doses and may be an alternative therapy for treatment-resistant major depressive disorder. We hypothesized that the use of low-dose ketamine as an anesthetic adjunct in ECT would more rapidly improve depression while maintaining hemodynamic stability than ECT with propofol alone. METHODS: Institutional ethics approval was obtained, and the use of ketamine in this study was approved by Health Canada. This is a randomized, double-blinded, placebo-controlled trial that involved ketamine administration at 0.5 mg/kg IV in addition to propofol anesthesia for ECT. The primary outcome was the number of ECT treatments required to achieve a 50% reduction in the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included the number of ECT treatments required to achieve a 25% reduction in MADRS score, as well as any differences in the Clinical Global Impression Scale for Severity, hemodynamic variables, and seizure duration. Adverse events were recorded for safety assessment. RESULTS: A total of 45 patients completed the study. No difference was found between groups with respect to the primary or secondary outcomes. The ketamine group showed a trend towards a decreased dose of propofol required to achieve adequate anesthesia. No adverse events were reported. CONCLUSION: Low-dose ketamine does not improve psychiatric outcomes in the setting of propofol-based anesthesia for ECT. Specifically, ketamine did not reduce the number of ECT sessions necessary to achieve a 50 or 25% reduction in MADRS scores. Reassuringly, the fact that no differences in hemodynamic variables or unexpected adverse events occurred suggests that low-dose ketamine may be safely used in this setting should clinical indications warrant its use. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02579642.

Retrospective Observational Study of Daytime Add-On Administration of Zopiclone to Difficult-to-Treat Psychiatric Inpatients With Unpredictable Aggressive Behavior, With or Without EEG Dysrhythmia.

Managing violent behavior is a particularly challenging aspect of hospital psychiatric care. Available pharmacological interventions are often unsatisfactory. Aim: To assess the effectiveness and safety of daytime zopiclone add-on administration in violent and difficult-to-treat psychiatric inpatients. Methods: Chart review of inpatients treated with daytime zopiclone, between 2014 and 2018, with up to 12 weeks follow-up. Effectiveness was retrospectively assessed with the Clinical Global Impression rating scale (CGI) and the frequency and severity of aggressive incidents recorded with the Staff Observation Aggression Scale-Revised (SOAS-R). Results: Forty-five (30 male, 15 female) cases, 18-69 years age range, average (SD) baseline CGI-S score of 5.4 (1.0), and a variety of diagnoses. Sixty-nine percent showed CGI-S improvement of any degree. For patients with at least one aggressive incident within 7 days prior to initiation of zopiclone (N = 22), average (SD) SOAS-R-Severity LOCF to baseline change was -3.5 (2.7) P < 0.0001. Most patients reported no side effects; 24% reported one or more side effects, and 11% discontinued zopiclone due to sedation (4), insomnia (1) or slurred speech (1). No SAEs were recorded. Zopiclone maximum daily dose correlated with CGI-S baseline-to-LOCF change (rho = -0.5, P = 0.0003). The ROC AUC of zopiclone maximum daily dose and improvement on CGI-S was 0.84 (95% CI 0.70-0.93, P < 0.0001). The ROC AUC of zopiclone maximum daily dose and SOAS-R-N improvement was 0.80 (95% CI 0.58-0.92; P = 0.0008) and maximum Youden's index value was achieved at a dose of >30 mg. Conclusions: Zopiclone doses >30 mg daily achieved the best anti-aggressive effect.

Economic factors and suicide rates: associations over time in four countries.

OBJECTIVE: Suicides account for more than 30,000 deaths per year in the US alone. Suicide rates change over time, and the factors influencing them remain poorly understood. Economic factors, in particular unemployment, have been suggested as a major influence. However, the evidence for this has been inconsistent, which may be partly explained by shortcomings of the statistical methods used. METHODS: Time series analytical techniques (unit root and co-integration tests) were applied to test the associations over time between economic factors, i.e. unemployment, real gross domestic product per capita (RGDP) and the consumer price index (CPI) and death rates by suicide as collected by national agencies in the UK (1901-2006), US (1900-1997), France (1970-2004) and Italy (1970-2001). Traditional correlation analyses were used when appropriate. RESULTS: Co-integration and correlation tests showed a long-run association between economic factors and suicide rates. Increase/decrease of unemployment predicted an increase/decrease of suicide rates over long historical periods and in different nations. RGDP and the CPI were also linked with suicide rates, but this was not consistently so and the direction of the association varied. CONCLUSIONS: Unemployment is a major factor influencing suicide rates over long periods of time and in different national contexts. It needs to be considered as a confounding factor in evaluations of suicide prevention strategies.

Schneider's first rank symptoms and continuous performance disturbance as indices of dysconnectivity of left- and right-hemispheric components of language in schizophrenia.

BACKGROUND: Here we investigate pathophysiological dimensions (language disturbance, negative symptoms, lateralisation and the continuous performance test) in relation to ICD-10 and DSM-IV concepts of diagnosis. METHODS: A total of 32 consecutive psychotic patients with at least one Schneider's first rank symptom (SFRS), 15 depressed patients without SFRS and 17 normal volunteers were assessed with the Clinical Language Disorder Rating Scale (CLANG), SFRS, "pure defect" Huber's basic symptoms (HBS), handedness (Annett's pegboard task), and the A-X Continuous Performance Test (AX-CPT). RESULTS: CLANG total score (an index of severity of language disorder) was correlated with the severity of SFRS, a higher leftward shift of handedness, and poorer performance on AX-CPT. Receiver operating characteristic (ROC) analysis showed that only CLANG and AX-CPT variables had adequate predictive validity in separating cases of ICD-10 schizophrenia from other diagnoses. The logistic regression model predicting the presence of ICD-10 schizophrenia was statistically significant using CLANG and AX-CPT variables, but not SFRS or other variables. HBS did not correlate with other variables and did not predict ICD-10 diagnosis. CONCLUSIONS: A cross-sectional diagnosis based on language disturbance and CPT performance yields a diagnostic construct largely overlapping with the ICD-10 definition of schizophrenia. We suggest that Schneider's first rank symptoms (that play a large role in the DSM-IV concept) can be considered an index of left hemisphere dysconnectivity for language whereas CPT dysfunction reflects dysconnectivity of the right hemisphere for those remoter ("spatial") associations that are closer to Bleuler's core defect and to the chronicity implicit in the ICD definition. Thus the dimensions of language disturbance in psychosis can be traced to specific cortico-cortical dysconnectivities.

Disintegration of the components of language as the path to a revision of Bleuler's and Schneider's concepts of schizophrenia. Linguistic disturbances compared with first-rank symptoms in acute psychosis.

BACKGROUND: The 20th century ended without a resolution of the debate about the supremacy of Schneider's psychopathological conceptualisation of schizophrenia (the first-rank symptoms) over Bleuler's 'four As' (disorders of association and affect, ambivalence and autism). AIMS: To examine the relationships between linguistic deviations and symptoms in patients with acute psychosis. METHOD: We assessed language disturbances and first-rank symptoms with the Clinical Language Disorder Rating Scale (CLANG) in 30 consecutive patients with acute psychosis, selected for the presence of at least one active first-rank symptom, and 15 control participants with depression but no psychotic symptoms. RESULTS: Strong positive correlations were found between the CLANG factor 'poverty' and first-rank delusions of control and between semantic/phonemic paraphasias and verbal auditory hallucinations [corrected]. Language disturbances were superior to nuclear symptoms in discriminating ICD-10 schizophrenia from other psychoses. CONCLUSIONS: Evaluating the features of psychosis as deviations in the cerebral organisation of language paves the way to a concept of psychosis that supersedes these traditional but competing categorical concepts.