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Lithium continuation therapy following ketamine in patients with treatment resistant unipolar depression: a randomized controlled trial.

ABSTRACT: The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is associated with rapid but transient antidepressant effects in patients with treatment resistant unipolar depression (TRD). Based on work suggesting that ketamine and lithium may share overlapping mechanisms of action, we tested lithium compared to placebo as a continuation strategy following ketamine in subjects with TRD. Participants who met all eligibility criteria and showed at least an initial partial response to a single intravenous infusion of ketamine 0.5?mg/kg were randomized under double-blind conditions to lithium or matching placebo before receiving an additional three infusions of ketamine. Subsequent to the ketamine treatments, participants remained on lithium or placebo during a double-blind continuation phase. The primary study outcome was depression severity as measured by the Montgomery-Åsberg Depression Rating Scale compared between the two groups at Study Day 28, which occurred ~2 weeks following the final ketamine of four infusions. Forty-seven participants with TRD were enrolled in the study and underwent an initial ketamine infusion, of whom 34 participants were deemed to have at least a partial antidepressant response and were eligible for randomization. Comparison between treatment with daily oral lithium (n?=?18) or matching placebo (n?=?16) at the primary outcome showed no difference in depression severity between groups (t₃₂?=?0.11, p?=?0.91, 95% CI [-7.87, 8.76]). There was no difference between lithium and placebo in continuing the acute antidepressant response to ketamine. The identification of a safe and effective strategy for preventing depression relapse following an acute course of ketamine treatment remains an important goal for future studies.

SUBMITTER: Costi S

PROVIDER: S-EPMC6784998 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Project description:ImportanceThe 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.ObjectiveTo evaluate whether selected clinical features were associated with differential improvement with ketamine vs ECT.Design, setting, and participantsThis 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.ExposuresEligible participants were randomized 1:1 to receive either 6 infusions of ketamine or 9 treatments with ECT over 3 weeks.Main outcomes and measuresAssociation 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.ResultsAmong 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 relevanceIn 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.

Project description:BACKGROUND:Multiple lines of evidence support a role for the glutamatergic system in the pathophysiology of major depressive disorder (MDD). Ketamine, an N-methyl-D-aspartate antagonist, rapidly improves depressive symptoms in individuals with treatment-resistant depression. The neural mechanisms underlying this effect remain unknown. METHODS:In this preliminary study, 20 unmedicated participants with treatment-resistant MDD underwent positron emission tomography to measure regional cerebral glucose metabolism at baseline and following ketamine infusion (single dose of .5mg/kg intravenous over 40minutes). Metabolic data were compared between conditions using a combination of region-of-interest and voxelwise analyses, and differences were correlated with the associated antidepressant response. RESULTS:Whole-brain metabolism did not change significantly following ketamine. Regional metabolism decreased significantly under ketamine in the habenula, insula, and ventrolateral and dorsolateral prefrontal cortices of the right hemisphere. Metabolism increased postketamine in bilateral occipital, right sensorimotor, left parahippocampal, and left inferior parietal cortices. Improvement in depression ratings correlated directly with change in metabolism in right superior and middle temporal gyri. Conversely, clinical improvement correlated inversely with metabolic changes in right parahippocampal gyrus and temporoparietal cortex. CONCLUSIONS:Although preliminary, these results indicate that treatment-resistant MDD subjects showed decreased metabolism in the right habenula and the extended medial and orbital prefrontal networks in association with rapid antidepressant response to ketamine. Conversely, metabolism increased in sensory association cortices, conceivably related to the illusory phenomena sometimes experienced with ketamine. Further studies are needed to elucidate how these functional anatomical changes relate to the molecular mechanisms underlying ketamine's rapid antidepressant effects.

Project description:Chronic pain is a disabling illness, often comorbid with depression. We performed a randomized controlled pilot study on mindfulness-based cognitive therapy (MBCT) targeting depression in a chronic pain population. Participants with chronic pain lasting ≥ 3 months; DSM-IV major depressive disorder (MDD), dysthymic disorder, or depressive disorder not otherwise specified; and a 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C₁₆) score ≥ 6 were randomly assigned to MBCT (n = 26) or waitlist (n = 14). We adapted the original MBCT intervention for depression relapse prevention by modifying the psychoeducation and cognitive-behavioral therapy elements to an actively depressed chronic pain population. We analyzed an intent-to-treat (ITT) and a per-protocol sample; the per-protocol sample included participants in the MBCT group who completed at least 4 of 8 sessions. Changes in scores on the QIDS-C₁₆ and 17-item Hamilton Depression Rating Sale (HDRS₁₇) were the primary outcome measures. Pain, quality of life, and anxiety were secondary outcome measures. Data collection took place between January 2012 and July 2013. Nineteen participants (73%) completed the MBCT program. No significant adverse events were reported in either treatment group. ITT analysis (n = 40) revealed no significant differences. Repeated-measures analyses of variance for the per-protocol sample (n = 33) revealed a significant treatment × time interaction (F₁,₃₁ = 4.67, P = .039, η²p = 0.13) for QIDS-C₁₆ score, driven by a significant decrease in the MBCT group (t₁₈ = 5.15, P < .001, d = >1.6), but not in the control group (t₁₃ = 2.01, P = .066). The HDRS₁₇ scores did not differ significantly between groups. The study ended before the projected sample size was obtained, which might have prevented effect detection in some outcome measures. MBCT shows potential as a treatment for depression in individuals with chronic pain, but larger controlled trials are needed. ClinicalTrials.gov identifier: NCT01473615.

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Lithium continuation therapy following ketamine in patients with treatment resistant unipolar depression: a randomized controlled trial.

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