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A single infusion of ketamine improves depression scores in patients with anxious bipolar depression.

ABSTRACT: OBJECTIVE:Patents with anxious bipolar disorder have worse clinical outcomes and are harder to treat with traditional medication regimens compared to those with non-anxious bipolar disorder. Ketamine has been shown to rapidly and robustly decrease symptoms of depression in depressed patients with bipolar disorder. We sought to determine whether baseline anxiety status reduced ketamine's ability to decrease symptoms of depression. METHODS:Thirty-six patients with anxious (n = 21) and non-anxious (n = 15) treatment-resistant bipolar depression (types I and II; concurrently treated with either lithium or valproate) received a single infusion of ketamine (0.5 mg/kg) over 40 min. Post-hoc analyses compared changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HDRS) in anxious versus non-anxious depressed patients with bipolar disorder through 14 days post-infusion. Anxious bipolar depression was defined as DSM-IV bipolar depression plus a HDRS Anxiety/Somatization Factor score of ? 7. RESULTS:A linear mixed model revealed a significant effect of anxiety group on the MADRS (p = 0.04) and HDRS (p = 0.04). Significant drug effects (all p < 0.001) suggested that both anxious and non-anxious groups had an antidepressant response to ketamine. The drug-by-anxiety interactions were not significant (all p > 0.28). CONCLUSIONS:Both anxious and non-anxious patients with bipolar depression had significant antidepressant responses to ketamine, although the anxious depressed group did not show a clear antidepressant response disadvantage over the non-anxious group. Given that anxiety has been shown to be a predictor of poor treatment response in bipolar depression when traditional treatments are used, our findings suggest a need for further investigations into ketamine's novel role in the treatment of anxious bipolar depression.

SUBMITTER: Ionescu DF

PROVIDER: S-EPMC4431955 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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A single infusion of ketamine improves depression scores in patients with anxious bipolar depression.

Ionescu Dawn F DF Luckenbaugh David A DA Niciu Mark J MJ Richards Erica M EM Zarate Carlos A CA

Bipolar disorders 20141114 4

<h4>Objective</h4>Patents with anxious bipolar disorder have worse clinical outcomes and are harder to treat with traditional medication regimens compared to those with non-anxious bipolar disorder. Ketamine has been shown to rapidly and robustly decrease symptoms of depression in depressed patients with bipolar disorder. We sought to determine whether baseline anxiety status reduced ketamine's ability to decrease symptoms of depression.<h4>Methods</h4>Thirty-six patients with anxious (n = 21) a ...[more]

PMID: 25400146

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Project description:BACKGROUND:Ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists (NMDAR antagonists) recently demonstrated antidepressant efficacy for the treatment of refractory depression, but effect sizes, trajectories and possible class effects are unclear. METHOD:We searched PubMed/PsycINFO/Web of Science/clinicaltrials.gov until 25 August 2015. Parallel-group or cross-over randomized controlled trials (RCTs) comparing single intravenous infusion of ketamine or a non-ketamine NMDAR antagonist v. placebo/pseudo-placebo in patients with major depressive disorder (MDD) and/or bipolar depression (BD) were included in the analyses. Hedges' g and risk ratios and their 95% confidence intervals (CIs) were calculated using a random-effects model. The primary outcome was depressive symptom change. Secondary outcomes included response, remission, all-cause discontinuation and adverse effects. RESULTS:A total of 14 RCTs (nine ketamine studies: n = 234; five non-ketamine NMDAR antagonist studies: n = 354; MDD = 554, BD = 34), lasting 10.0 ± 8.8 days, were meta-analysed. Ketamine reduced depression significantly more than placebo/pseudo-placebo beginning at 40 min, peaking at day 1 (Hedges' g = -1.00, 95% CI -1.28 to -0.73, p < 0.001), and loosing superiority by days 10-12. Non-ketamine NMDAR antagonists were superior to placebo only on days 5-8 (Hedges' g = -0.37, 95% CI -0.66 to -0.09, p = 0.01). Compared with placebo/pseudo-placebo, ketamine led to significantly greater response (40 min to day 7) and remission (80 min to days 3-5). Non-ketamine NMDAR antagonists achieved greater response at day 2 and days 3-5. All-cause discontinuation was similar between ketamine (p = 0.34) or non-ketamine NMDAR antagonists (p = 0.94) and placebo. Although some adverse effects were more common with ketamine/NMDAR antagonists than placebo, these were transient and clinically insignificant. CONCLUSIONS:A single infusion of ketamine, but less so of non-ketamine NMDAR antagonists, has ultra-rapid efficacy for MDD and BD, lasting for up to 1 week. Development of easy-to-administer, repeatedly given NMDAR antagonists without risk of brain toxicity is of critical importance.

Project description:INTRODUCTION:While the psychiatric benefits of ketamine have been verified through clinical trials, there is limited information about ketamine augmentation in patients with treatment-resistant bipolar depression (TRBPD). Hence, in the present study, we investigate the therapeutic efficacy and functional brain alterations associated with multi-infusion ketamine augmentation in patients with TRBPD. METHODS:The present three-week study included 38 patients with TRBPD, all of whom received a series of nine ketamine injections over the study period. The Hamilton Depression Rating Scale (HAMD) was used to assess the effects of multi-infusion ketamine combined with mood stabilizers. Brain function was evaluated by global functional connectivity density (gFCD). RESULTS:Adjunctive treatment with multiple infusions of ketamine, when combined with a mood stabilizer, could effectively alleviate depressive symptoms for one week, yet the symptoms began to relapse during the second week. Functional brain alterations were detected via gFCD. Specifically, gFCD reductions were mainly found in the bilateral insula, right caudate nucleus, and bilateral inferior frontal gyrus, while increased gFCD was mainly located in the bilateral postcentral gyrus, subgenual anterior cingulate cortex, bilateral thalamus, and cerebellum. Although gFCD alterations were sustained for up to three weeks after the first ketamine infusion, the antidepressant effects of ketamine augmentation sharply declined from the end of the second week of treatment. CONCLUSIONS:Multi-infusion ketamine augmentation can rapidly alleviate depressive symptoms in patients with TRBPD. The clinical effects were primarily visible in the first week after treatment and partially sustained for two weeks; however, the therapeutic effects and related functional brain alterations sharply decreased from the end of the second week. Based on these findings, we demonstrated that the clinical efficacy and functional brain alterations induced by ketamine augmentation are transient.

Project description:BackgroundDue to unmet clinical needs for efficient drugs with a rapid onset of antidepressant effects, we aimed to evaluate the efficacy of single-dose ketamine in different subgroups of patients with major depression and establish whether repeated ketamine administration could be a viable strategy to maintain treatment gains.MethodsElectronic databases (Medline via PubMed, Embase, Cochrane Library, Trip Database) were systematically searched until February 22, 2019, for published peer-reviewed randomized controlled trials (RCTs) concerning a single and repeated administration of ketamine in patients with major depression. All relevant RCTs were selected and critically appraised, and a meta-analysis of eligible studies was performed.ResultsA total of 20 studies were included in the meta-analysis. The largest effect of ketamine vs. controls in reducing depressive symptoms was observed at 24 h (SMD = - 0.89; 95% CI - 1.24; - 0.53; p < 0.00001); however, a significant difference was shown for up to 7 days after a single dose. Significant differences compared with controls were observed for up to 7 days in treatment-resistant patients and when ketamine was added to ongoing antidepressant treatment, while there were no significant differences at 7 days when ketamine was used as monotherapy. In patients with major depression, initial antidepressant effects of ketamine were maintained during repeated dosing. At 2-3 weeks of repeated ketamine treatment, significant reduction of depression severity scores was observed: SMD = - 0.70; 95% CI - 1.15; - 0.25 or SMD = - 0.81; 95% CI - 1.41; - 0.20 (depending on the dosing regimen used); p ≤ 0.009 vs placebo.ConclusionsOur meta-analysis revealed rapid and robust antidepressant effects of single-dose ketamine in patients with treatment-resistant depression (TRD). By pooling data from RCTs, we showed for the first time that repeated ketamine administration is effective in sustaining initial antidepressant effects observed after single dosing.

Project description:Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe. ClinicalTrials.gov : Treatment Resistant Depression (Pilot), NCT01179009.

Project description:This study evaluated efficacy and safety of intravenous subanesthetic doses of esketamine using an administration time of 10 minutes in patients with treatment-resistant depression and bipolar depression.A retrospective chart review was conducted to identify patients who met the inclusion criteria for treatment-resistant depression and bipolar depression according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria, and these patients received rapid infusion of esketamine between June 2012 and December 2015. The Montgomery-Åsberg Depression Rating Scale (MADRS) was administered to measure and score depressive symptom severity before infusion and at 24 hours, 72 hours, and 7 days after infusion. In addition, Clinical Global Impression scale was administered before and 7 days after esketamine infusion.Esketamine was administered to 30 patients. A total of 27 patients met the inclusion criteria and had MADRS evaluation data, which showed that 23 had unipolar and 4 had bipolar depression. Thirteen patients (48.1%) showed therapeutic response (MADRS reduction ≥50%) within 1 week (7 days) of intervention. Remission (MADRS <7) was observed in 10 patients (37.0%) in the same period. Therapeutic response and remission frequencies were seen in 16 (59.3%) and 11 (40.7%) patients, respectively, within 24 hours following drug infusion. The most relevant side effect observed during the esketamine infusion was dissociative symptoms ranging from mild to severe, which was reported by 11.1% of patients as a very disturbing experience.This study was done retrospectively, had a small sample size, and there was no comparative group.The present study demonstrates that rapid infusion of esketamine is possibly not the optimal choice to administer this drug for treatment-resistant depression due to tolerability reasons. Further controlled studies are required to investigate efficacy, safety, and tolerability profiles among the different types of ketamines and methods of using this drug in depressed patients.

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A single infusion of ketamine improves depression scores in patients with anxious bipolar depression.

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A single infusion of ketamine improves depression scores in patients with anxious bipolar depression.

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