Dataset Information

Brain-derived neurotrophic factor serum levels following ketamine and esketamine intervention for treatment-resistant depression: secondary analysis from a randomized trial.

ABSTRACT:

Objectives

Evidence suggests that ketamine's influence on brain-derived neurotrophic factor (BDNF) might be involved in its mechanism of rapid antidepressant action. We aimed to evaluate the differential impact of ketamine and esketamine on serum BDNF levels and its association with response patterns in treatment-resistant depression (TRD).

Methods

Participants (n = 53) are from a randomized, double-blind clinical trial comparing the efficacy of single-dose ketamine (0.5mg/kg, n = 27) and esketamine (0.25mg/kg, n = 26) in TRD. Depression severity was assessed before and 24 hours, 72 hours, and 7 days after the intervention, using the Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected before infusion, 24 hours, and 7 days afterwards.

Results

There were no significant changes in BDNF levels at post-infusion evaluation points, and no difference in BDNF levels comparing ketamine and esketamine. Both drugs exhibited similar therapeutic effect. There was no association between BDNF levels and response to treatment or severity of depressive symptoms.

Conclusion

There was no significant treatment impact on BDNF serum levels - neither with ketamine nor esketamine - despite therapeutic response. These results suggest that ketamine or esketamine intervention for TRD has no impact on BDNF levels measured at 24 hours and 7 days after the infusion.

SUBMITTER: Caliman-Fontes AT

PROVIDER: S-EPMC9991420 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

Brain-derived neurotrophic factor serum levels following ketamine and esketamine intervention for treatment-resistant depression: secondary analysis from a randomized trial.

Caliman-Fontes Ana Teresa AT Leal Gustavo C GC Correia-Melo Fernanda S FS Paixão Camilla S CS Carvalho Michelle S MS Jesus-Nunes Ana Paula AP Vieira Flavia F Magnavita Guilherme G Bandeira Igor D ID Mello Rodrigo P RP Beanes Graziele G Silva Samantha S SS Echegaray Mariana M Carvalho Lucas P LP Machado Paulo P Sampaio Aline S AS Cardoso Taiane de A TA Kapczinski Flávio F Lacerda Acioly L T ALT Quarantini Lucas C LC

Trends in psychiatry and psychotherapy 20230307

<h4>Objectives</h4>Evidence suggests that ketamine's influence on brain-derived neurotrophic factor (BDNF) might be involved in its mechanism of rapid antidepressant action. We aimed to evaluate the differential impact of ketamine and esketamine on serum BDNF levels and its association with response patterns in treatment-resistant depression (TRD).<h4>Methods</h4>Participants (n = 53) are from a randomized, double-blind clinical trial comparing the efficacy of single-dose ketamine (0.5mg/kg, n = ...[more]

PMID: 34904800

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Project description:INTRODUCTION:The use of ketamine as an option in the treatment of depressive disorder is growing rapidly, supported by numerous clinical trials attesting its efficacy and safety. Esketamine, the S (+) enantiomer of ketamine, is the most widely used form in the anesthetic environment in some countries, and new studies have shown that it may also be effective in depression and with better tolerability. However, no study so far has directly compared esketamine with racemic ketamine. Here we propose a protocol of a clinical trial to evaluate esketamine as a noninferior medication when compared to ketamine in the treatment of patients with treatment-resistant depression. METHODS/DESIGN:This study protocol is for a randomized, controlled, double-blind noninferiority clinical trial. Subjects will be 18 years or older, with major depression characterized as treatment-resistant. Participants will receive a single infusion of either esketamine (0.25?mg/kg) or ketamine (0.5?mg/kg) over 40 minutes. The primary outcome will be the difference in remission rates between the 2 treatment arms at 24 and 72?hours after drug infusion. Secondary outcomes will include other timepoints, measurements of cognition, dissociation, and blood biomarkers. DISCUSSION:A head-to-head study is the best way to evaluate whether the esketamine is in fact comparable to the racemic ketamine in terms of both efficacy and safety, and, if positive, it would be an initial step to increase the access to that type of treatment worldwide. ETHICS AND DISSEMINATION:The study was approved by the local Institutional Review Board (University Hospital Professor Edgard Santos-Federal University of Bahia-Number: 46657415.0.0000.0049). Subjects will only participate after voluntarily agreeing and signing the Informed Consent Form. The study findings will be published in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION:This trial has been registered in the Japan Primary Registries Network (JPRN): UMIN000032355, which is affiliated with the World Health Organization.

Project description:BackgroundCurrent theory suggests that treatment-resistant depression (TRD) involves impaired neuroplasticity resulting in cognitive and neural rigidity, and that clinical improvement may require increasing brain flexibility and adaptability.AimsIn this hypothesis-generating study, we sought to identify preliminary evidence of brain flexibility correlates of clinical change within the context of an open-label ketamine trial in adolescents with TRD, focusing on two promising candidate markers of neural flexibility: (a) entropy of resting-state functional magnetic resonance imaging (fMRI) signals; and (b) insulin-stimulated phosphorylation of mammalian target of rapamycin (mTOR) and glycogen synthase-3-beta (GSK3β) in peripheral blood mononuclear cells.MethodsWe collected resting-state functional magnetic resonance imaging data and blood samples from 13 adolescents with TRD before and after a series of six ketamine infusions over 2 weeks. Usable pre/post ketamine data were available from 11 adolescents for imaging and from 10 adolescents for molecular signaling. We examined correlations between treatment response and changes in the central and peripheral flexibility markers.ResultsDepression reduction correlated with increased nucleus accumbens entropy. Follow-up analyses suggested that physiological changes were associated with treatment response. In contrast to treatment non-responders (n=6), responders (n=5) showed greater increase in nucleus accumbens entropy after ketamine, together with greater post-treatment insulin/mTOR/GSK3β signaling.ConclusionsThese data provide preliminary evidence that changes in neural flexibility may underlie symptom relief in adolescents with TRD following ketamine. Future research with adequately powered samples is needed to confirm resting-state entropy and insulin-stimulated mTOR and GSK3β as brain flexibility markers and candidate targets for future clinical trials.Clinical trial nameKetamine in adolescents with treatment-resistant depressionURL: https://clinicaltrials.gov/ct2/show/NCT02078817Registration number: NCT02078817.

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.

Dataset Information

Brain-derived neurotrophic factor serum levels following ketamine and esketamine intervention for treatment-resistant depression: secondary analysis from a randomized trial.

Objectives

Methods

Results

Conclusion

Publications

Brain-derived neurotrophic factor serum levels following ketamine and esketamine intervention for treatment-resistant depression: secondary analysis from a randomized trial.

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