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Sustained Improvement of Negative Self-Schema After a Single Ketamine Infusion: An Open-Label Study.

ABSTRACT: Conventional antidepressants have several important limitations, including a lack of direct effects on negative self-schema, which is at the core of Beck's cognitive theory of depression. Based on previous studies showing a positive effect of ketamine on negative cognition, we compared reductions in negative self-schema between responders and non-responders to a single infusion of ketamine. In an open-label study, 26 participants with treatment-resistant depression received 0.5 mg/kg ketamine via infusion. Depression symptoms were assessed at baseline, 24 h, and 7 days after treatment with Montgomery-Åsberg Depression Rating Scale (MADRS) and Beck Depression Inventory (BDI-II). Nine of the 26 participants fulfilled response criteria after 24 h. Of these, eight still fulfilled response criteria after 7 days. Response was defined as a reduction in MADRS total score of 50% or more. Responders improved significantly more than non-responders both 24 h and 7 days after ketamine treatment on the following BDI-II items: item 1 ("Sadness"), item 7 ("Self-Dislike"), and item 8 ("Self-Criticalness"). These results suggest an important therapeutic effect of ketamine on negative self-schema, which is a fundamental cognitive aspect of depression. This effect is unique and might be associated with ketamine's profound effects on neuroplasticity. Small sample size and lack of a placebo control group are the major limitations of this study.

SUBMITTER: Hasler G

PROVIDER: S-EPMC7341975 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Sustained Improvement of Negative Self-Schema After a Single Ketamine Infusion: An Open-Label Study.

Hasler Gregor G Suker Samir S Schoretsanitis Georgios G Mihov Yoan Y

Frontiers in neuroscience 20200701

Conventional antidepressants have several important limitations, including a lack of direct effects on negative self-schema, which is at the core of Beck's cognitive theory of depression. Based on previous studies showing a positive effect of ketamine on negative cognition, we compared reductions in negative self-schema between responders and non-responders to a single infusion of ketamine. In an open-label study, 26 participants with treatment-resistant depression received 0.5 mg/kg ketamine vi ...[more]

PMID: 32714138

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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: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:NMDA receptor antagonists have a vital role in extinction, learning, and reconsolidation processes. During the reconsolidation window, memories are activated into a labile state and can be reconsolidated in an altered form. This concept might have significant clinical implications in treating PTSD. In this pilot study we tested the potential of a single infusion of ketamine, followed by brief exposure therapy, to enhance post-retrieval extinction of PTSD trauma memories. 27 individuals diagnosed with PTSD were randomly assigned to receive either ketamine (0.5 mg/kg 40 min; N = 14) or midazolam (0.045 mg/kg; N = 13) after retrieval of the traumatic memory. 24 h following infusion, participants received a four-day trauma-focused psychotherapy. Symptoms and brain activity were assessed before treatment, at the end of treatment, and at 30-day follow-up. Amygdala activation to trauma scripts (a major biomarker of fear response) served as the main study outcome. Although PTSD symptoms improved equally in both groups, post-treatment, ketamine recipients showed a lower amygdala (-0.33, sd = 0.13, 95%HDI [-0.56,-0.04]) and hippocampus (-0.3 (sd = 0.19), 95%HDI [-0.65, 0.04]; marginal effect) reactivation to trauma memories, compared to midazolam recipients. Post-retrieval ketamine administration was also associated with decreased connectivity between the amygdala and hippocampus (-0.28, sd = 0.11, 95%HDI [-0.46, -0.11]), with no change in amygdala-vmPFC connectivity. Moreover, reduction in fractional anisotropy in bi-lateral uncinate fasciculus was seen in the Ketamine recipients compared with the midazolam recipients (right: post-treatment: -0.01108, 95% HDI [-0.0184,-0.003]; follow-up: -0.0183, 95% HDI [-0.02719,-0.0107]; left: post-treatment: -0.019, 95% HDI [-0.028,-0.011]; follow-up: -0.017, 95% HDI [-0.026,-0.007]). Taken together it is possible that ketamine may enhance post-retrieval extinction of the original trauma memories in humans. These preliminary findings show promising direction toward the capacity to rewrite human traumatic memories and modulate the fear response for at least 30 days post-extinction. When combined with psychotherapy for PTSD, further investigation of ketamine dose, timing of administration, and frequency of administration, is warranted.

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Sustained Improvement of Negative Self-Schema After a Single Ketamine Infusion: An Open-Label Study.

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Sustained Improvement of Negative Self-Schema After a Single Ketamine Infusion: An Open-Label Study.

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