Flávia Vieira

Trends Psychiatry Psychother, vol.0, nAheadOfPrint, p.0-0, 2023

Learning objective: After participating in this activity, learners should be better able to: • Analyze the effects of ketamine and esketamine on individuals with treatment-resistant depression Introduction: Cognitive impairment is commonly present in individuals with treatment-resistant depression, especially in attention, memory, and executive functions. These deficits are related to symptom severity, remission rates, and functional impairments during and after the acute phase of the disorder. Ketamine, an N-methyl-D-aspartate antagonist previously used as an anesthetic, brings promising antidepressant results. This study systematically reviews the neurocognitive effects of ketamine and esketamine in patients with treatment-resistant major depressive disorder. Methods: Systematic searches were conducted at Embase, PubMed, and PsycINFO using the terms depression, ketamine, and cognition. Title, abstract, and full-text reading were conducted independently by two of the authors (BSM and CSL). Risk of bias, study design, neuropsychological outcomes, and neuroimaging data were recorded. Results: From a total of 997 hits, 14 articles were included. One study reported cognitive impairment after ketamine treatment for processing speed and verbal memory. Five studies reported improvements in processing speed, verbal memory, visual memory, working memory, or cognitive flexibility. The esketamine study suggested no changes to performance. Lower attention, slower processing speed, and higher working memory are reported as predictors of antidepressant response. Brain areas for emotional and reward processing, including the amygdala, insula, and orbitofrontal cortex, show a normalizing tendency after ketamine. Conclusions: Ketamine and esketamine do not seem to exert significant deleterious neurocognitive effects in the short or long term in individuals with treatment-resistant depression. Results suggest neuropsychological functions and brain areas commonly impaired in treatment-resistant depression may especially benefit from subanesthetic ketamine infusions. Key questions that remain unanswered are discussed.

Direct-acting antivirals (DAAs) have been approved in recent years to treat patients infected by the Hepatitis C virus (HCV). The DAAs treatment is well tolerated and increases sustained virological response (SVR), but there is no consensus about the neuropsychological functioning related to the treatment. This systematic review aims to provide an overview of the recent findings exploring the cognitive effects of DAAs treatment in patients with HCV. After a systematic search on PubMed, Embase, Scopus, and LILACS, studies that assessed neuropsychological data related to DAAs treatment were included. We found nine articles, considering the inclusion and exclusion criteria. Three other manuscripts were included after searching for the references listed in the previously mentioned articles. We observed methodological heterogeneity in terms of neuropsychological tests used, cognitive domain explored, and the sample characteristic presented between the studies. Studies presented data from HCV subjects monoinfected with or without cirrhosis, advanced liver disease, and post-transplant patients; and HCV subjects coinfected with Human Immunodeficiency virus (HIV). Most results from the 12 studies that explored the effect of DAAs treatment in HCV subjects’ neurocognitive functioning demonstrated cognitive improvement following treatment. In general, HCV and HCV/HIV subjects improved processing speed, verbal fluency, and verbal/visual episodic memory. The DAAs treatment is effective for neurocognitive functioning in HCV mono-infected and coinfected subjects, with or without advanced liver disease, since neuropsychological scores increased after treatment. Further studies, however, are needed to confirm these findings.

We aimed to analyze the efficacy and safety of arketamine, the R(−)-enantiomer of ketamine, for treatment-resistant depression (TRD) in humans. Open-label pilot trial, seven subjects with TRD received a single intravenous infusion of arketamine (0.5 mg/kg); primary outcome was change in Montgomery–Åsberg Depression Rating Scale (MADRS) 24 h after. Mean MADRS dropped from 30.7 before infusion to 10.4 after one day, a mean difference of 20.3 points [CI 95% 13.6–27.0; p < 0.001]; dissociation was nearly absent. Arketamine might produce fast-onset and sustained antidepressant effects in humans with favorable safety profile, like previously reported with animals; further controlled-trials are needed.

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. 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. 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. 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. This trial has been registered in the Japan Primary Registries Network (JPRN): UMIN000032355, which is affiliated with the World Health Organization.