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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.

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Chronic Hepatitis C is a disease related to the Hepatitis C virus (HCV), associated with adverse extrahepatic manifestations on the Central Nervous System, with neurological and neuropsychological effects, 1 induction of depression, fatigue, sleep disturbances 2-4 and worse health-related quality of life-HRQoL. 5 These neuropsychiatric and neurocognitive changes have been reported in cases of non-cirrhotic infection, 6 in minimal hepatic encephalopathy 7,8 and in more severe cases of hepatic encephalopathy.Interferon based-treatment (IFN) for HCV is related to a decrease of neuropsychological functions, such as executive function and attention, 9-11 as well as neuropsychiatric dysfunction involving depression, anxiety, fatigue and deterioration of HRQoL. 12,13

Background: Major depressive disorder (MDD) is a leading cause of disability worldwide and most people do not achieve symptom remission. Treatment-resistant depression (TRD) is characterized by the failure of at least one adequate trial of a major class of antidepressant, with adequate time and dosage. We aimed to identify clinical predictors of depressive symptom remission and response 24 h and 7 days after racemic ketamine and esketamine infusions. Methods: A randomized, double-blind, active-controlled, non-inferiority trial using ketamine and esketamine in TRD. Individuals diagnosed with MDD according to Diagnostic and Statistical Manual of Mental Disorders version IV and fulfilling TRD criteria were recruited from March 2017 to June 2018. Participants received a single subanesthetic dose of ketamine (0.5 mg/kg) or esketamine (0.25 mg/kg) for 40 min. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) and symptom remission was defined as a MADRS score ≤7 and response defined as ≥50% reduction in depressive symptom severity, 24 h and 7 days after the infusion. Clinical variables were selected based on previous clinical trials. Stepwise backward logistic regression was used, considering a confidence level of 95%.Results: 61 subjects were included: 39 (63.9%) were females with a mean age of 47.2 � 14.9. Higher number of therapeutic failures (Odds Ratio (OR) = 0.677; 95% confidence interval (CI): 0.47-0.97) and higher severity of illness (OR = 0.912; 95%

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