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A. Perez

Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial

December 17, 2014 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

The glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine displays rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the potential for adverse neurocognitive effects in this population has not received adequate study. The current study was designed to investigate the delayed neurocognitive impact of ketamine in TRD and examine baseline antidepressant response predictors in the context of a randomized controlled trial. In the current study, 62 patients (mean age=46.2±12.2) with TRD free of concomitant antidepressant medication underwent neurocognitive assessments using components of the MATRICS Consensus Cognitive Battery (MCCB) before and after a single intravenous infusion of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg). Participants were randomized to ketamine or midazolam in a 2:1 fashion under double-blind conditions and underwent depression symptom assessments at 24, 48, 72 h, and 7 days post treatment using the Montgomery–Asberg Depression Rating Scale (MADRS). Post-treatment neurocognitive assessment was conducted once at 7 days. Neurocognitive performance improved following the treatment regardless of treatment condition. There was no differential effect of treatment on neurocognitive performance and no association with antidepressant response. Slower processing speed at baseline uniquely predicted greater improvement in depression at 24 h following ketamine (t=2.3, p=0.027), while controlling for age, depression severity, and performance on other neurocognitive domains. In the current study, we found that ketamine was devoid of adverse neurocognitive effects at 7 days post treatment and that slower baseline processing speed was associated with greater antidepressant response. Future studies are required to further define the neurocognitive profile of ketamine in clinical samples and to identify clinically useful response moderators.

Murrough, J. W., Burdick, K. E., Levitch, C. F., Perez, A. M., Brallier, J. W., Chang, L. C., … & Iosifescu, D. V. (2014). Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial. Neuropsychopharmacology. https://dx.doi.org/10.1038/npp.2014.298

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Ketamine safety and tolerability in clinical trials for treatment-resistant depression

September 2, 2014 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

OBJECTIVE: Ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the safety and tolerability of ketamine in this population have not been fully described. Herein we report the largest study to date of the safety, tolerability, and acceptability of ketamine in TRD.

METHOD: Data from 205 intravenous (IV) ketamine infusions (0.5 mg/kg over 40 minutes) in 97 participants with DSM-IV-defined major depressive disorder (MDD) were pooled from 3 clinical trials conducted between 2006 and 2012 at 2 academic medical centers. Safety and tolerability measures included attrition, adverse events (AEs), hemodynamic changes, and assessments of psychosis and dissociation.

RESULTS: The overall antidepressant response rate, defined as a ≥ 50% improvement in Montgomery-Asberg Depression Rating Scale score, was 67% (65 of 97 participants). Four of 205 infusions (1.95%) were discontinued due to AEs. The overall attrition rate was 3.1% (3 of 97). In the first 4 hours after the infusion, the most common general AEs were drowsiness, dizziness, poor coordination, blurred vision, and feeling strange or unreal. Approximately one third of individuals experienced protocol-defined hemodynamic changes. Ketamine resulted in small but significant increases in psychotomimetic and dissociative symptoms (all P <.05). There were no cases of persistent psychotomimetic effects, adverse medical effects, or increased substance use in a subgroup of patients with available long-term follow-up information.

CONCLUSIONS: In this relatively large group of patients with TRD, ketamine was safe and well tolerated. Further research investigating the safety of ketamine in severe and refractory depression is warranted.

Wan, L. B., Levitch, C. F., Perez, A. M., Brallier, J. W., Iosifescu, D. V., Chang, L. C., … & Murrough, J. W. (2014). Ketamine safety and tolerability in clinical trials for treatment-resistant depression. The Journal of clinical psychiatry. https://dx.doi.org/10.4088/JCP.13m08852

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Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder

June 11, 2014 / Anxiety Disorders / PTSD, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Importance  Few pharmacotherapies have demonstrated sufficient efficacy in the treatment of posttraumatic stress disorder (PTSD), a chronic and disabling condition.

Objective  To test the efficacy and safety of a single intravenous subanesthetic dose of ketamine for the treatment of PTSD and associated depressive symptoms in patients with chronic PTSD.

Design, Setting, and Participants  Proof-of-concept, randomized, double-blind, crossover trial comparing ketamine with an active placebo control, midazolam, conducted at a single site (Icahn School of Medicine at Mount Sinai, New York, New York). Forty-one patients with chronic PTSD related to a range of trauma exposures were recruited via advertisements.

Interventions  Intravenous infusion of ketamine hydrochloride (0.5 mg/kg) and midazolam (0.045 mg/kg).

Main Outcomes and Measures  The primary outcome measure was change in PTSD symptom severity, measured using the Impact of Event Scale–Revised. Secondary outcome measures included the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression–Severity and –Improvement scales, and adverse effect measures, including the Clinician-Administered Dissociative States Scale, the Brief Psychiatric Rating Scale, and the Young Mania Rating Scale.

Results  Ketamine infusion was associated with significant and rapid reduction in PTSD symptom severity, compared with midazolam, when assessed 24 hours after infusion (mean difference in Impact of Event Scale–Revised score, 12.7 [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][95% CI, 2.5-22.8]; P = .02). Greater reduction of PTSD symptoms following treatment with ketamine was evident in both crossover and first-period analyses, and remained significant after adjusting for baseline and 24-hour depressive symptom severity. Ketamine was also associated with reduction in comorbid depressive symptoms and with improvement in overall clinical presentation. Ketamine was generally well tolerated without clinically significant persistent dissociative symptoms.

Conclusions and Relevance  This study provides the first evidence for rapid reduction in symptom severity following ketamine infusion in patients with chronic PTSD. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with this disabling condition.

Feder, A., Parides, M. K., Murrough, J. W., Perez, A. M., Morgan, J. E., Saxena, S., … & Charney, D. S. (2014). Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA psychiatry, 71(6), 681-688. https://dx.doi.org/10.1001/jamapsychiatry.2014.62
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Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial

October 1, 2013 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

OBJECTIVE:
Synthesize and assess the available scientific evidence from the period 2008-2012 on interventions of demonstrated efficacy in the treatment and rehabilitation of adolescents and adults engaged in the problematic use of alcohol and other substances.

METHODS:
A systematic review was undertaken with search and analysis of national and international literature on the subject in Spanish and English in the main international databases: PubMed/MEDLINE, LILACS, Embase, PsycINFO, SciELO, the databases of the York University Centre for Reviews and Dissemination (DARE, ETS Database), the Cochrane Library, and other sources of gray literature. The search criteria included randomized clinical trials and systematic reviews but excluded observational studies, qualitative studies, and articles of poor methodological quality.

RESULTS:
The final sample consisted of 69 studies. The psychosocial interventions shown to be effective were cognitive behavioral therapy, family interventions, self-help interventions using the Internet, couples behavioral therapy, community strengthening and family training, telephone monitoring and support, and integrated therapy for substance abuse disorder with anxiety and depression comorbidity. Pharmacological interventions of demonstrated effectiveness were acamprosate, lysergic acid diethylamide (LSD), and benzodiazepines in problematic alcohol use, as well as maintenance therapy with high-dose opioids.

CONCLUSIONS:
The demonstrated effectiveness of psychosocial and pharmacological interventions is slight but significant. However, strongly multidisciplinary interventions that use a cognitive behavioral approach and the involvement of people close to the consumer, as well as some of the specific pharmacological interventions, have been shown to yield the best results in terms of indicators of abstinence and prevention of relapses.

Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al Jurdi, R. K., Green, C. E., Perez, A. M., … Mathew, S. J. (2013). Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. American Journal of Psychiatry, 170(10), 1134-1142. http://dx.doi.org/10.1176/appi.ajp.2013.13030392
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