Neurocognitive performance and serial intravenous subanesthetic ketamine in treatment-resistant depression

Paulo R. Shiroma, C. Sophia Albott, Brian Johns, Paul Thuras, Joseph Wels and
Kelvin O. Lim

The International Journal of Neuropsychopharmacology, 2014, Volume 17, Issue 11, 1805–1813,

Doi : 10.1017/S1461145714001011

 

Abstract

The N-methyl-D-aspartate glutamate receptor antagonist ketamine has demonstrated rapid anti-depressant effects in treatment-resistant depression (TRD). However, evaluation of ketamine’s neurocognitive aspects in TRD has started to be explored. This study aims to (1) examine baseline neurocognitive performance and change in severity of depressive symptoms through six ketamine infusions, (2) examine the neurocognitive effects after completion of serial infusions and whether changes were associated to relapse to depression. Six IV infusions of 0.5 mg/Kg ketamine over 40 min were conducted on a Monday–Wednesday–Friday schedule during a 12-d period on 15 patients with TRD followed by a 4-wk observational period. Neurocognitive functioning was assessed using the CogState battery at baseline and at each follow-up visit. Tasks were designed to test attention, memory (working, visual, and verbal), speed of processing, and set shifting. The likelihood of response through six infusions was greater among depressed subjects with lower attention at baseline (F(1,13) = 5.59, p = 0.034). Significant improvement was found in scores of visual memory (F(4,33.82) = 5.12, p = 0.002), simple working memory (F(4, 24.85) = 3.29, p = 0.027) and complex working memory (F(4, 32.76) = 4.18, p = 0.008) after the last ketamine infusion. However, neurocognitive changes were accounted for by improvement in the severity of depressive symptom. The acute neurocognitive effect after completion of repeated infusions was not associated with the likelihood of subsequent relapse during follow-up. Our findings suggest a potential baseline neurocognitive predictor of ketamine response and the apparently lack of short-term neurocognitive impairment after completion of six ketamine infusions in TRD.

Introduction

Ketamine, a non-competitive, high-affinity antagonist of the N-methyl-D-aspartate (NMDA) type glutamate receptor used for induction and maintenance of anesthesia (Green and Li, 2000), has been recently investigated for its high efficacy and rapid antidepressant effect. However, side effects of ketamine have raised some concerns. In 2013, the United Kingdom government upgraded ketamine from a Class C drug to a Class B drug based on recommendations from the Advisory Council on the Misuse of Drugs concerning bladder damage on ketamine drug users with ‘more research needed on the long-term neurocognitive effects’.

Studies in healthy subjects suggested that subanesthetic doses of ketamine as a psychopharmacologic probe disrupt information encoding that occurs during drug administration but does not impair recall for previously learned information (Morgan et al., 2004; Krystal et al., 2005). Other studies have found evidence for selective impairments in aspects of executive functioning (Krystal et al., 1994b; Morgan et al., 2009), while no impairments have been reported (Morgan et al., 2004; Parwani et al., 2005). Ketamine administration at subanesthetic doses appears to carry a very low risk of adverse events in experimental psychopharmacology studies (Perry et al., 2007). These findings are consistent with the lack of long-term effects reported with anesthetic doses of ketamine (Corssen et al., 1971; Moretti et al., 1984).

Given recent interest of ketamine use in treatment-resistant depression (TRD), the neurocognitive effects has just started to be explored. Murrough and colleagues (Murrough et al., 2013b) reported impairments in memory recall immediately after a single ketamine infusion was completed. The strategy of repeated ketamine infusions suggest that more than a single infusion achieve better antidepressant outcomes (Murrough et al., 2013a; Rasmussen et al., 2013; Shiroma et al., 2014); however, the short-term neurocognitive effects after completion of treatment are not known.

This study aims to (1) examine the association of baseline neurocognitive performance and the change in severity of depressive symptoms through six consecutive infusions among TRD subjects, (2) examine the neurocognitive effects of serial ketamine infusions during follow-up and whether changes in neurocognition were associated to relapse from antidepressant response.

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