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

Abstract

The N-methyl-D-aspartate glutamate receptor antagonist ketamine has demonstrated rapid antidepressant 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.

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

“…Notably, processing speed was not associated with depression symptom severity at baseline. Our finding is also broadly consistent with a recent report describing an association between reduced attention at baseline and improved antidepressant response to ketamine (Shiroma et al, 2014). Both processing speed and attention have been linked to dopamine functioning within prefrontal-subcortical circuits (Cropley et al, 2006), and ketamine is known to modulate dopamine signaling within the striatum and prefrontal cortex in animals (Moghaddam et al, 1997) and humans (Kegeles et al, 2000;Rabiner, 2007;Smith et al, 1998).…”

“…Our group first reported circumscribed memory impairment immediately following a single ketamine dose (0.5 mg/kg) administered as a slow infusion over 40 min (Murrough et al, 2013c). Subsequently, two open-label studies explored the neurocognitive effects of up to six ketamine infusions in patients with treatment-resistant unipolar or bipolar depression and found no evidence of impairment (Diamond et al, 2014;Shiroma et al, 2014). The current study featured a relatively large sample size and a two-site, randomized controlled design and yielded results consistent with these prior reports.…”

“…If ketamine were to be approved for use in clinical practice, it would very likely be administered in a repeated fashion over weeks, months, or longer. Although very early data on repeated infusions exist (Diamond et al, 2014;Shiroma et al, 2014), much more research will be required to establish the potential cognitive risks of longer-term repeated ketamine treatments for patients with severe or refractory forms of mood disorders.…”

“…It will be important going forward for clinical studies of ketamine or other mechanistically novel rapid-acting antidepressants to utilize standardized neurocognitive assessments to avoid the problem of 'approximate replication' (Kapur et al, 2012). For example, the study by Shiroma et al (2014) found that impaired attention, but not impaired processing speed per se, was associated with improved antidepressant response to ketamine. This discrepancy could be, in part, due to the differences in neurocognitive assessments utilized (the MCCB was utilized in the current study, compared with the CogState battery (Collie et al, 2003) in the study by Shiroma et al (2014)).…”

“…For example, the study by Shiroma et al (2014) found that impaired attention, but not impaired processing speed per se, was associated with improved antidepressant response to ketamine. This discrepancy could be, in part, due to the differences in neurocognitive assessments utilized (the MCCB was utilized in the current study, compared with the CogState battery (Collie et al, 2003) in the study by Shiroma et al (2014)). The current study examined neurocognitive function using a comprehensive battery, but optimal biomarker assessments will likely require multi-modal data acquisition, potentially including neuroimaging (Zarate et al, 2013), quantitative electroencephalography (qEEG) (Cook et al, 2013), and peripheral blood markers (Uddin, 2014).…”