Effects of Ketamine on Thought Disorder, Working Memory, and Semantic Memory in Healthy Volunteers

Abstract

Background: The N-methyl-d-aspartate receptor antagonist, ketamine, produces a clinical syndrome of thought disorder, perceptual distortion, and cognitive impairment.

Methods: We have administered ketamine to healthy volunteers to characterize the formal thought disorder and specific memory dysfunction associated with ketamine. Ten healthy volunteers underwent a double-blind, placebo-controlled, ketamine infusion (0.12 mg/kg bolus and 0.65 mg/kg/hour). Thought disorder was evaluated with the Scale for the Assessment of Thought, Language and Communication. Cognitive testing involved working and semantic memory tasks.

Results: Ketamine produced a formal thought disorder, as well as impairments in working and semantic memory. The degree of ketamine-induced thought disorder significantly correlated with ketamine-induced decreases in working memory and did not correlate with ketamine-induced impairments in semantic memory.

Conclusions: This study characterizes the formal thought disorder associated with ketamine and may suggest that ketamine-induced deficits in working memory are associated with ketamine-induced thought disorder.

Introduction

Several lines of evidence suggest that the N-methyl-d-aspartate (NMDA) receptor is involved in the pathogenesis of schizophrenia. Postmortem studies have revealed decreased density of glutamatergic receptors in schizophrenic patients Kerwin et al 1988, Kornhuber et al 1989, and at least one study of cerebrospinal fluid (CSF) has shown lower levels of glutamate in schizophrenic patients than in healthy controls (Kim et al 1980). Furthermore, administration of NMDA antagonists such as phencyclidine (PCP) to healthy volunteers reproduces many of the symptoms of schizophrenia Luby et al 1959, Davies and Beech 1960. In schizophrenic patients, administration of PCP exacerbates existing symptoms and may reactivate those in remittance Luby et al 1959, Ban et al 1961.

The toxicity of PCP (Olney et al 1989) has led to the use of the NMDA antagonist, ketamine, to examine the effects of NMDA antagonism on thought and behavior Krystal et al 1994, Malhotra et al 1996. At subanesthetic doses, ketamine induces a clinical syndrome characterized by thought disturbance, perceptual alterations, emotional withdrawal, and cognitive dysfunction in healthy volunteers Krystal et al 1994, Malhotra et al 1996. Because its behavioral profile resembles many of the clinical features of schizophrenia, ketamine has been proposed as a pharmacologic model of the illness.

We have previously found the Brief Psychiatric Rating Scale (BPRS) item, conceptual disorganization, to demonstrate the most significant effect from ketamine (Malhotra et al 1996). Others have similarly found a very marked effect of ketamine on the BPRS factor containing conceptual disorganization (Krystal et al 1994). In terms of specific cognitive effects, we found that ketamine produced marked deficits on two measures of explicit memory, free recall and recognition memory (Malhotra et al 1996). Ketamine has also been associated with impaired performance on delayed recall, another measure of explicit memory, as well as on the semantic memory task of verbal fluency Krystal et al 1994, Ghoneim et al 1985. All of these memory functions may be considered together as components of memory requiring long-term storage. In addition, ketamine causes deficits on the Wisconsin Card Sorting Test (WCST), a task that includes a significant working memory component (Krystal et al 1994). It has been hypothesized that deficits in specific memory systems are associated with formal thought disorder in schizophrenia. Goldman-Rakic (1994) and others have suggested that working memory may underlie thought disorder, while Goldberg and Weinberger (1995) have proposed the involvement of semantic memory.

Previous studies of formal thought disorder and memory dysfunction caused by ketamine raise several methodologic issues. First, thought disorder has been measured with the single BPRS item conceptual disorganization, or the three-item BPRS factor thought disturbance Krystal et al 1994, Malhotra et al 1996. Many elements of formal thought disorder are poorly measured by these limited ratings. Another issue relates to the cognitive tests that have been utilized. The putative working memory task previously employed, the WCST, involves multiple cognitive processes in addition to working memory Goldman-Rakic 1994, Axelrod et al 1994. In addition, the attention or vigilance tasks employed in the past have included significant working memory components Krystal et al 1994, Malhotra et al 1996. Thus, it has been difficult to isolate which cognitive domains are primarily affected by ketamine.

In this study, we further examined the effects of ketamine on thought disorder and memory function. We utilized a comprehensive measure of thought disorder, the Scale for the Assessment of Thought, Language and Communication (TLC). The TLC is a clinical interview based scale that assesses specific aspects of thought disorder, including thought formation and communication (Andreasen 1978). In addition, we examined memory function during ketamine administration with two separate verbal fluency tasks that contain significant semantic memory components, and a working memory task. A simple measure of vigilance involving immediate response to a visual stimulus that minimizes the working memory contribution was also utilized. Further, the relationships between ketamine-induced effects on thought disorder and the two memory tasks were examined to provide information about the relative contributions of working and semantic memory to formal thought disorder under conditions of glutamatergic perturbation.