Interactive effects of subanesthetic ketamine and subhypnotic lorazepam in humans

Abstract

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with psychotogenic and dissociative effects in healthy humans. These cognitive and perceptual effects in humans are reportedly reduced by benzodiazepine premedication. This study assessed the interactive effects of a ketamine (i.v. bolus of 0.26 mg/kg followed by an infusion of 0.65 mg/kg per hour) and lorazepam 2 mg., PO, in humans. Twenty-three healthy subjects completed 4 test days involving the oral administration of lorazepam or matched placebo 2 h prior to the i.v. infusion of ketamine or placebo. Ketamine: 1) produced behaviors similar to the positive and negative symptoms of schizophrenia as assessed by the Brief Psychiatric Rating Scale (BPRS); 2) evoked perceptual alterations as measured by the Clinician-Administered Dissociative States Scale (CADSS); 3) impaired performance on the Wisconsin Card Sorting Test (WCST) and other tests sensitive to frontal cortical impairment; and 4) had amnestic effects. Lorazepam produced attention impairments, concrete proverb interpretations, and recall impairments. Lorazepam reduced ketamine-associated emotional distress and there was a non-significant trend for it to decrease perceptual alterations produced by ketamine. However, it failed to reduce many cognitive and behavioral effects of ketamine, including psychosis. Further, lorazepam exacerbated the sedative, attention-impairing, and amnestic effects of ketamine. There was no evidence of pharmacokinetic interaction between these medications. These data suggest that subhypnotic lorazepam and ketamine show a spectrum of interactive effects, ranging from antagonism to potentiation.

Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists

“…The current study replicated the subjective similarity of ketamine effects to ethanol in ethanol-dependent patients despite using a different ketamine infusion paradigm than the earlier study (Krystal et al 1998b). Consistent with the more rapid rise in ketamine blood levels and higher plasma ketamine levels associated with the current bolus and constant infusion paradigm relative to the previous slow infusion study (Krystal et al 1998a), the ethanol-like effects of ketamine were judged to be more intense on the CVES relative to the prior study. Nimodipine had no significant ethanol-like effects in this study.…”

“…The limited psychotogenic propensity of ethanol at doses typically associated with human intoxication may reflect the capacity of ethanol facilitation of GABA A receptor function to moderate its NMDA antagonist effects (Grant and Lovinger 1995). Consistent with this hypothesis, some reduction in the perceptual effects of ketamine in healthy human subjects was produced by lorazepam pretreatment (Krystal et al 1998a). However, preclinical data suggest that the capacity of ethanol to block L-type VSCCs (Crews et al 1996) may also protect against its psychotogenic potential.…”

“…As in previous studies from our group (Anand et al 2000;Krystal et al 1999b;Krystal et al 1998a;Krystal et al 1994a) psychosis was assessed using the four key positive symptoms from the BPRS: (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) and negative symptoms were assessed using three key items (blunted affect, emotional withdrawal, and motor retardation). Dysphoric mood responses were assessed using the anxious depression factor derived from the BPRS (anxiety, guilt feelings, depressive mood, somatic concern, tension, and motor retardation; (Hedlund and Vieweg 1980).…”

Acute Effects of Ketamine on Memory Systems and Psychotic Symptoms in Healthy Volunteers

“…Hence deficits in verbal fluency may well reflect semantic memory deficits. Conflicting results have been obtained from ketamine studies with fluency tasks of both impaired (Adler et al, 1998) and preserved (Ghoneim et al, 1985) category fluency, and similar findings of an impairment to verbal fluency in some (Adler et al, 1998;Krystal et al, 1994Krystal et al, , 1998, but not all (Krystal et al, 1999;Newcomer et al, 1999) studies. Findings concerning ketamine's effects on working memory are also conflicting.…”

The G72/G30 Gene Complex and Cognitive Abnormalities in Schizophrenia

“…The association of G72 with psychosis and the potential relationship between G72 and NMDA function are consistent with several lines of evidence suggesting that cortical glutamatergic neurotransmission may be compromised in schizophrenia (for reviews see Goff and Coyle, 2001;Tsai and Coyle, 2002;Krystal et al, 2002): (1) there is neuropathologic evidence of glutamate receptor abnormalities in prefrontal and temporal cortices that has been described in studies of post-mortem tissue of patients with schizophrenia (Deakin et al, 1989;Tsai et al, 1995;MeadorWoodruff and Healy, 2000); (2) drugs that reduce glutamatergic transmission at NMDA receptors in normal human subjects, such as ketamine, produce a range of cognitive impairments, including those in attention/working memory, word generation, and episodic memory that are somewhat similar to those found in patients with schizophrenia, as well as a range of symptoms often found in schizophrenia (Krystal et al, 2000;Krystal et al, 1998;Malhotra et al, 1996); and (3) animal models that involve knockdowns of NMDA receptor subunit genes (Gainetdinov et al, 2001) or chronic administration of NMDA antagonists (Jentsch and Roth, 1999) have produced animals whose behavior and brain function are in some respects 'schizophrenia-like.' However, it remains unclear if differences between long-term and short-term modulation of the glycine site are present (Lin et al, 1998) or if effects of G72 are age-specific.…”