D. Abi-Saab

Interactive effects of subanesthetic ketamine and haloperidol in healthy humans

Abstract Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with prominent psychoactive effects in humans. This study evaluated whether the oral administration of haloperidol 5 mg would block the effects of an intravenous ketamine infusion (bolus of 0.26 mg/kg followed by 0.65 mg/kg per hour). Twenty healthy subjects completed 4 test days involving the oral administration of haloperidol or matched placebo 2 h prior to the intravenous infusion of ketamine or saline. Ketamine produced cognitive, behavioral, neuroendocrine, and physiologic effects in the healthy subjects that were similar to previous reports. Haloperidol pretreatment reduced impairments in executive cognitive functions produced by ketamine as measured by proverb interpretations and the Wisconsin Card Sorting Test. However, it failed to block the capacity of ketamine to produce psychosis, perceptual changes, negative symptoms, or euphoria in healthy subjects. These data outline an important, but functionally delineaeted modulation of ketamine effects by dopamine2 receptors and other sites of haloperidol action.

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 (IV 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 IV 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.

Dissociation of ketamine effects on rule acquisition and rule implementation: possible relevance to NMDA receptor contributions to executive cognitive functions.

BACKGROUND The demands of the Wisconsin Card Sorting Test (WCST) change with experience. This report contains two studies designed to examine N-methyl-D-aspartate (NMDA) receptor contributions to the executive components of WCST performance. These aspects of WCST performance figure more prominently in the initial completion of this task than in subsequent task repetitions in healthy populations. METHODS In the first study, healthy subjects (n = 15) completed the WCST on two occasions separated by 1 week. In the second study, healthy subjects (n = 22) completed two test days spaced by approximately 1 week, during which, they completed the WCST and other assessments after administration of the NMDA antagonist ketamine (intravenous bolus 0.26 mg/kg followed by infusion of 0.65 mg/kg/hour) or matched placebo. RESULTS In the first study, subjects reduced the number of total and perseverative errors with a single repetition of the WCST. In the second study, ketamine significantly increased the number of total errors and the number and percent of perseverative errors on the first, but not the second test day. Similarly, it reduced the number of category criteria met on the first, but not second test day. Ketamine also increased distractibility, impaired recall, produced psychosis, altered perception, and had effects resembling the negative symptoms of schizophrenia. However, only WCST performance showed order dependency. CONCLUSIONS This order dependency further implicates NMDA receptors in executive cognitive functions associated with the frontal cortex.

IV Glycine and oral D-cycloserine effects on plasma and CSF amino acids in Healthy humans

BACKGROUND The amino acid glycine, modulates neurotransmission via actions at GLY-A receptor and GLY-B receptor. The latter are coagonist sites associated with N-Methyl-D-Aspartate (NMDA) glutamate receptors. The central bioavailability of peripherally administered glycine has not been adequately characterized in humans. METHODS Healthy human subjects were administered either oral D-cycloserine (50 mg or placebo) and intravenous glycine (saline, 100 mg/kg or 200 mg/kg) in random order over 4 test days under double-blind conditions. Cerebrospinal fluid was collected by lumbar puncture performed on the first test day was analyzed to determine amino acid levels. The acoustic startle response was measured on the second test day. RESULTS Intravenous glycine dose-dependently increased both serum and CSF glycine and serine levels. Neither glycine nor DCS produced any significant effects on behavior, cognition or the acoustic startle response. Neither IV glycine nor DCS were associated with any toxicity. CONCLUSIONS Thus, peripheral glycine administration raised CSF glycine levels without producing any clear central nervous system effects. Glycine and D-cycloserine did not worsen cognitive test performance and did not induce behavioral symptoms on their own. The possibility that glycine and D-cycloserine enhanced cognitive test performance cannot be excluded given the psychometric limitations of the test battery.

Feasibility, Safety, and Efficacy of the Combination of D -Serine and Computerized Cognitive Retraining in Schizophrenia: An International Collaborative Pilot Study

The combination of pharmacotherapy and cognitive retraining (CRT) for the cognitive deficits of schizophrenia may be more efficacious than either approach alone, but this has not yet been tested. This study evaluated the feasibility, safety, tolerability, and efficacy of 12 weeks of D-serine, combined with CRT in the treatment of cognitive deficits in schizophrenia at two academic sites in parallel, in India and the United States. In a randomized, partial double-blind, placebo-controlled, parallel-group design, 104 schizophrenia subjects (US site=22, Indian site=82) were randomized to: (1) D-serine (30 mg/kg)+CRT (5 h/week), (2) D-serine+control CRT, (3) CRT+placebo D-serine, and (4) placebo+control CRT. Completion rates were 84 and 100% in the Indian and US samples, respectively. On various outcome measures of safety and tolerability, the interventions were well tolerated. D-Serine and CRT did not show any significant effect on the Global Cognitive Index, although both interventions showed differential site effects on individual test performance. CRT resulted in a significant improvement in Verbal Working Memory, and a trend toward improvement in Attention/Vigilance. This is the first study to demonstrating the feasibility, safety, and tolerability of combination pharmacotherapy and CRT in a multicenter international clinical trial. These preliminary findings provide support for future studies using higher doses of D-serine that have been shown to be efficacious or other pharmacotherapies, along with the newer cognitive remediation strategies that are individualized and that target basic information processing.

The effect of alcohol on the neuropsychological functioning of recently abstinent cocaine-dependent subjects.

Neuropsychological deficits in the areas of learning, memory, attention, and abstraction abilities have been associated with cocaine dependence, especially during the period of early abstinence. Although cocaine users tend to be multidrug users, few studies have focused on the combined effect of alcohol and cocaine on neuropsychological functioning. Consistent with prior research, results from the current study indicated that cocaine-dependent subjects showed a significantly greater degree of neuropsychological impairment as compared to controls. In addition, cocaine-dependent subjects with a history of alcohol disorder showed less memory impairment but similar impairments in attention and overall neuropsychological functioning as cocaine subjects with no such history. The vasodilatation produced by alcohol may attenuate some of the vasoconstriction and neurotoxic effects of cocaine, accounting for the fewer deficits in this group.

The implications of memory profiles in schizophrenia on vocational and neuropsychological functioning.

Studies in schizophrenia suggest that verbal learning and memory may distinguish three subgroups of patients: an unimpaired memory profile group and two groups that have memory profiles similar to those seen in cortical and subcortical dementias. Using the Hopkins Verbal Learning Test, Revised edition (HVLT-R), this study attempted to differentiate patients into three memory profile groups and to examine the validity of these groups with respect to vocational outcomes and neuropsychological functioning. Results from this study replicated previous findings and extended them by demonstrating a link to vocational outcome. In addition, the proportion of patients in each group closely resembled that obtained in previous studies. Specifically, the relatively unimpaired memory group (42%) showed overall better memory and neuropsychological performance than the two impaired groups, the subcortical group (38%) showed impaired recall but intact recognition and deficits in visuospatial functioning, and the cortical group (20%) showed deficits in recall, recognition, and sustained attention/executive functioning. There were no clinical differences between the three groups, but both the unimpaired and subcortical groups increased the number of hours worked following a vocational rehabilitation program. Given these differences, more research is warranted to explore the effect of memory impairment subtypes on vocational outcome measures.

I.V. glycine/d-cycloserine to facilitate NMDA function in humans

35428, but not to BZT. WIN 35428 curves in cocaine users was shifted to the right of the control curve while BZT inhibition curves in cocaine addicts overlapped with the controls. Similarly, there was a decrease in responsiveness of [3H]GBR 12935 binding to nomifensine in rats 6 weeks following withdrawal from a week-long cocaine treatment; the nomifensine curve was shifted to the right of the saline control curve, in the saline treated group, the estimated ICso was 0.001 mM, while in the cocaine group it was I mM. These results are consistent with an altered pharmacological profile of DATR associated with chronic intake of cocaine.