Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia.

CONTEXT: The alpha7 nicotinic acetylcholine receptor gene, CHRNA7, is associated with genetic transmission of schizophrenia and related cognitive and neurophysiological sensory gating deficits. Cognitive dysfunction is responsible for significant psychosocial disability in schizophrenia. Nicotine, a low-potency agonist at the alpha7 receptor, has some positive effects on neurophysiological and neurocognitive deficits associated with schizophrenia, which suggests that more effective receptor activation might meaningfully enhance cognition in schizophrenia. OBJECTIVES: To determine if 3-[(2,4-dimethoxy)benzylidene]anabaseine (DMXB-A), a natural alkaloid derivative and a partial alpha7 nicotinic cholinergic agonist, significantly improves neurocognition, and to assess, by effects on P50 auditory evoked potential inhibition, whether its neurobiological actions are consistent with activation of alpha7 nicotinic receptors. DESIGN: Randomized, double-blind crossover trial of 2 drug doses and 1 placebo. SETTING: General clinical research center. PATIENTS: Twelve persons with schizophrenia who did not smoke and were concurrently treated with antipsychotic drugs. One person was withdrawn because of a transient decrease in white blood cell count. INTERVENTION: Administration of DMXB-A. MAIN OUTCOME MEASURES: Total scale score of the Repeatable Battery for the Assessment of Neuropsychological Status and P50 inhibitory gating. RESULTS: Significant neurocognitive improvement was found on the Repeatable Battery for the Assessment of Neuropsychological Status total scale score, particularly for the lower DMXB-A dose compared with placebo. Effects were greater than those of nicotine in a similar study. Significant improvement in P50 inhibition also occurred. Patients generally tolerated the drug well. CONCLUSIONS: An alpha7 nicotinic agonist appears to have positive effects on neurocognition in persons with schizophrenia. Longer trials are needed to determine the clinical utility of this novel treatment strategy.

Effects of nicotine on cognitive deficits in schizophrenia.

Several lines of evidence suggest a pathophysiological role for nicotinic receptors in schizophrenia. Activation by nicotine alters physiological dysfunctions, such as eye movement and sensory gating abnormalities, but effects on neuropsychological performance are just beginning to be investigated. Nicotine-induced desensitization and the well-known tachyphylaxis of nicotinic receptors may confound such efforts. In all, 20 schizophrenics, 10 smokers, and 10 nonsmokers were assessed following the administration of nicotine gum and placebo gum. The Repeatable Battery for the Assessment of Neuropsychological Status was administered. Nicotine affected only the Attention Index; there were no effects on learning and memory, language, or visuospatial/constructional abilities. Attentional function was increased in nonsmokers, but decreased in nicotine-abstinent smokers after nicotine administration. The effects of nicotine in schizophrenia do not extend to all areas of cognition. Effects on attention may be severely limited by tachyphylaxis, such that decremented performance occurs in smokers, while modest effects may be achieved in nonsmokers.

Cognitive outcomes after on- versus off-pump coronary artery bypass surgery.

BACKGROUND: The Randomized On versus Off Bypass trial found no difference for a global cognitive outcome measure for patients receiving on-pump versus off-pump coronary artery bypass graft surgery (CABG). In this report, we present the baseline patient characteristics that were predictive of post-CABG cognitive decline as well as compare cognitive outcomes between treatment arms. METHODS: A neuropsychological battery was administered preoperatively and at 1 year after undergoing CABG. Stepwise regression was used to identify demographic or clinical risk factors associated with cognitive decline. Neuropsychological data were converted to demographically corrected T scores to provide impairment levels. RESULTS: Overall 1,156 patients (581 on-pump, 575 off-pump) completed match-paired neuropsychological assessments at baseline and 1-year follow-up. Baseline cognitive score, age, education level, and ethnicity predicted cognitive decline after CABG. Only 20% of either group had mild impairment at baseline on three of the test scores, and less than 10% had severe impairment on individual tests at either time. Few subjects in either group transitioned to clinically impaired levels at follow-up on individual tests. CONCLUSIONS: At baseline, lower cognitive function, older age, lower education, and ethnicity other than white were predictive of cognitive decline after CABG. Patients in both groups demonstrated low frequencies of cognitive impairment on individual tests at baseline and follow- up, and few patients in either group were classified as impaired at 1-year follow-up on individual tests. In general, the Randomized On versus Off Bypass study documented that neither on-pump nor off-pump CABG adversely impacts long-term brain function.