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Proof-of-Concept Trial of an  7 Nicotinic Agonist in Schizophrenia
Ann Olincy, MD;
Josette G. Harris, PhD;
Lynn L. Johnson, PharmD;
Vicki Pender, BS;
Susan Kongs, BS;
Diana Allensworth, BS;
Jamey Ellis, BS;
Gary O. Zerbe, PhD;
Sherry Leonard, PhD;
Karen E. Stevens, PhD;
James O. Stevens, DVM, PhD;
Laura Martin, MD;
Lawrence E. Adler, MD;
Ferenc Soti, PhD;
William R. Kem, PhD;
Robert Freedman, MD
Arch Gen Psychiatry. 2006;63:630-638.
Context The  7 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 7 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 7 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 7 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 One person was withdrawn because of a transient decrease in white blood cell count.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 7 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.
Author Affiliations: Department of Veterans Affairs Schizophrenia Research Center and Veterans Integrated Service Network 19 Mental Illness Research, Education and Clinical Centers (Drs Olincy, Harris, Johnson, Zerbe, Leonard, K. E. Stevens, J. O. Stevens, Martin, Adler, and Freedman; Mss Pender, Kongs, and Allensworth; and Mr Ellis), Departments of Psychiatry (Drs Olincy, Harris, Johnson, Zerbe, Leonard, K. E. Stevens, J. O. Stevens, Martin, Adler, and Freedman; Mss Pender, Kongs, and Allensworth; and Mr Elis), Preventive Medicine and Biometics (Dr Zerbe), and Pharmacology (Drs Leonard and Freedman), University of Colorado School of Medicine, Denver; and Department of Pharmacology and Toxicology, University of Florida School of Medicine, Gainesville (Drs Soti and Kem).
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