A series of human and animal investigations has suggested that altered expression and function of the alpha7-nicotinic cholinergic receptor may be responsible for the auditory sensory gating deficit characterized in schizophrenia patients and their relatives as diminished suppression of an auditory-evoked response (P50) to repeated stimuli. This finding, in conjunction with evidence for familial transmission of this sensory gating deficit, suggests a pathogenic role of the gene for the alpha7-nicotinic receptor in schizophrenia. This article considers the possible effects of this dysfunction in a broader context. Not only is this dysfunction consistent with difficulties in sensory gating, but it might also predispose patients to problems with learning efficiency and accuracy. Such learning problems could underlie schizophrenia patients' delusional thinking, hallucinations, and social dysfunction. In addition, heavy smoking in many schizophrenia patients is consistent with the high concentration of nicotine necessary to activate the receptor and with the receptor's extremely rapid desensitization. Finally, the receptor's possible role in cell growth and differentiation should be considered in connection with developmental deficits and other cellular abnormalities in schizophrenia.

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.

Objective-Nicotinic acetylcholine receptors are possible therapeutic targets for schizophrenia, as shown by neurobiological and molecular evidence for deficiencies in expression of α 7 -nicotinic receptors. Patients' heavy smoking suggests attempted self-medication through this mechanism. The agent 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A) is a partial α 7 -nicotinic agonist and can be taken orally. A phase 1 trial showed evidence for cognitive enhancement in schizophrenia.Method-Thirty-one subjects with schizophrenia received DMXB-A at two different doses and placebo for periods of 4 weeks in a three-arm, two-site, double-blind, crossover phase 2 trial. The MATRICS Consensus Cognitive Battery assessed cognitive effects, and the Scale for the Assessment of Negative Symptoms (SANS) and Brief Psychiatric Rating Scale (BPRS) assessed clinical effects. Subjects continued their current antipsychotic drug during the trial and were nonsmokers.Results-There were no significant differences in the MATRICS cognitive measures between DMXB-A and placebo over the three treatment arms, but the patients experienced significant improvement at the higher DMXB-A dose on the SANS total score and nearly significant improvement on the BPRS total score. Improvement was most notable on the SANS anhedonia and alogia subscales. Examination of the first treatment arm showed effects of DMXB-A on the attention/vigilance and working memory MATRICS domains, compared to baseline. Five subjects developed mild tremor, and nearly half had mild nausea while taking DMXB-A.Address correspondence and reprint requests to Dr. Freedman, Department of Psychiatry C249-32, University of Colorado Health Sciences Center, Denver, CO 80262; Robert.Freedman@UCHSC.edu. Dr. Freedman has a patent through the Department of Veterans Affairs (VA) on the CHRNA7 gene sequence. The VA has also filed a patent disclosure for the use of nicotinic agonists for schizophrenia. Drs. Kem and Soti have patents through the University of Florida on the manufacture and use of DMXB-A (also known as GTS-21) and have a research grant from CoMentis; Dr. Kem is also a consultant for CoMentis. Dr. Buchanan is on the data safety monitoring boards of Pfizer and Wyeth; is a consultant for Memory Pharmaceuticals, Roche, and Organon; is on advisory boards for AstraZeneca, GlaxoSmithKline, Pfizer, and Solvay; and has received drug samples for research from Ortho-McNeil Neurologics and Janssen. Ms. Ball receives grant support and study medication from Eli Lilly. Dr. Gold has been a consultant for Pfizer and receives royalty payments for the Brief Assessment of Cognition in Schizophrenia. Dr. Stevens receives research support from GlaxoSmithKline and Johnson & Johnson and owns equity in Sierra Puente. Drs. Olincy, Martin, and Johnson receive re-search support from Lundbeck. All other authors report no competing interests. One therapeutic target identified by the MATRICS is the α 7 -nicotinic acetylcholine receptor. A possible role for the receptor in schizophrenia was first identi...

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.

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