In light of the limitations of first- and second-generation antipsychotics and other pharmacological agents for the treatment of cognitive impairments in schizophrenia, the demonstration of an acute benefit of DMXB-A for cognitive performance and sensory gating is of considerable potential interest. Patients with schizophrenia are characterized by a broad range of cognitive impairments (Nuechterlein et al., 2004). These impairments have been shown to be a major determinant of poor functional outcome (Green et al., 2004). The NIMH has made a substantial commitment to facilitate the development of new pharmacological treatments for cognitive impairments through their funding of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia (TURNS) initiatives. The MATRICS process selected the α7 nicotinic receptor as one of the top targets for the treatment of cognitive impairments in patients with schizophrenia (Geyer and Tamminga, 2004).

In the current study, 12 subjects with schizophrenia were administered DMXB-A, an α7 nicotinic receptor partial agonist. The study was designed to assess the proof of concept that increased stimulation of the α7 nicotinic receptor would enhance performance on a cognitive battery and improve sensory gating, as measured by the P50 dual click paradigm. There is extensive preclinical and clinical rationale for this approach, but few drugs are available to directly assess the efficacy of the approach. The results clearly support the benefit of this approach, but a number of questions will need to be addressed in future studies before the ultimate utility of this approach is known. The most important issue is whether the acute efficacy observed with essentially a single dose will translate to a persistence of an effect with chronic drug administration. Tachyphylaxis develops rapidly with repeated stimulation of the α7 nicotinic receptor. Preclinical data suggest that this may not be an issue with DMXB-A, but long-term exposure data are required to directly address this issue. Second, two DMXB-A doses were evaluated. The results were different between the two doses, but how different is unclear, because of the small sample size. Preclinical data suggest that α7 nicotinic receptor partial agonists may show an inverse u-shaped response curve. The loss of efficacy at higher doses underscores the importance and potential difficulty in delineating the most effective dose range. Third, subjects who used nicotine products in the last month were excluded from the study. Patients with schizophrenia who do not smoke cigarettes are in the minority, and perhaps represent less than a third of the total population. The question of whether the beneficial effect of the drug would generalize to patients who smoke cigarettes will eventually need to be evaluated. Finally, the most pronounced effect was observed for the RBANS attention index. This effect is consistent with previous studies of acute nicotine administration in patients with schizophrenia. Future studies will need to evaluate whether the effect of DMXB-A is largely limited to attention or whether it will have significant benefit for other cognitive domains.

In summary, the demonstration that the acute administration of DMXB-A produces improved performance on a neuropsychological battery is an important first step in developing a novel therapeutic approach for one of the most critical areas of schizophrenia therapeutics.

References:

Nuechterlein KH, Barch DM, Gold JM, Goldberg TE, Green MF, Heaton RK. Identification of separable cognitive factors in schizophrenia. Schizophr Res. 2004; 72: 29-39. Abstract

Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res. 2004;7 2: 41-51. Abstract

Geyer MA, Tamminga CA. Measurement and treatment research to improve cognition in schizophrenia: neuropharmacological aspects. Psychopharm. 2004; 174: 1-2.

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