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Cholinergic Drug Improves Cognition in Nonsmokers With Schizophrenia

28 September 2012. Genetic, behavioral, and neurophysiological evidence has converged to implicate dysfunctional α7 nicotinic acetylcholine receptors (nAChRs) in neurocognitive symptoms of schizophrenia. In a short preliminary study published in the September issue of The American Journal of Psychiatry, researchers found that the α7 agonist tropisetron improved cognition and rescued a neural measure of cognitive function.

The α7 subtype of nAChR modulates sensory gating, including the inhibitory P50 evoked response to repeated auditory stimuli; deficits in this response, which some researchers believe may contribute to the disordered thought processes characteristic of schizophrenia, is a well-replicated endophenotype seen in the illness.

Animal studies and smaller-scale human trials have suggested that the P50 deficit, and overall cognitive function, might be normalized by α7 nAChR agonists (for a review, see AhnAllen, 2012; also see SRF related news story), though there have been mixed results with one such agonist, DMXB-A (Olincy et al., 2006; Freedman et al., 2008; also see SRF related news story; SRF news story). However, this therapeutic strategy has now gained some new legs from a study by Thomas and Therese Kosten and lead author Xiang Yang Zhang at Baylor College of Medicine and colleagues in Shantou, Zhongshan, Beijing, and Nanjing, China.

Nonsmoking Chinese patients with schizophrenia who had received comparable doses of risperidone for one month were tested for the P50 response and for overall cognitive functioning with a Mandarin translation of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Forty patients exhibited significant deficits in the P50 response and were randomized to receive either placebo or a 5, 10, or 20 mg dose of tropisetron, a high-affinity partial agonist of the α7 nAChR, for 10 days. On day 10, the P50 response was measured in all groups, and the RBANS was administered again.

All three treatment groups had significant improvements on the RBANS over the placebo group, both in RBANS total scores and on scores measuring particular cognitive functions (though patients in the 10-mg group showed better performance on immediate memory than the placebo group, while those in the 20-mg group were significantly better at delayed memory tasks). Significant effects on the inhibitory P50 response were also seen in all treatment groups compared to the placebo group, and there was a significant correlation between cognitive improvement as measured by the RBANS and normalization of the P50 response.

In an aside, the researchers also report striking anecdotal evidence for tropisetron’s therapeutic effects: without prompting by investigators, about half of the patients who received the drug spontaneously “remarked that they could think more clearly or concentrate better and could remember things easier or better.”

The authors consider the combined results to be sufficiently encouraging to “strongly support” launching a trial enrolling a larger number of patients tropisetron’s effects on P50 gating and on cognition over a longer term; such a trial is now under way.—Pete Farley.

Reference
Zhang XY, Liu L, Liu S, Hong X, Chen da C, Xiu MH, Yang FD, Zhang Z, Zhang X, Kosten TA, Kosten TR. Short-term tropisetron treatment and cognitive and p50 auditory gating deficits in schizophrenia. Am J Psychiatry. 2012 Sep 1;169(9):974-81. Abstract

 
Comments on News and Primary Papers
Comment by:  Britta Hahn
Submitted 7 October 2012 Posted 7 October 2012

The study by Zhang et al. (2012) provides further evidence for the therapeutic potential of partial α7 nicotinic acetylcholine receptor (nAChR) agonists in the treatment of the cognitive deficits associated with schizophrenia. Given the impact of this symptom group on psychosocial functioning (Green et al., 2004; Tan, 2009) and the current absence of effective treatments, the importance of such findings is easily seen. Tropisetron administered over 10 days improved immediate and delayed memory subscales of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and improved P50 auditory gating deficits in 40 non-smoking inpatients with schizophrenia.

The evidence for enhanced auditory gating was strong, with the reduction in the S2/S1 ratio being entirely due to a decrease in S2 amplitude with no change in S1. By limiting the study sample to patients who displayed P50 gating deficits at baseline (~40 percent of all screened patients), the authors may...  Read more


View all comments by Britta Hahn

Comment by:  Georg Winterer (Disclosure)
Submitted 30 October 2012 Posted 30 October 2012

The paper of Zhang et al. once more presents promising findings suggesting that nicotinic α7 (partial) agonists may eventually be used as cognition enhancers in schizophrenia. Since several completed studies about the effect of nicotinic agonists on P50 gating and cognitive parameters are now around, we should try to figure out what distinguishes the negative and positive studies.

In the particular case of tropisetron, it certainly needs to be acknowledged that this drug also is a serotonin 5-HT3 antagonist. Previous studies (e.g., Adler et al., 2005) have already suggested that drugs that act as antagonists at this receptor improve P50 gating. Since antagonism of 5-HT3 increases release of acetylcholine, this may add to the direct partial agonist effect of tropisetron at the (low affinity) α7 nicotinic receptor as well as other nicotinic receptors, including high-affinity α4β2 receptors. In this regard, we should also acknowledge that agonists that act at other nicotinic receptors (α4β2) are now...  Read more


View all comments by Georg Winterer
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