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A randomized exploratory trial of an ?-7 nicotinic receptor agonist (TC-5619) for cognitive enhancement in schizophrenia.

ABSTRACT: This exploratory trial was conducted to test the effects of an alpha7 nicotinic receptor partial agonist, TC-5619, on cognitive dysfunction and negative symptoms in subjects with schizophrenia. In the United States and India, 185 outpatients (18-60 years; male 69%; 46% tobacco users) with schizophrenia treated with quetiapine or risperidone monotherapy were randomized to 12 weeks of placebo (n=91) or TC-5619 (n=94; orally once daily 1?mg day 1 to week 4, 5?mg week 4 to 8, and 25?mg week 8 to 12). The primary efficacy outcome measure was the Groton Maze Learning Task (GMLT; executive function) of the CogState Schizophrenia Battery (CSB). Secondary outcome measures included: CSB composite score; Scale for Assessment of Negative Symptoms (SANS); Clinical Global Impression-Global Improvement (CGI-I); CGI-severity (CGI-S); and Subject Global Impression-Cognition. GMLT statistically favored TC-5619 (P=0.036) in this exploratory trial. SANS also statistically favored TC-5619 (P=0.030). No other secondary outcome measure demonstrated a drug effect in the total population; there was a statistically significant drug effect on working memory in tobacco users. The results were typically stronger in favor of TC-5619 in tobacco users and occasionally better in the United States than in India. TC-5619 was generally well tolerated with no clinically noteworthy safety findings. These results support the potential benefits of TC-5619 and alpha7 nicotinic receptor partial agonists for cognitive dysfunction and negative symptoms in schizophrenia.

SUBMITTER: Lieberman JA

PROVIDER: S-EPMC3629385 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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A randomized exploratory trial of an α-7 nicotinic receptor agonist (TC-5619) for cognitive enhancement in schizophrenia.

Lieberman Jeffrey A JA Dunbar Geoffrey G Segreti Anthony C AC Girgis Ragy R RR Seoane Frances F Beaver Jessica S JS Duan Naihua N Hosford David A DA

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20121218 6

This exploratory trial was conducted to test the effects of an alpha7 nicotinic receptor partial agonist, TC-5619, on cognitive dysfunction and negative symptoms in subjects with schizophrenia. In the United States and India, 185 outpatients (18-60 years; male 69%; 46% tobacco users) with schizophrenia treated with quetiapine or risperidone monotherapy were randomized to 12 weeks of placebo (n=91) or TC-5619 (n=94; orally once daily 1 mg day 1 to week 4, 5 mg week 4 to 8, and 25 mg week 8 to 12) ...[more]

PMID: 23303043

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Project description:IntroductionAQW051, an α7-nicotinic acetylcholine receptor partial agonist, enhanced cognitive function in rodent models of learning and memory. This study evaluated brain activation during performance of a working memory task (WMT) and an episodic memory task (EMT), and the effect of AQW051 on task-related brain activation and performance in subjects with schizophrenia.MethodsThis was a double-blind, randomized, placebo-controlled, multicenter, 2-period cross-over trial (NCT00825539) in participants with chronic, stable schizophrenia. Participants, stratified according to smoking status, were randomized (1:1:1:1:1:1) to 1 of 6 sequence groups that determined the study drug dose (AQW051 7.5mg, 50mg or 100mg) and order of administration versus placebo. The primary outcome was brain activation in a priori target regions of interest (ROIs) during performance of the WMT and EMT, measured using functional magnetic resonance imaging. The effect of AQW051 on task-related (EMT and WMT) brain activation and performance was also assessed, as were safety and tolerability.ResultsOverall, 60 of 68 enrolled participants completed the study (AQW051 then placebo: 7.5mg n=9; 50mg n=11; 100mg n=10. Placebo then AQW051: 7.5mg n=10; 50mg n=11; 100mg n=9). Significant task-related brain activation (5% significance level) was observed with placebo. During the WMT, a medium effect size was observed in the inferior prefrontal cortex with AQW051 100mg versus placebo (0.431; p=0.105). During the EMT encoding phase, a large effect size was observed in the anterior hippocampus (0.795; p=0.007) and a medium effect size in the posterior hippocampus (0.476; p=0.079) with AQW051 7.5mg. No other medium/large effect sizes were observed with any dose on either task. Effects on brain activation were generally not associated with changes in cognitive performance. AQW051 was well tolerated with an acceptable safety profile.ConclusionsOverall, no consistent effects of AQW051 on brain regions involved in the performance of a WMT or EMT were observed; however, this study presents a model for evaluating potential response to pharmacological interventions for cognitive impairment in schizophrenia.

Project description:Importance:Withdrawal from nicotine is an important contributor to smoking relapse. Understanding how reward-based decision making is affected by abstinence and by pharmacotherapies such as nicotine replacement therapy and varenicline tartrate may aid cessation treatment. Objective:To independently assess the effects of nicotine dependence and stimulation of the nicotinic acetylcholine receptor on the ability to interpret valence information (reward sensitivity) and subsequently alter behavior as reward contingencies change (cognitive flexibility) in a probabilistic reversal learning task. Design, Setting, and Participants:Nicotine-dependent smokers and nonsmokers completed a probabilistic reversal learning task during acquisition of functional magnetic resonance imaging (fMRI) in a 2-drug, double-blind placebo-controlled crossover design conducted from January 21, 2009, to September 29, 2011. Smokers were abstinent from cigarette smoking for 12 hours for all sessions. In a fully Latin square fashion, participants in both groups underwent MRI twice while receiving varenicline and twice while receiving a placebo pill, wearing either a nicotine or a placebo patch. Imaging analysis was performed from June 15, 2015, to August 10, 2016. Main Outcome and Measures:A well-established computational model captured effects of smoking status and administration of nicotine and varenicline on probabilistic reversal learning choice behavior. Neural effects of smoking status, nicotine, and varenicline were tested for on MRI contrasts that captured reward sensitivity and cognitive flexibility. Results:The study included 24 nicotine-dependent smokers (12 women and 12 men; mean [SD] age, 35.8 [9.9] years) and 20 nonsmokers (10 women and 10 men; mean [SD] age, 30.4 [7.2] years). Computational modeling indicated that abstinent smokers were biased toward response shifting and that their decisions were less sensitive to the available evidence, suggesting increased impulsivity during withdrawal. These behavioral impairments were mitigated with nicotine and varenicline. Similarly, decreased mesocorticolimbic activity associated with cognitive flexibility in abstinent smokers was restored to the level of nonsmokers following stimulation of nicotinic acetylcholine receptors (familywise error-corrected P?<?.05). Conversely, neural signatures of decreased reward sensitivity in smokers (vs nonsmokers; familywise error-corrected P?<?.05) in the dorsal striatum and anterior cingulate cortex were not mitigated by nicotine or varenicline. Conclusions and Relevance:There was a double dissociation between the effects of chronic nicotine dependence on neural representations of reward sensitivity and acute effects of stimulation of nicotinic acetylcholine receptors on behavioral and neural signatures of cognitive flexibility in smokers. These chronic and acute pharmacologic effects were observed in overlapping mesocorticolimbic regions, suggesting that available pharmacotherapies may alleviate deficits in the same circuitry for certain mental computations but not for others. Trial Registration:clinicaltrials.gov Identifier: NCT00830739.

Dataset Information

A randomized exploratory trial of an ?-7 nicotinic receptor agonist (TC-5619) for cognitive enhancement in schizophrenia.

Publications

A randomized exploratory trial of an α-7 nicotinic receptor agonist (TC-5619) for cognitive enhancement in schizophrenia.

Similar Datasets

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