Acute effects of mecamylamine and varenicline on cognitive performance in non-smokers with and without schizophrenia

Abstract

Rationale: Nicotinic acetylcholine receptors (nAChRs) have been implicated in the pathophysiology of cognitive deficits in the domains of attention and memory in schizophrenia. While nicotinic agonists and antagonists have been proposed as smoking cessation aids, few comparisons have been made of these agents on cognitive performance in individuals with schizophrenia.

Objectives: This study investigated the acute effects of a nAChR antagonist, mecamylamine, and partial agonist, varenicline, on cognitive function in non-smokers with and without schizophrenia.

Methods: Single oral doses of mecamylamine 10 mg, varenicline 1 mg, and placebo were administered 1 week apart in random order to adults with schizophrenia (n = 30) and to healthy volunteers (n = 41) in a double-blind, crossover design. The primary outcome of interest was sustained attention as assessed with hit reaction time variability (HRT-SD) on the identical pairs continuous performance test (CPT-IP).

Results: Mecamylamine worsened performance on CPT-IP HRT-SD, a measure of attention, compared to varenicline in both groups. Performance on mecamylamine was worse than performance on both placebo and varenicline on several additional measures of attention, including CPT-IP hit reaction time (HRT) and random errors at various levels of task difficulty. There was a treatment by diagnosis interaction, such that mecamylamine worsened performance on CPT-IP 2-digit HRT, 3-digit random errors, and 4-digit hit rate compared to placebo and varenicline in participants with schizophrenia; effects not observed in controls.

Conclusions: These findings support a role for nAChRs in attention and suggest that those with schizophrenia may be particularly sensitive to nAChR blockade.

Figures

Figure 1

Sustained attention as assessed with the standard deviation of the hit reaction time on the identical pairs continuous performance task was worse in both those with and without schizophrenia on mecamylamine than varenicline, while neither differed from placebo.

Fig. 2

Treatment effects of mecamylamine, varenicline, and placebo on hit rate (top row), random errors (second row), hit reaction time (third row) in the continuous performance test, identical pairs version (CPT-IP) with 2-digit (left column), 3-digit (middle), and 4-digit (right) targets. For outcome variables that showed a significant treatment by diagnosis (schizophrenia vs. control) interaction, the interaction graph is shown in place of the main effect graph. In each panel, bars or data points that do not share common letters are different at a significance level of p<0.05 (Tukey-adjusted). In all three interactions, CPT-IP performance was worse on mecamylamine in those with schizophrenia compared to performance on varenicline or placebo, while performance of controls was unaffected by either medication.