Effects of Moderate-Dose Treatment With Varenicline on Neurobiological and Cognitive Biomarkers in Smokers and Nonsmokers With Schizophrenia or Schizoaffective Disorder

Abstract

Context Nicotine administration transiently improves many neurobiological and cognitive functions in schizophrenia. It is not yet clear which nAChR subtype(s) is responsible for these seemingly pervasive nicotinic effects in schizophrenia. Objective α4β2 is a key nAChR subtype for nicotinic actions. We investigated the effect of varenicline, a relatively specific α4β2 partial agonist/antagonist, on key biomarkers that are associated with schizophrenia and are previously shown to be responsive to nicotinic challenge in humans. Design double-blind, parallel, randomized, placebo controlled trial in schizophrenia patients to examine effects of varenicline on biomarkers at short-term (2 week) and long-term (8 week), using a slow titration and moderate dosing strategy for retaining α4β2 specific effect while minimizing side effects. Setting Outpatients. Participants 69 smoking and nonsmoking patients randomized; 64 completed week 2; 59 completed week 8. Intervention(s) varenicline. Main Outcome Measure(s) prepulse inhibition, sensory gating, antisaccade, spatial working memory, eyetracking, processing speed, and sustained attention. Results Moderate dose of varenicline 1) reduced P50 sensory gating deficit after a long-term (p=0.006) but not short-term treatment; significant in nonsmokers but not in smokers; 2) reduced startle reactivity (p=0.015) regardless of baseline smoking status; and 3) improved executive function by reducing antisaccade error rate (p=0.034) regardless of smoking status. Moderate dose varenicline had no significant effect on spatial working memory, predictive and maintenance pursuit, processing speed, or sustained attention by Connor’s CPT. Clinically, there was no evidence of exacerbation of psychiatric symptoms, psychosis, depression, or suicidality using a gradual titration, 1 mg daily dose. Conclusions Moderate dose varenicline has a unique treatment profile on core schizophrenia related biomarkers. Further development is warranted for specific nAChR compounds and dosing/duration strategy to target subgroup of schizophrenia patients with specific biological deficits. ClinicalTrials.gov Identifier: NCT00492349

Varenicline and Adverse Cardiovascular Events: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials

“…After the removal of duplicates and screening of titles and abstracts, 68 trials underwent full‐text review. In total, 38 RCTs met all eligibility criteria and were included in our meta‐analysis 10, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49…”

Cognitive Effects of Very Low Nicotine Content Cigarettes, With and Without Nicotine Replacement, in Smokers With Schizophrenia and Controls

“…Others, as in the present study, have not found that SS and CS differ in their responses to nicotine manipulations. 23,28 Some of this inconsistency may be due to different demands of the tasks involved; for example, the visual working memory task in the current study appears less demanding than that used by Sacco et al 7 Thus, more demanding tasks may reveal differential effects of nicotine manipulations on cognitive performance in SS versus CS.…”

“…The CPT-II, CANTAB, and other tasks assessing these domains have been found to be sensitive to smoking or nicotine manipulations in SS or CS in previous studies. 6,7,13,[21][22][23][24][25] The CPT-II was administered on a Dell desktop computer and the CANTAB tests were administered on a Dell laptop computer with a 15″ monitor and a touchscreen overlay (MagicTouch, Keytec, Inc.). Participants began with the MOT test, followed by the RVP, SRT, DMS, and CPT-II tests; alternate test versions,when available, were used across sessions to reduce practice effects.…”

The effect of nicotine on sensorimotor gating is modulated by a CHRNA3 polymorphism

“…However, varenicline reduced startle reactivity regardless of smoking status (Hong et al 2011a). The notion that the α4β2 nAChR agonist varenicline did not enhance PPI speaks in favor of the idea that PPI is mainly modulated at the α3 nAChR subtype, possibly at the α3β2 or the α3β4 receptors.…”

“…In a recent clinical trial, the α4β2 nAChR agonist varenicline did not improve PPI in a sample of smoking and non-smoking patients with schizophrenia or schizoaffective disorder (Hong et al 2011a). However, varenicline reduced startle reactivity regardless of smoking status (Hong et al 2011a).…”