Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder

Abstract

Context: The administration of nicotine transiently improves many neurobiological and cognitive functions in schizophrenia and schizoaffective disorder. It is not yet clear which nicotinic acetylcholine receptor (nAChR) subtype or subtypes are responsible for these seemingly pervasive nicotinic effects in schizophrenia and schizoaffective disorder.

Objective: Because α4β2 is a key nAChR subtype for nicotinic actions, we investigated the effect of varenicline tartrate, a relatively specific α4β2 partial agonist and antagonist, on key biomarkers that are associated with schizophrenia and are previously shown to be responsive to nicotinic challenge in humans.

Design: A double-blind, parallel, randomized, placebo-controlled trial of patients with schizophrenia or schizoaffective disorder to examine the effects of varenicline on biomarkers at 2 weeks (short-term treatment) and 8 weeks (long-term treatment), using a slow titration and moderate dosing strategy for retaining α4β2-specific effects while minimizing adverse effects.

Setting: Outpatient clinics.

Participants: A total of 69 smoking and nonsmoking patients; 64 patients completed week 2, and 59 patients completed week 8. Intervention Varenicline.

Main outcome measures: Prepulse inhibition, sensory gating, antisaccade, spatial working memory, eye tracking, processing speed, and sustained attention.

Results: A moderate dose of varenicline (1) significantly reduced the P50 sensory gating deficit in nonsmokers after long-term treatment (P = .006), (2) reduced startle reactivity (P = .02) regardless of baseline smoking status, and (3) improved executive function by reducing the antisaccadic error rate (P = .03) regardless of smoking status. A moderate dose of varenicline had no significant effect on spatial working memory, predictive and maintenance pursuit measures, processing speed, or sustained attention by Conners' Continuous Performance Test. 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 treatment with varenicline has a unique treatment profile on core schizophrenia-related biomarkers. Further development is warranted for specific nAChR compounds and dosing and duration strategies to target subgroups of schizophrenic patients with specific biological deficits.

Trial registration: ClinicalTrials.gov NCT00492349.

Figures

Figure 1

Consort flow diagram.

Figure 2

Varenicline treatment effects on PPI and P50 sensory gating. Moderate dose varenicline significantly reduced startle reactivity as measured by the acoustic startle response amplitude in schizophrenia patients compared with placebo (combined smokers and nonsmokers), significant only in week 8 (A); but did not significantly changed %PPI to the startle response (combined smokers and nonsmokers) (B). P50 gating (S2/S1 ratio) was significantly increased (reduced ratio) by moderate dose varenicline compared with placebo; the effect was significant at week 8 in the entire sample (C) and in the nonsmoker subgroup (D) but not significant in the smoker subgroup (E) although the varenicline effect followed the same pattern in both groups. Note that reduced S2/S1 ratio implies improved gating function. P50 average evoked potential amplitude was not significantly different between varenicline and placebo for response to the first click S1 in the entire sample (F) but was significantly reduced by varenicline compared with placebo for response to the second click S2 (G) (combined smokers and nonsmokers). Numbers of subjects (n) in parentheses are subjects with usable data available at baseline (same in all figures below). Numbers of subjects may vary in subsequent time points. Please refer to Figure 1. ALL: smokers and nonsmokers. NSK: nonsmokers. SK: smokers.

Figure 3

Error rate (A) and positional error (B) are the primary outcome measures from the antisaccade and memory saccade tasks, respectively. Moderate dose varenicline improved antisaccade performance but not memory saccade performance compared with placebo in schizophrenia patients (combined smokers and nonsmokers). Numbers of subjects may vary in different time points. Please refer to Figure 1. ALL: smokers and nonsmokers.

Figure 4

Varenicline effect on smoking and clinical symptoms. Cigarette per day (CPD) was significantly reduced by varenicline in schizophrenia smokers (A). Trends of improving rather than worsening total psychiatric symptoms as measured by BPRS total score (B), or psychosis as measured by BPRS psychosis subscale (C) were found (combined smokers and nonsmokers). Notably, apparent treatment differences were manifest early after the start of the treatment and remained relatively constant. Numbers of subjects may vary in different time points. Please refer to Figure 1. ALL: smokers and nonsmokers. NSK: nonsmokers. SK: smokers.