Effects of Varenicline on Plasticity in Schizophrenia

Overview

This laboratory pilot study will explore the effects of varenicline tartrate on long-term potentiation (LTP)-like mechanisms of (1) the motor cortex and (2) the dorsolateral prefrontal cortex (DLPFC) and working memory in non-smoking patients with schizophrenia and healthy controls using a Paired Associative Stimulation (PAS) method. The present study will use this novel PAS method to evaluate the effects of five doses of varenicline (Champix) 0.5 mg BID treatment on neuroplasticity changes and working memory in 28 non-smokers with schizophrenia and 28 non-smoking controls in a placebo-controlled, double-blinded, cross-over design. The hypothesis is that varenicline will increase LTP-like facilitation of the DLPFC as compared with placebo in patients with schizophrenia, with less or a null effect in healthy controls. Likewise, it is hypothesized that varenicline will specifically improve working memory in patients with schizophrenia as compared with placebo and healthy controls. We Hypothesize that: 1.Patients with Schizophrenia(SCZ) will have reduced cortical LTP and impaired working memory compared to healthy controls 2. Sub-chronic varenicline challenge will attenuate the cortical LTP and working memory deficit in patients with SCZ. 3.Reversal of the cortical LTP deficit by varenicline in patients with SCZ will be associated with improvement in working memory.

The experimental laboratory study will be designed as a randomized, double-blinded, placebo-controlled acute treatment trial. Paired Associative Stimulation (PAS)-induced cortical evoked activity and Working Memory (WM) will be assessed in healthy non-smokers and non-smokers with SCZ, after five doses of varenicline tartrate (0.5 mg/dose) and placebo treatment. PAS will be induced by pairing transcranial magnetic stimulation with peripheral nerve stimulation, 25 msec apart (hence PAS-25). In part 1, motor cortex plasticity will be assessed as changes in motor evoked potential comparing pre to post PAS up tp 120 min after PAS. In part 2, DLPFC evoked cortical activity will be assessed using EEG comparing pre to post PAS. Effects of varenicline and PAS-25 on WM will evaluated using a computerized N-back task, assessed directly before the PAS testing. The whole experimental session will be repeated for each participant twice: once with varenicline tartrate treatment and once with placebo treatment, two weeks apart.