Effects of varenicline on motor cortical plasticity in non-smokers with schizophrenia

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Abstract

Background

Nicotinic acetylcholine receptors (nAChR) have been implicated in the pathophysiology of schizophrenia, and deficits in this system may contribute to high rates of cigarette smoking in this population. nAChR stimulation may modulate neuroplasticity, or long-term potentiation (LTP), which is a key mediator of cognitive performance. Varenicline is a nAChR partial agonist that may improve cognitive deficits in both smokers and non-smokers with schizophrenia; however, the mechanism by which varenicline alters cognition in schizophrenia remains unclear. Thus, the aim of this randomized, double-blind, placebo-controlled, crossover study was to determine the effects of varenicline on LTP-like plasticity indexed through transcranial magnetic stimulation (TMS) in non-smokers with schizophrenia.

Methods

Varenicline (0.5 mg BID × 5 doses) or placebo was administered to 9 non-smokers with schizophrenia and 10 non-smoker healthy subjects. LTP-like plasticity was induced by TMS and paired associative stimulation (PAS) at 0.1 Hz to the left motor cortex and measured every 15 min for two hours post-PAS.

Results

There was a significant diagnosis × medication interaction on peak potentiation (F (3, 34) = 6.04, p < 0.02) and post-hoc analyses indicated that varenicline significantly increased LTP in schizophrenia and decreased LTP in healthy subjects.

Conclusions

These preliminary findings suggest that varenicline may produce differential effects in non-smoking schizophrenia compared to control subjects. Given the role of LTP in learning and memory, these observations may suggest the potential for varenicline in the treatment of cognitive deficits in patients with schizophrenia.

Introduction

Schizophrenia is a severe neuropsychiatric illness affecting approximately 1% of individuals worldwide (Saha et al., 2005), and is characterized by positive, negative, and cognitive symptoms. Cognitive deficits remain one of the most important predictors of poor functional outcome in schizophrenia (Green, 2006), yet there are currently no effective treatments. Nicotine alters cognitive performance via nicotinic acetylcholine receptors (nAChRs). Interestingly, cigarette smoking prevalence in schizophrenia is very high (de Leon and Diaz, 2005, Mackowick et al., 2012, McClave et al., 2010), and nAChR density and number are reduced in post-mortem brains of patients with schizophrenia compared to non-psychiatric subjects (Guan et al., 1999, Severance and Yolken, 2008). Smokers with schizophrenia may perform better than non-smokers on some cognitive tasks (Harris et al., 2004, Morisano et al., 2013, Smith et al., 2006, Wing et al., 2011). Mechanisms that underlie nicotine's procognitive effects in schizophrenia are, however, poorly understood.

nAChRs are widely dispersed throughout the brain and likely contribute to a variety of downstream processes involved in learning, memory, and cognition (Becker et al., 2013, Jones et al., 1999), that are, in turn, reliant on functional neuroplasticity (Martin et al., 2000). Long-term potentiation (LTP) is one form of Hebbian neuroplasticity (Hebb, 1949) that occurs when synaptic strength increases in response to coincident activation of neighboring cells. Associative LTP occurs when presynaptic inputs from different regions converge onto the same post-synaptic cell (Levy and Steward, 1983), providing a temporal framework for how brain regions communicate and form lasting connections. Nicotine, by activating nAChRs, can alter LTP at the pre-synaptic or post-synaptic level by altering Ca2 + flux into the cell and increasing the likelihood of response (Ji et al., 2001), and by modifying the density of glutamatergic receptors on the cell surface (Levy and Aoki, 2002). LTP can be measured in vivo using a non-invasive brain stimulation technique called paired associative stimulation (PAS).

The PAS paradigm pairs right peripheral nerve stimulation (PNS) at 0.1 Hz 25 ms before delivery of a transcranial magnetic stimulation (TMS) pulse to the contralateral motor cortex (Stefan et al., 2000). These paired stimulations are administered for 30 min, and the motor-evoked potential (MEP) amplitude is assessed before and after PAS to determine the extent of potentiation (Stefan et al., 2000). Studies have shown reliable and long-lasting potentiation induced in the motor cortex using the PAS paradigm (Classen et al., 2004, Rajji et al., 2011, Stefan et al., 2000), reflective of the properties of LTP. Subjects with schizophrenia demonstrate deficits in motor cortical plasticity compared to non-psychiatric subjects using the PAS paradigm, evaluated at 0, 15, 30, and 60 min post-PAS (Frantseva et al., 2008). Patients in this study also showed a relationship between LTP and motor skill learning during a rotary pursuit task, suggesting that the PAS protocol may be a neurophysiological measure of LTP in humans (Frantseva et al., 2008).

Varenicline is a nAChR partial agonist at the α4β2 receptor and a full agonist at the α7 receptor (Coe et al., 2005). It is one of the most effective smoking cessation medications available, and appears to be safe and tolerable in smokers with schizophrenia (Shim et al., 2012, Williams et al., 2012). In addition to improving cessation outcomes in patients with schizophrenia (Evins et al., 2014, Williams et al., 2012), varenicline has been shown to enhance cognition (Hong et al., 2011, Roh et al., 2014, Shim et al., 2012, Smith et al., 2009) and blunt abstinence-induced deficits in cognition in smokers (Liu et al., 2011, Wing et al., 2013). Only one study has evaluated the effects of varenicline on PAS-induced LTP, and found that varenicline had no effect on LTP in healthy non-smokers (Batsikadze et al., 2015), perhaps due to a ceiling effect of nAChR function or to single dose methodology. In contrast, non-smokers with schizophrenia may selectively benefit from varenicline due to pre-existing deficits in nAChR density and function (Breese et al., 2000, Leonard et al., 2000).

As patients with schizophrenia show impaired nAChR function as well as cognitive deficits, the aim of this study was to use varenicline to determine whether nAChRs are involved in mediating LTP-like plasticity in schizophrenia. To eliminate the potential confounds of cigarette smoking and withdrawal, we studied biochemically-verified non-smokers. Using a randomized, placebo-controlled, double blind crossover design, our objective was to examine whether varenicline given at 0.5 mg bid for 5 doses affects LTP-like plasticity in schizophrenia versus healthy subjects. We hypothesized that PAS-induced LTP would be impaired in non-smokers with schizophrenia, and that varenicline would selectively improve these deficits relative to non-smoking healthy subjects.

Section snippets

Subjects

A total of 9 non-smokers with a diagnosis of schizophrenia or schizoaffective disorder (confirmed by Structured Clinical Interview for the DSM-IV (First et al., 2002)) and 10 non-smoker non-psychiatric healthy subjects completed this study. Inclusion criteria for both non-smokers with schizophrenia and healthy subjects were: 1) age between 18 and 55 years, 2) biochemically verified current non-smoking status, 3) IQ score ≥ 90 as determined by the Wechsler Test of Adult Reading (Wechsler, 2001),

Results

A total of 24 subjects were initially enrolled in this study. Two subjects dropped out before completion, and three subjects displayed potentiation of > 2.5 standard deviations above the mean and were not suitable for analysis, leaving a total of 19 (see CONSORT Diagram, Fig. 3). Demographic information is presented in Table 1. There were no differences in sex (χ2 = 1.31, p = 0.25), race (χ2 = 2.55, p = 0.28), age (t = 0.15, p = 0.88), and years of education (t (17) =  1.13, p = 0.27). However, patients with

Discussion

In this preliminary study, we evaluated the effects of the nicotinic partial agonist varenicline (1.0 mg/day in twice daily dosing) over 5 doses on PAS-induced LTP in 9 non-smokers with schizophrenia compared to 10 healthy non-smokers. Varenicline significantly enhanced peak potentiation in non-smokers with schizophrenia compared to healthy subjects, suggesting that the effects of varenicline on cognitive processes may be mediated by enhancement of neuroplasticity.

Varenicline was administered

Conclusion

This is a preliminary study to assess the effects of varenicline on PAS-induced LTP in non-smokers with schizophrenia compared to healthy subjects. Varenicline significantly affected peak potentiation in patients with schizophrenia versus healthy subjects.

These results provide valuable insights into the role of nAChRs in the pathophysiology of schizophrenia that may be independent of smoking status. Deficits in neuroplasticity in schizophrenia may form the basis of many phenotypic

Contributors

ACB collected and analyzed the data, and prepared the manuscript. TPG, MSB, MSG, RZ, TR, and ZJD designed and wrote the study protocol. All authors contributed to and have approved the final manuscript.

Funding

This work was supported in part by the Canadian Institutes of Health Research (CIHR) grant MOP#115145, by a contract from Pfizer, Inc. (Contract#WI172662) to Dr. George, and by a studentship from the Institute of Medical Sciences, University of Toronto (to Ms. Bridgman).

Conflict of interest

Dr. George reports research contract support from Pfizer for varenicline related industry and investigator-initiated studies, and is a consultant for Novartis and the Canadian Council for Substance Abuse (CCSA). All other authors have no conflicts to declare.

Acknowledgment

We thank Emily Simpkin, RN for subject medical evaluations, and Maryam Sharif-Razi and Marya Morozova for technical assistance.

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