Early nicotine withdrawal and transdermal nicotine effects on neurocognitive performance in schizophrenia

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Abstract

As cigarette smoking prevalence rates approach 90% in schizophrenia, an important emerging question is the role of nicotine in the disease-related disturbance in cognition. We therefore tested a total of 38 male cigarette smokers (22 schizophrenia, 16 normal control), matched on nicotine dependence, on the Attention Network Test (ANT) at three nicotine conditions (baseline, 8 h overnight withdrawal, 3 h 21 mg nicotine patch). The results indicated that the groups did not differ in performance on either of three ANT measures (alertness, orienting, and executive) across baseline, patch, and withdrawal conditions. However, in comparison to the controls, the participants with schizophrenia showed faster ANT reaction time (RT) for the nicotine patch in relation to the baseline condition. In comparison to controls, the participants with schizophrenia also showed reduced ANT accuracy at withdrawal but not at patch condition. These results suggest that overall processing speed and accuracy are affected differently by nicotine levels in participants with schizophrenia, with evidence supporting greater impairment from withdrawal and greater improvement from nicotine administration.

Introduction

Prevalence rates of cigarette use in schizophrenia approach 70–90% (Dalack et al., 1998), and the reasons for increased use are not well understood (McCloughen, 2003). Smokers with schizophrenia have elevated rates of lung cancer (Lichtermann et al., 2001), cardiovascular disease (Osby et al., 2000), tardive dyskinesia (Chong et al., 2003) and polydipsia (de Leon et al., 2002). Biological abnormalities of nicotinic acetylcholine receptors are also established in schizophrenia including α4β2 (hippocampus, Freedman et al., 1995; striatum, Durany et al., 2000) and α7 subunits (hippocampus, Leonard et al., 1998, Leonard et al., 2000).

Smoking may ameliorate many well described cognitive deficits in schizophrenia. Nicotine is known to enhance cognition (Kumari et al., 2003), including attention and memory (George et al., 2001, Levin et al., 1996), which are impaired in schizophrenia (Fioravanti et al., 2005). Previous studies in schizophrenia report improved reaction time with nicotine spray (Smith et al., 2006) but impaired accuracy at withdrawal with a return to baseline following smoking reinstatement (Sacco et al., 2005).

The Attention Network Test (ANT), a novel means of evaluating attention functioning, has received empirical support in the literature (Fan et al., 2002, Fan et al., 2005). In combining flanker (Eriksen and Eriksen, 1974) and cue reaction time (Posner, 1980) paradigms, the ANT provides a measure of the efficiency of three independent networks of attention, referred to as alerting, orienting, and executive (Fan et al., 2002). Each network is associated with differential activation of particular networks of neuroanatomical regions (Fan et al., 2002, Fan et al., 2005). The alerting network, which uses warning signals to provide for faster information processing, is associated with norepinephrine frontal and parietal circuits within the right hemisphere (Coull et al., 1996, Marrocco et al., 1994). The orienting network, which uses directional warning signals to facilitate stimuli location detection, is associated with thalamic, frontal and superior parietal regions (Corbetta et al., 2000, Rafal and Posner, 1987). The executive network, which provides resolution of conflict, processing of novel stimuli and error detection, is associated with the anterior cingulate cortex and lateral prefrontal cortex (Bush et al., 2000, Posner and DiGirolamo, 1998).

The use of the ANT as a cognitive measure has been reported in schizophrenia (Nestor et al., 2007, Gooding et al., 2006, Wang et al., 2005). It has been also used to assess nicotine impact. Following overnight abstinence in cigarette smokers, 21 mg nicotine patch had no effect on attention networks but both nicotinized and denicotinized cigarettes improved alerting attention (Kleykamp et al., 2007). In schizophrenia, attention studies using the ANT are inconsistent. Wang et al. (2005) report more impaired orienting and executive network function in schizophrenia compared to a control group. In contrast, Nestor et al. (2007) reported reduced alerting network function, which was associated with a smaller white matter fiber tract in the cingulum bundle. Gooding et al. (2006) suggest a specificity of executive attention dysfunction in schizophrenia as well as poorer reaction time and accuracy rates to controls. Despite the variability, the ANT is a useful method of attention assessment in schizophrenia.

We examined the effects of nicotine levels on attention networks and performance functioning in schizophrenia. Using a design that included repeated administration of the ANT at baseline, post-overnight withdrawal and post-transdermal nicotine patch, we planned to understand how nicotine might impact attention networks and performance measures (i.e., RT and accuracy). We predicted that persons with schizophrenia would demonstrate greater impairment in attention network function in comparison to control participants. Nicotine level was expected to predict outcomes (transdermal patch > baseline > withdrawal), with a schizophrenia diagnosis associated with greater impairment. In addition, we analyzed performance measures to better understand how they are affected by nicotine levels manipulations.

Section snippets

Participants

Participants, 18–60 years old, with DSM-IV (SCID-P; First et al., 1997) schizophrenia or schizoaffective disorder were recruited from the VA Boston Healthcare System. Control participants, 18–60 years old, were recruited from the community. Exclusion criteria for schizophrenia participants included alcohol/drug abuse (past year) and dependency (past five years), allergy/hypersensitivity to adhesives, current smoking cessation treatment, history of seizure disorder, neurological illnesses, or

Nicotine analyses

Three participants (2 control, 1 schizophrenia) were removed from analyses given abnormally high nicotine levels (z-score > 2.50; Stevens, 1999). These abnormal levels were found at baseline (1 control), withdrawal (1 control, 1 schizophrenia) and nicotine patch (1 control). One control participant had elevated nicotine levels at both baseline and nicotine patch assessments. Analyses were completed with 21 participants with schizophrenia and 14 controls.

A 2 × 3 mixed-model ANOVA with one

Discussion

The study examined the effects of nicotine on ANT performance in schizophrenia. Results indicated that the groups did not differ in performance on either of three ANT measures (alertness, orienting, and executive) across baseline, patch, and withdrawal conditions. However, compared to controls, the participants with schizophrenia showed faster ANT RT for the nicotine patch in relation to the baseline condition. The participants with schizophrenia also showed reduced ANT accuracy at withdrawal

Role of funding source

This work was supported by a Schizophrenia Dissertation Fellowship from the Supreme Council 33° of the Scottish Rite Masonic Organization and Harvard Medical School (CGA), Manfred Meier Neuropsychology Scholarship from the American Psychological Foundation and Division 40 — Clinical Neuroscience of the American Psychological Association (CGA), Craig R. Bollinger Memorial Dissertation Research Grant from the Graduate Student Assembly at the University of Massachusetts Boston (CGA), and a Stanley

Contributors

Authors AhnAllen and Nestor designed the study and wrote the protocol. Author AhnAllen managed the literature searches and analyses. Authors AhnAllen and Nestor undertook the statistical analysis, and author AhnAllen wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest

All authors declare that they have no conflicts of interest.

Acknowledgements

The authors acknowledge and appreciate the contribution of all research participants who participated in this study. We would also like to thank Jane Adams, Ph.D. and Tiffany Cunningham, Ph.D. for their contributions to this project development.

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