Early nicotine withdrawal and transdermal nicotine effects on neurocognitive performance in schizophrenia
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.
References (49)
- et al.
Cognitive and emotional influences in the anterior cingulate cortex
Trends in Cognitive Sciences
(2000) - et al.
The effectiveness of nicotine-patch therapy for smoking cessation in patients with schizophrenia
International Journal of Nursing Studies
(2004) - et al.
A fronto-parietal network for rapid visual information processing: a PET study of sustained attention and working memory
Neuropsychologia
(1996) - et al.
Polydipsia and schizophrenia in a psychiatric hospital: a replication study
Schizophrenia Research
(2002) Measuring tobacco smoke exposure: Quantifying nicotine/cotinine concentration in biological samples by colorimetry, chromatography and immunoassay methods
Journal of Pharmaceutical and Biomedical Analysis
(2004)- et al.
Human post-mortem striatal α4β2 nicotinic acetylcholine receptor density in schizophrenia and Parkinson's syndrome
Neuroscience Letters
(2000) - et al.
The activation of attentional networks
NeuroImage
(2005) - et al.
Nicotine replacement therapy
Primary Care
(1999) - et al.
Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia
Biological Psychiatry
(1995) - et al.
Attentional network task performance in patients with schizophrenia–spectrum disorders: evidence of a specific deficit
Schizophrenia Research
(2006)
Nicotine effects on brain function and functional connectivity in schizophrenia
Biological Psychiatry
Cognitive effects of nicotine in humans: an fMRI study
NeuroImage
Cognitive mechanisms of nicotine on visual attention
Neuron
Smoking and schizophrenia: abnormal nicotinic receptor expression
European Journal of Pharmacology
Nicotine–haloperidol interactions and cognitive performance in schizophrenia
Neuropsychopharmacology
Arousal systems
Current Opinion in Neurobiology
Semantic disturbance in schizophrenia and its relationship to the cognitive neuroscience of attention
Biological Psychology
Attentional networks and cingulum bundle in chronic schizophrenia
Schizophrenia Research
Selective anterior cingulated cortex deficit during conflict solution in schizophrenia: An event-related potential study
Journal of Psychiatry Research
Mortality and causes of death in schizophrenia in Stockholm county, Sweden
Schizophrenia Research
Tobacco use in schizophrenia: a study of cotinine concentrations in the saliva of patients and controls
European Psychiatry
Selective impairment of attentional networks of orienting and executive control in schizophrenia
Schizophrenia Research
Increased nicotine and cotinine levels in smokers with schizophrenia and schizoaffective disorders is not a metabolic effect
Schizophrenia Research
Scale for the Assessment of Negative Symptoms (SANS)
Cited by (44)
The effects of acute nicotine administration on cognitive and early sensory processes in schizophrenia: a systematic review
2020, Neuroscience and Biobehavioral ReviewsCitation Excerpt :In parallel, seven randomized placebo-controlled crossover blinded trials investigated the effects of acute nicotine administration in schizophrenia subjects only, either in schizophrenia smokers alone (Boggs et al., 2013; Ghiasi et al., 2013; Levin et al., 1996; Smith et al., 2002) or between the schizophrenia smoker and schizophrenia nonsmoker subgroups (Harris et al., 2004; Quisenaerts et al., 2014; Smith et al., 2006). Finally, two trials involving both schizophrenia and non-schizophrenia controls did not include a placebo condition (AhnAllen et al., 2008; Myers et al., 2004). Four placebo-controlled studies observed statistically significant improvements of cognitive performance after acute nicotine administration in schizophrenia patients.
Effects of nicotine on inhibitory control in humans
2019, Neuroscience of Nicotine: Mechanisms and TreatmentEmergent Cognitive Impairment During Early Nicotine Withdrawal
2017, Negative Affective States and Cognitive Impairments in Nicotine DependenceSchizophrenia, smoking status, and performance on the matrics Cognitive Consensus Battery
2016, Psychiatry ResearchSubtype-selective nicotinic acetylcholine receptor agonists can improve cognitive flexibility in an attentional set shifting task
2016, NeuropharmacologyCitation Excerpt :The notable observation of heavy tobacco use amongst patients with schizophrenia (Chapman et al., 2009; Miyata, 2008; Tidey et al., 2005) highlights the notion of self-medication to remediate the cognitive deficits. Studies have shown that acute nicotine exposure can improve cognition, independent of smoking in patients diagnosed with schizophrenia (AhnAllen et al., 2008; Barr et al., 2008; Sacco et al., 2005). With the limited array of medications to enhance cognition, there has been a growing interest in targeting nAChRs, particularly those that activate combinations of nicotinic subunits (α2-10, β2-4), with the most predominant isoforms α4β2 and α7 subtypes which are implicated in attentional deficits (Freedman et al., 1997).
Pharmacological Treatment of Cognitive Dysfunction in Neuropsychiatric Disorders
2015, Cognitive Enhancement: Pharmacologic, Environmental and Genetic Factors