The Effects of Transdermal Nicotine on Cognition in Nonsmokers with Schizophrenia and Nonpsychiatric Controls
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Neuropsychopharmacology (2008) 33, 480–490 & 2008 Nature Publishing Group All rights reserved 0893-133X/08 $30.00 www.neuropsychopharmacology.org The Effects of Transdermal Nicotine on Cognition in Nonsmokers with Schizophrenia and Nonpsychiatric Controls 1,2,3 1,2 1 1,2,3 1,2 Ruth S Barr , Melissa A Culhane , Lindsay E Jubelt , Rana S Mufti , Michael A Dyer , 1,3 3,4 2,3 1,3 1,3 Anthony P Weiss , Thilo Deckersbach , John F Kelly , Oliver Freudenreich , Donald C Goff ,1,2,3 and A Eden Evins* 1 2 The Schizophrenia Program of the Massachusetts General Hospital, Boston, MA, USA; The Addiction Research Program of the Massachusetts 3 4 General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Cognitive Neuroscience Program of the Massachusetts General Hospital, Boston, MA, USA Abundant evidence indicates that the neuronal nicotinic acetylcholine receptor (nAChR) system is integral to regulation of attentional processes and is dysregulated in schizophrenia. Nicotinic agonists may have potential for the treatment of cognitive impairment in this disease. This study investigated the effects of transdermal nicotine on attention in individuals with schizophrenia (n ¼ 28) and healthy controls (n ¼ 32). All participants were nonsmokers in order to eliminate confounding effects of nicotine withdrawal and reinstatement that may occur in the study of smokers. Subjects received 14 mg transdermal nicotine and identical placebo in a randomized, placebo- controlled, crossover design. A cognitive battery was conducted before and 3 h after each patch application. The primary outcome measure was performance on the Continuous Performance Test Identical Pairs (CPT-IP) Version. Nicotine significantly improved the performance on the CPT-IP as measured by hit reaction time, hit reaction time standard deviation and random errors in both groups. In addition, nicotine reduced commission errors on the CPT-IP and improved the performance on a Card Stroop task to a greater extent in those with schizophrenia vs controls. In summary, nicotine improved attentional performance in both groups and was associated with greater improvements in inhibition of impulsive responses in subjects with schizophrenia. These results confirm previous findings that a single dose of nicotine improves attention and suggest that nicotine may specifically improve response inhibition in nonsmokers with schizophrenia. Neuropsychopharmacology (2008) 33, 480–490; doi:10.1038/sj.npp.1301423; published online 18 April 2007 Keywords: schizophrenia; nicotine; smoking; cognition; attention; nonsmokers INTRODUCTION administration in smokers with schizophrenia and in nonsmoking first-degree relatives of patients with schizo- Accumulated evidence suggests that dysregulation of the phrenia (Adler et al, 1992, 1993; Freedman et al, 1997; neuronal nicotinic acetylcholine receptor (nAChR) system Leonard et al, 2002). Nicotine also improves disease- contributes to the pathophysiology of schizophrenia. associated deficits in prepulse inhibition (PPI) of the Postmortem studies have revealed a reduction in low- acoustic startle response (Kumari et al, 2001) and affinity nAChRs in the hippocampus, and reduced smoking- oculomotor function, with improvements reported in related upregulation of high-affinity nAChRs in the cortex, smooth pursuit eye movement (SPEM) and antisaccade hippocampus, and caudate at all levels of smoking error rates (Olincy et al, 1998, 2003; Depatie et al, 2002; compared with controls (Freedman et al, 1995; Breese Sherr et al, 2002; Avila et al, 2003). These findings, et al, 2000). Deficient P50 auditory sensory gating has been combined with the observation that the prevalence of linked to polymorphisms at the site of the a7nAChR gene on cigarette smoking is much higher in schizophrenia com- chromosome 15q14 and is transiently reversed by nicotine pared with the general population, (Hughes, 1986; de Leon et al, 2002) have led to the hypothesis that smoking These data have been accepted for presentation in part at the represents a form of self-medication for patients with International Congress on Schizophrenia Research, Colorado Springs, psychiatric illness, particularly schizophrenia (Glassman, 30 March 2007. 1993; Dalack et al, 1998; Kumari and Postma, 2005). *Correspondence: Dr AE Evins, Schizophrenia Program and Director, Addiction Research Program Massachusetts General Hospital, 25 Cognitive dysfunction is thought to have a significant Staniford Street, Boston, MA 02114, USA, Tel: + 1 617 912 7832, Fax: impact on functional outcome in schizophrenia, and + 1 617 723 3919, E-mail: [email protected] intensive research is being focused on identification of Received 26 January 2007; revised 12 March 2007; accepted 13 March treatments for cognitive impairment in this disorder 2007 (Green, 1996, 2000; Marder and Fenton, 2004; Marder Effects of nicotine on cognition in schizophrenia RS Barr et al 481 et al, 2004). There is increasing evidence that nAChR controls. The study was carried out in accordance with the stimulation has beneficial effects on cognitive function in Declaration of Helsinki and was approved by the Institu- schizophrenia, possibly via presynaptic modulation of tional Review Boards of the Massachusetts Department of dopamine and/or glutamate release (McGehee et al, 1995; Mental Health and the Massachusetts General Hospital. All George et al, 2000; Picciotto et al, 2000; Wonnacott et al, participants were assessed by a doctoral level investigator as 2000). The administration of both short- and long-acting competent to consent and signed informed consent prior to preparations of nicotine to individuals with schizophrenia participation. has been associated with improved neuropsychological Nonsmokers with schizophrenia on a stable dose of performance (Levin et al, 1996b; Depatie et al, 2002; Smith antipsychotic medication were recruited from the out- et al, 2002, 2006; Harris et al, 2004; Jacobsen et al, 2004; patient population of an urban community mental health Myers et al, 2004). Acute administration of the selective clinic. Diagnosis of schizophrenia or schizoaffective dis- a7nAChR partial agonist, DMXB-A, improved P50 gating order depressed type by DSM-IV criteria was confirmed by compared with placebo (Olincy et al, 2006) and adminis- clinical interview and medical record review by a study tration of the nAChR antagonist, mecamylamine, blocked psychiatrist (RB or EE). Control participants were recruited smoking-associated improvements in performance on using advertising in local press and internet sites. Eligible attentional and visuospatial working memory (VSWM), participants were aged 18–65 years, scored X35 on the implying that nAChR activation mediates smoking-related Wide Range Achievement Test-3rd version (WRAT 3 blue cognitive enhancement (Sacco et al, 2005). If nAChR form, Jastak Associates, Wilmington, DE, USA), and were activation improves cognitive dysfunction in schizophrenia, nonsmokers for X3 months prior to enrollment. Self-report then smoking abstinence would be expected to result in of nonsmoking status was confirmed by semi-quantitative deterioration in cognitive performance. Performance on a salivary cotinine o10 ng/ml (NicalertTM, JANT Pharmacal VSWM task deteriorated in those with schizophrenia and Corporation, Encino, CA, USA) and expired air carbon improved in smokers with no psychiatric illness during monoxide (CO) o9 p.p.m., measured using a Bedfont Micro early smoking abstinence (George et al, 2002), and seven Smokerlyzer III (Bedfont Scientific Ltd., Kent, UK). Subjects days of smoking abstinence resulted in significant impair- were excluded if they met criteria for diagnosis of substance ments in psychomotor performance amongst smokers with abuse or dependence other than caffeine in the past month schizophrenia (Evins et al, 2005b). by self-report or tested positive on a salivary drug screen In summary, current evidence suggests that nicotinic for phenylcyclidine (PCP), tetrahydrocannabinol (THC), agonists may have a therapeutic use for the treatment of cocaine, opiates, methamphetamine, amphetamine (Accutest cognitive dysfunction in schizophrenia and possibly other Saliva TestTM, JANT Pharmacal Corporation, Encino, CA, neuropsychiatric disorders (Levin et al, 1996a; White and USA) or alcohol (ALCO Screen, CHEMATICS, Inc., North Levin, 1999; Kelton et al, 2000). However, many studies Webster, IN, USA). Other exclusion criteria for both investigating the effects of nicotinic stimulation in schizo- schizophrenia and control groups were lifetime diagnosis phrenia have been conducted in smokers who have under- of cognitive impairment secondary to head injury, dementia gone a brief period of abstinence from smoking prior to or general medical illness, use of investigational medication testing of nicotine effects. Under such circumstances, in the past month, current diagnosis of major depressive cognitive benefits observed following the nicotine admin- disorder, current unstable medical illness including hyper- istration may be confounded by reversal of nicotine tension or ischemic heart disease, or a known allergy to withdrawal symptoms or limited by tachyphylaxis (Harris constituents of the nicotine patch. Individuals with schizo- et al, 2004). We, therefore, performed the following study to phrenia were excluded if there was evidence of recent investigate the acute effects of nicotine on cognition in deterioration in their mental state such as a change in nonsmokers with schizophrenia and healthy controls.