Schizophrenics have high prevalence rates of cigarette smoking (58-88 percent) compared to the general population (-25 percent), and are often nicotine-dependent smokers who have considerable difficulty quitting smoking. Several factors may predispose these patients to cigarette smoking including alleviation of dysphoric mood states, improvements in extrapyramidal symptoms and deficits in information processing and neuropsychological function, as well as genetic factors that determine a vulnerability to both nicotine dependence and schizophrenia. Schizophrenic patients have deficits in cognitive function, including executive function (Wisconsin Card Sorting Test; WCST), verbal and spatial working memory Visuospatial Working Memory (VSWM)], response inhibition (Stroop Color-Word Test; SCWT), attention and concentration (Continuous Performance Test; CPT) and information processing {prepulse inhibition (PPI) of the startle response}. Preliminary evidence suggests that cigarette smoking can improve, and abstinence can worsen, cognitive function in schizophrenic patients. Nicotine withdrawal has been associated with reductions in central dopamine (DA) function in animal and human studies, and several of the above tasks are dependent, in part, on prefrontal cortical DA function. Our preliminary results suggest that smoking abstinence impairs visuospatial working memory (VSWM) in schizophrenic smokers, but improves VSWM in healthy smokers. However, the effects of cigarette smoking and abstinence on cognitive function in schizophrenic vs. healthy smokers have not been carefully evaluated. In the present studies, we will evaluate the effects of cigarette smoking and abstinence on cognitive tests known to be deficient in schizophrenic patients, including neuropsychological tests (WCST, SCWT, CPT, WSPT, VSWM) and PPI. After baseline testing, schizophrenic (n=25) and healthy control (n=25) smokers will undergo overnight smoking abstinence, followed by repeat testing, and then subsequent testing after resuming smoking. A group of schizophrenic (n=25) and healthy (n=25) non-smokers will serve as controls and complete the same sequence of testing. We will also assess the role of high-affinity nicotinic acetylcholine receptors (nAChRs), using pre-treatment with the nAChR antagonist mecamylamine (0.0, 5.0 and 10.0 mg/day), in mediating the effect of cigarette smoking on these cognitive assessments. Accordingly, these studies may provide data on the mechanisms by which cigarette smoking alters cognitive function in schizophrenic vs. control smokers, and suggest novel treatment approaches for both nicotine dependence and cognitive dysfunction in schizophrenic disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA014039-03
Application #
6634347
Study Section
Special Emphasis Panel (ZRG1-BBBP-1 (01))
Program Officer
Aigner, Thomas G
Project Start
2001-03-01
Project End
2005-08-31
Budget Start
2003-03-01
Budget End
2005-08-31
Support Year
3
Fiscal Year
2003
Total Cost
$211,331
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Mackowick, Kristen M; Barr, Mera S; Wing, Victoria C et al. (2014) Neurocognitive endophenotypes in schizophrenia: modulation by nicotinic receptor systems. Prog Neuropsychopharmacol Biol Psychiatry 52:79-85
Wing, Victoria C; Tang, Yi-Lang; Sacco, Kristi A et al. (2013) Effect of COMT Val(158)Met genotype on nicotine withdrawal-related cognitive dysfunction in smokers with and without schizophrenia. Schizophr Res 150:602-3
Morisano, Dominique; Wing, Victoria C; Sacco, Kristi A et al. (2013) Effects of tobacco smoking on neuropsychological function in schizophrenia in comparison to other psychiatric disorders and non-psychiatric controls. Am J Addict 22:46-53
Weinberger, Andrea H; McKee, Sherry A; George, Tony P (2012) Smoking cue reactivity in adult smokers with and without depression: a pilot study. Am J Addict 21:136-44
Wing, Victoria C; Bacher, Ingrid; Sacco, Kristi A et al. (2011) Neuropsychological performance in patients with schizophrenia and controls as a function of cigarette smoking status. Psychiatry Res 188:320-6
Hitsman, Brian; Moss, Taryn G; Montoya, Ivan D et al. (2009) Treatment of tobacco dependence in mental health and addictive disorders. Can J Psychiatry 54:368-78
Weinberger, Andrea H; Hitsman, Brian; Papandonatos, George D et al. (2009) Predictors of abstinence and changes in psychiatric symptoms in a pooled sample of smokers with schizophrenia receiving combination pharmacotherapy and behavioral therapy for smoking cessation. J Clin Psychopharmacol 29:601-3
Woznica, Andrea A; Sacco, Kristi A; George, Tony P (2009) Prepulse inhibition deficits in schizophrenia are modified by smoking status. Schizophr Res 112:86-90
Rabin, Rachel A; Sacco, Kristi A; George, Tony P (2009) Correlation of prepulse inhibition and Wisconsin Card Sorting Test in schizophrenia and controls: effects of smoking status. Schizophr Res 114:91-7
Moss, Taryn G; Sacco, Kristi A; Allen, Taryn M et al. (2009) Prefrontal cognitive dysfunction is associated with tobacco dependence treatment failure in smokers with schizophrenia. Drug Alcohol Depend 104:94-9

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