, Volume 219, Issue 1, pp 25–34 | Cite as

Varenicline as a smoking cessation aid in schizophrenia: effects on smoking behavior and reward sensitivity

  • Sunny J. Dutra
  • Luke E. Stoeckel
  • Sara V. Carlini
  • Diego A. Pizzagalli
  • A. Eden EvinsEmail author
Original Investigation



Smoking rates are up to five times higher in people with schizophrenia than in the general population, placing these individuals at high risk for smoking-related health problems. Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, is a promising aid for smoking cessation in this population. To maximize treatment efficacy while minimizing risks, it is critical to identify reliable predictors of positive response to varenicline in smokers with schizophrenia.


Negative symptoms of schizophrenia are related to dysfunctions in the brain reward system, are associated with nicotine dependence, and may be improved by nicotine or nicotinic receptor agonists, suggesting that smoking cessation may be especially difficult for patients with substantial negative symptoms. The purpose of the study was to evaluate negative symptoms as predictors of response to varenicline.


Patients with schizophrenia (N = 53) completed a 12-week smoking cessation trial combining varenicline with cognitive behavioral therapy. Negative symptoms were assessed via the Scale for the Assessment of Negative Symptoms (Andreasen 1983). Outcomes included smoking abstinence as assessed by self-report and expired carbon monoxide. Change in performance on a probabilistic reward task was used as an index of change in reward sensitivity during treatment.


At week 12, 32 participants met criteria for 14-day point-prevalence abstinence. Patients with lower baseline symptoms of affective flattening (more typical affect) were more likely to achieve smoking abstinence and demonstrated larger increases in reward sensitivity during treatment.


These data suggest that affective flattening symptoms in smokers with schizophrenia may predict response to varenicline.


Nicotine Schizophrenia Varenicline Reward Anhedonia Affective flattening Smoking cessation 



The study was funded by NIDA R01 DA021245 (Evins). This grant supported Dr. Evins’ effort on the project. During the study, Dr. Stoeckel was partially supported by the Harvard Medical School Zinberg Fellowship in Clinical Addiction Research and a NIDA Loan Repayment Program Grant, and Dr. Pizzagalli was partially supported by NIMH grants R01MH68376 and R21MH078979.

Disclosures/conflicts of interest

The authors declare no competing financial interests. Dr. Evins has received research support from GSK, Janssen and Pfizer, and honoraria or consulting fees from Boehringer-Ingelheim and Pfizer. Dr. Pizzagalli has received research support and consulting fees from ANT Inc. and honoraria and consulting fee from AstraZeneca.


  1. Alhatem F, Black JE (2009) Varenicline-induced mania in a bipolar patient. Clin Neuropharm 32:117–118CrossRefGoogle Scholar
  2. Andreasen N (1983) Scale for the Assessment of Negative Symptoms (SANS). University of Iowa, Iowa CityGoogle Scholar
  3. Anghelescu I (2009) Successful smoking cessation and improvement of negative symptoms with varenicline in a stable schizophrenia patient. J Neuropsyc Clin Neurosci 21:102–110CrossRefGoogle Scholar
  4. Barr RS, Culhane MA, Jubelt JE et al (2008a) The effects of transdermal nicotine on cognition in nonsmokers with schizophrenia and nonpsychiatric controls. Neuropsychopharmacology 33:480–490PubMedCrossRefGoogle Scholar
  5. Barr RS, Pizzagalli DA, Culhane MA, Goff DC, Evins AE (2008b) A single dose of nicotine enhances reward responsiveness in non-smokers: implications for development of dependence. Biol Psychiatry 63:1061–1065PubMedCrossRefGoogle Scholar
  6. Berridge KC, Kringelbach ML (2008) Affective neuroscience of pleasure: reward in humans and animals. Psychopharmacology 199:457–480PubMedCrossRefGoogle Scholar
  7. Berridge KC, Robinson TE, Aldridge JW (2009) Dissecting components of reward: ‘liking’, ‘wanting’, and learning. Curr Opin Pharmacol 9:65–73PubMedCrossRefGoogle Scholar
  8. Bobes J, Arango C, Garcia-Garcia M, Rejas J (2010) Healthy lifestyle habits and 10-year cardiovascular risk in schizophrenia spectrum disorders: an analysis of the impact of smoking tobacco in the CLAMORS schizophrenia cohort. Schizophr Res 119:101–109PubMedCrossRefGoogle Scholar
  9. Brody AL, Olmstead RE, London ED et al (2004) Smoking-induced ventral striatum dopamine release. Am J Psychiatry 161:1211–1218PubMedCrossRefGoogle Scholar
  10. Bruce ML, Leaf PJ, Florio L, Hoff RA (1994) Psychiatric status and 9-year mortality data in the New Haven epidemiological catchment area study. Am J Psychiatry 151:716–721PubMedGoogle Scholar
  11. Bunney BS, Chiodo LA, Grace AA (1991) Midbrain dopamine system electrophysiological functioning: a review and new hypothesis. Synapse 9:79–94PubMedCrossRefGoogle Scholar
  12. Cahill K, Stead LF, Lancaster T (2008) Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 3:CD006103Google Scholar
  13. Caskey NH, Jarvik ME, Wirshing WC (1999) The effects of dopaminergic D2 stimulation and blockade on smoking behavior. Exp Clin Psychopharm 7:72–78CrossRefGoogle Scholar
  14. Cinemre B, Akdag ST, Metin O, Doganavsargil O (2010) Varenicline-induced psychosis. CNS Spectr 15:469–472Google Scholar
  15. Crunelle CL, Miller ML, De Bruin K, Van Den Brink W, Booij J (2009) Varenicline increases striatal dopamine D2/3 receptor binding in rats. Addict Biol 14:500–502PubMedCrossRefGoogle Scholar
  16. Czermak C, Lehofer M, Wagner EM et al (2004) Dopamine D3 receptor expression in blood lymphocytes of smokers is negatively correlated with daily number of smoked cigarettes: a peripheral correlate of dopaminergic alterations in smokers. Nicotine Tob Res 6:49–54PubMedCrossRefGoogle Scholar
  17. Dagher A, Bleicher C, Aston JAD, Gunn RN, Clarke PBS, Cumming P (2001) Reduced dopamine D1 receptor binding in the ventral striatum of cigarette smokers. Synapse 42:48–53PubMedCrossRefGoogle Scholar
  18. Dalack GW, Healy DJ, Meador-Woodruff JH (1998) Nicotine dependence in schizophrenia: clinical phenomena and laboratory findings. Am J Psychiatry 155:1490–1501PubMedGoogle Scholar
  19. Davis KL, Kahn RS, Davidson M (1991) Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 148:1474–1486PubMedGoogle Scholar
  20. Everitt BJ, Robbins TW (2005) Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 8:1481–1489PubMedCrossRefGoogle Scholar
  21. Evins AE, Goff DC (2008) Varenicline treatment for smokers with schizophrenia: a case series. J Clin Psychiatry 69:1016PubMedCrossRefGoogle Scholar
  22. Fagerstrom K (2002) The epidemiology of smoking: health consequences and benefits of cessation. Drugs 62:1–9PubMedCrossRefGoogle Scholar
  23. Fagerstrom K, Balfour DJ (2006) Neuropharmacology and potential efficacy of new treatments for tobacco dependence. Expert Opin Investig Drugs 15:107–116PubMedCrossRefGoogle Scholar
  24. Fatemi SH (2008) Varenicline efficacy and tolerability in a subject with schizophrenia. Schizophr Res 103:328–329PubMedCrossRefGoogle Scholar
  25. Fehr C, Yakushev I, Hohmann N et al (2008) Association of low striatal dopamine D2 receptor availability with nicotine dependence similar to that seen with other drugs of abuse. Am J Psychiatry 16:507–514CrossRefGoogle Scholar
  26. Foulds J (2006) The neurobiological basis for partial agonist treatment of nicotine dependence: varenicline. Int J Clin Pract 60:571–576PubMedCrossRefGoogle Scholar
  27. Freedman R (2007) Exacerbation of schizophrenia by varenicline. Am J Psychiatry 164:1269PubMedCrossRefGoogle Scholar
  28. Fukui K, Kobayashi T, Hayakawa S et al (1995) Smoking habits in chronic schizophrenics. Arukoru Kenkyuto Yakabutsu Izon 30:447–454Google Scholar
  29. Gholson LJ (2008) Possible varenicline-induced paranoia and irritability in a patient with major depressive disorder, borderline personality disorder, and methamphetamine abuse in remission. J Clin Psychopharmacol 28:720–721CrossRefGoogle Scholar
  30. Ginovart N, Farde L, Halldin C, Swahn CG (1999) Changes in striatal D2-receptor density following chronic treatment with amphetamine as assessed with PET in nonhuman primates. Synapse 31:154–162PubMedCrossRefGoogle Scholar
  31. Glassman AH (1993) Cigarette smoking: implications for psychiatric illness. Am J Psychiatry 150:546–553PubMedGoogle Scholar
  32. Goff DC, Henderson DC, Amico E (1992) Cigarette smoking in schizophrenia: relationships to psychopathology and medication side effects. Am J Psychiatry 149:1189–1194PubMedGoogle Scholar
  33. Grace AA (1991) Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 41:1–24PubMedCrossRefGoogle Scholar
  34. Hall RG, Duhamel M, McClanahan R et al (1995) Level of functioning, severity of illness, and smoking status among chronic psychiatric patients. J Nerv Ment Dis 183:468–471PubMedCrossRefGoogle Scholar
  35. Hautus MJ (1995) Corrections for extreme proportions and their biasing effects on estimated values of d'. Beh Res Methods Instrum Comput 27:46–51Google Scholar
  36. Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO (1991) The Fagerstrom Test for Nicotine Dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br J Addict 86:1119–1127PubMedCrossRefGoogle Scholar
  37. Heerey EA, Bell-Warren KR, Gold JM (2008) Decision-making impairments in the context of intact reward sensitivity in schizophrenia. Biol Psychiatry 64:62–69PubMedCrossRefGoogle Scholar
  38. Heinz A, Knable MB, Coppola R et al (1998) Psychomotor slowing, negative symptoms and dopamine receptor availability—an IBZM SPECT study in neuroleptic-treated and drug-free schizophrenic patients. Schizophr Res 31:19–26PubMedCrossRefGoogle Scholar
  39. Irving JM, Clark EC, Crombie IK, Smith WC (1988) Evaluation of a portable measure of expired-air carbon monoxide. Prev Med 17:109–115PubMedCrossRefGoogle Scholar
  40. Joyce EM, Collinson SL, Crichton P (1996) Verbal fluency in schizophrenia: relationship with executive function, semantic memory and clinical alogia. Psychol Med 26:39–49PubMedCrossRefGoogle Scholar
  41. Jubelt L, Barr R, Goff D, Logvinenko T, Weiss A, Evins A (2008) Effects of transdermal nicotine on episodic memory in non-smokers with and without schizophrenia. Psychopharmacology 199:89–98PubMedCrossRefGoogle Scholar
  42. Juckel G, Schlagenhauf F, Koslowski M et al (2006) Dysfunction of ventral striatal reward prediction in schizophrenia. Neuroimage 29:409–416PubMedCrossRefGoogle Scholar
  43. Kim JS, Komhuber HH, Schmid-Burgk W, Holzmiller B (1980) Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia. Neurosci Lett 20:379–382PubMedCrossRefGoogle Scholar
  44. Kinon BJ, Lieberman JA (1996) Mechanisms of action of atypical antipsychotic drugs: a critical analysis. Psychopharmacology (Berl) 124:2–34CrossRefGoogle Scholar
  45. Martinot JL, Palliere-Martinot ML, Loc’h C et al (1994) Central D2 receptors and negative symptoms of schizophrenia. Br J Psychiatry 164:27–34PubMedCrossRefGoogle Scholar
  46. Montague PR, Dayan P, Sejnowski TJ (1996) A framework for mesencephalic dopamine systems based on predictive Hebbian learning. J Neurosci 16:1936–1947PubMedGoogle Scholar
  47. Moore RJ, Vinsant SL, Nader MA, Porrino LJ, Friedman DP (1998) Effect of cocaine self-administration on striatal dopamine D1 receptors in rhesus monkeys. Synapse 28:1–9PubMedCrossRefGoogle Scholar
  48. Nisell M, Nomikos GG, Svensson TH (1995) Nicotine dependence, midbrain dopamine systems and psychiatric disorders. Basic Clin Pharmacol Toxicol 76:157–162Google Scholar
  49. Patkar AA, Gopalakrishnan R, Lundy A, Leone FT, Weinstein SP (2002) Relationship between tobacco smoking and positive and negative symptoms in schizophrenia. J Nerv Ment Dis 190:604–610PubMedCrossRefGoogle Scholar
  50. Pizzagalli DA, Jahn AL, O’Shea JP (2005) Toward an objective characterization of an anhedonic phenotype: a signal detection approach. Biol Psychiatry 57:319–327PubMedCrossRefGoogle Scholar
  51. Pizzagalli DA, Evins AE, Schetter EC et al (2008) Single dose of a dopamine agonist impairs reinforcement learning in humans: behavioral evidence from a laboratory-based measure of reward responsiveness. Psychopharmacology (Berl) 196:221–232CrossRefGoogle Scholar
  52. Pizzagalli DA, Iosifescu D, Hallett LA, Ratner KG, Fava M (2009) Reduced hedonic capacity in major depressive disorder: evidence from a probabilistic reward task. J Psychiatr Res 43:76–87CrossRefGoogle Scholar
  53. Popkin MK (2008) Exacerbation of recurrent depression as a result of treatment with varenicline. Am J Psychiatry 165:774PubMedCrossRefGoogle Scholar
  54. Preacher KJ, Hayes AF (2004) SPSS and SAS procedures for estimating indirect effects in simple mediation models. Behav Res Meth Ins C 36:717–731CrossRefGoogle Scholar
  55. Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 18:247–291PubMedCrossRefGoogle Scholar
  56. Roth RM, Flashman LA, Saykin AJ, McAllister TW, Vidaver R (2004) Apathy in schizophrenia: reduced frontal lobe volume and neuropsychological deficits. Am J Psychiatry 161:157–159PubMedCrossRefGoogle Scholar
  57. Schmidt K, Nolte-Zenker B, Patzer J, Bauer M, Schmidt LG, Heinz A (2001) Psychopathological correlates of reduced dopamine receptor sensitivity in depression, schizophrenia, and opiate and alcohol dependence. Pharmacopsychiatry 34:66–72PubMedCrossRefGoogle Scholar
  58. Schultz W (2002) Getting formal with dopamine and reward. Neuron 36:241–263PubMedCrossRefGoogle Scholar
  59. Scott DJ, Domino EF, Heitzeg MM et al (2007) Smoking modulation of μ-opioid and dopamine D2 receptor-mediated neurotransmission in humans. Neuropsychopharmacol 32:450–457CrossRefGoogle Scholar
  60. Seeman P (2006) Targeting the dopamine D2 receptor in schizophrenia. Expert Opin Ther Targets 10:515–531PubMedCrossRefGoogle Scholar
  61. Silver H, Feldman P (2005) Evidence for sustained attention and working memory in schizophrenia sharing a common mechanism. J Neuropsychiatry Clin Neurosci 17:391–398PubMedCrossRefGoogle Scholar
  62. Silvestri S, Negrete JC, Seeman MG, Shammi CM, Seeman P (2004) Does nicotine affect D2 receptor upregulation? A case control study. Acta Psychiatr Scand 109:313–317PubMedCrossRefGoogle Scholar
  63. Smith RC, Singh A, Infante M, Khandat A, Kloos A (2002) Effects of cigarette smoking and nicotine nasal spray on psychiatric symptoms and cognition in schizophrenia. Neuropsychopharmacology 27:479–497PubMedCrossRefGoogle Scholar
  64. Smith RC, Lindenmayer JP, Davis JM et al (2009) Cognitive and antismoking effects of varenicline in patients with schizophrenia or schizoaffective disorder. Schizophr Res 110:149–155PubMedCrossRefGoogle Scholar
  65. Tripp G, Alsop B (1999) Sensitivity to reward frequency in boys with attention deficit hyperactivity disorder. J Clin Child Psychol 28:366–375PubMedCrossRefGoogle Scholar
  66. Tupperainen H, Kuikka JT, Viinamaki H, Husso M, Tiihonen J (2010) Dopamine D2/3 receptor binding potential and occupancy in midbrain and temporal cortex by haloperidol, olanzepine and clozapine. Psychiatry Clin Neurosci 63:529–537CrossRefGoogle Scholar
  67. Volkow ND, Wang G, Fowler JS et al (1999) Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels. Am J Psychiatry 156:1440–1443PubMedGoogle Scholar
  68. Wechsler D (2001) Wechsler Test of Adult Reading (WTAR). The Psychological Corporation, San AntonioGoogle Scholar
  69. Winterer G (2010) Why do patients with schizophrenia smoke? Curr Opin Psychiatr 23:112–119CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Sunny J. Dutra
    • 1
  • Luke E. Stoeckel
    • 2
  • Sara V. Carlini
    • 2
  • Diego A. Pizzagalli
    • 3
  • A. Eden Evins
    • 2
    Email author
  1. 1.Department of PsychologyYale UniversityNew HavenUSA
  2. 2.Department of PsychiatryMassachusetts General HospitalBostonUSA
  3. 3.Department of PsychiatryBelmontUSA

Personalised recommendations