Schizophrenia and Smoking: Etiology, Withdrawal, and Therapeutic Possibilities

1. Schizophrenia and Smoking:Etiology, Withdrawal, and Therapeutic Possibilities Andrew B. Hughes East Tennessee State University Schizophrenia and Smoking

2. Background • Schizophrenia is a mental disorder affecting about 1% of the population, and of the schizophrenic population, between 58% and 92% are dependent on nicotine (Dalack et al, 1998). • Out of the general ‘normal’ population, between 20% and 30% are dependent on nicotine (Breslau et al, 2001). Schizophrenia and Smoking

3. The Role of Nicotine • Deficient dopamine neurons in the mesocorticolimbic pathway of the brain have been implicated as a neural basis of the negative symptoms of schizophrenia. • Alleviation of these symptoms appears to be caused by nicotine, a psychoactive chemical commonly found in cigarettes; however, the severe health effects of smoking make this co-morbid addiction a major health concern among patients with schizophrenia (Arnold et al, 1996). Schizophrenia and Smoking

4. The Self-Medication Hypothesis • Animal models of schizophrenia have shown that administration of nicotine directly stimulates the mesocorticolimbic pathway, particularly the dopamine neurons which have been shown to be deficient in schizophrenia. • Thus, it has been hypothesized that individuals with schizophrenia self-medicate with nicotine to alleviate the negative symptoms associated with the disorder (Knable et al, 1997). Schizophrenia and Smoking

5. Further Evidence • Signal processing of the dopamine neurons in this area has been shown to be defective, and may cause the ‘sensory flooding’ associated with the abnormal social behavior of patients with schizophrenia. • Interestingly, nicotine alleviates this deficiency in sensory gating, and obviously suggests a major cause for increased smoking in patients with schizophrenia (Adler et al, 1998). Schizophrenia and Smoking

6. A Complex Interaction • Since nicotine has been shown to stimulate the dopamine neurons in the mesocorticolimbic pathway, a self-medication hypothesis is certainly possible. • However, clinical research has uncovered startling relationships between schizophrenia and smoking that have yet to be researched in depth. Schizophrenia and Smoking

7. Withdrawal • A major concern among the population of patients with schizophrenia that are addicted to smoking is that quitting is rarely successful. • This low rate of success has led some researchers to investigate the differences between this population and that of the normal population. Schizophrenia and Smoking

8. Withdrawal • In fact, clinical observations have often reported an exacerbation of the symptoms of schizophrenia when the patients attempt to quit smoking (Dalack et al, 1999). • Further, dopamine release in cortical regions is reduced by nicotine withdrawal (Vezina et al, 1992). • Clearly, withdrawal from nicotine in this patient population is much greater in an already dopamine-deficient system. Schizophrenia and Smoking

9. Therapeutic Possibility for Withdrawal • Nicotinic acetylcholine receptors (NAChRs) are proteins that are a sub-class of the acetylcholine group of receptors located post-synaptically among neurons. • Obviously, their main binding neurotransmitter is nicotine, and are involved primarily in attention and memory (Adler et al, 1998). Schizophrenia and Smoking

10. Therapeutic Possibility for Withdrawal • As spatial working memory and attentional deficits are commonly associated with schizophrenia, NAChRs have been implicated as a cause of these deficits. • An antagonist to block these receptors would conceivably block the exacerbation of attention- and memory-related deficits upon withdrawal to nicotine (Zevin et al, 2000). Schizophrenia and Smoking

11. Therapeutic Possibility for Withdrawal • In fact, recent research found that there are clinically significant effects of smoking abstinence on neuropsychological performance, and that the effects of smoking withdrawal was dose-dependently blocked by mecamylamine (MEC) administration, a NAChR antagonist, in smokers with schizophrenia (Sacco et al, 2005). Schizophrenia and Smoking

12. A Problem with Self-Medication • There is still debate whether it is the actual nicotine relieving the symptoms of schizophrenia, or if the act of smoking produces anxiolytic effects from the temporary withdrawal of smoking. • If the self-medication hypothesis is fundamentally correct, it would be expected that increased smoking would be accompanied by alleviation of the more severe forms of schizophrenia; however, research has shown a more complex interaction. Schizophrenia and Smoking

13. A Problem with Self-Medication • For example, higher doses of nicotine have not been shown to alleviate more severe cases of schizophrenia, such that the beneficial effects of nicotine are restricted to mildly afflicted patients with low doses of typical antipsychotics (Aguilar et al, 2005). • Typical antipsychotics (i.e. Olanzapine, Clozapine) are associated with motor side-effects that nicotine has been shown to alleviate. Schizophrenia and Smoking

14. A Problem with Self-Medication • In other words, it appears that nicotine is helping with the side-effects of medication, and not necessarily with the effects of schizophrenia. • Thus, it still remains to be determined why more severe forms of schizophrenia are associated with increased levels of smoking. Schizophrenia and Smoking

15. An Alternative Hypothesis • An area of the mesocorticolimbic pathway known as the nucleus accumbens is particularly involved in the reinforcing effects of drugs. • The “shell” of the nucleus accumbens is directly stimulated by the psychoactive properties of drugs, whereas the “core” is stimulated by the associative effects of drugs (Spring et al, 2003). • In other words, the act of doing the drug stimulates a different area of the nucleus accumbens than the actual drug, such that the act of doing drugs is comparably addictive as the actual drugs themselves. Schizophrenia and Smoking

16. An Alternative Hypothesis • Research is currently investigating this complex interaction between the reinforcing and associative effects of drugs. • Although a nicotinic receptor agonist may alleviate the physiological need for nicotine, the addiction to the associative effects of smoking still needs to be resolved. • Thus, treatment for an addiction to smoking among patients with schizophrenia may need to be a two-fold program. Schizophrenia and Smoking

17. Summary • Out of the schizophrenic population, between 58% and 92% are dependent on nicotine. • It has been hypothesized that individuals with schizophrenia self-medicate with nicotine to alleviate the symptoms of schizophrenia. • Withdrawal from nicotine in this patient population is much greater in an already dopamine-deficient system. • NAChR agonists, devoid of harmful effects, may be beneficial for pharmacological treatment of cognitive dysfunction associated with schizophrenia. • Treatment for an addiction to smoking among patients with schizophrenia may need to be a two-fold program, accounting for the reinforcing and associative effects of drug use. Schizophrenia and Smoking

18. References • Adler, L.E., Hoffer, L.D., Waldo, M., Harris, J.G., Griffith, J., Stevens, K., Flach, K., Nagamoto, H., Bickford, P., Leonard, S., & Freedman, R. (1998). Schizophrenia, sensory gating, and nicotine receptors. Schizophr. Bull., 24: 189-202. • Aguilar, M.C., Gurpegui, M., Diaz, M.J., & De Leon, J. (2005). Nicotine dependence and symptoms in schizophrenia. British Journal of Psychiatry, 186: 215-221. • Arnold, S.E. & Trojanowski, J.Q. (1996). Recent advances in defining the neuro-pathology of schizophrenia. Acla. Neuropathol., 92: 217-231. • Breslau, N., Johnson, E.O., Hiripi, E., & Kessler, R. (2001). Nicotine dependence in the United States: prevalence, trends, and smoking persistence. Arch. Gen. Psychiatry, 58: 810-816. • Dalack, G.W., Healy, D.J., & Meador-Woodruff, J.H. (1998). Nicotine dependence and schizophrenia: clinical phenomenon and laboratory findings. Am. J. Psychiatry, 155: 1490-1501. • Dalack, G.W., Becks, L., Hill, E., Pomerleau, O.F., & Meador-Woodruff, J.H. (1999).Nicotine withdrawal and psychiatric symptoms in cigarette smokers with schizophrenia. Neuropsychopharmacology, 21(2): 195- 202. Schizophrenia and Smoking

19. References, cont. • Knable, M.B. & Weinberger, D.R. (1997). Dopamine, the prefrontal cortex and schizophrenia. J. Psychopharmacol., 11: 123-131. • Sacco, K.A., Termine, A., Syal, A., Dudas, M.M., Vessicchio, J.C., Krishnan- Sarin, S., Jatlow, P.I., Wexler, B.E., & George, T.P. (2005). Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Arch. Gen. Psychiatry, 62: 649-659. • Spring, B., Pingitore, R., & McChargue D.E. (2003). Reward value of cigarette smoking for comparably heavy smoking schizophrenic, depressed, and nonpatient smokers. American Journal of Psychiatry, 160(2): 316-322. • Vezina, P., Blanc, G., Glowinski, J., & Tassin, J.P. (1992). Nicotine and morphine differentially activate brain dopamine in prefrontal cortical and subcortical terminal fields: effects of acute and repeated injections. J. Pharmacol. Exp. Ther., 261: 484-490. • Zevin, S., Jacob, P. III, & Benowitz, N.L. (2000). Nicotine-mecamylamine interactions. Clin. Pharmacol.Ther., 68: 58-66. Schizophrenia and Smoking