Smoking and tardive dyskinesia in male patients with chronic schizophrenia

Abstract

Interactions between smoking and movement disorders include the contrasting associations of more cigarette smoking with reductions in Parkinson's disease and increases in tardive dyskinesia (TD) symptoms. Here we examine the relationship between smoking and TD in a large sample of inpatients with schizophrenia. We used cross-sectional naturalistic methods to analyze the prevalence and severity of neuroleptic-induced TD in relation to cigarette smoking among 764 male chronic and medicated inpatients meeting DSM-IV criteria for schizophrenia. We administered a detailed questionnaire including general information, medical and psychological conditions, and smoking behaviors. We evaluated TD severity using the abnormal involuntary movement scale (AIMS) and psychopathology using the Positive and Negative Syndrome Scale (PANSS). The main statistical analyses used cross-tabulations for the prevalence of TD by smoking and multivariate regression analyses for continuous measures (AIMS and PANSS). We found that the prevalence of TD did not significantly differ between smokers (41% = 237/578) and non-smokers (37% = 69/186). Secondary outcomes showed a significant association between the AIMS total score and age, duration of illness and hospitalization times. Thus, smoking was not associated with TD in male Chinese schizophrenics, but consistent with previous reports, older patients with a longer duration of illness and more hospitalizations showed greater severity of TD.

Introduction

Tardive dyskinesia (TD) manifests as involuntary, hyperkinetic, abnormal movements that usually follow long-term treatment with neuroleptic drugs. This syndrome is potentially irreversible and linked with poor quality of life (Browne et al., 1996) and increased medical morbidity and mortality (Ballesteros et al., 2000, Correll and Schenk, 2008). Prevalence rates of TD vary between 15% and 70% in neuroleptic-treated samples (Correll and Schenk, 2008, Nilsson et al., 1997). The pathogenesis of TD remains to be fully clarified, but may be associated with striatal dopamine receptor supersensitivity (Kirch et al., 1987). The most consistently reported risk factors are age, female sex, longer duration of antipsychotic treatment, higher antipsychotic drug dose, poor antipsychotic response, smoking, diabetes mellitus, early extrapyramidal symptoms and history of alcohol abuse and/or dependence (Jeste, 2000). Although the new atypical antipsychotic agents may have a lower risk for inducing TD (Correll et al., 2004, Jeste, 2004, Kane, 2004, Remington, 2007), some naturalistic studies report high TD prevalence rates with new atypical antipsychotics (Ghaemi et al., 2008) or similar incidence rates with typical and atypical antipsychotic drugs (Lee et al., 2005). Classical antipsychotics are front-line therapeutics in most developing countries (de Jesus et al., 2009). Hence, TD remains a problem for the foreseeable future despite the widespread introduction of atypical antipsychotic medications. Despite a considerable amount of research, the etiology and pathophysiology of TD remain poorly understood (Lohr et al., 2003). Thus, the knowledge of potential risk factors remains an important issue. Identification of these risk factors could help guide pharmacotherapy in order to avoid facilitating the development of TD.

Numerous epidemiological studies show that cigarette smoking is associated with a lower risk of idiopathic Parkinson's disease (PD) (Elbaz and Moisan, 2008). This has led to the hypothesis that nicotine exposure may protect against the development of PD (Thacker et al., 2007). The pathophysiological basis of PD (idiopathic or neuroleptic-induced) is believed to be the reverse of TD (Rascol and Fabre, 2001, Yassa et al., 1987). Thus, smoking might be expected to aggravate and foster the development of TD. However, the underlying mechanisms for the association between TD and smoking remain unclear. Suggested neurobiological mechanisms for this association of smoking and TD include increased dopaminergic activity from nicotine leading to dopamine receptor hypersensitivity (Diehl et al., 2009). The dopamine receptor hypersensitivity hypothesis of TD suggests that smokers who are given neuroleptics may develop a greater degree of dopamine receptor hypersensitivity in the nigrostriatal and mesolimbic systems due to a combination of receptor blockade by neuroleptics and a decrease in CNS dopamine turnover caused by nicotine (Andersson et al., 1981). This relationship between TD and smoking is consistent with the theory attributing dyskinesia to nigrostriatal hypersensitivity to dopamine (Dilsaver and Smeltzer, 1988), and would result in an increased prevalence of TD among schizophrenic patients who smoke (Diehl et al., 2009, Kirch et al., 1987).

However, the effect of smoking on TD is still unclear. Epidemiological studies have shown mixed results on smoking's association with TD with some finding an increased incidence of TD in smokers (Binder et al., 1987, Chong et al., 2003, Nilsson et al., 1997, Yassa et al., 1987) while others find no relationship between smoking and TD (Menza et al., 1991, Youssef and Waddington, 1987). A more recent longitudinal clinical trial showed a strong correlation between the amount of smoking and severity of TD (Diehl et al., 2009). Furthermore, repeated measurements revealed a positive correlation between changes in cigarette consumption and changes of the severity of TD, suggesting a possible cause–effect-relationship between smoking and TD (Diehl et al., 2009). Thus, the role of smoking in potentially increasing the risk of TD is still unclear.

The literature on smoking and TD in a Chinese population is scanty. One study of Chinese in Singapore that included 291 schizophrenics with and without TD reported an increased incidence of TD in smokers; however, the smokers were treated with significantly higher antipsychotic doses, which may account for the increased incidence (Chong et al., 2003). Smoking increases neuroleptic metabolism by inducing hepatic microsomal enzymes and thereby lowers neuroleptic blood levels in smokers (Kelly and McCreadie, 1999). This lowering of blood levels may lead smokers to receive higher doses of neuroleptics than nonsmokers.

In the present study, we examined the association between cigarette smoking and TD in a large sample of Chinese inpatients with schizophrenia. We had also looked at the relationship of smoking to prescribed antipsychotic dose. While gender is a major determinant of smoking behaviors in all countries (de Leon et al., 2002; 2005), few women smoke in China among the general population (male/female: 67.1% versus 7.1%) (Lee et al., 2009) and among patients with schizophrenia (male/female: 52.0% versus 4.5%) (Tang et al., 2007). Thus, the smoking rate in our female schizophrenic inpatients was too low for gender comparisons (Zhang et al., 2010). The reasons for such a large sex discrepancy in Chinese smoking rates are unknown, but cultural, traditional and social differences between Western and Chinese societies contribute (Hao et al., 1998, Tang et al., 2007). Thus, we focused on the prevalence and severity of TD in smoking and non-smoking Chinese schizophrenic males alone. To our best knowledge, this is the largest study designed to evaluate the association of smoking with TD with the primary outcome of differences between smokers and non-smokers in their rates and severity of TD. The secondary outcomes were the associations of TD severity with age, duration of illness, negative symptoms and number of hospitalizations among male patients with schizophrenia.