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Smoking and Movement Disorders in Psychiatric Patients Matthew A. Menza, Nancy Grossman, Margaret Ronald Cody, and Nancy Forman
Previous studies have suggested that tardive dyskinesia may occur more frequently in patients who smoke. Further evidence of an interaction between smoking and movement disorders includes the low lifetime exposure to cigarettes fourul in Parkinson's disease patients. In this study 126 patients with chronic psychiatric illnesses were blindly evaluated for tardive dyskinesia, neuroleptic-induced parkinsoaism, and akathisia. Patients who smoked received significantly higher doses of neuroleptics but did no: have significantly more frequent or more severe tardive dyskinesia or parkinsonism. Fen.ale smokers did have significantly more akathisia. These results are discus~'ed with regard to interactions between smoking, central dopaminergic tone, and the psychopathology of extrapyramidal syndromes. The effect of smoking on neuroleptic blood levels as well as clinical s37nptomatology is also discussed.
Introduction The association in several large epidemiological studies of a lower l f f e ~ e exposure to smoking in patients with Parkinson's disease (PD) compared with controls (Kahn 1966; Hammond 1966; Nefzger et al 1968; Kessler et al 1971; Martilla and Rinne 1980; Bauman et ai |980; Godwin-Austen et al 1982), as well as the demonstration that nicotine stimdates release of dopamine from nigrostriatal neurons (Balfour 1982; Pomerleau and P o m e r l ~ 1984; Chesselet 1984), has led to the examination of the effect of nicotine on a variety of movement disorders. Tardive dyskinesia frl)) in parficdar has been studied in relation to smoking in three previous studies. Two of these studies found an increased incidence of TD in smokers (Binder et al 1987; Yassa et al 1987) and one study found no relations~p between smoking and TD (Youssef and Waddinton 1987). In this study we examine the relationship between movement disorders and smoking in a large sample of outpatients with psychiatric illnesses.
Methods "'~..~- study population consisted of 12 patients with chronic psychiatric ~ e s s e s who attended outp~.tient medication groups at a local Community Mental Health Center. Diagnoses were determined by the treating psychiatrist using DSM-III-R criteria. All patients
From The Department of Psychiatry, Robert Wood Johnson University Medical School, New Brunswick, New $ersey. Address reprint requests to Matthew A. Menza, M.D., Robert Wood Johnson University Hospital, Department of Psychianv, I Robert Wood Iohnson Place-CN 19, New Bnmswick, NJ 08903-G019. Received August 22, 1990; revised January ] 1, 1991. © 1991 Society of Biological Psychiatry 0(106-3223/91/$03.50
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Table I. C ~ c a l and D e m o ~ iiii
S ~ Total Males Females White Black
66 (52%) 40 (58%) 26 (46%) 56 (55%) 10 (43%)
60 (48%) 29 (42~) 31 (54%) 45 (45%) 13 ($7%)
126 69 $7 101 23
Affective Other LO! Age
7 (41%) 3 (33%) 14 years 38.9
I0 (59%) 6 (67%) 17 yems 41.5
17 9 I;5.5 40.1
LOI, Lengthof Illness (average).
gave an informed consent. A variety of clinical and demographic information was obtained by chart review. Smoking history was obtained by a questionnaire that asked the patient for detailed information on length and quantity of smoking. One of us (NG) w ~ was blind to ~ patients' smoking status rated each patient for TD, parkinsonism, and akathisia. TD was rated with the Simpson Tardive Dyskinesia Scale (Simpson et al 1979). Scores are reported for the total 35 item scale (riD) as well as for a general rating of overall severity from 0 to 5 (Global TD). Parkinsonism was rated using a modified Simpson-Angus Extrapyramidal Rating Scale (Simpson and Angus 1970; Adler et al 1986). Total extrapyramidal symptoms scores (EPS) are reported as well as the objective rating of akathisia (AKA) rated on a 0--4 scale. A visual analogue scale for subjective akathisia (AKA-SUB) is also reported (Adler et al 1986). Neuroleptic doses are reported as chlorpromazine-equivalents (CPZ-EQ). Results Table 1 lists the main demographic and clinical variables in this sample of 126 patients. When the sample was divided into smokers and nonsmokers there were no significant differences in any of the listed variables including age, sex, race, diagnosis, or length of illness. The main movement variables are listed in Table 2. A total of 36 patients ~ . - ~ j .au clinically• ssgnmcant s ~ (greater than or equal to z on the Simpson-Angus global TD). There were no differences in frequency of TD between smokers (19 of 66, 29%) and nonsmokers (17 of 60, 28%). Additionally, when various subpopulations were examined, for example, schizophrenics, males, females, greater than I pack/day, less than 1 pack/day, blacks and whites, no significant differences in the rates of TD were found between smokers and nonsmokers. TD scores were also compared between groups of patients who had never smoked, those who were former smokers, and current smokers. There were no significant differences between groups nor did any combination of groups (e.g., current + tormer versus never) yield statistical significance. Patients with a diagnosis of schizopl~-enia were also compared to those patients with affective diso~er diagnoses: affectively ill patients smoked less (p < 0.05), received significantly less neuroleptic (p < 0.005), and had significantly less EPS (p < 0.03). There were, however, no significant differences between groups in akathisia or tardive dyskinesia.
Smoking tagl Movement Disorders
Table 2. Movement Variables
Global "i'D ( > 2 ) Mild TD Moderate-severe T D EPS Neuroleptics (CPZ-EQ) Akathisia Akathisia-sub~ctive
19 (29%) 9 (14%) 10 (15%) 3.53 ! 146 1.2 35.5
17 (26%) 8 03%) 9 03%) 4.5 719 .85 28.7
36 (29%) 17 ( | 4 % ) 19 (15%,)
NS NS NS NS p < 0o~ p < 0.005 NS
Smokers received significantly more neuroleptic (1146 C P Z - E Q ) ~ nonsmokers (719 CPZ-EQ) (Kuskall-Walfis X2 = 10.67 , p -- 0.0011). This was B e for b o ~ men and women independently (men, X 2 - 3 . 9 8 , p < 0.05; women, X 2 = 5 . 3 8 , p 0.02).
There was significantly more akathisia in smokers than in nonsmokers (Kuskall-Walfis X2 - 3.86, p < 0.05), although this difference was restricted to f e ~ e s ( X 2 --'~ 7.69, p = 0.005) and not males (X2 = 0.01, p = NS). Subjective akathisia did not differ between smokers and nonsmokers. Extrapyramidai symptoms showed a s m l a r pattern of no differences between male sraoke~ .and nonsmokers (X2 = 0.43, p = N S ) a l ~ g h females showed a trend towards less EPS t~,:" smokers (X2 = 2.86, p = 0.09). Spearman correlational coefficients (Table 3) revealed s i ~ c a n t relations~ps between the m o u n t smoked per day and subjective akathisia (r = 0.25, p < 0.02), as wen as trends for objective akathisia (r = 0.18, p < 0.09) and EPS (r = - 0 . 1 9 , p < 0 . ~ ) . Neither measure of TD was significantly correlated with any smoking m e ~ . Neuroleptic dose was significantly correlated with packs per day (r = 0.23, p < 0.05) and subjective akathisia (r = 0.29, p < 0.01). Age was correlated with #obal TD (r = 0.30, p < 0.001), TD (r = 0.18, p < 0.05) ~ EPS (r = 0.24, p < 0.01). Length of illness was significanUy correlated with both TD (r = 0.24, p < 0.01) and global TD (r = 0.25, p < 0.01).
Table 3. Spearman Correlation Coefficients
Neumlep Pack/Day Pack-Yr Age LOI TD Glob TD EPS AKA "p < o . 1 0
bp < 0.05 Cp < 0.01
< o.ool •p < 0.0001
-0.23 b 0.09 -0.16" -0.06 0.06 -. .
- 0.06 0.06 0.0008 0.18 b 0.24* --.
- 0.~ 0.02 0.05 0.30 d 0.25* 0.8(F -. .
- 0. I0 - 0.19" - 0.13 0.23* O. 12 - 0.01 0.1 !
0.09 0.17" 0.12 - 0.10 0.14 ' 0.49 ~ 0.38 e 0.04
AKASUB 0.29 ~ 0.25 c 0. !0 - 0.11 0.08 0fob 0.03 -0.08 0-40 ~
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Discussion The main findings of this study were: 1. Patients who smoked (both men and women) m:eived significantly higher doses of ne~leptJcs. 2. There were no differences between smokers ~ nonsmokers in rates or severity of TD, despite the comparison of a variew of subgroups including s c h i z ~ c n i c diagnosis, gender, race, diagnosis, severe ~ , heavy smoking, or light smoking. 3. Female smokers had significantly higher ratings than female nonsmokers of akathisia (both objectively and subjectively). 4. There were no other significant differences in EPS between smokers and nonsmokers. Three previous studies have addressed the association between TD and smoking. Two studies found increased rates of TD in smokers (Binder et al 1987; Yassa et al 1987) and one found no differences between these groups (Youssef and Waddinton 1987). None of these studies reports on akathisia and o ~ y ~ reported on parkinsonian EPS (Yassa et al 1987), which were found to be no different in smokers and nonsmokers. One study found, as we did, i ~ d3ses of neuroleptics in smokers (Yassa et al 1987), while one study found no difference between groups (Binder et al 1987). ]'here are numerous methodologic issues that may help to explain some of these differences. It is not clear if the raters were blind to the smoking status of the patients in any of the other studies. All ~ of ~ previous studies recorded smoking data from informants other than the patiet,ts. And finally, two of the previous studies involved only inpatients (Binder et al 1987; Youssef and Waddinton 1987) while ours and that of Yassa et al (1987) involved outpatients. We suggest, however, that the interactions between neuroleptic dose, movement disorder, and cigarette smoking may help to explain these varying results and are consistent with the d o p a m i ~ i c activity of nicotine. Extrapyramidal movement disonlers such as parkinsonism appear to be due to decreased nigrostriatal dopaminergic function while choreoathetoid movement disorders such as TD appear to be due to increased nigrostrial dopaminergic function (Jeste and Wyatt 1982). Nicotine appears to have significant effects brain barrier (Oldendorf 1974) and binds to a wide variety of neurons including nigrostriatal and mesolimbic dopamine neurons (Clarke and Pert 1985). Acutely, nicotine promotes the release of dopamine (Balfour 1982; Pomerleau and Pomerleau 1984, Chesselet 1984) ~ d an increase in firing rates of dopaminergic neurons (Aceto and Martin 1982; Balfour 1984)..The data on the effect of chronic nicotine are mixed, with studies indicating either a continued increase or a decrease in dopaminergic tone (Kirch et al 1987; Fung and Lau 1988; Weiner et al 1989). Cigarette smoke and nicotine inhibit prolactin secretion, presumably through dopaminergic stimulation (Eneroth et al 1977). Nicotine also induces ty-rosine hydroxylase, the rate-limiting enzyme in dopamine synthesis (Naguira et al 1978). In humans and animals nicotine is also effective in reinforcing drag self-administration paradigms that are mediated by mesolimbic dopaminergic systems Henningfield and Goldberg 1983). Cigarette smoking also lowers neuroleptic levels by stimulating hepatic microsomal enzymes (Vinarova et al 1984; Jann et al 1985) and by increasing the clearance of neuroleptics (Jann et al 1985). Another interesting interaction between dopaminer~c tone and smoking is the asso-
Smoking and Movement Disorders
u ~ PsYcHo'my I99|~109-1|$
ciation between Parkinson's disease and nonsmoking that has been ~ y de~strated in numerous large studies since 1966 ( K ~ 1966; Hammond 1966; Nefzger et 1968; Kessler and Diamond 1971; Martilla and Rinne 1980; Baumann et ~ 1980; ~ w i n Austen et al 1982). Two theories have been widely discussed concerning ~ s relationship. One suggests that smoking protects against PD (Kessler and Diamond 1971; Calne 1983: Kessler 1978; Giorguieff-Chesselet et al 1979; Lichtcnsteiger et al 1982: Balfour 1982~ Kirch et al 1988), while the other sees nonsmoking as an epiphenomenon of a premorbid personality, associated with PD (Duvoisin et al 1981: Ward et al 1983; Golbe et al 1986; Menza et al 1990), which may in itself be dependent on dopaminergic tone (Menza et al 1990). As can be seen, there are a variety of complex interactions between cigare~'te smoking, neuroleptics, and movement disorders. Nicotine lowers neuroleptic blood levels ~ also raises CNS dopaminergic tone, at least acutely. The net result of either of these acfi~s would, speculatively, be increased dopaminergic st~nulation, decreased ~ , a ~ increased TD. These actions are also consistent with our findings of increased neuroleptic dose in smokers but no concomitant increase in TD and EPS (wi~ the exception of akathisia). Again, these actions of nicotine are consistent with the si~ficant positive correlation that we found between smoking and neuroleptic dose and the negative correlation between EPS and srnol~ing. These interactions may make clear that while were no increases in TD, as seen in previous studies, the reason may be that smokers in this study were receiving higher doses of neuroleptics. Without actual blood levels ef neuroleptics, the mechanism cannot be further elucidated. These data raise interesting questions involving the effects of cigarette smoking on other clinical issues such as psychosis, mood, and anxiety that may be related to dopaminergic tone. Furthermore, as our data are cross-sectional they raise questions as to the long-term interactions between neuroleptics, movement disorders, and smvldng. We suggest that future studies involving cigarette smoking in patients with psychia~c illness evaluate a range of movement disorders as well as a variety of clinical psyc~a~c conditions. In addition, attention to blood levels and estimates of l~etime exposure to neuroleptics are critical. References Aceto MD, Martin BR (1982): Central actions of nicotine. Mad Res Ret, 2:43-62. Adler L, Angrist B, Peselow E, et al (1986): A controlled assessment of Wopranolol in the treatn~n~ of neuroleptic-induced akathisia. Br J Psych 149:42-45. Balfour D~K (1982): The effects of nicotine on brain neurotransmitter systems. Pharmacol Ther 16:269-282. Balfour DJK (1984): The effects of nicotine on brain ne~_!~__ns~er systems. In Balfour D ~ (ed), Nicotine and the Tobacco Smoking Habit. Oxford: Pergamon Press. Baumann RJ, Jameson HD, McKean HE, et al (1980): Cigarette smo~g and Parkman's disease: I. A comparison of cases with matched neighbors. Neurology 30:839-843. Binder RL, Kazamatsuri H, Nishimura T, McNeil D (1987): Smoking ~.; ~d~ve dyskinesia. Biol Psychiatry 22:1280-1282. Caine DB (1983): Current views of Parkinson's disease. Can J Neurol Sci 10:l 1-!5. Chesselet MF (1984)" Presynap~_'c re~ula~on of neurotransmitter release in the brain: facts an~ hypothesis. Neuroscience 12:347-375. Clarke PB, Pert A (1985): Autoradiographic evidence for nicotine receptors on mgrosWiatal and mesolimbic dopaminergic neurons. Brain Res 348:355-358.
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