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The association between schizophrenia and smoking: Unexplained by either the illness or the prodromal period
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Schizophrenia Research 104 (2008) 214 – 219 www.elsevier.com/locate/schres
The association between schizophrenia and smoking: Unexplained by either the illness or the prodromal period Francisco J. Diaz a , Diana M. Velásquez a , Margaret T. Susce b , Jose de Leon b,⁎ b
a Department of Statistics, Universidad Nacional, Medellin, Colombia University of Kentucky Mental Health Research Center at Eastern State Hospital, and University of Kentucky Colleges of Medicine, Lexington, Kentucky, United States
Received 23 April 2008; received in revised form 4 June 2008; accepted 9 June 2008 Available online 22 July 2008
Abstract Age at onset of daily smoking (AODS) was compared in schizophrenia (N = 258), mood disorders (N = 166) and controls (N = 381) to replicate a different AODS in schizophrenia patients, and to confirm that this is not necessarily explained by the prodromal period. The cumulative hazard curves for schizophrenia, mood disorders and controls were significantly different (p b 0.001), even after controlling for gender and education (p b 0.001). After excluding the patients who started smoking within 5 years of starting psychiatric medication, the cumulative hazard curve for schizophrenia patients was significantly different from that for ever-smoker controls (p = 0.002), even after adjusting for gender and education (p = 0.03). © 2008 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; Mood disorders; Tobacco; Nicotine; Smoking; Survival analysis
1. Introduction A meta-analysis showed that there is a significant worldwide association between schizophrenia and current smoking (de Leon and Diaz, 2005). In the meta-analysis, the association was obvious when comparing with the general population (the significant combined odds ratio [OR] was 5.3), but can still be detected when comparing with patients with other severe mental illnesses (SMIs) (a significant combined OR of 1.9). Thus, the prevalence of current smoking in ⁎ Corresponding author. Mental Health Research Center at Eastern State Hospital, 627 West Fourth St., Lexington, KY 40508, United States. Tel.: +859 246 7563; fax: +859 246 7019. E-mail address: [email protected] (J. de Leon). 0920-9964/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2008.06.004
patients with other SMIs tended to be between that of schizophrenia patients and normal controls. In crosssectional studies, current smoking reflects increased ever smoking and/or decreased smoking cessation. Since smoking behaviors of SMI patients rank between those in schizophrenia and the general population, differences are noted between schizophrenia and other SMI patients, and between other SMI patients and the general population. Four possible components may contribute to higher current smoking levels in schizophrenia than in the general population: increased ever smoking in all SMIs (difference in ever smoking between the general population and SMI), increased ever smoking specific to schizophrenia (difference in ever smoking between SMI and schizophrenia), decreased smoking cessation in SMI (difference in
F.J. Diaz et al. / Schizophrenia Research 104 (2008) 214–219
smoking cessation between the general population and SMI), and decreased smoking cessation specific to schizophrenia (difference in smoking cessation between SMI and schizophrenia; de Leon et al., 2007). Although the literature supports the existence of the first three components, there is scant evidence that the last component (schizophrenia-specific decreased smoking cessation) exists in reality (de Leon et al., 2007). The current study focuses on only one of the four components, increased ever smoking rates specific to schizophrenia patients. The increased ever smoking specific to schizophrenia patients can be inferred from the ratio between the ever smoking OR of 3.1 compared with the general population and the OR of 2.0 compared with patients with other SMIs (de Leon and Diaz, 2005). The measure of ever smoking in cross-sectional studies refers to people who start smoking. An increase in ever smoking reflects an increase in smoking initiation. One difficulty involved in investigating ever smoking in these cross-sectional studies is that ever smoking may be affected by gender and education, and the possibility that a young non-smoker patient may become a smoker later (de Leon and Diaz, 2005). Thus, ever smoking from a cross-sectional study is an imperfect measure of smoking initiation. Smoking initiation can be better measured by survival analysis, which accounts for the above possibility. Using survival analysis in a relatively small Kentucky sample, some of us compared the age at onset of daily smoking (AODS) in 66 schizophrenia, 51 mood-disordered patients and 404 controls, after controlling for gender and education (de Leon et al., 2002). The AODS in schizophrenia was significantly different not only from that in controls but also from that in mood disorders. Mood-disordered patients had a cumulative hazard curve that was between those of schizophrenia and controls, but the difference between mood-disordered patients and controls became nonsignificant after controlling for confounders. The three populations appeared to have essentially the same smoking initiation rates before age 20. However, from ages 20 to 29, schizophrenia patients had the highest initiation rates. A replication study in Spain that included 250 schizophrenia outpatients and 290 controls yielded similar results (Gurpegui et al., 2005). After controlling for confounding variables, the AODS in schizophrenia was significantly different from that in controls. From ages 20 to 29, schizophrenia patients had higher initiation rates. Thus, when tobacco is easily available, normal controls rarely start daily smoking after age 20, but schizophrenia patients have an increased risk of starting daily smoking until age 30.
215
In people vulnerable to schizophrenia, an increase in daily smoking during their 20s may reflect smoking initiation before the prodromal period of schizophrenia, during the prodromal period, or after the onset of schizophrenia. To rule out this increased smoking initiation as being determined by the prodromal period, some of us compared the AODS of 107 schizophrenia patients who started daily smoking at least 5 years before schizophrenia onset with the AODS of the 290 controls, finding that schizophrenia patients still had a significantly higher hazard of starting smoking. After excluding the never-smoker controls, schizophrenia and control cumulative hazard curves were still significantly different (adjusting for gender and education, χ2 = 20.7, df = 1, p b 0.001). Thus, if one assumes that 5 years is enough to eliminate prodromal effects, people with vulnerability to schizophrenia who have not experienced prodromal symptoms may have a higher risk of becoming addicted to nicotine. This suggests that increased smoking in schizophrenia may be explained by reasons other than prodromal changes, self-medication, psychiatric treatment, or patient imitation or institutionalization, and indicate probable genetic factors (de Leon, 1996). This Kentucky study is the third one comparing AODS in schizophrenia with that in mood disorders or controls. It sought to replicate for the second time a different AODS in schizophrenia patients, and to confirm that the prodromal period does not appear to explain this difference. The study included mooddisordered patients as a comparison group representing patients with other SMIs. Another objective was to confirm that smoking initiation rates of those with other SMIs are intermediate between schizophrenia patients and controls. 2. Methods 2.1. Sample A sample of patients with SMI from Central Kentucky was collected during a pharmacogenetics investigation (de Leon et al., 2005). The current study included 424 patients with DSM-IV schizophrenia (N = 258) or mood disorders (N = 166) who had never used cigars, pipes or snuff regularly. The total sample has been described previously (de Leon et al., 2006), but smoking and AODS in these subsamples are described in Table 1. The control group included 381 volunteers who had never regularly used cigars, pipes or snuff; they were recruited from churches,
216
F.J. Diaz et al. / Schizophrenia Research 104 (2008) 214–219
Table 1 Description of DSM-IV schizophrenia and mood-disordered patients, and Kentucky volunteers All subjectsa Characteristic
Mean ± SD Age (years) Percentages Gender Male Race Caucasian African-American Others Education ≤High school Smoking Current daily smoking Ever daily smoking
Schizophrenia
Mood disorders
Volunteers
N = 258b
N = 166c
N = 381
43 ± 12
44 ± 12
35 ± 11
57% (148)
42% (69)
24% (90)
78% (201) 21% (54) 1% (3)
88% (146) 10% (16) 2% (4)
66% (253) 29% (111) 5% (17)
75% (193)
62% (103)
49% (188)
74% (190) 83% (215)
62% (103) 74% (123)
26% (98) 44% (167)
Ever daily smokers Sample
Mean ± SD Age (years) Cigarettesd AFPM AODS HSIf Percentages Gender Male Race Caucasian African-American Other Education ≤ High school Smoking Current daily smoking Heavy daily smokingj
Schizophrenia
Mood disorders
Volunteers
N = 215
N = 123
N = 167
43 ± 11 28 ± 17 24 ± 9 18 ± 7e 4.0 ± 1.7g
45 ± 12 24 ± 13 28 ± 10 17 ± 6 3.4 ± 1.7h
38 ± 11 17 ± 10 – 17 ± 4 2.8 ± 1.7i
59% (127)
46% (57)
23% (39)
81% (174) 19% (40) 1% (1)
86% (106) 12% (15) 2% (2)
64% (107) 32% (54) 4% (6)
76% (163)
70% (86)
66% (110)
88% (190) 42% (80/190)
84% (103) 33% (34/103)
59% (98) 14% (14/98)
SD: standard deviation; AFPM: age at first psychiatric medication; AODS: age at onset of daily smoking; HSI: heaviness of smoking index (Diaz et al., 2005). People who ever regularly used tobacco products other than cigarettes such as pipe, cigars or snuff were not included in these samples. b Included 151 patients with DSM-IV schizophrenia and 107 with schizoaffective disorder. These are clinical diagnoses made by treating physicians. c Included 67 patients with DSM-IV major depression and 99 with bipolar disorder. These are clinical diagnoses made by treating physicians. d Number of cigarettes smoked per day by daily smokers. e One schizophrenia patient who was an ever daily smoker did not provide her AODS. Thus, the average AODS for schizophrenia patients was computed without including this subject. In survival analyses, the AODS of this subject was treated as censored at her first cigarette's age. f Mean HSIs were computed for current daily smokers. g Only 120 current smokers with schizophrenia provided an HSI. h Only 72 current smokers with mood disorders provided an HSI. i Only 88 current-smoker controls provided an HSI. j Heavy daily smoking was defined as smoking ≥30 cigarettes per day among current daily smokers. This definition was used in the prior Kentucky study (de Leon et al., 2002). The Spanish study used a slightly different definition (smoking N30 cigarettes per day; Gurpegui et al., 2005). a
community organizations and the University of Kentucky, and were not currently treated by a psychiatrist. This is a subsample from a sample
described elsewhere (de Leon et al., 2002). All subjects were 18 years or older and signed an approved consent form.
F.J. Diaz et al. / Schizophrenia Research 104 (2008) 214–219
217
2.2. Statistics The subjects' tobacco smoking history was recorded (Table 1). Nicotine dependence was measured by the Heaviness of Smoking Index (HSI), which provides scores ranging between 0 and 4. The limitations and strengths of this index have been studied before (Diaz et al., 2005). As in the prior studies (de Leon et al., 2002; Gurpegui et al., 2005), survival analyses of AODS were performed by using cumulative hazard curves (Fig. 1) (Klein and Moeschberger, 1997). The slope of a cumulative hazard curve at a particular age measures the hazard of starting daily smoking at that age. The steeper the curve is, the higher the hazard is. The curves for schizophrenia patients, mood-disordered patients and controls were compared by using log-rank stratified tests that controlled for gender and education level. Education was dichotomized into low (high school or lower) and high (some college or higher) levels. To rule out prodromal changes, self-medication, psychiatric treatment, or patient imitation or institutionalization as possible explanations for the differences
Fig. 2. Cumulative hazard curves for patients with schizophrenia who started daily smoking at least 5 years before starting to take psychiatric medication (N = 111) and controls who had ever smoked (N = 172). The 2 curves were significantly different (log-rank χ2 = 9.4, df = 1, p = 0.002), even after controlling for gender and education level (stratified log-rank χ2 = 4.8, df = 1, p = 0.03).
between schizophrenia patients and controls, the cumulative hazard curve for patients who started smoking at least 5 years before starting psychiatric medication was compared with that for ever-smoker controls. The literature considers the schizophrenia prodromal period to last for up to 1 year (Elkhazen et al., 2003) or up to 2 years (McGlashan, 2003). Thus, the above analysis probably excluded all patients who started smoking during or after the prodromal period (Gurpegui et al., 2005). 3. Results
Fig. 1. Cumulative hazard curves for patients with schizophrenia (N = 258), patients with mood disorders (N = 166) and controls (N = 381). The 3 curves were significantly different (log-rank χ2 = 86.5, df = 2, p b 0.001), even after controlling for gender and education level (stratified log-rank χ2 = 43.3, df = 2, p b 0.001). After controlling for gender and education, both schizophrenia (χ2 = 36.5, df = 1, p b 0.001) and mood-disordered (χ2 = 27.4, df = 1, p b 0.001) patients differed significantly from controls, but schizophrenia and mood-disordered patients did not differ significantly from each other (p = 0.8). For a particular cumulative hazard curve, the hazard of becoming a daily smoker at a particular age is the slope of the curve at that age. To compute the curves, the ages at onset of daily smoking (AODS) of the subjects who had never smoked were considered censored at those subjects' current ages (de Leon et al., 2002).
When including all subjects the cumulative hazard curves for schizophrenia, mood disorders and controls were significantly different (p b 0.001), even after controlling for gender and education (p b 0.001) (Fig. 1). Similarly to previous studies (de Leon et al., 2002; Gurpegui et al., 2005), while the hazard of becoming a daily smoker decreased substantially in normal controls after the age of about 20, the hazard in schizophrenia patients continued to be high for at least 10 years after age 20. After controlling for confounders, mood-disordered patients were significantly different from controls but not from schizophrenia patients (Fig. 1). After excluding the patients who started smoking within 5 years before starting psychiatric medication, the cumulative hazard curve for schizophrenia patients was significantly different from that for ever-smoker controls (p = 0.002), even after adjusting for gender and education (p = 0.03) (Fig. 2). In this subgroup of subjects, during adolescence, schizophrenia patients had a significantly
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F.J. Diaz et al. / Schizophrenia Research 104 (2008) 214–219
higher hazard of becoming daily smokers than controls of comparable age. Analogous analyses did not yield significant differences between mood-disordered patients and controls (unadjusted p = 0.08; after adjusting for gender and education, p = 0.2). 4. Discussion During adolescence, schizophrenia patients who started smoking at least 5 years before starting psychiatric medication had a higher hazard of starting daily smoking than normal controls of comparable age. (An analogous comparison between mood-disordered patients and controls did not yield significant results.) This suggests our main conclusion: neither schizophrenia illness, nor treatment, nor the prodromal period appears to explain the association between schizophrenia and daily cigarette smoking. A genetic vulnerability to smoking in people prone to schizophrenia may be a better explanation or, at least, should be included in any explanation. This study also confirms that some people vulnerable to schizophrenia are prone to become daily smokers later in their 20s, when other people rarely initiate daily smoking (de Leon et al., 2002; Gurpegui et al., 2005). Other recent data support our hypothesis that vulnerability to schizophrenia may be associated with increased vulnerability to smoking initiation (de Leon, 1996). Smokers from the British general population had a 70% greater risk of experiencing incident psychotic symptoms when compared to nonsmokers (Wiles et al., 2006). Cigarette smoking was associated with greater schizotypy in first degree relatives of schizophrenia patients, suggesting there is an overlap between genetic vulnerability to schizophrenia and cigarette smoking (Esterberg et al., 2007). A Finnish study suggested that smoking initiation was earlier in schizophrenia than in other psychoses and that the increased likelihood of smoking was associated with paternal smoking (Riala et al., 2005). Some neurophysiological research supports the vulnerability hypothesis. A genetic neurophysiological abnormality in schizophrenia patients and their relatives, which is associated with a dysfunction in a hippocampal nicotine receptor (α7), may be temporarily corrected by a high peak of nicotine (Freedman et al., 1997). Also, Leonard et al. (2002) found that an α7 promoter polymorphism was more frequent in schizophrenia patients than controls, and may be a marker of the neurophysiological abnormalities that increase schizophrenia risk. These survival analyses did not find significant differences between schizophrenia and mood disorders
as did our first Kentucky study. Patients with mood disorders rank between schizophrenia patients and the general population in current smoking, but the difference between patients with schizophrenia and mood disorders is small, particularly after controlling for confounders; therefore, larger samples may be needed to find significant differences between these two groups of patients. 5. Conclusion This and two prior studies (de Leon et al., 2002; Gurpegui et al., 2005) suggest that vulnerability to schizophrenia may be associated with a higher risk of becoming a daily smoker. Prospective studies of patients with first psychotic episode or subjects at risk of developing schizophrenia may be required to better establish the interaction between schizophrenia vulnerability, AODS and age of schizophrenia onset. Role of the funding source No pharmaceutical organization had any role in the writing of this paper for publication. The original pharmacogenetic study at the University of Kentucky Mental Health Research Center was supported by several sources: a researcher-initiated grant from Roche Molecular Systems, Inc., a NARSAD Independent Investigator Award to Jose de Leon, M.D, and internal resources. Statistical analyses were conducted without additional external support. Contributors Jose de Leon, M.D., designed the study. Francisco J. Diaz, Ph.D., and Diana M. Velásquez, B.S., undertook the statistical analyses. Francisco J. Diaz, Ph.D., and Jose de Leon, M.D., wrote the first draft of the manuscript. All authors have contributed to and have approved the final manuscript. Conflict of interest The authors have no conflict of interest. Acknowledgments The authors thank Lorraine Maw, M.A., for editorial assistance.
References de Leon, J., 1996. Smoking and vulnerability for schizophrenia. Schizophr. Bull. 22, 405–409. de Leon, J., Diaz, F.J., 2005. A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophr. Res. 76, 135–157. de Leon, J., Diaz, F.J., Rogers, T., Browne, D., Dinsmore, L., 2002. Initiation of daily smoking and nicotine dependence in schizophrenia and mood disorders. Schizophr. Res. 56, 47–54. de Leon, J., Gurpegui, M., Diaz, F.J., 2007. Epidemiology of comorbid tobacco use and schizophrenia: thinking about risks and protective factors. J. Dual Diag. 3, 9–25. de Leon, J., Susce, M.T., Diaz, F.J., Rendon, D.M., Velásquez, D.M., 2006. Variables associated with alcohol, drug and daily smoking cessation in patients with severe mental illnesses. J. Clin. Psychiatry. 66, 1447–1455.
F.J. Diaz et al. / Schizophrenia Research 104 (2008) 214–219 de Leon, J., Susce, M.T., Pan, R.M., Fairchild, M., Koch, W., Wedlund, P.J., 2005. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J. Clin. Psychiatry 66, 15–27. Diaz, F.J., Jané, M., Saltó, E., Pardell, H., Salleras, L.l., Pinet, C., de Leon, J., 2005. A brief measure of high nicotine dependence for busy clinicians and large epidemiological surveys. Aust. N.Z. J. Psychiatry 39, 161–168. Elkhazen, C., Chauchot, F., Canceil, O., Krebs, M.O., Bayle, F.J., 2003. Prodromal symptoms of schizophrenia (in French). Encephale 29, 469–477. Esterberg, M.L., Jones, E.M., Compton, M.T., Walker, E.F., 2007. Nicotine consumption and schizotypy in first-degree relatives of individuals with schizophrenia and non-psychiatric controls. Schizophr. Res. 97, 6–13. Freedman, R., Coon, H., Myles-Worsley, M., Orr-Urtreger, A., Olincy, A., Davis, A., Polymerpoulos, M., Holik, J., Hopkins, J., Hoff, M., Rosenthal, J., Waldo, M.C., Reimherr, F., Wender, P., Yaw, J., Yo ung, D.A., Breese, C.R., Adams, C., Patterson, D., Adler, L.E., Kruglyak, L., Leonard, S., Byerley, W., 1997. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc. Nat. Acad. Sci. U.S.A. 94, 587–592.
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Gurpegui, M., Martínez-Ortega, J.M., Aguilar, M.C., Diaz, F.J., Quintana, H.M., de Leon, J., 2005. Smoking initiation and schizophrenia: a replication study in a Spanish sample. Schizophr. Res. 76, 113–118. Klein, J.P., Moeschberger, M.L., 1997. Survival Analysis. Techniques for Censored and Truncated Data. Springer, New York. Leonard, S., Gault, J., Adams, C., Breese, C.R., Rollins, Y., Adler, L.E., Olincy, A., Freedman, R., 1998. Nicotinic receptors, smoking and schizophrenia. Restor. Neurol. Neurosci. 12, 195–201. McGlashan, T.H., 2003. Commentary: progress, issues, and implications in prodromal research: an inside view. Schizophr. Bull. 29, 851–858. Riala, K., Hakko, H., Isohanni, M., Pouta, A., Rasanen, P., 2005. Is initiation of smoking associated with the prodromal phase of schizophrenia? J. Psychiatry Neurosci. 30, 26–32. Wiles, N.J., Zammit, S., Bebbington, P., Singleton, N., Meltzer, H., Lewis, G., 2006. Self-reported psychotic symptoms in the general population. Results from the longitudinal study of the British National Psychiatric Morbidity Study. Br. J. Psychiatry 188, 519–526.
Schizophrenia Research 104 (2008) 214 – 219 www.elsevier.com/locate/schres
The association between schizophrenia and smoking: Unexplained by either the illness or the prodromal period Francisco J. Diaz a , Diana M. Velásquez a , Margaret T. Susce b , Jose de Leon b,⁎ b
a Department of Statistics, Universidad Nacional, Medellin, Colombia University of Kentucky Mental Health Research Center at Eastern State Hospital, and University of Kentucky Colleges of Medicine, Lexington, Kentucky, United States
Received 23 April 2008; received in revised form 4 June 2008; accepted 9 June 2008 Available online 22 July 2008
Abstract Age at onset of daily smoking (AODS) was compared in schizophrenia (N = 258), mood disorders (N = 166) and controls (N = 381) to replicate a different AODS in schizophrenia patients, and to confirm that this is not necessarily explained by the prodromal period. The cumulative hazard curves for schizophrenia, mood disorders and controls were significantly different (p b 0.001), even after controlling for gender and education (p b 0.001). After excluding the patients who started smoking within 5 years of starting psychiatric medication, the cumulative hazard curve for schizophrenia patients was significantly different from that for ever-smoker controls (p = 0.002), even after adjusting for gender and education (p = 0.03). © 2008 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; Mood disorders; Tobacco; Nicotine; Smoking; Survival analysis
1. Introduction A meta-analysis showed that there is a significant worldwide association between schizophrenia and current smoking (de Leon and Diaz, 2005). In the meta-analysis, the association was obvious when comparing with the general population (the significant combined odds ratio [OR] was 5.3), but can still be detected when comparing with patients with other severe mental illnesses (SMIs) (a significant combined OR of 1.9). Thus, the prevalence of current smoking in ⁎ Corresponding author. Mental Health Research Center at Eastern State Hospital, 627 West Fourth St., Lexington, KY 40508, United States. Tel.: +859 246 7563; fax: +859 246 7019. E-mail address: [email protected] (J. de Leon). 0920-9964/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2008.06.004
patients with other SMIs tended to be between that of schizophrenia patients and normal controls. In crosssectional studies, current smoking reflects increased ever smoking and/or decreased smoking cessation. Since smoking behaviors of SMI patients rank between those in schizophrenia and the general population, differences are noted between schizophrenia and other SMI patients, and between other SMI patients and the general population. Four possible components may contribute to higher current smoking levels in schizophrenia than in the general population: increased ever smoking in all SMIs (difference in ever smoking between the general population and SMI), increased ever smoking specific to schizophrenia (difference in ever smoking between SMI and schizophrenia), decreased smoking cessation in SMI (difference in
F.J. Diaz et al. / Schizophrenia Research 104 (2008) 214–219
smoking cessation between the general population and SMI), and decreased smoking cessation specific to schizophrenia (difference in smoking cessation between SMI and schizophrenia; de Leon et al., 2007). Although the literature supports the existence of the first three components, there is scant evidence that the last component (schizophrenia-specific decreased smoking cessation) exists in reality (de Leon et al., 2007). The current study focuses on only one of the four components, increased ever smoking rates specific to schizophrenia patients. The increased ever smoking specific to schizophrenia patients can be inferred from the ratio between the ever smoking OR of 3.1 compared with the general population and the OR of 2.0 compared with patients with other SMIs (de Leon and Diaz, 2005). The measure of ever smoking in cross-sectional studies refers to people who start smoking. An increase in ever smoking reflects an increase in smoking initiation. One difficulty involved in investigating ever smoking in these cross-sectional studies is that ever smoking may be affected by gender and education, and the possibility that a young non-smoker patient may become a smoker later (de Leon and Diaz, 2005). Thus, ever smoking from a cross-sectional study is an imperfect measure of smoking initiation. Smoking initiation can be better measured by survival analysis, which accounts for the above possibility. Using survival analysis in a relatively small Kentucky sample, some of us compared the age at onset of daily smoking (AODS) in 66 schizophrenia, 51 mood-disordered patients and 404 controls, after controlling for gender and education (de Leon et al., 2002). The AODS in schizophrenia was significantly different not only from that in controls but also from that in mood disorders. Mood-disordered patients had a cumulative hazard curve that was between those of schizophrenia and controls, but the difference between mood-disordered patients and controls became nonsignificant after controlling for confounders. The three populations appeared to have essentially the same smoking initiation rates before age 20. However, from ages 20 to 29, schizophrenia patients had the highest initiation rates. A replication study in Spain that included 250 schizophrenia outpatients and 290 controls yielded similar results (Gurpegui et al., 2005). After controlling for confounding variables, the AODS in schizophrenia was significantly different from that in controls. From ages 20 to 29, schizophrenia patients had higher initiation rates. Thus, when tobacco is easily available, normal controls rarely start daily smoking after age 20, but schizophrenia patients have an increased risk of starting daily smoking until age 30.
215
In people vulnerable to schizophrenia, an increase in daily smoking during their 20s may reflect smoking initiation before the prodromal period of schizophrenia, during the prodromal period, or after the onset of schizophrenia. To rule out this increased smoking initiation as being determined by the prodromal period, some of us compared the AODS of 107 schizophrenia patients who started daily smoking at least 5 years before schizophrenia onset with the AODS of the 290 controls, finding that schizophrenia patients still had a significantly higher hazard of starting smoking. After excluding the never-smoker controls, schizophrenia and control cumulative hazard curves were still significantly different (adjusting for gender and education, χ2 = 20.7, df = 1, p b 0.001). Thus, if one assumes that 5 years is enough to eliminate prodromal effects, people with vulnerability to schizophrenia who have not experienced prodromal symptoms may have a higher risk of becoming addicted to nicotine. This suggests that increased smoking in schizophrenia may be explained by reasons other than prodromal changes, self-medication, psychiatric treatment, or patient imitation or institutionalization, and indicate probable genetic factors (de Leon, 1996). This Kentucky study is the third one comparing AODS in schizophrenia with that in mood disorders or controls. It sought to replicate for the second time a different AODS in schizophrenia patients, and to confirm that the prodromal period does not appear to explain this difference. The study included mooddisordered patients as a comparison group representing patients with other SMIs. Another objective was to confirm that smoking initiation rates of those with other SMIs are intermediate between schizophrenia patients and controls. 2. Methods 2.1. Sample A sample of patients with SMI from Central Kentucky was collected during a pharmacogenetics investigation (de Leon et al., 2005). The current study included 424 patients with DSM-IV schizophrenia (N = 258) or mood disorders (N = 166) who had never used cigars, pipes or snuff regularly. The total sample has been described previously (de Leon et al., 2006), but smoking and AODS in these subsamples are described in Table 1. The control group included 381 volunteers who had never regularly used cigars, pipes or snuff; they were recruited from churches,
216
F.J. Diaz et al. / Schizophrenia Research 104 (2008) 214–219
Table 1 Description of DSM-IV schizophrenia and mood-disordered patients, and Kentucky volunteers All subjectsa Characteristic
Mean ± SD Age (years) Percentages Gender Male Race Caucasian African-American Others Education ≤High school Smoking Current daily smoking Ever daily smoking
Schizophrenia
Mood disorders
Volunteers
N = 258b
N = 166c
N = 381
43 ± 12
44 ± 12
35 ± 11
57% (148)
42% (69)
24% (90)
78% (201) 21% (54) 1% (3)
88% (146) 10% (16) 2% (4)
66% (253) 29% (111) 5% (17)
75% (193)
62% (103)
49% (188)
74% (190) 83% (215)
62% (103) 74% (123)
26% (98) 44% (167)
Ever daily smokers Sample
Mean ± SD Age (years) Cigarettesd AFPM AODS HSIf Percentages Gender Male Race Caucasian African-American Other Education ≤ High school Smoking Current daily smoking Heavy daily smokingj
Schizophrenia
Mood disorders
Volunteers
N = 215
N = 123
N = 167
43 ± 11 28 ± 17 24 ± 9 18 ± 7e 4.0 ± 1.7g
45 ± 12 24 ± 13 28 ± 10 17 ± 6 3.4 ± 1.7h
38 ± 11 17 ± 10 – 17 ± 4 2.8 ± 1.7i
59% (127)
46% (57)
23% (39)
81% (174) 19% (40) 1% (1)
86% (106) 12% (15) 2% (2)
64% (107) 32% (54) 4% (6)
76% (163)
70% (86)
66% (110)
88% (190) 42% (80/190)
84% (103) 33% (34/103)
59% (98) 14% (14/98)
SD: standard deviation; AFPM: age at first psychiatric medication; AODS: age at onset of daily smoking; HSI: heaviness of smoking index (Diaz et al., 2005). People who ever regularly used tobacco products other than cigarettes such as pipe, cigars or snuff were not included in these samples. b Included 151 patients with DSM-IV schizophrenia and 107 with schizoaffective disorder. These are clinical diagnoses made by treating physicians. c Included 67 patients with DSM-IV major depression and 99 with bipolar disorder. These are clinical diagnoses made by treating physicians. d Number of cigarettes smoked per day by daily smokers. e One schizophrenia patient who was an ever daily smoker did not provide her AODS. Thus, the average AODS for schizophrenia patients was computed without including this subject. In survival analyses, the AODS of this subject was treated as censored at her first cigarette's age. f Mean HSIs were computed for current daily smokers. g Only 120 current smokers with schizophrenia provided an HSI. h Only 72 current smokers with mood disorders provided an HSI. i Only 88 current-smoker controls provided an HSI. j Heavy daily smoking was defined as smoking ≥30 cigarettes per day among current daily smokers. This definition was used in the prior Kentucky study (de Leon et al., 2002). The Spanish study used a slightly different definition (smoking N30 cigarettes per day; Gurpegui et al., 2005). a
community organizations and the University of Kentucky, and were not currently treated by a psychiatrist. This is a subsample from a sample
described elsewhere (de Leon et al., 2002). All subjects were 18 years or older and signed an approved consent form.
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2.2. Statistics The subjects' tobacco smoking history was recorded (Table 1). Nicotine dependence was measured by the Heaviness of Smoking Index (HSI), which provides scores ranging between 0 and 4. The limitations and strengths of this index have been studied before (Diaz et al., 2005). As in the prior studies (de Leon et al., 2002; Gurpegui et al., 2005), survival analyses of AODS were performed by using cumulative hazard curves (Fig. 1) (Klein and Moeschberger, 1997). The slope of a cumulative hazard curve at a particular age measures the hazard of starting daily smoking at that age. The steeper the curve is, the higher the hazard is. The curves for schizophrenia patients, mood-disordered patients and controls were compared by using log-rank stratified tests that controlled for gender and education level. Education was dichotomized into low (high school or lower) and high (some college or higher) levels. To rule out prodromal changes, self-medication, psychiatric treatment, or patient imitation or institutionalization as possible explanations for the differences
Fig. 2. Cumulative hazard curves for patients with schizophrenia who started daily smoking at least 5 years before starting to take psychiatric medication (N = 111) and controls who had ever smoked (N = 172). The 2 curves were significantly different (log-rank χ2 = 9.4, df = 1, p = 0.002), even after controlling for gender and education level (stratified log-rank χ2 = 4.8, df = 1, p = 0.03).
between schizophrenia patients and controls, the cumulative hazard curve for patients who started smoking at least 5 years before starting psychiatric medication was compared with that for ever-smoker controls. The literature considers the schizophrenia prodromal period to last for up to 1 year (Elkhazen et al., 2003) or up to 2 years (McGlashan, 2003). Thus, the above analysis probably excluded all patients who started smoking during or after the prodromal period (Gurpegui et al., 2005). 3. Results
Fig. 1. Cumulative hazard curves for patients with schizophrenia (N = 258), patients with mood disorders (N = 166) and controls (N = 381). The 3 curves were significantly different (log-rank χ2 = 86.5, df = 2, p b 0.001), even after controlling for gender and education level (stratified log-rank χ2 = 43.3, df = 2, p b 0.001). After controlling for gender and education, both schizophrenia (χ2 = 36.5, df = 1, p b 0.001) and mood-disordered (χ2 = 27.4, df = 1, p b 0.001) patients differed significantly from controls, but schizophrenia and mood-disordered patients did not differ significantly from each other (p = 0.8). For a particular cumulative hazard curve, the hazard of becoming a daily smoker at a particular age is the slope of the curve at that age. To compute the curves, the ages at onset of daily smoking (AODS) of the subjects who had never smoked were considered censored at those subjects' current ages (de Leon et al., 2002).
When including all subjects the cumulative hazard curves for schizophrenia, mood disorders and controls were significantly different (p b 0.001), even after controlling for gender and education (p b 0.001) (Fig. 1). Similarly to previous studies (de Leon et al., 2002; Gurpegui et al., 2005), while the hazard of becoming a daily smoker decreased substantially in normal controls after the age of about 20, the hazard in schizophrenia patients continued to be high for at least 10 years after age 20. After controlling for confounders, mood-disordered patients were significantly different from controls but not from schizophrenia patients (Fig. 1). After excluding the patients who started smoking within 5 years before starting psychiatric medication, the cumulative hazard curve for schizophrenia patients was significantly different from that for ever-smoker controls (p = 0.002), even after adjusting for gender and education (p = 0.03) (Fig. 2). In this subgroup of subjects, during adolescence, schizophrenia patients had a significantly
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higher hazard of becoming daily smokers than controls of comparable age. Analogous analyses did not yield significant differences between mood-disordered patients and controls (unadjusted p = 0.08; after adjusting for gender and education, p = 0.2). 4. Discussion During adolescence, schizophrenia patients who started smoking at least 5 years before starting psychiatric medication had a higher hazard of starting daily smoking than normal controls of comparable age. (An analogous comparison between mood-disordered patients and controls did not yield significant results.) This suggests our main conclusion: neither schizophrenia illness, nor treatment, nor the prodromal period appears to explain the association between schizophrenia and daily cigarette smoking. A genetic vulnerability to smoking in people prone to schizophrenia may be a better explanation or, at least, should be included in any explanation. This study also confirms that some people vulnerable to schizophrenia are prone to become daily smokers later in their 20s, when other people rarely initiate daily smoking (de Leon et al., 2002; Gurpegui et al., 2005). Other recent data support our hypothesis that vulnerability to schizophrenia may be associated with increased vulnerability to smoking initiation (de Leon, 1996). Smokers from the British general population had a 70% greater risk of experiencing incident psychotic symptoms when compared to nonsmokers (Wiles et al., 2006). Cigarette smoking was associated with greater schizotypy in first degree relatives of schizophrenia patients, suggesting there is an overlap between genetic vulnerability to schizophrenia and cigarette smoking (Esterberg et al., 2007). A Finnish study suggested that smoking initiation was earlier in schizophrenia than in other psychoses and that the increased likelihood of smoking was associated with paternal smoking (Riala et al., 2005). Some neurophysiological research supports the vulnerability hypothesis. A genetic neurophysiological abnormality in schizophrenia patients and their relatives, which is associated with a dysfunction in a hippocampal nicotine receptor (α7), may be temporarily corrected by a high peak of nicotine (Freedman et al., 1997). Also, Leonard et al. (2002) found that an α7 promoter polymorphism was more frequent in schizophrenia patients than controls, and may be a marker of the neurophysiological abnormalities that increase schizophrenia risk. These survival analyses did not find significant differences between schizophrenia and mood disorders
as did our first Kentucky study. Patients with mood disorders rank between schizophrenia patients and the general population in current smoking, but the difference between patients with schizophrenia and mood disorders is small, particularly after controlling for confounders; therefore, larger samples may be needed to find significant differences between these two groups of patients. 5. Conclusion This and two prior studies (de Leon et al., 2002; Gurpegui et al., 2005) suggest that vulnerability to schizophrenia may be associated with a higher risk of becoming a daily smoker. Prospective studies of patients with first psychotic episode or subjects at risk of developing schizophrenia may be required to better establish the interaction between schizophrenia vulnerability, AODS and age of schizophrenia onset. Role of the funding source No pharmaceutical organization had any role in the writing of this paper for publication. The original pharmacogenetic study at the University of Kentucky Mental Health Research Center was supported by several sources: a researcher-initiated grant from Roche Molecular Systems, Inc., a NARSAD Independent Investigator Award to Jose de Leon, M.D, and internal resources. Statistical analyses were conducted without additional external support. Contributors Jose de Leon, M.D., designed the study. Francisco J. Diaz, Ph.D., and Diana M. Velásquez, B.S., undertook the statistical analyses. Francisco J. Diaz, Ph.D., and Jose de Leon, M.D., wrote the first draft of the manuscript. All authors have contributed to and have approved the final manuscript. Conflict of interest The authors have no conflict of interest. Acknowledgments The authors thank Lorraine Maw, M.A., for editorial assistance.
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