Assessment of cigarette smoking status with respect to symptomatic manifestation in first-episode schizophrenia patients

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ScienceDirect Comprehensive Psychiatry xx (2015) xxx – xxx www.elsevier.com/locate/comppsych

Assessment of cigarette smoking status with respect to symptomatic manifestation in first-episode schizophrenia patients Błażej Misiak a, b,⁎, Andrzej Kiejna a , Dorota Frydecka a b

a Department of Psychiatry, Wroclaw Medical University, 10 Pasteur Street, 50-367 Wroclaw, Poland Department of Genetics, Wroclaw Medical University, 1 Marcinkowski Street, 50-368 Wroclaw, Poland

Abstract Objective: It has been repeatedly found that cigarette smoking may influence schizophrenia psychopathology. However, little is known about the relationship between nicotine consumption and symptomatic manifestation of first-episode schizophrenia (FES). Method: We recruited 109 minimally medicated FES patients. Cigarette smoking was assessed using the Fagerström test for nicotine dependence (FTND) and pack-year index. Psychopathology on the day of recruitment was examined using the Positive and Negative Syndrome Scale (PANSS). Results: Smokers had significantly lower severity of negative and depressive symptoms in comparison with non-smokers. Patients with severe nicotine dependence had significantly later age of psychosis onset in comparison with those with mild nicotine dependence and nonsmokers. Significantly lower severity of negative and depressive symptoms was also observed in patients with severe nicotine dependence in comparison with non-smokers. The associations between the severity of nicotine dependence and scores of negative and depressive symptoms as well as age of psychosis onset remained significant after co-varying for gender, education, duration of untreated psychosis (DUP) and measures of antipsychotic treatment. Conclusion: Our results indicate that cigarette smoking might be associated with less severe negative and depressive symptoms as well as delayed age of psychosis onset. However, longitudinal studies are required to indicate the direction of causality. © 2014 Elsevier Inc. All rights reserved.

1. Introduction Prevalence of cigarette smoking in schizophrenia patients has been estimated at 70–80% and is significantly higher than in the general population [1]. Schizophrenia patients tend to self-administer more nicotine during cigarette smoking, consume higher nicotine containing cigarettes and have lower cessation rates [2,3]. According to the recent meta-analysis, these findings are also relevant to firstepisode psychosis subjects, who have also higher prevalence rates of cigarette smoking when compared with the general population and tend to smoke about five years prior to the onset of psychosis [4]. This phenomenon points to the burden of cardiovascular risk that is a major contributor of increased mortality rates in this group of patients.

⁎ Corresponding author at: Department of Psychiatry, Wroclaw Medical University, 10 Pasteur Street, 50–367 Wroclaw, Poland. Tel.: +48 71 784 16 05; fax: +48 71 784 16 02. E-mail address: [email protected] (B. Misiak). http://dx.doi.org/10.1016/j.comppsych.2014.11.024 0010-440X/© 2014 Elsevier Inc. All rights reserved.

One of possible explanations of high smoking rates in these patients originates from pharmacodynamic and pharmacokinetic activities of antipsychotics that block postsynaptic dopamine D2 receptors [5]. In this regard, patients may smoke to restore dopaminergic transmission via central effects of nicotine on dopaminergic system. Another point is that nicotine may enhance the metabolism of antipsychotics due to induction of the 1A2 isoform of cytochrome P450 (CYP1A1) [6]. Smoking might be a selfhealing process that alleviates side effects of antipsychotics, negative symptoms and cognitive deficits by normalizing sensory gating deficits and prepulse-inhibition abnormalities [7], as well as increasing pre-frontal cortex release of dopamine [8,9]. Finally, the addiction vulnerability hypothesis states that there might be shared genetic factors underlying the development of nicotine dependence and schizophrenia [10]. Although neurophysiological studies have provided grounds for understanding high prevalence of cigarette smoking in schizophrenia, results from studies investigating associations between tobacco use and schizophrenia

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psychopathology are inconsistent. There are studies showing either higher or lower severity of positive [11,12] and negative symptoms [13–19] in schizophrenia smokers. These discrepancies might be attributed to the use of various tools and definitions for assessment of smoking, differences in sample size as well as differences in medication status. In addition, ethnic differences and underlying genetic heterogeneity could point to inconsistencies reported in various studies. Jiang et al. [14,44], also noticed that the Positive and Negative Syndrome Scale (PANSS), which is commonly used in studies looking at the relationship between cigarette smoking and psychopathology, represents the admixture of five symptomatic dimensions that do not overlap with its three subscales. Therefore, the lack of more accurate insight into symptom dimensions of schizophrenia might have led to overlook significant associations between nicotine dependence and schizophrenia psychopathology. It has been found that sensory gating deficits occur already in at risk for psychosis individuals and drug-naïve firstepisode schizophrenia (FES) patients [20–22]. In addition, cigarette smoking may improve sensory gating in FES patients [21,22]. Recent studies also indicate that these deficits are associated with higher severity of negative symptoms [23,24]. However, there is only one study on drug-naïve FES patients from Chinese population showing higher rates of positive symptoms scores and unaltered severity of negative symptoms in schizophrenia smokers [25]. In turn, the influence of cigarette smoking in Caucasian FES patients has not been explored so far. Therefore, in this study we aimed at investigating the relationship between nicotine dependence and psychopathology assessed by PANSS in minimally medicated FES patients of Caucasian ethnicity. 2. Materials and methods 2.1. Subjects We recruited 109 first-episode schizophrenia patients (61 males aged 25.64 ± 4.95 years and 48 females aged 30.25 ± 7.78 years). A diagnosis of schizophrenia was based on ICD-10 and DSM-IV criteria and confirmed using the Operational Criteria for Psychotic Illness (OPCRIT) checklist. Duration of untreated psychosis (DUP) was defined as the time from appearance of first prodromal symptoms to initiation of antipsychotic treatment. All patients were Caucasians and were recruited from the same psychiatric hospital. There were the following exclusion criteria: mental retardation and/or general brain disorder, drug and/or alcohol abuse/dependence during one year prior to the onset of psychosis, positive urine screening for illicit drugs (cannabis, amphetamine, opiates and ecstasy) and severe somatic comorbidities. Treatment duration was 5.48 ± 4.19 days and chlorpromazine equivalent was 148.16 ± 116.45 mg/day on the day of recruitment. Patients were receiving olanzapine (59 subjects), risperidone (25 subjects) and amisulpride (3 subjects) in monotherapy. There were 22 drug-naïve patients. Agitation and hostility

were managed with temporary injections of haloperidol and benzodiazepines. The study was approved by the Ethics Committee at Wroclaw Medical University (Poland) and all patients gave an informed consent. 2.2. Measures The whole course of the disorder was assessed using the OPCRIT checklist, while psychopathology on the day of recruitment was evaluated using PANSS. Based on previous studies [14,44], PANSS subscales were divided into five symptom dimensions (factors): positive (P1, P3, P6 and G9), negative (N2, N3, N4, N6, G7), excitement (P4, P7 and G1), depression (G2, G3 and G6) and cognitive (G10 and G12). Patients were regarded as smokers if they reported smoking more than one cigarette per day for at least 1 year. All patients, who smoked were administered the Fagerström Test for Nicotine Dependence (FTND). Nicotine dependence was classified as high/severe (FTND ≥ 7) and mild/ moderate (FTND b 7). Additionally, pack-year index was calculated by multiplying the number of packs of cigarettes smoked per day (20 cigarettes per pack) by the number of years the patient has reported to smoke. 2.3. Statistics The comparison of smokers and non-smokers was performed using Mann–Whitney U test (age, illness duration, chlorpromazine equivalent, treatment duration, PANSS subscales scores and PANSS factors), χ 2 test (gender and unemployment rate) and Fisher exact test (marital status and education). Same tests were used for the comparison of non-smokers, patients with mild and severe nicotine dependence. Spearman's rank correlation coefficient was used to test the relationship between FTND score or pack-year index and PANSS subscales scores, PANSS factors scores, chlorpromazine equivalent as well as treatment duration. Scores of PANSS factors and age of psychosis onset were compared between non-smokers, patients with mild and severe nicotine dependence using an analysis of covariance (ANCOVA) with gender, education, DUP and antipsychotic treatment measures (treatment duration, chlorpromazine equivalent and type of antipsychotic drug) as covariates. Differences were considered as statistically significant if the p-value was less than 0.05. Statistical analysis was performed using the STATISTICA 10 software.

3. Results General characteristics of patients with respect to smoking status were shown in Table 1. Both groups did not differ significantly in terms of age, gender, education level, unemployment rate, marital status, chlorpromazine equivalent dosage and treatment duration (p N 0.05). Smokers had significantly lower scores of negative

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symptoms as measured by PANSS when compared with non-smoking patients (16.67 ± 6.06 vs. 19.38 ± 6.82, p = 0.036). However, there was no significant difference in scores of positive symptoms and general psychopathology evaluated by PANSS. Analysis of symptom dimensions covered by PANSS revealed significantly lower severity of negative factor and depression factor scores in smokers in comparison with non-smokers (10.32 ± 4.65 vs. 12.68 ± 5.35, p = 0.018 and 4.90 ± 1.39 vs. 5.94 ± 2.38, p = 0.028; respectively). Smoking was not associated with differences in scores of positive, excitement and cognition factors. Table 2 presents differences in clinical and sociodemographic data with respect to the severity of nicotine dependence assessed by means of FTND. There were no significant differences between non-smokers, patients with mild and severe nicotine dependence in terms of gender, education level, medication status (treatment duration, chlorpromazine equivalent and type of antipsychotic treatment) (p N 0.05). Patients with severe nicotine dependence were significantly older than those with mild nicotine dependence (30.35 ± 6.13 vs. 26.47 ± 7.11 years, p = 0.036). Similarly, age of psychosis onset was significantly later in patients with severe nicotine dependence in comparison with those with mild nicotine dependence (29.82 ± 5.92 vs. 25.91 ± 6.88 years, p = 0.027) and nonsmokers (29.82 ± 5.92 vs. 26.16 ± 6.38 years, p = 0.016). The score of PANSS negative symptoms scale was

Table 1 General characteristics of patients with respect to smoking status. Smokers, n = 40 Age (years) Age of psychosis onset (years) Gender (M/F) Education (higher/other than higher) Unemployment rate (%) Merital status (single/married) DUP (weeks) CPZ (mg/day) Treatment duration (days) FTND Pack-year index PANSS (P) PANSS (N) PANSS (G) PANSS (total score) PANSS (positive factor) PANSS (negative factor) PANSS (excitement factor) PANSS (depression factor) PANSS (cognitive factor)

28.12 27.57 25/15 4/36 52.50 34/6 30.60 165.00 6.00 5.47 6.52 22.57 16.67 39.57 78.82 15.95 10.32 5.67 4.90 7.10

± 6.91 ± 6.70

Non-smokers, n = 69

27.41 26.16 36/33 16/53 55.07 57/12 ± 23.87 63.98 ± 103.89 138.41 ± 3.41 5.18 ± 1.99 ± 4.28 ± 5.23 21.98 ± 6.06 19.38 ± 7.64 41.12 ± 13.47 82.48 ± 3.78 16.15 ± 4.65 12.68 ± 2.98 4.91 ± 1.39 5.94 ± 2.08 7.14

p⁎

± 6.65 ± 6.39

0.618 0.277 0.295 0.086 0.795 0.745 ± 101.25 0.070 ± 122.81 0.182 ± 4.58 0.180 ± 5.37 0.592 ± 6.82 0.036 ± 8.31 0.396 ± 14.95 0.271 ± 3.92 0.700 ± 5.35 0.018 ± 2.27 0.288 ± 2.38 0.028 ± 1.94 0.912

Abbreviations: CPZ – chlorpromazine equivalent, DUP – duration of untreated psychosis, FTND – Fagerström Test for Nicotine Dependence, PANSS – the Positive and Negative Syndrome Scale. Significant differences (p b 0.05) were marked in bold characters. ⁎ p-value refers to the comparison of mean ranks using the Mann–Whitney U test with exception of gender and the number of unemployed subjects (χ2 test) as well as education and marital status (Fisher exact test).

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significantly lower in patients with severe nicotine dependence in comparison with non-smokers (4.88 ± 3.84 vs. 19.38 ± 6.82, p = 0.014). There were no significant between group differences in scores of positive symptoms and general psychopathology assessed using PANSS subscales (p N 0.05). The analysis of symptom dimensions (factors) covered by PANSS revealed that patients with severe nicotine dependence had significantly lower scores of negative factor (8.88 ± 2.66 vs. 12.68 ± 5.35, p = 0.008) and depression factor (4.47 ± 1.37 vs. 5.94 ± 2.38, p = 0.017). Non-smokers, patients with mild and severe nicotine dependence did not differ significantly with respect to positive, excitement and cognition factors (p N 0.05). After co-varying for gender, education, measures of antipsychotic treatment (chlorpromazine equivalent dosage, treatment duration and medication type) and DUP, non-smokers, patients with mild and severe nicotine dependence differed significantly in terms of age of psychosis onset (F = 8.75, p = 0.004), negative factor score (F = 4.09, p = 0.046) and depression factor score (F = 5.78, p = 0.018). The model including the severity of schizophrenia symptoms assessed by PANSS subscales, instead of PANSS factors, was not significant (p N 0.05 for corrected model). Correlations between PANSS symptoms scores and FTND score, pack-year index score as well as treatment status (chlorpromazine equivalent and treatment duration) were shown in Table 3. There was a significant negative correlation between FTND score and the severity of negative symptoms as assessed by PANSS scales (r = −0.233, p b 0.05) and PANSS factors (r = −0.251, p b 0.01) as well as depression factor score (r = −0.231, p b 0.05). As similar to FTND score, there was a significant negative relationship between pack-year index score and the severity of negative symptoms as assessed by PANSS scales (r = −0.225, p b 0.05) and PANSS factors (−0.236, p b 0.05) as well as depression factor score (r = −0.220, p b 0.05). There were no significant correlations between FTND score, pack-year index score, treatment duration and chlorpromazine equivalent.

4. Discussion To the best of our knowledge, it is the first study investigating the relationship between cigarette smoking and psychopathology in FES patients from Caucasian population. In this study, we found that cigarette smoking is associated with lower severity of negative symptoms. However, this difference was significant only in the comparison of patients with severe nicotine dependence and non-smokers. Simultaneously, we did not reveal the influence of cigarette smoking on the severity of positive symptoms. To date, there is only one study on drug-naïve FES patients from Chinese population showing higher severity of positive symptoms in smoking patients in comparison with non-smokers [25]. It might be speculated that the exposition to antipsychotics in our study may

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Table 2 Differences in symptom dimensions (factors) assessed by means of the Positive and Negative Syndrome Scale (PANSS) with respect to the severity of nicotine dependence.

Age (years) Age of psychosis onset (years) Gender (M/F) Education (higher/other than higher) DUP (weeks) Type of medication (OLA/RIS/AMIS) CPZ (mg/day) Treatment duration (days) PANSS (P) PANSS (N) PANSS (G) PANSS (positive factor) PANSS (negative factor) PANSS (excitement factor) PANSS (depression factor) PANSS (cognition factor)

Non-smokers (n = 69)

Mild dependence Severe dependence Non-smokers vs. mild Non-smokers vs. severe Mild vs. severe (n = 23) (n = 17) dependence (p) dependence (p) dependence (p)

27.41 ± 6.65 26.16 ± 6.38 36/33 16/53 63.98 ± 101.25 23/44/2 138.41 ± 122.81 6.00 ± 3.41 21.98 ± 5.37 19.38 ± 6.82 41.12 ± 8.31 16.15 ± 3.92 12.68 ± 5.35 4.91 ± 2.27 5.94 ± 2.38 7.14 ± 1.94

26.47 ± 7.11 25.91 ± 6.88 14/9 2/21 32.74 ± 29.98 16/7/0 145.65 ± 108.62 6.00 ± 4.09 22.87 ± 4.64 18.00 ± 7.08 39.87 ± 6.49 15.74 ± 3.16 11.39 ± 5.52 5.83 ± 2.87 5.22 ± 1.35 6.96 ± 1.89

30.35 ± 6.13 29.82 ± 5.92 11/6 2/15 27.71 ± 11.72 12/5/0 191.18 ± 93.93 6.00 ± 2.32 22.17 ± 6.05 14.88 ± 3.84 39.17 ± 9.16 16.23 ± 4.58 8.88 ± 2.66 5.47 ± 3.20 4.47 ± 1.37 7.29 ± 2.36

0.389 0.667 0.629 0.223 0.091 0.670 0.713 0.319 0.445 0.334 0.548 0.467 0.232 0.211 0.247 0.707

0.056 0.016 0.562 0.506 0.279 0.844 0.063 0.266 0.996 0.014 0.457 0.838 0.008 0.747 0.017 0.796

0.036 0.027 1.000 1.000 0.414 0.997 0.125 0.988 0.631 0.208 0.826 0.588 0.221 0.569 0.148 0.665

p-value refers to the comparison of mean ranks using the Mann–Whitney U test with exception of gender and the number of unemployed subjects (χ 2 test) as well as education and marital status (Fisher exact test). Abbreviations: CPZ – chlorpromazine equivalent, DUP – duration of untreated psychosis, FTND – Fagerström Test for Nicotine Dependence, PANSS – the Positive and Negative Syndrome Scale (P – positive symptoms score, N – negative symptoms score, G – general psychopathology score). Significant differences (p b 0.05) were marked in bold characters.

underlie discordant results; however, the analysis of covariance did not confirm the confounding effect of antipsychotic treatment on our results. Similarly, there was no significant correlation between the measures of antipsychotics treatment (chlorpromazine equivalent and treatment duration) and the pack-year index or FTND score. The most likely explanation of discordant results between our study and the study by Zhang et al. [25], originates from ethnic differences. Indeed, it has been found that polymorphisms in genes involved in cholinergic transmission that might be risk variants for nicotine dependence have various distribution across different ethnicities [26–29]. Similarly, ethnic Table 3 Correlations between Fagerström Test for Nicotine Dependence (FTND) score, pack-year index and clinical parameters.

CPZ (mg/day) Treatment duration (days) Illness duration PANSS (P) PANSS (N) PANSS (G) PANSS (total score) PANSS (positive factor) PANSS (negative factor) PANSS (excitement factor) PANSS (depression factor) PANSS (cognition factor)

FTND score

Pack-year index

0.164 0.138 −0.152 0.025 −0.233⁎ −0.094 −0.136 −0.025 −0.251⁎⁎ 0.080 −0.231⁎ −0.008

0.174 0.123 −0.160 0.047 −0.225⁎ −0.114 −0.136 −0.013 −0.236⁎ 0.077 −0.220⁎ −0.021

Spearman's rank correlation coefficients are provided. CPZ – chlorpromazine equivalent, PANSS – the Positive and Negative Syndrome Scale. ⁎ p b 0.05. ⁎⁎ p b 0.01.

variation exists in the associations between polymorphisms of dopaminergic transmission genes and schizophrenia susceptibility (for review see [30]). Studies on medicated schizophrenia patients have also provided mixed results. In some studies smoking has been found to improve the severity of negative symptoms [12,18,19,31,32]. Other authors have revealed deleterious effects of cigarette smoking on the severity of negative symptoms [13,16,17]. Similar inconsistencies exist in assessment of positive symptoms [11,12]. However, our results are in agreement with the study from Caucasian population that also revealed lower severity of negative symptoms in schizophrenia smokers [18]. Importantly, Jiang et al. [14] concluded that the simple operationalization of schizophrenia psychopathology in terms of PANSS subscales may point to these discrepancies since PANSS includes the admixture of symptom dimensions. Following this notion, we implemented the analysis of PANSS proposed by Jiang et al. [14]. We found that after controlling for possible confounders, a dimensional approach to PANSS, but not the analysis of PANSS subscales scores, provides significant associations between schizophrenia symptoms and the severity of nicotine dependence. To date, less attention has been paid to the influence of cigarette smoking on affective symptoms. We showed that more severe nicotine dependence is related to lower severity of depression symptoms. These findings were significant after controlling for possible confounders (gender, education, DUP, measures of antipsychotic treatment). It has been found that the anatomical connection between nicotine consumption and the severity of depression symptoms is

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associated with the mesolimbic reward pathway. Nicotine may stimulate dopaminergic neurons within this brain circuitry, especially in ventral tegmental area and nucleus accumbens [33]. Taking into account these interactions, cigarette smoking might be perceived as the reinforcement of the brain reward system that alleviates depressive symptoms. However, previous studies on schizophrenia patients did not confirm these findings unequivocally. In the 10-year longitudinal study by Kotov et al. [34], depression severity was found to predict nicotine consumption. Authors found that each additional DSM depression symptom was associated with consuming an extra cigarette per day. These findings suggest that schizophrenia patients may increase tobacco consumption to alleviate depressive symptoms. Less is known about the effects of cigarette smoking on depression symptoms in schizophrenia since the majority of previous studies focused on the relationship between smoking and positive or negative but did not analyze affective symptoms. Other cross-sectional studies did not confirm self-medication effects of smoking with respect to depression symptoms in schizophrenia [35–37]. Finally, we found that patients with severe or mild nicotine dependence have later age of psychosis onset than non-smokers. Although we did not determine the age of smoking initiation, it has been repeatedly shown that the vast majority of schizophrenia patients start smoking before illness onset [4] and there are also studies showing that nicotine consumption may delay the onset of psychosis [38,39]. In addition, in the longitudinal study with a 26-year follow-up performed by Zammit et al. [40], cigarette smoking was found to serve as a protective factor with respect to the development of schizophrenia. It has been also proposed that schizophrenia patients may initiate smoking to alleviate neurophysiological and cognitive deficits that are present before the development of overt psychotic symptoms [41,42]. This assumption is corroborated by our findings of lower severity of negative and depression symptoms in FES patients with nicotine dependence. However, the recent meta-analysis did not confirm the relationship between cigarette smoking and the age of psychosis onset [43]. Therefore, our results should be interpreted with caution as later age of psychosis onset may simply reflect longer duration of cigarette smoking and thus stronger nicotine dependence. Our study has some limitations that require further discussion. Firstly, a cross-sectional design of this study does not enable to draw conclusions on reciprocal interactions between cigarette smoking and psychopathological manifestation of FES. Therefore, our results cannot be perceived as an unequivocal support for the self-medication hypothesis since patients with less severe negative and depressive symptoms might be simply more able to seek out cigarettes and smoke. An important limitation is also that we excluded patients with current illicit substance use disorders, who are prone to use tobacco and might have more severe psychopathology. Another point is that patients were not

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drug-naïve. However, they were minimally medicated and the measures of antipsychotic treatment (chlorpromazine equivalent, medication type and treatment duration) did not differ significantly between smokers and non-smokers as well as were not associated with pack-year index or FTND score. It should also be noted that we did not assess extrapyramidal symptoms, levels of antipsychotics or cotinine. Hence, we are not able to indicate as to whether between-group differences in the severity of negative and depressive symptoms are due to the direct activity of nicotine or the indirect effects via increased metabolism of antipsychotics. However, it is likely that the prevalence of extrapyramidal symptoms in our sample was low due to short treatment duration and a low dose of antipsychotics. In addition, we did not determine the age of smoking initiation that would support our findings that cigarette smoking is associated with later age of psychosis onset. Finally, it should be noted that multiple comparisons were conducted creating the possibility of type I error. In summary, we found that cigarette smoking might be associated with the severity of negative and depressive symptoms as well as delayed age of psychosis onset. Longitudinal studies of subjects at risk for psychosis are required to indicate the direction of causality. Future studies should also look into possible genetic underpinnings of this relationship as they are also involved in the development of nicotine dependence and may differ across ethnicities.

Conflicts of interest None to declare. Acknowledgment This study was supported by the research grant funded by National Science Center (DEC-2011/03/N/NZ5/0024). Błażej Misiak was supported by the START scholarship provided by the Foundation for Polish Science. References [1] de Leon J, Diaz FJ. A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophr Res 2005;76:135-57. [2] Olincy A, Young DA, Freedman R. Increased levels of the nicotine metabolite cotinine in schizophrenic smokers compared to other smokers. Biol Psychiatry 1997;42:1-5. [3] Strand JE, Nyback H. Tobacco use in schizophrenia: a study of cotinine concentrations in the saliva of patients and controls. Eur Psychiatry 2005;20:50-4. [4] Myles N, Newall HD, Curtis J, Nielssen O, Shiers D, Large M. Tobacco use before, at, and after first-episode psychosis: a systematic meta-analysis. J Clin Psychiatry 2012;73:468-75. [5] Winterer G. Why do patients with schizophrenia smoke? Curr Opin Psychiatry 2010;23:112-9. [6] de Leon J. Atypical antipsychotic dosing: the effect of smoking and caffeine. Psychiatr Serv 2004;55:491-3.

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