Effects of cigarette smoking on psychopathology scores in patients with schizophrenia: An experimental study

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1 Substance Abuse ISSN: (Print) (Online) Journal homepage: Effects of cigarette smoking on psychopathology scores in patients with schizophrenia: An experimental study Robert C. Smith MD, PhD, Mauricio Infante MD, Akeela Ali BA, Sanjay Nigam MD & Antonis Kotsaftis PhD To cite this article: Robert C. Smith MD, PhD, Mauricio Infante MD, Akeela Ali BA, Sanjay Nigam MD & Antonis Kotsaftis PhD (2001) Effects of cigarette smoking on psychopathology scores in patients with schizophrenia: An experimental study, Substance Abuse, 22:3, , DOI: / To link to this article: Published online: 13 Dec Submit your article to this journal Article views: 60 Citing articles: 18 View citing articles Full Terms & Conditions of access and use can be found at

2 Substance Abuse, VoL 22, No. 3,2001 Effects of Cigarette Smoking on Psychopathology Scores in Patients With Schizophrenia: An Experimental Study Robert C. Smith, MD, PhD, 1,2,7 Mauricio Infante, MD, 2,3 Akeela Ali, BA, 2,4 Sanjay Nigam, MD, 2,5 and Antonis Kotsaftis, PhD 1,2,6 Cigarette smoking and/or nicotine administration have been shown to transiently ameliorate several psychophysiological deficits in patients with schizophrenia such as indicators of deficient sensory gating and attention, but acute effects of smoking on positive and negative symptoms in schizophrenia have not been evaluated in experimental paradigms. The current study assessed whether smoking of cigarettes, after 6-12 h abstinence, transiently alters the expression of negative and/or positive symptoms in patients with schizophrenia who have a history of regular smoking. In a double-blind, placebo controlled study patients with schizophrenia participated in two sessions in which they smoked either cigarettes moderately high in nicotine content or denicotinized cigarettes. They were interviewed pre-and postsmoking to obtain ratings of PANSS and SANS scales, and had blood pressure and pulse serially recorded before and after smoking. Pulse rate and blood pressure were slightly higher after smoking in the high nicotine cigarette session. Negative symptom scores on both scales were significantly lower after cigarette smoking compared to same-day predrug baseline, but there were no differences in active versus denicotinized cigarette drug effects. These results suggest that acute smoking of cigarettes reduces negative symptoms in patients with schizophrenia in this experimental paradigm. Future work needs to identify the mechanism responsible for this behavioral effect. KEY WORDS: cigarette smoking; nicotine; schizophrenia; negative symptoms. 1 Department of Psychiatry, New York University Medical School, Hewlett, NewYork. 2 Manhattan Psychiatric Center, New York, New York. 3 Present address: Department of Psychiatry, Mayo Clinic, Rochester, Minnesota. 4 Present address: Department of Psychology, Long Island University, Brooklyn, NewYork. 5 Present address: Department of Psychiatry, University of Missouri, Columbia, Missouri. 6 Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York. 7 To whom correspondence should be addressed at Department of Psychiatry, New York University Medical School, C/O P.O. Box 316, Hewlett, New York ; robert.smith@med.nyu.edu /01/ $19.50/ Association for Medical Education and Research in Substance Abuse

3 176 Smith, Infante, Ali, Nigam, and Kotsaftis INTRODUCTION Patients with schizophrenia have a higher rate of cigarette smoking than patients with other psychiatric diagnoses or patients without definite psychiatric diagnoses (1, 2). Prevalence rates of smoking among patients with schizophrenia have ranged from 80-90% in some studies (1). Increased rates of smoking among schizophrenic patients may result from several influences. Some researchers have argued that nicotine reduces blood levels of some psychotropic drugs and may reduce side effects. Alternatively, nicotine may compensate for physiological deficits in schizophrenia (2). Recent reports suggest that nicotine transiently corrects some of the psychophysiological abnormalities found in patients with schizophrenia. Specifically smoking cigarettes transiently corrects a diminished gating response of the P50 auditory evoked potential in a two-tone prepulse habituation paradigm, and corrects abnormalities in smooth pursuit eye movements (3-5). Some of these effects have been hypothesized to be mediated by al nicotinic receptors in the hippocampus (1,3). However, nicotine also has effects on the brain dopamine system in ways that may functionally increase dopamine pulse in the mesolimbic and mesocortical system, and these effects may also be relevant to the drug's effects in patients with schizophrenia. Negative symptoms and poor cognitive functioning in schizophrenia have been hypothesized to be potentially related to a hypodopaminergic input into the mesolimbic and frontal mesocortical systems of the brain (6,7). One of the physiological effects of acute nicotine treatment studied in the rodent brain is an increase in burst firing of dopaminergic neurons in the ventral tegmental area and increased dopamine release in the nucleus accumbens and frontal mesolimbic dopaminergic system (8). Dopaminergic release in the ventral tegmental system may be associated with a subtype of nicotinic receptors rich in the ar3 and possibly a4 components of the nicotinic receptor (1, 9). Glassman (2) as well as other researchers have suggested that patients with schizophrenia may smoke at such a high rate because the dopamine release in the mesolimbic and mesocortical system produced by nicotine may transiently compensate for this hypodopaminergic state; therefore, smoking may be a from of self-medication to transiently compensate for hypothesized deficiencies in the brain mesocortical dopaminergic system. Traditional neuroleptics, which block D2 dopamine receptors reduce positive schizophrenic symptoms. Nicotine's effects on increasing dopamine firing and release could be a basis for an increase in positive symptoms in patients with schizophrenia who smoke cigarettes. Thus far, the relationship between smoking and schizophrenic clinical symptoms has been primarily explored in cross-sectional studies. Cross-sectional studies of comparative symptoms in schizophrenic smokers and nonsmokers have produced results that are conflicting or difficult to interpret. Goff et al. (10) reported that schizophrenics who are smokers had higher total Brief Psychiatric Rating Scale (BPRS) scores and higher positive and negative subscores of symptoms on this scale than nonsmoking schizophrenics. Zeidonis et al. (11) reported that patients with schizophrenia who smoked had higher positive symptoms than nonsmokers, and schizophrenics who had smoked heavily had the lowest number of negative symptoms. Hall et al. (12) on the other hand, reported that schizophrenics who had formerly smoked,

4 Smoking and Schizophrenic Symptoms 177 but were no longer smoking substantially at time of assessment, had lower levels of negative symptoms on a BPRS subscale than schizophrenics who were smokers. Hammera et al. (13) and Dalack and Meadow-Woodruff (14) reported that abstinence from nicotine or decreased nicotine use may be associated with an exacerbation of schizophrenic symptoms. However, in none of these studies is the temporal relationship between smoking and changes in schizophrenic symptoms clearly defined. One interpretation of the cross-sectional results could be that smoking is a marker for more severe symptomatic forms of schizophrenia, and smoking a cigarette may transiently reduce some of these symptoms for a brief period of time. Another interpretation is that nicotine or smoking itself increases certain schizophrenic symptoms. In order to clarify these interpretations, studies of the effects of acute or chronically administered cigarettes or nicotine within defined time frames are needed. This study investigates the effects acute smoking of high nicotine and denicotinized cigarettes on positive and negative symptoms in chronic schizophrenic patients, using an experimental design with double-blind control. On the basis of the research and interpretations discussed earlier, we hypothesized that smoking cigarettes with high nicotine content would decrease negative symptoms and increase positive symptoms in schizophrenic patients. The effects of smoking on heart rate and blood pressure have been used as a simple physiological assessment of nicotine's effects in many experimental studies conducted in humans. Therefore, we incorporated these measures as an indicator of nicotine's physiological effects in our proposed experiment. On the basis of previous studies of the effects of smoking and nicotine cardiovascular measures in normals (15-17), we anticipated that cigarettes high in nicotine content would produce a greater increase in pulse rate and blood pressure. MATERIALS AND METHOD Subjects Subjects were 15 male patients, age (mean ± SD) 43.6 ±6.8 years, who carried a diagnosis of schizophrenia (n = 14) or schizoaffective disorder (n = 1), and who were current smokers, recruited from an inpatient tertiary care hospital. Subjects were chronically hospitalized schizophrenics with a mean current hospitalization of 14.7 ± 5.5 years. All subjects signed informed consent for participation in the research project approved by an IRB. All patients were being treated with one or more neuroleptic drugs and some patients were also treated with additional supplementary psychotropic medications. The patients' medication was stable over the time of the study. The neuroleptic drugs the patients were on were clozapine - 5 patients, olanzapine - 6 patients, risperidone - 3 patients, fluphenazine - 1 patient, haloperidol decanoate -1 patient. Mean neuroleptic dose (in chlorpromazine equivalents (18)) was ± 580.7). Accessory medications that patients were on included the following: valproic acid - 5 patients, benztropine mesylate - 2 patients, trihexyphenidyl - 1 patient, desipramine - 1 patient.

5 178 Smith, Infante, Ali, Nigam, and Kotsaftis Experimental Design and Measures Baseline evaluations included Fagerstrom tolerance scale (19) and baseline and experimental sessions' evaluations included interview ratings of psychopathology on the Positive and Negative Symptom Scale (PANSS) (20) and Scale for Assessment of Negative Symptoms (SANS) (21). PANSS and SANS ratings were usually performed by a consensus of two raters, but occasionally a single trained rater performed the evaluations. In the experimental sessions the same interviewer rated the patient in the presmoking and postsmoking session of each of two different experimental days. PANSS and SANS ratings were performed by raters who had achieved at least 80% reliability on total scores on these scales. The intraclass correlation coefficient (22) was used to assess interrater reliability for each of four partially overlapping sets of occasions for comparing ratings of several pairs of joint raters. Each set of joint raters filled out their scores independently. Rating occasions for calculating the ICC measure included baseline interviews, experimental presmoking and postsmoking interviews, and other tape recorded patients' interviews. The patients and rating occasions for different sets of joint raters were not the same for all raters. ICC's were calculated on at least 12 rating occasions performed by each set of two joint raters; for some sets of joint rating occassions a considerably larger set of rating occasions was used (25-47). Mean ICC is the average of ICC from four pairs of joint raters. Mean [mean ± SD] ICC's for total and component scores on the PANSS and SANS scales, were as follows: PANSS total = 0.97 ±.02, PANSS positive = 0.92 ±.06, PANSS negative = 0.96 ±.02, SANS total = 0.95 ±.03, SANS Global = 0.95 ±.04, SANS Affective Flattening total = 0.83 ±.11, SANS Alogia total = 0.86 ±.03. Subjects' blood pressure and pulse were assessed during the experimental sessions, with a Marshall 92 automatic blood pressure monitor, at two time points in the morning before smoking and three time points after smoking. The mean of duplicate reading at each time point was taken as the value of that time point. The experimental design was a randomized double-blind crossover design, with two experimental sessions on different days within a 2-week period. Research cigarettes were obtained from the Tobacco Research Institute. In one session the subjects smoked cigarettes moderately high in nicotine content (1.9 mg); in the other session, they smoked denicotinized (placebo) cigarettes with very low nicotine content (0.1 mg). The order of sessions (high vs. denicotinized cigarette) was randomized. Subjects were abstinent from cigarettes and caffeinated beverages in the morning for at least 4 h while they were under constant observation, before any of the presmoking interviews, and at least 6 h before they smoked an experimental cigarette. During the cigarette abstinent hours, subjects could request candy and decaffeinated sodas. (Many patients may have been abstinant from cigarette smoking for a longer period of time. Although the hospital's rules prohibited smoking during the preceding night [after 10 P.M.], patients often violated these rules. Evening and night hospital staff could not be relied upon to strictly enforce no smoking rules so we cannot provide an exact estimate of the number of hours of cigarette abstinence.) Between 10:30-11:30 A.M. subjects had a min semistructured interview in which they were rated for a) a series of interview assessed items from the PANSS scale [see

6 Smoking and Schizophrenic Symptoms 179 appendix for list of items ] and b) the Affective Flattening and Alogia subscales from the SANS scale. ( The SANS modified total score in this report is the sum of the score on Alogia and Affective Flattening). These PANSS and SANS items were selected because they could be assessed from interview-based data alone, reflected primarily negative, positive, depressive or anxiety symptoms, and could be adequately covered in a brief min interview. Between 12:00 and 13:00 h subjects began smoking two cigarettes in a special smoking room. They were given one cigarette and, when they had finished smoking that first cigarette, were given a second cigarette to smoke. All subjects smoked two cigarettes. Approximately 10 min after finishing their second cigarette they were again interviewed to obtain PANSS and SANS scale ratings. After the interview, subjects smoked additional cigarettes and later were tested in a series of neuropsychological tests. Results of these tests will be reported separately. Statistical Analysis Statistical analysis used SPSS general linear model analysis of variance (ANOVA) for repeated measures. Order was a between-subjects factor in the ANOVA. Drug or smoking effects is the comparison of the values in the presmoking versus postsmoking sessions on the same experimental day. Because baseline negative symptom scores were correlated with smoking effects, we performed additional analyses of covariance, using baseline scores as covariate, to examine whether the observed effects could be totally "explained" by differences in baseline scores. Pearson correlations were computed to assess the relationships between variables. Because in some conditions, distributions of SANS modified total or SANS component scores appeared to deviate from normality and this deviation was significant on the Shapiro-Wilk test, analysis of SANS scores were performed on a transformation of these scores ([1+ original SANS score] 1/2 ) whose distribution more closely approximated a normal distribution. RESULTS Within 2 weeks prior to the experimental intervention we assessed the patients' baseline level of psychopathology with the PANSS and SANS scales. The group had moderate level of symptom severity as evidenced by their scores (mean ± SD) on the PANSS positive symptom scale: 19.8 ± 4.8, the PANSS negative symptom scale: 20.3 ± 5.2, the PANSS total score: 71.3 ± Baseline SANS scores were total: 37.4 ± 15.1, Global: 9.4 ± 3.7, Affective Flattening subscale: 12,7 ± 7.4; Alogia subscale: 4.3 ± 3.3. Fagerstrom tolerance mean scores were 6.4 ± 1.6. In order to assess whether abstinence from cigarettes for up to 12 months produced higher psychopathology in the presmoking experimental session evaluation, due to withdrawal from smoking, we compared baseline psychopathology scores, when the patients were not prevented from smoking, and predrug experimental day scores, when he was deprived from smoking for several hours. PANSS and SANS scores were not increased by abstinence from cigarettes. Presmoking SANS modified

7 180 Smith, Infante, AH, Nigam, and Kotsaftis total and modified PANSS negative symptom scores on experimental days were not significantly different from these same scores on baseline evaluation, when subjects where not deprived of cigarettes for several hours. The statistical analyses aimed to detect changes in the interviewer assessed symptom scores related to the act of smoking itself, and to the differences in nicotine content of the denicotinized and high nicotine cigarettes (Table I, Fig. 1). Analysis of interview rating data showed that negative symptoms significantly decreased after smoking in both high nicotine and denicotinized sessions (presmoking vs. postsmoking effect from repeated measures ANOVA). Overall multivariate analysis I Hgh Nicotine Pre High Nicotine Post Denicotinized Pre I Denicotinized Post ** High Nicotine Cigarette Denicotinized Cigarette Cigarette Type and Time Fig. 1. Effects of High Nicotine and Denicotinized Cigarette on SANS total negative symptom scores. SANS transformed modified total score [SANS TRMT\ = Sum of SANS Affective Flattening and Alogia items; transformation for normalization is (1 + SANS TRMT) 1 / 2. SANS TRMT: Pre- vs. postsmoking F = 12.10, df = 1,13 P =.004; Interaction (Cigarette type x prepost) F =.301, df = 1,13, P = NS. Individual session pre versus postsmoking comparison, paired Mest: **p <.01, *p <.02.

8 I Table I. Psychopathology Scores and Blood Pressure and Pulse in High Nicotine and Denicotinized Cigarette Smoking Sessions Psychopathology score PANSS mod positive PANSS mod negative symptoms PANSS anxietytension SANS affective flattening transformed total SANS alogia transformed total Pulse (bpm) Diastolic blood pressure (mm) High nicotine cigarette session Presmoking ± ± ± ± ± ± ± Postsmoking ± ± db ± ± ± ± Denicotinized cigarette session Presmoking ± ± ± ± ± ± ± Postsmoking ± ± ± ± ± ± dt Smoking effect* F Analysis of variance" P Nicotine drug effect c Note: Each number presents mean ± SD, n = 15. PANSS mod = PANSS modified (see Appendix for items included in these subscales). Analysis of variance = factorial repeated measures analysis of variance with cigarette type and pre- versus posttime as repeated measures and order of drug administration as between-subjects factor. Transformed scores are (1 + value) 1/2. "For all ANOVAS df = 1,13. *pre- vs. postsmoking. c Interaction high vs. denicotinized cigarette x pre- vs. postsmoking. F P n I 3

9 182 Smith, Infante, Ali, Nigam, and Kotsaftis of negative symptom measures showed a significant cigarette effect (Wilks X. =.341, F = 4.822, df = 4,10/> =.020). Subsequent univariate statistics from the same ANOVA showed that the PANSS negative symptom score was significantly decreased after smoking (p =.001), and also the (transformed) SANS modified total and SANS component scores of Affective Flattening and Alogia were significantly decreased after smoking (p = ) PANSS anxiety-tension scores showed a nonsignificant trend (p <.08) for decrease after smoking. PANSS positive symptom score showed no significant change. There was no significant decrease in PANSS depression in either the high nicotine or denicotinized cigarette session. However, our analysis showed no difference between the high nicotine and denicotinized cigarette. The interaction effect from the analysis of variance (high nicotine vs. denicotinized cigarettes x pre- vs. postsmoking) yielded nonsignificant results (Table I, Fig. 1). The extent of decrease was similar in the high nicotine and the denicotinized cigarette sessions. There were no statistically significant effects of order of high nicotine versus denicotinized cigarette sessions except for the depression score, where high nicotine cigarette first showed an increase in PANSS depression, post- versus presmoking ratings, and high nicotine cigarette later showed a decrease in depression. Severity of baseline negative symptoms correlated significantly with the postsmoking decrease in negative symptoms during both the high nicotine and denicotinized cigarette smoking sessions, with higher baseline scores correlated with a greater decrease in negative symptoms. This was true for both changes in negative symptoms measured by the modified PANSS negative symptom score, (r = , p = ) and for changes in negative symptoms measured by SANS modified total score after smoking (r = , p <.005). There was no marked difference in magnitude of the correlations between change in negative symptoms and baseline PANSS or SANS negative symptom score in the high nicotine (r = ) versus the denicotinized (r = ) cigarette sessions, and none of the pairs of correlations were significantly different. To determine whether the effect of cigarette smoking could be completely explained by differences in baseline negative symptoms, baseline scores were entered into an analysis of covariance of experimental sessions effects. Analysis of covariance of SANS scores, using SANS modified total baseline score as covariate, continued to show a significant presmoking versus postsmoking effect on the decrease in SANS modified total scores (F = 6.79, df = 1,12p =.023) as well as an interaction effect of baseline scores and pre-post difference (F = 19.25, df = 1,12F =.001). There were no significant correlations between PANSS baseline positive symptoms and changes in positive symptoms after smoking. Cigarettes with high nicotine content produced a trend for slightly higher increase in pulse rate than the denicotinized cigarette, although in the overall analysis of variance this difference did not reach statistical significance for a drug effect (see Table I). However, after smoking the first two cigarettes pulse increased, in the high nicotine cigarette session, by 7.5 bpm from presmoking value in the same day (paired t = 2.94, df = 14, p =.011), and only 2.5 bpm from presmoking values in the denicotinized cigarette session (paired t = 0.76, df = 14, p = ns). Analysis of variance showed a strong trend (p <.06, Table I) for diastolic pressure to increase slightly

10 Smoking and Schizophrenic Symptoms 183 more in the high nicotine (3.8 mm) than in the denicotinized cigarette (0.1 mm) sessions. There were no significant correlations between changes in pulse rate or blood pressure and symptom changes after smoking either the high nicotine or denicotinized cigarettes. DISCUSSION This is the first study to use a placebo controlled experimental design to study the acute effects of cigarettes on positive and negative symptom expression in chronic smokers with schizophrenia. In this initial sample, the lack of confirmation of our prediction, that cigarettes high in nicotine content would decrease negative symptoms in patients with schizophrenia more than denicotinized cigarettes, may arise from several sources. The fact that smoking cigarettes, both high or very low in nicotine content, produced significant decreases in negative symptoms, suggests that the act of smoking cigarettes itself, and/or other components of cigarette smoke rather than nicotine, may be responsible for the behavioral effect. Conditioned responses to smoking cigarettes may have induced some of the behavioral and physiological responses. O'Brien et al. (23) have proposed that drug conditioned cues may be involved in some of the physiological and addictive properties of drugs of abuse. Westman etal. (24) recently reported that, in volunteer normal chronic smokers, denicotinized cigarettes had many of the similar subjective effects as the standard cigarettes smoked in their experiment. It is also possible that the social contact involved in the experiment or motor influences in the act of smoking cigarettes may have helped mediate the behavioral effects we observed. Alternatively, one of the other components of cigarettes, other than nicotine, which were present equally in the high and low nicotine cigarettes, may have influenced negative symptoms. For example, several groups (25-27) have reported decreases in platelet or brain MAO activity produced by cigarettes, which could theoretically increase brain dopamine activity. Nicotine itself does not inhibit MAO activity. However, the time course to reach physiologically meaningful degrees of MAO inhibition in vivo may take days or weeks of cigarette smoking, and this is too long to account for the immediate effects on negative symptoms that we report. It is possible that raters' knowledge of the time of the interview (i.e. presmoking vs. postsmoking) could have influenced their ratings on rating scores and accounted for a "smoking effect." However, our findings that a smoking effect was found only for negative symptoms and not for positive symptoms, anxiety, or depression, make this explanation less plausible. Finally the small sample size may have been insufficient for detecting a significant "nicotine dose" effect, if the mean difference was small and the finding not consistent over all subjects. Since we did not measure nicotine or cotinine blood levels in this experiment, we cannot rule out the possibility that our subjects had substantial drug levels before beginning the experiment, or that the very low nicotine content of the denicotinized cigarette (0.1 mg) also produced substantial increases in nicotine levels. This can make more uncertain the interpretation of our findings. However, with at least 6 h of

11 184 Smith, Infante, Ali, Nigam, and Kotsaftis nicotine and caffeine deprivation before smoking, we would expect the high nicotine cigarette, which had approximately 19 times the nicotine content of the denicotinized cigarette, to have produced much higher nicotine peak blood levels in the half hour after smoking, as previous results of Pomerleau (17) have reported using similar cigarettes. Moreover, the changes in pulse and blood pressure suggest that the high nicotine cigarette had the expected greater physiological effect. The slightly greater changes in heart rate and diastolic blood pressure produced by the high nicotine cigarette compared to the denicotinized cigarette are consistent with a physiological effect of nicotine on commonly measured parameters reported in some other experiments, and the magnitude of these cardiovascular changes we report with the high nicotine cigarette are similar to those reported in some other studies of smoking or nicotine nasal spray (15,16,28). To determine whether these effects of cigarette smoking on schizophrenic negative symptoms are reliable, additional studies with larger samples, and measurement of nicotine blood levels would be informative. Since our study used only male patients with schizophrenia, we cannot generalzie our results to female patients. To clarify whether the effects are due to nicotine or other components of cigarettes similar studies using other forms of nicotine administration (nicotine nasal spray, nicotine inhaler, and nicotine patch) would be useful to examine whether acute administration of nicotine by these delivery systems produces similar decreases in negative symptoms in patients with schizophrenia. If drugs with nicotine content had a similar effect on negative symptoms, this could provide a rationale for suggesting that alternative nicotine therapies might ameliorate some hypothesized deficits in schizophrenia that may contribute to the high rate of smoking in this disorder. APPENDIX Items in modified PANSS scale used in pre-and postinterview on smoking day: Positive symptoms: Pl-delusions, P2-conceptual disorganization, P3-hallucinatory behavior, P5-grandiosity, P6-suspiciousness/persecution, P7-hostility. Negative symptoms: Nl-blunted affect, N2-poor rapport, N6-lack of spontaneity, NTstereo-typed thinking. General symptoms: G2-anxiety, G4-tension, G6-depression G8-uncooperativeness, G9-unusual thought content, Gil-poor attention. At baseline evaluation the full PANSS scale, not the abbreviated version specified above, was used. ACKNOWLEDGMENT Supported, in part, by a NARSAD Independent Investigator Award to Dr. Smith.

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