Varenicline prevents affective and cognitive exacerbation during smoking abstinence in male patients with schizophrenia

Psychiatry Research 190 (2011) 79–84

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Psychiatry Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s

Varenicline prevents affective and cognitive exacerbation during smoking abstinence in male patients with schizophrenia Mu-En Liu a, Shih-Jen Tsai b, Shwu-Yuh Jeang a, Su-Lin Peng a, Shang-Liang Wu c, Ming-Chao Chen d, Yung-Lang Tsai e, Szu-Tung Yang a,⁎ a

Department of Psychiatry, Long Cyuan Veterans Hospital, Pingtung, Taiwan Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan Bureau of Health Promotion, Department of Health, Taichung, Taiwan d Department of Psychiatry, Kaohsiung Kai-Suan Psychiatric Hospital, Kaohsiung, Taiwan e Department of Psychiatry, Tainan Municipal Hospital, Tainan, Taiwan b c

a r t i c l e

i n f o

Article history: Received 16 November 2010 Received in revised form 26 January 2011 Accepted 19 April 2011 Keywords: Anxiety Cognition Depression Tobacco Schizophrenia Varenicline

a b s t r a c t To explore the effects of varenicline on the psychopathology and cognition of chronic inpatients with schizophrenia, we conducted a non-randomized control group time series investigation between March 2009 and April 2010. In a mandatory smoking cessation intervention, 41 male inpatient smokers were scheduled to undergo either a 5-week varenicline treatment (varenicline group) or the use of no drugs (non-treatment group). Depression (HAM-D), anxiety (HAM-A), and psychosis (PANSS) were evaluated at baseline, and at the 2nd, 4th, 8th and 12th week after abstinence; four neuropsychological tests, including Digit Span Forward and Backward (DSF and DSB), and Trail Making Test-A and -B, were evaluated at baseline and at the 4th, 8th and 12th week. .Thirty patients completed the study. Among 15 patients in the non-treatment group, the HAM-D, HAM-A, DSF, and DSB scores were exacerbated during the 2–8 weeks of abstinence, but there were no changes in psychotic symptoms and the other two neuropsychological tests. Compared with the nontreatment group, varenicline users experienced less impairment in HAM-D and HAM-A scores at the 2nd and 4th weeks, and in DSF tasks at the 4th week after abstinence. In conclusions, varenicline can attenuate abstinence-induced adverse outcomes and appears to be well-tolerated in smokers with schizophrenia. © 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction It is readily apparent to clinicians working with chronic schizophrenic patients that this population is prone to cigarette smoking, and often quite heavy smoking. The high prevalence of smoking in patients with schizophrenia is important from a health perspective (Hughes et al., 1986; Shinozaki et al., 2011). Thus, the development of safe and effective tobacco cessation intervention in this population is of considerable public health significance. Evidence suggests that nicotine, which acts at the neuronal nicotinic acetylcholine receptors (nAChRs), is one of the active components in cigarette smoke responsible for cigarette addiction (Kenny and Markou, 2001; McCloughen, 2003). Biochemical, psychophysiological and neuropharmacological studies have demonstrated that patients with schizophrenia may have deficits related to the number or functioning of nicotinic receptors in their brain (McCloughen, 2003). Thus,

⁎ Corresponding author at: Department of Psychiatry, Longcyuan Veterans Hospital, Pingtung, Taiwan No.1, Anping Lane 1, Jausheng Rd., Neipu Shiang, Pingtung, Taiwan 91245, R.O.C. Tel.: + 886 8 7704115x770; fax: + 886 8 7708447. E-mail address: [email protected] (S.-T. Yang). 0165-1781/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2011.04.018

nAChRs play a considerable role in psychopathological changes in schizophrenic smokers during tobacco abstinence. Varenicline, a partial agonist at the α4β2 nAChRs, and a full agonist at the α7 nAChRs, is a new and efficacious treatment for nicotine dependence. It causes partial stimulation of the nAChRs-mediated release of dopamine in the reward center, and competitive inhibition of receptor binding by nicotine delivered while smoking (Hays and Ebbert, 2008; Rollema et al., 2009). Varenicline's clinical effects have been widely examined in healthy subjects. These trials documented treatment-related reductions in smoking urges and withdrawalrelated negative effects, as well as improvements in cognitive function (Patterson et al., 2009; Rollema et al., 2009). However, very few clinical studies have explored varenicline's effects on psychiatric patients, and have reported inconsistent results with schizophrenia. In a case series of 19 smokers with schizophrenia, patients did not experience worsening in psychiatric symptoms with varenicline treatment (Evins and Goff, 2008). On the contrary, other case reports have suggested varenicline may have adverse psychiatric effects in patients with mental illness (Kohen and Kremen, 2007; Liu et al., 2009). Varenicline could produce significant improvements in the cognitive function of 12 schizophrenic smokers on some cognitive test scores primarily associated with verbal learning and memory, but

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not in scores on visual-spatial learning or memory, or attention (Smith et al., 2009). In contrast, Waldo et al. reported varenicline had no significant effects on the scores of any of the memory tests or on the composite memory score (Waldo et al., 2010). Recently, the Taiwan government implemented a “Tobacco Hazard Control Act”, which forbids smoking in hospitals, including chronic psychiatric wards. Smoking cessation is often associated with depressed mood, restlessness and anxiety. To investigate varenicline's effects on schizophrenic smokers, we conducted a quasi-experimental study to characterize the comprehensive effects of varenicline on mood, psychotic symptoms, and cognitive function in patients with schizophrenia during smoking abstinence. We hypothesized that varenicline would attenuate abstinence-induced exacerbation of psychopathology and cognitive dysfunction. 2. Methods 2.1. Subjects Subjects were male chronic ward inpatients with schizophrenia and an absence of current non-nicotine substance use disorders, as determined by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (American Psychiatric Association, 1994). Patients were nicotine-dependent cigarette smokers consuming at least 10 cigarettes per day in the hospital before they entered the study, and all of them had been hospitalized for more than 3 months. They were required to have been on stable doses of antipsychotic drugs for at least 6 weeks. None of the subjects had a history of serious medical illness. Written informed consent was obtained from all participants, and the study was approved by the Institutional Review Board of Kaohsiung Veterans General Hospital. 2.2. Study design This study adopted a “non-randomized control group time series (5 times) design” using an untreated control group; subjects were divided into a varenicline group, composed of subjects choosing the use of varenicline to quit smoking, and a nontreatment group. All participants were smoking during the time they were on the inpatient unit until the time they were in a stable condition and received stable doses of antipsychotic drugs for at least 6 weeks. Then they completed a 12-week mandatory smoking abstinence phase. In the varenicline group, subjects received a total 5 weeks of varenicline treatment, including a 1-week run-up phase prior to abstinence and a 4week maintenance phase at the beginning of abstinence. Depression, anxiety, and psychosis were evaluated five times, at baseline for 2–3 weeks before nicotine abstinence, then at the 2nd, 4th, 8th and 12th week after abstinence; neuropsychological tests were evaluated 4 times, at baseline, and at the 4th, 8th and 12th week. The study was conducted between March 2009 and April 2010. 2.3. Drug dosage For the varenicline group, treatment was initiated with a 1-week dose run-up period, at a dose of 0.5 mg once daily for 3 days, 0.5 mg twice daily for the next 4 days; and then a 4-week maintenance period with the target dose of 1.0 mg twice daily starting from day 1 (i.e., the target quitting date) to the end of the 4th week. Then, the patients stopped varenicline usage. Patients in the non-treatment group did not receive medication for smoking cessation. 2.4. Assessment of smoking cessation motivation and psychiatric symptoms The baseline level of nicotine dependence was estimated with the Fagerstrom Test for Nicotine Dependence (FTND) (Heatherton et al., 1991). The baseline motivation to cease smoking was evaluated by the Contemplation Ladder (Biener and Abrams, 1991). Smoking status was measured by self-reported smoking everyday during the study. Depressive and anxious symptoms were evaluated with the Hamilton Scale for Depression (HAM-D) (Hamilton, 1960), and the Hamilton Scale for Anxiety (HAM-A) (Hamilton, 1959). Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), including four subscales (positive, negative, general, total scores) (Kay et al., 1987). All scales were rated at baseline, and the 2nd, 4th, 8th and 12th week after abstinence by a psychiatric doctor (SYJ) who was blind to the subjects’ medication status.

performance (Berman et al., 1997; Karatekin and Asarnow, 1998). The Digit Span task consists of two subtests. In both tests, sequences composed of random digits were presented orally one after another. In the DSF task, participants were required to verbally repeat these digits in the order in which they were presented. In the DSB task, participants were required to produce the digits in the reverse order of presentation. The separate scores for each of the tests were based on the number of correct items recalled. The TMT-A involves connecting numbers in succession, while the TMT-B requires subjects to connect numbers and letters alternately in successive order. We recorded the total time taken to connect all items correctly on both the TMT-A and TMT-B; the lengths of time taken for the TMT-A and TMT-B were then used in the analysis. The tests were performed at baseline, and at the 4th, 8th and 12th week after abstinence. These cognitive tests were conducted by a trained research nurse who was blind to the subjects’ medication status. 2.6. Side effects Patients were asked an open ended question to report to the medical staff at least once a week during treatment any varenicline side effects. Although no specific scale was employed to rate the severity, all reported side effects were recorded. Patients who did not take varenicline were also asked an open ended question about "uncomfortable feelings" during study as a comparison. 2.7. Statistical analysis Analyses were performed on both the completers and the intent-to-treat (ITT) population, which was defined as patients who had both baseline and 1 postabstinence visits. The last observation carried forward (LOCF) approach was used to impute missing visits and early withdrawals. Between-group comparisons of continuous variables were performed using t tests, and the Wilcoxon test was used as a nonparametric alternative. Fisher's exact tests were used for between-group comparisons of categorical variables at baseline. Five ratings of psychiatric symptoms, and 4 ratings of cognitive functions were analyzed using the Generalized Estimating Equations (GEE) (Zeger and Liang, 1992) and repeated measures ANOVA in SPSS.17.0. The baseline heterogeneity (differences existing before the intervention) between the varenicline and non-treatment groups and the changes in outcome variables resulting from the passage of time were all controlled by applying the GEE method. Nonsignificant effects are not presented (p N 0.05) unless they were of specific meaning.

3. Results 3.1. Subject characteristics Forty-one male subjects were included initially and grouped voluntarily. Twenty subjects chose varenicline and 21 subjects chose to quit without extra medication. During the 12-week evaluation, 30 of 41 participants (73%) completed all assessments and were included in the analysis. In the varenicline group, 5 of 20 subjects dropped out: 4 subjects were discharged and 1 subject transferred to the medical ward due to urinary tract infection. In the non-treatment group, 6 of 21 subjects dropped out: 5 subjects were discharged and 1 subject was transferred to the medical ward due to an accidental fall with head trauma. All patients reported no smoking during the study period. There were 30 completers with age ranging from 28 to 61 years old (mean ± standard deviation: 44.20 ± 8.10). They had been ill for 21.1 ± 8.6 years (ranging from 6 to 41 years) and had been hospitalized for 9.3 ± 7.0 months (ranging from 3 to 33 months). They had received 6 to 14 years of education (10.8 ± 1.8 years). Twenty-three patients were on typical antipsychotics, and the mean daily dosage in chlorpromazine equivalents (Davis, 1976) was 478 ± 298 mg. On average, they smoked 15.9 ± 7.6 cigarettes daily, and the level of nicotine addiction was moderate to severe (FTND score: 5.3 ± 2.0). None of them had a history of quitting attempts and baseline motivation to quit was low (Contemplation Ladder score: 2.2 ± 0.4). There were no differences in the above characteristics between the varenicline group and the non-treatment group (Table 1).

2.5. Neuropsychological testing

3.2. Psychiatric outcomes For cognitive evaluation, patients underwent four neuropsychological tests: the Digit Span Forward and Backward tests (DSF and DSB) as measures for attention and verbal working memory, and the Trail Making Test-A and -B (TMT-A and TMT-B) for visual–spatial organization and visual–motor tracking (Reitan and Wolfson, 1985). These tasks have been widely used with schizophrenic patients to evaluate cognitive

For the completer population, there were no differences in the baseline HAM-D, HAM-A, and PANSS scores between these two groups (Table 2). In the non-treatment group, the mean HAM-D and

M.-E. Liu et al. / Psychiatry Research 190 (2011) 79–84 Table 1 Demographic and clinical characteristics of smokers with schizophrenia (N = 30). Baseline measure

Study medication

Age (years) Education (years) Age of onset (years) Duration of hospitalization (months) Cigarettes per day Duration of smoking (years) FTND score Motivation to quit Antipsychotic class Chlorpromazine equivalents (mg/day) Antipsychotic medications (N)

p value

Non-treatment (N = 15)

Varenicline (N = 15)

43.20 ± 8.62 10.93 ± 2.05 22.73 ± 4.59 10.73 ± 9.22

45.20 ± 7.70 10.67 ± 1.68 23.40 ± 4.66 7.87 ±3.42

0.508 0.700 0.696 0.269

16.40 ± 7.26 24.07 ± 7.53 5.47 ± 1.92 2.13 ± 0.35

15.33 ± 8.12 28.13 ± 5.17 5.20 ±2.18 2.20 ±0.41

0.707 0.095 0.725 0.638

556.00 ± 269.20

400.00 ± 313.96

0.155

Clozapine (4) Olanzapine (1) Clothiapine (2) Fluanxol (2) Loxapine (4) Sulpiride (2)

Clozapine (1) Risperidone (1) Chlorpromazine(2) Clopixol (1) Fluanxol (3) Loxapine (1) Thioridazine (4) Sulpiride (2)

Each number represents mean ± standard deviation. FTND, Fagerstrom Test for Nicotine Dependence.

HAM-A scores at the 2nd ,4th , and 8th week were significantly higher than the mean at the baseline (p b 0.001,b0.001, and 0.012 in HAM-D; p b 0.001,b0.001, and 0.005 in HAM-A, respectively). On the other hand, varenicline users showed no prominent changes in depression and anxiety before and after abstinence. The degree of exacerbation of the non-treatment group was significantly greater than that of the varenicline group at the 2nd and 4th weeks, for both depression (p = 0.014 and 0.042, respectively) and anxiety (p b 0.001 and 0.009, respectively) (Table 3, Figs. 1 and 2). Therefore, varenicline significantly prevented the exacerbation of depression and anxiety after abstinence. No patients developed suicidal ideation or plans during the entire course. For psychotic symptoms, we found no significant increase or decrease in any of the PANSS subscales (positive, negative, general, total) in either group during the entire study. 3.3. Cognitive outcomes

Table 3 Measurements of depression and anxiety. Variable HAM-D Intercept Group 1 vs. Group 0 Visit 1 vs. Visit 0 Visit 2 vs. Visit 0 Visit 3 vs. Visit 0 Visit 4 vs. Visit 0 Interaction of Visit 1 and Interaction of Visit 2 and Interaction of Visit 3 and Interaction of Visit 4 and HAM-A Intercept Group 1 vs. Group 0 Visit 1 vs. Visit 0 Visit 2 vs. Visit 0 Visit 3 vs. Visit 0 Visit 4 vs. Visit 0 Interaction of Visit 1 and Interaction of Visit 2 and Interaction of Visit 3 and Interaction of Visit 4 and

Study medication

p value

Non-treatment (N = 15)

Varenicline (N = 15)

HAM-D HAM-A PANSS-Positive PANSS-Negative PANSS-General PANSS-Total DSF DSB TMT-A TMT-B

11.60 ± 2.59 10.20 ± 2.24 12.27 ± 1.94 20.00 ± 3.96 36.27 ± 6.08 68.53 ± 10.27 7.67 ± 1.23 4.40 ± 1.18 52.80 ± 17.47 112.27 ± 33.63

11.33 ± 1.84 10.47 ± 1.60 13.73 ± 3.06 20.13 ± 4.53 34.93 ± 6.16 68.80 ± 11.16 7.80 ± 1.01 4.53 ± 0.92 51.60 ± 22.29 116.13 ± 49.46

0.747 0.710 0.128 0.932 0.555 0.946 0.871 0.804 0.749 0.733

Each number represents mean ± standard deviation. HAM-D, Hamilton Scale for Depression; HAM-A, Hamilton Scale for Anxiety. PANSS, Positive and Negative Syndrome Scale. DSF, Digit Span Forward; DSB, Digit Span Backward; TMT-A, Trail Making Test-A; TMT-B, Trail Making Test –B.

Standard error

t

p

0.8 0.8 0.8 0.8 0.8 1.1 1.1 1.1 1.1

-0.4 3.9 3.7 2.6 1.3 -2.5 -2.1 -1.2 -1.1

0.725 b0.001⁎ b0.001⁎ 0.012⁎

Group Group Group Group

11.6 -0.3 2.9 2.8 1.9 1.0 -2.7 -2.2 -1.3 -1.1

Group Group Group Group

10.2 0.3 4.9 3.1 2.0 0.9 -4.5 -2.6 -1.1 -0.5

0.7 0.7 0.7 0.7 0.7 1.0 1.0 1.0 1.0

0.4 7.1 4.4 2.9 1.2 -4.5 -2.6 -1.1 -0.5

0.703 b0.001⁎ b0.001⁎ 0.005⁎ 0.216 b0.001⁎ 0.009⁎

0.188 0.014⁎ 0.042⁎ 0.238 0.291

0.253 0.637

in Table 4. The measures of the DSF and DSB scores at the 4th and 8th weeks were significantly lower than at the baseline collection (p b 0.001 and 0.048 in DSF; P b 0.001 and 0.023 in DSB, respectively) in the non-treatment group. DSF performance did not change with

16 15

Total HAM-D Score

Baseline measure

Regression coefficient

HAM-D, Hamilton Scale for Depression; HAM-A, Hamilton Scale for Anxiety. Group 1, for the varenicline group; 0, for the non-treatment group. Visit 0, for the pretest; 1 for the second week; 2 for the fourth week; 3 for the eighth week; 4 for the twelfth week. Intercept, baseline score of the non-treatment group. Group 1 vs. Group 0, difference between varenicline and non-treatment groups at baseline. Visit 1 vs. Visit 0, change between visit 0 and visit 1 in non-treatment group. Visit 2 vs. Visit 0, change between visit 0 and visit 2 in non-treatment group. Visit 3 vs. Visit 0, change between visit 0 and visit 3 in non-treatment group. Visit 4 vs. Visit 0, change between visit 0 and visit 4 in non-treatment group. Interaction of Visit 1 and Group, difference between varenicline and non-treatment groups in change visit 0 − visit 1. Interaction of Visit 2 and Group, difference between varenicline and non-treatment groups in change visit 0 − visit 2. Interaction of Visit 3 and Group, difference between varenicline and non-treatment groups in change visit 0 − visit 3. Interaction of Visit 4 and Group, difference between varenicline and non-treatment group in change visit 0 − visit 4. The change in the varenicline group is given by the change in the non-treatment group plus the interaction term. * p b 0.05.

The baseline scores of the varenicline and non-treatment groups for these four neurological tests showed no significant differences. The effects of varenicline on neuropsychological measurements are shown

Table 2 Baseline psychopathology and cognitive performance of smokers with schizophrenia (N = 30).

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*

*

14 13 12 11 10 Baseline

4 Weeks

8 Weeks

12 Weeks

Weeks After Abstinence Fig. 1. The effects of nicotine abstinence with varenicline treatment on HAM-D score. Total score (mean ± standard error) is presented for non-treatment group (closed circles) and varenicline group (open circles). * p b 0.05 in the figure indicates significant differences in change at each time point (compared to baseline) between varenicline and non-treatment groups.

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8.5

17

8.0 **

15

7.5

14

DSF score

Total HAM-A Score

16

** 13 12

7.0 6.5 6.0

11

5.5

10

5.0

**

9 Baseline

4 Weeks

8 Weeks

4.5

12 Weeks

Baseline

Weeks After Abstinence

4 Weeks

8 Weeks

12 Weeks

Weeks After Abstinence

Fig. 2. The effects of nicotine abstinence with varenicline treatment on HAM-A score. Total score (mean ± standard error) is presented for non-treatment group (closed circles) and varenicline group (open circles). ** p b 0.01 in the figure indicates significant differences in change at each time point (compared to baseline) between varenicline and non-treatment groups.

Fig. 3. The effects of nicotine abstinence with varenicline treatment on DSF score. The score (mean ± standard error) is presented for non-treatment group (closed circles) and varenicline group (open circles). ** p b 0.01 in the figure indicates significant differences in change at each time point (compared to baseline) between varenicline and non-treatment groups.

time among the varenicline users, and the degree of exacerbation of the non-treatment group was significantly greater than that of the varenicline group at the 4th week (Fig. 3). There were no significant differences in the changes in DSB scores with time between the two groups (Fig. 4). These results showed that the performances of the non-treatment patients on the DSF and DSB worsened significantly after smoking abstinence, and that varenicline had a beneficial effect on avoiding the deterioration of DSF performance. For the TMT-A and TMT-B performance, there was no significant change with time in either group during the study.

Similar results were noted by repeat measure ANOVA analysis (psychiatric outcome in Supplementary Table 1; cognitive outcomes in Supplementary Table 2). For the ITT population, subject characteristics and baseline psychopathology and cognitive performance were showed in Supplementary Tables 3 and 4. The changes of psychiatric and cognitive outcomes were similar to that in completer population (Supplementary Tables 5 and 6).

Table 4 Measurements of cognitive function.

During the first week, 8 subjects in the varenicline group complained of adverse effects, including nausea (2 subjects), vomiting (2 subjects), fatigue (1 subject), dry mouth (1 subject), muscle stiffness (1 subject) and headache (1 subject). The number decreased with time, and only 1 subject reported mild tiredness at the end of 5 weeks of treatment. All side effects were mild in severity and did not lead to a wish to discontinue varenicline. Subjects in the nontreatment group had no specific complaints or uncomfortable feelings.

Regression coefficient

Standard error

t

p

DSF Intercept Group 1 vs. Group 0 Visit 2 vs. Visit 0 Visit 3 vs. Visit 0 Visit 4 vs. Visit 0 Interaction of Visit 2 and Group Interaction of Visit 3 and Group Interaction of Visit 4 and Group

7.7 0.1 -2.3 -0.8 -0.3 2.1 0.5 0.1

0.4 0.4 0.4 0.4 0.6 0.6 0.6

0.3 -5.8 -2.0 -0.7 3.8 0.9 0.2

0.740 b 0.001* 0.048* 0.507 b 0.001* 0.349 0.815

DSB Intercept Group 1 vs. Group 0 Visit 2 vs. Visit 0 Visit 3 vs. Visit 0 Visit 4 vs. Visit 0 Interaction of Visit 2 and Group Interaction of Visit 3 and Group Interaction of Visit 4 and Group

4.4 0.1 -1.9 -0.9 -0.1 0.2 -0.1 0.1

5.0 4.5

0.4 0.4 0.4 0.4 0.5 0.5 0.5

0.4 -5.0 -2.3 -0.2 0.4 -0.1 0.1

0.724 b 0.001* 0.023* 0.860 0.708 0.901 0.901

DSF, Digit Span Forward; DSB, Digit Span Backward. Group 1, for the varenicline group; 0, for the non-treatment group. Visit 0, for the pretest; 2 for the fourth week; 3 for the eighth week; 4 for the twelfth week. Intercept, baseline score of the non-treatment group. Group 1 vs. Group 0, difference between varenicline and non-treatment groups at baseline. Visit 2 vs. Visit 0, change between visit 0 and visit 2 in the non-treatment group. Visit 3 vs. Visit 0, change between visit 0 and visit 3 in the non-treatment group. Visit 4 vs. Visit 0, change between visit 0 and visit 4 in the non-treatment group. Interaction of Visit 2 and Group, difference between varenicline and non-treatment groups in change visit 0 − visit 2. Interaction of Visit 3 and Group, difference between varenicline and non-treatment groups in change visit 0 − visit 3. Interaction of Visit 4 and Group, difference between varenicline and nontreatment groups in change visit 0 − visit 4. The change in the varenicline group is given by the change in the non-treatment group plus the interaction term. * p b 0.05.

4.0

DSB score

Variable

3.4. Medication-related adverse events

3.5 3.0 2.5 2.0 Baseline

4 Weeks

8 Weeks

12 Weeks

Weeks After Abstinence Fig. 4. The effects of nicotine abstinence with varenicline treatment on DSB score. The score (mean ± standard error) is presented for non-treatment group (closed circles) and varenicline group (open circles).

M.-E. Liu et al. / Psychiatry Research 190 (2011) 79–84

4. Discussion This was a quasi-experimental study of varenicline use in chronically ill male inpatients with schizophrenia. Since patients with schizophrenia may smoke to alleviate withdrawal and to remediate dysfunction in the nAChRs and their receptor dynamics (McCloughen, 2003), varenicline may modulate the nicotinic imbalance in the brains of schizophrenics and have beneficial effects on smoking abstinence (Hays and Ebbert, 2008; Smith et al., 2009). For nicotine withdrawal, the non-treatment group showed a timelimited exacerbation in depression, anxiety and some cognitive functions during the 2–8 weeks post-cessation, and then steady improvement thereafter. Despite several decades of research, the natural history of nicotine withdrawal has not been fully established. Some studies indicated that withdrawal symptoms increase within the first week post-cessation, and gradually decline and stabilize within 3–4 weeks after that (Hughes et al., 1991; Hughes, 1992). However, Piasecki et al. (1998, 2000) found that two-thirds of smokers showed persistent or late-onset exacerbation of symptoms. Consistent with the findings of Gilbert et al. (1999, 2002), we demonstrated that withdrawal symptoms remain elevated during the first 30 days of abstinence in non-treated participants. The subjects in non-treatment group had increased the HAM-D scores from 11.6 ± 2.6 to 14.5 ± 2.5, and HAM-A scores from 10.2 ± 2.2 to 15.1 ± 2.2 during the first two week of nicotine abstinence. According to American Psychiatric Association Task Force for the Handbook of Psychiatric Measures (2000), a symptomatic with a HAM-D score of 8 to 13 points is interpreted as mild depression, and a score of 14 to 18 points is labeled as moderate depression. On the other hand, the HAM-A score for the definition of mild anxiety ranges from 8 to 14 points, and of moderate anxiety from 15 to 23 points (Matza et al., 2010). Thus, patients might be categorized into different severity groups before and after abstinence, and these changes affect patients’ mental stability and alter the clinicians’ perceptions of the patients on the clinical significance of the magnitude. Varenicline use in this study did not improve depression and anxiety, but effectively attenuated the exacerbation associated with nicotine withdrawal. Recent evidence indicates clearly that symptom exacerbation is not seen with smoking cessation treatment in schizophrenia (Weinberger et al., 2009; Tsoi et al., 2010). Since we enrolled chronic schizophrenic patients with mild severity in affective symptoms at the beginning of the study (HAM-D: 11.47 ± 2.20; HAMA 10.33 ± 1.91), varenicline might not promote symptoms reduction. Its antidepressant and anxiolytic effects were only able to prevent symptoms exacerbation. Patterson et al. (2009) found that smokers who received varenicline had fewer withdrawal symptoms, smoking urges and negative affects than did those who did not receive varenicline. In addition, Smith et al. (2009) demonstrated that varenicline had a beneficial effect on smoking abstinence with no significant increases in psychopathology scores, and no patient developed signs of clinical depression or suicidal ideation during treatment. On the other hand, a trend toward symptom exacerbation at the 8th week visit (1 month after stopping varenicline) was noted in the varenicline group. Since the symptoms of nicotine withdrawal appear to last over a period of several weeks (Gilbert et al., 1999, 2002), the protective effect of varenicline might disappear after stopping and the symptoms may exacerbate again. We observed no significant changes in psychotic symptoms in either group before and after nicotine abstinence. Although psychosis is not the target symptom of nicotine withdrawal (American Psychiatric Association, 1994), studies of smoking cessation in patients with schizophrenia have found exacerbation of psychotic symptoms (Glynn and Sussman, 1990; Dalack and Meador-Woodruff, 1996). However, some studies (Dalack et al., 1999; Weinberger et al., 2007) and our report suggest that abstinence from cigarettes does not significantly alter psychotic symptoms.

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Cognitive impairment is one of the most common symptoms during nicotine abstinence. We therefore examined the protective effect of varenicline on cognitive function, using four neuropsychological tests: the DSF, DSB, TMT-A, and TMT-B. The DSF tasks relied on sequential and verbal elements, and the DSB, TMT-A, or TMT-B tasks required executive processing and visual-spatial elements (Reitan and Wolfson, 1985; Reynolds, 1997). In the non-treatment group, the changes in DSF performance were in close accordance with the changes in depressive and anxious symptoms during abstinence. Varenicline treatment significantly reversed abstinence-induced cognitive deficits in DSF tasks, despite the lack of an enhancing effect. Several clinical studies have shown similar results. In healthy smokers, varenicline had beneficial effects on sustained attention and working memory during abstinence (Patterson et al., 2009), and also produced significant improvements in cognitive tests primarily associated with verbal learning and memory in smokers with schizophrenia (Smith et al., 2009). Varenicline's beneficial effect on cognitive processes might be related to the modulation of several neurotransmitter systems found in the brain, as has been reported in animal experiments (Rollema et al., 2009). For example, the involvement of β2 nAChRs in varenicline's cognitive protective effect is supported by evidence that the effects of nicotine withdrawal on cognition are altered in β2 nAChR subunit knockout mice (Portugal et al., 2008). On the other hand, it was found that varenicline did not have a significant ability to attenuate DSB performance impairment during abstinence. In one study (Owen et al., 2000), participants either had to remember digits in the forward recall, or in backward recall. The authors found that both of these tasks engaged the mid-ventrolateral frontal cortex, but only when participants were recalling in reverse order did the mid-dorsalateral frontal cortex become activated. Recent hemodynamic study also suggests that the DSB task is more demanding and requires greater activation of the prefrontal cortex than the DSF task (Kaneko et al., 2011). In our study, varenicline attenuating DSF performance during abstinence but not DSB scores indicates that varenicline may make distinct activation on the different brain areas, and its protective effect on cognitive performance could be detected easily by neuropsychological assessments with low levels of task difficulty. There were no changes in TMT-A and TMT-B tasks before and after abstinence in patients with or without varenicline administration. This suggested that varenicline might have a selective effect on cognitive function, and more specific mechanisms should be explored to explain these differences in future studies. There have been case reports, and an FDA advisory, about the possible psychiatric side-effects of varenicline, including activation of psychotic or manic symptoms, depression and suicidal ideation or attempts (Kohen and Kremen, 2007; FDA, 2008) According to a pooled analysis study of ten placebo-controlled trails, there were no varenicline related suicidal ideation or behaviors among smokers without current psychiatric disorders (Tonstad et al., 2010). At the same time, the authors reported two cases of suicidal ideation and one completed suicide among three open-label trials that were excluded from the analysis. Gunnell et al. (2009) also found several episodes of suicidal thought and attempt in patients prescribed varenicline in United Kingdom. However, there was no clear evidence of an increased risk of self harm behaviors associated with varenicline compared with other smoking cessation medications. Nevertheless, our study did not find that varenicline increased psychotic symptoms, depression or suicidal ideation in the patients. Although 8 of 15 patients complained of the physical side effects of varenicline, these adverse effects were generally minor and did not lead to a wish to stop varenicline usage. Another study with a small sample size suggested that these side effects might not be very common in patients with schizophrenia treated with varenicline (Smith et al., 2009). Accordingly, in our study, varenicline had minor physical side effects, and no psychiatric adverse events were observed.

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Due to the implementation of Tobacco Hazard Control Act, we enforced the patient to quit smoking and did not offer cigarette anymore. Then a successful cessation rate was not the target outcome in this study because of mandatory abstinence. However, the aversive aspects of nicotine cessation are thought to be powerful motivational factors contributing to the maintenance of the tobacco habit. Indeed, depression, anxiety and cognitive deficits were the most prominent symptoms of nicotine withdrawal, and could predict smoking relapse (Kenny and Markou, 2001; Dolan et al., 2004). Collectively, these findings have led to the suggestion that varenicline could reduce the exacerbation of symptoms caused by cigarette abstinence and increase the rate of successful cessation (Evins and Goff, 2008; Patterson et al., 2009). Although we used a quasi-experimental design, no differences between these two groups in demographic characteristics were noted and no confounding variables had to be controlled. However, there are several limitations, including the small sample size and lack of a direct placebo control. Furthermore, given that the patients voluntarily grouped themselves in a certain condition, the decision may have predisposed them to biased psychiatric and cognitive outcomes. Finally, the study enrolled chronic male inpatients only. Acutely ill inpatients, stable outpatients or female patients may respond differently to varenicline treatment, and generalizations of our findings to all smokers with schizophrenia probably should not be made. In summary, this prospective quasi-experimental study provides evidence of varenicline's beneficial effects on nicotine abstinence in schizophrenic inpatients. Varenicline may prevent the exacerbation of depression and anxiety, and cognitive deficit in patients with schizophrenia during smoking cessation, although no improvement effect was noted. Our findings suggest that varenicline may be a clinically useful treatment for tobacco abstinence in smokers with schizophrenia, and appears to be safe and well-tolerated. Supplementary materials related to this article can be found online at doi:10.1016/j.psychres.2011.04.018. References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. American Psychiatric Association, Washington, DC. American Psychiatric Association Task Force for the Handbook of Psychiatric Measures, 2000. Handbook of Psychiatric Measures. American Psychiatric Association, Washington, D.C. Berman, I., Viegner, B., Merson, A., Allan, E., Pappas, D., Green, A.I., 1997. Differential relationships between positive and negative symptoms and neuropsychological deficits in schizophrenia. Schizophrenia Research 25, 1–10. Biener, L., Abrams, D.B., 1991. The Contemplation Ladder: validation of a measure of readiness to consider smoking cessation. Health Psychology 10, 360–365. Dalack, G.W., Meador-Woodruff, J.H., 1996. Smoking, smoking withdrawal and schizophrenia: case reports and a review of the literature. Schizophrenia Research 22, 133–141. Dalack, G.W., Becks, L., Hill, E., Pomerleau, O.F., Meador-Woodruff, J.H., 1999. Nicotine withdrawal and psychiatric symptoms in cigarette smokers with schizophrenia. Neuropsychopharmacology 21, 195–202. Davis, J.M., 1976. Comparative doses and costs of antipsychotic medication. Archives of General Psychiatry 33, 858–861. Dolan, S.L., Sacco, K.A., Termine, A., Seyal, A.A., Dudas, M.M., Vessicchio, J.C., Wexler, B.E., George, T.P., 2004. Neuropsychological deficits are associated with smoking cessation treatment failure in patients with schizophrenia. Schizophrenia Research 70, 263–275. Evins, A.E., Goff, D.C., 2008. Varenicline treatment for smokers with schizophrenia: a case series. The Journal of Clinical Psychiatry 69, 1016. FDA, 2008. FDA alert -varenicline (marketed as Chantix) information. http://fda.gov/ cder/infopage/varenicline/defalut.htm. Gilbert, D.G., McClernon, F.J., Rabinovich, N.E., Dibb, W.D., Plath, L.C., Hiyane, S., Jensen, R.A., Meliska, C.J., Estes, S.L., Gehlbach, B.A., 1999. EEG, physiology, and task-related mood fail to resolve across 31 days of smoking abstinence: relations to depressive traits, nicotine exposure, and dependence. Experimental and Clinical Psychopharmacology 7, 427–443. Gilbert, D.G., McClernon, F.J., Rabinovich, N.E., Plath, L.C., Masson, C.L., Anderson, A.E., Sly, K.F., 2002. Mood disturbance fails to resolve across 31 days of cigarette abstinence in women. Journal of Consulting and Clinical Psychology 70, 142–152. Glynn, S.M., Sussman, S., 1990. Why patients smoke. Hospital & Community Psychiatry 41, 1027–1028. Gunnell, D., Irvine, D., Wise, L., Davies, C., Martin, R.M., 2009. Varenicline and suicidal behaviour: A cohort study based on data from the General Practice Research Database. British Medical Journal 339, b3805.

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