A double-blind placebo-controlled cross over trial of bupropion in smoking reduction in schizophrenia

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Schizophrenia Research

Letter to the Editors

A double-blind placebo-controlled cross over trial

of bupropion in smoking reduction in schizophrenia

Dear Editors,

Schizophrenia is a major, debilitating disease

which affects 1% of the world population today.

Schizophrenia is also associated strongly with comor-

bid substance abuse (Frances, 1996). Several reports

find a strong association between smoking and

schizophrenia with prevalence rates ranging from

74% to as high as 90% (Patkar et al., 2002) as

compared to the national average of 30% in non-

schizophrenic individuals.

Nicotine cessation studies in schizophrenia are few

(Dalack et al., 1998) but potentially promising (Evins et

al., 2001;Weiner et al., 2001; George et al., 2002) using

bupropion HCl, a unicyclic aminoketone atypical

antidepressant which was approved by the FDA under

the name Zyban for use in cigarette smoking cessation.

Recent evidence suggests that bupropion acts as a non-

competitive antagonist of high affinity nicotinic ace-

tylcholine receptors (Slemmer et al., 2000), potentially

explaining some of its antismoking effects. Three

recent reports (Evins et al., 2001; Weiner et al., 2001;

George et al., 2002) now suggest that bupropion may

be a useful medication for treatment of smoking in

schizophrenic subjects. We sought to replicate these

studies using a double-blind crossover design compar-

ing Zyban to placebo. Ten subjects who met DSM-IV

criteria for schizophrenia or schizoaffective disorder

and nicotine dependence were screened for this study.

After complete description of the study to subjects,

written consent from the 10 eligible subjects was

obtained and these subjects were randomized to two

study groups. The protocol was approved by the

Human IRB of the University of Minnesota School of

Medicine and the Minneapolis VAMedical Center and

0920-9964/$ - see front matter D 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.schres.2005.02.021

the study was conducted at the Tobacco Research

Center. The trial was an 8 week, randomized, fixed-

dose, double-blind, cross over trial of bupropion HCL

or placebo in outpatient subjects with schizophrenia or

schizoaffective disorder. At study entry, all subjects

were evaluated with the SCID-I for DSM-IV, Beck

Depression Inventory (BDI), Brief Psychiatric Rating

Scale (BPRS), Simpson–Angus Akathisia Scale,

Abnormal Involuntary Movements Scale (AIMS),

Hamilton Depression Scale (HAM-D), Side Effect

Profile, Positive and Negative Symptoms Scale for

Schizophrenia (PANSS, SANS and SAPS), Fagerstrom

Test for Nicotine Dependence (FTND), Hughes–

Hatsukami Withdrawal Scale, urine cotinine, nicotine

and metabolites, number of cigarettes smoked per day,

and expired breath carbon monoxide (CO) levels.

Subjects were evaluated at the end of 21 days of

treatment using all of the aforementioned tests, again

after a one week wash out, followed by a cross over to

the alternative treatment regimen and finally after

further 21 days of treatment. On days 3, 7, 14, 32, 36,

and 50, subjects were evaluated using the Hughes/

Hatsukami Scale, SANS, BPRS, and the Side Effect

Profile. Both subjects and research staff were blind to

study medication assignment. Safety and tolerability

were evaluated by monitoring the frequency and

severity of adverse events (anxiety, dizziness, flu-like

symptoms, headache, insomnia, nausea and worsening

of psychosis), changes from baseline in various scores

and modifications in body weight, vital signs, ECG or

other clinically relevant physical changes. SAS (for

Windows, Release 8.02) was used to perform the

statistical analysis. Statistical significance was set at

0.05. Mixed models were used to investigate whether

the treatments would lead in changes of the bio-

markers of interest.

Ten subjects entered the study and nine finished.

One subject withdrew from the study. The subjects

76 (2005) 353–356

Letter to the Editors354

were encouraged to reduce their smoking rates,

rather than to quit entirely. This format, as well as

the reliance on patient report, resulted in variable

rates of cigarette smoking per day, which man-

ifested in no difference in cigarette number per day.

Other measures, which were more rigorous, showed

some encouraging results (Fig. 1). During the

active bupropion HCl phase, subjects showed

reductions in exhaled carbon monoxide, urine

cotinine and urine nicotine and metabolites (Fig.

1) as compared to the placebo phase which showed

nonsignificant increases in all three measures.

Bupropion showed neither indication of increasing

positive symptoms of schizophrenia nor indications

of increased side effects. As seen in Fig. 1, there

were nonsignificant decreases in positive, negative

and side effect symptoms in both active and

placebo phases.

Baseline End of Trial

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Fig. 1. Levels of CO exhalation, urinary cotinine, nicotine and metabolites

on bupropion and placebo.

The results of this study confirmed previous

reports (Evins et al., 2001; Weiner et al., 2001;

George et al., 2002) that bupropion HCL is a safe

medication which can be administered to subjects

with schizophrenia without exacerbating positive

symptoms. Our results, however, showed a trend for

reduction in exhaled carbon monoxide, urine cotinine

and nicotine metabolites in schizophrenic subjects

who were actively smoking. The major reason for our

inability to show a demonstrated significant reduction

in smoking may be the short intervals of study, the

cross over design masking the long-term effects of

bupropion, and small N.

Recent double-blind placebo controlled studies

indicate the efficacy of bupropion in smoking

cessation in nonpsychiatric smokers (Douglas et al.,

1999) as well as in smokers with past history of major

depression and alcoholism (Hayford et al., 1999). In




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Scale for Assessment of Negative Symptoms

Scale for Assessment of Positive Symptoms

Side Effect Profile

as well as scores for SANS, SAPS and side effect profile in subjects

Letter to the Editors 355

an open-label 14 week trial, Weiner et al. (2001)

examined the efficacy, tolerability and safety of

supportive group therapy and adjunctive bupropion

SR (150 mg twice daily) for nicotine addiction in

patients with schizophrenia. Use of bupropion in

combination with supportive group therapy helped

patients decrease their cigarette consumption (Weiner

et al., 2001). In a different study, Evins et al. (2001)

conducted a 3 month, double-blind, placebo-con-

trolled trial of bupropion SR (150 mg daily) added

to a concurrent CBT program with 3 month follow-up

in 19 stable outpatients with schizophrenia. Bupro-

pion treatment was associated with significantly

greater reduction in smoking (66%) vs. placebo

(11%) during the active and follow-up periods.

Bupropion treatment was also associated with

improvement in negative symptoms and stability of

psychotic and depressive symptoms in the schizo-

phrenic subjects (Evins et al., 2001). Finally, a recent

report by George et al. (2002) conducted a placebo-

controlled trial of bupropion (150 mg twice daily) in

32 subjects with schizophrenia or schizoaffective

disorder and showed significantly higher trial end-

point abstinence rates in bupropion-treated compared

to placebo-treated subjects (50% vs. 12.5%). These

authors also showed that bupropion was not only well

tolerated and safe but that it significantly reduced

negative symptoms in the schizophrenic subjects

(George et al., 2002).

In conclusion, we performed a double-blind cross

over study of smoking reduction in subjects with

schizophrenia and schizoaffective disorder comparing

bupropion HCL to placebo. While our results only

provided a nonsignificant trend for reduction in

nicotine consumption, probably because of our short

treatment period, cross over design, and small sample

size, we did show that bupropion HCL is a safe agent

in schizophrenic subjects with potential efficacy for

smoking reduction in this population. Despite the

safety profile of bupropion in our small sample of

schizophrenic subjects, the possibility of drug inter-

actions with antipsychotics should be considered due

to bupropionTs action as an inhibitor of cytochrome

P2D6. Future carefully designed studies should help

clarify the pharmacogenetic mechanisms important in

smoking reduction strategies, which are currently

available to reduce smoking in this vulnerable

population.

Acknowledgement

This study was supported by a NIH center grant

(NIH P50 DA013333). We are grateful to Ms. L.

Iversen for secretarial assistance.

References

Dalack, G.W., Healy, D.J., Meador-Woodruff, J.H., 1998. Nicotine

dependence and schizophrenia: clinical phenomenon and

laboratory findings. Am. J. Psychiatry 155, 1490–1501.

Douglas, E.J., et al., 1999. A controlled trial of sustained-release

bupropion, a nicotine patch, or both for smoking cessation. N.

Engl. J. Med. 340, 685–691.

Evins, A.E., Mays, V.K., Rigotti, N.A., et al., 2001. A pilot trial of

bupropion added to cognitive behavioral therapy for smoking

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Frances, R.J., 1996. Schizophrenia and substance abuse. Psychiatr.

Ann. 26, 523–527.

George, T.P., Vessicchio, J.C, Termine, A., et al., 2002. A placebo-

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Hayford, K.E., et al., 1999. Efficacy of bupropion for smoking

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Patkar, A.A., Gopalakrishnan, R., Lundy, A., Leone, F.T., Certa,

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Weiner, E., Ball, M.P., Summerfelt, A., et al., 2001. Effects of

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S.H. Fatemi

Department of Psychiatry, Division of Neuroscience

Research, University of Minnesota Medical School,

MMC 392, 420 Delaware Street SE, Minneapolis,

MN 55455, USA

E-mail address: [email protected].

Corresponding author.

J.M. Stary




MN 55455, USA

Letter to the Editors356

D.K. Hatsukami




MN 55455, USA

Cancer Center, University of Minnesota Medical

School, Minneapolis, MN, 55455, USA

S.E. Murphy

Cancer Center, University of Minnesota Medical

School, Minneapolis, MN, 55455, USA

8 December 2004

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A double-blind placebo-controlled cross over trial of bupropion in smoking reduction in schizophrenia