International journal of collaborative research on internal medicine & public health (ijcrimph)

1223 International Journal of Collaborative Research on Internal Medicine & Public Health
A placebo-controlled trial of bupropion for improving the
positive and negative symptoms of schizophrenia
Dr.Omid.Rezaee 1, SaeedeMasafiM 2*, Dr.Mohamadreza 3, Farshad,Akbarpour 4
1 Department of Psychiatry, University of Social Welfare & Rehabilitation Science, Tehran, Iran. 2 Department of Psychology, Science and ResearchBranch, Islamic AzadUniversity, Tehran, Iran., 3 Khodaie Ardakani.Department of Psychiatry, University of Social Welfare & Rehabilitation Science, Tehran, Iran. 4 Psychiatric ABSTRACT
Background: Recently, researches have expressed renewed interest in therapeutic effects of
bupropion on the positive and negative symptoms in schizophrenics.
Aim & Objective: In current study, was designed a 12-week double-blind, parallel-groups to
examine the comparative efficacy of bupropion compared to placebo for improving the positive
and negative symptoms of schizophrenia.

Methods/Study Design: Eligible participants were 40 patients who met DSM-IV criteria for
schizophrenia and were randomly assigned to the standard therapeutic dose of bupropion (150
mg/day for the first 3 days, followed by 300 mg/day) administered orally for a total of 8 weeks
(n=20) or an identical appearing placebo tablet added to their usual medication regimen (n=20).
The study endpoints were the scales of positive and negative symptoms of schizophrenia by the
two scales for the assessment of positive symptoms (SAPS) and negative symptoms (SANS).
Results/Finding: : After the completion of treatment schedules, both groups demonstrated
similar significant improvements in all positive symptoms, adjusted for baseline variables.
However, it appeared that the avolition-apathy score of negative symptoms was reduced more in
the group treated with bupropion compared to the placebo group.
Conclusion: Bupropion has potential efficacy for avolition-apathy as main negative symptoms
in schizophrenics who were able to tolerate bupropion and complete 12-week bupropion
treatment regimen. However, no change in positive symptoms may be essentially appeared.


Keywords: placebo, bupropion, positive symptoms negative symptoms, schizophrenia,
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Introduction:

Schizophrenia is a debilitating psychiatric disorder that consists of severe disturbances in
thoughts, cognitions, mood, perceptions, and relationships with others1. The hallmark symptoms
of schizophrenia are mainly classified as positive symptoms including delusions, paranoia,
hallucinations and disorganized thoughts and also negative symptoms including poor motivation,
lack of emotional expression, and inability to form appropriate social relationships2.
Several randomized and controlled trials revealed the efficacy of some classic and conventional
antipsychotic agents such as second-generation antipsychotics and adjunctive agents for
improving the positive and negative symptoms in treatment-refractory inpatients with
schizophrenia3-7. However, some others could demonstrate that the current available treatment
protocols appear to have modest benefits8. Because of the notable limitations of routine
antipsychotics in treatment responsiveness, the use of other medications targeting positive and
negative symptoms besides or in conjunction with antipsychotic agents is expected.
In the recent decade, researchers have expressed renewed interest in therapeutic effects of
bupropion an atypicalaon these symptoms. This agent
as a stronand as well as-10 . Investigations about the impact of bupropion administration on positive and
negative symptoms have been little. In a study by George et al, it was demonstrated that negative
symptoms scores of schizophrenia were reduced by about 15% in the bupropion group which
were treated with 300mg/day for 10 days compared to the placebo group. However, positive
symptoms of these patients were not affected11. In another study, patients diagnosed with
schizophrenia were examined for the effects of bupropion and supportive group therapy on
schizophrenia symptoms. Bupropion treatment was associated with an 18% drop in the negative
symptoms scores; however, the difference was not significant. But a significant decrease was
seen in the negative symptom of alogia factor score12. However, in some reports, it was even
suggested that the patients with no previous psychiatric history may experience positive
psychotic symptoms after treatment with 300 mg/day bupropion13.
The current study was designed to examine the comparative efficacy of bupropion for positive
and negative symptoms. We used a 12-week double-blind, parallel-groups design to examine the
comparative efficacy of bupropion compared to placebo.
Material and Method:

Current study was a double-blind, placebo-controlled randomized clinical trial conducted in at
the Razi Psychiatric Teaching Hospital, University of Social Welfare and Rehabilitation Sciences
in Iran in compliance with the ethical principles of the Declaration of Helsinki. Eligible
participants were 40 patients who met DSM-IV criteria for schizophrenia. Exclusion criteria
were:
1) Concurrent drug abuse or alcoholism;
2) organic brain disorders or mental retardation; 3) any medical condition that contraindicated
use of bupropion; 4) history of seizure disorder; 5) an allergy to bupropion
6) any cancer in the year prior to randomization; 7) pregnancy, lactating or likely to become
pregnant. We were also excluded the subjects who had previously used bupropion. All
participants or their families provided written informed consent before participating in the study.
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Participants were randomly assigned to the standard therapeutic dose of bupropion (150 mg/day
for the first 3 days, followed by 300 mg/day) administered orally for a total of 8 weeks (n=20) or
an identical appearing placebo tablet added to their usual medication regimen (n=20).
Participants, investigators, and study staff were blinded to treatment assignment.
Baseline data were collected from the hospital recorded files, including demographics, medical
history, education level, marital status, age of disease onset, and laboratory parameters. Cigarette
smoking was defined as tobacco use within the 12 months prior to the interview and daily use of
cigarettes was recorded14. The study endpoints were the scales of positive and negative
symptoms of schizophrenia by the two scales for the assessment of positive symptoms (SAPS)
and negative symptoms (SANS). These scales are designed to assess positive and negative
symptoms principally those that may be occurred in schizophrenia. These two instruments were
collected based on a standard clinical interview in order to evaluate the subject's symptoms. The
positive symptoms include hallucinations, delusions, bizarre behavior, and positive formal
thought disorder. Also, the negative symptoms include affective flattening or blunting, alogia,
avolition-apathy, and anhedonia-asociality. All assessments are conducted on a six-point scale
(0=no symptom to 5=very severe symptom) and the higher the score in each subscale, the more
symptomatic the individual is. Positive and negative symptoms were assessed by the sum of
scores on the four positive symptoms items as well as the four negative symptoms items15.
Data are expressed as mean ± standard deviation (SD) for quantitative variables and were
summarized by absolute frequencies and percentages for categorical variables. Continuous
variables were compared using t test or non-parametric Mann-Whitney U test whenever the data
did not appear to have normal distribution or when the assumption of equal variances was
violated across the groups. Categorical variables across the two groups were compared using the
Chi-square test or Fisher's exact test if required. To compare the differences in the improvement
of outcome between the bupropion and placebo groups, analysis of covariance (ANCOVA) was
used on the positive and the negative symptoms scores adjusting for demographic characteristics,
marital status, education level, age of disease onset, duration of drug use and cigarette smoking
as well as number of smoked cigarette before drugs administrating. Statistical significance level
was set at P G 0.05. For the statistical analysis, the statistical software SPSS version 13.0 for
windows (SPSS Inc., Chicago, IL) was used.
statistical software SPSS version 13.0 for windows (SPSS Inc., Chicago, IL) was used.
RESULTS:

The mean age of the total study population was 46.78 ± 7.16 years (aged 31-60 years) and the
mean weight was 66.35 ± 13.66 kg (range 46-114 kg). Twenty two patients (55.0%) were single
and only 7.5% of them had college degree. The mean age of disease onset was 23.35 ± 7.08
years that in 25% was less than 20 years. Eighty percent of subjects reported daily smoking in
the previous 12 months with the average consumption of 11.13 ± 10.02 cigarettes per day.
There were no importance baseline differences between the two study groups regarding
demographics, education level, marital status, disease duration, history of tobacco use, number of
daily consumed cigarette as well as laboratory parameters (Table 1). After the completion of
treatment schedules, both groups demonstrated similar significant improvements in all positive
symptoms, adjusted for baseline variables. However, it appeared that the avolition-apathy score of
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negative symptoms was reduced more in the group treated with bupropion compared to the
placebo group (Table 2).
Discussion:
Little evidence has been suggested for the efficacy and effectiveness of bupropion on the positive
and negative schizophrenia symptoms. The major finding of current study was that bupropion
had potential efficacy for avolition-apathy as main negative symptoms in schizophrenics who
were able to tolerate bupropion treatment and complete our 8-week double-blind study.
However, no change in positive symptoms was essentially observed. Despite very sample size
and low power of our study to detect differences between the two treatment approaches, we
revealed a significant effect of bupropion on avolition-apathy symptom. This result is consistent
with some other interventional studies. In a study by Evins et al, bupropion treatment was
associated with improvement in the negative symptoms and greater stability of psychotic and
depressive symptoms, compared with placebo16. But, some others failed to demonstrate a
significant advantage for this medication17. Avolition-apathy generally manifests as lacking
desires, lack of energy, motivation and persistence in schizophrenic patients. In avolition, patient
is not able to start or complete any major tasks and in apathy appearance, entire lack of emotions
or motivation is occurred. Based on different aspects of these symptoms, patients might suffer
from severe social and economic impairment during their live. Patients may display less attention
to hygienic habits than normal and clothing may appear untidy and begrimed. They may bathe
infrequently and overall may be appeared as dilapidated and disheveled18.
Little empirical investigation has been conducted on potential psychological or pharmacological
treatment protocols for apathy. It seems that the agents that induce dopamine release and/or
delay dopamine reuptake in the central nervous system can promise to use in apathy. Among
these, atypical antipsychotics have received especially attention and have been demonstrated to
reduce apathy in several schizophrenic populations.
The preclinical and clinical researches have been demonstrated that bupropion acts via dual
inhibition of dopamine reuptake. Studies on animal samples also confirmed that acute
administration of bupropion could decrease firing of dopamine neurons in the brain stems in a
dose-dependent manner. Therefore this inhibitory effect may be associated with a unique clinical
profile for improving avolition-apathy in schizophrenia. Besides, because bupropion is a
selective norepinephrine and dopamine reuptake inhibitor that has no effect on serotonergic
system, common observable side effects which related to other antidepressants, such as weight
gain, sexual dysfunction or sedation are not associated with bupropion use and therefore this
drug can be superior to other agents for preventing avolition-apathy.
Despite these hypotheses, the mechanism by which bupropion may stabilize this symptom
among schizophrenics is already unknown and need to more investigation on human models.
In conclusion, our finding suggests that the bupropion therapy can be a clinically useful
treatment for improving negative symptoms particularly avolition-apathy in patients with
schizophrenia and also appears to be safe and well-tolerated. However, it was no evidence of any
benefit of this drug for positive symptoms in these patients, which sugge sts that the field still
lacks an effective treatment for these symptoms.
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Table1. Baseline characteristics of smoker schizophrenic groups administered bupropion or placebo Item Data are presented as mean ± SD or n (%) Table2. Scales for the assessment of positive and negative symptoms in the groups treated with bupropion and placebo Vol. 4 No. 6 (2012)
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Data are presented as mean ± SD or n (%) Vol. 4 No. 6 (2012)

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