The characteristics of side-effects of bromperidol in schizophrenic patients
Abstract
Abstract The characteristics of the side-effects of bromperidol was investigated in 33 acutely exacerbated schizophrenic patients. The most frequently observed side-effects were extrapyramidal symptoms. Acute dystonia developed in 10 of 33 patients, and the mean age was significantly lower (P < 0.05) in patients with dystonia (27.3 ± 6.2 years) than that in patients without dystonia (41.5 ± 12.9 years). Plasma drug concentrations were not associated with side-effects. These findings suggest that acute dystonia is affected by age factor, and that daily dosage or monitoring of drug concentration is unlikely to be a useful marker for the prediction of side-effects during bromperidol treatment.
INTRODUCTION
The overall efficacy of bromperidol has been reported to be similar to or slightly better than that of haloperidol.1–4 In addition, bromperidol may have a faster onset of action1,3 and a more activating effect than haloperidol.4 Consequently, this drug has been widely used in Japan as well as in Europe and other countries.
Fewer side-effects with low doses (2–4 mg/day) of bromperidol were reported in several studies,1–3 while medium doses (about 12 mg/day) of bromperidol resulted in a relatively high incidence of extrapyramidal symptoms (EPS) such as tremor, akathisia and salivation.4 These findings suggest some relationship between side-effects and daily dosages or plasma concentrations of bromperidol. However, the precise spectrum and quantitative analyses of side-effects of bromperidol in relation to plasma drug concentration have not yet been clearly shown.
The aim of the present study was to clarify the characteristics of the side-effects of bromperidol together with its relationship with plasma drug concentrations during bromperidol treatment with fixed-dose schedule.
SUBJECTS AND METHODS
Thirty-three acutely exacerbated patients (17 males, 16 females) participated in the study on admission. The mean ± SD of age, bodyweight, duration of illness and Brief Psychiatric Rating Scale (BPRS)5 scores before the treatment were 37.3 ± 12.8 years, 59.7 ± 13.1 kg, 119 ± 101 months and 25 ± 6, respectively. All patients fulfilled the DSM-IV criteria6 for schizophrenia. It was confirmed by interviews with patients or their families that no patient had received any medication for at least 1 month. The present study was approved by the Ethics Committee of Hirosaki University Hospital, and written informed consent to participate in the study was obtained from patients or their families before the study.
On the first night of admission, the only medica-tion allowed was flunitrazepam 2–4 mg. Next morning, blood samplings (10 mL) was performed at 08.00 h. Assessment of pretreatment clinical status using BPRS for schizophrenic symptoms and Udvalg for Kliniske Undersøgelser (UKU) side-effects rating scales7 for side-effects was performed. Thereafter, bromperidol (Impromen®, Yoshitomi Pharmaceutical, Osaka, Japan) was administered in two equally divided doses at 08.00 h and 20.00 h for 3 weeks. Patients were randomly allocated to one of three fixed doses: 6 mg/day (n = 10), 12 mg/day (n = 13) and 18 mg/day (n = 10). No other drug was given except biperiden 6 mg/day (n = 16) for moderate extrapyramidal side-effects, flunitrazepam (2 mg/day, n = 11 and 4 mg/day, n = 17) for insomnia and sennoside (12–48 mg/day, n = 8) as a laxative for constipation. Patients' compliance was confirmed by nursing staff. During bromperidol treatment, blood samplings and clinical assessments by BPRS and UKU scales were conducted at weekly intervals in the same manner as performed on the second day of admission.
Plasma concentrations of bromperidol and reduced bromperidol were determined in duplicate using the high-performance liquid chromatographic (HPLC) methods.8
Nineteen items of the UKU side-effects rating scales were divided into three subgroups such as psychic symptoms, EPS and autonomic symptoms.9 A pretreatment score was subtracted from one obtained during the treatment and was recorded as a drug-associated side-effect. Thus, a symptom that occurred or was more exacerbated during the treatment was defined as a side-effect. The 18 items of BPRS were divided into five subgroups (positive, excitement, cognitive, negative and anxiety-depression symptoms).10 Weekly average scores of subgrouped side-effects were used for statistical analysis. In analysis of EPS, the data in patients treated with biperiden were excluded after administration of biperiden.
Statistical analyses were performed using Student's t-test, ANOVA followed by Tukey test, multiple regression analyses with dummy variables (male = 0, and female = 1) and Spearman's rank test. A P-value less than 0.05 was regarded as statistically significant. All analyses were performed using SPSS 8.1 J for windows (SPSS Japan Inc., Tokyo, Japan).
RESULTS
No significant difference was found in age, gender, bodyweight, duration of illness, baseline BPRS scores or subgrouped side-effect scores among the three different dose groups (6, 12 and 18 mg/day).
The most frequently observed side-effects were EPS such as hypokinesia (68%), tremor (61%), akathisia (56%) and increased salivation (43%). The incidences of EPS gradually increased during 3-week treatment except for dystonia, which was mainly observed within 1 week. Psychic and autonomic side-effects were relatively infrequent, and the incidences were almost unchanged or slightly decreased throughout the study period.
Ten out of 33 patients (30%) had dystonic reaction. Table 1 shows the clinical profiles of patients with and without dystonic reaction. The mean age and duration of illness in patients who had dystonic reaction were significantly lower than that in patients without this adverse effect (Table 1). Such factors as gender difference, drug dosage and plasma concentrations of bromperidol and reduced bromperidol did not affect the development of dystonia induced by bromperidol treatment. On the other hand, no differences were found in age, gender, dose or plasma drug concentration between patients with and without each EPS symptom except dystonia.
| With dystonia | Without dystonia | Significance | |
|---|---|---|---|
| Gender (M/F) | 7/3 | 10/13 | NS |
| Age (years) | 27.3 ± 6.2 | 41.5 ± 12.9 | P < 0.001 |
| Bodyweight (kg) | 64.7 ± 12.4 | 57.5 ± 13.4 | NS |
| Duration of illness (months) | 53.9 ± 34.4 | 147.8 ± 109.6 | P < 0.01 |
| Daily dosage (mg/day) | 13.2 ± 3.8 | 11.5 ± 5.1 | NS |
| Bromperidol concentration (ng/mL) | 7.1 ± 3.8 | 6.9 ± 5.3 | NS |
| Reduced bromperidol concentration (ng/mL) | 1.3 ± 0.7 | 1.7 ± 2.1 | NS |
- NS, not significant.
Multiple regression analyses showed no correlation between clinical profiles of the patients and subgrouped side-effects.
The scores of psychic side-effects were negatively correlated with percentage improvement in BPRS scores of positive (rs = –0.440, P < 0.01), excitement (rs = –0.469, P < 0.01), cognitive (rs = –0.535, P < 0.01) and anxiety-depression (r = –0.478, P < 0.01) factors of schizophrenic symptoms, while the scores of EPS were negatively correlated with negative symptoms (rs = –0.414, P < 0.05).
DISCUSSION
In the present study, well randomization was conducted since there were no differences in age, bodyweight and severity of psychotic symptoms at baseline (BPRS scores) among the three dosage groups. However, such pharmacokinetic factors as drug doses and concentrations were unlikely to predict severity of any side-effects including EPS.
Side-effects of bromperidol are characterized by predominant EPS in contrast to relatively fewer psychic and autonomic side-effects. This side-effect spectrum is probably explained by the fact that the main pharmacological property of bromperidol is potent and selective antagonistic effects for dopamine D2 receptors.11 Although EPS were observed in almost half of the cases treated with bromperidol in the present study, fewer sedative and anticholinergic side-effects may be an advantage of bromperidol treatment.
Among EPS, acute dystonia should be particularly warned of in the initial phase of bromperidol treatment. The incidence of bromperidol-induced dystonia was relatively low (30%) compared with the results of fluphenazine (34%), nemonapride (51%) and haloperidol (60%) in other previous reported surveys.12–14 The present study showed that patients who were younger and had a shorter duration of illness are at higher risk for developing acute dystonia (Table 1). Also, 70% of patients with dystonic reactions were males. Therefore, young male patients are at a high risk for acute dystonia and require coadministration of anticholinergic drugs when initiating bromperidol treatment.
It may be noteworthy that there were some relationships between the development of side-effects and the improvement in clinical symptoms during bromperidol treatment. A previous study also suggested that the treatment-resistant side-effects are strongly related to treatment failure at higher dosage of antipsychotics.15 Likewise, the negative relationship between EPS scores and the percentage improvement in negative symptoms in the present study probably demonstrates that the existence of considerable EPS had significant influence on an assessment of negative symptoms. It may be necessary but difficult to distinguish negative-like symptoms associated with neuroleptic treatment from true negative symptoms by a natural process of schizophrenia, although the possibility that EPS directly cause deterioration of negative symptoms16 cannot be entirely excluded like a close relationship between akinesia and depression.17 However, negative relationships between psychic side-effects and the improvement in positive, excitement, cognitive and anxiety-depression symptoms can be simply interpreted as a phenomena that poor therapeutic response tends to be associated with increased sensitivity for psychic side-effects in schizophrenic patients.
In conclusion, predominant side-effects of bromperidol are EPS. Monitoring of drug concentration is unlikely to be useful in predicting most EPS. The existence of considerable EPS may lead to unimproved negative symptoms of schizophrenia.
ACKNOWLEDGMENTS
We would like to thank Mr Yoshimasa Inoue, Pharmaceutical Research Division, Mitsubishi Pharma Corporation, for providing us with technical support of HPLC. This study was supported by the Hirosaki Research Institute for Neurosciences.
