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Keywords:

  • haloperidol;
  • manic episode;
  • zotepine

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Aims:  Atypical antipsychotics are increasingly used in the management of acute mania. This study was conducted to investigate the efficacy and tolerability of zotepine compared to haloperidol in combination with a mood stabilizer (lithium or valproate) for treatment of acute mania.

Methods:  This was a multi-center, randomized, rater-blinded, parallel-group, flexible-dose study. Forty-five hospitalized patients with moderate-to-severe manic, bipolar disorder (DSM-IV) were randomly assigned to a zotepine or a haloperidol 4-week treatment group.

Results:  There was no significant between-group difference in the Young Mania Rating Scale total scores between the zotepine and haloperidol groups (−23.7 ± 12.1 vs –22.3 ± 11.0, respectively). The adverse events in both groups were mild to moderate. The haloperidol group reported a higher incidence of treatment-related adverse events, especially parkinsonism and akathisia, compared to the zotepine group. Serum uric acid decreased more in the zotepine group than in the haloperidol group.

Conclusion:  In combination with a mood stabilizer, zotepine appears to be as effective as haloperidol in treating moderate-to-severe mania in the acute phase, but has the advantages of lowering hyperuricemia and fewer extrapyramidal side-effects. Double-blinded studies with larger sample sizes are warranted to confirm these findings.

MOOD STABILIZERS SUCH as lithium or valproic acid are used as first-line therapy for treatment of acute mania.1,2 Hospitalized and acutely manic patients usually need a combination of mood stabilizers and antipsychotic agents for better symptom control.1,2 In many countries, first-generation antipsychotics (FGA) are often used in such cases. Their advantages include proven anti-mania effects, rapid-acting intramuscular preparations useful for treating agitation, and lower cost compared to second-generation antipsychotics (SGA).3 However, FGA possess some undesirable side-effects, including extrapyramidal side-effects (EPS), long-term risk of tardive dyskinesia (TD), and induction of depressive symptoms.4 The risk of TD is a major concern when treating manic patients, as many studies have found a higher prevalence of TD in bipolar patients than in schizophrenic patients.5,6 SGA are better alternatives because they are associated with fewer EPS and less long-term risk of TD.7 In addition, some studies show that SGA may be helpful in treating depressive symptoms associated with bipolar disorder and are not inducers of depressive symptoms.8–11

Recent studies have shown that many SGA, either alone or in combination with mood stabilizers, are effective in treating acute mania.12 Second generation antipsychotics, including olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole, are indicated for treating acute mania by the US Food and Drug Administration. Zotepine is regarded as one of the SGA. It belongs to the multi-acting receptor targeted agent (MARTA) category. Zotepine has strong sedative effects and fewer EPS than FGA. Therefore, it has some advantages in treating acute manic patients. Nonetheless, few studies demonstrate its anti-manic effects.13,14 Many studies of these drugs have methodological problems, such as small sample sizes, nonrandom assignment, or lack of sufficient controls. Additionally, the efficacy of zotepine in combination with mood stabilizers has never been assessed in hospitalized patients with severe mania. Therefore, a study was initiated to compare the efficacy and tolerability of zotepine, in combination with a mood stabilizer, with haloperidol in treating hospitalized patients with moderate-to-severe mania.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

This study was conducted at three medical centers in Taiwan from May 2004 to December 2005. It was conducted in accordance with the principles of the Helsinki Declaration and Good Clinical Practice. The study protocol was approved by the Ethics Committees of Taoyuan Mental Hospital and Chang Gung Memorial Hospital. All patients (or their legal representatives) gave their written informed consent after receiving a full explanation of the study procedures.

Inclusion and exclusion criteria

Patients fulfilled the following criteria for participation: aged 20–65 years; met the criteria for DSM-IV bipolar I disorder manic episode; had a Young Mania Rating Scale (YMRS) total score no less than 20; and the patient or legal guardian gave written, informed consent prior to enrollment. Exclusion criteria included: a DSM-IV diagnosis of a psychotic disorder other than bipolar I disorder manic or mixed episode; unstable major systemic illness; history of neurological disorders or brain injury; substance abuse or dependence (other than coffee or tobacco) within 1 month before the study; previous treatment with clozapine; use of two mood stabilizers at the same time over 2 weeks in the past 6 months; and recent pregnancy or lactation or intent to get pregnant.

Study design

After undergoing a 3-day washout of mood stabilizers, antipsychotics, anticonvulsants, antidepressants, propranolol or anticholinergic drugs, the patients who fulfilled all the above inclusion criteria were randomly assigned (using computer-generated random numbers in a two-block design) to receive a 1:1 ratio of either zotepine or haloperidol in combination with lithium or valproate. If patients received depot medications, their screening day was scheduled at least one injection cycle before the last injection. The study period was 4 weeks. This study was rater-blinded to zotepine and haloperidol assignment. The raters received video training on how to evaluate the YMRS. They also participated in an inter-rater reliability survey of patients with manic symptoms before the study. The inter-rater reliability (intra-class correlation coefficient = 0.794) was good.

After the randomization phase, anticholinergic drugs, propranolol, other antipsychotics, mood stabilizers, antidepressants, and dopamine agonists were discontinued. However, in patients with acute dystonia, parkinsonism, or akathisia, anticholinergic drugs or propranolol were resumed after the randomization phase and the dose and frequency of use were recorded. Intramuscular and oral lorazepam (not more than 8 mg/day) were allowed to treat agitation or violent behavior.

Psychiatric symptoms and safety assessments

During the randomization phase prior to enrollment, the YMRS (11 items, total score range: 0–60),15 Hamilton Depression Rating Scale (HAMD, 17 items, total score range: 0–52),16 Brief Psychiatric Rating Scale (BPRS, 18 items, total score range: 7–126),17 Clinical Global Impression-Severity (CGI-S, range: 1–7),18 Simpson Angus Scale (SAS, 10 items, total score range: 0–40),19 Barnes Akathisia Scale (BAS, four items, total score range: 0–14),20 and Abnormal Involuntary Rating Scale (AIMS, 10 items, total score range: 0–40)21 were used to assess the severity of mood symptoms, psychotic symptoms, and EPS. These ratings were carried out at baseline, weeks 1, 2, and 4, or at the terminal visit. Adverse events, bodyweight, vital signs, concomitant medications, and the study medication dosages were also recorded.

The primary efficacy measurement of this study was to compare the change in YMRS total score from baseline to end-point between the zotepine and haloperidol groups. The secondary efficacy measurements were BPRS, HAMD, and CGI-S total scores. Treatment response was defined a priori as reduction in YMRS total score equal to or greater than 50% from the baseline score. SAS, AIMS and BAS total scores were used as measures of safety. Additionally, adverse events, vital signs and concomitant medication were considered in the safety evaluation.

Dosing strategy

This study had a flexible dosage design, with the dose ranges for zotepine and haloperidol of 25–450 mg/day and 2–25 mg/day, respectively. The suggested initial doses of zotepine and haloperidol were 25 mg/day and 2 mg/day, respectively. The initial doses of lithium and valproate were 600–900 mg/day and 200–500 mg/day, respectively. Dose titration of the antipsychotics was at the discretion of the non-blinded investigators. Lithium and valproate doses were titrated on the basis of serum levels and at the clinician's request. Lithium and valproate doses were titrated to targeted serum levels (lithium, 0.5–1.0 mEq/L; valproate, 50–100 µg/mL), even if the patients achieved clinical response. The dosage could be lowered only when the patients could not tolerate the side-effects of the lithium or valproate.

Vital signs (pulse, systolic and diastolic blood pressures) and bodyweight were measured at screening, baseline, week 2, and week 4, or at the terminal visit of the study. Hematological parameters, serum chemical parameters, and urinalysis results were obtained at screening and week 4 or at the terminal visit.

Statistical methods

The intent-to-treat population included those patients who had at least one efficacy assessment post baseline and were also in good compliance with the study protocol. Efficacy analyses were performed on data from the intent-to-treat population. Safety analyses were performed on data from all patients who took at least one dose of study medication. In the case of missing data, the last-observation-carried-forward-method was used. Non-parametric tests such as the Wilcoxon rank sum test and Wilcoxon signed rank test were used for between-group differences and within-group differences of continuous variables.

The χ2-test or Fisher's exact test were used for evaluation of between-group differences of categorical data. All results are expressed as means and standard deviations. All hypothesis testing was two-sided, with the significance level set at P < 0.05. The data were analyzed using spss, English version 13.0 (spss, Chicago, IL, USA).

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient assignment and demographics

Forty-five patients fulfilled all criteria and underwent randomization, with 22 patients assigned to the zotepine group and 23 to the haloperidol group. A total of four patients (one in the zotepine group and three in the haloperidol group) withdrew their consent and were not assessed post-baseline. The 41 remaining patients were treated with study medications and assessed at least once post-baseline. Two patients from the zotepine group (one due to urticaria and one due to protocol deviation) and four patients from the haloperidol group (three due to EPS and one due to protocol deviation) withdrew early.

The demographics (Table 1), baseline severity of mood symptoms, psychotic symptoms, and EPS (Table 2) are summarized in the Tables. At baseline, there were no significant differences between the groups with respect to age, sex, duration of bipolar disorder, scores on the SAS, BAS, and AIMS, or bodyweight. Total scores on the YMRS, BPRS, HAMD, and CGI-S at baseline did not differ significantly between the groups. On average, the study population was composed of acutely bipolar patients, about 40 years of age, with moderate-to-severe mood symptoms.

Table 1.  Demographic characteristics
 ZotepineHaloperidolP-value*
n = 22n = 23
  • *

    Wilcoxon rank sum test or χ2 method.

Age (years)39.1 ± 12.941.8 ± 10.80.6
Sex (M/F)11/119/140.6
Duration of illness (years)6.6 ± 6.911.7 ± 9.10.1
Bodyweight (kg)66.4 ± 18.961.5 ± 10.60.5
Table 2.  Baseline severity of mood symptoms, psychotic symptoms, and extrapyramidal syndrome
 ZotepineHaloperidolP-value*
n = 21n = 20
  • *

    Wilcoxon rank sum test.

  • AIMS, Abnormal Involuntary Movement Scale; BAS, Barnes Akathisia Scale; BPRS, Brief Psychiatric Rating Scale; CGI-S, Clinical Global Impression Severity of Illness Scale; HAMD, Hamilton Depression Rating Scale; SAS, Simpson Angus Scale; YMRS, Young Mania Rating Scale.

YMRS33.7 ± 6.935.8 ± 5.90.4
CGI-S4.9 ± 0.65.1 ± 0.50.4
BPRS38.5 ± 9.240.0 ± 8.00.5
HAMD5.0 ± 4.45.8 ± 5.00.5
SAS1.6 ± 4.93.7 ± 7.60.8
BAS0.41 ± 1.920.96 ± 2.500.2
AIMS0.27 ± 0.550.96 ± 1.670.1

Dosages and serum levels of study medications

At baseline, the zotepine dose was 32.1 ± 19.6 mg/day and the haloperidol dose was 2.5 ± 1.1 mg/day. In both groups, the dosages increased gradually. The maximum dose was 116.7 ± 61.9 mg/day for zotepine and 10.8 ± 6.8 mg/day for haloperidol. At the end-point, the dose was 100.0 ± 49.4 mg/day for zotepine and 8.9 ± 6.8 mg/day for haloperidol.

Within the zotepine group, eight patients received combined treatment with lithium while 13 received zotepine with valproate. Within the haloperidol group, the lithium-to-valproate ratio was 7:13. The dosage of lithium or valproate did not significantly differ between groups, whether at baseline, maximum, or the study end-point (Table 3). Nor did the mean serum levels of lithium or valproate differ significantly between groups, whether at week 1, 2, 3, or 4 (Table 4). All patients achieved therapeutic serum levels of lithium or valproate, except for two in the zotepine group and one in the haloperidol group; their serum levels were below the lower limits, but they had good treatment responses.

Table 3.  Mean dose of lithium and valproate administered to the zotepine and haloperidol groups
 ZotepineHaloperidol
n = 21n = 20
LithiumValproateLithiumValproate
n = 8n = 13n = 7n = 13
  1. Between-group differences in mean dose were insignificant.

Initial dose900.0 ± 160.4646.2 ± 312.6857.1 ± 113.4661.5 ± 401.1
Final dose1125.0 ± 310.5803.9 ± 363.11157.1 ± 207.01011.5 ± 353.1
Maximum dose1200.0 ± 277.8907.7 ± 278.31200.0 ± 245.01126.9 ± 326.4
Table 4.  Mean serum level of lithium and valproate administered to the zotepine and haloperidol groups
 ZotepineHaloperidol
LithiumValproateLithiumValproate
(mmol/L)(µg/dL)(mmol/L)(µg/dL)
  1. Between-group differences in mean serum level were insignificant.

Week 1 (mean ± SD)0.64 ± 0.3169.09 ± 27.160.55 ± 0.2968.98 ± 15.40
Week 2 (mean ± SD)0.78 ± 0.3274.07 ± 20.520.72 ± 0.3576.77 ± 16.37
Week 3 (mean ± SD)0.79 ± 0.2569.14 ± 18.840.71 ± 0.2974.76 ± 14.31
Week 4 (mean ± SD)0.77 ± 1.7068.79 ± 19.020.74 ± 0.2578.30 ± 14.90

Efficacy data

Primary efficacy measures

Both groups showed significant improvement in YMRS total scores from baseline to end-point (zotepine, –23.7 ± 12.1, P < 0.01; haloperidol, –22.3 ± 11.0, P < 0.01). Although statistically significant efficacy of both zotepine and haloperidol was evident beginning in week 1 (Fig. 1), there was no between-group difference in the amount of improvement (Table 5).

image

Figure 1. Young Mania Rating Scale (YMRS) score at each visit. Significantly reduced since week 1 (P < 0.001) in both treatment groups. (–◆–) Haloperidol + mood stabilizer (MS) (n = 20); (inline image) zotepine + MS (n = 21).

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Table 5.  Between-group differences in the change in severity of mood and change in psychotic symptoms from baseline to end-point
 ZotepineHaloperidolP-value*
n = 21n = 20
  • *

    Wilcoxon rank sum test.

  • BPRS, Brief Psychiatric Rating Scale; CGI-S, Clinical Global Impression Severity of Illness Scale; HAMD, Hamilton Depression Rating Scale; YMRS, Young Mania Rating Scale.

YMRS−23.7 ± 12.1−22.3 ± 11.00.5
HAMD−1.62 ± 4.56−2.85 ± 5.100.5
BPRS−13.3 ± 10.5−12.3 ± 7.40.9
CGI-S−2.05 ± 1.40−2.00 ± 1.300.9
Secondary efficacy measures

All secondary efficacy measures, except total HAMD scores, improved significantly for both groups (Fig. 2). HAMD score improved significantly only in the haloperidol group (Fig. 3). Both groups had 15 patients who responded to treatment (15/22, 71% in the zotepine group and 15/23, 75% in the haloperidol group). Sixteen of 22 (76%) patients in the zotepine group and 14 of 23 patients (70%) in the haloperidol group were much improved or very much improved at the study end-point.

image

Figure 2. Brief Psychiatric Rating Scale (BPRS) score over time. Significantly reduced since week 1 (P < 0.005) in both treatment groups. (–◆–) Haloperidol + mood stabilizer (MS) (n = 20); (inline image) zotepine + MS (n = 21).

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image

Figure 3. Hamilton Depression Rating Scale (HAMD) score at each visit. Haloperidol group was significantly improved compared to baseline (P < 0.05) from week 2. (–◆–) Haloperidol + mood stabilizer (MS) (n = 20); (inline image) zotepine + MS (n = 21).

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Safety data

Adverse events

All patients who received treatment were included in the safety evaluation (n = 45). Twelve of 22 patients (54.5%) in the zotepine group and 18 of 23 patients (78.3%) in the haloperidol group experienced at least one adverse event; the severity was classified as mild to moderate. The most frequent treatment-related adverse events (frequency ≥5%) were constipation, parkinsonism, and somnolence in the zotepine group, and parkinsonism and akathisia in the haloperidol group (Table 6).

Table 6.  Number of patients who experienced treatment-related adverse events
 ZotepineHaloperidolP-value*
n = 22n = 23
  • *

    χ2-test.

Central & peripheral nervous system symptoms4 (18.2%)17 (73.9%)<0.001
 Parkinsonism4 (18.2%)14 (60.9%) 
 Akathisia07 (30.4%) 
 Tremor01 (4.3%) 
Gastrointestinal symptoms6 (27.3%)3 (13.0%)0.233
 Constipation5 (22.7%)1 (4.3%) 
 Diarrhea1 (4.5%)1 (4.3%) 
 Abdominal Pain01 (4.3%) 
Psychiatric symptoms2 (9.1%)1 (4.3%)0.524
 Somnolence2 (9.1%)0 
 Insomnia01 (4.3%) 
Nervous system symptoms

The overall treatment-related incidence of nervous system adverse events was lower in the zotepine group than the haloperidol group. In the zotepine group, four of 22 patients (18%) reported parkinsonism problems, while no patient reported symptoms of akathisia. In the haloperidol group, 14 of 23 patients (61%) reported symptoms consistent with parkinsonism, and seven patients (30%) reported akathisia. Parkinsonism occurred in 18 patients who used anticholinergic agents as concomitant medication (four [18%] in the zotepine group and 14 [61%] in the haloperidol group). Akathisia occurred in seven patients who used propranolol as the concomitant medication (seven [30%] in the haloperidol group).

The mean change in total SAS score did not differ between groups except in the first week, when the magnitude of the decrease was greater in the zotepine group than in the haloperidol group (P = 0.02). Similarly, the magnitude of the BAS score decrease was greater in the zotepine group than in the haloperidol group at the fourth week (P = 0.01). There were no between-group differences in SAS or AIMS score changes. The haloperidol group, but not the zotepine group, showed a significant increase in BAS score in the fourth week (P < 0.05).

Bodyweight, glucose, lipid, and uric acid

Weight gain during the 4-week study was higher in the zotepine than in the haloperidol group (2.46 ± 2.94 and –0.31 ± 2.95 kg, respectively; P = 0.003). The between-group difference in incidence of clinically significant weight gain (≥5% increase from baseline) was not significant (32% [7/22] and 13% [3/23], respectively; P = 0.1).

At the end-point, neither group showed significant change in fasting glucose or cholesterol. However, uric acid levels differed significantly between the groups (−2.4 ± 1.6 for zotepine and 0.4 ± 1.4 mg/dL for haloperidol; P < 0.05).

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In this randomized, controlled study to evaluate the efficacy and safety of zotepine in combination with mood stabilizers in Chinese patients with bipolar manic episodes, we found that zotepine (average dose, 100 mg/day) was effective, safe, and well-tolerated for the treatment of acutely relapsed patients with bipolar mania or mixed episode, and that haloperidol (9 mg/day) had similar efficacy. Rapid onset of efficacy and significant improvement as early as week 1 after starting treatment were noted in both groups, according to YMRS total, BPRS total, and CGI-S total scores. These improvements were sustained throughout the 4-week study.

The efficacy data of this study was similar to that of previous zotepine studies. In a previous report, zotepine monotherapy (250 mg/day as a loading dose) was effective in the treatment of acute and severe manic patients, 75% of whom were classified as responders; the mean decrease in YMRS total score was 27.2.14 The degree of decrease in YMRS total score in both the zotepine and haloperidol groups of our study were higher than those seen in double-blind mania adjunctive therapy trials of risperidone (−14.3 and –14.5), olanzapine (−13.1), and quetiapine (−13.8).22–25 Many factors limited direct comparison of the magnitude of efficacy between studies, such as placebo effect (our study lacked a placebo control group), observational bias (our study was rater-blinded), lack of titration of study medications (in our study, they were titrated according to clinical situation) or sample size (in our study, the sample was small). Despite that, the efficacy of zotepine for the control of manic symptoms was comparable to that of other atypical antipsychotics.

Our study demonstrated that both the zotepine and haloperidol groups had HAMD total scores that decreased from baseline to study end-point, but only the haloperidol group had a statistically significant difference between baseline and the study end-point. Our results may be due to the small sample size. Further studies with a larger sample size are needed to confirm the results.

Extrapyramidal side-effects have a negative impact on treatment compliance and thus, limit the effectiveness and tolerability of antipsychotics. In our study, the incidence of parkinsonism (18% for zotepine vs 61% for haloperidol) and akathisia (0% for zotepine vs 30% for haloperidol) were significantly lower in patients treated with zotepine than with haloperidol. This result was compatible with less frequent use of concomitant anticholinergic medications (18% vs 61%) and of concomitant propranolol (0% vs 30%) in the zotepine group. A previous study also showed that EPS occurred less frequently in patients treated with zotepine than with conventional antipsychotics.26 In our study, EPS symptoms occurred significantly less frequently in the zotepine group in the first week (as indicated by the change in SAS score, P < 0.05) and at the fourth week (as indicated by the change in BAS score, P < 0.05).

Many patients with bipolar disorder eat excessively in the manic phase and have problems with bodyweight gain and hyperuricemia. Weight gain is also a potentially serious side-effect associated with the use of some antipsychotics. In this short-term study, bodyweight increased more (2.46 ± 2.94 and –0.31 ± 2.95 kg, respectively, P < 0.005) in the zotepine group, but serum uric acid decreased more significantly in the zotepine group (−2.4 ± 1.6 and 0.4 ± 1.4 in haloperidol group, respectively, P < 0.05). While this finding is compatible with previous findings of zotepine-associated weight gain, zotepine may be helpful for patients with hyperuricemia.27–29

The limitations of our study include: (i) overestimation of the effectiveness of both study medications due to lack of a placebo control group; (ii) possible influence of un-blinded primary care physicians and patients because of blind-rater design; (iii) the short duration of the study did not permit inferences concerning long-term use; and (iv) inadequate statistical power because of small sample size.

In summary, although our study was limited for the reasons given above, the results still have important implications for clinicians treating severe, acute mania with zotepine in a hospital setting. More studies on zotepine, especially larger, double-blind studies and comparisons with other SGA are needed to confirm the efficacy of zotepine for manic control.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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