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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.
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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.