Methods: Patients (n = 302) with bipolar I disorder (manic episode) were randomised to 12 weeks' double-blind treatment with quetiapine (flexibly dosed up to 800 mg/day), placebo, or haloperidol (up to 8 mg/day). The primary efficacy outcome variable was change from baseline to Day 21 in Young Mania Rating Scale (YMRS) score. Results: YMRS score improved with quetiapine at Day 21 (−12.29 versus −8.32 for placebo; P < 0.01). The difference in favor of quetiapine increased by Day 84 (−17.52 versus −9.48; P < 0.001). Haloperidol also showed an advantage over placebo at Days 21 and 84 (P < 0.001). There was no significant difference in efficacy measures between quetiapine and haloperidol groups at any assessment except Day 21. The only common adverse event with quetiapine was somnolence (12.7%). Extrapyramidal symptoms (EPS), including akathisia, occurred at 59.6% with haloperidol, 12.7% with quetiapine, 15.8% with placebo. Most quetiapine responders (84%) received a dose of 400–800 mg/day. Conclusions: Quetiapine was effective and well tolerated. The efficacy and tolerability profile of haloperidol (including its propensity for EPS) supported study validity.
Bipolar disorder is a devastating illness that is usually chronic, recurring, and associated with considerable morbidity, mortality, and caregiver burden. While pharmacotherapy can substantially reduce morbidity, many patients do not fully respond to standard treatments and have poor long-term outcomes following hospitalisation for a manic episode (Dittmann et al., 2002 and Keck et al., 1998).
First-line options for the treatment of mania include monotherapy with lithium, divalproex, or an antipsychotic. When choosing an antipsychotic, treatment guidelines generally recommend the use of atypical antipsychotics over conventional (typical) antipsychotics based on their equivalent efficacy and more favorable tolerability profile (American Psychiatric Association, 2002, Goodwin, 2003 and Grunze et al., 2003).
The general effectiveness of atypical antipsychotics offers an improvement over their therapeutic predecessors, the conventional antipsychotics. The atypical agents, however, are not without adverse events. For example, some atypical agents are associated with clinically significant weight gain, QTc prolongation, and extrapyramidal symptoms (EPS) within their therapeutic dose range. Moreover, patients with bipolar disorder often receive polypharmacotherapy with a potentially additive effect on the overall adverse event burden. Studies that can identify specific atypical antipsychotics that combine broad efficacy with favorable tolerability are warranted, particularly as adherence to pharmacotherapy is influenced by these factors.
Several atypical antipsychotics have been shown to be effective as monotherapy and combination therapy in the treatment of mania, in large, randomized, placebo-controlled clinical studies (Tohen et al., 1999, Tohen et al., 2000, Tohen et al., 2002, Keck et al., 2003, Segal et al., 1998, Hirschfeld et al., 2004, Yatham et al., 2003 and Sachs et al., 2002).
Quetiapine fumarate (Seroquel®) has demonstrated efficacy as monotherapy in the treatment of schizophrenia. The safety profile of quetiapine in populations with schizophrenia is favorable relative to placebo and active comparators (Kasper et al., 2001, Arvanitis and Miller, 1997, Copolov et al., 2000, Emsley et al., 2000 and Small et al., 1997). Specifically, placebo-level EPS and serum prolactin concentration, as well as moderate weight gain, have been noted with quetiapine.
Results from several preliminary clinical studies suggested that quetiapine is effective and well tolerated in the treatment of mania associated with bipolar disorder (DelBello et al., 2002, Vieta et al., 2002, Ghaemi et al., 2003, Chisholm et al., 2001, Dunayevich et al., 2001, Sajatovic et al., 2001, Zarate et al., 2000 and Kasper et al., 2001). The present study was undertaken to further characterize the effectiveness of quetiapine when used as monotherapy for the treatment of bipolar mania for up to 12 weeks of double-blind, parallel-group treatment.
