- First Online:
- Cite this article as:
- Keating, G.M. & Robinson, D.M. Drugs (2007) 67: 1077. doi:10.2165/00003495-200767070-00008
- 106 Views
Quetiapine (Seroquel®) is the only atypical antipsychotic approved in the US for use as monotherapy in both bipolar mania and depression, offering potential compliance advantages. Monotherapy with oral quetiapine 300 mg/day is effective in the treatment of patients with bipolar I or II depression. Rapid and sustained improvements in depressive and anxiety symptoms are seen with quetiapine, as well as improvements in health-related quality of life (HR-QOL). Quetiapine is generally well tolerated in bipolar depression and is not associated with an increased risk of treatment-emergent mania. Thus, despite the current lack of data from active comparator trials, quetiapine monotherapy should be considered a first-line option for the acute treatment of bipolar depression.
The precise mechanism of action of quetiapine in bipolar depression is unknown, although it has been suggested that its antidepressant activity may be linked to its higher affinity for serotonergic than dopaminergic receptors. Quetiapine is not associated with elevation of prolactin levels and has a low propensity to induce extrapyramidal symptoms, most likely reflecting its relatively low affinity for, and its rapid dissociation from, dopamine D2 receptors.
Oral quetiapine is rapidly absorbed and undergoes extensive hepatic metabolism, meaning that dosage adjustment may be needed in patients with hepatic impairment. Caution is recommended when quetiapine is co-administered with cytochrome P450 (CYP) 3A4 inhibitors such as ketoconazole, erythromycin, itraconazole and fluconazole. In addition, higher maintenance dosages of quetiapine may be needed in patients receiving concomitant CYP3A4 inducers (e.g. phenytoin, carbamazepine).
The efficacy of monotherapy with oral quetiapine 300 or 600 mg/day in adults with bipolar I or II disorder and a major depressive episode was demonstrated in two well designed 8-week trials (the BOLDER I and II trials) [n = 511 and 467]. In both BOLDER I and II, Montgomery-Åsberg Depression Rating Scale (MADRS) total scores at week 8 were reduced from baseline to a significantly greater extent with quetiapine than with placebo (the change from baseline in MADRS total scores was the primary endpoint). In addition, the proportion of patients who had responded or were in remission at week 8 was significantly higher with quetiapine than with placebo. No additional benefit was seen in patients receiving quetiapine 600 mg/day compared with those receiving quetiapine 300 mg/day.
Improvements in Hamilton Depression Rating Scale (HAM-D) total and HAM-D item 1 (depressed mood) scores were significantly greater with quetiapine than with placebo, as were improvements on the Clinical Global Impression-Severity of Illness scale. In terms of anxiety symptoms, improvements from baseline in Hamilton Anxiety Rating Scale total scores were significantly greater with quetiapine than with placebo.
In both the BOLDER I and II trials, HR-QOL was improved to a significantly greater extent with quetiapine 300 mg/day than with placebo, as shown by the change from baseline in Quality of Life Enjoyment and Satisfaction Questionnaire Short Form scores. A significantly greater improvement in the quality of sleep occurred with quetiapine 300 or 600 mg/day than with placebo, as shown by the change from baseline in Pittsburgh Sleep Quality Index scores (assessed only in BOLDER I). Sheehan Disability Scale (SDS) scores (assessing functional improvement) were improved to a significantly greater extent with quetiapine 600 mg/day than with placebo, although no significant difference was seen between quetiapine 300 mg/day and placebo recipients (SDS scores were assessed only in BOLDER II).
Apost hoc pooled analysis of the BOLDER I and II trials revealed significantly greater reductions in mean MADRS item 10 (suicidal thoughts) and HAM-D item 3 (suicide) scores in patients receiving quetiapine than in those receiving placebo. Among quetiapine recipients, the incidence of treatment-emergent suicidal ideation or suicide attempt was low and similar to that seen in placebo recipients.
Exploratory subgroup analyses revealed that quetiapine was effective in reducing MADRS total scores in patients with bipolar I depression and patients with rapid-cycling bipolar disorder. In patients with bipolar II depression, quetiapine was significantly more effective than placebo in a combined analysis of the BOLDER I and II trials, and in BOLDER II alone, but not in BOLDER I alone (the separate BOLDER trials were not powered to detect between-treatment differences in subgroups of patients).
Quetiapine was generally well tolerated in patients with bipolar depression, according to the results of the BOLDER I and II trials. In BOLDER I, the incidence of dry mouth, sedation, somnolence, dizziness and constipation was significantly higher in patients receiving quetiapine 300 or 600 mg/day than in patients receiving placebo. Changes in scores on the Simpson-Angus Rating Scale and the Barnes Akathisia Rating Scale did not differ between quetiapine and placebo recipients. Compared with placebo, quetiapine was not associated with an increased risk of treatment-emergent mania in either trial. Only modest weight gain was seen in quetiapine recipients in these short-term studies and there were no significant differences between quetiapine and placebo recipients in terms of fasting serum glucose levels.