Quetiapine (Seroquel®) is an orally administered atypical
antipsychotic that is indicated for the treatment of
schizophrenia and
bipolar disorder, including
bipolar depression. An extended-release (XR) formulation of
quetiapine is also available. This review summarizes the pharmacological properties, efficacy and tolerability of
quetiapine and
quetiapine XR in patients with
bipolar depression.
Quetiapine is an antagonist at both
serotonin 5-HT2 and
dopamine D2 receptors, and its
antipsychotic effects are thought to stem from interactions at these receptors. The
antidepressant effects of
quetiapine are poorly understood, but may be related to antagonism of 5-HT2A receptors in cortical regions, partial agonism of 5-HT1A in the prefrontal cortex in association with increased extracellular
dopamine release in the region, or to reduced synaptic reuptake of
noradrenaline resulting from inhibition of the
noradrenaline reuptake transporter by the
quetiapine metabolite
norquetiapine. The efficacy and tolerability of
quetiapine was evaluated in five 8-week, randomized, double-blind, placebo-controlled, multicentre or multinational trials in patients with a major depressive episode (
MDE) associated with
bipolar disorder. Across trials, monotherapy with oral
quetiapine 300 or 600 mg/day (or
quetiapine XR 300 mg/day) produced significantly greater improvements than placebo in depressive symptoms (primary endpoint), according to the change in the Montgomery-Asberg Depression Rating Scale total score. In general,
quetiapine and
quetiapine XR were also associated with significantly higher
MDE response and remission rates than placebo. Across trials,
quetiapine and
quetiapine XR produced significantly greater improvements in global severity of illness scores than placebo, according to changes in the Clinical Global Impressions scale score. There were no differences in treatment outcomes between
quetiapine 300 mg/day and 600 mg/day dosage groups. Patients with
bipolar depression who responded to
quetiapine during two 8-week acute treatment trials also benefited from continuing
quetiapine therapy for up to 52 weeks. Compared with
quetiapine responders randomized to placebo,
quetiapine responders who continued
quetiapine 300 or 600 mg/day had a significantly reduced risk of recurrence of any mood events and of depression mood events, but not of hypomanic/manic events. In a randomized, double-blind, placebo-controlled trial,
quetiapine maintenance
therapy for up to 104 weeks was more efficacious than placebo or
lithium in prolonging the time to recurrence of any mood event (primary endpoint). Patients in this trial had bipolar I disorder with
mania, depression or a mixed episode as the index episode, and the trial included only patients who were responsive to acute phase
quetiapine, which may have introduced a positive bias in favour of
quetiapine over
lithium during maintenance
therapy.
Quetiapine 300 or 600 mg/day and
quetiapine XR 300 mg/day was generally well tolerated in patients with
bipolar depression, with most treatment-emergent adverse events being of mild to moderate severity. The most frequent adverse events occurring during the acute treatment phase were dry mouth, sedation,
somnolence,
dizziness (
quetiapine and
quetiapine XR),
constipation (
quetiapine) and increased appetite (
quetiapine XR). Extrapyramidal symptoms (EPS) occurred across
quetiapine and placebo groups, but there were no significant differences between
quetiapine and placebo recipients on objective measures of EPS and
akathisia. In some trials,
quetiapine recipients experienced significantly greater
weight gain than placebo recipients. Across trials, some
quetiapine recipients had clinically relevant increases in
blood glucose or
lipid parameters, although these also occurred in patients from other treatment groups. The clinical significance of these changes is uncertain. In conclusion,
quetiapine and
quetiapine XR are valuable additions to the first-line treatments for
bipolar depression. Further head-to-head trials of
quetiapine versus other drug regimens that are effective in
bipolar depression would be of considerable interest.