AstraZeneca's Seroquel

AstraZeneca?s Seroquel

On October 20, 2006, the FDA approved an additional indication for AstraZeneca?s quetiapine fumarate (Seroquel). Quetiapine previously was approved for the treatment of schizophrenia and bipolar disorder. The added indication is for use in the treatment of major depressive episodes associated with bipolar disorder.¹ Quetiapine also received FDA approval in January 2004 for acute manic episodes as mono-therapy or as adjunct therapy to divalproex or lithium.¹ It is now the first and only single medication approved by the FDA to treat both depressive and acute manic episodes associated with bipolar disorder.

Pharmacology/Pharmacokinetics

Quetiapine is a psychotropic agent that belongs to the dibenzothiazepine-derivative class. It is an antagonist for multiple neurotransmitter receptors such as dopamine, serotonin, adrenergic a₁ and a₂, and histamine₁. Quetiapine has no appreciable affinity to benzodiazepine or cholinergic muscarinic receptors.² The proposed efficacy of quetiapine in bipolar disorder and schizophrenia is the antagonism of serotonin type 2 and dopamine type 2. The exact mechanism of action is unknown.

Quetiapine oral tablets are rapidly absorbed, widely distributed, and extensively metabolized by the liver. Patients with hepatic insufficiency may need dosage adjustments. No dosage adjustment is needed for patients with renal insufficiency.²

Clinical Trials

The efficacy of quetiapine for acute mania was evaluated in 3 randomized, double-blind, placebo-controlled trials enrolling patients diagnosed with bipolar I disorder, with or without psychotic features, utilizing the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) scale.³ Two of the trials were monotherapy trials, and the third was adjunctive.^(2,4) In a 12-week monotherapy trial, investigators randomized patients to receive either quetiapine, placebo, or haloperidol. Quetiapine was titrated up by 100 mg/day through day 4, up to 600 mg on day 5, and up to 800 mg/day from day 6 until the end of the study. Haloperidol also underwent 4 days of titration.⁴ The second 12-week mono-therapy study randomized 302 participants to quetiapine, placebo, or lithium.^2,4 The primary efficacy end points for both monothera-py studies were changes from baseline scores at day 21 and day 84, using the Young Mania Rating Scale (YMRS).

The quetiapine-treated group had a higher improvement in YMRS scores, compared with the placebo group, at day 21 and day 84 in the first study and in the second study.⁴ The 3-week adjunctive trial randomized 191 patients to a mood stabilizer (lithium or divalproex) in an unblinded fashion. Once the participants attained therapeutic levels, they were randomized to quetiapine or matching placebo. The quetiapine-plus-mood-stabilizer arm demonstrated a higher response rate than the mood-stabilizer-alone arm on the YMRS.⁴

Treatment-emergent depression was lower in the quetiapine-treated groups than in the placebo groups in both monotherapy studies. The adjunctive study showed no effect on treatment-emergent depression.⁴ The efficacy of quetiapine for the treatment of depressive episodes in patients diagnosed with bipolar I and II disorder was demonstrated in 2 double-blind, randomized, placebo-controlled trials. Inclusion criteria were a diagnosis of bipolar I or II defined by DSM-IV and a major depressive episode experienced by the patient, defined by the Hamilton Depression Rating Scale.⁴ Patients were randomized and titrated to receive quetiapine 300 or 600 mg/day or matching placebo for 8 weeks.^5,6 Efficacy was measured by evaluating improvement from baseline to week 8, utilizing the Montgomery-Asberg Depression Rating Scale.

The response rate by week 8 was significantly higher for quetiapine-treated patients versus placebo in both studies.^5,6 Quetiapine monotherapy also demonstrated superiority on other outcome measures, such as quality of life, quality of sleep, and anxiety symptoms. The incidence of treatment-emergent mania was lower in the quetiapine group than in the placebo group in both studies.

Safety

The most common adverse events with quetiapine are dry mouth, headache, dizziness, somnolence, and weight gain.^2,4 Similar to other antide-pressants, quetiapine has a boxed warning concerning an increased risk of suicidality in children and adolescents.² Patients should be monitored closely when quetiapine therapy is initiated. Quetiapine is not approved for the treatment of dementia-related psychosis.

Ms. Domenici and Dr. Patel are both pharmacists at Brigham and Women?s Hospital, Boston, Mass. Ms. Sindjeu is a sixth-year PharmD candidate from Northeastern University School of Pharmacy currently on clinical clerkship in the Investigational Drug Service at Brigham and Women?s Hospital.

References

1. Seroquel. Drugs@FDA Web site. Available at: www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

2. Seroquel [package insert]. Wilmington, Del: AstraZeneca Pharmaceuticals LP; 2004.

3. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Association; 1994.

4. AstraZeneca Healthcare Professional Letter. Wilmington, Del: AstraZeneca Pharmaceuticals LP.

5. Calabrese JR, Keck PE, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or bipolar II depression. Am J Psychiatry. 2005;162:1351-1360.

6. Thase ME, Macfadden W, Weisler RH, et al. Efficacy of quetiapine monotherapy in bipolar I and bipolar II depression: a double-blind, placebo-controlled study (the BOLDER II study). J Clin Psychopharmacol. 2006;26(6):600-609.