Subscribe to Biological Therapies in Psychiatry -  Choose your plan >
IN THIS ISSUE:
October 2009

Divalproex for Mania in Children and Adolescents: A Negative Study
The first double-blind study of divalproex (Depakote) in pediatric patients with bipolar disorder found no greater efficacy than placebo.

Chamomile Calms
A double-blind study suggests efficacy for chamomile as an alternative treatment for anxiety.

Quetiapine for GAD and MDD
In a variety of studies, quetiapine (Seroquel) was found to be effective in treating generalized anxiety and major depressive disorders.

In Brief
Valproate Does Not Improve Agitation in Patients with Dementia; Three More Atypical Antipsychotics May Be Approved for Pediatric Patients

Child and Adolescent Topics
Keep an eye out for BTP's new icon denoting articles about children and adolescents.

Quetiapine for GAD and MDD

October 2009

Patients with major depressive disorder (MDD) or generalized anxiety disorder (GAD) who do not respond completely to first- or second-line treatments sometimes receive prescriptions for antipsychotics, either as monotherapy or in addition to their antidepressant or antianxiety medications. Last year, we reported on several short-term studies of quetiapine (Seroquel) and aripiprazole (Abilify) for these indications (2008;31:6-8,11-12,38). Patient outcomes were generally favorable, but there were concerns about adverse effects, particularly akathisia and weight gain. A series of studies funded by Astra Zeneca, manufacturer of quetiapine, have examined its use singly and as an adjunct for treating patients with GAD and MDD.

Kahn and coauthors conducted a trial of 951 GAD patients.1 In double-blind fashion, patients were randomized to receive quetiapine extended-release (XR), 50 mg/day, 150 mg/day, or 300 mg/day; or placebo for 8 weeks. Mean improvement in the Hamilton Anxiety Scale (HAM-A) total score from baseline to week 8 was significantly (P < .001) greater than placebo for the 50- and 150-mg/day doses but not for the 300-mg/day dose. Similarly, response rates were significantly higher (P < .05) at the 50- and 150-mg/day doses compared with placebo but not at the 300-mg/day dose. The proportion of patients rated much or very much improved at week 8 was 66.2% at 50 mg/day, 67.3% at 150 mg/day, 58.0% at 300 mg/day, and 56.9% on placebo. Again, the lower two doses separated significantly from placebo, but the higher dose did not. The most common adverse effects were somnolence and sedation. As dosage increased, the percentage of patients gaining substantial amounts of weight similarly increased.

Chouinard and others treated 873 GAD patients for 8 weeks with quetiapine XR, 50 mg/day or 150 mg/day; paroxetine (Paxil and others), 20 mg/day; or placebo.2 Both doses of quetiapine, as well as paroxetine, were statistically significantly superior to placebo at week 8. Quetiapine but not paroxetine was statistically superior to placebo at day 4. Again, fatigue and somnolence were more common with quetiapine than with placebo. As expected, weight increased, and metabolic indices worsened.

In a similar design, Merideth et al randomly assigned 854 GAD patients to 8 weeks of treatment with quetiapine XR, 150 mg or 300 mg/day; escitalopram (Lexapro), 10 mg/day; or placebo.3 Once again, both doses of quetiapine, as well as escitalopram, "beat" placebo at week 8. Both quetiapine doses but not escitalopram showed statistical superiority at day 4. Adverse events were comparable to those observed in the other studies.

Katzman and coworkers treated 433 GAD patients with open-label quetiapine until they achieved symptom stability (minimum of 12 weeks).4 Patients were then randomized to quetiapine XR, flexibly dosed between 50 and 300 mg/day, or placebo for up to 1 year. Quetiapine XR monotherapy proved superior to placebo in preventing relapse to a predetermined level of anxiety symptoms.

Weisler and coworkers randomly assigned 723 MDD patients to 8 weeks of treatment with quetiapine XR, 50, 150, or 300 mg/day, or placebo.5 All 3 doses of quetiapine were statistically superior to placebo, beginning as early as day 4.

Montgomery and associates randomized 612 MDD patients to 6 weeks of treatment with quetiapine XR, 150 or 300 mg/day, duloxetine (Cymbalta), or placebo.6 Both doses of quetiapine as well as duloxetine were significantly (P < .001) superior to placebo at week 6.

Of 1854 MDD patients treated with open-label quetiapine in a study by Datto et al, 787 responded to treatment and were randomly assigned to continue quetiapine or to switch to placebo.7 Quetiapine was superior to placebo in preventing the recurrence of depression.

El-Khalili and coworkers studied MDD patients with an incomplete response to antidepressant therapy.8 For 6 weeks, 446 patients were randomized to receive quetiapine XR, 150 or 300 mg/day, or placebo, in addition to their antidepressant. At the higher dose, quetiapine achieved statistical significance as early as week 1, and this continued throughout the study. Response and remission rates at the higher dose were statistically superior to placebo. The lower dose, however, did not demonstrate superiority to placebo in this trial.

In a similar research design, Bauer and others randomized 493 MDD patients with an inadequate response to antidepressant treatment to 6 weeks of adjunctive quetiapine XR, 150 or 300 mg/day, or placebo.9 Both doses of quetiapine were superior to placebo as early as week 1, and statistical superiority continued through week 6.

In summary, most studies found quetiapine XR to be statistically superior to placebo at 50-mg, 150-mg, and 300-mg/day doses for patients with either GAD or MDD after 6 to 8 weeks, and sometimes as early as 4 days. One study1 found the lower doses to be superior to placebo, but not 300 mg/day, while another study8 found 300 mg/day to be superior to placebo but not 150 mg/day. Paroxetine2 and escitalopram3 were both statistically superior to placebo for patients with GAD at 8 weeks, but not after 4 days. Duloxetine was statistically superior to placebo after 6 weeks in patients with MDD.6

The categories we use to identify psychopharmacologic agents—antipsychotics, antidepressants, anxiolytics—are insufficiently descriptive. We routinely prescribe antidepressants to treat anxiety disorders. As the studies featured here have demonstrated, agents labeled as antipsychotics can be efficacious—alone and in combination—for symptoms of depression and anxiety. Aripiprazole was recently approved by the U.S. Food and Drug Administration for labeling as an adjunct in the treatment of MDD in adults. The combination of olanzapine and fluoxetine (Symbyax) also won approval for treatment-resistant depression. In the near future, quetiapine, alone or as an adjunct, may receive approval to list MDD as a labeled indication. The question for physicians is where these agents belong in a treatment algorithm for MDD and GAD.

Specific forms of psychotherapy, such as cognitive behavioral therapy, are effective in treating GAD and nonpsychotic MDD of mild to moderate severity. Antidepressants obviously are considered as pharmacologic treatments for these conditions. Antipsychotic agents, such as quetiapine, have very different adverse effect profiles. Their long-term side effects, and potential adverse effects on health, must be taken into account when discussing and deciding with patients which treatment is optimal at each juncture in their treatment.

1Kahn A, Joyce M, Eggens I, Baldytcheva I, Brecher M: Extended release quetiapine fumarate (quetiapine XR) monotherapy in the treatment of patients with generalized anxiety disorder (GAD). Poster presented at the Anxiety Disorders Association of America Congress, Savannah, Georgia, March 6-9, 2008.

2Chouinard G, Ahokas A, Bandelow B, Bobes J, Eggens I, Liu S, Brecher M: Once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in generalized anxiety disorder (GAD): A placebo-controlled study with active-comparator paroxetine. Poster presented at the Anxiety Disorders Association of America Congress, Savannah, Georgia, March 6-9, 2008.

3Merideth C, Cutler A, Neijber A, She F, Eriksson H: Efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in the treatment of generalised anxiety disorder (GAD). Presented at the 21st Congress of the European College of Neuropsychopharmacology, Barcelona, Spain, August 30 - September 3, 2008.

4Katzman M, Brawman-Mintzer O, Reyes E, Olausson B, Liu S, Brecher M: Extended release quetiapine fumarate (quetiapine XR) monotherapy in maintenance treatment of generalized anxiety disorder (GAD): Efficacy and tolerability results from a randomized placebo-controlled trial. Poster presented at the 161st annual meeting of the American Psychiatric Association, Washington, DC, May 3-8, 2008.

5Weisler R, Joyce M, McGill L, Lazarus A, Åström M, Brecher M: Extended release quetiapine fumarate (quetiapine XR) monotherapy for major depressive disorder: A double-blind, placebo-controlled study. Poster presented at the 161st annual meeting of the American Psychiatric Association, Washington, DC, May 3-8, 2008.

6Montgomery S, Cutler A, Lazarus A, Schollin M, Brecher M: Extended release quetiapine fumarate (quetiapine XR) monotherapy in the treatment of patients with major depressive disorder (MDD). Poster presented at the 16th European Congress of Psychiatry, Nice, France, April 5-9, 2008.

7Datto C, Lam RW, Lepola U, Sweitzer D, Eriksson H, Brecher M: Double-blind study of extended release quetiapine fumarate (quetiapine XR) monotherapy for maintenance treatment of major depressive disorder (MDD). Poster presented at the 161st annual meeting of the American Psychiatric Association, Washington, DC, May 3-8, 2008.

8El-Khalili N, Joyce M, Atkinson S, Buynak R, Datto C, Lindgren P, Eriksson H, Brecher M: Adjunctive extended-release quetiapine fumarate (quetiapine XR) in patients with major depressive disorder and inadequate antidepressant response. Poster presented at the 161st annual meeting of the American Psychiatric Association, Washington, DC, May 3-8, 2008.

9Bauer M, Pretorius HW, Earley W, Lindren P, Brecher M: Effect of once-daily extended release quetiapine fumarate (quetiapine XR) as add-on to antidepressants in major depressive disorder (MDD). Poster presented at the 16th European Congress of Psychiatry, Nice, France, April 5-9, 2008.