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Abilify(R) (Aripiprazole) Approved by U.S. FDA for Add-On Treatment of Major Depressive Disorder

PRINCETON, NJ and TOKYO, JAPAN -- November 20, 2007 -- The U.S. Food and Drug Administration (FDA) approved the supplemental New Drug Application for Abilify(R) (aripiprazole) as adjunctive, or add-on, treatment to antidepressant therapy (ADT) in adults with major depressive disorder (MDD). Abilify is the first medication approved by the FDA as add-on treatment for MDD.

"The approval of this new add-on treatment option is critical for adults suffering from depression who cannot find sufficient relief for their symptoms with antidepressants alone," said Madhukar Trivedi, MD, Professor and Chief-Division of Mood Disorders, University of Texas Southwestern Medical School, Dallas, Texas. "Now physicians have a proven new option they can add to their patients' antidepressant treatments to help them feel better and relieve unresolved depressive symptoms."

The approval is based on results from two six-week, double-blind, randomized, placebo-controlled, multicenter studies (n=743). The results from both studies demonstrated significant improvement in depressive symptoms in adult patients with a primary diagnosis of major depressive disorder who had experienced an inadequate response* to monotherapy with one or more ADTs in the current episode and then added Abilify® (aripiprazole) to their treatment regimens.

Major depressive disorder affects millions of U.S. adults at some point in their lives.2 A recent study evaluated different treatment approaches, including adjunctive medications and switching strategies, in patients with MDD.1 The study found that 63% of patients did not achieve adequate relief of depressive symptoms following the initial treatment with an antidepressant alone.1 Additionally, the study demonstrated that the use of adjunctive medications in treatment may be useful to improve unresolved depressive symptoms.1

Clinical Trial Design and Findings
Two 6-week, double-blind, randomized, placebo-controlled, multicenter studies evaluated the efficacy and safety of add-on Abilify in adult patients with a primary diagnosis of major depressive disorder who had experienced an inadequate response to prior antidepressant therapy (one to three courses) in the current episode.

After an eight-week prospective treatment phase with one ADT plus single-blind placebo to confirm inadequate response to ADT, 743 participants entered a six-week randomized treatment phase during which they continued their ADT plus double-blind adjunctive placebo or adjunctive Abilify® (aripiprazole). All study participants received one of the commonly prescribed ADTs, including selective serotonin reuptake inhibitors (SSRIs): Lexapro® (escitalopram), Prozac® (fluoxetine), Paxil CR® (paroxetine controlled-release), Zoloft® (sertraline); or a serotonin-norepinephrine reuptake inhibitor (SNRI): Effexor XR® (venlafaxine extended release).

The dosage range for adjunctive Abilify was 2-20 mg/day (15 mg/day was the maximum dose for patients receiving Abilify as an adjunct to Paxil CR or Prozac). The primary efficacy endpoint was the mean change from baseline -- the end of the prospective treatment phase -- to the end of the randomized treatment phase in a standard measure called Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale used to assess depressive symptoms. A reduction in MADRS Total Score represents an improvement in depressive symptoms.

The key secondary endpoint was the Sheehan Disability Scale (SDS), a three-item self-rated instrument used to assess the impact of depression on three domains of functioning (work/school, social life and family life) with each item scored from zero (not at all) to 10 (extreme). Safety evaluations included incidence of adverse reactions, discontinuation rate due to adverse reactions and laboratory measures.

For the primary endpoint, both studies showed that taking Abilify plus an ADT provided superior improvement in depressive symptoms to ADT alone at study endpoint (week six), as measured by the reduction of the MADRS Total Scores.3 For the secondary endpoint, Abilify plus an ADT was also superior to placebo plus ADT in reducing the mean SDS Total Score in one study.

In these studies, adjunctive Abilify demonstrated no clinically important differences on metabolic parameters, including prolactin, fasting glucose, HDL, LDL and total cholesterol. The median% change from baseline in triglycerides was 5% for adjunctive Abilify-treated patients vs 0% for adjunctive placebo-treated patients. In the studies, weight gain greater than or equal to 7% increase from baseline was seen in 5% of adult patients treated with adjunctive Abilify and 1% of adjunctive placebo-treated patients. The mean change from baseline in weight was 1.7 kg for adjunctive Abilify and 0.4 kg for adjunctive placebo.

In a pool of two placebo-controlled trials of patients, the rate of discontinuation due to adverse reactions with the use of adjunctive Abilify compared to placebo plus ADT was 6% vs 2%, respectively. The most commonly observed adverse reactions (incidence greater than or equal to 5% and at least twice the incidence of placebo plus ADT) associated with the use of adjunctive Abilify® (aripiprazole) were akathisia (25% vs 4%), restlessness (12% vs 2%), insomnia (8% vs 2%), constipation (5% vs 2%), fatigue (8% vs 4%) and blurred vision (6% vs 1%).

About Major Depressive Disorder
Major depressive disorder is a serious mental illness4 characterized by one or more major depressive episodes.5 Depression affects approximately 13 to 14 million adults,2 or about 6.7% of the adult population in a given year,6 and is one of the most common mental health disorders.7 Depression is one of the leading causes of disability in the U.S.8 In 2000, the total economic burden of treating depression in the U.S. was $83.1 billion, with workplace costs, including missed days and lack of productivity due to illness, accounting for the majority of the total economic burden (62%).9 Other economic burdens in 2000 included $26.1 billion (31%) for treatment costs and $5.4 billion (7%) for suicide-related costs.9

About Abilify® (aripiprazole)
The first and only available dopamine partial agonist, Abilify is indicated as adjunctive treatment to antidepressant therapy in adults with major depressive disorder.

Initially approved in November 2002, over 12.5 million prescriptions have been written for Abilify in the U.S.10 through June 2007.

Abilify is available by prescription only. Abilify Tablets should be taken once daily with or without food and are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg and 30 mg strengths. As adjunctive treatment to antidepressant therapy in adults with major depressive disorder, Abilify Oral starting dose is 2 mg/day to 5 mg/day with a maximum dose of 15 mg/day. Dose adjustments of up to 5 mg/day should occur gradually, at intervals of no less than 1 week.


REFERENCES:
1 Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report. Am J Psych. 2006;163:1905-1917.
2 Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the national comorbidity survey replication (NCS-R). JAMA. June 18 2003;289(23):3095-3105.
3 Berman RM, Marcus RN, Swanink R, et al. The Efficacy and Safety of Aripiprazole as Adjunctive Therapy in Major Depressive Disorder: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study. J Clin Psychiatry. 2007;68:843-853.
4 National Alliance on Mental Illness (NAMI) Web site. About Mental Illness: Major Depression. 2006. Available at:
http://www.nami.org/Template.cfm?Section=By_Illness&Template=/TaggedPage/TaggedPageDisplay.cfm&TPLID=54&ContentID=23039&lstid=326. Accessed August 2007.
5 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text revision. Washington DC, American Psychiatric Association, 2000.
6 Kessler RC, Chiu WT, Demler OD, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the national comorbidity survey replication. Arch Gen Psychiatry. 2005;62:617-627.
7 Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime Prevalence and Age-of-Onset Distributions of DSMIV
Disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593-602.
8 Michaud CM, McKenna MT, Begg S, et al. The burden of disease and injury in the United States 1996. Population Health Metrics. 2006;4:11.
9 Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in the United States: How did it change between 1990 and 2000? J Clin Psychiatry. 2003;64(12):1465-1475.
10 IMS Auditrac NGPS: Abilify total monthly retail prescriptions: Data accessed July 2007.


SOURCE: Bristol-Myers Squibb Company and Otsuka Pharmaceutical Co., Ltd.

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