Seroquel Evaluation On Improvement In Short And Long-Term Symptoms

Main Category: Depression
Also Included In: Anxiety / Stress;  Psychology / Psychiatry
Article Date: 06 May 2008 - 3:00 PDT

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AstraZeneca (NYSE:AZN) announced new study data on SEROQUEL XR™ (quetiapine fumarate) Extended-Release Tablets (quetiapine XR) for the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD) in adult patients. The results from the studies were presented today at the 161st Annual Meeting of the American Psychiatric Association (APA) in Washington, DC. In February 2008, the company submitted a supplemental new drug application (sNDA) for quetiapine XR for the treatment of MDD as monotherapy, adjunct therapy, and maintenance therapy. AstraZeneca plans to submit an sNDA for quetiapine XR for the treatment of GAD as short-term and maintenance therapy during the second quarter of 2008.

The quetiapine XR clinical development programmes for MDD and GAD included seven Phase III, placebo-controlled studies in MDD as well as four Phase III, placebo-controlled studies in GAD. The three MDD studies presented today investigated once daily quetiapine XR in the treatment of adult patients diagnosed with MDD - as monotherapy in both short-term and maintenance treatment and as short-term adjunct treatment, when compared with placebo.1,2,3 The two GAD studies presented today investigated treatment with quetiapine XR in adult patients diagnosed with GAD - as monotherapy in both short-term and maintenance treatment versus placebo4,5. Across all MDD and GAD studies presented today, efficacy with quetiapine XR was superior to placebo, as assessed by the primary endpoints. In addition, the safety and tolerability of quetiapine XR in these studies were consistent with the known safety profile of quetiapine (further information below).

MDD is the leading cause of disability in the US affecting 15 million American adults and studies have shown that at least one-third of patients with MDD treated with antidepressants fail to achieve a satisfactory response.6,7 GAD affects about 6.8 million adults in the U.S., with women twice as likely to develop it compared to men, and approximately 30% of patients do not achieve an adequate response to acute treatment.8,9,10

AstraZeneca has investigated the use of quetiapine XR, an atypical antipsychotic, in the treatment of MDD as well as GAD, aiming to develop another potential treatment option for patients including those patients who have failed or had an inadequate response to existing treatments.

Quetiapine XR MDD Clinical Studies

In the quetiapine XR clinical development program in MDD, short-term monotherapy studies (Studies 1, 2, 3, and 4) and short-term adjunct therapy studies (Studies 6 and 7) used the change in Montgomery-Åsberg Depression Rating Scale (MADRS)* scores as the primary assessment of depression symptoms. In the long-term study (Study 5), the primary assessment was time to a depressed event using criteria including the MADRS. Doses of 50 mg, 150 mg and 300 mg/day of quetiapine XR were studied in the MDD program.11

"New MDD therapy options are urgently clearly needed. Studies have shown that at least one-third of MDD patients who are treated with antidepressants fail to achieve a satisfactory response," said Dr. Richard Weisler, Adjunct Professor of Psychiatry at University of North Carolina School of Medicine, Adjunct Assistant Professor at Duke University Medical Center and lead investigator on the MDD acute monotherapy study presented today. "Additionally, for those patients who do achieve a response from treatment with antidepressants, it may often take a few weeks of treatment before a benefit is seen. In the acute monotherapy study presented today at APA, patients taking SEROQUEL XR had a significant improvement in depressive symptom scores as early as the fourth day of treatment compared with patients taking placebo."

The following MDD studies were presented at the APA meeting:

-- Study 1 (Poster # NR3-101) - In a six-week, multicenter, double-blind study, 723 patients were randomized to receive quetiapine XR 50mg/day, 150mg/day or 300mg/day, or placebo. At week 6 all quetiapine XR groups had significantly reduced mean MADRS score versus placebo (-11.07): -13.56 (p<0.05) for 50 mg/day; -14.50 (p<0.001) for 150 mg/day; and -14.18 (p<0.01) for 300 mg/day. By Day 4, all quetiapine XR groups had significantly reduced mean MADRS scores versus placebo (-3.27): -4.91 (p<0.01) for 50 mg/day; -5.43 (p<0.001) for 150 mg/day; and -5.35 (p<0.001) for 300mg/day. The most common AEs with quetiapine XR ( 5% and double rate of placebo in any group) were dry mouth, sedation, somnolence, dizziness, constipation, backpain, irritability and myalgia.1

-- Study 6 (Poster # NR3-088) - In a six-week, multicenter, double-blind study, 446 patients who had had an inadequate response to previous antidepressant treatment were randomized to receive antidepressant plus quetiapine XR 150 mg/day, quetiapine XR 300 mg/day, or placebo. Quetiapine XR 300mg/day plus antidepressant (AD) showed statistically significant advantage versus placebo plus AD for 1) change in MADRS total score at Week 6 (-14.70 versus -11.7; p<0.01); 2) improvement in MADRS from Week 1 onwards; 3) response (58.9% versus 46.2%; p<0.05); and 4) remission (42.5% versus 24.5%; p<0.01; remission defined as MADRS score ≤ 8). For quetiapine XR 150 mg/day plus AD, improvements in these variables were not significantly different versus placebo, except for MADRS improvement at Weeks 1 and 2. The most common AEs with quetiapine XR during the treatment phase ( 5% and double rate of placebo in any group) were dry mouth, somnolence, sedation, dizziness, constipation, fatigue, and weight increase. 3

-- Study 5 (Poster # NR3-017) - In this maintenance study, 787 patients were randomized to double-blind treatment and dose-adjusted as clinically indicated. The risk of a depressed event was significantly reduced for SEROQUEL XR compared with placebo suggesting increased time to event (HR = 0.34 [0.25, 0.46]; p<0.001). In total, fifty-five (14.2%) quetiapine XR-treated patients and 132 (34.4%) placebo-treated patients experienced a depressed event. Open label AEs were similar to previous experience with quetiapine. The most common Adverse Event (AE) with quetiapine XR during the randomized treatment period ( 5% and double the rate of placebo) was weight increase2.

Quetiapine XR and GAD clinical studies

In the quetiapine XR clinical development program in GAD, short-term studies (Studies 9, 10 and 11) used the Hamilton Rating Scale for Anxiety (HAM-A) as the primary assessment of anxiety symptoms12. In the long-term study (Study 12), the primary assessment was time from randomization to an anxiety event5. Doses of 50 mg, 150 mg and 300 mg/day of quetiapine XR were studied in the GAD program4,5,13,14. While treatment for GAD typically includes an antidepressant, approximately 30% of patients do not achieve an adequate response to short-term treatment.10

"Given that many people suffering from generalized anxiety disorder do not achieve an adequate response from current treatments, new treatment options are needed; specifically for those who are not suited for, or cannot tolerate, existing therapies or who are simply not benefiting enough from the previously available approaches," said Professor Martin Katzman, Assistant Professor at the University of Toronto, and the Northern Ontario School of Medicine.

The following GAD studies were presented at the APA meeting:

-- Study 9 (Poster # NR3-138) - In this ten-week (8 weeks active, 2 weeks tapering discontinuation) multicenter, double-blind, placebo-controlled study 951 patients were randomized to receive quetiapine XR 50 mg/day, 150 mg/day, 300 mg/day or placebo. The mean change from baseline to week 8 in HAM-A total score was significantly greater for quetiapine XR 50 mg/day (-13.31, p<0.001) and 150 mg/day (-13.54 p<0.001), but not 300 mg/day (-11.87, p=0.24), versus placebo (-11.10). Quetiapine XR 50 mg/day, 150 mg/day, and 300 mg/day significantly reduced HAM-A total score as early as Week 1 (-7.47, -8.19, and -7.23, respectively) compared with placebo (-5.94).HAM-A response (HAM-A reduction of ≥ 50% at week 8) was significantly higher for 50 mg/day (60.3%, p<0.05) and 150 mg/day (61.5%, p<0.05), but not for 300 mg/day (54.9%, p=0.37), versus placebo (50.7 %). HAM-A remission (HAM-A ≤ 7 at week 8) was significantly higher for 150 mg/day versus placebo (37.2% versus 27.6%; p<0.05) and was 36.1% (p=0.08) and 28.6% (p=0.96), for 50 mg/day and 300 mg/day doses, respectively. The most common AEs with quetiapine XR during the treatment phase ( 5% and double rate of placebo in any group) were dry mouth, somnolence, sedation, and constipation4.

-- Study 12 (Poster # NR3-140) - This long-term study involving 1248 patients was a multicenter, randomized-withdrawal, parallel-group, placebo-controlled, Phase III trial that comprised four periods: an enrollment/washout period of up to 28 days, an open-label run-in treatment period of four to eight weeks, an open-label stabilization treatment period of 12 to 18 weeks, and a randomized withdrawal treatment period of up to 52 weeks (n=433). The quetiapine XR dose was flexible-50 mg, 150 mg, or 300 mg once daily, based on the clinical judgment of the investigator. The primary assessment was time from randomization to an anxiety event. The risk of an anxiety event was significantly reduced for quetiapine XR compared with placebo, suggesting increased time to the event (HR=0.19 [0.12, 0.31]; p<0.001). Twenty-two (10.2%) quetiapine XR-treated patients and 84 (38.9%) placebo-treated patients experienced an anxiety event (p<0.001). Open label and randomized phase AEs were similar to previous experience with quetiapine. There were no AEs with quetiapine XR during the randomized treatment period reported at an incidence of 5% and double the rate of placebo.5

About Major Depressive Disorder

Major depressive disorder is a serious medical illness affecting 15 million American adults, or approximately 5 to 8 percent of the adult population in a given year. Depression occurs twice as frequently in women as in men. Unlike normal emotional experiences of sadness, loss, or passing mood states, major depressive disorder is persistent and can significantly interfere with an individual's thoughts, behavior, mood, activity, and physical health. Among all medical illnesses, major depressive disorder is the leading cause of disability in the U.S. and many other developed countries.6

Symptoms of major depressive disorder characteristically represent a significant change from how a person functioned before the illness. The symptoms of depression include: persistently sad or irritable mood; pronounced changes in sleep, appetite, and energy; difficulty thinking, concentrating, and remembering; physical slowing or agitation; lack of interest in or pleasure from activities that were once enjoyed; feelings of guilt, worthlessness, hopelessness, and emptiness; recurrent thoughts of death or suicide; and persistent physical symptoms for two or more weeks that do not respond to treatment, such as headaches, digestive disorders, and chronic pain. 6 Symptomatically, a major depressive episode in MDD is similar to a depressive episode of bipolar disorder with the major distinguishing feature between the disorders being the absence of manic or hypomanic symptoms in MDD. 9 It has been reported that 69 percent of patients with bipolar disorder were misdiagnosed, with the most frequent misdiagnosis being MDD.16

Without treatment, the frequency of depressive illness as well as the severity of symptoms tends to increase over time. Left untreated, depression can lead to suicide. 6

About Generalized Anxiety Disorder

GAD is characterized by chronic anxiety, exaggerated worry, and tension, even when there is little or nothing to provoke it. People with GAD anticipate disaster and are overly concerned about health issues, money, family problems, or difficulties at work8,9.

People with GAD can't seem to get rid of their concerns, even though they usually realize that their anxiety is more intense than the situation warrants. They can't relax, startle easily, and have difficulty concentrating. Often they have trouble falling asleep or staying asleep. Physical symptoms that often accompany the anxiety include fatigue, sleep disturbance, headaches, muscle tension, muscle aches, difficulty swallowing, trembling, twitching, irritability, sweating, nausea, lightheadedness, having to go to the bathroom frequently, feeling out of breath, and hot flushes. GAD is diagnosed when someone excessively worries about a number of everyday problems for at least 6 months. 8,9

In the U.S. GAD affects about 6.8 million adults, with women twice as likely to develop GAD as men. The disorder comes on gradually and can begin across the life cycle. GAD rarely occurs alone and is often accompanied by other anxiety disorders, depression, or substance abuse. Genetic factors are also thought to be involved.8,9

About SEROQUEL and SEROQUEL XR

Launched in 1997, it is estimated that SEROQUEL has been prescribed to more than 22 million* patients worldwide. It is approved in 88 countries for the treatment of schizophrenia, in 79 countries for the treatment of bipolar mania, and in 11 countries including the US for the treatment of bipolar depression.

SEROQUEL XR™ is approved in the US and 25 further countries for the treatment of schizophrenia in adult patients and for maintenance treatment of schizophrenia in adult patients. It was launched in the US in 2007 and earlier this year AstraZeneca announced the submission of regulatory applications in both the US and European Union for SEROQUEL XR in the treatment of manic episodes associated with bipolar disorder, and the treatment of depressive episodes associated with bipolar disorder. An sNDA for SEROQUEL XR seeking approval for the treatment of Major Depressive Disorder in the US was also announced in February. SEROQUEL XR is not approved for these indications at this time and the applications remain under review by the regulatory authorities.

About AstraZeneca

AstraZeneca is a major international healthcare business engaged in the research, development, manufacturing and marketing of meaningful prescription medicines and supplier for healthcare services. AstraZeneca is one of the world's leading pharmaceutical companies with healthcare sales of $29.55 billion and is a leader in gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infectious disease medicines. In the United States, AstraZeneca is a $13.35 billion dollar healthcare business with 12,200 employees committed to improving people's lives. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4Good Index.

*Based on assumptions: (1) estimated number of prescriptions per patient based upon IMS APLD data; and (2) IMS Prescription data for SEROQUEL covering 13 major markets in which this data is available since the time of launch.

SEROQUEL XR is a trademark of the AstraZeneca group of companies.

For more information visit http://www.astrazeneca.com or http://www.astrazeneca-us.com .

References

1. Weilser R, Joyce M, McGill L, et al. Extended release Quetiapine fumarate (quetiapine XR) monotherapy for major depressive disorder (MDD): a double-blind, placebo-controlled study. Presented at APA 2008.

2. Datto C, Lam RW, Lepola U, et al. Double-blind study of extended release quetiapine fumarate (quetiapine XR) monotherapy for maintenance treatment of major depressive disorder (MDD). Presented at APA 2008.

3. El-Khalili N, Joyce M, Atkinson S, et al. Adjunctive extended-release quetiapine fumarate (quetiapine XR) in patients with major depressive disorder and inadequate antidepressant response. Presented at APA 2008.

4. Joyce M, Khan A, Atkinson S, et al. Efficacy and safety of extended release Quetiapine fumarate (quetiapine XR) monotherapy in patients with generalized anxiety disorder (GAD). Presented at APA 2008.

5. Katzman M, Brawman-Mintzer O, Reyes E, et al. Double-blind study of extended release quetiapine fumarate (quetiapine XR) monotherapy for maintenance treatment of generalized anxiety disorder.

6. National Alliance on Mental Illness: Major Depression Fact Sheet. 2007. Available here. Accessed November 30, 2007.

7. Nemeroff, CB. Prevalence and Management of Treatment-Resistant Depression. J Clin Psychiatry. 2007;68:17-25.

8. National Institute of Mental Health: Anxiety Disorders. NIH Publication No. 06-3879. Available here. Accessed March 20, 2008.

9. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000: 472-475.

10. Rickels K. Pharmacotherapy of Generalized Anxiety Disorder. J Clin Psychiatry. 2002;63(suppl 14): 9-16.

11. Data on file. DA-SXR-12

12. Lundbeck Institute. Psychiatric Rating Scales. PDF available here. Accessed on May 5, 2006.

13. Data on file. DA-SXR-15

14. Chouinard G, Bandelow B, Ahokas A, et al. Once-daily extended release of quetiapine fumarate (quetiapine XR) monotherapy in generalized anxiety disorder: a Phases III, double-blind, placebo-controlled study [poster]. Presented at: The Annual Meeting of The American College of Neuropsychopharmacology; December 9-13, 2007, Boca Raton, FL, USA..

15. Schmitt R, Gazalle FK, Silva de Lima M, et al. The efficacy of antidepressants for generalized anxiety disorder: a systematic review and meta-analysis. The Brazilian Journal of Psychiatry. 2005; 27(1):18-24.

16. Hirschfeld RM, Lewis L, Vornik LA. Perceptions and Impact of Bipolar Disorder: How Far Have We Really Come? Results of the National Depressive and Manic-Depressive Association 2000 Survey of Individuals with Bipolar Disorder. J Clin Psychiatry. 2003;64:161-174.

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