Seroquel for depressive phase of bipolar disorder

Astra Zeneca today filed an sNDA (an NDA to expand the number of indications for which the drug may be prescribed "on label") for Seroquel for the treatment of the depressive phase (most of the time for BP II) of bipolar disorder.

The data looks good, and approval should go quickly because the drug already has toxicology etc data.

Study showed a statistically significant decrease in depression scores that continued to improve over the course of the study.

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Learn to recognize early warning signs of recurrence

It is wise to get medical attention early if you think you are heading for an episode of mania. By contacting your doctor early, you can help ensure that you get adequate treatment as early as possible in the course of an episode.

There are many signs and symptoms that a person with bipolar disorder may experience if he or she is heading for an episode of mania. Studies have found that the signs and symptoms listed below are common before an episode of mania.

Sleeping less or lack of interest in sleep
Engaging in impulsive activities
Having racing thoughts
Acting more irritable than usual
Becoming excited easily or feeling restless
Spending recklessly
Extreme change in weight or appetite

Keep a Mood Tracking Diary
A Mood Tracking Diary is a place where you can keep a daily record of information about your mood and how you are feeling. You can share this information with your treatment team and may even choose to show it to a loved one.

It may help you and your health care team determine how well medications and therapies are working for you
It may help you and your health care team recognize early symptoms or triggers of an episode so that you can get medical attention early. It may help you and your health care team recognize factors that cause your mood to change, such as stress and sleep disturbances. It may help you remember to take your medication. Remember, this information is no substitute for your doctor's judgment and advice.

Important Safety Information

SEROQUEL is indicated for the treatment of acute manic episodes associated with bipolar I disorder.

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared with placebo. SEROQUEL is not approved for the treatment of patients with dementia-related psychosis.

Side effects can occur with all medications. A rare, but serious, side effect that has been reported with this kind of medicine, including SEROQUEL, is known as NMS or neuroleptic malignant syndrome. NMS is characterized by muscle rigidity and fever. Other serious side effects, which have been reported, include tardive dyskinesia (uncontrollable movements).

There have been reports of elevated blood sugar and diabetes associated with the use of SEROQUEL and other drugs in its class. If you have diabetes, or possible risk factors like obesity, or if diabetes runs in your family, you should talk to your doctor about checking your blood sugar before starting SEROQUEL and throughout treatment. If you develop symptoms of elevated blood sugar or diabetes, including excessive thirst, increased urination, overeating, or weakness, contact your doctor. Complications from elevated blood sugar or diabetes can be serious and even life-threatening.

The most commonly observed side effects associated with the use of SEROQUEL in clinical studies were drowsiness, dry mouth, dizziness, constipation, weakness, abdominal pain, sudden drop in blood pressure when standing, sore throat, abnormal liver tests, upset stomach, and weight gain.

This is not a complete summary of safety information. Please discuss the full Prescribing Information with your health care provider.

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I have been on Seroquel for a year now, and since it was such a new medicine at the time, I signed up for their newsletter. In AstraZeneca's latest newsletter, dated 12/22/05, they state that Seroquel is approved for treatment of mania in bi-polar I patients. In the entire year I've been on it, I have yet to read where they recommend it for bi-polar II patients, or the treatment of the depressive side of bi-polar. See for yourelf above, or check out the website - www.seroquel.com

I am very interested in where you found this information, becasue I can't imagine only having to take ONE med for my BP I.

Dolfin

Reports about supplemental applications will show up in the business section of the newspaper (higher stockholder value), or trade mags, or as brief communications in psych journals....They're just trying to hype the drug.

You haven't seen this new use referred to at the official website because it's not approved yet. Before AstraZeneca can change the wording of the drug monograph and patient information sheet to show the new indication, the FDA must approve the supplemental application, and any proposed wording changes in those documents. In short, your newsletter site will be the last place this news will show up.

Until then, of course, any doctor is still free to prescribe the drug "off-label" for bipolar depression. If and when the supplemental is approved, it will be a labelled use.

Lar

Exactly correct. They have filed the sNDA with the FDA but it has not yet been approved for the depressive phase of bipolar disorder.

I would not expect the approval process to take long if the clinical data is as good as they imply. This is no longer a new chemical entity - it has been through all the tox studies and there is a fair amount of clinical experience with it. I'm thinking three to six months.

In the meantime, docs can (and have been) prescribing it for the depressive phase. If the dx is bipolar disorder and the drug is approved for that, the insurance companies will pay for it without digging into whether the patient is up or down. The importance of it is that it will now be official, and that will allow Astra Zeneca to promote the drug for the depressive part of bipolar disorder and as a monotherapy for bipolar disorder and grow the market. I fully expect they have clinical studies under way for major depressive disorder, because it is being used off label for that as well.

So yes, it is conceivable that responders to the drug may only have to take one drug. Conceivable. The Astra Zeneca press release below states as much.

Meant to mention that Seroquel has a label warning for hyperglycemia and diabetes. It's a rare complication, but fasting blood sugar levels need to be occasionally monitored. Weight gain is possible. There are other atypical antipsychotic risk factors to be properly informed about about before taking this drug (e.g. tardive dyskinesia, neuroleptic malignant syndrome).

Here is the original press release from AstraZeneca, which was put out yesterday, December 30th. It's long, but I include it for Dolfin's benefit.

AstraZeneca Submits sNDA for SEROQUEL(R) for Bipolar Depression Treatment [FRZGXSK]

-- Filing Seeks Approval of SEROQUEL as a Monotherapy Treatment for Bipolar Depression --

WILMINGTON, Del., Dec. 30 /PRNewswire-FirstCall/ -- AstraZeneca (NYSE: AZN) today announced that it has submitted a supplemental New Drug Application (sNDA) with the US Food and Drug Administration (FDA) to seek approval for a new indication for SEROQUEL(R) (quetiapine fumarate) for the treatment of patients with depressive episodes associated with bipolar disorder. SEROQUEL is currently approved for the treatment of acute manic episodes associated with bipolar I disorder and the treatment of schizophrenia.

"AstraZeneca is dedicated to improving patients' lives and developing new treatments for mental illness," said Wayne Macfadden, MD, US Medical Director for SEROQUEL. "This sNDA submission is an important milestone in the history of SEROQUEL. If SEROQUEL receives approval from the FDA to treat bipolar depression, it would be the only single agent indicated to treat both the depressive and manic episodes associated with bipolar disorder."

The sNDA submission is based on results from the clinical trial program known as BOLDER (BipOLar DEpRession), which comprises two studies: BOLDER I and BOLDER II. Both studies were double-blind, placebo-controlled trials of outpatients (N=1,045) with bipolar I or II disorder. Patients were randomized to receive eight weeks of treatment with fixed doses of SEROQUEL (300 mg or 600 mg) or placebo administered once daily. In both studies, patients receiving SEROQUEL, as compared to those receiving placebo, showed a statistically significant decrease in depression scores* at week one, and scores continued to decrease throughout the eight-week study. More than half of the SEROQUEL treated patients in each trial met the criteria for remission.(1)
Additionally, SEROQUEL was shown to have similar safety profiles in both BOLDER I and II. The most common adverse effects reported in these trials included dry mouth, sedation, somnolence, dizziness, and constipation.(1)

Bipolar disorder, which affects more than 7 million American adults(2), consists of recurring episodes of mania and depression. Patients with bipolar disorder are symptomatic almost half of their lives, and approximately two- thirds of that time is spent in the depressed phase of the illness(3). Prolonged periods of sadness, unexplained loss of energy, persistent lethargy, and recurring thoughts of death or suicide characterize depressive episodes(4). Up to 50 percent of patients with bipolar depression attempt suicide, and approximately 10 to 15 percent commit suicide(5). Furthermore, bipolar disorder is often misdiagnosed, and patients may suffer up to ten years before a correct diagnosis is made(6).

SEROQUEL(R) (quetiapine fumarate) is the #1 prescribed atypical antipsychotic in the United States(10) and has a well-established safety and efficacy profile. In 2004, sales for SEROQUEL reached $2 billion. SEROQUEL has had more than 13 million patient exposures worldwide since its launch in 1997.

ABOUT BIPOLAR DISORDER

Bipolar I disorder consists of recurring episodes of mania with or without depression. Bipolar II disorder consists of recurring episodes of depression and hypomania, a milder form of mania(8). In the long term, patients with bipolar I disorder spend three times longer in the depressed state than in mania. Patients with bipolar II disorder have traditionally been difficult to treat as they spend almost forty times longer in the depressed state than in mania(9). Without appropriate treatment, patients usually suffer for a lifetime with periods of wellness and functioning punctuated by severe episodes of illness. Both men and women are equally at risk for this illness, which most often emerges in adolescence or young adulthood and recurs throughout life(8).

IMPORTANT SAFETY INFORMATION

SEROQUEL is indicated for the treatment of acute manic episodes associated with bipolar I disorder, as either monotherapy or adjunct therapy with lithium or divalproex, and the treatment of schizophrenia. Patients should be periodically reassessed to determine the need for continued treatment. It is recommended that SEROQUEL be taken in divided doses twice daily. SEROQUEL is not currently approved for the treatment of the depressive phase of bipolar disorder.

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk (1.6 to 1.7 times) of death compared to placebo (4.5% vs. 2.6%, respectively). SEROQUEL is not approved for the treatment of patients with dementia-related psychosis.

Prescribing should be consistent with the need to minimize the risk of tardive dyskinesia. A rare condition referred to as neuroleptic malignant syndrome has been reported with this class of medications, including SEROQUEL.

Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics, including SEROQUEL(R) (quetiapine fumarate). Patients starting treatment with atypical antipsychotics who have or are at risk for diabetes should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing.
Precautions include the risk of seizures, orthostatic hypotension, and cataract development.

The most commonly observed adverse events associated with the use of SEROQUEL in clinical trials for schizophrenia and bipolar mania were somnolence, dry mouth, dizziness, constipation, asthenia, abdominal pain, postural hypotension, pharyngitis, SGPT increase, dyspepsia, and weight gain.

For full Prescribing Information for SEROQUEL, please visit the Web site http://www.seroquel.com.

ABOUT ASTRAZENECA

AstraZeneca is a major international healthcare business engaged in the research, development, manufacture and marketing of prescription pharmaceuticals and the supply of healthcare services. It is one of the world's leading pharmaceutical companies with healthcare sales of over $21.4 billion and leading positions in sales of gastrointestinal, cardiovascular, respiratory, oncology and neuroscience products. In the United States, AstraZeneca is a $9.6 billion healthcare business with more than 12,000 employees. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4Good Index.

For more information about AstraZeneca, please visit: http://www.astrazeneca-us.com.

This press release contains forward-looking statements with respect to AstraZeneca's business. By their nature, forward-looking statements and forecasts involve risks and uncertainties because they relate to events and depend on circumstances that will occur in the future. There are a number of factors that could cause actual results and developments to differ materially. For a discussion of those risks and uncertainties, please see the company's Annual Report/Form 20-F for 2004.

References

* Depression scores were measured by the Montgomery-Asberg Depression Rating Scale (MADRS).1a The MADRS scale measures the severity of a number of depressive symptoms including mood and sadness, tension, sleep, appetite, energy, concentration, and suicidal ideation.(7) The MADRS score decreases as depressive symptoms improve. Remission was defined as a MADRS score of </=12. In BOLDER I, mean change in MADRS scores were at week eight from baseline (-)16.7 for SEROQUEL 600 mg and (-)16.4 for SEROQUEL 300 mg vs. (-)10.3 for placebo; (p<0.001).1d The corresponding mean changes in BOLDER II were (-)16.0,(-)16.9, and (-)11.9, respectively (p<0.001).
(1) Data on file, DA-SER-35
(2) Hirschfeld et al. Screening for Bipolar in the Community. J Clin Psychiatry. 2003;64:53-59.
(3) Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59:530-537.
(4) Depression and Bipolar Support Alliance (DBSA), 730 N. Franklin Street, Suite 501, Chicago, Illinois 60610-7224. Introduction to Depression and Bipolar Disorder. Available at: http://www.dbsalliance.org/PDF/IntroBrochureC2.pdf. Accessed December 7, 2005.
(5) Hawton, et al. Suicide and Attempted Suicide in Bipolar Disorder: A Symptomatic Review of Risk Factors. J Clin Psychiatry. 2005;66:693-704.
(6) Depression and Bipolar Support Alliance (DBSA). Facts About Bipolar Disorder. Accessed at http://www.dbsalliance.org/media/bipolarfacts.html. Accessed December 7, 2005.
(7) Lundbeck Institute. Psychiatric Rating Scales. PDF available at: http://www.brainexplorer.org/factshe...%20Scales.pdf. Accessed December 7, 2005.
(8) Kramlinger K. Mayo Clinic on Depression. Rochester, Minn.: Mayo Clinic Health Information, 2001.
(9) Calabrese JR, Keck PE, Macfadden W, et al, for the BOLDER Study Group. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162;1351-1360.
(10) All atypical prescriptions: Total prescriptions Jan 05 to Oct 05. New prescriptions Sept 04 to Oct 05 IMS Health. National Prescription Audit. SOURCE AstraZeneca