SEROQUEL Exhibits Distinct Mechanism Of Action And Reduces The Risk Of A Mood Event In Bipolar I Disorder

Main Category: Bipolar
Also Included In: Depression
Article Date: 16 Oct 2007 - 7:00 PDT

email to a friend   printer friendly   view / write opinions   rate article

New long-term clinical trial data presented recently at the European Congress of Neuropsychopharmacology (ECNP) in Vienna showed that SEROQUEL® (quetiapine fumarate) in combination with lithium or divalproex significantly increases the time to recurrence of any mood event in patients with bipolar I disorder.1 Further pre-clinical data demonstrated that three neurotransmitter pathways are targeted by SEROQUEL in the brain - this may contribute to its unique clinical profile.2 This data also showed that dosing with SEROQUEL causes occupancy of NET - transporter for norepinephrine, a neurotransmitter which is known to have a role in depression.

A large-scale, international, double-blind study (Study 126) investigated the time to recurrence of a mood event (manic, mixed, or depressed) in 1461 patients with bipolar I disorder initially stabilised with SEROQUEL (400-800 mg/day) plus lithium or divalproex.1 After stabilisation for a minimum of 12 weeks, 703 patients were randomised to maintenance treatment with SEROQUEL in combination with lithium or divalproex, or placebo in combination with lithium or divalproex for up to 104 weeks. Compared with placebo, fewer patients in the SEROQUEL group had a mood event, defined as a manic, mixed or depressed episode (49.0% versus 18.5%). SEROQUEL combination treatment also significantly reduced the risk of recurrence of a mood event in comparison with placebo plus lithium or divalproex (hazard ratio 0.28; p<0.0001). When examined according to mood event type, this reduction in risk was similar for both manic and depressed events.

"The results clearly show that maintenance treatment with SEROQUEL plus lithium or divalproex increased the time to recurrence of any mood event in patients with bipolar I disorder", said Professor Eduard Vieta, Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, Spain. "These findings are extremely encouraging for patients and clinicians - they indicate that the future may hold new developments in the choice of well-tolerated treatments that are able to control both the symptoms of mania and depression for patients over the long term."

Long-term treatment with SEROQUEL was generally well tolerated - the most commonly reported (³5%) adverse events in patients treated with SEROQUEL plus a mood stabilizer during the randomized treatment phase were somnolence (5.7%), nasopharyngititis (5.4%) and headache (5.1%). Additional tolerability results were presented which included combined results from Study 126 and a second similarly designed, large-scale, double-blind study (Study 127). Pooled data showed a greater incidence of blood glucose increases to hyperglycemic levels in patients randomised to Seroquel and mood stabiliser (10.7%, 18.0 patients per 100 patient-years) than in patients randomised to placebo and mood stabiliser (4.6%, 9.5 patients per 100-patient years). Seroquel prescribing information is being updated to include additional details regarding these data. These data highlighted SEROQUEL's potential as adjunct treatment for prevention of mood episodes associated with bipolar disorder. At this time, SEROQUEL is not approved anywhere in the world for bipolar maintenance treatment: a submission was made to the FDA in July 2007 and European submissions are being prepared.

A pre-clinical study also presented at ECNP used brain imaging with positron emission tomography (PET) to investigate the mechanism of action of SEROQUEL in non-human primates. SEROQUEL (quetiapine), both directly and indirectly (via its major active metabolite norquetiapine), was found to target the dopamine D2 and the serotonin 5-HT2A receptors in the brain at blood concentrations similar to those during treatment with clinically recommended doses of SEROQUEL in humans. Additionally, SEROQUEL's major active metabolite norquetiapine was shown to target NET - the transporter for norepinephrine (noradrenaline). Inhibition of NET elevates norepinephrine (noradrenaline) levels in specific areas of the brain, an effect that is associated with antidepressant action.

Professor Lars Farde, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden and AstraZeneca Pharmaceuticals, Södertälje, Sweden said: "The unique receptor binding profile of SEROQUEL combined with the new PET scans show that quetiapine and norquetiapine occupy three key sites in the brain, one of which is particularly associated with depression. We believe that this mechanism may be responsible for the improvements seen in a broad range of symptoms when patients with schizophrenia and bipolar disorder are treated with SEROQUEL."

On October 13, Professor Lakshmi Yatham concluded the AstraZeneca satellite symposium entitled Diagnosis, treatment and receptors: the key to patient recovery in mood disorders. Professor Yatham from the University of British Colombia, Vancouver, Canada, discussed the mechanisms of action of atypical antipsychotics and in particular SEROQUEL, where he presented recent data on the combined action of SEROQUEL at the NET, 5-HT2A and dopamine D2 receptors, and suggested that this may contribute to the antidepressant and mood-stabilising properties observed in studies of patients with bipolar disorder - studies that together separate SEROQUEL from most other agents used in this disease setting.

Notes: Launched in 1997, it is estimated that SEROQUEL has been prescribed to more than 25 million* patients worldwide. It is approved in 88 countries for the treatment of schizophrenia, in 77 countries for the treatment of bipolar mania, and in 11 countries including the USA for the treatment of bipolar depression. SEROQUEL XR was launched for the treatment of schizophrenia in the US in 2007, and its clinical development program and planned regulatory filings extend through bipolar disorder to major depressive disorder (MDD) and generalized anxiety disorder (GAD).

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 $26.47 billion and leading positions in sales of gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infection products. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4Good Index.

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

References

1. Vieta E et al. Efficacy and safety of quetiapine in combination with lithium/divalproex as maintenance treatment for bipolar I disorder. Presented at the European Congress of Neuropsychopharmacology, Vienna, Austria, 13-17 October, 2007.

2. Nyberg S et al. PET-measured D2, 5-HT2, and NET occupancy by quetiapine and N-desalkyl-quetiapine in non-human primates. Presented at the European Congress of Neuropsychopharmacology, Vienna, Austria, 13-17 October, 2007.

* This estimate is based upon: (1) assumptions as to persistence (the number of prescriptions per patient) based upon 2002 market research; and (2) projections of prescriptions since launch based upon information available in the US and 13 of the 50 other countries in which SEROQUEL is marketed.

For further information, please visit:
AstraZeneca
or http://www.seroquel.com