Annual sales are approx. $4.7bn. The patent expires in the US in 2011; however, in Canada it has already expired. Several pharmaceutical companies are now making generic versions of Quetiapine.
Quetiapine is indicated for the treatment of schizophrenia, depressive episodes associated with bipolar disorder, acute manic episodes associated with bipolar I disorder (as either monotherapy or adjunct therapy to lithium or valproate), and maintenance treatment of bipolar I disorder (as adjunct therapy to lithium or divalproex). Quetiapine received its initial indication from the U.S. Food and Drug Administration for treatment of schizophrenia in 1997. In 2004, it received its second indication for the treatment of mania-associated bipolar disorder. It is sometimes used off-label, often as an augmentation agent, to treat such conditions as obsessive-compulsive disorder, post-traumatic stress disorder, restless legs syndrome, autism, alcoholism, depression, Tourette syndrome, and has been used by physicians as a sedative for those with sleep disorders or anxiety disorders.
In 2005, Quetiapine and other antipsychotics were examined by the National Institutes of Mental Health with the aim of uncovering the comparative efficacy of "second generation" anti-psychotics versus older anti-psychotics (known as "first generation" or "typical anti-psychotics"). Such information could be very important to the public, as the newer drugs are far more expensive than their older counterparts. Published in the New England Journal of Medicine, the CATIE Trial (which stands for "Clinical Antipsychotic Trials of Interventional Effectiveness") were somewhat mixed. First, 74% of trial participants (of the 1,493 people that were in the different treatment groups) discontinued from the trial before it ended. The majority of people discontinued treatment due to intolerable side effects or lack of efficacy. Olanzapine (Zyprexa) was considered the most effective in terms of the time it took patients to drop out of the study (although it was associated with greater weight gain and glucose intolerability which are factors that play a role in people developing diabetes). All of the other treatments (such as Seroquel) were considered to be similar to the generic (and dramatically less expensive) drug perphenazine. The CATIE trial was supported by a grant (N01 MH90001) from the NIMH and by the Foundation of Hope of Raleigh, N.C. The individual pharmaceutical companies, whose drugs were used, donated all of the study medication.
A 2005 British Medical Journal report showed that Quetiapine was ineffective in reducing agitation among Alzheimer's patients, whose consumption of the drug then constituted 29% of sales; in fact, Quetiapine was found to make cognitive functioning worse in elderly patients with dementia.
Use of Quetiapine to minimize the symptoms of opioid withdrawal has been studied.
In 2007-2008, studies were conducted on Quetiapine™s efficacy in treating generalized anxiety disorder and major depression. In April 2009, the FDAs Psychopharmacologic Drugs Advisory Committee held a public meeting to discuss whether those study results supported FDA approval for anxiety and depression, with emphasis on the risks of metabolic side effects and of tardive dykinesia and sudden cardiac death.
The antipsychotic effect of quetiapine is thought by some to be mediated through antagonist activity at dopamine, norepinephrine, alpha-adrenergic receptors, histamine and serotonin receptors. Specifically the D1 and D2 dopamine receptor, the alpha-1 and alpha-2 adrenergic receptor, and 5-HT1A and 5-HT2 serotonin receptor subtypes are antagonized. Serial PET scans evaluating the D2 receptor occupancy of quetiapine have demonstrated that quetiapine very rapidly disassociates from the D2 receptor. Theoretically, this allows for normal physiological surges of dopamine to elicit their normal effects in areas such as the nigrostriatal and tuberoinfundibular pathways, thus minimizing the risk of side effects such as pseudo-parkinsonism as well as elevations in prolactin.
Quetiapine also has an antagonistic effect on the histamine H1 receptor. This is thought to be responsible for the sedative effect of the drug.
Quetiapine is available under the brand name Seroquel. It was originally available in 25 mg, 50 mg, 100 mg, 200 mg, and 300 mg tablets. 400 mg tablets have since been introduced to increase dosing flexibility. AstraZeneca said on 29/Oct/09 that it had reached a $520 million agreement to settle two federal investigations and two whistle-blower lawsuits over the sale and marketing of its blockbuster psychiatric drug Seroquel.
One of the investigations related to â€śselected physicians who participated in clinical trials involving Seroquel,â€ť AstraZeneca disclosed in a government filing. The other case related to off-label promotion of the drug.
As a result of aggressive marketing, Seroquel has been increasingly used for children and elderly people for indications not approved by the Food and Drug Administration. Doctors are permitted to prescribe any approved drug for off-label uses.
Seroquel was the top-selling antipsychotic drug in America. It had $17 billion in sales in the United States since 2004, according to IMS Health, a research firm.
Tony Jewell, a company spokesman, declined to be more specific about the physicians or clinical trials under investigation. He said the company was in final negotiations to settle the whistle-blower suits and reach a corporate integrity agreement with the Justice Department.
The name of the whistle-blowers and other details of the suits remained sealed in federal court.
Sustained-release quetiapine (Seroquel XR)
AstraZeneca has submitted a New Drug Application for a sustained-release version of quetiapine in the United States, Canada, and the European Union in the second half of 2006 for treatment of schizophrenia. AstraZeneca will retain the exclusive right to market sustained release quetiapine until 2017.
On May 18, 2007, AstraZeneca announced that the U.S. Food and Drug Administration has approved Seroquel XR for acute treatment of schizophrenia. During its 2007 Q2 earnings conference, AstraZeneca announced plans to launch Seroquel XR in the U.S. during August 2007. However, Seroquel XR has only become available in U.S. pharmacies after the FDA approved Seroquel XR for use as maintenance treatment for schizophrenia, in addition to acute treatment of the illness, on November 16, 2007. The company has not provided a reason for the delay of Seroquel XR's launch.
Health Canada approved sale of Seroquel XR on September 27, 2007.
Seroquel XR was approved for the treatment of bipolar depression and bipolar mania by the U.S. Food and Drug Administration (FDA) in early October, 2008. According to AstraZeneca, Seroquel XR is "the first medication approved by the FDA for the once-daily acute treatment of both depressive and manic episodes associated with bipolar."
On July 31, 2008, Handa Pharmaceuticals (based in Fremont, California, USA) announced that its Abbreviated New Drug Application (â€śANDAâ€ť) for Quetiapine Fumarate Extended-Release Tablets, the generic version of AstraZeneca™s SEROQUELÂ® XR, has been accepted for filing by the U.S. Food and Drug Administration.
On December 1, 2008, Biovail announced that the U.S. FDA has accepted the company's Abbreviated New Drug Application (ANDA) to market its own version of sustained-release quetiapine. Biovail's sustained-release tablets will compete with AstraZeneca's Seroquel XR.
On December 24, 2008, AstraZeneca notified its shareholders that the U.S. FDA has asked for additional information on the company's application to expand the use of sustained-release quetiapine for treatment of depression.
Quetiapine has multiple side effects, some of them common, a few of them rare but both serious and possibly even life-threatening.
The most common side effect of quetiapine is sedation, and it is marketed as one of the most sedating of all antipsychotics, albeit those efficacy claims are contested. Beginning users may feel extremely tired and 'out of it' for the first few days, sometimes longer. Quetiapine's newest indication, for bipolar depression, usually specifically calls for the entire dose to be taken before bedtime due to its sedative effects. Although quetiapine is approved by the FDA only for the treatment of schizophrenia and bipolar disorder, it is frequently prescribed off-label for other purposes, including insomnia and the treatment of anxiety disorders. The sedative effects may disappear after some time on the drug, or with a change of dosage, and with possibly different, non-sedative side effects emerging.
Common side effects include weight gain, constipation, headache and dry mouth. Six to seven percent of patients may experience tachycardia. Less common side effects (less than 1% of patients) include abnormal liver tests, dizziness, upset stomach, substantial weight gain, a stuffy nose, akathisia and increased paranoia.
There is a risk of development of tardive dyskinesia, an incurable neurological disorder, with any prolonged use of quetiapine and some other neuroleptic drugs. However, quetiapine is believed to cause tardive dyskinesia somewhat less often than typical antipsychotics based on the data sources which point to placebo-level incidence of extrapyramidal side effects.
The rare, but life-threatening, neuroleptic malignant syndrome may also result from quetiapine use.
Weight gain can be a problem for some patients using quetiapine, by causing the patient's appetite to persist even after meals. However, this effect may occur to a lesser degree compared to some other atypical antipsychotics such as olanzapine or clozapine.
As with other atypical antipsychotics, there is evidence suggesting a link to the development of diabetes and blood sugar disorders. However this remains controversial due to disparities between the results of studies. In the United States, two separate lawsuits ”over claims that quetiapine use has led to diabetesâ€”have been filed in federal court. A Delaware state court is scheduled to hear a trial alleging a link between Seroquel and diabetes in June 2009. The Delaware case will be the first case to go to trial on allegations that AstraZeneca withheld information about a link between Seroquel and diabetes.
Studies conducted on beagles have resulted in the formation of cataracts. While there are reports of cataracts occurring in humans, controlled studies including thousands of patients have not demonstrated a clear causal association between quetiapine therapy and this side effect. (Reference needed to April 2006 results of CATIE study.) However, the Seroquel website still recommends users have eye examinations every six months.
As with some other antipsychotics, quetiapine may lower the seizure threshold, and should be taken with caution in combination with drugs such as bupropion.
A recent comparative study of antipsychotics drugs has found that quetiapine mono treatment was associated with increased risk of death relative to the other analyzed treatments.
Recreational useQuetiapine is not currently classified as a controlled substance. Reports of quetiapine abuse have emerged in the medical literature, however, while the drug is usually abused through the crushing and snorting of tablets (insufflation), there have also been reports of intravenous abuse and intravenous co-administration with cocaine. This is commonly referred to as a "Q-Ball" . A 2004 letter to the editor of the American Journal of Psychiatry provided an anecdotal estimate that up to 30% of inmates who were seen for psychiatric services in the Los Angeles County Jail were faking psychotic symptoms in an attempt to obtain quetiapine. Because not all inmates are seen for services, the estimated percent of the total inmate population who appeared to be faking symptoms to obtain quetiapine would be less than 30%. Also known as "quell" or "Susie-Q", the drug may be more commonly abused in prisons due to its capacity to be regularly prescribed as a sedative and the unavailability in prison of more commonly abused substances. A letter to the editor which appeared in the January 2007 American Journal of Psychiatry has proposed a need for additional studies to explore the addiction-potential of quetiapineť. The letter reports that its authors are physicians who work in the Ohio correctional system. They report that â€śprisoners ... have threatened legal action and even suicide when presented with discontinuation of quetiapineâ€ť and that they have â€śnot seen similar drug-seeking behavior with other second-generation antipsychotics of comparable efficacyť.Along with benzodiazepines, atypical antipsychotics have sometimes been used to "come down" off cocaine or amphetamines. When used in this manner the slang term "downer" is often applied. Quetiapine may be used as a substitute to addictive benzodiazepines or sleeping tablets such as zolpidem because it often induces similar sedative effects on the patient.
- ^ "QUETIAPINE FUMARATE". Electronic Orange Book. Food and Drug Administration. April 2007. http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=020639&TABLE1=OB_Rx.
- ^ AstraZeneca (2004-01-13). "AstraZeneca Receives FDA Approval for SEROQUEL in Bipolar Mania". Press release. http://www.prnewswire.co.uk/cgi/news/release?id=115109.
- ^ Croissant B, Klein O, Gehrlein L, Kniest A, Hermann D, Diehl A, Mann K. (December 2006). "Quetiapine in relapse prevention in alcoholics suffering from craving and affective symptoms: a case series". Eur Psychiatry 21 (8): 570-573.
- ^ Quetiapine treatment of children and adolescents with Tourette's disorder. Fall 2003, retrieved January 27, 2007.
- ^ Becker PM (September 2006). "Treatment of sleep dysfunction and psychiatric disorders". Curr Treat Options Neurol 8 (5): 367-375.
- ^ Jeffrey A. Lieberman, T. Scott Stroup, Joseph P. McEvoy, Marvin S. Swartz, Robert A. Rosenheck, Diana O. Perkins, Richard S.E. Keefe, Sonia M. Davis, Clarence E. Davis, Barry D. Lebowitz, Joanne Severe, and John K. Hsiao (2005-09-22). "Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia". New England Journal of Medicine 353: 1209â€“1223. http://content.nejm.org/cgi/content/full/353/12/1209.
- ^ Clive Ballard, Marisa Margallo-Lana, Edmund Juszczak, Simon Douglas, Alan Swann, Alan Thomas, John O'Brien, Anna Everratt, Stuart Sadler, Clare Maddison, Lesley Lee, Carol Bannister, Ruth Elvish, Robin Jacoby (2005). "Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial". BMJ 330: 874. doi:10.1136/bmj.38369.459988.8F. PMID 15722369. http://www.bmj.com/cgi/content/full/330/7496/874.
- ^ Pinkofsky HB, Hahn AM, Campbell FA, Rueda J, Daley DC, Douaihy AB (2005). "Reduction of opioid-withdrawal symptoms with quetiapine". J Clin Psychiatry 66 (10): 1285-1288.
- ^ "April 7-8, 2009: Psychopharmacologic Drugs Advisory Committee Meeting Announcement". http://www.fda.gov/AdvisoryCommittees/Calendar/ucm136250.htm. Retrieved 2009-08-27.
- ^ AstraZeneca (PDF). Seroquel (quietapine fumarate) tablets. 276521. http://www1.astrazeneca-us.com/pi/Seroquel.pdf.
- ^ Kapur, S. (2001). "Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?:a new hypothesis.". American Journal of Psychiatry 158: 360â€“369. doi:10.1176/appi.ajp.158.3.360. PMID 11229973. http://ajp.psychiatryonline.org/cgi/content/abstract/158/3/360.
- ^ "Schizophrenia: From Circuits to Symptoms". Medscape Today. http://www.medscape.com/viewarticle/484929_8. Retrieved 2007-06-05.
- ^ AstraZeneca (2006-07-18). "AstraZeneca Submits an NDA For Sustained Release Formulation Seroquel XR. For the treatment of schizophrenia.". Press release. http://www.astrazeneca.com/pressrelease/5256.aspx. Retrieved 2007-01-01.
- ^ AstraZeneca (2006-10-19). "AstraZeneca Submits EU and Canadian Regulatory Filings for Sustained Release Formulation SEROQUEL XR for the Treatment of Schizophrenia". Press release. http://www.astrazeneca.com/pressrelease/5275.aspx. Retrieved 2007-01-01.
- ^ AstraZeneca (2007-05-18). "FDA Approves AstraZeneca™s Once-Daily SEROQUEL XR Extended-Release Tablets For The Treatment Of Schizophrenia". Press release. http://www.astrazeneca.com/pressrelease/5330.aspx. Retrieved 2007-08-02.
- ^ AstraZeneca (2007-07-26). "Second Quarter and Half Year Results 2007". Press release. http://www.astrazeneca.com/pressrelease/5341.aspx. Retrieved 2007-08-02.
- ^ AstraZeneca (2007-11-16). "Seroquel XR Receives Approval from FDA for Maintenance Treatment of Schizophrenia". Press release. http://www.astrazeneca.com/pressrelease/5360.aspx. Retrieved 2007-12-03.
- ^ Notice of Compliance Information - Seroquel XR September 27, 2007, retrieved December 3, 2007
- ^ Biovail (2008-12-28). "Biovail Announces Filing of ANDA for Quetiapine XR Tablets". Press release. http://www.biovail.com/english/Investor%20Relations/Latest%20News/default.asp?s=1&state=showrelease&releaseid=1230930.
- ^ AstraZeneca (2008-12-24). "AstraZeneca Receives FDA Complete Response Letter on Seroquel XR for Major Depressive Disorder". Press release. http://www.astrazeneca.com/media/latest-press-releases/seroquel-MDD-FDA-response?itemId=4477598. Retrieved 2008-12-28.
- ^ Jon A. Shaw, John E. Lewis, Shlomo Pascal, Rakesh K. Sharma, Rosemarie A. Rodriguez, Ramiro Guillen, Marilyn Pupo-Guillen (2001-12-01). "A Study of Quetiapine: Efficacy and Tolerability in Psychotic Adolescents". Journal of Child and Adolescent Psychopharmacology 11 (4): 415-424. doi:10.1089/104454601317261591. http://www.liebertonline.com/doi/abs/10.1089/104454601317261591.
- ^ a b Shankar Vedantam (2009-03-18). "A Silenced Drug Study Creates An Uproar". The Washington Post. http://www.washingtonpost.com/wp-dyn/content/article/2009/03/17/AR2009031703786.html.
- ^ S. Nassir Ghaemi and James Y. Ko (October 2001). "Quetiapine-related tardive dyskinesia". Am J Psychiatry 158 (10): 1737. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11579018&dopt=Abstract.
- ^ D. Ghelber and R.H. Belmaker (May 1999). "Tardive dyskinesia with quetiapine". Am J Psychiatry 156 (5): 796-797. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10327920&dopt=Abstract.
- ^ Ann Knef (2007-08-02). "Seroquel suit claims 'so much' is poured into marketing and away from research". The Madison St. Clair Record. http://www.madisonrecord.com/news/198781-seroquel-suit-claims-so-much-is-poured-into-marketing-and-away-from-research.
- ^ a b Phil Milford (2009-03-11). "AstraZeneca May Link Seroquel, Diabetes, Doctor Says". Bloomberg.com (Bloomberg L.P.). http://www.bloomberg.com/apps/news?pid=newsarchive&sid=ayzJsK2HlF6s.
- ^ Seroquel website
- ^ Tiihonen, J. (2009). "11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study)" (PDF). The Lancet 374: 620â€“627. doi:10.1016/S0140-6736(09)60742-X. http://press.thelancet.com/fin11.pdf.
- ^ a b Brian M. Waters and Kaustubh G. Joshi (January 2007). "Intravenous Quetiapine-Cocaine Use ("Q-Ball")". Am J Psychiatry (American Psychiatric Association) 164: 173-a-174. doi:10.1176/appi.ajp.164.1.173-a. http://ajp.psychiatryonline.org/cgi/content/full/164/1/173-a.
- ^ Joseph M. Pierre, Igor Shnayder, Donna A. Wirshing, and William Wirshing (September 2004). "Intranasal Quetiapine Abuse". Am J Psychiatry (American Psychiatric Association) 161: 1718. http://ajp.psychiatryonline.org/cgi/content/full/161/9/1718.
- ^ Emil R. Pinta, and Robert E. Taylor (January 2007). "Quetiapine addiction?". Am J Psychiatry 164: 174.