Annual sales are approximately $1.3 billion worldwide. Quetiapine was developed by AstraZeneca from 1992–1996 as an improvement from first generation antipsychotics. It was first approved by the FDA in 1997. There are now several generic versions of quetiapine.
Quetiapine (Seroquel) 25 mg tablets, next to US one-cent coin for comparison.
Seroquel XR 150 mg tablet box
Quetiapine fumarate is primarily used to treat schizophrenia or bipolar disorder.
A Cochrane Review comparing quetiapine to other atypical antipscychotic agents tentatively concluded that it may be less efficacious than olanzapine and risperidone; produce fewer movement related side effects than paliperidone, aripiprazole, ziprasidone, risperidone and olanzapine; and produce weight gain similar to risperidone, clozapine and aripiprazole. A second Cochrane Review comparing quetiapine to typical antipsychotics concluded that quetiapine
Has efficacy against positive symptoms that appears no better than typical antipsychotics, but might be more efficacious for negative symptoms.
Has discontinuation rates similar to those of typical antipyschotics, but fewer of these discontinations were due to adverse events
Produces fewer side effects, particularly movement related side effects.
Produces suicide attempt, suicide, death, QTc prolongation, low blood pressure, tachycardia, sedation, gynaecomastia, galactorrhoea, menstrual irregularity and white blood cell count at a rate similar to first generation antipscyhotics.
Asmal L, Flegar SJ, Wang J, Rummel-Kluge C, Komossa K, Leucht S (2013). "Quetiapine versus other atypical antipsychotics for schizophrenia". Cochrane Database Syst Rev11: CD006625. doi:10.1002/14651858.CD006625.pub3. PMID24249315.
Quetiapine and clozapine are the most widely used medications for the treatment of Parkinson's disease psychosis due to their very low extrapyramidal side effect liability. Owing to the risks associated with clozapine (e.g. agranulocytosis, diabetes mellitus, etc.), clinicians often attempt treatment with quetiapine first, although the evidence to support quetiapine's use for this indication is significantly weaker than that of clozapine.
Somnolence (drowsiness; of 15 antipsychotics quetiapine causes the 5th most sedation. Extended release (XR) formulations tend to produce less sedation, dose-by-dose than the immediate release formulations)
Neuroleptic malignant syndrome a rare and potentially fatal complication of antipsychotic drug treatment. It is characterised by the following symptoms: tremor, rigidity, hyperthermia, tachycardia, mental status changes (e.g. confusion), etc.
Tardive Dyskinesia. A rare and often irreversible neurological condition characterised by involuntary movements of the face, tongue, lips and rest of the body. Most commonly occurs after prolonged treatment with antipsychotics. It is believed to be particularly uncommon with atypical antipsychotics, especially quetiapine and clozapine
Approximately 10,000 lawsuits against AstraZeneca alleging that quetiapine caused problems ranging from slurred speech and chronic insomnia to deaths.
Both typical and atypical antipsychotics can cause tardive dyskinesia. According to one study, rates are lower with the atypicals at 3.9% as opposed to the typicals at 5.5%. Although Quetiapine and Clozapine are atypical antipsychotics, switching to these atypicals is an option to minimize symptoms of tardive dyskinesia caused by other atypicals.
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. However, the Seroquel website still recommends users have eye examinations every six months.
As with some other anti-psychotics, quetiapine may lower the seizure threshold, and should be taken with caution in combination with drugs such as bupropion.
Quetiapine should be discontinued gradually, with careful consideration from the prescribing doctor, to avoid withdrawal symptoms or relapse.
The British National Formulary recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse. Due to compensatory changes at dopamine, serotonin, adrenergic and histamine receptor sites in the central nervous system, withdrawal symptoms can occur during abrupt or over-rapid reduction in dosage. However, despite increasing demand for safe and effective antipsychotic withdrawal protocols or dose-reduction schedules, no specific guidelines with proven safety and efficacy are currently available.
Withdrawal symptoms reported to occur after discontinuation of antipsychotics include nausea, emesis, lightheadedness, diaphoresis, dyskinesia, orthostatic hypotension, tachycardia, insomnia, nervousness, dizziness, headache, excessive non-stop crying, and anxiety. Some have argued that additional somatic and psychiatric symptoms associated with dopaminergic super-sensitivity, including dyskinesia and acute psychosis, are common features of withdrawal in individuals treated with neuroleptics.
Most instances of acute overdosage result only in sedation, hypotension and tachycardia, but cardiac arrythmia, coma and death have occurred in adults. Serum or plasma quetiapine concentrations are usually in the 1–10 mg/L range in overdose survivors, while postmortem blood levels of 10–25 mg/L are generally observed in fatal cases.
Pregnancy and lactation
Placental exposure is least for quetiapine compared to other atypical antipsychotics. The evidence is insufficient to rule out any risk to the foetus but available data suggests it is unlikely to result in any major foetal malformations. It is secreted in breast milk and hence quetiapine-treated mothers are advised not to breastfeed.
This means Quetiapine is a dopamine, serotonin, and adrenergic antagonist, and a potent antihistamine with clinically negligible anticholinergic properties.[dubious– discuss] Quetiapine binds strongly to serotonin receptors; the drug acts as partial agonist at 5-HT1A receptors. 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 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. Some of the antagonized receptors (serotonin, norepinephrine) are actually autoreceptors whose blockade tends to increase the release of neurotransmitters.
Norquetiapine's 2D molecular structure
Norquetiapine's 3D molecular structure in ball and stick format
At very low doses, quetiapine acts primarily as a histamine receptor blocker (antihistamine) and α1-adrenergic blocker. When the dose is increased, quetiapine activates the adrenergic system and binds strongly to serotonin receptors and autoreceptors. At high doses, quetiapine starts blocking significant amounts of dopamine receptors. Use of low-dose quetiapine is not recommended except temporarily during drug titration period (less than 30 days).
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.
AstraZeneca 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. The sustained-release quetiapine is marketed mainly as Seroquel XR. Other marketing names are Seroquel Prolong, Seroquel Depot and Seroquel XL
On May 18, 2007, AstraZeneca announced that the U.S. FDA 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 become available in U.S. pharmacies only 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.
The FDA approved Seroquel XR for the treatment of bipolar depression and bipolar mania 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, announced that its abbreviated new drug application (“ANDA”) for quetiapine fumarate extended-release tablets, the generic version of AstraZeneca’s SEROQUEL XR, has been accepted by the FDA.
On December 1, 2008, Biovail announced that the FDA had accepted the company's 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 shareholders that the FDA had asked for additional information on the company's application to expand the use of sustained-release quetiapine for treatment of depression.
Quetiapine received its initial indication from U.S. FDA for treatment of schizophrenia in 1997. In 2004, it received its second indication for the treatment of mania-associated bipolar disorder. In 2007 and 2008, studies were conducted on quetiapine’s efficacy in treating generalized anxiety disorder and major depression. In April 2009, the Psychopharmacologic Drugs Advisory Committee of the FDA held a public meeting to discuss whether study results supported the FDA's approval for anxiety and depression, with risks of metabolic side-effects and of tardive dyskinesia and sudden cardiac death.
In April 2010, AstraZeneca settled a longstanding U. S. Department of Justice investigation into its aggressive marketing of Seroquel for such off-label uses with a $520-million fine. According to the Department of Justice, "the company recruited doctors to serve as authors of articles that were ghostwritten by medical literature companies and about studies the doctors in question did not conduct. AstraZeneca then used those studies and articles as the basis for promotional messages about unapproved uses of Seroquel."
Multiple lawsuits have been filed in relation to quetiapine's side-effects, in particular, diabetes. In 2009, documents unsealed in litigation against AstraZeneca indicated that Dr. Charles Schulz, Chair of the Department of Psychiatry at the University of Minnesota and a consultant for AstraZeneca, had misrepresented the benefits of Seroquel in research presentations and press releases.
AstraZeneca has been sued by the U.S. government (resulting from a qui tam lawsuit filed by Stefan P. Kruszewski) over the marketing of quetiapine. A $520-million settlement was reached on October 29, 2009.
In 2004, a young man named Dan Markingson committed suicide in a controversial Seroquel clinical trial at the University of Minnesota while under an involuntary commitment order. A group of University of Minnesota bioethicists charged that the trial involved an alarming number of ethical violations, but the university declined to investigate. Quetiapine may have been a factor in the deaths of several US veterans who were taking large doses as part of a cocktail of drugs for PTSD.[relevant?– discuss]
In Australia, Professor Patrick McGorry, a key mental-health advisor, proposed a trial in Melbourne in 2011. Its purpose was to investigate whether Seroquel would decrease or delay the risk that people aged between 15 and 40 with early signs of mental illness, might develop a later psychotic disorder. However in July 2011, psychiatrists, psychologists and researchers from Australia, New Zealand, Canada, Britain and the US lodged a complaint with the ethics committee of Melbourne Health. They opposed the trial as "unethical" and "dangerous".
Quetiapine is not classified as a controlled substance; "abusive self-administration seems to be driven by quetiapine’s sedative and anxiolytic effects (to help with sleep or to 'calm down') rather than by its antipsychotic properties." Reports of quetiapine abuse have emerged in medical literature. In addition to oral administration, the drug is also taken intranasally by snorting pulverized tablets (insufflation). There have been reports of intravenous abuse and intravenous co-administration with cocaine as well. 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. Also known as "quell", "Snoozeberries", 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 that appeared in the January 2007 American Journal of Psychiatry has proposed a “need for additional studies to explore the addiction-potential of quetiapine”. The letter reports that its authors are physicians who work in the Ohio correctional system. They report that “prisoners ... have threatened legal action and even suicide when presented with discontinuation of quetiapine” and that they have “not seen similar drug-seeking behavior with other second-generation antipsychotics of comparable efficacy”. It has also been reported that when Seroquel is used with methadone, it causes the user to experience a buzz, or opioid euphoria.
Following the issue of the Class-4 Drug Alert, Reckitt Benckiser (UK) Ltd received further reports of rogue blister strips in cartons of two additional batches of Nurofen Plus tablets. One of the new batches contained Seroquel XL 50 mg tablets and one contained the Pfizer product Neurontin 100 mg capsules.
Following discussions with the MHRA's Defective Medicines Report Centre (DMRC), Reckitt Benckiser (UK) Ltd decided to recall all remaining unexpired stock of Nurofen Plus tablets in any pack size, leading to a Class-1 Drug Alert. The contamination was later traced to in-store tampering by a customer.
^Asmal L, Flegar SJ, Wang J, Rummel-Kluge C, Komossa K, Leucht S (2013). "Quetiapine versus other atypical antipsychotics for schizophrenia". Cochrane Database Syst Rev11: CD006625. doi:10.1002/14651858.CD006625.pub3. PMID24249315.
^Suttajit S, Srisurapanont M, Xia J, Suttajit S, Maneeton B, Maneeton N (2013). "Quetiapine versus typical antipsychotic medications for schizophrenia". Cochrane Database Syst Rev5: CD007815. doi:10.1002/14651858.CD007815.pub2. PMID23728667.
^Thase ME, Macfadden W, Weisler RH, Chang W, Paulsson B, Khan A, Calabrese JR (2006). "Efficacy of Quetiapine Monotherapy in Bipolar I and II Depression". Journal of Clinical Psychopharmacology26 (6): 600–9. doi:10.1097/01.jcp.0000248603.76231.b7. PMID17110817.
^ abcKomossa K, Depping AM, Gaudchau A, Kissling W, Leucht S (Dec 8, 2010). "Second-generation antipsychotics for major depressive disorder and dysthymia.". The Cochrane database of systematic reviews (12): CD008121. doi:10.1002/14651858.CD008121.pub2. PMID21154393.
^Spielmans GI, Berman MI, Linardatos E, Rosenlicht NZ, Perry A, Tsai AC. Adjunctive Atypical Antipsychotic Treatment for Major Depressive Disorder: A Meta-Analysis of Depression, Quality of Life, and Safety Outcomes. PLoS Med [Internet]. 2013 Mar 12 [cited 2013 Oct 9];10(3) e1001403. Available from: http://dx.doi.org/10.1371/journal.pmed.1001403
^ abcBritish National Formulary (BNF) 65. London, UK: Pharmaceutical Press. 2013. p. 235. ISBN9780857110848.
^ abcRossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN978-0-9805790-9-3.
^Coe HV, Hong IS (May 2012). "Safety of low doses of quetiapine when used for insomnia". The Annals of pharmacotherapy46 (5): 718–22. doi:10.1345/aph.1Q697. PMID22510671.
^Maglione M, Maher AR, Hu J, et al. (September 2011). "Off-Label Use of Atypical Antipsychotics: An Update". PMID22132426.
^Mukaddes NM, Abali O (2003). "Quetiapine Treatment of Children and Adolescents with Tourette's Disorder". Journal of Child and Adolescent Psychopharmacology13 (3): 295–9. doi:10.1089/104454603322572624. PMID14642017.
^ abGroup, BMJ, ed. (March 2009). "4.2.1". British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. "Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse."
^Gefvert O, Lundberg T, Wieselgren IM, Bergström M, Långström B, Wiesel F, Lindström L (April 2001). "D2 and 5HT2A receptor occupancy of different doses of quetiapine in schizophrenia: a PET study". European Neuropsychopharmacology11 (2): 105–110. doi:10.1016/S0924-977X(00)00133-4. PMID11313155.