|Systematic (IUPAC) name|
|2-(2-(4-dibenzo[b,f][1,4]thiazepine- 11-yl- 1-piperazinyl)ethoxy)ethanol|
|Licence data||US FDA:|
|Pregnancy cat.||B3 (AU) C (US)|
|Legal status||Prescription Only (S4) (AU) POM (UK) ℞-only (US)|
|Metabolism||Hepatic via CYP3A4-catalysed sulfoxidation to its active metabolite norquetiapine (N-desalkylquetiapine)|
|Half-life||7 hours (parent compound); 9-12 hours (active metabolite, norquetiapine)|
|Excretion||Renal (73%), faeces (20%)|
|Mol. mass||383.5099 g/mol|
|Solubility in water||3.29 mg/mL (20 °C)|
|(what is this?)|
Quetiapine (// kwi-TY-ə-peen) (branded as Seroquel, Xeroquel, Ketipinor) is a short-acting atypical antipsychotic approved for the treatment of schizophrenia, bipolar disorder, and along with an antidepressant to treat major depressive disorder.
Annual sales are approximately $5.7 billion worldwide, with $2.9 billion in the United States. The U.S. patent, which was set to expire in 2011, received a pediatric exclusivity extension which pushed its expiration to March 26, 2012. The patent has already expired in Canada. 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, such as Quepin, Syquel and Ketipinor.
- 1 Medical uses
- 2 Adverse effects
- 3 Pharmacology
- 4 Synthesis
- 5 Dosage
- 6 Society and culture
- 7 References
- 8 External links
Quetiapine fumarate is primarily used to treat either schizophrenia or bipolar disorder.
There is tentative evidence of benefit of quetiapine versus placebo in schizophrenia, however definitive conclusions are not possible due to the high rate of people not finishing trials (greater than 50%) and the lack of data on economic outcomes, social functioning or quality of life.
It is debatable whether, as a class, typical or atypical antipsychotics are better. Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages. While quetiapine has lower rates of extrapyramidal side effects, there is greater sleepiness and rates of dry mouth.
In those with bipolar disorder, it is used for depressive episodes, acute manic episodes associated with bipolar I disorder (as either monotherapy or adjunct therapy to lithium, valproate or lamotrigine), and maintenance treatment of bipolar I disorder (as adjunct therapy to lithium or divalproex).
Major depressive disorder
Quetiapine does not decrease agitation among people with Alzheimer's, whose usage of the drug once constituted 29% of sales. Quetiapine worsens intellectual functioning in the elderly with dementia and therefore is not recommended.
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.) quetiapine treatment is usually tried first even though the evidence to support quetiapine's use in this indication is significantly weaker than that for clozapine.
- Very common (>10% incidence) adverse effects
- Dry mouth
- 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)
- Common (1-10% incidence) adverse effects
- High blood pressure
- Orthostatic hypotension
- High pulse rate
- High blood cholesterol
- Elevated serum triglycerides
- Abdominal pain
- Increased appetite
- Increased liver enzymes
- Nasal congestion
- Dyspepsia (Indigestion)
- Peripheral oedema
- Extrapyramidal disease — quetiapine and clozapine are noted for their relative lack of extrapyramidal side effects
- Weight gain — SMD 0.43 kg when compared to placebo. Produces roughly as much weight gain as risperidone, less weight gain than clozapine, olanzapine and zotepine and more weight gain than ziprasidone,lurasidone, aripiprazole and asenapine. As with many other atypical antipsychotics this action is likely due to its actions at the H1 histamine receptor and 5-HT2C receptor.
- Rare (<1% incidence) adverse effects
- Prolonged QT interval (had an odds ratio for prolonging the QT interval over placebo of 0.17)
- Sudden cardiac death
- Diabetic ketoacidosis
- Restless legs syndrome
- Hyponatraemia, low blood sodium.
- Jaundice, yellowing of the eyes, skin and mucous membranes due to an impaired ability of the body to clear bilirubin, a by product of haem breakdown.
- Pancreatitis, pancreas swelling.
- Agranulocytosis, a potentially fatal drop in white blood cell count.
- Leukopenia, a drop in white blood cell count, not as severe as agranulocytosis.
- Neutropenia, a drop in neutrophils, the cell of the immune cells that defends the body against bacterial infections.
- Anaphylaxis, a potentially fatal allergic reaction.
- Hypothyroidism, underactive thyroid gland.
- Myocarditis, swelling of the myocardium.
- Hepatitis, swelling of the liver.
- Suicidal ideation
- Priapism. A prolonged and painful erection.
- Stevens-Johnson syndrome. A potentially fatal skin reaction.
- 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
There is an emerging controversy regarding quetiapine fatalities. The deaths of at least six U.S. military veterans who were given drug cocktails including quetiapine have been attributed to its inclusion by military doctors to treat PTSD. Approximately 10,000 lawsuits against AstraZeneca for problems ranging from slurred speech and chronic insomnia to death have been filed by individuals from civilian populations.
It is marketed as one of the most sedating of all anti-psychotics, although those claims are contested. Beginning users may feel extremely tired and 'out of it' for the first few days, and 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. 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.
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.
Weight gain can be a problem for some, with quetiapine causing more weight gain than fluphenazine, haloperidol, loxapine, molindone, olanzapine, pimozide, risperidone, thioridazine, thiothixene, trifluoperazine, and ziprasidone, but less than chlorpromazine, clozapine, perphenazine, and sertindole.
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.
A recent comparative study of anti-psychotics drugs has found that quetiapine mono treatment was associated with increased risk of death relative to the other analyzed treatments (but still better than no anti-psychotics drug treatment at all).
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. According to Eli Lilly internal documents, discontinuation of atypical neuroleptics similar to seroquel can also cause psoriasis, gingivitis and other inflammatory conditions, dyspepsia, headache, high blood sugar and other health conditions unrelated to psychiatric condition. 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. This has led some to suggest that the withdrawal process might itself be psychosis-mimetic, producing psychotic-like symptoms even in previously healthy patients, indicating a possible pharmacological origin of mental illness in a yet unknown percentage of patients currently and previously treated with antipsychotics. This question is unresolved, and remains a highly controversial issue among professionals in the medical and mental health communities, as well the public.
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.
|Receptor||Quetiapine (Cloned human receptors)||Norquetiapine (Cloned human receptors)|
|D1||994.5||99.8 (Rat receptor)|
|α1B||14.6||46.4 (Rat receptor)|
|M1||489||38.3 (Rat receptor)|
- D1 (IC50 = 1268nM), D2 (IC50 = 329nM), D3, and D4 receptor antagonist
- 5-HT1A (IC50 = 717nM) partial agonist, 5-HT2A (IC50 = 148nM), 5-HT2C, and 5-HT7 receptor antagonist
- α1-adrenergic (IC50 = 94nM) and α2-adrenergic receptor (IC50 = 271nM) antagonist
- H1 receptor (IC50 = 30nM) antagonist
- mACh receptor (IC50 = >5000nM) antagonist
This means Quetiapine is a dopamine, serotonin, and adrenergic antagonist, and a potent antihistamine with clinically negligible anticholinergic properties. 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.
The synthesis of quetiapine begins with a dibenzothiazepinone. The lactam is first treated with phosphoryl chloride to produce a dibenzothiazepine. A nucleophilic substitution is used to introduce the sidechain.
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).
Due to compensatory changes at dopamine, serotonin, adrenergic and histamine receptor sites in the central nervous system, a gradual reduction in dosage is recommended to minimise or avoid withdrawal symptoms. Withdrawal symptoms reported to occur after discontinuation of quetiapine include insomnia, nausea, emesis, lightheadedness, diaphoresis, orthostatic hypotension, tachycardia, as well as nervousness, dizziness, headache, and anxiety. The present evidence suggests that these symptoms affect a small number of susceptible individuals treated with quetiapine.
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 and Seroquel Depot.
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.
Society and culture
In the United States, the Food and Drug Administration (FDA) has approved quetiapine for the treatment of schizophrenia and of acute manic episodes associated with bipolar disorder (bipolar mania) and for treatment of bipolar depression. In 2009, quetiapine XR was approved as adjunctive treatment of major depressive disorder.
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. (resulting from a qui tam lawsuit filed by Stefan P. Kruszewski) government 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? ]
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.
Nurofen Plus tampering case
In August 2011, the UK's Medicines and Healthcare products Regulatory Agency (MHRA) issued a class-4 drug alert following reports that some batches of Nurofen plus contained Seroquel XL instead.
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.
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