Quetiapine

Quetiapine, sold under the brand name Seroquel among others, is an atypical antipsychotic medication used for the treatment of schizophrenia, bipolar disorder, and major depressive disorder.[6][7] Despite being widely used as a sleep aid due its sedating effect, the benefits of such use do not appear to generally outweigh the side effects.[8] It is taken by mouth.[6]

Quetiapine
Clinical data
Pronunciation/kwɪˈtaɪ.əpiːn/ kwi-TY-ə-peen
Trade namesSeroquel, Temprolide, others
AHFS/Drugs.comMonograph
MedlinePlusa698019
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Routes of
    administration    		By mouth
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability100%[1]
    Protein binding83%[2]
    MetabolismLiver via CYP3A4-catalysed sulfoxidation to its active metabolite norquetiapine (N-desalkylquetiapine)[3]
    Elimination half-life7 hours (parent compound); 9–12 hours (active metabolite, norquetiapine)[2][4]
    ExcretionKidney (73%), faeces (20%)[1][2][4][5]
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.131.193
    Chemical and physical data
    FormulaC21H25N3O2S
    Molar mass383.51 g·mol−1
    3D model (JSmol)
    Solubility in water3.29 mg/mL (20 °C)
      (verify)

    Common side effects include sleepiness, constipation, weight gain, and dry mouth.[6] Other side effects include low blood pressure with standing, seizures, a prolonged erection, high blood sugar, tardive dyskinesia, and neuroleptic malignant syndrome.[6] In older people with dementia, its use increases the risk of death.[6] Use in the third trimester of pregnancy may result in a movement disorder in the baby for some time after birth.[6] Quetiapine is believed to work by blocking a number of receptors including serotonin and dopamine.[6]

    Quetiapine was developed in 1985 and approved for medical use in the United States in 1997.[6][9] It is available as a generic medication.[10] In the United States, the wholesale cost is about US$12 per month as of 2017.[11] In the United Kingdom, a month's supply costs the NHS about £60 as of 2017.[10] In 2017, it was the 76th most commonly prescribed medication in the United States, with more than ten million prescriptions.[12][13]

    Medical uses
    Quetiapine (Seroquel) 25 mg tablets, next to US one-cent coin for comparison
    Seroquel XR 150 mg tablet box

    Quetiapine is primarily used to treat schizophrenia or bipolar disorder.[14] Quetiapine targets both positive and negative symptoms of schizophrenia.[15]

    Schizophrenia

    A 2013 Cochrane review compared quetiapine to typical antipsychotics:

    Quetiapine compared to typical antipsychotics for schizophrenia[16]
    Summary
    Quetiapine may not differ from typical antipsychotics in the treatment of positive symptoms, general psychopathology, and negative symptoms. However, it causes fewer adverse effects in terms of abnormal ECG, extrapyramidal effects, abnormal prolactin levels and weight gain.[16]

    In a 2013 comparison of 15 antipsychotics in effectiveness in treating schizophrenia, quetiapine demonstrated standard effectiveness. It was 13-16% more effective than ziprasidone, chlorpromazine, and asenapine and approximately as effective as haloperidol and aripiprazole.[17]

    There is tentative evidence of the benefit of quetiapine versus placebo in schizophrenia; however, definitive conclusions are not possible due to the high rate of attrition in trials (greater than 50%) and the lack of data on economic outcomes, social functioning, or quality of life.[18]

    It is debatable whether, as a class, typical or atypical antipsychotics are more effective.[19] Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages.[20] While quetiapine has lower rates of extrapyramidal side effects, there is greater sleepiness and rates of dry mouth.[18]

    A Cochrane review comparing quetiapine to other atypical antipsychotic 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. They concluded that it 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 antipsychotics.[21]

    Bipolar disorder

    In those with bipolar disorder, quetiapine is used to treat depressive episodes; acute manic episodes associated with bipolar I disorder (as either monotherapy or adjunct therapy to lithium; valproate or lamotrigine); acute mixed episodes; and maintenance treatment of bipolar I disorder (as adjunct therapy to lithium or divalproex).

    Major depressive disorder

    Quetiapine is effective when used by itself[7] and when used along with other medications in major depressive disorder (MDD).[7][22] However, sedation is often an undesirable side effect.[7]

    In the United States,[4] the United Kingdom[23] and Australia (while not subsidised by the Australian Pharmaceutical Benefits Scheme for treatment of MDD), quetiapine is licensed for use as an add-on treatment in MDD.[24]

    Alzheimer's disease

    Quetiapine does not decrease agitation among people with Alzheimer's. Quetiapine worsens intellectual functioning in the elderly with dementia and therefore is not recommended.[25]

    Others

    The use of low doses of quetiapine for insomnia, while common, is not recommended; there is little evidence of benefit and concerns regarding adverse effects.[26][27]

    It is sometimes used off-label, often as an augmentation agent, to treat conditions such as Tourette syndrome,[28] musical hallucinations[29] and anxiety disorders.[30]

    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.[31][32]

    Adverse effects

    Sources for incidence lists:[1][4][23][24][32][33]

    Very common (>10% incidence) adverse effects
    • Dry mouth
    • Dizziness
    • Headache
    • 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)[17]
    Common (1–10% incidence) adverse effects
    Rare (<1% incidence) adverse effects
    • 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[24]

    Both typical and atypical antipsychotics can cause tardive dyskinesia.[34] According to one study, rates are lower with the atypicals at 3.9% as opposed to the typicals at 5.5%.[34] Although quetiapine and clozapine are atypical antipsychotics, switching to these atypicals is an option to minimize symptoms of tardive dyskinesia caused by other atypicals.[35]

    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.[36]

    As with some other anti-psychotics, quetiapine may lower the seizure threshold,[37] and should be taken with caution in combination with drugs such as bupropion.

    Discontinuation

    The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[38] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[39] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[39] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[39] Symptoms generally resolve after a short period of time.[39]

    There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[40] It may also result in reoccurrence of the condition that is being treated.[41] Rarely tardive dyskinesia can occur when the medication is stopped.[39]

    Pregnancy and lactation

    Placental exposure is least for quetiapine compared to other atypical antipsychotics.[32] 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.[2][5][33] It is secreted in breast milk and hence quetiapine-treated mothers are advised not to breastfeed.[2][5][33]

    Overdose

    Most instances of acute overdosage result in only sedation, hypotension and tachycardia, but cardiac arrhythmia, 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.[42] Non-toxic levels in postmortem blood extend to around 0.8 mg/kg, but toxic levels in postmortem blood can begin at 0.35 mg/kg.[43][44]

    Pharmacology

    Pharmacodynamics
    See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications
    Quetiapine (and metabolite)[45][46]
    SiteQTPNQTPActionRef
    SERT>10,000927Blocker[46]
    NET>10,00058Blocker[46]
    DAT>10,000>10,000ND[46]
    5-HT1A320–43245Partial agonist[46][47]
    5-HT1B1,109–2,0501,117ND[46][47]
    5-HT1D>10,000249ND[46][47]
    5-HT1E1,250–2,40297ND[46][47]
    5-HT1F2,240NDND[47]
    5-HT2A96–10148Antagonist[46][47]
    5-HT2BND14Antagonist[46]
    5-HT2C2,502107Antagonist[46]
    5-HT3>10,000394Antagonist[46]
    5-HT4NDNDNDND
    5-HT5A3,120768ND[46]
    5-HT61,865503Antagonist[46]
    5-HT730776Antagonist[46]
    α1A22144Antagonist[46]
    α1B3995Antagonist[46]
    α2A2,230–3,630237Antagonist[46][47]
    α2B90–747378Antagonist[46][47]
    α2C28.7–350736Antagonist[46][47]
    β1>10,000>10,000ND[46][47]
    β2>10,000>10,000ND[46][47]
    D1712214Antagonist[46]
    D2245196Antagonist[46]
    D2L700NDAntagonist[47]
    D2S390NDAntagonist[47]
    D3340–483567Antagonist[46][47]
    D41,2021,297Antagonist[46]
    D4.21,600NDAntagonist[47]
    D51,7381,419Antagonist[46]
    H12.2–113.5Antagonist[46][47]
    H2>10,000298Antagonist[46]
    H3>10,000>10,000ND[46]
    H4>10,0001,660ND[46]
    M185839Antagonist[46]
    M21,339453ND[46]
    M3>10,00023Antagonist[46]
    M4542110ND[46]
    M51,94223Antagonist[46]
    σ1220–3,651>10,000ND[46][47]
    σ21,3441,050ND[46]
    NMDA
    (PCP)    		>10,000NDAntagonist[46]
    VDCC>10,000NDND[46][47]
    hERGND>10,000
    (IC50)    		ND[46]
    Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site. All data are for human cloned proteins, except σ1 (guinea pig), σ2 (rat), and VDCC (rat).[46][47]

    Quetiapine has the following pharmacological actions:[48][49][50][51][52][53][54][55]

    This means quetiapine is a dopamine, serotonin, and adrenergic antagonist, and a potent antihistamine with some anticholinergic properties.[56] Quetiapine binds strongly to serotonin receptors; the drug acts as partial agonist at 5-HT1A receptors.[57] Serial PET scans evaluating the D2 receptor occupancy of quetiapine have demonstrated that quetiapine very rapidly disassociates from the D2 receptor.[58] 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.[59] Some of the antagonized receptors (serotonin, norepinephrine) are actually autoreceptors whose blockade tends to increase the release of neurotransmitters.

    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.[49][60] Off-label prescriptions, e.g. for chronic insomnia, of low-dose quetiapine is not recommended due to the harmful side-effects.[61]

    When treating schizophrenia, antagonism of D2 receptor by quetiapine in the mesolimbic pathway relieves positive symptoms and antagonism of the 5HT2A receptor in the frontal cortex of the brain relieves negative symptoms.[15][62][63] Quetiapine has fewer extrapyramidal side effects and is less likely to cause hyperprolactinemia when compared to other drugs used to treat schizophrenia, so is used as a first line treatment.[64][65]

    Pharmacokinetics

    The major active metabolite of quetiapine is norquetiapine (N-desalkylquetiapine).[46] Quetiapine has a half-life of 7 hours. It is excreted primarily via the kidneys (73%) and in faeces (20%) after hepatic metabolism, the remainder (1%) is excreted as the drug in its unmetabolized form.[62][66]

    Skeletal formula of norquetiapine

    Chemistry

    Quetiapine is a tetracyclic compound and is closely related structurally to clozapine, olanzapine, loxapine, and other tetracyclic antipsychotics.

    Synthesis

    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.[67]

    History

    Sustained-release

    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.[68][69] AstraZeneca was to 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.[70] During its 2007 Q2 earnings conference, AstraZeneca announced plans to launch Seroquel XR in the U.S. during August 2007.[71] 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.[72] 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.[73]

    In early October 2008, the FDA approved Seroquel XR for the treatment of bipolar depression and bipolar mania. 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.[74] 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.[75]

    Society and culture

    Regulatory status

    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.[76] In 2009, quetiapine XR was approved as adjunctive treatment of major depressive disorder.[77]

    Quetiapine received its initial indication from U.S. FDA for treatment of schizophrenia in 1997.[78] In 2004, it received its second indication for the treatment of mania-associated bipolar disorder.[79] In 2007 and 2008, studies were conducted on quetiapine's efficacy in treating generalized anxiety disorder and major depression.

    Patent protection for the product ended in 2012; however, in a number of regions, the long-acting version remained under patent until 2017.[80]

    Cost

    In the United States as of 2015, the branded extended-release 400 mg pills cost between US$9.68 and US$23.16 each.[81] In 2017, the short-acting version had a wholesale cost of about US$12 per month.[11]

    In the United Kingdom, a month's supply, as of 2017, costs the NHS approximately £107.45.[10] This is following an increase of 30 to 70 fold in 2017/2018.[82]

    Lawsuits

    In April 2010, the U. S. Department of Justice fined Astra-Zeneca $520 million for the company's aggressive marketing of Seroquel for off-label uses.[76] 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."[76]

    Multiple lawsuits have been filed in relation to quetiapine's side-effects, in particular, diabetes.[83][84][85][86]

    Approximately 10,000[87] lawsuits[88] have been filed against AstraZeneca, alleging that quetiapine caused problems ranging from slurred speech and chronic insomnia to deaths.

    Controversy

    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.[89] A group of University of Minnesota bioethicists charged that the trial involved an alarming number of ethical violations.[90]

    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.[91]

    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.[92] The contamination was later traced to in-store tampering by a customer.[93]

    gollark: THIS IS IN CAPITALS therefore IT IS RIGHT
    gollark: LIBERAL still does not see how this is LIBERAL
    gollark: I'M JUST KIND OF ANNOYED BECAUSE I LOOKEDAT pine64 AND THEIR STUFF LOOKS GOOD BUT I HAVE NO IDEA WHERE IT'S ACTUALLY AVAILABLE HERE
    gollark: HOW IS THAT LIBERAL
    gollark: Yes. Admittedly it might not be easier in America, but still.

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