Quetiapine

"Quell" redirects here. For the video game, see Quell (video game). For the wearable, see Quell (wearable).

Quetiapine
Clinical data
Pronunciation /kwˈt.əpn/ kwi-TY-ə-peen
Trade names Seroquel
AHFS/Drugs.com Monograph
MedlinePlus a698019
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration
Oral
ATC code N05AH04 (WHO)
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability 100%[1]
Protein binding 83%[2]
Metabolism Hepatic via CYP3A4-catalysed sulfoxidation to its active metabolite norquetiapine (N-desalkylquetiapine)[3]
Biological half-life 7 hours (parent compound); 9–12 hours (active metabolite, norquetiapine)[2][4]
Excretion Renal (73%), faeces (20%)[1][2][4][5]
Identifiers
CAS Number 111974-69-7 YesY
PubChem (CID) 5002
IUPHAR/BPS 50
DrugBank DB01224 YesY
ChemSpider 4827 YesY
UNII BGL0JSY5SI YesY
KEGG D08456 YesY
ChEBI CHEBI:8707 YesY
ChEMBL CHEMBL716 YesY
ECHA InfoCard 100.131.193
Chemical and physical data
Formula C21H25N3O2S
Molar mass 383.5099 g/mol
3D model (Jmol) Interactive image
Solubility in water 3.29 mg/mL (20 °C)
  (verify)

Quetiapine, marketed as Seroquel, is an atypical antipsychotic approved for the treatment of schizophrenia, bipolar disorder, and along with an antidepressant to treat major depressive disorder. It is also sometimes used as a sleep aid because of its sedating effect but this use is not recommended.[6]

Annual sales are approximately $1.3 billion worldwide.[7] Quetiapine was developed by AstraZeneca from 1992 to 1996. It was first approved by the FDA in 1997. There are now several generic versions.[8]

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.[9]

Schizophrenia

A second Cochrane Review[10] comparing quetiapine to typical antipsychotics concluded that quetiapine

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.[12]

It is debatable whether, as a class, typical or atypical antipsychotics are more effective.[13] Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages.[14] While quetiapine has lower rates of extrapyramidal side effects, there is greater sleepiness and rates of dry mouth.[12]

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.[11]

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), and maintenance treatment of bipolar I disorder (as adjunct therapy to lithium or divalproex).[15][16]

Major depressive disorder

Quetiapine is effective when used by itself[17] and when used along with other medications in major depressive disorder (MDD).[17][18] However, sedation is often an undesirable side effect.[17]

In the United States,[4] the United Kingdom[19] and Australia (in this indication it isn't covered by the Pharmaceutical Benefits Scheme), quetiapine is licensed for use as an adjunct in the treatment of MDD.[20]

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.[21]

Other

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.[22][23]

It is sometimes used off-label, often as an augmentation agent, to treat conditions such as Tourette syndrome,[24] musical hallucinations[25] and anxiety disorders.[26]

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.[27][28]

Adverse effects

Sources for incidence lists:[1][4][19][20][28][29]

Very common (>10% incidence) adverse effects
Common (1–10% incidence) adverse effects
Rare (<1% incidence) adverse effects

Both typical and atypical antipsychotics can cause tardive dyskinesia.[32] According to one study, rates are lower with the atypicals at 3.9% as opposed to the typicals at 5.5%.[32] Although Quetiapine and Clozapine are atypical antipsychotics, switching to these atypicals is an option to minimize symptoms of tardive dyskinesia caused by other atypicals.[33]

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.[34]

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[35] still recommends users have eye examinations every six months.

As with some other anti-psychotics, quetiapine may lower the seizure threshold,[36] and should be taken with caution in combination with drugs such as bupropion.

Discontinuation

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.[37] 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.[38][39] 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.[40][41]

Overdosage

Most instances of acute overdosage result only in 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]

Pregnancy and lactation

Placental exposure is least for quetiapine compared to other atypical antipsychotics.[28] 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][29] It is secreted in breast milk and hence quetiapine-treated mothers are advised not to breastfeed.[2][5][29]

Pharmacology

Comparison of affinities (Ki, nM)[45][46][47][48]
Receptor Quetiapine
(Cloned human receptors)
Norquetiapine
(Cloned human receptors)
D1 994.5 99.8 (Rat receptor)
D2 379 196
D3 340 -
D4 2019 -
5-HT1A 394.2 45
5-HT2A 118 48
5-HT2C 1843 107
5-HT6 33 / 1864 -
5-HT7 307 76
α1A 22 144
α1B 14.6 46.4 (Rat receptor)
α2A 3630 237
α2C 28.85 -
H1 6.9 3.5
H2 41.24 -
M1 489 38.3 (Rat receptor)
M3 1631.5 -
NET >10000 12

Quetiapine has the following pharmacological actions:[49][50][51][52]

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.[53] Serial PET scans evaluating the D2 receptor occupancy of quetiapine have demonstrated that quetiapine very rapidly disassociates from the D2 receptor.[54] 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.[55] Some of the antagonized receptors (serotonin, norepinephrine) are actually autoreceptors whose blockade tends to increase the release of neurotransmitters.

Skeletal formula of norquetiapine

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.[56]

Dosage

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.[57][58] Off-label prescriptions, e.g. for chronic insomnia, of low-dose quetiapine is not recommended due to the harmful side-effects.[59]

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 trouble sleeping, nausea, vomiting, lightheadedness, sweating, feeling light headed when standing, fast heart rate, 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.[38]

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[37]

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.[60][61] 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.[62] During its 2007 Q2 earnings conference, AstraZeneca announced plans to launch Seroquel XR in the U.S. during August 2007.[63] 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.[64] 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.[65]

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.[66] 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.[67]

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.[68] In 2009, quetiapine XR was approved as adjunctive treatment of major depressive disorder.[69]

Quetiapine received its initial indication from U.S. FDA for treatment of schizophrenia in 1997.[70] In 2004, it received its second indication for the treatment of mania-associated bipolar disorder.[71] In 2007 and 2008, studies were conducted on quetiapine’s efficacy in treating generalized anxiety disorder and major depression.

Cost

In the United States as of 2015 the branded extended release 400 mg pills cost between 9.68 and 23.16 USD each.[72]

Lawsuits

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.[68] 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."[68]

Multiple lawsuits have been filed in relation to quetiapine's side-effects, in particular, diabetes.[73][74][75][76]

Approximately 10,000[77] lawsuits[78] 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.[79] A group of University of Minnesota bioethicists charged that the trial involved an alarming number of ethical violations.[80]

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.[81]

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.[82] The contamination was later traced to in-store tampering by a customer.[83]

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