Quetiapine

Clinical data
Pronunciation	/kwɪˈtaɪ.əpiːn/ kwi-TY-ə-peen
Trade names	Seroquel, Seroquel XR, Temprolide, others
AHFS/Drugs.com	Monograph
MedlinePlus	a698019
License data	US DailyMed: Quetiapine
Pregnancy category	AU: B3
Routes of administration	By mouth
Drug class	Atypical antipsychotic
ATC code	N05AH04 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[2] BR: Class C1 (Other controlled substances)[3] CA: ℞-only UK: POM (Prescription only) US: WARNING[1]Rx-only
Pharmacokinetic data
Bioavailability	100%[4]
Protein binding	83%[5]
Metabolism	Liver via CYP3A4-catalysed sulfoxidation to its active metabolite norquetiapine (N-desalkylquetiapine)[8]
Elimination half-life	7 hours (parent compound); 9–12 hours (active metabolite, norquetiapine)[5][6]
Excretion	Kidney (73%), feces (20%)[4][5][6][7]
Identifiers
IUPAC name 2-(2-(4-Dibenzothiazepine-11-yl-1-piperazinyl)ethoxy)ethanol
CAS Number	111974-69-7 Y
PubChem CID	5002
IUPHAR/BPS	50
DrugBank	DB01224 Y
ChemSpider	4827 Y
UNII	BGL0JSY5SI
KEGG	D08456 Y
ChEBI	CHEBI:8707 Y
ChEMBL	ChEMBL716 Y
CompTox Dashboard (EPA)	DTXSID9023546
ECHA InfoCard	100.131.193
Chemical and physical data
Formula	C21H25N3O2S
Molar mass	383.51 g·mol−1
3D model (JSmol)	Interactive image
Solubility in water	3.29 mg/mL (20 °C)
SMILES N\1=C(\c3c(Sc2c/1cccc2)cccc3)N4CCN(CCOCCO)CC4
InChI InChI=1S/C21H25N3O2S/c25-14-16-26-15-13-23-9-11-24(12-10-23)21-17-5-1-3-7-19(17)27-20-8-4-2-6-18(20)22-21/h1-8,25H,9-16H2 Y Key:URKOMYMAXPYINW-UHFFFAOYSA-N Y
(verify)

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.^[9][10] Despite being widely used as a sleep aid due to its sedating effect, the benefits of such use may not outweigh its undesirable side effects.^[11] It is taken orally.^[9]

Common side effects include sleepiness, constipation, weight gain, and dry mouth.^[9] Other side effects include low blood pressure with standing, seizures, a prolonged erection, high blood sugar, tardive dyskinesia, and neuroleptic malignant syndrome.^[9] In older people with dementia, its use increases the risk of death.^[9] Use in the third trimester of pregnancy may result in a movement disorder in the baby for some time after birth.^[9] Quetiapine is believed to work by blocking a number of receptors, including those for serotonin and dopamine.^[9]

Quetiapine was developed in 1985 and approved for medical use in the United States in 1997.^[9][12] It is available as a generic medication.^[13] In 2021, it was the 62nd most commonly prescribed medication in the United States, with more than 10 million prescriptions.^[14][15] It is on the World Health Organization's List of Essential Medicines.^[16]

Medical uses

Quetiapine is primarily used to treat schizophrenia or bipolar disorder.^[17] Quetiapine targets both positive and negative symptoms of schizophrenia.^[18]

Schizophrenia

A 2013 Cochrane review compared quetiapine to typical antipsychotics:

Quetiapine compared to typical antipsychotics for schizophrenia^[19]

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.[19]
Outcome Findings in words Findings in numbers Quality of evidence Global state No clinical significant response There is no clear difference between people given quetiapine and those receiving typical antipsychotic drugs. These findings are based on data of moderate quality. RR 0.96 (0.75 to 1.23) Moderate Mental state Average positive symptom score (PANSS) On average, people receiving quetiapine scored higher (worse) than people treated with typical antipsychotic drugs. There was, however, no clear difference between the groups. This finding is based on data of moderate quality. MD 0.02 higher (0.39 lower to 0.43 higher)* Moderate Average negative symptom score (PANSS) On average, people receiving quetiapine scored lower (better) than people treated with typical antipsychotic drugs. This finding is based on data of moderate quality. MD 0.82 lower (1.59 to 0.04 lower)* Moderate Cognitive function Average score On average, people receiving quetiapine scored higher (better) than people treated with typical antipsychotic drugs. There was no clear difference between the groups. This finding is based on data of very limited quality. MD 1.55 higher (0.62 lower to 3.72 higher)* Very low Leaving the study early For any reason Quetiapine is not clearly more acceptable than typical antipsychotic drugs. These findings are based on data of moderate quality. RR 0.91 (0.81 to 1.01) Moderate Adverse effects Extrapyramidal effects Quetiapine may reduce the chance of experiencing these movement disorders. This finding is based on data of moderate quality. RR 0.17 (0.09 to 0.32) Moderate Prolactin level Average level (ng/mL) On average, people receiving quetiapine scored lower (better) than people treated with typical antipsychotic drugs. There was a clear difference between the groups. This finding is based on data of moderate quality. MD 16.20 lower (23.34 to 9.07 lower)* Moderate *The meaning of these findings for day-to-day care is not clear

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.^[20]

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.^[21]

It is debatable whether, as a class, typical or atypical antipsychotics are more effective.^[22] Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages.^[23] While quetiapine has lower rates of extrapyramidal side effects, there is greater sleepiness and rates of dry mouth.^[21]

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.^[24]

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^[10] and when used along with other medications in major depressive disorder (MDD).^[10][25] However, sedation is often an undesirable side effect.^[10]

In the United States,^[6] the United Kingdom^[26] 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.^[27]

Alzheimer's disease

Quetiapine does not decrease agitation among people with Alzheimer's disease. Quetiapine worsens intellectual functioning in the elderly with dementia and therefore is not recommended.^[28]

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.^{[29][30][31][32][33][34]} A 2022 network meta-analysis of 154 double-blind, randomized controlled trials of drug therapies vs. placebo for insomnia in adults found that quetiapine did not demonstrate any short-term benefits in sleep quality. Quetiapine, specifically, had an effect size (standardized mean difference) against placebo for treatment of insomnia of 0.05 (95% CITooltip confidence interval –1.21 to 1.11) at 4 weeks of treatment, with the certainty of evidence rated as very low.^[35] Doses of quetiapine used for insomnia have ranged from 12.5 to 800 mg, with low doses of 25 to 200 mg being the most typical.^[36][29][30] Regardless of the dose used, some of the more serious adverse effects may still possibly occur at the lower dosing ranges, such as dyslipidemia and neutropenia.^[37][38] These safety concerns at low doses are corroborated by Danish observational studies that showed use of specifically low-dose quetiapine (prescriptions filled for tablet strengths >50 mg were excluded) was associated with an increased risk of major cardiovascular events as compared to use of Z-drugs, with most of the risk being driven by cardiovascular death.^[39] Laboratory data from an unpublished analysis of the same cohort also support the lack of dose-dependency of metabolic side effects, as new use of low-dose quetiapine was associated with a risk of increased fasting triglycerides at 1-year follow-up.^[40]

It is sometimes used off-label, often as an augmentation agent, to treat conditions such as Tourette syndrome,^[41] musical hallucinations^[42] and anxiety disorders.^[43]

Quetiapine and clozapine are the most widely used medications for the treatment of Parkinson's disease psychosis due to their relatively low extrapyramidal side-effect liability.^[44] 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.^[45][46]

Adverse effects

Sources for incidence lists:^{[4][6][26][27][46][47]}

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.)^[20]

Common (1–10% incidence) adverse effects

• Extrapyramidal disease: Quetiapine and clozapine are noted for their relative lack of extrapyramidal side effects.^[20][26][46]
• 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.^[20] As with many other atypical antipsychotics, this action is likely due to its actions at the H₁ histamine receptor and 5-HT_2C receptor.^[8]

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^[27]

Both typical and atypical antipsychotics can cause tardive dyskinesia.^[48] According to one study, rates are lower with the atypicals at 3.9% as opposed to the typicals at 5.5%.^[48] Although quetiapine and clozapine are atypical antipsychotics, switching to these atypicals is an option to minimize symptoms of tardive dyskinesia caused by other atypicals.^[49]

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.^[50]

As with some other anti-psychotics, quetiapine may lower the seizure threshold,^[51] 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.^[52] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.^[53] Other symptoms may include restlessness, increased sweating, and trouble sleeping.^[53] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.^[53] Symptoms generally resolve after a short period of time.^[53]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.^[54] It may also result in reoccurrence of the condition that is being treated.^[55] Rarely tardive dyskinesia can occur when the medication is stopped.^[53]

Pregnancy and lactation

Placental exposure is least for quetiapine compared to other atypical antipsychotics.^[46] 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.^[5][7][47] It is secreted in breast milk and hence quetiapine-treated mothers are advised not to breastfeed.^[5][7][47]

Abuse potential

In contrast to most other antipsychotic drugs, which tend to be somewhat aversive and often show problems with patient compliance with prescribed medication regimes, quetiapine is sometimes associated with drug misuse and abuse potential, for its hypnotic and sedative effects. It has a limited potential for misuse, usually only in individuals with a history of polysubstance abuse and/or mental illness, and especially in those incarcerated in prisons or secure psychiatric facilities where access to alternative intoxicants is more limited. To a significantly greater extent than other atypical antipsychotic drugs, quetiapine was found to be associated with drug-seeking behaviors, and to have standardised street prices and slang terms associated with it, either by itself or in combination with other drugs (such as "Q-ball" for the intravenous injection of quetiapine mixed with cocaine). The pharmacological basis for this distinction from other second generation antipsychotic drugs is unclear, though it has been suggested that quetiapine's comparatively lower dopamine receptor affinity and strong antihistamine activity might mean it could be regarded as more similar to sedating antihistamines in this context. While these issues have not been regarded as sufficient cause for placing quetiapine under increased legal controls, prescribers have been urged to show caution when prescribing quetiapine to individuals with characteristics that might place them at increased risk for drug misuse.^{[56][57][58][59][60]}

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.^[61] 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.^[62][63]

Pharmacology

Pharmacodynamics

Quetiapine (and metabolite)^[64][65]

Site	QTP	NQTP	Action	Ref
SERTTooltip Serotonin transporter	>10,000	927	Blocker	[65]
NETTooltip Norepinephrine transporter	>10,000	58	Blocker	[65]
DATTooltip Dopamine transporter	>10,000	>10,000	ND	[65]
5-HT1A	320–432	45	Partial agonist	[65][66]
5-HT1B	1,109–2,050	1,117	ND	[65][66]
5-HT1D	>10,000	249	ND	[65][66]
5-HT1E	1,250–2,402	97	ND	[65][66]
5-HT1F	2,240	ND	ND	[66]
5-HT2A	96–101	48	Antagonist	[65][66]
5-HT2B	ND	14	Antagonist	[65]
5-HT2C	2,502	107	Antagonist	[65]
5-HT3	>10,000	394	Antagonist	[65]
5-HT4	ND	ND	ND	ND
5-HT5A	3,120	768	ND	[65]
5-HT6	1,865	503	Antagonist	[65]
5-HT7	307	76	Antagonist	[65]
α1A	22	144	Antagonist	[65]
α1B	39	95	Antagonist	[65]
α2A	2,230–3,630	237	Antagonist	[65][66]
α2B	90–747	378	Antagonist	[65][66]
α2C	28.7–350	736	Antagonist	[65][66]
β1	>10,000	>10,000	ND	[65][66]
β2	>10,000	>10,000	ND	[65][66]
D1	712	214	Antagonist	[65]
D2	245	196	Antagonist	[65]
D2L	700	ND	Antagonist	[66]
D2S	390	ND	Antagonist	[66]
D3	340–483	567	Antagonist	[65][66]
D4	1,202	1,297	Antagonist	[65]
D4.2	1,600	ND	Antagonist	[66]
D5	1,738	1,419	Antagonist	[65]
H1	2.2–11	3.5	Antagonist	[65]
H2	>10,000	298	Antagonist	[65]
H3	>10,000	>10,000	ND	[65]
H4	>10,000	1,660	ND	[65]
M1	858	39	Antagonist	[65]
M2	1,339	453	ND	[65]
M3	>10,000	23	Antagonist	[65]
M4	542	110	ND	[65]
M5	1,942	23	Antagonist	[65]
σ1	220–3,651	>10,000	ND	[65][66]
σ2	1,344	1,050	ND	[65]
NMDA (PCP)	>10,000	ND	Antagonist	[65]
VDCCTooltip Voltage-dependent calcium channel	>10,000	ND	ND	[65][66]
hERGTooltip Human Ether-à-go-go-Related Gene	ND	>10,000 (IC50Tooltip Half-maximal inhibitory concentration)	ND	[65]
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).[65][66]

Quetiapine has the following pharmacological actions:^{[67][68][69][70][71][72][73][74]}

• Dopamine D₁, D₂, D₃, D₄, and D₅ receptor antagonist
• Serotonin 5-HT_1A receptor partial agonist, 5-HT_2A, 5-HT_2B, 5-HT_2C, 5-HT₃, 5-HT₆, and 5-HT₇ receptor antagonist, and 5-HT_1B, 5-HT_1D, 5-HT_1E, and 5-HT_1F receptor ligand
• α₁- and α₂-adrenergic receptor antagonist
• Histamine H₁ receptor antagonist
• Muscarinic acetylcholine receptor antagonist

This means quetiapine is a dopamine, serotonin, and adrenergic antagonist, and a potent antihistamine with some anticholinergic properties.^[75] Quetiapine binds strongly to serotonin receptors; the drug acts as partial agonist at 5-HT_1A receptors.^[76] Serial PET scans evaluating the D₂ receptor occupancy of quetiapine have demonstrated that quetiapine very rapidly disassociates from the D₂ receptor.^[77] 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.^[78] 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.^[68][79] Due to the drug's sedating H₁ activity, it is often prescribed at low doses for insomnia. While some feel that low doses of drugs with antihistamine effects like quetiapine and mirtazapine are safer than drugs associated with physical dependency or other risk factors, concern has been raised by some professionals that off-label prescribing has become too widespread due to underappreciated hazards.^[80]

When treating schizophrenia, antagonism of D₂ receptor by quetiapine in the mesolimbic pathway relieves positive symptoms and antagonism of the 5-HT_2A receptor in the frontal cortex of the brain may relieve negative symptoms and reduce severity of psychotic episodes.^[18][81][82] 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.^[83][84]

Pharmacokinetics

Peak levels of quetiapine occur 1.5 hours after a dose.^[85] The plasma protein binding of quetiapine is 83%.^[85] The major active metabolite of quetiapine is norquetiapine (N-desalkylquetiapine).^[65] Quetiapine has an elimination half-life of 6 or 7 hours.^[85][5][6] Its metabolite, norquetiapine, has a half-life of 9 to 12 hours.^[5][6] Quetiapine is excreted primarily via the kidneys (73%) and in feces (20%) after hepatic metabolism, the remainder (1%) is excreted as the drug in its unmetabolized form.^[81][85]

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.^[86]

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.^[87][88] 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 18 May 2007, AstraZeneca announced that the U.S. FDA approved Seroquel XR for acute treatment of schizophrenia.^[89] During its 2007 Q2 earnings conference, AstraZeneca announced plans to launch Seroquel XR in the U.S. during August 2007.^[90] 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 16 November 2007.^[91] The company has not provided a reason for the delay of Seroquel XR's launch.

Health Canada approved sale of Seroquel XR on 27 September 2007.^[92]

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 31 July 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 1 December 2008, Biovail announced that the FDA had accepted the company's ANDA to market its own version of sustained-release quetiapine.^[93] Biovail's sustained-release tablets will compete with AstraZeneca's Seroquel XR.

On 24 December 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.^[94]

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.^[95] In 2009, quetiapine XR was approved as adjunctive treatment of major depressive disorder.^[96]

Quetiapine received its initial indication from U.S. FDA for treatment of schizophrenia in 1997.^[97] In 2004, it received its second indication for the treatment of mania-associated bipolar disorder.^[98] 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.^[99]

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.^[95] 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."^[95]

Multiple lawsuits have been filed in relation to quetiapine's side-effects, in particular, diabetes.^{[100][101][102][103]}

Approximately 10,000^[104] lawsuits^[105] 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.^[106] A group of University of Minnesota bioethicists charged that the trial involved an alarming number of ethical violations.^[107]

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