The drug is typically among two antipsychotics (the other beingolanzapine) to have superior efficacy for the treatment of bipolar disorder. Quetiapine is one of only two antipsychotics (the other iscariprazine) that produce equal efficacy as standalone therapies for mixed manic-depressive mood swings as they do in combination with anSSRI antidepressant. But it is less potent thanclozapine,amisulpride,olanzapine,risperidone, andpaliperidone in alleviatingpsychotic symptoms or treating schizophrenia.
Medical uses
Quetiapine (Seroquel) 25 mg tablets, next toUS one-cent coin for comparisonSeroquel XR 150 mg tablet box
Quetiapine is primarily used to treat schizophrenia and bipolar disorder.[18] It targets both positive and negative symptoms of schizophrenia.[19]
Schizophrenia
A 2013 Cochranereview compared quetiapine to typical antipsychotics:
Quetiapine compared to typical antipsychotics for schizophrenia[20]
There is no clear difference between people given quetiapine and those receiving typical antipsychotic drugs. These findings are based on data of moderate quality.
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.
On average, people receiving quetiapine scored lower (better) than people treated with typical antipsychotic drugs. This finding is based on data of moderate quality.
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.
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.
*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 thanziprasidone,chlorpromazine, andasenapine and approximately as effective ashaloperidol andaripiprazole.[21]
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.[22]
It is debatable whether, as a class,typical oratypical antipsychotics are more effective.[23] Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages.[24] While quetiapine has lower rates of extrapyramidal side effects, there is greater sleepiness and rates of dry mouth.[22]
In those withbipolar disorder, quetiapine is used to treat depressive episodes; acute manic episodes associated withbipolar I disorder (as either monotherapy or adjunct therapy tolithium;valproate orlamotrigine); 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[11] and when used along with other medications inmajor depressive disorder (MDD),[11][26] but sedation is often an undesirable side effect.[11]
In the United States,[7] the United Kingdom[27] and Australia (while not subsidised by the AustralianPharmaceutical Benefits Scheme for treatment of MDD), quetiapine is licensed for use as an add-on treatment in MDD.[28]
Alzheimer's disease
Quetiapine does not decrease agitation among people withAlzheimer's disease. Quetiapine worsens intellectual functioning in the elderly with dementia and therefore is not recommended.[29]
Insomnia
The use of low doses of quetiapine forinsomnia, while common, is not recommended; there is little evidence of benefit and concerns regarding adverse effects.[30][31][32][33][34][35] 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 aneffect size (standardized mean difference) againstplacebo for treatment of insomnia of 0.05 (95%CITooltip confidence interval –1.21 to 1.11) at 4weeks of treatment, with thecertainty of evidence rated as very low.[36] Doses of quetiapine used for insomnia have ranged from 12.5 to 800mg, with low doses of 25 to 200mg being the most typical.[37][30][31] Regardless of the dose used, some of the more serious adverse effects may still possibly occur at the lower dosing ranges, such asdyslipidemia andneutropenia.[38][39] Increases in serum triglycerides, LDL-C, and fasting blood glucose have been observed following quetiapine treatment at doses typically used off-label in the treatment of insomnia.[40][41] 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 ofZ-drugs, with most of the risk being driven by cardiovascular death.[42] 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.[43]
Quetiapine andclozapine are the most widely used medications for the treatment ofParkinson's disease psychosis due to their relatively low extrapyramidal side-effect liability.[47] 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.[48][49]
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.)[21]
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[28]
Both typical and atypical antipsychotics can causetardive dyskinesia.[52] According to one study, rates are lower with the atypicals at 3.9% as opposed to the typicals at 5.5%.[52] Although quetiapine and clozapine are atypical antipsychotics, switching to these atypicals is an option to minimize symptoms of tardive dyskinesia caused by other atypicals.[53]
As with some other anti-psychotics, quetiapine may lower theseizure threshold,[55] and should be taken with caution in combination with drugs such asbupropion.
Discontinuation
TheBritish National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[56] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[57] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[57] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[57] Symptoms generally resolve after a short period of time.[57]
There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[58] It may also result in reoccurrence of the condition that is being treated.[59] Rarely tardive dyskinesia can occur when the medication is stopped.[57]
Pregnancy and lactation
Placental exposure is least for quetiapine compared to other atypical antipsychotics.[49] 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.[6][8][50] It is secreted in breast milk and hence quetiapine-treated mothers are advised not to breastfeed.[6][8][50]
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 withdrug 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 withcocaine). 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 sedatingantihistamines 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.[60][61][62][63][64]
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.[65] 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.[66][67]
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), andVDCC (rat).[69][70]
This means quetiapine is adopamine,serotonin, andadrenergic antagonist, and a potentantihistamine with someanticholinergic properties.[78] Quetiapine binds strongly to serotonin receptors; the drug acts as apartial agonist at 5-HT1A receptors and as an antagonist to all other serotonin receptors it has affinity for.[79] Serial PET scans evaluating the D2 receptor occupancy of quetiapine have demonstrated that quetiapine very rapidly disassociates from the D2 receptor.[80] Theoretically, this allows for normal physiological surges of dopamine to elicit normal effects in areas such as thenigrostriatal andtuberoinfundibular pathways, thus minimizing the risk of side-effects such as pseudo-parkinsonism as well as elevations inprolactin.[81] Some of the antagonized receptors (serotonin, norepinephrine) are actuallyautoreceptors whose blockade tends to increase the release of neurotransmitters.
At very low doses, quetiapine acts primarily as a histamine receptor blocker (antihistamine) andα1-adrenergic blocker. When the dose is increased, quetiapine activates the adrenergic system and binds strongly to serotonin receptors andautoreceptors. At high doses, quetiapine starts blocking significant amounts of dopamine receptors.[72][82] 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 andmirtazapine 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.[83]
When treating schizophrenia, antagonism of D2 receptor by quetiapine in the mesolimbic pathway relieves positive symptoms and antagonism of the 5-HT2A receptor in the frontal cortex of the brain may relieve negative symptoms and reduce severity of psychotic episodes.[19][84][85] 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.[86][87]
Since the noradrenaline transporter is responsible for most of the dopamine clearance in the prefrontal cortex, norquetiapine blocks reuptake of dopamine too, accumulating the dopamine in the synapse.[88]
In May 2007, the US FDA approved Seroquel XR for acute treatment of schizophrenia.[93] During its 2007 Q2 earnings conference, AstraZeneca announced plans to launch Seroquel XR in the U.S. during August 2007.[94] 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.[95] 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.[96]
In October 2008, the FDA approved Seroquel XR for the treatment of bipolar depression and bipolar mania.
In December 2008,Biovail announced that the FDA had accepted the company's ANDA to market its own version of sustained-release quetiapine.[97] Biovail's sustained-release tablets will compete with AstraZeneca's Seroquel XR.
In 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.[98]
Quetiapine received its initial approval from the US FDA for the treatment of schizophrenia in 1997.[3][101] In 2004, it received its second indication for the treatment of mania-associated bipolar disorder.[102] 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.[103]
Lawsuits
In April 2010, the U. S. Department of Justice fined AstraZeneca $520 million for the company's aggressive marketing of Seroquel foroff-label uses.[99] 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."[99]
Multiple lawsuits have been filed in relation to quetiapine's side-effects, in particular,diabetes.[104][105][106][107]
Approximately 10,000[108] lawsuits[109] 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 namedDan Markingson committed suicide in a controversial Seroquel clinical trial at the University of Minnesota while under an involuntary commitment order.[110] A group of University of Minnesota bioethicists charged that the trial involved an alarming number of ethical violations.[111]
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 productNeurontin 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.[113] The contamination was later traced to in-store tampering by a customer.[114]
^abcdefgh"Quetiapine Fumarate". The American Society of Health-System Pharmacists.Archived from the original on 29 August 2017. Retrieved26 March 2017.
^World Health Organization (2023).The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization.hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
^"quetiapine-fumarate".The American Society of Health-System Pharmacists.Archived from the original on 10 February 2011. Retrieved3 April 2011.
^abcdeLeucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, et al. (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis".Lancet.382 (9896):951–962.doi:10.1016/S0140-6736(13)60733-3.PMID23810019.S2CID32085212.
^abAnderson SL, Vande Griend JP (March 2014). "Quetiapine for insomnia: A review of the literature".American Journal of Health-System Pharmacy.71 (5):394–402.doi:10.2146/ajhp130221.PMID24534594.
^Maglione M, Maher AR, Hu J, Wang Z, Shanman R, Shekelle PG, et al. (September 2011). Off-Label Use of Atypical Antipsychotics: An Update (Report).PMID22132426.
^Maglione M, Maher AR, Hu J, Wang Z, Shanman R, Shekelle PG, et al. (2011).Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Reviews, No. 43. Rockville: Agency for Healthcare Research and Quality.PMID22973576.
^Coe HV, Hong IS (May 2012). "Safety of low doses of quetiapine when used for insomnia".The Annals of Pharmacotherapy.46 (5):718–722.doi:10.1345/aph.1Q697.PMID22510671.S2CID9888209.
^Wine JN, Sanda C, Caballero J (April 2009). "Effects of quetiapine on sleep in nonpsychiatric and psychiatric conditions".The Annals of Pharmacotherapy.43 (4):707–713.doi:10.1345/aph.1L320.PMID19299326.S2CID207263320.
^Mukaddes NM, Abali O (2003). "Quetiapine treatment of children and adolescents with Tourette's disorder".Journal of Child and Adolescent Psychopharmacology.13 (3):295–299.doi:10.1089/104454603322572624.PMID14642017.
^Kyle K, Bronstein JM (June 2020). "Treatment of psychosis in Parkinson's disease and dementia with Lewy Bodies: A review".Parkinsonism & Related Disorders.75:55–62.doi:10.1016/j.parkreldis.2020.05.026.PMID32480308.S2CID219168745.In clinical practice, quetiapine is more readily used than clozapine, given its improved side effect profile compared to clozapine. Despite frequent use in clinical practice, its efficacy in PDP is less clear. ... The quetiapine evidence base is thus ambiguous, lacking consistent support from RCTs in PDP. In DLB there is reliance upon retrospective studies, with the inherent limitations therein. As with clozapine, sedation and orthostasis can be limiting factors. In clinical practice, despite the paucity of consistent evidence, quetiapine has been the first line antipsychotic therapy due to its side effect profile and lower neuroleptic sensitivity risk.
^Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, et al. (November 1999). "Antipsychotic-induced weight gain: a comprehensive research synthesis".The American Journal of Psychiatry.156 (11):1686–96.doi:10.1176/ajp.156.11.1686.PMID10553730.S2CID38635470.
^Joint Formulary Committee BMJ, ed. (March 2009). "4.2.1".British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192.ISBN978-0-85369-845-6.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.
^Moncrieff J (July 2006). "Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse".Acta Psychiatrica Scandinavica.114 (1):3–13.doi:10.1111/j.1600-0447.2006.00787.x.PMID16774655.S2CID6267180.
^Chiappini S, Schifano F (February 2018). "Is There a Potential of Misuse for Quetiapine?: Literature Review and Analysis of the European Medicines Agency/European Medicines Agency Adverse Drug Reactions' Database".Journal of Clinical Psychopharmacology.38 (1):72–79.doi:10.1097/JCP.0000000000000814.hdl:2299/19835.PMID29210868.S2CID3292900.
^Vento AE, Kotzalidis GD, Cacciotti M, Papanti GD, Orsolini L, Rapinesi C, et al. (2020). "Quetiapine Abuse Fourteen Years Later: Where Are We Now? A Systematic Review".Substance Use & Misuse.55 (2):304–313.doi:10.1080/10826084.2019.1668013.PMID31573374.S2CID203621793.
^Baselt R (2008).Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 1355–1357.
^Roth BL, Driscol J."PDSP Ki Database".Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved14 August 2017.
^abcdefghijklmnopqrSchotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, et al. (March 1996). "Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding".Psychopharmacology.124 (1–2):57–73.doi:10.1007/bf02245606.PMID8935801.S2CID12028979.
^abRichelson E, Souder T (November 2000). "Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds".Life Sciences.68 (1):29–39.doi:10.1016/S0024-3205(00)00911-5.PMID11132243.
^Miyamoto SE, Duncan GE, Goff DC, Lieberman JA (2002)."Therapeutics of schizophrenia". In Davis KL, Charney D, Coyle JT, Nemeroff C (eds.).Neuropsychopharmacology: the fifth generation of progress. American College of Neuropsychopharmacology.ISBN978-0-7817-2837-9.
^National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Sep 18]. Chapel Hill (NC): University of North Carolina. 1998-2013. Available from:"...list shows the top 100 Receptors/Targets in Ki". Archived fromthe original on 8 November 2013. Retrieved5 July 2013.
^Chew ML, Mulsant BH, Pollock BG, Lehman ME, Greenspan A, Mahmoud RA, et al. (July 2008). "Anticholinergic activity of 107 medications commonly used by older adults".Journal of the American Geriatrics Society.56 (7):1333–1341.doi:10.1111/j.1532-5415.2008.01737.x.PMID18510583.S2CID11448976.
^Kapur S, Seeman P (March 2001). "Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: A new hypothesis".The American Journal of Psychiatry.158 (3):360–369.doi:10.1176/appi.ajp.158.3.360.PMID11229973.
^Gefvert O, Lundberg T, Wieselgren IM, Bergström M, Långström B, Wiesel F, et al. (April 2001). "D(2) and 5HT(2A) receptor occupancy of different doses of quetiapine in schizophrenia: a PET study".European Neuropsychopharmacology.11 (2):105–110.doi:10.1016/S0924-977X(00)00133-4.PMID11313155.S2CID29460397.
^ab"Quetiapine".www.drugbank.ca. Retrieved23 January 2019.
^"Seroquel"(PDF).FDA. Archived fromthe original(PDF) on 14 February 2011. Retrieved23 January 2019.
^Nemeroff CB, Kinkead B, Goldstein J (2002). "Quetiapine: preclinical studies, pharmacokinetics, drug interactions, and dosing".The Journal of Clinical Psychiatry.63 (Suppl 13):5–11.PMID12562141.
^Kasper S, Müller-Spahn F (May 2000). "Review of quetiapine and its clinical applications in schizophrenia".Expert Opinion on Pharmacotherapy.1 (4):783–801.doi:10.1517/14656566.1.4.783.PMID11249516.S2CID22978385.
^"QUETIAPINE FUMARATE".Electronic Orange Book. Food and Drug Administration. April 2007. Archived fromthe original on 5 January 2009. Retrieved24 May 2007.
