Quetiapine

Quetiapine
Systematic (IUPAC) name
2-(2-(4-dibenzo[b,f][1,4]thiazepine- 11-yl- 1-piperazinyl)ethoxy)ethanol
Clinical data
Trade names Seroquel
AHFS/Drugs.com monograph
MedlinePlus a698019
Pregnancy cat. C(US)
Legal status ℞-only (US)
Routes Oral
Pharmacokinetic data
Bioavailability 9%
Metabolism Hepatic
Half-life 6 hours
Excretion Renal
Identifiers
CAS number 111974-69-7 Y
ATC code N05AH04
PubChem CID 5002
IUPHAR ligand 50
DrugBank DB01224
ChemSpider 4827 Y
UNII BGL0JSY5SI Y
KEGG D08456 Y
ChEBI CHEBI:8707 Y
ChEMBL CHEMBL716 Y
Chemical data
Formula C21H25N3O2S 
Mol. mass 383.5099 g/mol
SMILES eMolecules & PubChem
 Y(what is this?)  (verify)

Quetiapine ( /kwɨˈtaɪ.əpiːn/ kwi-ty-ə-peen) (branded as Seroquel, Ketipinor), is an atypical antipsychotic approved for the treatment of schizophrenia, and bipolar disorder.

Annual sales are approximately $5.7 billion worldwide, and $2.9 billion in the United States.[1] The U.S. patent,[2] which was set to expire in 2011, received a pediatric exclusivity extension which pushed its expiration to March 26, 2012.[3] The patent has already expired in Canada. There are now several generic versions of quetiapine, such as Quepin.[4]

Contents

Medical uses

Quetiapine is used to treat either schizophrenia or bipolar disorder.[5]

Schizophrenia

It is debatable whether, as a class, typical or atypical antipsychotics are better.[6] Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages.[7]

Bipolar

In those with bipolar 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).[8]

Alzheimer's

Quetiapine is ineffective in reducing agitation among people with Alzheimer's, whose usage of the drug once constituted 29% of sales. Quetiapine worsens cognitive functioning in the elderly with dementia[9] and thus is not recommended.

Other

It is sometimes used off-label, often as an augmentation agent, to treat conditions such as obsessive-compulsive disorder, post-traumatic stress disorder, autism, alcoholism, Borderline Personality Disorder, depression,[10] Tourette syndrome,[11] and has been used by physicians as a sedative for those with sleep disorders or anxiety disorders.[12]

Adverse effects

The most common side-effect of quetiapine is somnolence. Other common side-effects include: sluggishness, fatigue, dry mouth, sore throat, dizziness, abdominal pain, constipation, upset stomach, orthostatic hypotension, inflammation or swelling of the sinuses or pharynx, increased appetite, and weight gain.[13]

It is marketed as one of the most sedating of all anti-psychotics, although those claims are contested.[14] 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.[15] According to one study, rates are lower with the atypicals at 3.9% as opposed to the typicals at 5.5%.[15] Although Quetiapine and Clozapine are atypical antipsychotics, switching to these atypicals is an option to minimize symptoms of tardive dyskinesia caused by other atypicals.[16]

Weight gain can be a problem for some patients. Quetiapine has been found to cause more weight gain than fluphenazine, haloperidol, loxapine, molindone, olanzapine, pimozide, risperidone, thioridazine, thiothixene, trifluoperazine, and ziprasidone, but less than chlorpromazine, clozapine, perphenazine, and sertindole when calculated according to a fixed effects model.[17]

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

As with some other anti-psychotics, quetiapine may lower the seizure threshold[19], and should be taken with caution in combination with drugs such as bupropion.

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.[20]

Discontinuation

Quetiapine should be discontinued gradually 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.[21] 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. Withdrawal symptoms reported to occur after discontinuation of quetiapine include nausea, emesis, lightheadedness, diaphoresis, dyskinesia, orthostasis, tachycardia, nervousness, dizziness, headache, excessive non-stop crying, and anxiety. The present evidence suggests that these symptoms affect a small number of susceptible individuals treated with Quetiapine.[22][23]

Overdosage

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.[24]

Pharmacology

Comparison of affinities (Ki, nM)[25]
Receptor Quetiapine Norquetiapine
D1 428 99.8
D2 626 489
5-HT1A 1040 191
5-HT2A 38 2.9
α1B 14.6 46.4
α2 617 1290
H1 4.41 1.15
M1 1086 38.3
NET >10000 34.8

Quetiapine has the following pharmacological actions:[26][27][28][29]

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. Serial PET scans evaluating the D2 receptor occupancy of quetiapine have demonstrated that quetiapine very rapidly disassociates from the D2 receptor.[30] 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.[31] Some of the antagonized receptors (serotonin, norepinephrine) are actually autoreceptors whose blockade tends to increase the release of neurotransmitters.

Norquetiapine is the active metabolite of quetiapine. It has most of the effects of quetiapine with similar potencies, and is also a potent norepinephrine reuptake inhibitor and muscarinic antagonist. Note that the data below is from another source (the official prescribing info for Seroquel), and the measure is different from the above (Ki vs. IC50). There are still order-of-magnitude discrepancies for D1, α1, H1 and M1.

Synthesis

Warawa, E. J.; Migler, B. M.; 1988, U.S. Patent 4,879,288.

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.[32][33] Use of low-dose quetiapine is not recommended except temporarily during drug titration period (less than 30 days).[34]

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, orthostasis, 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.[22]

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[21]

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.[35][36] 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 FDA approved Seroquel XR for acute treatment of schizophrenia.[37] During its 2007 Q2 earnings conference, AstraZeneca announced plans to launch Seroquel XR in the U.S. during August 2007.[38] However, Seroquel XR has only become available in U.S. pharmacies 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.[39] 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.[40]

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.[41] 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.[42]

Society and culture

Legal status

Quetiapine received its initial indication from the U.S. Food and Drug Administration for treatment of schizophrenia in 1997.[43] In 2004, it received its second indication for the treatment of mania-associated bipolar disorder.[44] 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 US Food and Drug Administration (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.[45]

Controversy

AstraZeneca has been sued by the U.S. government over the marketing of quetiapine. A $520 million settlement was reached on October 29, 2009.[46]

Several American soldiers and veterans have died while taking Seroquel for PTSD.[47]

Multiple lawsuits have been filed in relation to quetiapine's side-effects, in particular, diabetes.[48][49][50][51]

In Australia, Professor Patrick McGorry, a key mental health adviser proposed a trial in Melbourne in 2011. It was to investigate whether Seroquel would decrease or delay the risk of people aged between 15 and 40 with early signs of mental illness, developing 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[52] as "unethical" and "dangerous".

Recreational use

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."[53] Reports of quetiapine abuse have emerged in the medical literature, however, while the drug is usually abused through the crushing and snorting of tablets (insufflation), there have also been reports of intravenous abuse and intravenous co-administration with cocaine.[54] This is commonly referred to as a "Q-Ball".[54] 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.[55] 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.[56]

Date rape

Quetiapine has sometimes been used as a date rape drug, causing persons to lose consciousness before a sexual attack, especially when coadministered with alcohol.[57][58]

Nurofen plus error

In August 2011 The UKs Medicines and Healthcare Regulatory Agency (MHRA) issued a class 4 drug alert following reports that some batches of Nurofen plus contained Seroquel XL instead.[59]

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.[60]

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Acridine • Anthracene • Dibenzazepine • Dibenzocycloheptene • Dibenzodiazepine • Dibenzothiazepine • Dibenzothiepin • Dibenzoxazepine • Dibenzoxepin • Phenothiazine • Pyridazinobenzoxazine • Pyridinobenzodiazepine • Thioxanthene
Antidepressants
7-OH-Amoxapine • Amezepine • Amineptine • Amitriptyline • Amitriptylinoxide • Amoxapine • Aptazapine • Azepindole • Azipramine • Butriptyline • Cianopramine • Ciclazindol • Ciclopramine • Clomipramine • Cotriptyline • Cyanodothiepin • Demexiptiline • Depramine/Balipramine • Desipramine • Dibenzepin • Dimetacrine • Dosulepin/Dothiepin • Doxepin • Enprazepine • Esmirtazapine • Fluotracen • Hepzidine • Homopipramol • Imipramine • Imipraminoxide • Intriptyline • Iprindole • Ketipramine • Litracen • Lofepramine • Losindole • Loxapine • Maprotiline • Mariptiline • Mazindol • Melitracen • Metapramine • Mezepine • Mianserin • Mirtazapine • Naranol • Nitroxazepine • Nortriptyline • Noxiptiline • Octriptyline • Opipramol • Oxaprotiline • Pipofezine • Pirandamine • Propizepine • Protriptyline • Quinupramine • Setiptiline/Teciptiline • Tandamine • Tampramine • Tianeptine • Tienopramine • Trimipramine
Antihistamines
Antipsychotics
Acetophenazine • Amoxapine • Asenapine • Butaclamol • Butaperazine • Carphenazine • Carpipramine • Chlorpromazine • Chlorprothixene • Ciclindole • Clocapramine • Clomacran • Clorotepin • Clotiapine • Clozapine • Cyanothepin • Doclothepin • Docloxythepin • Erizepine • Flucindole • Flumezapine • Fluotracen • Flupentixol • Fluphenazine • Gevotroline • Homopipramol • Isofloxythepin • Levomepromazine/Methotrimeprazine • Loxapine • Maroxepin • Meperathiepin • Mesoridazine • Metitepine • Metoxepin • Mosapramine • Naranol • Octomethothepin • Olanzapine • Oxyclothepin • Oxyprothepin • Peradithiepin • Perathiepin • Perazine • Perphenazine • Periciazine • Piperacetazine • Pipotiazine • Piquindone • Prochlorperazine • Promazine • Prothipendyl • Quetiapine • Sulforidazine • Thiethylperazine • Thiopropazate • Thioridazine • Thiothixene • Tilozepine • Trifluoperazine • Triflupromazine • Trifluthepin • Zotepine • Zuclopenthixol
Others
Atiprosin • Carbamazepine • Carvedilol • Cyclobenzaprine • Darenzepine • Elanzepine • Eslicarbazepine acetate • Etazepine • Licarbazepine • Methylene Blue • Monatepil • Nuvenzepine • Oxcarbazepine • Oxitriptyline • Pirenzepine • Pirolate • Pitrazepin • Pizotifen • Profenamine • Rispenzepine • Serazapine • Siltenzepine • Telenzepine • Zolenzepine