Seroquel

Quetiapine

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Quetiapine

Systematic (IUPAC) name
2-(2-(4-dibenzo[b,f][1,4]thiazepine- 11-yl- 1-piperazinyl)ethoxy)ethanol
Identifiers
CAS number	111974-69-7
ATC code	N05AH04
PubChem	CID 5002
IUPHAR ligand ID	50
DrugBank	DB01224
ChemSpider	4827
Chemical data
Formula	C21H25N3O2S
Mol. mass	383.5099 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	9%
Metabolism	Hepatic
Half-life	6 hours
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	C(US)
Legal status	℞-only (US)
Routes	Oral
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Quetiapine (pronounced /kwɨˈtaɪ.əpiːn/ kwi-TYE-ə-peen), marketed by AstraZeneca as Seroquel and by Orion Pharma as Ketipinor, both as a quetiapine fumarate salt of the drug, is an atypical antipsychoticschizophrenia, bipolar I mania, bipolar II depression, bipolar I depression, and used off-label for a variety of other purposes, including insomnia and anxiety disorders. used in the treatment of

Annual sales are approximately $4.7 billion worldwide, and $2.9 billion in the U.S.^[1] The patent in the U.S., which was set to expire in 2011, received a pediatric exclusivity extension, which pushed its expiration to March 26, 2012.^[2] The patent already expired in Canada. Several pharmaceutical companies are now making generic versions of quetiapine. Quepin is a generic version manufactured and marketed by Specifar ABEE, Athens, Greece.^[3]

Controversy arose over AstraZeneca's aggressive marketing of the Seroquel for off-label uses, including treatment of PTSD in veterans. Several American soldiers and veterans have died while taking Seroquel.^[4]

Contents [show] 1 Uses 1.1 Investigations 2 Pharmacology 3 Forms 3.1 Dosage 3.2 Sustained-release quetiapine 4 Side effects 4.1 Withdrawal effects 5 Overdosage 6 Recreational use 7 Federal investigations 8 Chemistry 9 References 10 Further reading 11 External links

[edit] Uses

Quetiapine (Seroquel) 25 mg tablets, next to US one-cent coin for comparison.

Quetiapine is indicated for the treatment of schizophrenia, depressive episodes associated with bipolar disorder, acute manic episodes associated with bipolar I disorder (as either monotherapy or adjunct therapy to lithium or valproate), and maintenance treatment of bipolar I disorder (as adjunct therapy to lithium or divalproex). Quetiapine received its initial indication from the U.S. Food and Drug Administration for treatment of schizophrenia in 1997.^[5] In 2004, it received its second indication for the treatment of mania-associated bipolar disorder.^[6] It is sometimes used off-label, often as an augmentation agent, to treat conditions such as obsessive-compulsive disorder, post-traumatic stress disorder, restless legs syndrome, autism, alcoholism, depression,^[7] Tourette syndrome,^[8] and has been used by physicians as a sedative for those with sleep disorders or anxiety disorders.^[9]

In 2005, the National Institute of Mental Health examined quetiapine and other antipsychotics to uncover the comparative efficacy of "second generation" anti-psychotics against older anti-psychotics (known as "first generation" or "typical anti-psychotics"). Such information could be important to the patients, as the newer drugs are far more expensive than their older counterparts. Published in the New England Journal of Medicine, the results of the CATIE ("clinical antipsychotic trials of interventional effectiveness") trial were somewhat mixed. 74% of trial participants (of the 1,493 people who were in different treatment groups) discontinued before the trial ended. The majority of the participants discontinued treatment due to intolerable side effects or lack of efficacy. Olanzapine (Zyprexa) was considered the most effective in terms of the time it took patients to drop out of the study, although it was associated with greater weight gain and glucoseperphenazine.^[10] The CATIE trial was supported by a grant (N01 MH90001) from the NIMH and by the Foundation of Hope of Raleigh, N.C. The individual pharmaceutical companies, whose drugs were used, donated all of the study medication. intolerability found in diabetes patients. The effects of all other treatments (such as Seroquel) were considered to be similar to the effects of the generic (and dramatically less expensive) drug,

A report in British Medical Journal in 2005 showed that quetiapine was ineffective in reducing agitation among Alzheimer's patients, whose usage of the drug constituted 29% of sales. In fact, quetiapine was found to worsen cognitive functioning in elderly patients with dementia.^[11]

Use of quetiapine to minimize the symptoms of opioid withdrawal has been studied.^[12]

[edit] Investigations

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.^[13]

In 2010 AstraZeneca was ordered to pay $520 million in a settlement with State and Federal authorities. According to the settlement AstraZeneca promoted the sale and use of Seroquel for uses not approved by the FDA, and paid illegal kickbacks to doctors. As a result of their promotional activity, physicians prescribed Seroquel for children, adolescents and dementia patients in long term care facilities.^[14]

[edit] Pharmacology

Quetiapine has the following pharmacological actions:^{[15][16][17][18]}

• D₁ (IC₅₀ = 1268nM), D₂ (IC₅₀ = 329nM), D₃, and D₄ receptor antagonist
• 5-HT_1A (IC₅₀ = 717nM), 5-HT_2A, 5-HT_2C, and 5-HT₇ receptor antagonist
• α₁-adrenergic (IC₅₀ = 94nM) and α₂-adrenergic receptor (IC₅₀ = 271nM) antagonist
• H₁ receptor (IC₅₀ = 30nM) antagonist
• mACh receptor (IC₅₀ = >5000nM) antagonist (There are contradictions on whether or not this blocks acetylcholine receptors.)

This means Quetiapine is dopamine, serotonin and adrenergic antagonist, anticholinergic substance and antihistamine. 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^[19] 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.^{[citation needed]} receptor.