Quetiapine

Quetiapine (/kwɨˈtaɪ.əpiːn/ kwi-TY-ə-peen) (developed and marketed as Seroquel by AstraZeneca) is an atypical antipsychotic approved for the treatment of schizophrenia, bipolar disorder, and along with an antidepressant to treat major depressive disorder.

Annual sales are approximately $1.3 billion worldwide. Quetiapine was developed by AstraZeneca from 1992â€"1996 as an improvement from first generation antipsychotics. It was first approved by the FDA in 1997. There are now several generic versions of quetiapine.

Medical uses

Quetiapine fumarate is primarily used to treat schizophrenia or bipolar disorder.

Schizophrenia

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. A second Cochrane Review comparing quetiapine to typical antipsychotics concluded that quetiapine

• Has efficacy against positive symptoms that appears no better than typical antipsychotics, but might be more efficacious for negative symptoms.
• Has discontinuation rates similar to those of typical antipsychotics, but fewer of these discontinuations were due to adverse events.
• Produces fewer side effects, particularly movement related side effects.
• 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.

Asmal L, Flegar SJ, Wang J, Rummel-Kluge C, Komossa K, Leucht S (2013). "Quetiapine versus other atypical antipsychotics for schizophrenia". Cochrane Database Syst Rev 11: CD006625. doi:10.1002/14651858.CD006625.pub3. PMID 24249315. 

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).

Major depressive disorder

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

In the US, the UK 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.

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.

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.

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

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.

Adverse effects

Sources for incidence lists:

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)

Common (1-10% incidence) adverse effects

• Extrapyramidal disease â€" quetiapine and clozapine are noted for their relative lack of extrapyramidal side effects
• Weight gain â€" 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. As with many other atypical antipsychotics this action is likely due to its actions at the H₁ histamine receptor and 5-HT2C receptor.

Rare (<1% incidence) adverse effects

• Prolonged QT interval (had an odds ratio for prolonging the QT interval over placebo of 0.17)
• Sudden cardiac death
• Syncope
• Diabetic ketoacidosis
• Restless legs syndrome
• Hyponatraemia, low blood sodium.
• Jaundice, yellowing of the eyes, skin and mucous membranes due to an impaired ability of the body to clear bilirubin, a by product of haem breakdown.
• Pancreatitis, pancreas swelling.
• Agranulocytosis, a potentially fatal drop in white blood cell count.
• Leukopenia, a drop in white blood cell count, not as severe as agranulocytosis.
• Neutropenia, a drop in neutrophils, the cell of the immune cells that defends the body against bacterial infections.
• Eosinophilia
• Anaphylaxis, a potentially fatal allergic reaction.
• Seizure
• Hypothyroidism, underactive thyroid gland.
• Myocarditis, swelling of the myocardium.
• Cardiomyopathy
• Hepatitis, swelling of the liver.
• Suicidal ideation
• Priapism. A prolonged and painful erection.
• Stevens-Johnson syndrome. A potentially fatal skin reaction.

• 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

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

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.

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 still recommends users have eye examinations every six months.

As with some other anti-psychotics, quetiapine may lower the seizure threshold, 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. 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. 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.

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 1â€"10 mg/L range in overdose survivors, while postmortem blood levels of 10â€"25 mg/L are generally observed in fatal cases.

Pregnancy and lactation

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

Pharmacology

Quetiapine has the following pharmacological actions:

• D₁ (IC₅₀ = 1268nM), D₂ (IC₅₀ = 329nM), D₃, and D₄ receptor antagonist
• 5-HT_1A (IC₅₀ = 717nM) partial agonist, 5-HT_2A (IC₅₀ = 148nM), 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

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-HT_1A receptors. Serial PET scans evaluating the D₂ receptor occupancy of quetiapine have demonstrated that quetiapine very rapidly disassociates from the D₂ receptor. 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. Some of the antagonized receptors (serotonin, norepinephrine) are actually autoreceptors whose blockade tends to increase the release of neurotransmitters.

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.

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

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, orthostatic hypotension, 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.

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

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. 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. During its 2007 Q2 earnings conference, AstraZeneca announced plans to launch Seroquel XR in the U.S. during August 2007. 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. 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.

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. 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.

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. In 2009, quetiapine XR was approved as adjunctive treatment of major depressive disorder.

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

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. 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."

Multiple lawsuits have been filed in relation to quetiapine's side-effects, in particular, diabetes.

Approximately 10,000 lawsuits 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. A group of University of Minnesota bioethicists charged that the trial involved an alarming number of ethical violations.

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.

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. The contamination was later traced to in-store tampering by a customer.

References

External links

• "Quetiapine". MedlinePlus. The American Society of Health-System Pharmacists, Inc. 2008-09-01. 
• NAMI summary
• Internet Drug List summary
• Compound #1802: Quetiapine ChemBank
• Intranasal Quetiapine Abuse
• U.S. National Library of Medicine: Drug Information Portal - Quetiapine
• Seroquel Adverse Events Reported to the FDA
• Australian Public Assessment Report for Quetiapine (as fumarate)