Quetiapine

Quetiapine (pronounced kwe-TYE-a-peen or kwəˈtɑɪəˌpiːn ), marketed by AstraZeneca with the brand name Seroquel, belongs to a series of neuroleptics known as "atypical antipsychotics", which have, over the last four decades, become increasingly popular alternatives to "typical antipsychotics", such as haloperidol (Haldol).

Uses
Quetiapine has Food and Drug Administration (FDA) and international approvals for the treatment of schizophrenia and acute mania in bipolar disorder. It is also used off-label to treat other disorders, such as post-traumatic stress disorder, alcoholism, obsessive compulsive disorder, anxiety disorders, hallucinations in Parkinson's disease patients using ropinirole, and as a sedative for those with sleep disorders. It has also shown to be effective as monotherapeutic treatment of depressive episodes associated with bipolar depression, for which AstraZeneca is currently seeking FDA approval. 

Chemistry
Quetiapine (shown in figure) is 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine, C21H25N3O2S. Dosages are based on milligrams of this base. The Seroquel formulation is as a fumarate salt with the chemical formula C42H50N6O4S2·C4H4O4 and systematic name 2-[2-(4-dibenzo [b,f] [1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol fumarate (2:1) (salt).

Pharmacology
The antipsychotic effect of quetiapine is thought to be mediated through antagonist activity at dopamine and serotonin receptors. Specifically the D1, D2, 5-HT1A and 5-HT2 receptor subtypes are antagonized. 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 their normal effects in areas such as the nigrostriatal and tuberoinfundibular pathways, thus minimizing the risk of side effects such as pseudo-parkinsonism and elevations in prolactin.

Quetiapine also has an antagonistic effect on the histamine H1 receptor. This may be responsible for the sedative effect of the drug.

Forms
Quetiapine is available under the brand name Seroquel. It was originally available in 25mg, 100mg, 200mg, and 300mg tablets, however 50mg and 400mg tablets were added to increase dosing flexibility. AstraZeneca is planning to soon release a sustained release formula (Seroquel SR) to lessen the number of pills patients need to remember taking daily. AstraZeneca has also patented this formula so it can still profit from Quetiapine when its original patent expires. They will market this drug not only for Schizophrenia and Bipolar Disorder, but also for Major depressive disorder and General anxiety disorder.

Dosage
Quetiapine is available in 25, 100, 150, 200 and 300 mg oral doses. While the effective dose for schizophrenia is typically between 300 and 600 mg daily, doses as high as 1000 mg daily are sometimes prescribed. Initial dosage is typically 100 to 300 mg (but may be as low as 25 to 50 mg), sometimes prescribed in divided doses throughout the day (typically evening and morning). Dosage for sleep disorders is typically 25 to 100 mg. Initial reaction to quetiapine may be somnolence. As such, care is taken to avoid over exposure to the drug during the first few doses. After a patient becomes more familiar with the effects, the dosage may be "ramped up." The dosage of Quetiapine is often increased faster than with other atypical antipsychotics; AstraZeneca claims that a healthcare provider can "achieve up to 800mg/day in less than a week." Such large doses are provided throughout a full day in divided, roughly equal doses.

Care is needed when starting dosages in elderly patients. The usual dosage adjustments come in four or more steps. The order usually begins with 25mg at night, then proceeds to 50mg at night, then 25mg at day and 50mg at night, followed by 50mg in the day and then 50mg at night. The dosage may then be gradually increased if needed. This dosage schedule is similar to the one required for younger adults.

Side effects
The most common side effect is sedation, and is prescribed specifically for this effect in patients with sleep disorders. Seroquel will put the patient into a drowsy state, and will help the patient fall asleep. It is one of the most sedating of all anti psychotic drugs, rivaling even the most sedating older antipsychotics. Even though official guidelines call for the quetiapine dosage to be divided throughout the day, many prescriptions call for the entire dose to be taken before bedtime because of its sedative effects. Although quetiapine is approved by the FDA for the treatment of schizophrenia and bipolar disorder, it is frequently prescribed for off-label purposes including insomnia or the treatment of anxiety disorders. Due to its sedative side effects, reports of quetiapine abuse (sometimes by insufflating crushed tablets) have emerged in medical literature; for the same reason, abuse of other antipsychotics, such as chlorpromazine (Thorazine), may occur as well, but research related to the abuse of typical antipsychotics is limited.

Other common side effects include: agitation, constipation, memory problems (anterograde amnesia in particular is very common), headache, abnormal liver tests, dizziness, upset stomach, substantial weight gain, and a stuffy nose feeling. They have the tendency to weaken with time, being most pronounced during the first week of treatment.

Two rare but serious side effects from quetiapine are neuroleptic malignant syndrome and tardive dyskinesia. However, quetiapine is believed to be less likely to cause extrapyramidal side effects and tardive dyskinesia   than typical antipsychotics. Weight gain can be a problem for some patients using quetiapine, by causing the patient's appetite to persist even after meals. However, this effect may occur to a lesser degree compared to some other atypical antipsychotics such as olanzapine or clozapine. Like other atypical antipsychotics, there is some evidence suggesting a link to the development of diabetes, however this remains unclear and controversial.

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. (Reference needed to April 2006 results of CATIE study.) However, the Seroquel website still recommends that you have your eyes examined every six months.

As with some other antipsychotics, quetiapine may lower the seizure threshold, and should be taken with care in combination with drugs such as Bupropion.

Abuse liability
Though not very common or confirmed, quetiapine has abuse potential due to its sedative side effect profile. Users may crush the pill and insufflate the substance for rapid onset, or ingest multiple times the recommended dose. For sensitive users, doses as low as 50mg could severly sedate the individual. Negative side effects are much more likely to occur when this medication is abused.