Quetiapine

Quetiapine ( ), sold under the brand name Seroquel among others, is an atypical antipsychotic medication used in the treatment of schizophrenia, bipolar disorder, and major depressive disorder. Despite being widely prescribed as a sleep aid due to its tranquillizing effects, the benefits of such use may not outweigh the risk of undesirable side effects. It is taken orally. It is available as a generic medication. In 2023, it was the most prescribed antipsychotic and 60th most commonly prescribed medication in the United States, with more than 10million prescriptions. It is on the World Health Organization's List of Essential Medicines.

The drug is typically among two antipsychotics (the other being olanzapine) to have superior efficacy for the treatment of bipolar disorder. Quetiapine is one of only two antipsychotics (the other is cariprazine) that produce equal efficacy as standalone therapies for mixed manic-depressive mood swings as they do in combination with an SSRI antidepressant. However, it is less potent than clozapine, amisulpride, olanzapine, risperidone, and paliperidone in alleviating psychotic symptoms or treating schizophrenia.

Medical uses

thumb|Quetiapine (Seroquel) 25 mg tablets, next to [[Penny (United States coin)|US one-cent coin for comparison]]

thumb|Seroquel XR 150 mg tablet box

Quetiapine is primarily used to treat schizophrenia and bipolar disorder. It targets both positive and negative symptoms of schizophrenia.

Schizophrenia

A 2013 Cochrane review compared quetiapine to typical antipsychotics:

{| class="wikitable"

|+ Quetiapine compared to typical antipsychotics for schizophrenia

! Summary

|Quetiapine may not differ from typical antipsychotics in the treatment of positive symptoms, general psychopathology, and negative symptoms. However, it causes fewer adverse effects in terms of abnormal ECG, extrapyramidal effects, abnormal prolactin levels and weight gain.

It is debatable whether, as a class, typical or atypical antipsychotics are more effective. Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages. While quetiapine has lower rates of extrapyramidal side effects, there is greater sleepiness and rates of dry mouth.

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); 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 but sedation is often an undesirable side effect.

Alzheimer's disease

Quetiapine does not decrease agitation among people with Alzheimer's disease. Quetiapine worsens intellectual functioning in the elderly with dementia and therefore is not recommended.

Insomnia

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. 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 an effect size (standardized mean difference) against placebo for treatment of insomnia of 0.05 (95% –1.21 to 1.11) at 4weeks of treatment, with the certainty of evidence rated as very low. Doses of quetiapine used for insomnia have ranged from 12.5 to 800mg, with low doses of 25 to 200mg being the most typical. 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. 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 of Z-drugs, with most of the risk being driven by cardiovascular death. 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.

Others

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 relatively 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.

;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

High blood pressure
Orthostatic hypotension
High pulse rate
High blood cholesterol
Elevated serum triglycerides
Abdominal pain
Constipation
Increased appetite
Vomiting
Increased liver enzymes
Backache
Asthenia
Insomnia
Lethargy
Tremor
Agitation
Nasal congestion
Pharyngitis
Fatigue
Pain
Dyspepsia (Indigestion)
Peripheral oedema
Dysphagia

Extrapyramidal disease: Quetiapine and clozapine are noted for their relative lack of extrapyramidal side effects.
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 According to one study, rates are lower with the atypicals at 3.9% as opposed to the typicals at 5.5%.

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.

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

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

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. 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.

Pharmacology

Pharmacodynamics

{| class="wikitable floatright" style="font-size:small;"

|+ Quetiapine (and metabolite)

| || >10,000 || 58 || Blocker ||

| 5-HT1B || 1,109–2,050 || 1,117 || ||

Dopamine D1, D2, D3, D4, and D5 receptor antagonist
Serotonin 5-HT1A receptor partial agonist, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptor antagonist, and 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F receptor ligand
α1- and α2-adrenergic receptor antagonist
Histamine H1 receptor antagonist
Muscarinic acetylcholine receptor antagonist

This means quetiapine is a dopamine, serotonin, and adrenergic antagonist, and a potent antihistamine with some anticholinergic properties. Quetiapine binds strongly to serotonin receptors; the drug acts as a partial agonist at 5-HT1A receptors and as an antagonist to all other serotonin receptors it has affinity for. 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.

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. 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 and mirtazapine 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.

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. 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.

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.

Pharmacokinetics

Peak levels of quetiapine occur 1.5 hours after a dose.

class=skin-invert-image|left|thumb|200px|Skeletal formula of norquetiapine

Chemistry

Quetiapine is a tetracyclic compound and is closely related structurally to clozapine, olanzapine, loxapine, and other tetracyclic antipsychotics.

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.

class=skin-invert-image|center|600px

History

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.

In May 2007, the United States FDA approved Seroquel XR for acute treatment of schizophrenia. During its 2007 Q2 earnings conference, AstraZeneca announced plans to launch Seroquel XR in the United States in August 2007. However, Seroquel XR has become available in American 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. 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.

In October 2008, the FDA approved Seroquel XR for the treatment of bipolar disorder, including its associated depression and manic episodes.

In December 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.

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.

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 approval from the US FDA for the 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.

Patent protection for the product ended in 2012; however, in a number of regions, the long-acting version remained under patent until 2017.

Lawsuits

In April 2010, the United States Department of Justice fined AstraZeneca $520 million for the company's aggressive marketing of Seroquel for off-label uses.

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 United Kingdom'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 tablets 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.