A Brief Review of Quetiapine

Quetiapine has dose-dependent clinical efficacy, inspiring Dr. Stephen Stahl (1, 2) to question whether it was a different drug at different doses. At low doses (50 mg per day), quetiapine has well-demonstrated hypnotic and sedative effects attributable to histamine 1-receptor blockade. With midrange doses (300 mg per day), mood effects are secondary to both dopaminergic (D2 receptor) and serotonergic (5HT2A receptor) blockade. With higher doses (800 mg per day), for the purposes of true antipsychotic activity, clinical effects are mediated through serotonergic, muscarinic, alpha adrenergic, and histaminergic receptor blockade (1, 2).

The metabolism of quetiapine is mediated by the cytochrome P450 system, and CYP 3A4 and CYP 2D6 are the predominant enzymes involved in drug transformation (1). With respect to the pharmacokinetic characteristics of quetiapine, the half-life of the parent compound is 7 hours, and the oral bioavailability of the drug in tablet form is nearly 100% of the bioavailability in oral solution. The time to peak plasma concentration is 1–2 hours for the immediate-release formulation. Plasma protein binding is 83%, and the volume of distribution of quetiapine is 10±4 L per kg (3).

Norquetiapine, the active metabolite of quetiapine, is thought to be responsible for the anxiolytic and antidepressant effects of quetiapine through inhibition of the norepinephrine transporter (NET) and serotonin receptor agonism (2). The sedative effects of quetiapine are sometimes diminished at higher doses, a phenomenon potentially attributable to the high affinity of norquetiapine for NET and resulting elevated synaptic norepinephrine levels.

Data related to use of quetiapine in pregnancy are extremely limited, although clear evidence of teratogenic effects is lacking. Risks to the newborn associated with third-trimester antipsychotic use include abnormal muscle movements and withdrawal symptoms (1). However, uncontrolled psychiatric conditions may also be associated with fetal harm; thus, the decision to initiate or discontinue antipsychotic therapy in pregnant patients should be made on a case-by-case basis.

One randomized placebo-controlled trial showed statistically significant improvements in Positive and Negative Syndrome Scale scores in youths ages 13–17 who had a diagnosis of schizophrenia (18). Although some evidence suggests a role for quetiapine in the treatment of bipolar mania, data related to its use in bipolar depression are limited (11). Additionally, there is limited evidence for the use of quetiapine in children with autism.

A less well-known consequence of quetiapine prescription is related to its potential for abuse. Quetiapine is the most abused drug among the SGAs and carries considerable street value (19). Street names for the drug include “Susie-Q,” “baby heroin,” and “quell,” and the combination of quetiapine with either heroin or cocaine is referred to as a “Q-ball”. Importantly, quetiapine can enhance the euphoric effects of recreational drugs, such as cocaine and heroin, but it can also be used to counter the effects of stimulants and mitigate withdrawal symptoms. Of note, quetiapine misuse is relevant in correctional settings, where clinicians may be more hesitant or unable to prescribe the medication, potentially leading to disruptions in care.

Histamine 1-receptor blockade leads to sedative effects and is also believed to be responsible for dose-dependent weight gain. Dizziness, hypotension, and syncope result from blockade of the alpha 1-adrenergic receptor (1). Anticholinergic side effects, particularly at high doses, are a consequence of muscarinic cholinergic receptor blockade. Classic adverse effects include blurred vision, dry mouth, urinary retention, constipation, and paralytic ileus (1, 2). Temperature dysregulation is a dose-independent adverse effect hypothesized to result from D2 and 5HT2A receptor antagonism. Importantly, compared with first-generation antipsychotics, quetiapine, an SGA, exhibits more transient D2 receptor activity and is therefore associated with a decreased incidence of extrapyramidal symptoms (EPS). Nevertheless, EPS and tardive dyskinesia are risks of quetiapine therapy (2). Quetiapine also has the potential to produce neuroleptic malignant syndrome because of its dopamine receptor blockade, although this side effect is rare. Metabolic side effects include triglyceride elevation, insulin resistance, and hypothyroidism at midrange and higher doses. Secondary to insulin resistance, quetiapine is associated with an increased risk of type 2 diabetes.

Lethal overdose is rare when quetiapine is taken alone. Quetiapine-related toxicity is typically associated with central nervous system (CNS) depression, leading to slurred speech, sedation, and hypotension. Notably, quetiapine has a black box warning associated with death in older adults with dementia, and higher doses are believed to exacerbate this risk (1).

Rifampin, carbamazepine, phenytoin, and phenobarbital all decrease quetiapine levels via CYP 3A4 enzymatic induction (1). Phenytoin has the potential to reduce quetiapine levels by up to five times. Conversely, ketoconazole and other medications of the same antifungal class are potent CYP 3A4 inhibitors, potentially leading to increased drug levels. Many antiviral medications used in the treatment of HIV, AIDS, and hepatitis C are also strong 3A4 inhibitors (20).

Quetiapine is a QT-prolonging medication, and concomitant use with amiodarone, sotalol, methadone, or fluoroquinolones comes with the risk of prolonged QT and Torsades de Pointes (20).

Medications used in the treatment of Parkinson’s disease (such as levodopa, ropinirole, or pramipexole) will interact with quetiapine, and combined use with dopamine antagonists (such as metoclopramide) is associated with the development of EPS (1, 20).

Antihypertensive medications and alpha adrenergic blockers, such as tamsulosin, can enhance the hypotensive effects of quetiapine. Other synergistic interactions include those with anticholinergic medications (tricyclic antidepressants, cholinesterase inhibitors, and antihistamines), antidiabetic agents, stimulants, and CNS depressants, such as opioids, benzodiazepines, and alcohol (1, 20). Quetiapine should be used cautiously in patients taking warfarin because an increased international normalized ratio has been observed with this combination. Additionally, an 11-fold increase in quetiapine levels has been reported when the drug is taken in combination with the antiemetic aprepitant (20).