Continuing Education Activity

Quetiapine is FDA approved for schizophrenia, acute manic episodes, and adjunctive treatment for major depressive disorder. Quetiapine is also used for several non-FDA-approved indications, such as generalized anxiety disorder. Quetiapine is available both as extended-release (once-daily dosing) or immediate-release (twice-daily dosing) tablets. This activity outlines the indications, mechanism of action, methods of administration, significant adverse effects, contraindications, monitoring, and toxicity of quetiapine, so providers can direct patient therapy successfully in instances where quetiapine provides a benefit to patient care.

Objectives:

• Outline the approved and off-label uses for quetiapine.
• Describe the adverse effects of quetiapine.
• Review the mechanism of action of quetiapine.
• Identify the importance of interprofessional communication regarding the adverse effects of quetiapine.

Indications

Quetiapine is FDA approved for schizophrenia, acute manic episodes, and adjunctive treatment for major depressive disorder. There is FDA indication through three 6-week trials and one 6-week trial for schizophrenia in adults and adolescents ages 13 to 17. The first trial showed that in adults, the maximal effect occurred at 300 mg per day. A mean of around 450 mg per day in the second trial showed superiority over placebo, and a mean of  500 mg per day in the third trial showed superiority over the group that received 50 mg a day. The researchers concluded that the effective range was from 150 mg to 750 mg for treating schizophrenia in adults. In the one six-week trial, the conclusion was that quetiapine, at an average dose of 400 mg/day to 800 mg/day, was superior to the placebo in adolescents. Two 12-week trials showed efficacy for mono-therapeutic effects.

Treatment for acute manic episodes associated with bipolar I disorder in adults with a majority at a dosing range of 400 mg/day to 800 mg/day. One three-week trial showed that quetiapine was effective as an adjunct treatment for acute manic episodes in bipolar I disorder to lithium or divalproex in adults. One three-week trial showed efficacy at 400 mg/day to 600 mg/day for mono-therapeutic treatment for bipolar I disorder for children and adolescents ages 10 to 17. Two trials showed effectiveness in the acute treatment of depressive episodes in bipolar I and II in adult patients. The drug showed efficacy at 300 mg/day, and no additional benefits were apparent at a high 600 mg/day dosage.[1] Two maintenance trials showed effectiveness in maintaining bipolar disorder at dosages of 400 mg/day to 800 mg/day.[2][3]

Quetiapine has uses in several non-FDA-approved indications, such as generalized anxiety disorder. Three randomized control trials have shown the efficacy of treatment in mono-therapeutic treatment over placebo. Research on other off-label uses has not been strong enough to advocate FDA approval, and more clinical trials are necessary.[4] Another clinical trial showed effectiveness in the mono-therapeutic treatment of major depressive disorder and as adjunctive with antidepressants. Other non-FDA approved: psychosis in patients with Parkinson's disease, insomnia, maintenance of schizophrenia, and chronic post-traumatic stress disorder (PTSD).[5][6] Adjunctive treatment with SSRI for obsessive-compulsive disorder (OCD), borderline personality disorder, decreasing aggression with psychiatric illness, major depressive disorder, and symptomatic treatment of insomnia, agitation, and anxiety.[7][8][9] A limited number of case reports support efficacy in these situations, yet it is still commonly prescribed for such off-label treatments. For these reasons, clinicians should avoid using long-term treatment as the side effects outweigh the unestablished benefits.

Mechanism of Action

Quetiapine has a strong affinity for the 5-HT2 receptor. Although quetiapine has many complex mechanisms, it mediates its pharmacological effect mainly via its 5HT2 antagonistic action. It also acts on dopaminergic D1 and D2 receptors. Quetiapine is an antagonist for D2 receptors and 5-HT2 receptors.[10] It is also suggested that the anxiolytic and antidepressant properties of both quetiapine and its active metabolite norquetiapine are due to the norepinephrine transporter (NET) inhibitory potential and partial agonist activity at the 5 HT1A receptor, respectively.[11]

Blocking the D2 receptor in mesocortical and mesolimbic pathways is indicated in the treatment of schizophrenia for negative and positive symptoms, respectively. Increased dopamine in these pathways has been shown to be associated with schizophrenia. Jensen et al. also reported that antidepressant activity is also mediated by its 5HT2A and 5-HT7 antagonistic properties. Furthermore, norquetiapine has an affinity for other receptors, such as H1 histamine receptor, 5-HT1E, 5-HT2A, 5-HT2B, 5-HT7 serotonergic receptors, M1, M3, and M5 muscarinic receptors, and α1-adrenergic receptors.[12]

Administration

Quetiapine is available both as quetiapine extended-release (ER; once-daily dosing) or quetiapine immediate release (IR; twice to three times daily dosing) tablets. The tablets are available in 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, and 400 mg tablets, with the ER dose formulation available in 50 mg, 150 mg, 200 mg, 300 mg, and 400 mg tablets. Figueroa et al. also reported that 800 mg/day is the maximum recommended dose for quetiapine IR formulation twice or thrice daily divided doses. After oral administration, it is promptly absorbed and reaches its peak plasma concentration in approximately 1 to 2 hours. The reported half-life (t1/2) for quetiapine is about 7 hours.[13][14][15]

Dosing is as follows (all dosing is oral):

For Schizophrenia

• IR: 150 to 750 mg daily in two or three divided doses; start at 25 mg twice daily, and titrate up to 300 to 800 mg daily in two or three divided doses, with daily increases of 50 to 150 mg. In elderly patients, increase 25 to 50 mg daily.
• ER: 400 to 800 mg each evening; start with 300 mg daily with up to 300 mg increases daily or as needed. In the elderly, start at 50 mg daily with 50 mg dose increments. Patients should not chew, crush, or cut the ER tablets.

For Bipolar I Disorder (manic)

• IR: 200 to 400 mg twice daily. Start at 50 mg twice daily, increasing by 100 mg a day to 200 mg twice daily by the fourth day, then begin increasing by 200 mg each day as needed. The maximum dose is 800 mg daily.

For Bipolar I Disorder (manic/mixed)

• ER: 400 to 800 mg each evening. Start at 300 mg daily for one day, then 600 mg in the evening for one day; adjust by 200 mg per day or as needed to a maximum dose of 800 mg daily. In the elderly, start with 50 mg in the evening with 50 mg increments daily for therapeutic effectiveness.

For Acute Depressive Bipolar Disorder 

• IR: 300 mg daily at bedtime; start at 50 mg at bedtime for one day, then 100 mg at bedtime for one day, 200 mg at bedtime for one day, then 300 mg at bedtime. The maximum dose is 600 mg daily, with doses over 300 mg daily rarely demonstrating effectiveness. For the elderly, start with 25 mg at bedtime, with 25 to 50 mg dose increases daily. 
• ER: 300 at bedtime; start with 50 mg in the evening, then 100 mg each evening for one day, 200 mg in the evening for one day, then 300 mg in the evening. The maximum dose is 300 mg daily. In the elderly, start with 50 mg in the evening, with 50 mg daily dose increments. Patients should not chew, crush, or cut the ER tablets.

As an adjunct treatment measure for various forms of major depressive disorder, the dose ranges from 50 to 300 mg daily with the IR form and 150 to 300 mg daily with the ER form, using similar titration schedules to a maximum of 300 mg daily.

For efficacy, a range of 300 mg to 800 mg a day should be optimal, and for some patients, prescribers can try a non-FDA-approved dose of 1200 mg to 1600 mg per day for benefits, with QT interval monitoring.

Adverse Effects

As with any antipsychotic drug, quetiapine is associated with an increased risk of death in dementia-related psychosis in elderly patients. Alongside this risk, neuroleptic malignant syndrome should be a consideration due to its D2 receptor blockage. It is the least likely of atypical antipsychotics to cause extrapyramidal symptoms. There is an increased risk for suicidal thoughts and behavior associated with drug treatment in major depressive disorder patients. Somnolence, orthostatic hypotension, and dizziness are the most common side effects of quetiapine. Somnolence and dizziness are due to the nature of quetiapine’s antagonism of H1 receptors, while antagonism causes hypotension for alpha-1 receptors.[16] Stroke, myocarditis, and coronary heart disease have also correlated with the use of this drug.[17]

Contraindications

There are currently no known FDA contraindications to quetiapine. However, there are several precautions to be considered when administering this drug. As mentioned before, quetiapine and other atypical antipsychotics are associated with an increased risk of death in elderly patients with dementia-related psychosis. Also, precaution is a consideration with drugs that increase QT intervals and patients with prolonged QT intervals. Drugs include Class I and Class III antiarrhythmics, antipsychotics, macrolides, fluoroquinolone, pentamidine, levomethadyl acetate, methadone, first-, and second-generation antipsychotics, tricyclic antidepressants, quinine, halofantrine, and albendazole. These combinations put the patient at risk for torsades de pointes. Precautions are also necessary for patients with a history of cardiac arrhythmia, hypokalemia, and hypomagnesemia.[18] The clinician should consider metabolic panels before starting the drug. Patients with diabetes mellitus should have their glucose monitored in an attempt to avoid hyperosmolar coma.[19] Quetiapine is not recommended for breastfeeding women, and a high benefit to risk rationale is necessary for use in pregnant women.[17]

Monitoring

The therapeutic range of quetiapine is between 100 ng/mL to 1000 ng/mL. As mentioned before, patients commonly experience somnolence, dizziness, and orthostatic hypotension. Within this therapeutic range, the patient might experience other common side effects such as tachycardia, dyspnea, cough, pharyngitis, rhinitis and nasal congestion, dry mouth, constipation, dyspepsia, abdominal pain, leukopenia, neutropenia, lethargy, hyperlipidemia, hyperglycemia, peripheral edema, sedation, weight gain, and tardive dyskinesia. Monitor the metabolic panel with a specific focus on fasting glucose, cholesterol and triglyceride levels, blood pressure, and weight. Patients should also receive a lens examination every six months during long-term treatment for cataract monitoring. Agranulocytosis is a very rare but reported side effect associated with quetiapine use.[17]

Toxicity

Quetiapine can be life-threatening if abused or misused. Toxicity is associated with levels greater than 1500 ng/mL in serum or plasma. Supportive care is the mainstay of treatment. In acute toxicity, measures are necessary to maintain the airway and ensure adequate oxygenation and ventilation. Gastric lavage and activated charcoal administration alongside a laxative to prevent further drug absorption are used if time appropriate. Plasma concentrations of quetiapine reach maximal levels within 1 to 2 hours of oral administration. ECG is a recommendation to monitor for possible Torsades de pointes or another arrhythmia due to QT-interval prolongation. Treat extrapyramidal effects with anticholinergic and hypotension with intravenous fluids and sympathomimetic agents such as A1 agonists. Management/treatment of neuroleptic malignant syndrome is possible by immediate withdrawal of quetiapine, followed by the management of symptoms.[20][21] 

Currently, no definitive antidote exists to reverse quetiapine toxicity; however, in a case report, the patient developed toxicity secondary to quetiapine, characterized by hypotension, tachycardia, altered sensorium, and electrocardiogram (ECG) showed a QT interval of 110 milliseconds. After the initial failure of symptomatic management, the patient was treated successfully after administration of Intravenous lipid emulsions (ILEs) (a source of calories and essential fatty acids rendered for patients who do not tolerate enteral nutrition) at a dose of 1.5 mg/kg for up to two doses 15 minutes apart. Rapid improvement was seen in the patient after 30 minutes. It is proposed that it might be because of the lipophilic nature of quetiapine.[22] Similarly, the beneficial effect of ILE was also reported by Bartos and Knudsen in resuscitating patients with cardiovascular collapse.[23] Another case series study reported successful reversal of significantly altered mental status with physostigmine (a muscarinic agonist).[24]

Enhancing Healthcare Team Outcomes

Quetiapine is associated with several potentially dangerous side effects. The nurse, pharmacist, and clinicians should communicate and work with an interprofessional team to monitor patients taking this medication. [Level 5]