Quetiapine


Article Author:
Jasdave Maan


Article Editor:
Abdolreza Saadabadi


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James Hughes
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Phillip Hynes
Tehmina Warsi


Updated:
5/5/2019 1:50:10 PM

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, respectively.  It was shown that in the first trial in adults that the maximal effect was seen at 300 mg per day. A mean of around 450 mg per day in the second trial showed superiority to placebo and a mean of  500 mg per day in the third trial showed superiority over the group that received 50 mg a day. Effective range was concluded to be from 150 mg to 750 mg for the treatment of schizophrenia in adults. In the one six-week trial, it was concluded 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 shown at a high 600 mg/day dosage.[1] Two maintenance trials showed effectiveness in the maintenance treatment of bipolar disorder at dosages of 400 mg/day to 800 mg/day.[2][3]

Quetiapine is used for 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 in other off labels has not been strong enough to advocate FDA approval and more clinical trials are needed.[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 disease, insomnia, maintenance of schizophrenia, 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, symptomatic treatment of insomnia, agitation, and anxiety.[7][8][9] There is a limited number of case reports that support efficacy in these situations, but yet commonly it is still prescribed for such off-label treatments. Long-term treatment for these reasons should be avoided as the side effects outweigh the unestablished benefits.

Mechanism of Action

Quetiapine is an antagonist for D2 receptors and 5-HT2 receptors. Quetiapine blocks 5HT1A, 5-HT2, D1,D2,H1, A1, and A2 receptors.  Quetiapine itself does not act on cholinergic or benzodiazepine receptors. However, a metabolite of quetiapine, norquetiapine, blocks M1 receptors. Blocking of 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 shown to be associated with schizophrenia.

Administration

Quetiapine is available both as quetiapine extended release (once daily dosing) or quetiapine immediate release (twice daily dosing) tablets. The tablets are available in 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, and 400 mg tablets. For efficacy, a range of 300 mg to 800 mg a day should be reached, and for some patients, a non-FDA approved 1200 mg to 1600 mg day can be attempted for benefits with QT interval monitoring.

Adverse Effects

As with any antipsychotic drugs, Quetiapine is associated with increased risk of death in dementia-related psychosis in elderly patients. Alongside this risk neuroleptic malignant syndrome should be considered 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.[10]Stroke, myocarditis and coronary heart disease have also been implicated with the use of this drug.[11]

Contraindications

There are currently no know FDA contraindications of Quetiapine. However, there are several precautions to be considered when administering this drug. As mentioned before Quetiapine, along with other atypical antipsychotics, is associated with increased risk of death in elderly patients with dementia-related psychosis. Also, precaution must be considered with drugs that increase QT interval and patients with prolonged QT intervals.  Drugs include Class I & class III antiarrhythmics, antipsychotics, macrolides, fluoroquinolone, pentamidine, levomethadyl acetate, methadone,  1st, and 2nd generation antipsychotics, tricyclic antidepressants, quinine, halofantrine, and albendazole. This puts the patient at risk for Torasedes de points. Precautions should also be taken in patients with a history of cardiac arrhythmia, hypokalemia, and hypomagnesemia.[12]Metabolic panels should be considered prior to administration of the drug. In patients with Diabetes Mellitus, patients should have their glucose monitored in an attempt to avoid hyperosmolar coma [13] Quetiapine is not recommended for women who are breastfeeding and high benefit to risk rationale needed for use in pregnant women.[11] 

Monitoring

The therapeutic range of quetiapine has been found to be 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 have an examination of lens every six months during long-term treatment for cataract monitoring. Agranulocytosis is a very rare but reported side effect associated with quetiapine use.[11]

Toxicity

Toxicity is associated with levels greater than 1500 ng/mL. Currently, an antidote does not exist to reverse quetiapine toxicity. In acute toxicity, measures should be taken to maintain airway, ensure adequate oxygenation, and ventilation. Gastric lavage and activated charcoal administration alongside a laxative to prevent further absorption of the drug if time appropriate. Plasma concentrations of Quetiapine reach maximal levels within 1 to 2 hours of oral administration. ECG is indicated 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 achieved by immediate withdrawal of quetiapine followed by management of symptoms.

Enhancing Healthcare Team Outcomes

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


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Quetiapine - Questions

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Which of the following antipsychotic medications is most likely to cause thyroid dysfunction?



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A 17-year-old girl is brought to the clinic by her father with claims that she owns a nearby hospital and is constructing another hospital nearby. She states she is hearing voices that tell her to bring down other hospitals and has been having meetings with the founder of the first hospital. She said she brought him here with her after their lunch meeting to make her father understand why she needs to drop out of school. She talks to the wall as if talking to someone there. Her delusions are confirmed. The patient’s father states that she had been on fluphenazine several years ago but stopped taking it because it caused severe spasms and arm stiffness. Her blood pressure is 120/80 mmHg, BMI 20, pulse 88 bpm, and oxygen saturation 97%. She is started on an initial target dosage of 350 mg daily of an atypical antipsychotic medication that is least known for extrapyramidal effects. When seen six months later, she had not improved and had gained 2.1 pounds, but her vitals were normal. What is the most likely reason for the treatment's failure?



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A 23-year-old man is brought to a psychiatric facility on an involuntary hold due to an acute manic episode. He has a previous history of bipolar type I disorder and has had five manic episodes in the past year. He has failed treatment with lithium, valproic acid, divalproex, carbamazepine, and lamotrigine. He recently started taking fluphenazine but had to discontinue due to spams and stiffness in his legs. The patient was started on 350 mg daily of quetiapine. He is discharged home after 2 weeks to his father and wife. Six months later he was re-hospitalized with another manic episode. The patients family states they had seen him take the medications every day, and he has no history of substance abuse. What is the next best step in the treatment of this patient?



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A 27-year-old male with a history of schizophrenia has been taking quetiapine for several years and has been responding well. On examination, his arms and legs show no signs of rigidity. The patient denies feeling restless or having spasms in the past few years. Which of the following could cause this patient to develop spasms, rigidity, and restlessness?



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Quetiapine - References

References

Systematic review of interventions for treating or preventing antipsychotic-induced tardive dyskinesia., Bergman H,Walker DM,Nikolakopoulou A,Soares-Weiser K,Adams CE,, Health technology assessment (Winchester, England), 2017 Aug     [PubMed]
Maneeton N,Maneeton B,Woottiluk P,Likhitsathian S,Suttajit S,Boonyanaruthee V,Srisurapanont M, Quetiapine monotherapy in acute treatment of generalized anxiety disorder: a systematic review and meta-analysis of randomized controlled trials. Drug design, development and therapy. 2016;     [PubMed]
Villarreal G,Hamner MB,Cañive JM,Robert S,Calais LA,Durklaski V,Zhai Y,Qualls C, Efficacy of Quetiapine Monotherapy in Posttraumatic Stress Disorder: A Randomized, Placebo-Controlled Trial. The American journal of psychiatry. 2016 Dec 1;     [PubMed]
Suttajit S,Srisurapanont M,Maneeton N,Maneeton B, Quetiapine for acute bipolar depression: a systematic review and meta-analysis. Drug design, development and therapy. 2014;     [PubMed]
Lindström L,Lindström E,Nilsson M,Höistad M, Maintenance therapy with second generation antipsychotics for bipolar disorder - A systematic review and meta-analysis. Journal of affective disorders. 2017 Apr 15;     [PubMed]
Garriga M,Solé E,González-Pinto A,Selva-Vera G,Arranz B,Amann BL,Saiz-Ruiz J,Pérez-Blanco J,Vieta E, Efficacy of quetiapine XR vs. placebo as concomitant treatment to mood stabilizers in the control of subthreshold symptoms of bipolar disorder: Results from a pilot, randomized controlled trial. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2017 Oct     [PubMed]
Yuan M,Sperry L,Malhado-Chang N,Duffy A,Wheelock V,Farias S,O'Connor K,Olichney J,Shahlaie K,Zhang L, Atypical antipsychotic therapy in Parkinson's disease psychosis: A retrospective study. Brain and behavior. 2017 Jun     [PubMed]
Nagata T,Nakajima S,Shinagawa S,Plitman E,Nakayama K,Graff-Guerrero A,Mimura M, Baseline Predictors of Antipsychotic Treatment Continuation and Response at Week 8 in Patients with Alzheimer's Disease with Psychosis or Aggressive Symptoms: An Analysis of the CATIE-AD Study. Journal of Alzheimer's disease : JAD. 2017     [PubMed]
Riedel M,Schmitz M,Østergaard PK,Ferrannini L,Franco MA,Alfano V,Vansvik ED, Comparison of the effects of quetiapine extended-release and quetiapine immediate-release on cognitive performance, sedation and patient satisfaction in patients with schizophrenia: a randomised, double-blind, crossover study (eXtRa). Schizophrenia research. 2015 Mar     [PubMed]
Weber SR,Wehr AM,Duchemin AM, Prevalence of antipsychotic prescriptions among patients with anxiety disorders treated in inpatient and outpatient psychiatric settings. Journal of affective disorders. 2016 Feb     [PubMed]
Solmi M,Murru A,Pacchiarotti I,Undurraga J,Veronese N,Fornaro M,Stubbs B,Monaco F,Vieta E,Seeman MV,Correll CU,Carvalho AF, Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review. Therapeutics and clinical risk management. 2017     [PubMed]
Aronow WS,Shamliyan TA, Effects of atypical antipsychotic drugs on QT interval in patients with mental disorders. Annals of translational medicine. 2018 Apr     [PubMed]
Jain V,Patel RK,Kapadia Z,Galiveeti S,Banerji M,Hope L, Drugs and hyperglycemia: A practical guide. Maturitas. 2017 Oct     [PubMed]

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