1. Dosage
HHSC does not support low-dose quetiapine use as non-FDA-approved sleep aid monotherapy. Data included in these criteria address available studies evaluating low-dose quetiapine in insomnia, the limits of these studies, as well as risks associated with quetiapine use for this indication. Additionally, evidence-based use of lower quetiapine doses for FDA-approved and pediatric purposes is also discussed.
1.1. Adults
Quetiapine, a dibenzothiazepine antipsychotic agent, is FDA-approved for acute manic and mixed episodes of bipolar disorder, acute depressive episodes associated with bipolar disorder, maintenance therapy of bipolar disorder when used adjunctively with lithium or divalproex, major depressive disorder when used as adjunctive therapy to antidepressants (extended-release formulation only), and schizophrenia.1-6 Recommended quetiapine dosages are summarized in Table 1.
Treatment Indication | Dosage Form | Usual Dosage Range | Maximum Recommended Dosage |
---|---|---|---|
BD treatment: depression | IR, ER | 300 mg/day | 300 mg/day |
BD treatment: mania | IR, ER | 400-800 mg/day | 800 mg/day |
BD: maintenance | IR, ER | 400-800 mg/day | 800 mg/day |
Major depressive disorder, adjunctive therapy | ER | 150-300 mg/day | 300 mg/day |
Major depressive disorder, adjunctive therapy | ER | 150-300 mg/day | 300 mg/day |
Schizophrenia: acute | IR | 150-750 mg/day | 750 mg/day |
Schizophrenia: maintenance | IR, ER | 00-800 mg/day | 800 mg/day |
Legend:
- BD = bipolar I disorder
- ER = extended-release
- IR = immediate-release
While not FDA-approved, quetiapine has been evaluated in adults with insomnia utilizing doses less than 150 mg/day in the literature. Measurements commonly used to assess insomnia treatment effectiveness include sleep period time (SPT; the duration of time from sleep onset to final awakening), total sleep time (TST; the difference of time between SPT and the time spent awake), and sleep efficiency (SE; the ratio of TST compared to the amount of time spent in bed).7 Patient-reported outcomes are also often assessed. The Spiegel Sleep Questionnaire (SSQ) is comprised of 7 items that are each scored from 1 to 5, with higher scores indicating positive outcomes.8 The Insomnia Severity Index scale (ISI) is a tool used to measure a patient’s perception of their insomnia. This instrument also consists of 7 items, but each item is scored from 0 to 4. Higher scores correlate with more severe insomnia.9 Clinical evidence of low-dose quetiapine use for insomnia is exhibited in Table 2.
Study | Population | Design | Intervention | Outcomes |
---|---|---|---|---|
Cohrs et al. 7 (2004) | 14 patients:
| DB, PC, R, crossover, single-center study Duration: 3 consecutive nights, 4 days apart | Quetiapine:
| Under standard sleep laboratory conditions:
Under Acoustic Stress:*
|
Juri et al. 10 (2005) | 14 patients:
| Open-label study Duration: 12 weeks | Quetiapine:
| Sleep Latency:
Safety:
|
Fernando et al. 11 (2005) | 1 patient:
| Case report | Quetiapine: titrated up to 200 mg at bedtime | Observations:
|
Sokolski et al. 12 (2006) | 1 patient:
| Case report | Quetiapine:
| Observations:
Safety:
|
Wiegand et al. 13 (2008) | 18 patients:
| Open-label pilot study Duration: 6 weeks | Quetiapine:
| Objective Sleep Parameters:
Safety:
|
Terán et al. 14 (2008) | 52 patients:
| Retrospective study Follow-up period of at least 60 days | Quetiapine:
| Change in SSQ:
Safety:
|
Pasquini et al. 15 (2009) | 6 patients:
| Case series Duration: 6 weeks | Quetiapine:
| Efficacy:
Safety:
|
Cates et al. 16 (2009) | 43 patients:
| Retrospective study | Quetiapine:
| Efficacy:
|
Tassniyom et al. 17 (2010) | 13 patients:
| R, DB, PC Sleep diary kept for 1 week prior to treatment | Quetiapine (Q):
Placebo (P):
| Efficacy:
|
Legend:
- BMI = body mass index
- DB = double-blind
- ISI = Insomnia Severity Index scale
- PC = placebo-controlled
- R = randomized
- SE = sleep efficiency
- SL = sleep latency
- SPT = sleep period time
- SSQ = Spiegel Sleep Questionnaire
- TST = total sleep time
- *Acoustic Stress = staccato piano tones ranging in pitch and tone intensity played in short spurts during the 8 hour bedtime period (duration: 4-5 seconds; interval: 30 – 90 seconds)
Based on available clinical evidence, low-dose quetiapine has shown some benefit for adult patients suffering from insomnia.7-19 Quetiapine not only improved the quantity of sleep, by increasing TST and SE, but also the quality of sleep, by increasing patient-reported outcomes. However, available results are based on data from case reports and uncontrolled trials and include few patients over 65 years of age or those in nursing homes. Too, the mechanism of action for low-dose quetiapine targets histamine H1 and alpha-1 adrenergic receptors rather than serotonergic and dopaminergic receptors, which may aid in promoting sleep but does not significantly impact mood or psychotic disorders. Additionally, quetiapine has been assigned black box warnings: increased mortality in elderly patients with dementia-related psychosis; and increased risk of suicidality in children, adolescents, and young adults taking antidepressants for major depressive and other psychiatric disorders. Other warnings include leukopenia, neutropenia, neuroleptic malignant syndrome, metabolic changes, and agranulocytosis.2, 3, 19-21 Commonly reported adverse events include xerostomia, morning sedation, and weight gain. Reports of weight gain despite the use of low quetiapine doses may predispose some patients to metabolic disturbances (e.g., diabetes, dyslipidemia) associated with second generation antipsychotic (SGA) use. 16, 19
Additionally, a nationwide active comparator-controlled study published in 2022 found that the use of low-dose quetiapine increases the risk of major adverse cardiovascular events and cardiovascular death compared to nonbenzodiazepine hypnotic drugs in the intention-to-treat analysis. The as-treated analysis found that low-dose quetiapine was associated with increased risk of major adverse cardiovascular events, non-fatal ischemic stroke, and cardiovascular death. Risk was found to be greater in females and those 65 years of age or older at initiation of therapy. The study also found that low-dose quetiapine was associated with increased risk of major adverse cardiovascular events, non-fatal ischemic stroke, and cardiovascular death when compared to selective serotonin reuptake inhibitors.20 Low-dose quetiapine should be avoided or used with caution for the off-label treatment of insomnia, especially when other FDA-approved agents for insomnia are available and more economically feasible.21 Patients with co-morbid conditions and insomnia, however, may find some benefit from low-dose quetiapine, with close monitoring for potential long-term adverse events12, 22.
A comparative effectiveness review published by the Agency for Healthcare Research and Quality (AHRQ) evaluated physician prescribing patterns for off-label uses of atypical antipsychotics. Researchers found one small trial (n = 13) in which physicians prescribed quetiapine to patients for insomnia and concluded that quetiapine may not be effective in managing insomnia; the strength of evidence used to determine the efficacy of quetiapine in insomnia was very low. 24
Quetiapine doses less than 150 mg/day are not routinely recommended. However, elderly patients (defined as 65 years of age and older) and debilitated patients may not tolerate higher initial quetiapine doses due to decreased oral quetiapine clearance. Slower titration schedules using doses of 25-50 mg/day until clinical response is achieved are necessary to avoid adverse events.1-6 Some patients have been managed with doses as low as 25 mg to 50 mg/day for psychosis and bipolar disorder. 25-27 Quetiapine is not FDA-approved for use in doses lower than 150 mg/day, except in elderly and debilitated patients, and will be reviewed.
1.2. Pediatrics
Quetiapine is FDA-approved for acute mania in bipolar disorder in pediatric patients 10-17 years of age, and acute management of schizophrenia in adolescents 13-17 years. Pediatric quetiapine dosages are summarized in Table 3. An additional column reflecting literature-based dosing included in the Texas Health and Human Services Psychotropic Medication Utilization Parameters for Children and Youth in Texas Public Behavioral Health (6th Version) is included in Table 3.
Treatment Indication | Dosage Form | Usual Dosage Range Per Age Group | Literature Based Maximum Dosage | Maximum Recommended Dosage |
---|---|---|---|---|
BD treatment: acute mania | IR, ER | 10-17 years of age: 400-600 mg/day |
| 600 mg/day |
Schizophrenia: acute | IR, ER | 13-17 years of age: 400-800 mg/day | Age 10-17 years: 800 mg/day | 800 mg/day |
Legend:
- BD = bipolar I disorder
- ER = extended-release
- IR = immediate-release
Currently there is no FDA-approved indication for low-dose quetiapine use (150 mg/day or less) in the pediatric population. Data have been published that address quetiapine safety and efficacy for the treatment of various conditions in the pediatric population, and some of the patients included were taking quetiapine doses of 150 mg/day or less. Summary details of these publications can be found in Table 4.
Evidence suggests that quetiapine use in children for a variety of indications including conduct disorder, attention-deficit/hyperactivity disorder, bipolar disorder, and other psychoses may be beneficial as monotherapy in some situations and as combination therapy in others. Although most trials used a mean dose greater than 300 mg/day, all studies presented in Table 4 utilized quetiapine doses of 150 mg/day or less. Based on the trials collectively, using quetiapine in patients younger than 18 years of age resulted in significantly improved scores on many of the psychiatric evaluations. Although average doses in the trials exceeded 150 mg/day, efficacy did not seem to be limited to higher quetiapine doses.29-39 However, many of these trials had several limitations that are important to consider. All trials were open-label trials, included very small numbers of participants, and were relatively short in duration. Only one trial was randomized, and most did not have a comparator or control group. 35-38
While efficacy results seem promising from these trials, there are important adverse effects associated with quetiapine use in children. Weight gain, other metabolic changes, and sedation/somnolence, well known adverse effects associated with quetiapine use, were frequently reported by trial participants 35-38. Moreno et al.40 published a trial examining the metabolic effects of quetiapine and other SGA medications on children being treated for bipolar disorder as well as other psychotic and nonpsychotic disorders. This study found that after three months of treatment with an SGA, over 70% of patients experienced abnormal weight gain. Due to the frequency of weight gain and sedation occurring with SGA use, Penzner et al.41 studied the effect of co-prescribing a stimulant, which can cause weight loss and insomnia, to neutralize the adverse effects of the antipsychotic. Investigators found no significant differences in body composition and metabolic profiles between SGA-treated patients managed concurrently with or without stimulants.
Low-dose quetiapine treatment for children with various psychotic or behavioral disorders has been beneficial in some cases. However, possible adverse events that may negatively impact health and quality of life need to be considered before treatment initiation.
Study | Age | Quetiapine Dosage | Disease State |
---|---|---|---|
Stathis et al. 29 | 15 to 17 years of age (mean age 16.7 yrs) | dose range 50 mg -200 mg/day (mean dose: 133 mg) | Posttraumatic stress disorder |
Findling et al. 30 (2006) | 6-12 years of age (mean age 8.9 yrs) | range 75mg -300 mg/day (median dose: 150 mg/day; mean dose: 4.4 mg/kg/day) | Conduct disorder |
Marchand et al. 31 | 4-17 years of age (mean age 10.8 yrs) | dose range 100 mg -1000 mg/day (mean dose: 407, plus or minus 230 mg/day) | Bipolar disorder |
Findling et al. 32 (2004) | 12-17 years of age (mean age 14.6, plus or minus 2.3 yrs) | mean maximum total daily dose range 100 mg - 450 mg/day (overall mean dose: 291.7 mg/day) | Autistic disorder |
Mukaddes et al. 33 | 8-16 years of age (mean age 11.4 plus or minus 2.4 yrs) | dose range 50 mg - 100 mg/day (mean dose: 72.9 mg plus or minus 22.5 mg/day) | Tourette’s disorder |
Tufan 34 | 17-year-old-female | 100 mg/day in divided doses (plus sertraline 50 mg/day) | Autism; pervasive developmental disorder with mental retardation and self-injurious behavior |
Arango et al. 35 | 12-18 years of age | dose range 73.2 mg – 992.4 mg/day (mean dose: 532.8 mg/day) | Schizophrenia; bipolar disorder |
Findling et al. 36 (2007) | 6-12 years of age | dose range 75 mg-350 mg/day (mean dose at study end: 158.3 mg/day) (methylphenidate administered adjunctively in majority of patients) | Conduct disorder |
Duffy et al. 37 | 13-20 years of age |
| Bipolar disorder |
Kronenberger et al. 38 | 12-16 years of age | dose range 120.2 mg – 538.2 mg/day (mean dose: 329.2 mg/day) (given in conjunction with methylphenidate) | ADHD*-combined type and disruptive behavior disorder with conduct disorder |
Golubchik et al. 39 | 13-17 years of age | dose range 50 mg-150 mg/day (mean dose: 122.7 plus or minus 39.5 mg/day) | Autistic spectrum disorder |