1.1. Adults

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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.

Table 1. Quetiapine Approved Adult Dosage Recommendations ^1-4
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.

Table 2. Quetiapine Studies/Case Reports for the Treatment of Insomnia
Study	Population	Design	Intervention	Outcomes
Cohrs et al. ⁷ (2004)	14 patients: healthy males age: 18-65 years	DB, PC, R, crossover, single-center study Duration: 3 consecutive nights, 4 days apart	Quetiapine: 25 mg one hour before bedtime 100 mg one hour before bedtime Control: placebo	Under standard sleep laboratory conditions: 25 mg: significant differences for SPT, TST, and SE compared to placebo 100 mg: significant difference for SPT compared to placebo Under Acoustic Stress:* 25 mg: significant differences for SPT, TST, and SE compared to placebo 100 mg: significant differences at SPT, TST and SE compared to placebo
Juri et al. ¹⁰ (2005)	14 patients: male and female Parkinson’s disease	Open-label study Duration: 12 weeks	Quetiapine: initial dose: 12.5 mg at bedtime dose adjusted according to response and tolerance mean dose: 31.9 mg at bedtime at week 12	Sleep Latency: decrease of 82 ± 65.4 vs 28.6 ± 22.7 minutes from baseline (p less than 0.05) no correlation between response and dose of levodopa or dopamine agonist Safety: two patients withdrew due to restless leg symptoms that subsided after quetiapine discontinuation two patients reported increased diurnal sleepiness no reports of orthostatic symptoms or significant changes in blood pressure
Fernando et al. ¹¹ (2005)	1 patient: 34-year-old male insomnia due to chronic back pain	Case report	Quetiapine: titrated up to 200 mg at bedtime	Observations: improved quality of sleep improved sleep latency
Sokolski et al. ¹² (2006)	1 patient: 42-year-old white male 25-year history of major depression insomnia exacerbated by phenelzine use	Case report	Quetiapine: initial dose: 6.25 mg at bedtime dose increased by 6.25 mg every 3 - 4 days until reached 25 mg at bedtime later increased to 37.5 mg at bedtime max dose: 50 mg at bedtime	Observations: insomnia dramatically improved patient slept 6 - 7 hours per night without interruption Safety: only reported adverse event was morning sedation; patient gradually habituated patient continued on phenelzine and quetiapine for more than 1 year with no report of adverse events
Wiegand et al. ¹³ (2008)	18 patients: primary insomnia	Open-label pilot study Duration: 6 weeks	Quetiapine: initial dose: 25 mg at bedtime increased to 50 mg at bedtime (n = 7) increased to 75 mg at bedtime (n = 1)	Objective Sleep Parameters: significant improvements in TST and SE initial improvements observed at 2 weeks and continued throughout study period sleep onset latency not significantly decreased no test variable showed a decline from baseline over the study period Safety: reports of xerostomia and morning sedation (frequency not defined) no reports of severe adverse events
Terán et al. ¹⁴ (2008)	52 patients: drug abusers in detoxification process insomnia as primary withdrawal symptom included both outpatients and inpatients	Retrospective study Follow-up period of at least 60 days	Quetiapine: median dose: 50 mg at bedtime mean dose: 62.35 mg at bedtime range: 22 mg - 225 mg at bedtime	Change in SSQ: 75% improvement from baseline (p less than 0.001) greatest improvement in mean score occurred in first week (p less than 0.001) benzodiazepine use decreased from baseline (83% vs 22.6% of patients) Safety: well tolerated no patients dropped out due to adverse events xerostomia most common adverse event (n=18; 34.5%)
Pasquini et al. ¹⁵ (2009)	6 patients: females localized breast cancer receiving tamoxifen	Case series Duration: 6 weeks	Quetiapine: initial dose: 25 mg one hour before bedtime max dose: 100 mg one hour before bedtime	Efficacy: swift improvement in insomnia in 5/6 patients patients moved from the moderate ISI category (score of 15 to 21) to absence of insomnia effect maintained after 6 weeks Safety: weight gain (n=2) dizziness (n=1)
Cates et al. ¹⁶ (2009)	43 patients: male and female psychiatric patients 19 – 65 years old receiving at least one other psychotropic medication mean BMI = 31	Retrospective study	Quetiapine: mean initial dose: 109.3 mg ± 47.3 per day mean final dose: 120.3 mg plus or minus 58.6 per day most common regimen: 100 mg at bedtime mean duration: 11.1 months plus or minus 8.2	Efficacy: Primary Outcome: changes in weight, BMI, and waist circumference compared to baseline mean weight gain of 4.9 lb over approximately 11 months statistically significant increase in weight (p = 0.037) statistically significant increase in BMI (p = 0.048) increase in waist circumference not statistically significant male mean increase in weight: 10.5 lb plus or minus 15.6 (p = 0.009) male mean increase in BMI: 1.3 points plus or minus 2.1 (p = 0.016) Secondary Outcome: (compared to baseline) correlation of metabolic changes with patient and treatment variables; no significant differences were found
Tassniyom et al. 17 (2010)	13 patients: primary insomnia mean age: 45.95 years	R, DB, PC Duration: 3 weeks Sleep diary kept for 1 week prior to treatment	Quetiapine (Q): 25 mg every night X 2 weeks Placebo (P): every night x 2 weeks	Efficacy: Primary Outcome: TST, sleep latency, daytime alertness/functioning, sleep satisfaction TST: increased 124.92 min (Q) vs 72.24 min (P) – NS SL: decreased 96.16 min (Q) vs 23.72 min (P) – NS Safety: dry lips, dry tongue, morning drowsiness in two Q patients

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 events^{12, 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.