Effects of the antipsychotic quetiapine on sleep and breathing: a review of clinical findings and potential mechanisms

Quetiapine is an antipsychotic medication indicated for schizophrenia and bipolar disorder. However, quetiapine also has hypnotic properties and as such is increasingly being prescribed at low doses ‘off‐label’ in people with insomnia symptoms. Pharmacologically, in addition to its dopaminergic properties, quetiapine also modulates multiple other transmitter systems involved in sleep/wake modulation and potentially breathing. However, very little is known about the impact of quetiapine on obstructive sleep apnoea (OSA), OSA endotypes including chemosensitivity, and control of breathing. Given that many people with insomnia also have undiagnosed OSA, it is important to understand the effects of quetiapine on OSA and its mechanisms. Accordingly, this concise review covers the existing knowledge on the effects of quetiapine on sleep and breathing. Further, we highlight the pharmacodynamics of quetiapine and its potential to alter key OSA endotypes to provide potential mechanistic insight. Finally, an agenda for future research priorities is proposed to fill the current key knowledge gaps.

Quetiapine ranks 64th among the most frequently prescribed medications in the United States (ClinCalc.com, 2023).In Norway there was a 10-fold increase in quetiapine prescribing rates from 2004 to 2014, while other antipsychotics have only had a modest increase.Only 2.6% of those prescriptions were for treatment of psychosis (Gjerden et al., 2017).A sampling of prescribing practices in New Zealand found quetiapine was prescribed as much as all other antipsychotics combined.In 2015, the number of prescriptions dispensed annually for quetiapine in Australia with a total population of 25 million was almost 1 million, of which 41% were for low doses of ≤100 mg (Lee, Pilgrim et al., 2018;Mabbott et al., 2016).While quetiapine is commonly used off-label, it is not recommended in clinical guidelines for the treatment of insomnia (FDA, 2020;Modesto-Lowe et al., 2021;Riemann et al., 2017).

| HYPNOTIC PRESCRIPTIONS FOR INSOMNIA SYMPTOMS
Primary care complaints of insomnia are very common, and population prevalence estimates of insomnia range from 6% to 22% (Chung et al., 2015;Haycock et al., 2021;Reynolds et al., 2019;Riemann et al., 2017;Sweetman, Melaku et al., 2021).While evidence-based guidelines recommend cognitive behavioural therapy for insomnia (CBT-I), access to trained sleep psychologists who are qualified to deliver CBT-I is limited and are insufficient considering the burden of disease (Haycock et al., 2022).
In the USA, 17% of women and 15% of men report use of a medication for insomnia (Zuo et al., 2022).In Australia, one study found 'pharmacotherapy was used for insomnia in about 90% of management occasions; non-pharmacological advice was given at about 20% of encounters; and onward referral in about 1% of encounters' (Miller et al., 2017).In another Australian study, 96% of primary care clinicians indicated that most of their patients with insomnia symptoms seek pharmaceutical solutions and not lifestyle changes (Sake et al., 2019).A Canadian study found that 5.5% of the adult population reported using a sedative hypnotic agent within the last month (Vozoris & Leung, 2011).
The rate of sedative hypnotic use in people aged >60 years was even higher at >9% and >7% in people who were obese (Vozoris & Leung, 2011), two major risk factors for obstructive sleep apnoea (OSA; Young et al., 2004).Given the increasing awareness of the possible deleterious effects of common hypnotics such as increased risk of falls and serious injury (Thomas et al., 2022) and potential addiction and misuse with benzodiazepine and z-drugs (such as zolpidem), many physicians are reluctant to prescribe these classes of medications.As a result, given the lack of CBT-I options and the need to address insomnia symptoms in their patients, many clinicians have turned to alternate medications with sleep promotion properties.Despite not being supported by insomnia clinical management guidelines, this has led primary care clinicians, sleep specialists, and patients to look for alternatives to manage insomnia with pharmaceutical agents such as the sedating antidepressants mirtazapine and amitriptyline (Bakker et al., 2023;Wong et al., 2017) and atypical antipsychotic medications like quetiapine.
Approximately 30%-40% of people with insomnia also have OSA (Sweetman et al., 2021a), a common sleep disorder characterised by repetitive reductions or obstructions in airflow and consequent periods of hypoxaemia and sleep disruption.Comorbid insomnia and sleep apnea (COMISA) is more difficult to treat than insomnia or OSA alone, and their combination may worsen the severity of each condition (Sweetman et al., 2021a).Difficulty maintaining sleep is the most common insomnia complaint in people with COMISA (Zhang et al., 2019).It is estimated that >80% of people with OSA are currently undiagnosed and untreated (Fleming et al., 2016;Peppard et al., 2013;Swanson et al., 2011;Young et al., 2002).Consequently, a substantial proportion of people who seek assistance from their healthcare providers for insomnia may also have underlying undiagnosed OSA.
Women with OSA often present with non-specific symptoms including sleep disruption consistent with insomnia, mood disturbances, nightmares, and fatigue, rather than the more recognised symptoms of loud snoring, gasping, and daytime sleepiness.Standard questionnaires designed to evaluate the likelihood of OSA are skewed to 'typical' presentations in men, not women (Geer & Hilbert, 2021).
Further, after menopause, the risk of OSA increases dramatically (Heinzer et al., 2015), yet symptoms are often attributed to menopause, not OSA.Women are far less likely to be referred to have objective diagnostic sleep testing then men, even when they present with similar symptoms (Lindberg et al., 2017).Consequently, this may contribute to the observed higher rates of medication use for insomnia in women than men.
Quetiapine is associated with significant weight gain and metabolic syndrome (Barton et al., 2020).Low-dose quetiapine has also been reported to increase the risk of major cardiovascular events compared to z-drugs and serotonin re-uptake inhibitors, particularly for women and the elderly in a Danish nationwide registry study (Højlund et al., 2022).Accordingly, it is essential to establish whether the potential therapeutic benefits of prescribing quetiapine off-label for insomnia in both men and women outweigh any potential adverse effects on sleep and breathing, and important health outcomes more broadly.
One can imagine a common clinical scenario whereby someone approaches their general practitioner to report a sleep problem that may comprise unrefreshed sleep, daytime fatigue, and multiple awakenings during the night.This is likely to be considered by both the patient and the general practitioner as indicative of insomnia, and primarily a problem of sleep maintenance.Thus, a prescription for a hypnotic may seem like a simple solution.However, given the increasing reluctance to prescribe z-drugs and benzodiazepines, and other influential factors, a prescription for off-label use of quetiapine may be considered.Given that OSA is very common in the community and frequently underdiagnosed, a substantial proportion of these individuals may have OSA either instead of, or in addition to, the identified insomnia symptoms.

| SEARCH METHOD
To assess the impact of quetiapine in people with OSA, we collected all articles on quetiapine in clinical trial studies that included polysomnography (PSG) and were published in peer-reviewed journals.Both randomised controlled trials (RCTs) and non-randomised studies with objective measurements of sleep were examined.A review of the literature was done independently by two reviewers and then subsequently the completeness of the literature was verified via an additional search to confirm all relevant articles were found.

| CURRENT KNOWLEDGE ON THE HYPNOTIC EFFECTS OF QUETIAPINE
Even at low doses (25 mg) quetiapine is a strong histamine H 1 receptor antagonist.This is considered the primary reason for its hypnotic and sedative effects (Jensen et al., 2008;Sato et al., 2015).Further, it is an antagonist to several other wake promoting and arousal systems including: dopamine, muscarinic acetylcholine, and 5-HT2 A-C receptors (Fang et al., 2016;Jones et al., 2001).PSG studies indicate that quetiapine can improve sleep architecture and increases total sleep time.An increase in N2 sleep has been observed consistently, and some studies report an improvement in sleep efficiency.Duration of light sleep (N1), deep/slow-wave sleep (N3), and rapid-eye-movement (REM) sleep has typically remained largely unaltered by quetiapine (Table 1) (Chakravorty et al., 2014;Cohrs et al., 2004;Fernandez et al., 2009;Gedge et al., 2010;Karsten et al., 2017;Wiegand et al., 2008).

| CURRENT UNDERSTANDING OF THE EFFECTS OF QUETIAPINE ON SLEEP-DISORDERED BREATHING
Less is known regarding how quetiapine affects sleep-disordered breathing.In one small study in people with Parkinson's disease, oxygen saturation during respiratory events reached an average of 81% with quetiapine treatment compared to 93% in the placebo arm.
While this was not statistically significant, further investigation as to the possibility of worsening hypoxaemia with quetiapine is required (Fernandez et al., 2009).
In another study, the apnea-hypopnea index (AHI), the standard metric of OSA severity, increased from 11 events/h of sleep at baseline to 43 events/h of sleep with quetiapine.This was both statistically and clinically significant (Khazaie et al., 2018) (Table 2).Another non-RCT noted there was no significant change in respiratory disturbance index between baseline and quetiapine.Unfortunately, however, neither data nor statistical inference were provided (Gedge et al., 2010).an individual has OSA continues to evolve with early definitions defining OSA as ≥5 respiratory events/h of sleep (Kapur et al., 2017).
The pathophysiology of OSA is heterogeneous with distinct endotypes, including low arousal threshold, high loop gain, and inadequate upper airway muscle responsiveness during sleep (Figure 1) (Altree & Eckert, 2022;Eckert, 2018;D.J. Eckert et al., 2013).Most individuals with OSA have some impaired anatomy with evidence of increased upper airway crowding and narrowing.Airway crowding and narrowing may be caused by excess adipose tissue, orthostatic fluid shifts during sleep, or muscle hypertrophy (Pépin et al., 2022).
Each of these factors, as well as a highly compliant pharyngeal airway, can increase the propensity for upper airway collapse during sleep.
Accordingly, theoretically, there is potential for both beneficial and detrimental effects on OSA (Table 3).

| Low arousal threshold
About one third of people with OSA have a low arousal threshold.
This manifests as a high propensity for cortical arousal, or 'waking up', to relatively minor respiratory disturbances prior to activation of other compensatory mechanisms.For example, people with a low arousal threshold endotype have fragmented sleep and typically wake up before there is sufficient respiratory stimulus (i.e., negative airway F I G U R E 1 Possible effects of quetiapine on obstructive sleep apnoea (OSA).Colour coding indicates how quetiapine may have detrimental (red), mixed (orange) or beneficial (green) effects on the key mechanistic causes (endotypes) that contribute to OSA.Increased weight gain is a common side-effect of quetiapine, which would be anticipated to increase narrowing and crowding; thus, increase upper airway collapsibility.
Quetiapine is an antagonist to several receptors, some may increase while others decrease responsiveness of the pharyngeal dilator muscles, also affecting collapsibility.As quetiapine has hypnotic properties, it would be expected to increase respiratory arousal threshold.Note: not all these studies reported key demographic information.However, where available, these data are included in column 1. Abbreviations: AD, alcohol dependency; AHI, apnea-hypopnea index; BMI, body mass index; PD, Parkinson's disease; RCT, randomised controlled trial; SD, standard deviation; SpO 2, oxygen saturation; Tx, treatment.
pressure and carbon dioxide [CO 2 ]) to activate upper airway muscles to restore airflow (Altree & Eckert, 2022).Dopamine via the ventral tegmental area in the midbrain influences sleep wake regulation (Oishi & Lazarus, 2017).Based on its reported hypnotic properties in the context of insomnia, (Cohrs et al., 2004;Wiegand et al., 2008), similar to other hypnotics (Eckert et al., 2011;Eckert et al., 2013;Eckert et al., 2014), quetiapine would be expected to increase the arousal threshold.This may reduce OSA severity in people with a low respiratory arousal threshold (Carter & Eckert, 2021).Conversely, further suppression of arousal with quetiapine in people who already have blunted arousal responses (i.e., those with a high arousal threshold) may worsen hypoventilation and hypoxaemia (Carter & Eckert, 2021).However, this has not been investigated.Thus, whether quetiapine can reduce OSA severity in people with a low arousal threshold endotype or worsen blood gas disturbances in those with a high arousal threshold remains unknown.

| High loop gain
During sleep, with the loss of behavioural inputs to breathe, CO 2 provides the main drive to breathe (Eckert, 2021).About one third of people with OSA have 'high loop gain', which is essentially characterised by an excessive response to small changes in CO 2 during sleep that leads to unstable breathing and sleep-disordered breathing pathogenesis (Baillieul et al., 2022;Eckert et al., 2013).Activation of serotonin 5-HT 2A receptors is required for hypercapnia (high CO 2 ) induced arousal from sleep (Buchanan et al., 2015;Smith et al., 2018).
The main peripheral sensor for CO 2 and respiratory afferent feedback is via the carotid bodies.Dopamine D 2 receptors inhibit carotid body chemoreceptors (Leonard & Nurse, 2020;Zapata et al., 1983).As quetiapine is an antagonist to both 5-HT2 A and D 2 receptors, its potential effects on respiratory control and breathing stability, including in people with high loop gain, are unclear and require investigation.

| Inadequate upper airway muscle responsiveness during sleep
During sleep, the genioglossus, the largest pharyngeal dilator, and other upper airway dilator muscles can compensate for an anatomically crowded, collapsible upper airway to maintain airway patency and adequate airflow (Sands et al., 2014).However, approximately one third of people with OSA have inadequate or poorly coordinated upper airway muscle responses to breathing disturbances during sleep (Altree & Eckert, 2022;Eckert et al., 2013).The 5-HT2 A receptors provide excitatory input to hypoglossal motor neurones in animal models (Fenik & Veasey, 2003).Hypoglossal motor neurone T A B L E 3 Pharmacological properties of quetiapine and potential effects on sleep and breathing.(which provide drive to genioglossus) responses, to chronic intermittent hypoxia are also dependent on 5-HT2 A in animal models (Li et al., 2019).Quetiapine is a 5-HT2 A antagonist.Accordingly, if these mechanisms are important in humans, quetiapine may decrease pharyngeal muscle activity and worsen OSA.Histamine also alters hypoglossal motor neurone excitability to chronic intermittent hypoxia and histamine can activate the genioglossus muscle (Liu et al., 2016;Xie et al., 2021).
While quetiapine blocks voltage-gated hERG potassium channels, even at low doses (100 mg), there are no data on how it affects tandem pore domain potassium channels (Kim et al., 2016;Lee, Choi et al., 2018).
Accordingly, given the potentially opposing mechanisms, it is unclear how quetiapine impacts this endotype and the related downstream effects on OSA severity.

| WEIGHT GAIN AND METABOLIC SYNDROME
Long-term use of quetiapine causes weight gain (Bernardo et al., 2021;Burin et al., 2022).This would be expected to increase upper airway crowding and narrowing making it more prone to collapse and thus, increasing OSA severity (Peppard et al., 2000;Wang et al., 2020).Quetiapine also increases the risk of metabolic syndrome with reported increases in triglycerides, total cholesterol, and low-density lipoprotein cholesterol (Bernardo et al., 2021;Burin et al., 2022).There is a bidirectional relationship between OSA and metabolic syndrome, compounding the severity of each condition (Gleeson & McNicholas, 2022).

| DISCUSSION AND SUMMARY
While quetiapine has an approved indication as an antipsychotic medication, it is now commonly prescribed for the management of insomnia symptoms.This is despite no evidence that this practice is safe in people with OSA, and not being registered or a recommended treatment for this purpose.1.The acute impact on OSA severity, including measures such as the hypoxic burden, and PSG parameters in people with a confirmed diagnosis of OSA.
2. The mechanistic effects on OSA endotypes and their potential to explain inter-individual differences in OSA severity (i.e., potential beneficial effects in some versus detrimental effects in others).
3. The effects on next day performance and alertness, with a specific focus on tasks such as driving and vigilance.
5. The longer-term effects of drug-related increases on weight gain and the accompanying impact on development of and potential worsening of OSA, and the associated consequences including cardiometabolic risk.
Addressing these research priorities would help establish the required evidence base to inform decisions about the relative harms versus benefits of the use of low-dose quetiapine for sleep complaints, particularly where insomnia overlaps with OSA.This proposed programme of work would also help inform personalised care to help identify potential patient subgroups who may be more likely to experience a net benefit, and vice versa, from quetiapine informed by underlying physiology.
As a dopamine and serotonin 5-HT 2A antagonist quetiapine may decrease carbon dioxide (CO 2 ) sensitivity and thus decrease loop gain.Refer to the text for further details.Background figure is a modified version of Respiratory System by Theresa Knott and is licensed under CC-BY-SA 3.0.T A B L E 2 Effect of quetiapine on key sleep disordered breathing parameters.
Accordingly, a key question remains-what might be the effects of off-label use of quetiapine in people with OSA and sleep maintenance problems?There is evidence that quetiapine improves sleep efficiency and total sleep time.These objective changes are likely accompanied by subjective improvements in sleep quality that further contribute to the continued prescription use of quetiapine in this scenario.However, as highlighted in this review, rigorous RCT data on the effects of quetiapine on sleep and breathing in people with OSA are scarce.Conceptually, quetiapine may have conflicting beneficial and deleterious effects on the key mechanisms, or endotypes, that contribute to OSA.Accordingly, the balance between these opposing mechanisms, and therefore, the effects of quetiapine on OSA severity, may vary widely between individuals depending on inter-individual differences in underlying pathophysiology.Given that a considerable proportion of the population has undiagnosed OSA with accompanying comorbid symptoms of sleep disturbance/difficulty maintaining sleep, it is crucial to systematically investigate the effects of quetiapine in the appropriate target populations as summarised in the section below.9| RECOMMENDATIONS FOR FUTURE RESEARCH ON QUETIAPINE, INSOMNIA, SLEEP, AND BREATHINGTo address the current knowledge gaps on the effects of low-dose quetiapine on sleep breathing, we have identified the following research priorities to investigate.Specifically, appropriately designed studies that include populations relevant to the clinical contexts in which quetiapine is likely to be prescribed are required.Examples include studies to determine the effects of low-dose quetiapine on: