Off-label use of atypical antipsychotics: Lack of evidence for their use in primary insomnia

Abstract

Atypical antipsychotics are some of the most commonly prescribed psychotropic medications in the United States. There is increasing off-label use despite lack of evidence to support it in some of these medical or psychiatric conditions. One of these growing uses is for the management of primary insomnia. This article discusses the literature on using atypical antipsychotics for managing primary sleep disturbances. Much of the research targeting insomnia is related to using antipsychotics for comorbid psychiatric or medical problems and secondary sleep complaints. For pharmacologic management of primary insomnia in the absence of other psychiatric or neurologic conditions for which atypical agents are helpful, other hypnotic agents should be tried. More research is required before expanding the prescribing of antipsychotics for insomnia.

 new generation of antipsychotics (APs) emerged in the 1990s, and their use has expanded well beyond the original indication for schizophrenia. At present, 10 atypical APs are available in the United States (Table 1).^1–13 Atypical APs have a different therapeutic mechanism of brain receptor antagonism on serotonin-2 (5-HT₂) receptor subtype compared to typical APs (ie, first-generation APs), which are primarily limited to dopamine-2 (D₂) receptor blockade. APs have gained approval for providing benefit in managing symptoms associated with bipolar disorder mania (acute and maintenance treatment) and depression, schizoaffective disorder, adjunctive treatment for unipolar depression, and irritability associated with autism. Beyond their FDA-approved uses, these second-generation antipsychotics (SGAs) are also evaluated for use in a variety of neuropsychiatric conditions currently considered off-label. These include attention-deficit hyperactivity disorder, behavioral disturbances of dementia and severe geriatric agitation, depression, eating disorders, personality disorders, insomnia, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), substance use and dependence disorders, and Tourette’s syndrome.¹⁴ For many of these conditions, the evidence for their use is inconclusive. With increasing off-label use and high costs, it is prudent to evaluate the evidence for their emergent use in these medical and psychiatric conditions.^15,16 This article reviews literature regarding the off-label use of atypical APs for the treatment of insomnia.  

INSOMNIA

Insomnia affects roughly one-third of adult Americans, with approximately 35% of adults reporting both occasional and chronic sleep problems. The overall prevalence of insomnia is 10%to 22%.^17,18 The International Classification of Sleep Disorders (ICSD-2) classifies chronic insomnia in adults as primary and secondary. Secondary insomnia, also referred to as comorbid insomnia, occurs when insomnia is a symptom of a medical or psychiatric illness, another sleep disorder, or substance abuse.¹⁹ Insomnia is a subjective disorder associated with unsatisfactory sleep respective to sleep onset, sleep maintenance, or early waking. Objective sleep measures by polysomnography are often associated with increased sleep latency (ie, the length of time that it takes to transition from wakefulness to sleep), reduced sleep efficiency, and an increased number and duration of awakenings. Insomnia can impair daytime functioning and well-being. If the sleep disturbance causes significant personal distress or marked impairment, treatment may be needed. Treatment can be in the form of both nonpharmacologic and pharmacologic interventions. 

Approved medications for treating insomnia include benzodiazepines (estazolam, flurazepam, quazepam, temazepam, triazolam), non-benzodiazepines (eszopiclone, zaleplon, zolpidem), melatonin receptor agonists (ramelteon), and tricyclic antidepressants (doxepin) (Table 2, page 365). Less commonly used hypnotics include specific barbiturates and chloral hydrate. Novel oral agents such as orexin receptor antagonists (ie, suvorexant) are being evaluated for their role in managing insomnia.²⁰ Sedating antidepressants (trazodone, mirtazapine) are commonly used off-label to promote sleep.²¹ Patients who require an antidepressant for depressed mood or anxiety and insomnia can certainly benefit from the use of a solo agent. A more concerning off-label practice is the use of atypical APs for insomnia. With very little scientific evidence for this practice, such use calls for thorough evaluation.

INCREASING OFF-LABEL USE OF ATYPICAL APs

Atypical APs are used off-label to treat psychiatric disorders more than any other class of psychotropic medication, including antidepressants/anxiolytics, mood stabilizers, benzodiazepines, and stimulants.²² Prescriptions of atypicals for off-label use is on the rise. The number of physician office visits for the SGAs, as a percentage of visits for all AP drugs, increased significantly from 48% in 1998 to 84% in 2002.²³ There was a corresponding decrease in the percentage of visits involving first-generation APs. Moreover, the growth in the number of visits involving APs over the 5-year period was substantial (120%) in visits with physicians, excluding psychiatrists. The investigators partly attribute this trend to targeted promotion by pharmaceutical companies and extensive off-label use of atypical APs. In a more recent evaluation, unlabeled use of APs increased from 4.4 million treatment-related visits in 1995 to 9 million in 2008.¹⁵ The cost associated with off-label AP use was estimated at $6 billion in 2008, of which roughly 90% was for uses with uncertain evidence to support use. There is a consensus that use of atypical APs continues to expand for non-approved indications despite the lack of well-defined studies to support such use and unknown risks of long-term use (ie, tardive dyskinesia) in nonpsychotic patients, even when used at low doses.^15,24 A product that is safe and effective for one indication may have a different risk-benefit ratio for another.²⁵ This is a growing area of concern, especially when atypical APs are prescribed for managing primary insomnia in the absence of comorbid psychiatric symptoms.

SEDATION AS A SIDE EFFECT

Antipsychotics differ in their pharmacology, efficacy, safety, and tolerability. The atypical APs have varying degrees of neurotransmitter blockade contributing to the different therapeutic and side effect profiles. For example, D₂ receptor blockade is responsible for the therapeutic effect of managing psychosis associated with schizophrenia. However, this same D₂ receptor antagonism in different neuronal pathways is also associated with causing AP-induced extrapyramidal movement disorders such as acute dystonia, akathisia, and pseudoparkinsonism.

The side effect of sedation caused by the atypical agents is associated with blocking histamine-1 (H₁), and the promotion of deep sleep is attributed to serotonin-2A (5-HT_2A) receptor blockade.²⁶   5-HT_2C receptor antagonism by atypical APs is implicated in increasing slow-wave sleep (SWS),a receptor mechanism that typical APs lack.²⁷ SWS corresponds to stage 3 sleep, the period of deep sleep in the normal sleep cycle. Essentially, the use of atypical APs for inducing and maintaining sleep is defended by the mechanism of receptor action and taking advantage of atypicals possessing these pharmacologic properties. Of note, conventional APs do not alter sleep architecture, therefore limiting their usefulness in targeting insomnia in the absence of comorbid conditions.²⁸ It may be efficient to use an atypical AP with sedating properties in a patient with psychotic or bipolar disorders who could benefit from improved or increased sleep. In doing so, polypharmacy may be avoided with unnecessary hypnotics. However, utilizing atypical APs solely for the purpose of managing primary insomnia may be associated with greater risk than benefit, especially when used long-term.

EVIDENCE FOR PRIMARY INSOMNIA

Atypical APs evaluated for their effect on sleep 

In a summary of the comparative effectiveness on off-label uses of atypical APs, the Agency for Healthcare Research and Quality concluded that data were inconclusive for the use of atypical APs for insomnia.¹⁴ The National Institutes of Health does not recommend atypical APs for treating chronic insomnia.¹⁷ This is based on the fact that studies demonstrating the usefulness in both short- and long-term management are lacking, and these agents are associated with significant risks.  

Despite insufficient research of atypical APs for primary insomnia, prescribers use quetiapine, olanzapine, or other agents to manage agitation that disrupts sleep and other forms of secondary insomnia (ie, insomnia due to a general medical condition).^29,30 When used for sleep, relatively low doses of atypical APs are utilized compared to doses required for schizophrenia and bipolar disorder management.^31,32  Some reports involve comorbid medical conditions for which an atypical agent proved to be useful for both primary psychiatric and comorbid sleep impairment. These reports need to be evaluated with great caution, as the usefulness to more generalizable populations for use in primary insomnia is extremely limited. Several of these studies or reports were not primarily designed to measure sleep improvement. When available, however, profiles on the impact of atypical APs on improving sleep parameters (Table 3) are described. There are few studies reporting on and evaluating their use specifically for targeting insomnia. The atypicals in these reports include quetiapine, olanzapine, and risperidone. Table 4 summarizes these findings.

Quetiapine  

Quetiapine has been prescribed most frequently for off-label use, and the majority of reports on the use of atypical APs for insomnia have been reported with quetiapine.³³ It has been suggested that quetiapine is a “promising” candidate for treatment of chronic primary insomnia due to its lack of receptor action at cholinergic, muscarinic, and benzodiazepine receptors.^34,35 It is increasingly used on an “as needed” basis for targeting insomnia.³⁰ However, the trend of increasing real-world use of quetiapine for targeting insomnia or other off-label use is also criticized and may constitute poor prescribing that is not supported by sufficient evidence of safety and efficacy.³⁶   

The only double-blind, randomized, controlled trial on the efficacy of quetiapine for primary insomnia comes from an outpatient psychiatry department in Thailand.³⁴ Thirteen patients aged 25 to 62 with a diagnosis of primary insomnia were administered quetiapine 25 mg for 2 weeks. Most were women (81%), and a majority (69%) reported other past hypnotic use; none had histories of substance abuse. Although there was a trend toward improvement in total sleep time (TST increased 125 min in the quetiapine group and 72 min in the placebo group; P=.193) and sleep latency (SL decreased by 96 and 24 min, respectively; P=.07), this was not statistically significant between groups. In addition, there was a greater difference in sleep satisfaction improvement (as measured by a visual analog scale) in the quetiapine group (18.33) versus placebo (12.17) with no statistical difference between groups (P=.505). Side effects reported in the quetiapine users included dry lips and tongue and daytime drowsiness; none were reported in the placebo group. The authors conclude that despite the lack of statistically significant study results, increasing the sleep time by 2 hours in insomniacs can be clinically significant. 

An open pilot study of 18 outpatients evaluated primary insomnia efficacy of quetiapine 25 mg/day to 75 mg/day for 6 weeks. The results indicated that low-dose quetiapine improved several objective and subjective sleep parameters.³⁵ Results from polysomnography ratings showed a statistically significant improvement in TST, increasing by an average of 37.6 min (P=.03). Pittsburgh Sleep Quality Index (PSQI)³⁷ scores improved for sleep quality, time, and efficiency.Sleep onset latency was not reduced, neither subjectively or objectively. Side effects included dry mouth and transient hangover effects in the morning.

The safety of using quetiapine when used for an insomnia indication in doses of ≤200 mg/day was evaluated in a retrospective chart review of 43 patients, of which 5 (11.6%) also received an additional hypnotic agent.³² The patients gained an average of 4.9 pounds over 11 months of treatment (P=.037). Another retrospective chart review of quetiapine in doses up to 100 mg/day or less was associated with an average weight gain of slightly less than 1 lb/month so that those using the agent for 1 year gained a mean weight of 10.58 lb (P<.001).³⁸ These studies underscore the importance of monitoring a patient’s body mass index even when using relatively low doses for insomnia.

A 77-year-old woman using quetiapine 25 mg/day for agitation and severe insomnia developed hepatotoxicity and died after 9 days of use.³⁹ Low doses are often used off-label in the elderly for managing psychosis related to dementia. Elderly individuals may be at greater risk for adverse drug reactions to atypical APs due to reduced drug clearance. Drug-related problems in the elderly include increased risk of cerebrovascular accidents and mortality in persons with dementia, impaired psychomotor function, syncope, and falls.⁴⁰ Caution is advised when using APs in geriatric populations for any use, even in low doses.

A pharma-sponsored study investigated the effects of quetiapine on sleep in 18 healthy male subjects (monitored in a sleep laboratory by polysomnography), excluding a diagnosis of insomnia or psychiatric illness.⁴¹ Quetiapine 25 mg and 100 mg (versus placebo) for 2 nights increased TST (P<.0001) and subjective sleep quality (P<.0001). However, periodic leg movements occurred at the 100-mg dose. Moreover, 2 low-weight patients withdrew from the study due to orthostatic hypotension-induced fainting after ingesting a 100-mg dose. After the first 100-mg dose on night 1, subjects felt less refreshed and more tired, compared to placebo. After night 2 100-mg administration, subjects felt more refreshed and less tired compared to placebo. Controlled dose-finding studies are needed to characterize sleep effects.

Additional reports on quetiapine use for improving sleep symptoms are related to managing secondary insomnia. Quetiapine is a treatment of choice for the management of psychotic symptoms in Parkinson’s disease for its ability to improve psychosis without exacerbating movement disorders.⁴² Quetiapine was described in an open-label trial as safe and effective in targeting insomnia associated with 14 nonpsychotic Parkinson’s patients taking anti-parkinsonian medications in an outpatient care center.⁴³ Patients started with quetiapine 12.5 mg at bedtime, up to 100 mg/day (mean dose at 12 weeks, 31.9 mg; range, 12.5–50 mg). Both the total PSQI and Epworth Sleepiness Scale (ESS)⁴⁴ scores improved significantly (P=.005 and P=.003, respectively) from initiation of treatment and at 12 weeks.Sleep latency showed the greatest improvement, decreasing from 82 to 28.6 minutes (P<.05). Two patients discontinued treatment due to worsening restless leg symptoms and increased daytime sleepiness. There were no reports of orthostatic hypotension, changes in blood pressure, or worsening of motor symptoms. The effect and tolerability of quetiapine on sleep in this population requires further research.

There are 2 reports on substance-induced sleep disorder improving with quetiapine treatment.^45,46 One involves a male patient with refractory depression taking phenelzine 45 mg/day developing insomnia as an adverse drug reaction. Quetiapine 50 mg/day improved his total sleep time for over a year, causing only initial, mild morning sedation.⁴⁵ The authors acknowledge the potential for the serotonin syndrome drug interaction and recommend starting quetiapine doses as low as 6.25 mg/day (one-fourth of the 25-mg tablet, the lowest strength available). The second report involves the use of quetiapine 25 to 100 mg/day to manage tamoxifen-induced insomnia in women treated for breast cancer.⁴⁶ The Insomnia Severity Index⁴⁷ indicated improvement in sleep for 5 of the 6 women treated over 6 weeks.

Sleep data from a previously published open-label trial on the use of quetiapine in 18 veterans with PTSD was analyzed for the effects of quetiapine on sleep.⁴⁸ The global scores for both the PSQI and a PTSD-specific addendum of the PSQI (PSQI-A)⁴⁹ decreased significantly from baseline to 6 weeks.Specifically associated with PTSD-related sleep disturbances, there was a decrease in anxiety and anger experienced during nightmares of traumatic events. The authors acknowledge that any potential benefit of quetiapine use should be weighed against adverse events risk such as metabolic complications.  

The American Academy of Sleep Medicine states that atypical APs may be considered for treatment of PTSD-related nightmares; however, the data are lacking and are of low grade.⁵⁰ Instead, prazosin (an alpha-1 receptor antagonist) and specific forms of cognitive behavioral therapy (ie, image rehearsal therapy) are first-line therapies for nightmare disorder in adults. Larger-scale studies demonstrating the beneficial use of quetiapine and other atypical APs to manage comorbid sleep and specific anxiety disorders are worth exploring.    

The next 7 studies or reports are listed because sleep outcomes were measured using quetiapine to improve sleep in comorbid psychiatric disorders (Table 4). The atypical APs have approved indications for use either as monotherapy or in combination with other psychotropics for schizophrenia, acute bipolar disorder, bipolar depression, and treatment-resistant depression.^28,51–54 Other populations where quetiapine was evaluated for sleep improvement included a retrospective chart review of polysubstance abuse–associated insomnia⁵⁵ and a case report of pain-interrupted sleep.⁵⁶ Of note, 7 of the 11 studies described above disclosed research funding or support from the manufacturer of quetiapine.^{28,41,48,52–55}   

There is no consensus on which of the 2 formulations of quetiapine has been used more frequently in reports of improving sleep. The next study did not evaluate sleep complaints and improvement in sleep quality as a result of quetiapine administration.⁵⁷ However, it was a 5-day study to compare the time course and intensity of sedation after morning administration of immediate-release (IR) versus extended-release (XR) quetiapine in 58 healthy subjects during dose initiation. It found that quetiapine XR was associated with a lower intensity of self-reported sedation compared with quetiapine IR after 1 hour on day 1 (primary end point). The level of sedation was lower with quetiapine XR compared with quetiapine IR for the first 7 hours post dosing, after which levels of sedation were comparable with both formulations.⁵⁷ This is due to the fact that the T_max is longer for the XR preparation (~6 hours) compared to IR (~1.5 hours). Based on this difference in plasma concentration-time curves, using the XR formulation would not be justified for use in managing patients whose main complaint is difficulty falling sleep, unless taken a few hours before bedtime. The implications that this will have in insomnia treatment will require further investigation.

With concerns about quetiapine used in patients long-term (ie, tardive dyskinesia, metabolic complications), conflicting observations about its effect on sleepand lack of current sufficient evidence, off-label use of quetiapine for chronic, primary insomnia should be discouraged.^58–60 

Olanzapine

Although olanzapine is more sedating than quetiapine, there are fewer reports of olanzapine for pharmacologic management of primary or secondary insomnia. Increase in objective sleep time and sleep continuity and in subjective sleep quality have been reported with olanzapine.^27,61–64 In a study of antidepressant-resistant depressed patients, 1 dose of olanzapine 2.5 to 10 mg added to existing antidepressants in 12 patients showed a significant improvement in sleep efficiency (P<.001) and increase in SWS (P<.01) for 3 weeks.⁶³ Patients found the olanzapine addition to be highly sedating-they spent more time asleep in bed and found it difficult to get up in the morning. However, they subjectively reported this as an improvement in sleep. The applicability of this finding may be limited to certain populations where sleep impairment is worsened by a comorbid psychiatric illness.

Delta sleep may be an abnormal trait in schizophrenia. Sleep-promoting effects of olanzapine 10 mg 1 hour before bedtime improved TST (P<.002) in 20 patients with schizophrenia when taken for 2 nights in an inpatient facility.⁶¹ The improvement in TST was attributed to the increase in sleep stages 2 (P<.05) and delta sleep (P<.01). This study is limited by the 2-day administration of olanzapine and no disclosure of any adverse drug reactions. The safety of olanzapine when used for insomnia cannot be determined by any of the mentioned studies.

Treating paradoxical insomnia is complex and may often be treated inappropriately with traditional hypnotic agents.¹⁹ Paradoxical insomnia is a primary insomnia-categorized sleep disorder complaint of severe insomnia or excessive sleepiness without objective evidence of sleep disturbance.¹⁹ Paradoxical insomnia may represent a somatic delusion associated with reality impairment.⁶⁵ Effective treatments are unknown; however, atypical APs have been investigated for this subtype of insomnia. A case report describes a 60-year-old woman with severe preoccupation with insomnia and recent suicidal ideation treated with olanzapine 2.5 mg twice daily for delusional disorder.⁶⁶ Previous trials of benzodiazepines and trazodone were unsuccessful; electroconvulsive therapy was also unsuccessful. After 6 weeks of olanzapine maintenance, the patient reported subjective improvements in sleep, with effects seen at monthly follow-ups for a year. A larger scale, 29-patient, cross-sectional study over a 2-year period compared the effects of olanzapine and risperidone for treating paradoxical insomnia.⁶⁵ For 8 weeks, the first group (n=14) was treated with olanzapine 10 mg/day, and the second group (n=15) with risperidone 4 mg/day daily. All participants completed the PSQI at baseline and at the end of the study. In both treatment groups, sleep quality improved (P<.001). When comparing the 2 treatments, patients treated with olanzapine showed greater improvement in sleep quality (as measured by the PSQI) than patients treated with risperidone (P<.04). There were no reports of adverse drug reactions to either AP. Longer term studies are needed to determine the effective durability and adverse reactions of APs for managing this insomnia subtype.

Risperidone 

There are few studies assessing the sleep effects of risperidone, an atypical AP described as having only moderate sedative effects, compared to the more sedating olanzapine.⁶⁷ Risperidone is also less sedating than quetiapine. In fact, an exploratory study comparing side effects between clozapine to risperidone found more self-reported insomnia associated with risperidone use (P<.002).⁶⁸ A study comparing the effects of typical and atypical APs on sleep activity and subjective sleep quality on healthy adults found that subjective sleep quality improved only with olanzapine 5 mg and not with risperidone 1 mg or haloperidol 3 mg.⁶⁴

The objective of the following study was to examine how the administration of morning versus evening low-dose risperidone affects sleep architecture in healthy humans. The subjects did not have insomnia complaints. In 10 healthy male volunteers, risperidone 0.5 mg oral solution increased stage 3 sleep and TST.⁶⁹ All participants completed 3 sets of 2 consecutive nights of polysomnography recordings with each set separated by a 2-week drug wash-out. Both morning and evening doses impaired sleep quality. There was no difference between either of these groups and placebo. Morning risperidone increased stage 3 sleep by 26.3% (P=.032) and evening administration increased total sleep time by 4.9% (P=.028) compared to placebo. No extrapyramidal events were reported during the study period. 

The following studies involved populations with a primary psychiatric condition. A study of 17 male combat veterans with PTSD treated with adjunctive risperidone 1 to 3 mg/day for 12 weeks had significantly decreased night-time awakening frequency as recorded in a sleep diary (P=.003).⁷⁰ However, awakenings as measured by the PSQI did not decrease after 12 weeks of risperidone. Moreover, the frequency of bad dreams associated with PTSD did not decrease with treatment. Adverse effects were not described in this report. In a different study, risperidone 0.5 to 1 mg for 2 weeks decreased wake time (P=.02), decreased REM sleep (P=0.02), and increased stage 2 sleep (P=.001) in 8 antidepressant-resistant depressed patients.⁷¹ However, there was no significant change in subjective sleep quality. Again, adverse drug reactions were not reported. Another study found that SWS in patients with schizophrenia taking risperidone was longer than those taking haloperidol (P<.05).⁷² However, none of the 10 patients had a current sleep problem for the past 3 months; therefore, conclusions about any therapeutic effects on insomnia cannot be made. One pilot study investigated the effects of risperidone on sleep quantity and quality in patient with schizophrenia with improvements noted in the risperidone-treated group (mean dose, 9.5 mg/day) compared to the patients treated with a typical AP (mean chlorpromazine equivalent dose of 606.3 mg).⁷³ Valid conclusions about the efficacy and safety of risperidone for treating insomnia cannot be made based on these studies alone. Better controlled and larger studies using risperidone are needed. Adverse drug reactions should also be measured and reported, even with short-term use. 

Ziprasidone  

There is 1 randomized, double-blind, placebo-controlled study that demonstrates improved sleep-consolidating properties under both standard and acoustic stress conditions in 12 healthy males taking ziprasidone 40 mg 2 hours before bedtime (P<.02).⁷⁴ There are no studies or reports on the use of ziprasidone for managing insomnia.  

Treatment guideline for insomnia: consensus, recommendations on the use of atypical APs

The British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia acknowledges that there is very little controlled-trial evidence for using atypical APs for sleep problems.⁷⁵ Although they concede that olanzapine and quetiapine improve sleep in healthy volunteers and quetiapine improves sleep in primary insomnia, there is no indication as first-line treatment. Interestingly, the Association cites reports of quetiapine abuse.⁷⁶ There are growing anecdotal and case reports of quetiapine drug-seeking behavior. Nonconventional routes of misused or abused administration include intranasal and intravenous, often by crushing the tablets.⁷⁶

From evidence-based American Academy of Sleep Medicine practice parameters, evidence-based and consensus-based recommendations led to a clinical guideline for management of adult chronic insomnia.²¹ A consensus statement states atypical APs as non–first-line therapy: atypical APs “may only be suitable for patients with comorbid insomnia who may benefit from the primary action of these drugs as well as from the sedating effect.” The experts recommend off-label administration of atypical APs to be avoided in light of the weak level of evidence supporting their efficacy for insomnia and the potential for significant adverse drug reactions.

The National Institutes of Health State-of-the-Science conference on Manifestations and Management of Chronic Insomnia in Adults acknowledges that sedating APs have been used in the treatment of insomnia.¹⁷ They state that their use in managing chronic insomnia cannot be recommended based on the significant risks with use and lack of studies demonstrating their usefulness. Atypical, sedating APs should be reserved for those who require it for other indications associated with sleep disturbance, where perhaps polypharmacy can be avoided.  

CONCLUSION

One person’s adverse drug reaction is another person’s therapeutic benefit. One could argue that using atypical APs for insomnia is an example of this. Despite increased prescribing of APs for many neuropsychiatric conditions, these uses are not necessarily supported by evidence-based, scientific literature. Clinical experience commonly identifies psychiatric conditions that are refractory to conventional treatment; therefore, atypical APs are often utilized as an augmentation strategy. Clinical trials demonstrate several atypical APs causing sedation as a side effect. There are inconclusive data, however, of the risk-to-benefit and comparative use of atypical APs for managing primary insomnia. Inappropriate off-label prescribing can still occur if based mostly on anecdotal reports and expert opinion from personal experience.²⁵ Their role in managing secondary insomnia may be logical in the context of targeting psychiatric and neurologic comorbidities. If used for this purpose, drug interactions and doses should be monitored carefully. 

In a possible attempt to expand the FDA-approved uses of the atypical agents, the pharmaceutical industry may have practitioners believe that low-dose atypical APs can be safely used to manage primary insomnia. In particular, the widespread use of sedating atypical APs for targeting chronic sleep complaints such as insomnia is concerning. Since benzodiazepine agonists are controlled substances with higher abuse potential, this may suggest to some that atypical APs are necessarily a safer alternative. Until there is long-term efficacy and comparative data to demonstrate that the benefit outweighs the risk to their use in targeting sleep disturbances in the absence of concomitant psychiatric conditions, their use should be discouraged for this sole purpose.

Justification for off-label prescribing is to provide the best available therapy for a particular patient, especially when other approved medications for the indication have failed.²⁵ When disclosing off-label use, the patient should be informed of the risks and benefits when weighing the choice of hypnotic medication. Such off-label use should consistently be based on reliable and founded scientific evidence that demonstrates safety for its use in managing insomnia, sometimes, long-term. For the case of using atypical APs for primary insomnia, the evidence is currently lacking. ■

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Table 1

Currently available atypical antipsychotics and their approved adult indications

FDA

approval date

Atypical  

Generic (Brand)

Indications

09/1989

Clozapine 

(Clozaril)

■ Treatment-resistant schizophrenia

■ Reduction in the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorders

12/1993

Risperidone 

(Risperdal,  

Risperdal Consta LAI) 

■ Schizophrenia

■
Bipolar I disorder–associated acute mania or mixed episodes, monotherapy and adjunctive therapy with lithium or valproate

■ Treatment of irritability associated with autistic disorder 

■
LAI indicated for schizophrenia and as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder

09/1996 

Olanzapine 

(Zyprexa) 

■ Schizophrenia

■
Bipolar I disorder–associated acute mania or mixed episodes, monotherapy and adjunctive therapy with lithium or valproate

■ Bipolar I disorder, maintenance as adjunctive therapy with lithium or valproate

■
Combined with fluoxetine, also indicated for bipolar I disorder depressive episodes, and treatmentresistant depression

09/1997

Quetiapine 

(Seroquel,  

Seroquel XR) 

■ Schizophrenia

■
Bipolar I disorder–associated acute mania or mixed episodes, monotherapy and adjunctive therapy with lithium or valproate

■ Bipolar I disorder, maintenance as adjunctive therapy with lithium or valproate

■ Bipolar depression

■
XR formulation is also indicated for major depressive disorder, adjunctive therapy with antidepressants

02/2001

Ziprasidone 

(Geodon) 

■ Schizophrenia

■ Bipolar I disorder–associated acute mania or mixed episodes, monotherapy

■ Bipolar I disorder, maintenance as adjunctive therapy with lithium or valproate

11/2002

Aripiprazole 

(Abilify) 

(Abilify Maintena LAI)

■ Schizophrenia

■
Bipolar I disorder–associated acute mania or mixed episodes, monotherapy and adjunctive therapy with lithium or valproate

■
Bipolar I disorder, maintenance as monotherapy and adjunctive therapy with lithium or valproate

■ Major depressive disorder, adjunctive therapy with antidepressants

■ Treatment of irritability associated with autistic disorder

■ LAI indicated for schizophrenia

12/2006

Paliperidone 

(Invega,  

Invega Sustenna LAI)

■ Schizophrenia

■
Schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers and/or antidepressants

■ LAI indicated for schizophrenia 

05/2009

Iloperidone
(Fanapt)

■ Schizophrenia

08/2009

Asenapine 

(Saphris)

■ Schizophrenia

■
Bipolar I disorder–associated acute mania or mixed episodes, monotherapy or adjunctive therapy with lithium or valproate

10/2010

Lurasidone 

(Latuda) 

■ Schizophrenia

■ Bipolar depression as monotherapy and as adjunctive therapy with lithium or valproate

Abbreviations: LAI, long-acting injection; XR, extended release. 

Formulary/Source: Refs 1–13

Table 2

Pharmacologic agents for insomnia

Agent

Generic (Brand)

Oral dosage range

(mg/day)^a

FDA-approved for insomnia

Adverse reactions

Benzodiazepine receptor agonists: benzodiazepines

Clonazepam 

(Klonopin) 

0.5–3

No 

Dizziness

Drowsiness

Amnesia 

Estazolam 

(Prosom) 

1–2

Yes 

Flurazepam 

(Dalmane) 

15–30

Yes 

Quazepam 

(Doral) 

7.5–15

Yes 

Temazepam 

(Restoril) 

7.5–30

Yes 

Triazolam 

(Halcion) 

0.125–0.5

Yes 

Benzodiazepine receptor agonists: non-benzodiazepines^b

Eszopiclone 

(Lunesta) 

1–3

Yes 

Unpleasant taste 

Dry mouth 

Headache 

Rash 

Zaleplon 

(Sonata) 

5–20

Yes

Dizziness

GI symptoms

Headache 

Zolpidem^c

(Ambien®, 

Ambien CR)

5–10

6.25–12.5 CR

Yes 

Dizziness  

Headache 

Melatonin receptor agonists

Ramelteon 

(Rozerem) 

8

Yes 

Drowsiness

Dizziness 

Nausea

Exacerbated insomnia

Melatonin^d

0.3–5

No 

Drowsiness

Headache

Mild depression

Other

Chloral hydrate

(Somnote)

250–1,000

Yes 

Nausea

Vomiting 

Residual sedation 

Hypotension

Tricyclic antidepressants

Doxepin 

(Silenor)

3–6

Yes 

Somnolence

Nausea

Amitriptyline^e

(Elavil) 

10–100

No 

Dry mouth 

Constipation 

Dizziness 

Tetracyclic antidepressant

Mirtazapine^e

(Remeron)

7.5–30

No 

Drowsiness

Dizziness 

Increased appetite

Weight gain 

Triazolopyridine antidepressant

Trazodone^e

(Desyrel, 

Oleptro) 

25–200

No 

Orthostatic       
Hypotension 

Dizziness

Headache 

Priapism 

Anticholinergic over-the-counter

Diphenhydramine

25–50

Yes

Dry mouth 

Constipation 

Blurred vision 

Tachycardia 

Daytime sedation 

Doxylamine

25

Yes 

Abbreviations: BZD-1, benzodiazepine receptor alpha-1 subtype; CR, extended release; GI, gastrointestinal.

^a Geriatric and usual adult dosage range.  

^b
Non-benzodiazepines are specific for gamma-aminobutyric acid (GABA)-A-alpha-1 receptors and have greater specificity for hypnotic effects compared to
anxiolytic, myorelaxant and anticonvulsant effects. 

^c Additional zolpidem products include Zolpimist oral spray, Edluar, and Intermezzo sublingual tablets. 

^d Melatonin is categorized by FDA as a dietary supplement.

^e Amitriptyline, mirtzapine and trazodone are not FDA-approved for the treatment of insomnia. 

Formulary/Source: Susie H. Park, PharmD, BCPP, FCSHP

Table 3

Sleep parameters

Parameter

Acronym

Goal for insomnia treatment

Sleep latency 

SL

Decrease 

Slow-wave sleep 

SWS

Increase 

Total sleep time 

TST

Increase 

Wake time after sleep onset

WASO

Decrease 

Formulary/Source: Susie H. Park, PharmD, BCPP, FCSHP

Table 4

Currently available atypical antipsychotics and their approved adult indications

First author/Published year

Type of study/

Study

duration 

Number of patients/

Patient age range (yr) 

Patient characteristics/

Daily  antipsychotic dose

Objective 

sleep quality

improvement  outcomes 

Subjective sleep quality

improvement  outcomes  

ADRs/

Comments 

Quetiapine

Tassniyom 

2010 

Double-[blind, placebo, randomized

controlled 

3 weeks

N=13

Outpatient 

25–62

Primary insomnia 

25 mg 

None mentioned 

Sleep diary:

Total sleep time; 

Sleep latency 

VAS:

Sleep satisfaction 

Dry lips

Dry tongue 

Daytime
drowsiness 

Cohrs 

2010 

Case series

Open-label 

3 weeks  

N=4 

21–48 

Acute bipolar disorder:

Mania 

(N=3)

Depression (N=1)  

100–800 mg

Polysomnography:

Total sleep time 

Increased REM latency 

None mentioned

Not listed

Gedge 

2010

Single-blind, open-label  

4 weeks  

N=11

Inpatient and outpatients 

Mean age: 44.3

Depression in  major depressive disorder or bipolar disorder

50–200 mg

Polysomnography:

No improvement in sleep efficiency and total sleep time  

PSQI:

Sleep quality 

Not listed

Pasquini 

2009

Open-label

Case series 

6 weeks  

N=6

38–52

Substance-induced sleep disorder (ie, tamoxifen 20 mg/day)

 25–100 mg

None mentioned

ISI

Weight gain 

Dizziness 

Terán

2008

Retrospective naturalistic 

chart review 

60 days 

N=52 

Inpatient and outpatients

(age not listed)

Polysubstance abuse withdrawal-induced insomnia  

25–225 mg 

None mentioned

SSQ:

Quality of sleep 

Time to fall asleep 

Dry mouth 

Concomitant benzodiazepines use declined 

Wiegand 

2008

Open pilot

6 weeks

N=18

Outpatients

(age not listed) 

Primary insomnia 

 25–75 mg

Most patients on 

25 mg

Polysomnography:

Total sleep time 

Sleep efficiency  

Sleep diary and PSQI:

Total score 

Sleep quality 

Total sleep time 

Sleep efficiency^a 

Dry mouth 

Transient morning hangover 

Keshavan 

2007

Cross-sectional, 

Treatment

versus naïve 

4 weeks 

N=70  

26–46

Stable Schizophrenia

Mean dose of 313.33 mg  

Polysomnography:

Increased REM counts 

Decreased delta counts 

PSQI:

No difference in sleep quality  compared to treatment-naïve 

Not listed

The other treatment group: risperidone

Sokolski

2006

Case report

Over 1 year  

N=1

42

Substance-induced sleep disorder (i.e, phenelzine 45–75 mg/day)

25–100 mg

None mentioned

Sleep quality self-report 

Transient, mild morning
sedation 

Todder

2006

Open-label

Case-control  

4 weeks 

N=27 

Inpatients 

21–76 

Treatment-resistant depression, unipolar or bipolar II insomnia or agitation  

50–800 mg

Mean dose of

340 mg

Actigraph:^b

No significant differences 

PSQI:

Total score

Sleep quality

Daytime sleepiness 

Patients also on venlafaxine or escitalopram for depression 

Robert

2005^c

Open-label

6 weeks

N=18

Outpatients 

18–80

PTSD-related sleep
disturbance 

25–300 mg 

None mentioned

PSQI

PSQI-A

Sedation

Dizziness 

Dry mouth

One patient developed hypersalivation and amblyopia^d

Juri 

2005

Open-label

Case series 

12 weeks

N=14 

Outpatients

59–76

Parkinson’s disease-related insomnia 

12.5–100 mg

Mean dose of 31.9 mg 

None mentioned

PSQI total 

ESS total 

Sleep onset 

Worsening of sleep disorder 

Yamashita

2004

Random assignment, open-label  

8 weeks 

N=92 

Inpatients 

28–84

Schizophrenia, previously on typical AP

Mean doses:

Olanzapine

16.5 mg 

Risperidone

7.4 mg 

Quetiapine

432.5 mg  

None mentioned

PSQI:

Total score 

Not listed 

Random
assignment to olanzapine, risperidone, quetiapine, and perospirone  

Olanzapine

Khazaie 

2013

Case series 

8 weeks 

N=29 

Iranian 

Outpatients 

Olanzapine

N=14

Risperidone 

N=15

Mean age: 53.4 

Paradoxical insomnia 

Olanzapine 10 mg 

Risperidone 4 mg 

Actigraph:

No significant difference in total sleep time between 2 treatments 

PSQI:

Sleep quality improved more with olanzapine compared to risperidone 

Not listed

Khazaie 

2010

Case report 

6 weeks;

1-year follow up  

N=1

60

Paradoxical insomnia 

Olanzapine 5 mg 

None mentioned

Improved sleep 

Not listed 

Sharpley 

2005

Open-label 

3 weeks 

N=12

Outpatient 

29–64 

SSRI-resistant major depressive disorder 

2.5–10 mg 

Polysomnography:

Sleep efficiency  

Not listed 

Next-day
sedation 

Yamashita

2004

See above 

Salin-Pascual 

1999

Case series 

N=20 

Inpatient 

Average age: 33.6 

Acute schizophrenia 

10 mg 

Polysomnography:

Increased delta sleep

Increased stage 2 sleep 

Increased total sleep time 

Not listed 

Not listed 

Risperidone

David 

2006 

Open-label 

12 weeks 

N=17 

Males 

50–66

Combat-related, chronic PTSD; partial responders to antidepressants 

1–3 mg   

None mentioned

Sleep diary:

Awakenings

PSQI:

Total score 

No improvement in awakenings or bad dreams   

Not listed

Yamashita

2004

See above 

Sharpley 

2003

Open-label 

2 weeks 

N=8

Outpatient 

27–55

Antidepressant-resistant major depressive disorder

0.5–1 mg 

Polysomnography:

Decreased wake time 

Decreased REM sleep 

No significant change in sleep quality 

Not listed 

Dursun 

1999

Pilot

Case-control 

Actigraph for 5 consecutive nights

Risperidone treatment for mean of 42.5 weeks

N=24

Outpatient

Risperidone N=8 

Typical AP

N= 8 

Control 

N=8 

Mean age: 36.1  

Control mean age: 33.8 

Stable, chronic schizophrenia 

Mean risperidone dose: 9.5 mg 

Mean chlorpromazine equivalent dose: 606.3 mg 

Actigraph:

Risperidone group had a better movement index compared to both typical AP and control groups 

VAS:

Sleep quality and morning sleepiness better in risperidone group compared to typical AP but same as control group 

Extrapyramidal side effects

Abbreviations: ADRs, adverse drug reactions; AP, antipsychotic;  ESS, Epworth Sleepiness Scale; ISI, Insomnia Severity Index; PSQI, Pittsburgh Sleep Quality Index;  PSQI-A, Pittsburgh Sleep Quality Index Addendum for PTSD (Germain A, et al. 2005); PTSD, posttraumatic stress disorder;  REM, rapid-eye movement;  SSQ, Spiegel Sleep Questionnaire; SSRI, selective serotonin reuptake inhibitor;  VAS, visual analog scale. 

a Sleep efficiency is expressed as a percentage; it is the actual sleep time as a percentage of time in bed.

b
An actigraph is a watchlike device worn on the nondominant hand that measures and records hand movement. Actigraph sleep measurements include sleep efficiency, time, and patterns.  

c The Robert S, et al. 2005 study is a subanalysis of a previous study: Hamner MB, Deitsch SE, Brodrick PS, et al. Quetiapine treatment in patients with post-traumatic stress disorder: an open trial of adjunctive therapy. J Clin Psychopharmacol. 2003;23:15–20.

d Amblyopia is an eye disorder characterized by an impaired vision in an eye that otherwise appears normal; “lazy eye.”  

Formulary/Source: Refs 28,34,35,43,45,46,48,51–55,61,63,65,66,70,71,73