Quetiapine for Insomnia: a Review of the Literature Sarah L

CLINICAL CONSULTATION Quetiapine

CLINICAL CONSULTATION

Quetiapine for insomnia: A review of the literature Sarah L. Anderson and Joseph P. Vande Griend opulation-based estimates have indicated that as many as 30% Purpose. The safety and efficacy of que- active control (e.g., zolpidem); the data that of adults have symptoms of in- tiapine for the treatment of insomnia in exist compare quetiapine to a placebo or P adults are reviewed. there is no comparison and all patients are somnia, and 10% experience daytime Summary. Quetiapine was developed for treated with quetiapine. Very few studies impairment or stress due to their the treatment of psychiatric disorders, but have evaluated quetiapine’s efficacy in the insomnia.1 Insomnia can result in its antagonism of histamine H1- and sero- treatment of insomnia using sleep objective decreased quality of life, decreased tonin type 2A receptors has the added effect testing, another limitation of the available work productivity, increased risk of of causing sedation. As such, quetiapine data on quetiapine. accidents (e.g., motor vehicle acci- is widely used off-label as a treatment for Conclusion. Robust studies evaluating the dents, work-related accidents), and insomnia. Due to quetiapine’s potential safety and efficacy of quetiapine for the increased health care utilization.1,2 adverse effects, guidelines for the treatment treatment of insomnia are lacking. Given its of insomnia have recommended the drug’s limited efficacy data, its adverse-effect pro- People with insomnia are more likely use only in patients with specific comorbid file, and the availability of agents approved to be absent from work and to use psychiatric disorders. The use of quetiapine by the Food and Drug Administration for more health care resources com- for the treatment of insomnia in the absence the treatment of insomnia, quetiapine’s pared with people without insomnia, of comorbid conditions has been evaluated benefit in the treatment of insomnia has resulting in increased costs to both in only two clinical trials of 31 patients in not been proven to outweigh potential patients and society.3,4 total, and very few studies have evaluated risks, even in patients with a comorbid Insomnia is often chronic in na- quetiapine use in patients with insomnia labeled indication for quetiapine. and other comorbidities. No trials have been Am J Health-Syst Pharm. 2014; 71:394- ture. In a population-based study conducted comparing quetiapine with an 402 of 388 adults with insomnia, 74% reported having insomnia for at least one year, and 46% continued to have insomnia after three years.5 The chronic nature of insomnia implies concomitant psychiatric disorder.1 as such, insomnia in the presence the potential for long-term drug The comorbid psychiatric disorder of a psychiatric disorder should be therapy, particularly with sedative most commonly associated with in- considered a comorbid condition.7 hypnotics, a controversial topic be- somnia is depression, but insomnia Common mechanisms are thought yond the scope of this article.6 has also been associated with anxiety, to underlie insomnia and psychiatric Insomnia is frequently associ- substance abuse, and posttraumatic disorders, suggesting that, while a ated with psychiatric disorders. Es- stress disorder.1-4,7-9 Insomnia can be person may be predisposed to both, it timates report that as many as 40% either a cause or a consequence of might be possible to treat both con- of patients with insomnia have a an underlying psychiatric disorder; ditions with the same treatment.1-4,8,9

Sarah L. Anderson, Pharm.D., BCPS, is Assistant Professor, Skaggs The authors have declared no potential conflicts of interest. School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, and Clinical Pharmacy Specialist, Denver Health Copyright © 2014, American Society of Health-System Pharma- Medical Center, Denver, CO. Joseph P. Vande Griend, Pharm.D., cists, Inc. All rights reserved. 1079-2082/14/0301-0394$06.00. BCPS, CGP, is Assistant Professor, Skaggs School of Pharmacy and DOI 10.2146/ajhp130221 Pharmaceutical Sciences, University of Colorado. Address correspondence to Dr. Anderson (sarah.anderson@ ucdenver.edu).

394 Am J Health-Syst Pharm—Vol 71 Mar 1, 2014 CLINICAL CONSULTATION Quetiapine

The Clinical Consultation section features the treatment of insomnia, particu- search was limited to clinical trials, articles that provide brief advice on how to larly in prison and military popula- human studies, and studies written handle specific drug therapy problems. All tions, with significant cost implica- in English. Of the 25 studies identi- articles are based on a systematic review tions. A recent study of low-dose fied using these criteria, 13 were in- of the literature. The assistance of ASHP’s quetiapine use (<100 mg daily) in cluded in this review. Twelve studies Section of Clinical Specialists and Scientists the New Jersey prison population were excluded because the enrolled in soliciting Clinical Consultation submis- highlighted the frequency of the participants did not have a diagnosis sions is acknowledged. Unsolicited submis- drug’s use for insomnia as well as of insomnia at baseline. sions are also welcome. the expense of brand-name que- Outpatient insomnia manage- tiapine (Seroquel, AstraZeneca).16 ment. Cohrs et al.21 performed a At the beginning of the study, as randomized, double-blind, placebo- many as 12 patients per psychiatrist controlled crossover study to exam- Rationale for and prevalence of were taking low-dose quetiapine ine the effects of quetiapine on the quetiapine use for insomnia for insomnia. The average whole- polysomnographic sleep structure Quetiapine is a dibenzothiaz- sale price was $4.50 per tablet of and subjective sleep quality of 14 epine derivative with Food and Drug quetiapine (50 or 100 mg) com- healthy men (mean age, 27 years old). Administration (FDA)-approved pared with $0.05 per tablet of hy- Each participant was studied three labeling for the treatment of schizo- droxyzine hydrochloride (100 mg), times for three consecutive nights phrenia and acute manic, depres- making quetiapine 90 times more four days apart. No treatment was sive, or mixed episodes of bipolar expensive than hydroxyzine, anoth- administered on night 0. On nights 1 I disorder; maintenance treatment er agent used to treat insomnia.16 and 2, participants received placebo, of bipolar I disorder in combina- A retrospective chart review of quetiapine 25 mg, or quetiapine 100 tion with lithium or divalproex; 692 soldiers treated with quetiapine mg orally one hour before sleep. and adjunctive treatment of major at Madigan Army Medical Center in Participants slept in standard sleep depressive disorder.10,11 Quetiapine Tacoma, Washington, revealed that laboratory conditions on night 1; on has also been used for the off-label the most common indications for night 2, acoustic stress was applied. treatment of anxiety disorders, de- quetiapine use were insomnia (57%) Compared with placebo, quetiapine mentia, autism, refractory obsessive- and anxiety (20%).17 Further, only improved sleep latency, total sleep compulsive disorder, delirium, and 9.4% of soldiers were prescribed time, and sleep efficiency (p < 0.01, insomnia.12,13 It exhibits a strong quetiapine for an FDA-approved p < 0.001, and p < 0.001, respective- affinity for antagonism at hista- indication. According to the Associ- ly) compared with placebo. Specific mine H1-receptors, similar to that ated Press, the Pentagon and the polysomnographic data are provided of diphenhydramine, amitriptyline, Department of Veterans Affairs spent in Table 1. Similar findings were mirtazapine, and doxepin, and has a $8.6 million and $125.4 million on noted in the subjective sleep quality moderate affinity for serotonin type quetiapine in 2009, respectively.18 scores and time scores on the visual 14 2A (5-HT2A) receptors. Antagonism Information on the use of quetiapine analog scale and sleep question- at these receptor sites is thought to be in the general population is more naires. The number of awakenings the primary mechanism behind que- elusive; however, off-label use is fre- experienced was fewer in participants tiapine’s sedative properties.14 Due to quent. In 2002, quetiapine was sixth randomized to quetiapine versus quetiapine’s potential adverse effects on the list of the top 16 drugs used to placebo but was not significantly dif- (e.g., orthostatic hypotension, weight treat insomnia.19 Quetiapine became ferent (p = 0.10). Overall, quetiapine gain, hyperlipidemia, hyperglyce- available in generic form in March was well tolerated. Two volunteers mia), guidelines for the treatment 2012 but is still considerably costly, withdrew from the study after ex- of insomnia have recommended the approximately $6–$7 per tablet for periencing orthostatic hypotension drug’s use only in patients who have 50- and 100-mg tablets.20 after receiving 100 mg of quetiapine; a comorbid psychiatric disorder and This article examines the safety these participants were not included in those “who may benefit from the and efficacy of quetiapine use for the in the data analysis. The other ad- primary action of [the drug] as well treatment of insomnia. verse effect of note was periodic leg as from the sedating effect.”15 movement, which was most preva- Despite the recommendation Literature review lent in the individuals who received to limit its use to individuals with A literature search was performed quetiapine 100 mg. This study was a comorbid psychiatric disorder, using PubMed and MEDLINE limited by its small sample size and the medical literature has reported (1950–April 2013) with the search the fact that subjects took quetiapine widespread use of quetiapine for terms quetiapine and insomnia. The for only two nights.

Am J Health-Syst Pharm—Vol 71 Mar 1, 2014 395 CLINICAL CONSULTATION Quetiapine

Insomnia disorder. To date, two based on both objective and subjec- used for the treatment of psychiatric published studies have evaluated tive data (Tables 1 and 2). Total sleep disorders. the use of quetiapine specifically for time and sleep efficiency evaluated by Tassniyom et al.23 conducted a the treatment of insomnia. In an polysomnography were significantly small, randomized, double-blind, open-label pilot study by Wiegand et improved at weeks 2 and 6 (p = 0.05). placebo-controlled trial in 16 Thai al.,22 18 adults with insomnia (demo- Similarly, the Pittsburgh Sleep Qual- adults with a diagnosis of insomnia graphics not reported) were treated ity Index (PSQI) score and subscores based on criteria established by the with quetiapine 25 mg orally at bed- were statistically improved at both Diagnostic and Statistical Manual, 4th time. The dosage of quetiapine was weeks 2 and 6 (Table 1). The most edition, Text Revision (DSM-IV-TR). increased to 50 mg in 7 patients and frequently reported adverse effects Participants’ mean age was 46 years, to 75 mg in 1 patient. Patients experi- were dry mouth and transient morn- and the majority were women. enced improvement in sleep param- ing hangover effects. Importantly, Patients were excluded if they had eters after two weeks and continued quetiapine promoted sleep in these comorbid psychiatric conditions or to show improvements at six weeks patients at dosages well below those were already receiving medications

Table 1. Subjective Evaluations of Quetiapine for Insomniaa

Ref. Intervention Evaluation Findings 22 Quetiapine 25–75 mg daily PSQI Quetiapine showed statistical improvement (p = 0.00) on the total score and subscale scores of sleep quality, total sleep time, and sleep efficiency at weeks 2 and 6. 23 Quetiapine 25 mg daily VAS Sleep satisfaction scores improved for both groups and were not statistically different (p = 0.505). 24 Quetiapine 315 ± 109 mg daily HAM-D Insomnia Subscale Quetiapine significantly (p < 0.001) improved items 4–6 compared to placebo. 25 Quetiapine 25–100 mg daily MADRS Insomnia Quetiapine plus fluoxetine improved the mean insomnia score sooner (p ≤ 0.01 for the first, second, and third follow-up visits) compared with the fluoxetine plus placebo group. 26 Quetiapine 300 or 600 mg PSQI Both doses of quetiapine showed statistical improvement daily (p < 0.001) at days 29 and 57 compared to placebo. 27 Quetiapine 300 or 600 mg MADRS Insomnia Both doses of quetiapine showed statistical improvement daily vs. paroxetine 20 mg (p < 0.05) on item 4 (reduced sleep) compared to daily paroxetine. 28 Quetiapine 12.5–50 mg daily PSQI PSQI improved in 11 patients and was reduced by 3.9 ± 3.8 points (p < 0.01). 29 Quetiapine 25–100 mg daily ISI For 5 of 6 patients, the ISI score moved from moderate insomnia to absence of insomnia at week 1 and was maintained through week 6. 30 Quetiapine 25–225 mg daily SSQ 75% improvement in global score; greatest improvements in overall quality of sleep and sleep latency. 31 Quetiapine 50–750 mg daily PSQI A significant time effect for total score occurred after vs. olanzapine 2.5–20 mg 8 weeks in both middle-aged and elderly patients, daily, risperidone 1–12 mg regardless of drug (p = 0.008). daily, and perospirone 4–48 mgb daily 33 Quetiapine 340 mg (mean) PSQI Most improved quality of sleep occurred in the patients daily in the upper quetiapine quartile (>360-mg mean daily dose). The strongest reduction in daytime sedation was observed in patients receiving the highest quetiapine doses. aPSQI = Pittsburgh Sleep Quality Index, VAS = visual analog scale, HAM-D = Hamilton Rating Scale for Depression, MADRS = Montgomery-Åsberg Depression Rating Scale, ISI = Insomnia Severity Index scale, SSQ = Spiegel Sleep Questionnaire. bNot available in the United States.

396 Am J Health-Syst Pharm—Vol 71 Mar 1, 2014 CLINICAL CONSULTATION Quetiapine known to cause sedation. Patients of the study may have been too short ficacy outcome was improvement received either placebo or quetiapine to determine if there was a difference in the Hamilton Rating Scale for 25 mg orally nightly for two weeks. between quetiapine and placebo with Depression (HAM-D) score, which A total of 13 participants (6 in the regard to improvement in sleep. included an evaluation of the sub- placebo group, 7 in the quetiapine None of the aforementioned stud- scale for insomnia (items 4–6). The group) completed the study. One ies reported on changes in metabolic insomnia subscale scores improved person in the quetiapine group variables (e.g., weight, waist circum- over baseline by week 2, and this ef- withdrew after being diagnosed with ference, fasting glucose concentra- fect was maintained through week 20 vertigo, and 2 participants in the tion, lipid profile). This was likely (Table 1). Of the 14 patients studied, placebo group withdrew citing lack not done due to the small sample 3 experienced hypotension and 2 had of efficacy; all 3 individuals withdrew sizes, short durations, and relatively daytime sedation, all of which were before receiving the intervention. healthy populations evaluated. noted to be mild and transient in Both the quetiapine and placebo Major depressive disorder. Šagud et nature. Four patients were noted to groups experienced increased total al.24 conducted a prospective, open- have hyperlipidemia at baseline, but sleep time (by 125 and 72 minutes, label, noncomparative, flexible-dose no metabolic outcomes (e.g., change respectively), decreased sleep latency study to evaluate the efficacy of in lipid values) were reported. The (by 96 and 24 minutes, respectively), quetiapine add-on therapy in 14 authors concluded that quetiapine and improved sleep satisfaction patients with major depressive disor- alleviated insomnia, a common and based on visual analog scale scores, der (defined using DSM-IV criteria) severe symptom of depression, in pa- but none of the differences between who were refractory to previous tients enrolled in this study and this groups were significant (p > 0.05) therapy. The mean age of patients was perceived as a beneficial effect. (Tables 1 and 2). Adverse effects was 53 years, and the majority were Garakani et al.25 evaluated the were observed only in the quetiap- men. Quetiapine 50 mg was added to ability of quetiapine to augment ine group and included dry lips, dry patients’ current antidepressant regi- fluoxetine therapy over eight weeks tongue, and daytime drowsiness. men at bedtime, with dosage increas- in 114 patients with major depres- The authors acknowledged that the es in increments of 50 mg; the mean sive disorder, as defined by DSM-IV small sample size rendered the study ± S.D. bedtime dose in study patients criteria. A total of 51 men (mean underpowered and that the duration was 315 ± 109 mg. The primary ef- age, 41 years) and 64 women (mean

Table 2. Objective Evaluations of Quetiapine for Insomnia via Polysomnography or Actigraphy

Mean ± S.D. No. Occurences ± S.D. Sleep Total Sleep Sleep Periodic Leg Ref. and Intervention Latency, min Time, min Efficiency, % Awakenings Movements 21 Quetiapine 25 mg daily 12.2 ± 6.1a,b 439.9 ± 20.5c 91.8 ± 4.2c 27 ± 7.7 62.2 ± 78.1 Quetiapine 100 mg daily 13.3 ± 8.5 a,b 441.4 ± 23.4c 92.0 ± 4.8c 24.9 ± 10.1 138.4 ± 153.8c Placebo 22.8 ± 18.4b 411.4 ± 37.7 85.8 ± 7.9 30.0 ± 11.3 41.2 ± 63.2 22 Quetiapine 25–75 mg daily 24.2 ± 19.0 395.6 ± 62.3d 89.9 ± 8.2d . . .e . . . 23 Quetiapine 25 mg daily 66.5 ± 51.2 347.5 ± 100.9 ...... Placebo 47.4 ± 30.4 361.9 ± 85.4 ...... 32 Quetiapine 340 mg (mean) 15.6 ± 18.1f 432 ± 66 82.7 ± 9.1f ...... daily No therapy (control) 24.5 ± 30.2 390 ± 54 77.0 ± 7.9 ...... ap < 0.005 compared with placebo. bSleep stage 2. cp < 0.001 compared with placebo. dp < 0.05 compared with baseline. eNot evaluated. fp < 0.05 at week 4 compared with control.

Am J Health-Syst Pharm—Vol 71 Mar 1, 2014 397 CLINICAL CONSULTATION Quetiapine age, 42 years) participated in this studies that randomized 1051 pa- majority of patients were women, randomized, double-blind, placebo- tients who were experiencing a major and the mean age was approximately controlled trial. The study allowed for depressive episode of bipolar I or 39 years. Both dosages of quetiapine flexible dosing of quetiapine (start- II disorder (as defined by DSM-IV produced significant improvements ing dosage of 25 mg daily adjusted criteria) to monotherapy with fixed- in sleep compared with placebo; in 25-mg increments every third dose quetiapine 300 or 600 mg daily the same was not true of paroxetine day to a maximum of 100 mg daily); or placebo for eight weeks. The ma- (Table 1). As in the BOLDER I study, the mean dosage was 47.3 mg daily. jority of patients were women, and the most common patient-reported Quetiapine and placebo were admin- the mean age was approximately 38 adverse effects of quetiapine were istered in the evening. All patients years. Data on the quality of sleep dry mouth, somnolence, and seda- received concurrent fluoxetine 20–40 from the BOLDER I trial (n = 511) tion. In the EMBOLDEN II study, mg daily. The main outcome mea- were analyzed. Improvements in 9–11.3% of patients in the quetiapine sure was the Montgomery-Åsberg PSQI scores for both dosages of groups experienced clinically signifi- Depression Rating Scale (MADRS) quetiapine at days 29 and 57 were cant weight gain (greater than 7% of score, with a focus on the sleep item. significant compared with placebo their baseline weight) compared with Patients were defined as having in- (p < 0.001) (Table 1). Although those receiving paroxetine (3.3%) or somnia at baseline if they scored 4 quantitative data were not reported, placebo (4.1%). The only statistically or greater on the reduced sleep ques- the most substantial benefits appear significant change in weight from tion of the MADRS. Overall, there to have been in sleep quality and baseline compared with placebo was no difference in response on the total sleep time. The improvements occurred in the quetiapine 600-mg MADRS or a difference in remission in PSQI scores correlated with im- group (mean ± S.D. weight change rates between groups; however, pa- provements in depression and anxi- from baseline of 1.7 ± 0.23 kg, p < tients who had insomnia at baseline ety symptoms, measured using the 0.001). More patients in the que- in the quetiapine plus fluoxetine MADRS, HAM-D, Hamilton Rating tiapine groups experienced clinically group experienced improvements Scale for Anxiety, and the Clinical relevant increases in cholesterol val- in sleep and anxiety. The insomnia Global Impression scale. The most ues, with 14.2–14.7% of quetiapine- scores of patients in the quetiapine common adverse events in the que- treated patients having a triglyceride plus fluoxetine group improved tiapine groups included dry mouth, concentration of ≥200 mg/dL at the quicker than those in the placebo sedation, and somnolence. Fewer end of the study; however, 13% of pa- plus fluoxetine group (Table 1). The than 4% of patients in each quetia- tients in the placebo group also had mean ± S.D. weight change from pine group reported insomnia as an significant increases in cholesterol baseline to weeks 8 and 9 of treat- adverse event. Patients in the que- values. A small percentage of patients ment was not statistically different tiapine groups were more likely to re- in the quetiapine groups (3–5.6%) between groups (–0.853 ± 2.79 kg in port weight gain as an adverse effect and in the paroxetine group (4.3%) the placebo group and –0.204 ± 2.404 (2.9% in the 300-mg group, 5.7% in had clinically significant increases kg in the quetiapine plus fluoxetine the 600-mg group) compared with in fasting blood glucose (concentra- group, p not reported). The most placebo (1.2%). It should be noted tions of ≥126 mg/dL). common patient-reported adverse that patients in the quetiapine groups Although the use of quetiapine effects in both groups were gastro- weighed more at baseline than those in these populations with insomnia intestinal symptoms (nausea, diar- in the placebo group (mean weights and concurrent unipolar or bipolar rhea, constipation), dizziness, and of 87.0, 85.6, and 83.4 kg in the 300- depression was shown to be effective sedation; sedation was significantly mg, 600-mg, and placebo groups, for improving sleep, it is unknown more common in the quetiapine plus respectively). whether the insomnia improved fluoxetine group (p = 0.006). Similar to the BOLDER I and because the depression improved or Bipolar depression. Endicott et II studies, the EMBOLDEN II (Ef- if the insomnia improved indepen- al.26 performed a secondary analy- ficacy of Monotherapy Seroquel in dently of the depression. sis on data from the BOLDER BipOLar DepressioN II) trial con- Parkinson’s disease. Juri et al.28 stud- (BipOLar DEpRession) I and II trials ducted by McElroy et al.27 random- ied 14 patients (11 men and 3 women) to evaluate the effects of quetiapine ized 740 patients with bipolar I or II with nonpsychotic Parkinson’s dis- monotherapy on quality of life and disorder and a major depressive epi- ease who received quetiapine for 12 sleep in patients with bipolar I and sode (as defined by DSM-IV criteria) weeks for the treatment of insomnia. II depressive episodes. The BOLDER to quetiapine 300 mg daily, quetiap- This was an open-label study that al- I and II trials were randomized, ine 600 mg daily, paroxetine 20 mg lowed for dosage adjustments based double-blind, placebo-controlled daily, or placebo for eight weeks. The on response; at the end of 12 weeks,

398 Am J Health-Syst Pharm—Vol 71 Mar 1, 2014 CLINICAL CONSULTATION Quetiapine the mean daily quetiapine dose on response. At the end of 60 days, antidepressant therapy on daytime was 31.9 mg (range, 12.5–50 mg). the mean dosage was 62.35 mg daily sleepiness and quality of sleep were Total PSQI and its subscale scores (range, 25–225 mg) at bedtime. Pa- evaluated over four weeks in 27 adult improved significantly over baseline tients were assessed using the Spiegel patients admitted for the treatment (p < 0.01), with the largest improve- Sleep Questionnaire and demon- of a major depressive episode.32,33 ment seen in sleep latency (reduced strated a 75% improvement in the During the treatment period, the from a mean ± S.D. time of 82 ± 65.4 global score over baseline (p < 0.001). mean daily quetiapine dose was 340 minutes to 28.6 ± 22.7 minutes). Two The greatest improvements occurred mg. Actigraphy data from the first patients with restless legs syndrome in overall quality of sleep and sleep and last seven nights (10:00 p.m. to at baseline discontinued treatment latency. Benzodiazepine use was also 6:00 a.m.) were used to objectively with quetiapine due to worsening of evaluated and had decreased from assess sleep quality. There were no these symptoms. 83% at baseline to 22.6% at 60 days. significant differences found in the Breast cancer. Pasquini et al.29 No patients discontinued therapy patients between weeks 1 and 4. Ac- studied 6 women with localized due to adverse effects, the most tigraphic data were also collected for breast cancer (TNM Stage I–IIIA) common of which was dry mouth 27 matched controls due to a lack of who were receiving tamoxifen 20 (34.6%). Metabolic effects were not normative actigraphic data. Com- mg daily and had a diagnosis of reported. pared with study patients, patients substance-induced sleep disorder. Inpatient management of insom- in the control group at week 4 had At baseline, the 6 participants had nia. Schizophrenia. Yamashita et al.31 significantly longer sleep latency been taking daily tamoxifen for at stratified 86 inpatient adults into two (p = 0.03), lower sleep efficiency least three months. Quetiapine treat- groups, elderly (older than 65 years) (p = 0.01), and shorter sleep time ment for insomnia was started at 25 and middle-aged (43–64 years), and (p = 0.02).32 A PSQI score was col- mg nightly and could be increased randomized these patients to switch lected at baseline and weekly for in 25-mg increments to a maximum from their baseline antipsychotic to study patients. Both the total PSQI daily dose of 100 mg. Five of the 6 one of four atypical antipsychotics, score and the PSQI daytime sleepi- women showed improvements in which included quetiapine (13 in the ness subscore showed significant insomnia at week 1 that persisted to elderly group, 12 in the middle-aged improvement over baseline for all week 6 based on the Insomnia Sever- group). These patients were admitted four weeks (p < 0.001). The largest ity Index scale. Two women reported to an inpatient psychiatric hospital improvement in sleep quality oc- weight gain (not quantified), and 1 in Japan. Antipsychotic dosages were curred in the patients receiving the reported dizziness at the six-week allowed to vary; the mean quetiapine highest dose of quetiapine (>364 follow-up visit. Interestingly, 2 of dosages at the end of the study were mg daily).33 There were no recorded the 6 women had previously taken a 409.6 mg daily in the elderly group instances of adverse metabolic or benzodiazepine and 1 had taken mir- and 541.7 mg daily in the middle-aged clinical effects or significant weight tazapine for insomnia. Although the group. Sleep was assessed via the PSQI gain (≥10% of baseline weight) over conclusions regarding the efficacy of at baseline and at eight weeks after the the four-week study.33 quetiapine for insomnia were posi- medication switch. PSQI scores were Similar to the studies that evalu- tive, it is difficult to draw generalized reported for all patients (not strati- ated quetiapine for the treatment of conclusions from a small study with fied by antipsychotic) and showed insomnia in outpatient adults with such a specific patient population. a significantly improved time effect unipolar or bipolar depression, it Addictive conditions. Terán et al.30 for total PSQI score and number of is unknown whether the insomnia reviewed the charts of 52 patients minutes spent in bed (p < 0.05). A improved because the psychiatric with polysubstance abuse who had logistic regression analysis found that disorder improved or the insomnia insomnia as their primary with- the use of quetiapine (as well as the improved independent of the psychi- drawal symptom and were treated use of olanzapine and risperidone) atric disorder. with quetiapine for insomnia. The was a predictor of improvement on majority of patients (n = 31) were the PSQI. The authors noted that 1 Safety of quetiapine for insomnia started on quetiapine in the inpatient patient in the elderly group who was The two studies that evaluated the setting; the remaining patients (n = treated with quetiapine dropped out use of quetiapine specifically for the 21) started quetiapine as outpatients. because of a hip fracture; otherwise, treatment of insomnia in the absence All had been followed for 60 days in safety concerns regarding quetiapine of comorbid conditions found that the outpatient setting. Quetiapine were not reported. the drug was generally well tolerated was initiated at 50–100 mg daily, Major depressive disorder. The ef- at a dosage of 25–75 mg nightly for and the dosage was adjusted based fects of quetiapine as an adjunct to two to six weeks.22,23 In each study,

Am J Health-Syst Pharm—Vol 71 Mar 1, 2014 399 CLINICAL CONSULTATION Quetiapine the adverse effects most commonly reports have also demonstrated the and sleep outcomes were statistically cited by patients in the quetiapine tendency for quetiapine to induce analyzed in healthy volunteers and groups were dry mouth and daytime Q-Tc-interval prolongation, particu- patients with primary insomnia, sedation, which are consistent with larly in patients taking concomitant respectively, in two studies21,22; such the common adverse effects noted drugs known to prolong the Q-T in- testing and analysis were not con- in the drug’s prescribing informa- terval (e.g., amiodarone, methadone) ducted in the four studies evaluating tion.10,11,22,23 Adverse-effect data from and in patients with underlying con- the use of quetiapine for insomnia the small, short-duration trials of ditions known to predispose some- in patients with unipolar or bipolar quetiapine for insomnia showed the one to Q-Tc-interval prolongation depression.24-27 In addition, no trials drug to be well tolerated, but it is (e.g., electrolyte imbalance, heart comparing quetiapine with an active unknown if this would hold true for failure).10,11,13 The obvious adverse control (e.g., zolpidem) have been longer durations of use in a larger effect of sedation exists with quetia- conducted; the data that exist com- number of patients. Recent safety pine use, but, in the case of insomnia pare quetiapine to a placebo or there reviews of quetiapine dosages of less treatment, sedation is a desired effect. is no comparison and all patients are than 300 mg per day have noted treated with quetiapine. This type of that the drug can cause harmful Discussion comparative data would be helpful to adverse effects.34-36 Low-dose quetia- Quetiapine was developed for the determine the true efficacy of que- pine (≤ 200 mg) at bedtime used for treatment of psychiatric disorders, tiapine in treating insomnia, particu- insomnia has been shown to cause but its antagonism of the H1- and larly in patients with a psychiatric significant increases in weight (p = 5-HT2A receptors has the added ef- comorbidity. The limited number 0.037) and body mass index (p = fect of causing sedation. As such, of trials combined with small sam- 0.048).34 The American Diabetes quetiapine is widely used as a treat- ple sizes, short durations, variable Association consensus development ment for insomnia. However, before populations (e.g., Parkinson disease, conference cautions that any medica- a practitioner recommends or pre- breast cancer), and predominantly tion that causes substantial weight scribes quetiapine for the treatment subjective evaluations (e.g., ques- gain could put a person at risk for de- of insomnia, several issues should be tionnaires) do not lend confidence veloping diabetes mellitus.37 The data considered. to the concept that quetiapine is a are mixed on whether diabetes or First, robust studies evaluating proven safe and effective treatment dyslipidemia is caused by quetiapine the safety and efficacy of quetiapine modality for insomnia. use, but the same consensus position for the treatment of insomnia are Second, quetiapine has gained a statement recommends that patients lacking. There are a limited number reputation as a drug of misuse and treated with second-generation anti- of studies, some of which evaluated abuse. Quetiapine has been referred psychotics, such as quetiapine, have niche populations whose data would to as several street names, includ- their weight, waist circumference, not be generalizable to the general ing “quell,” “Susie Q,” and “baby blood pressure, fasting glucose con- population. The use of quetiapine heroin.”39 Case reports of quetiapine centration, and fasting lipid panel for the treatment of insomnia in the abuse have described patients who routinely monitored.37 absence of comorbid conditions has have misused the drug orally, intra- Although the causality is ques- been evaluated in only two clini- nasally, and intravenously (achieved tionable, nonmetabolic adverse ef- cal trials of 31 patients in total.22,23 by crushing quetiapine tablets).40 fects that have been associated with Quetiapine studies in patients with Quetiapine has also been mixed low-dose quetiapine include restless insomnia and other comorbidities with illicit drugs, such as cocaine legs syndrome and periodic limb are not much more prevalent; the (“Q-ball”) or marijuana (“Maq-ball”).40 movements in sleep, daytime se- four trials included in this review It should be noted, however, that dation, dry mouth, akathisia, and that included patients with unipolar most reports of quetiapine abuse fatal hepatotoxicity.21-23,36 Tardive or bipolar depression evaluated just have occurred among prison inmates dyskinesia has also been associated 1379 patients.24-27 This is not a large or in inpatient psychiatric settings in with quetiapine use. While the risk number of patients, given the high patients with a history of substance of developing tardive dyskinesia is prevalence of insomnia and the high abuse, so the abuse potential may typically associated with increasing prevalence of quetiapine prescrib- not be generalizable to the overall dosages and longer treatment dura- ing.1,38 Very few of the studies evalu- population of people with insom- tions of therapy, it can occur with ated sleep using objective testing, nia.41 The implications for abuse by low dosages and during short treat- which is another limitation of the people using the drug for insomnia ment courses, such as those used to available data on quetiapine. Poly- are unknown. Quetiapine is not a treat insomnia.10,11,13 Postmarketing somnographic testing was performed controlled substance but, based on

400 Am J Health-Syst Pharm—Vol 71 Mar 1, 2014 CLINICAL CONSULTATION Quetiapine reports of abuse, may have the poten- 5. Morin CM, Bélanger L, LeBlanc M et pilot study. Psychopharmacology. 2008; al. The natural history of insomnia: a 196:337-8. Letter. tial to be misused in a patient desper- population-based 3-year longitudinal 23. Tassniyom K, Paholpak S, Tassniyom S ate for sleep. study. Arch Intern Med. 2009; 169:447-53. et al. Quetiapine for primary insomnia: Finally, off-label use of quetiapine 6. Shahid A, Chung SA, Phillipson R, Shapiro a double blind, randomized controlled for the treatment of insomnia has CM. An approach to long-term sedative trial. J Med Assoc Thai. 2010; 93:729-34. hypnotic use. Nat Sci Sleep. 2012; 4:53-61. 24. Šagud M, Mihaljević-Peleš A, Mück-Šeler medical–legal implications. Based on 7. American Psychiatric Association. High- D et al. Quetiapine augmentation in its known H -receptor antagonistic lights to changes from DSM-IV-TR to treatment-resistant depression: a natu- 1 DSM-5. www.psychiatry.org/File%20 ralistic study. Psychopharmacology. 2006; properties, the use of quetiapine Library/Practice/DSM/DSM-5/Changes- 187:511-4. for insomnia could be considered from-DSM-IV-TR–to-DSM-5.pdf 25. Garakani A, Martinez JM, Marcus S et “evidence-based off-label use”; none- (accessed 2013 Jun 11). al. A randomized, double-blind, and 8. Riemann D. Insomnia and comorbid placebo-controlled trial of quetiapine theless, such use is not supported by psychiatric disorders. Sleep Med. 2007; augmentation of fluoxetine in major de- the FDA-approved labeling for the 8(suppl 4):S15-20. pressive disorder. Int Clin Psychopharm. drug.42 Because quetiapine has the 9. Sateia MJ. Update on sleep and psychiat- 2008; 23:269-75. ric disorders. Chest. 2009; 135:1370-9. 26. Endicott J, Paulsson B, Gustafsson U et potential to cause serious adverse 10. Seroquel (quetiapine fumarate) package al. Quetiapine monotherapy in the treat- effects, including increased risk of insert. Wilmington, DE: AstraZeneca; ment of depressive episodes of bipolar I death in elderly patients; increased 2012. and II disorder: improvements in quality 11. Seroquel XR (quetiapine fumarate) pack- of life and quality of sleep. J Affect Disord. risk of suicidal thinking and behavior age insert. Wilmington, DE: AstraZeneca; 2008; 111:306-19. in children, adolescents, and young 2012. 27. McElroy SL, Weisler RH, Chang W et al. adults; cardiac dysrhythmias; and 12. Philip NS, Mello K, Carpenter LL et A double-blind, placebo-controlled study al. Patterns of quetiapine use in psy- of quetiapine and paroxetine as mono- metabolic dysfunctions (e.g., sig- chiatric inpatients: an examination of therapy in adults with bipolar depression nificant weight gain, hyperglycemia, off-label use. Ann Clin Psychiatry. 2008; (EMBOLDEN II). J Clin Psychiatry. 2010; hyperlipidemia), patients could pur- 20:15-20. 71:163-74. 13. Quetiapine. In: Drugdex System. Green- 28. Juri C, Chaná P, Tapia J et al. Quetiapine sue litigation against a prescribing wood Village, CO: Thomson Reuters for insomnia in Parkinson disease: results physician, a dispensing pharmacy, (Healthcare). Updated periodically. from an open-label trial. Clin Neurophar- or a drug manufacturer if harmed 14. Stahl SM. Selective histamine H1 antago- macol. 2005; 28:185-7. nism: novel hypnotic and pharmacologic 29. Pasquini M, Speca A, Biondi M. Quetia- by quetiapine used for an off-label actions challenge classical notions of anti- pine for tamoxifen-induced insomnia in indication. histamines. CNS Spectr. 2008; 13:1027-38. women with breast cancer. Psychosomat- 15. Schutte-Rodin S, Broch L, Buysse D et ics. 2009; 50:159-61. Conclusion al. Clinical guideline for the evaluation 30. Terán A, Majadas S, Galan J. Quetiapine and management of chronic insomnia in in the treatment of sleep disturbances Robust studies evaluating the adults. J Clin Sleep Med. 2008; 4:487-504. associated with addictive conditions: a safety and efficacy of quetiapine for 16. Reeves R. Guideline, education, and peer retrospective study. Subst Use Misuse. comparison to reduce prescriptions of 2008; 43:2169-71. the treatment of insomnia are lack- benzodiazepines and low-dose quetia- 31. Yamashita H, Mori K, Nagao M et al. ing. Given its limited efficacy data, pine in prison. J Correct Health Care. Influence of aging on the improvement its adverse-effect profile, and the 2012; 18:45-52. of subjective sleep quality by atypical an- 17. Levin A. Concern raised over antipsy- tipsychotic drugs in patients with schizo- availability of agents approved by chotic’s use for sleep problems. http:// phrenia: comparison of middle-aged and FDA for the treatment of insomnia, psychnews.psychiatryonline.org/news older adults. Am J Geriatr Psychiatry. quetiapine’s benefit in the treatment Article.aspx?articleid=116611 (accessed 2005; 13:377-84. 2013 Apr 4). 32. Todder D, Caliskan S, Baune BT. Night of insomnia has not been proven 18. Kime P. DoD cracks down on off- locomotor activity and quality of sleep to outweigh potential risks, even in label drug use. www.militarytimes.com/ in quetiapine-treated patients with de- patients with a comorbid labeled in- news/2012/06/military-dod-cracks-down- pression. J Clin Psychopharmacol. 2006; on-off-label-seroquel-use-061412w/ 26:638-42. dication for quetiapine. (accessed 2013 Apr 4). 33. Baune BT, Caliskan S, Todder D. Effects 19. Walsh JK. Drugs used to treat insomnia of adjunctive antidepressant therapy with References in 2002: regulatory-based rather than quetiapine on clinical outcome, quality 1. Roth T. Insomnia: definition, prevalence, evidence-based medicine. Sleep. 2004; of sleep and daytime motor activity in etiology, and consequences. J Clin Sleep 27:1441-2. patients with treatment-resistant depres- Med. 2007; 3(suppl):S7-10. 20. Thomson Reuters Micromedex Clinical sion. Hum Psychopharmacol Clin Exp. 2. Simon GE, VonKorff M. Prevalence, Evidence Solutions. http://thomsonreuters. 2007; 22:1-9. burden, and treatment of insomnia in com/products_services/healthcare/ 34. Cates ME, Jackson CW, Feldman JM et primary care. Am J Psychiatry. 1997; healthcare_products/clinical_deci_ al. Metabolic consequences of using low- 154:1417-23. support/micromedex_clinical_evidence_ dose quetiapine for insomnia in psychi- 3. Daley M, Morin CM, LeBlanc M et al. sols/med_safety_solutions/red_book atric patients. Community Ment Health J. Insomnia and its relationship to health- (accessed 2013 Apr 4). 2009; 45:251-4. care utilization, work absenteeism, pro- 21. Cohrs S, Rodenbeck A, Guan Z et al. 35. Gugger JJ, Cassagnol M. Low-dose que- ductivity and accidents. Sleep Med. 2009; Sleep-promoting properties of quetia- tiapine is not a benign sedative-hypnotic 10:427-38. pine in healthy subjects. Psychopharma- agent. Am J Addict. 2008; 17:454-5. 4. Wade AG. The societal costs of insom- cology. 2004; 174:421-9. 36. Coe HV, Hong IS. Safety of low doses of nia. Neuropsychiatr Dis Treat. 2011; 7:1- 22. Wiegand MH, Landry F, Brückner T et quetiapine when used for insomnia. Ann 18. al. Quetiapine in primary insomnia: a Pharmacother. 2012; 46:718-22.

Am J Health-Syst Pharm—Vol 71 Mar 1, 2014 401 CLINICAL CONSULTATION Quetiapine

37. American Diabetes Association, Ameri- can Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004; 27:596-601. 38. IMS Institute for Healthcare Informatics. The use of medicines in the United States: review of 2011. www.imshealth.com/ ims/Global/Content/Insights/IMS%20 Institute%20for%20Healthcare%20 Informatics/IHII_Medicines_in_U.S_ Report_2011.pdf (accessed 2012 Jun 29). 39. Sansone RA, Sansone LA. Is Seroquel developing an illicit reputation for misuse/ abuse? Psychiatry. 2010; 7:13-6. 40. Waters BM, Joshi KG. Intravenous quetiapine-cocaine use (“Q-ball”). Am J Psychiatry. 2007; 164:173-4. 41. Pinta ER, Taylore RE. Quetiapine ad- diction? Am J Psychiatry. 2007; 164:174. Letter. 42. Kesselheim AS. Off-label drug use and promotion: balancing public health goals and commercial speech. Am J Law Med. 2011; 37:225-57.

402 Am J Health-Syst Pharm—Vol 71 Mar 1, 2014