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 REVIEW ARTICLE

The effects of mirtazapine on sleep in patients with major depressive disorder

Christian R. Dolder, PharmD

Wingate University School of Pharmacy, Wingate, NC, USA, Pharmacy Department, Carolinas Medical Center-NorthEast, Concord, NC, USA

Michael H. Nelson, PhD, RPh

Pharmaceutical Sciences Department, Regis University, Denver, CO, USA

Cameron A. Iler, PharmD

Wingate University School of Pharmacy, Wingate, NC, USA

BACKGROUND: Mirtazapine is a commonly used antidepressant with a well-known ability to produce sedation. At the same time, its sleep-promoting effects in patients with major depressive disorder (MDD) are relatively unclear. The purpose of this article is to provide clinicians with a detailed review of mirtazapine’s sleep effects in patients with MDD.

METHODS: A literature search was conducted for studies involving mirtazapine in depressed patients that specifically assessed sleep.

RESULTS: Twenty-three studies met selection criteria and were included in this review. Of the 15 studies that included a general assessment of sleep, all noted improvement from baseline with mirtazapine. Twelve of the 23 trials were randomized, blinded, and controlled. Mirtazapine was superior to placebo but did not clearly differentiate itself from other antidepressants, with the exception of venlafaxine. Eight studies used detailed measures of sleep and consistently reported that mirtazapine produced significant improvement in sleep efficiency, total sleep time, and sleep quality. Few investigations combined detailed assessments of sleep along with a comparator antidepressant.

CONCLUSION: Mirtazapine is an antidepressant with sleep-promoting effects significantly greater than placebo, similar to tricyclic antidepressants, and somewhat similar to selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. These effects must be balanced with mirtazapine’s ability to cause sedation-related side effects.

KEYWORDS: mirtazapine, major depressive disorder, sleep

ANNALS OF CLINICAL PSYCHIATRY 2012;24(3):215-224

  INTRODUCTION

Mirtazapine is a widely used antidepressant considered a first-line treatment for major depressive disorder (MDD).1,2 Its unique pharmacologic profile makes mirtazapine a popular agent for use in combination with other antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).1,3 An effective antidepressant that also produces rapid and consistent improvement in sleep would be a beneficial therapy in many patients with MDD, considering the frequent sleep complaints among patients with depression.4-9 The well-known ability of mirtazapine to produce sedation and weight gain frequently is used by prescribers to target the respective depressive symptoms of poor sleep, poor appetite, and weight loss.1 In general, the use of SSRIs, SNRIs, and bupropion is associated with higher rates of insomnia compared with mirtazapine. Conversely, mirtazapine use is associated with higher rates of somnolence and fatigue than SSRIs, SNRIs, and bupropion.10 Despite mirtazapine’s well-known ability to produce somnolence, its actual effects on sleep in patients with MDD compared with other commonly prescribed antidepressants remain unclear.

Many reviews of the effects of antidepressants on sleep have been published, including several that involved mirtazapine.5,6,9,11,12 The current review adds to the available literature by focusing specifically on the sleep effects of mirtazapine in patients with MDD, using trials that reported sleep outcomes. The purpose of this article is to provide clinicians with a synopsis and analysis of mirtazapine’s sleep effects in patients with MDD.

  METHODS

We conducted a MEDLINE and International Pharmaceutical Abstracts search through May 2011 for articles or trials that involved humans, were written in English, and contained combinations of the following terms: mirtazapine, Org 3770, sleep, sleep disorders, depression, major depressive disorder, and mood disorders. This initial search identified 705 potential articles. To be included, studies must have assessed sleep or its components at baseline and during ≥1 follow-up time period. Studies that merely shared percentages of patients reporting such side effects as sedation, fatigue, or sleepiness were not included. Uncontrolled and nonrandomized trials were eligible for inclusion in the review in an effort to incorporate articles that assessed mirtazapine’s effects on sleep from a variety of perspectives and methodologies. The majority of patients enrolled in an investigation must have been diagnosed with MDD for a study to be included in the current review. In addition, subjects’ psychiatric diagnoses must have been verified using DSM criteria or International Classification of Diseases criteria. As a result of the initial search process, the references of published articles we identified were also examined for any additional trials appropriate for inclusion in this review. The pharmacologic and safety profiles of mirtazapine, as they relate to sleep, also are reviewed in an effort to more clearly place mirtazapine’s sleep effects into context.

Mirtazapine’s mechanism of sleep promotion

The sleep-promoting effects of mirtazapine are related to its unique pharmacologic profile. Mirtazapine is thought to produce its antidepressant effects via antagonism of alpha-2 autoreceptors, alpha-2 heteroreceptors, and serotonin (5-HT) subtype 2 and 3 receptors. These effects lead to an increased release of norepinephrine (due to alpha-2 receptor antagonism) and enhanced 5-HT1A–mediated serotonin transmission (due to antagonism of 5-HT2 and 5-HT3 receptors).3

In addition to accounting for its antidepressant properties, mirtazapine’s 5-HT2 receptor antagonism appears to contribute to its sleep-promoting properties. The control of serotonin on sleep-wake behavior has been extensively studied. Evidence suggests that 5-HT2A and 5-HT2C receptors play an important role in reduction of rapid eye movement (REM) sleep and slow wave sleep (SWS).13,14 Predictably, antagonists of 5-HT2 receptors have sleep-promoting properties. For example, the 5-HT2 antagonist nefazodone was found to have no suppressive effect on REM sleep (in contrast with many antidepressants)15 and the 5-HT2 antagonist olanzapine was found to increase SWS.16 In a Korean study of patients with MDD, the sleep-promoting effect of mirtazapine was found to vary by 5-HT2 genotype, providing additional evidence for the link between 5-HT2 antagonism and sleep promotion.17

The high affinity of mirtazapine for histamine (H1) receptors also appears to play an important role in sleep.3,18 Therefore, it is most likely that mirtazapine’s histaminic and serotonergic effects both lead to its sleep-promoting properties.19 It has been hypothesized that the short-term sleep benefits of mirtazapine are related to antagonism of both 5-HT2 and H1 receptors, whereas long-term sleep effects associated with mirtazapine appear to be related more to its antagonism of 5-HT2 receptors alone.6 This dual sleep mechanism may be important because tolerance to mirtazapine’s histaminic effects has been reported to develop 7 to 10 days after beginning treatment.3,20,21 The dose of mirtazapine also is a factor in its ability to improve sleep—daily doses of ≤30 mg tend to produce better sleep outcomes for patients.22 At higher doses, the antihistamine activity of mirtazapine appears to be partially offset by increased noradrenergic transmission.23-25

Insomnia and depression

Although mirtazapine’s pharmacologic profile appears to improve sleep, it is by no means the only antidepressant that can promote sleep. The relationship between sleep disturbances, depression, and the effective treatment of depression leads to a scenario where all antidepressants likely can improve sleep in some patients. Complaints of sleep disturbances are common in MDD, with >75% of patients with depression reporting some type of sleep dysfunction.4-9 Not only is poor sleep in MDD a source of distress for patients, but sleep disturbances have been implicated as predictors of worse outcomes.5,26-32 Sleep studies in patients with MDD generally show reduced sleep efficiency, increased sleep latency, more nocturnal awakenings, increased stages 1 and 2 sleep, reduced SWS (stages 3 and 4), and alterations in REM sleep compared with healthy subjects.5,9,33,34 For instance, patients with depression tend to experience poor sleep efficiency, which stems largely from reduced REM latency and excessive REM activity. Reductions in stages 3 and 4 sleep among patients with MDD also produce hormonal changes.6 Successful treatment of MDD with antidepressants can normalize or improve at least some of the sleep parameters previously mentioned.5,33,35-39 The resulting question is whether or not select agents are superior at improving sleep in patients with MDD. In this review, the sleep effects of mirtazapine are scrutinized.

  RESULTS

Twenty-three studies met selection criteria and were included in the review (see the TABLE for detailed study information). The trials were conducted for a mean duration of 9 weeks, and the mean number of patients was 171; however, the sample size ranged from 6 to 779 patients. In terms of trial design, 57% of the studies were randomized, double-blinded, and controlled, with the remainder of investigations (43%) being open-label. Twelve of the 23 studies had an antidepressant comparator arm. The majority of subjects were female (66%) and the mean age of patients enrolled in the trials was 51. The mean daily dose of mirtazapine in these studies was 36 mg, but this ranged from 17 to 77 mg.


TABLE

Studies examining the effect of mirtazapine on sleep in patients with major depressive disorder

Authors N Study design Patients Medication(s) Sleep outcome(s) Other
Claghorn et al, 199541 90 6-week, randomized, double-blind, placebo-controlled trial Outpatients with MDD; mean age 40; 49% female Mirtazapine mean dose 17 mg/d; placebo HAM-D sleep disturbance cluster: Statistically significant improvement during weeks 1 to 6 favoring mirtazapine vs placebo HAM-D total scores improved from baseline in both groups. Mirtazapine statistically significantly greater than placebo during weeks 1 to 4
Zivkov et al, 199553 251 6-week, randomized, double-blind, controlled trial Inpatients with MDD; mean age 47; 78% female Mirtazapine mean dose 40 mg/d; amitriptyline mean dose 151 mg/d HAM-D sleep disturbance factor: Both groups had similar improvement from baseline HAM-D total scores similarly improved from baseline in both groups
Hoyberg et al, 199648 115 6-week, randomized, double-blind, controlled trial Inpatients and outpatients with MDD; mean age 71; 83% female Mirtazapine mean dose 32 mg/d; amitriptyline mean dose 64 mg/d HAM-D sleep disturbance factor: Both groups had similar improvement from baseline HAM-D and MADRS total scores improved in both groups but no statistically significant difference
Wheatley et al, 199843 133 6-week, randomized, double-blind, controlled trial Outpatients with MDD; mean age 47; 57% female Mirtazapine mean dose 40 mg/d; fluoxetine mean dose 24 mg/d HAM-D sleep disturbance factor: Improvement with mirtazapine was not statistically significant compared with fluoxetine HAM-D total scores improved from baseline in both groups. Mirtazapine statistically significantly greater during weeks 3 and 4
Bruijn et al, 199945 107 4-week, randomized, double-blind, controlled trial Inpatients with MDD; mean age 47; 80% female Mirtazapine mean dose 77 mg/d; imipramine mean dose 235 mg/d HAM-D sleep disturbance cluster: Both groups had statistically significant improvement from baseline, but mirtazapine effect was attenuated when comparing week 2 vs week 4 scores Both groups improved statistically significantly from baseline on HAM-D total scores at week 2 but imipramine statistically significantly greater at week 4
Leinonen et al, 199956 270 8-week, randomized, double-blind, controlled trial Outpatients and inpatients with MDD; mean age 42; 62% female Mirtazapine mean dose 36 mg/d; citalopram mean dose 37 mg/d LSEQ: Both groups had statistically significant improvement from baseline in sleep latency, quality of sleep, and behavior following awakening. Mirtazapine statistically significantly greater than citalopram during weeks 1 to 4 Both groups improved from baseline on MADRS total scores; mirtazapine statistically significantly greater at week 2 only
Radhakishun et al, 200025 140 2-week, randomized, double-blind trial Outpatients with MDD Mirtazapine dose 15 to 30 mg/d, after 1 week mirtazapine 30 mg/d LSEQ: Both groups improved from baseline in sleep latency and sleep quality. “Little” change from baseline was noted for both groups on awakening from sleep and behaviors following awakening Both groups improved from baseline on HAM-D total scores
Winokur et al, 200019 6 2-week, open-label trial Outpatients with MDD Mirtazapine: Week 1: 15 mg/d; week 2: 30 mg/d Polysomnographic studies: Statistically significant improvement from baseline at weeks 1 and 2 in TST, sleep efficiency, and sleep latency. No significant changes in REM or SWS. HAM-D sleep factor: Significantly improved from baseline HAM-D total scores statistically significantly improved from baseline
Guelfi et al, 200147 157 8-week, randomized, double-blind, controlled trial Inpatients with severe, melancholic MDD; mean age 45; 66% female Mirtazapine mean dose 50 mg/d; venlafaxine mean dose 255 mg/d HAM-D sleep disturbance factor: Statistically significant improvement favoring mirtazapine over venlafaxine during weeks 1 to 8 Both groups improved from baseline on HAM-D and MADRS total scores; no between-group differences
Schatzberg et al, 200242 254 8-week, randomized, double-blind, controlled trial Outpatients with MDD; mean age 72; 64% female Mirtazapine mean dose 26 mg/d; paroxetine mean dose 27 mg/d HAM-D sleep disturbance factor: Both groups improved from baseline, but mirtazapine was statistically significantly improved compared with paroxetine on days 7, 14, and 42 Both groups improved from baseline on HAM-D total scores. Mirtazapine group had statistically significantly greater improvement on days 7, 14, 21, and 42
Schittecatte et al, 200255 17 12-week, open-label trial Patients participating in CREST sleep study with MDD; mean age 44; 41% female Mirtazapine mean dose 45 mg/d Polysomnographic studies: Statistically significant improvement from baseline in sleep parameters when measured on day 2 (TST, sleep efficiency, sleep latency, stage 2 sleep, REM, and SWS). Statistically significant improvement in TST and sleep efficiency persisted at 5 weeks. LSEQ: Statistically significant improvement in getting to sleep and periods of wakefulness at 4 weeks HAM-D total statistically significantly improved from baseline
Schittecatte et al, 200258 32 4-month, open-label trial Patients participating in CREST sleep study with MDD; mean age 39; 70% female Mirtazapine mean dose 47 mg/d; fluvoxamine mean dose 195 mg/d CREST: Patients receiving mirtazapine had REM normalization, whereas patients receiving fluvoxamine trended toward a blunted REM sleep response. Differences between mirtazapine and fluvoxamine were statistically significant HAM-D total scores improved from baseline in both groups; no statistically significant between-group differences
Roose et al, 200349 119 12-week, open-label trial Nursing home patients with depression; mean age 83; 72% female Mirtazapine mean dose 19 mg/d HAM-D sleep disturbance factor: Improved from baseline—no mention of significance HAM-D and CSDD total scores improved from baseline, but only HAM-D change score at day 84 was statistically significant
Winokur et al, 200352 19 8-week, randomized, double-blind, controlled trial Outpatients with MDD; mean age 42; 41% female Mirtazapine titrated to 45 mg/d; fluoxetine titrated to 40 mg/d Polysomnographic studies: Statistically significant improvement from baseline in sleep latency, sleep efficiency, and WASO in the mirtazapine group during weeks 2 to 8. No statistically significant changes in sleep stage or REM with mirtazapine. No changes found in fluoxetine group. TST and sleep latency at week 8 were significantly better in mirtazapine group vs fluoxetine group. HAM-D sleep items: Statistically significant improvement from baseline in both groups but no significant between-group differences HAM-D total scores statistically significantly improved from baseline in both groups but no significant between-group differences
Versiani et al, 200551 297 8-week, randomized, double-blind, controlled trial Outpatients with MDD; mean age 45; 72% female Mirtazapine 15 to 60 mg/d; fluoxetine 20 to 40 mg/d HAM-D sleep factor: Both groups improved but no statistically significant between-group differences. Quality-of-life sleep items: Statistically significantly greater improvement favoring mirtazapine over fluoxetine Improvements in HAM-D and MADRS total scores were similar between groups
Benkert et al, 200644 242 6-week, randomized, double-blind, controlled trial Outpatients with MDD; age 18 to 70 Mirtazapine rapid titration to 45 mg/d; venlafaxine rapid titration to 225 mg/d HAM-D sleep factor: Improvement from baseline in both groups but statistically significant improvement favoring mirtazapine on days 5, 8, 11, and 43 Improvement in HAM-D total scores noted in both groups; only statistically significant differences between groups on days 8 and 11, favoring mirtazapine
Freynhagen et al, 200620 594 6-week, open-label surveillance trial Outpatients with chronic pain syndrome and MDD; mean age 55; 66% female Mirtazapine mean dose 35 mg/d 4-point patient rating: Moderate to severe sleep disturbance of 85% at baseline and 8% at study conclusion Improvement in depression from baseline reported by patients
Schmid et al. 200650 10 4-week, open-label trial Inpatients with MDD; mean age 40; 70% female Mirtazapine mean dose 50 mg/d Sleep EEGs: Statistically significant improvement from baseline in TST, sleep efficiency, time spent awake, and stage 2 sleep from day 28. No significant changes in REM or SWS. HAM-D sleep disturbance factor: Statistically significant improvement from baseline to day 28 Statistically significant improvement from baseline in HAM-D and MADRS total scores
Shen et al, 200657 16 9-week, open-label study Outpatients with MDD; mean age 47; 88% female Mirtazapine mean dose 30 mg/d Polysomnographic studies: Mirtazapine statistically significant improvement from baseline in sleep quality and “biological markers of depression”—SWS, REM, WASO, and stage 3 sleep Statistically significant improvement from baseline in HAM-D total scores
Walinder et al, 200667 192 12-month, open-label naturalistic study Outpatients with MDD; mean age 50; 66% female Mirtazapine mean dose 34 mg/d MADRS sleep disturbance item: “The most prominent decrease found…early in the treatment” Statistically significant improvement in MADRS total scores compared with baseline throughout study
Cankurtaran et al, 200840 53 6-week, randomized, double-blind, controlled trial Oncology outpatients or inpatients with MDD, anxiety, or adjustment disorder. Mean age 46; 64% female Mirtazapine mean dose 16 mg/d; imipramine mean dose 23 mg/d; control HAM-D sleep disturbance cluster: Statistically significant improvement from baseline in mirtazapine group but not in imipramine or control groups Statistically significant improvement from baseline in HADS total scores in mirtazapine group only
Kim et al, 200854 42 4-week, open-label trial Oncology patients with MDD, depression NOS, or adjustment disorder with depressed mood; mean age 58; 45% female Mirtazapine mean dose 20 mg/d LSEQ: Significant improvement from baseline throughout study in TST, ease of getting to sleep, sleep quality, and behavior following awakening. Ease of morning awakening was significantly improved from baseline after day 3 Hypnotic MADRS total scores significantly improved from baseline in 26% of patients
Danileviciute et al, 200946 779 17-week, open-label trial Outpatients with MDD; mean age 52; 76% female Mirtazapine mean dose 29 mg/d HAM-D sleep disturbance cluster: Showed “clinically significant” improvement after the first week (duration of this effect unclear) Statistically significant improvement from baseline in HAM-D total scores
CREST: clonidine REM suppression test; CSDD: Cornell Scale for Depression in Dementia; EEG: electroencephalogram; HADS: Hospital Anxiety and Depression Scale; HAM-D: Hamilton Depression Rating Scale; LSEQ: Leeds Sleep Evaluation Questionnaire; MADRS: Montgomery-Åsberg Depression Rating Scale; MDD: major depressive disorder; NOS: not otherwise specified; REM: rapid eye movement; SWS: slow wave sleep; TST: total sleep time; WASO: wake after sleep onset

Improvement in depressive symptoms, most commonly assessed via the Hamilton Depression Rating Scale (HAM-D) or Montgomery-Åsberg Depression Rating Scale total scores, was reported in all 23 studies. In the 2 placebo-controlled trials, patients treated with mirtazapine had significantly greater improvement in depressive symptoms compared with those who received placebo.40,41 Among the 12 investigations with active controls, mirtazapine produced significantly greater improvement in depression rating scores in only 3 trials.40,42,43 Thus, mirtazapine-induced differences in sleep parameters in those studies with active control groups cannot be explained merely by differences in depressive symptoms, whereas improvement in sleep in the placebo-controlled studies may be explained, at least to some extent, by mirtazapine’s significant improvement in depression compared with placebo.

Changes in sleep were most commonly assessed using the HAM-D sleep disturbance factor, with 15 of the 23 studies using this measure.19,40-53 In all 15 of these studies, improvement from baseline in the HAM-D sleep disturbance factor was reported with mirtazapine. Four of these trials were open-label and without control arms.19,46,49,50 In all 4 of the open-label trials, HAM-D sleep factor scores from baseline improved with mirtazapine, with statistically significant improvement from baseline noted in 2 of 4 studies.19,50 Two placebo-controlled investigations measured sleep using the HAM-D sleep factor. In one 6-week trial, significant improvement in the HAM-D sleep factor was seen with mirtazapine vs placebo during weeks 1 through 6 of the study.41 In the other placebo-controlled trial, mirtazapine led to significant improvement from baseline in the HAM-D sleep factor, whereas placebo did not.40 The positive sleep-related findings for mirtazapine in these 2 trials is not surprising when considering that mirtazapine produced significantly greater improvement in overall depressive symptoms when compared with placebo.

Ten trials that measured sleep using the HAM-D sleep disturbance factor had active comparator arms, allowing for the most meaningful assessment of mirtazapine’s general effect on sleep in patients with depression. Four of these trials involved tricyclic antidepressants (TCAs),40,45,48,53 2 included venlafaxine,44,47 and 4 involved SSRIs.42,43,51,52 When examining the 4 TCA-controlled trials, mirtazapine did not differentiate itself in the 2 studies that used amitriptyline.48,53 Imipramine produced significantly greater improvement in the HAM-D sleep factor vs mirtazapine in 1 trial,45 whereas mirtazapine produced significantly greater improvement than imipramine on the same measure in another investigation.40 Of importance is that in the trial favoring imipramine, mirtazapine was administered at an uncommonly high mean daily dose of 77 mg.45 In the trial favoring mirtazapine, the mean daily dose of imipramine was an unusually low 23 mg.40 Taken together, these 4 TCA-controlled studies, which were 4 to 6 weeks in duration, demonstrated that mirtazapine and TCAs produced similar improvement in sleep as rated by the HAM-D sleep disturbance factor. In contrast, mirtazapine was found to produce significantly greater improvement in sleep than venlafaxine in both of the trials that used the SNRI as a comparator.44,47 Four studies compared mirtazapine with an SSRI in trials ranging from 6 to 8 weeks.42,43,51,52 Three of these studies compared mirtazapine with fluoxetine, and in all 3 trials no significant between-group differences were found in the HAM-D sleep disturbance factor.43,51,52 Mirtazapine did produce significantly greater improvement in sleep when compared with paroxetine.42 Based on the HAM-D sleep disturbance factor, TCAs, SNRIs, SSRIs, and mirtazapine all appear able to produce improvement in sleep in patients with MDD. Mirtazapine did not consistently outperform these other medications, but may produce greater improvement in sleep when compared with some SNRIs and SSRIs. Such a conclusion is limited by the relatively subjective and nonspecific nature of the HAM-D sleep disturbance factor as an assessment of sleep.

Four studies used the Leeds Sleep Evaluation Questionnaire (LSEQ), a subjective assessment of sleep but one that allows for more sleep components to be analyzed. Of the 4 trials that used the LSEQ, 2 were uncontrolled open-label studies,54,55 1 compared 2 doses of mirtazapine,25 and 1 compared mirtazapine with citalopram.56 In all 4 studies, significant improvement from baseline in sleep components was noted with mirtazapine. Sleep latency (all 4 trials)25,54-56 and sleep quality (3 out of 4 trials)25,55,56 were the most consistent sleep parameters that significantly improved from baseline in the mirtazapine groups. Total sleep time and behavior following awakening also significantly improved from baseline, but less consistently across the 4 studies. Leinonen et al56 used the LSEQ over an 8-week trial period to compare the sleep effects of mirtazapine and citalopram. Both groups experienced significant improvement in sleep components, but mirtazapine was noted to produce significantly greater improvement in sleep latency, sleep quality, and behavior following awakening for the first 4 weeks of the study. Taken together, these results demonstrate that mirtazapine produces consistent improvement in sleep latency and sleep quality in patients with depression, based on patient assessments. Derived from limited studies, mirtazapine may produce more improvement in sleep parameters than SSRIs, but the duration and magnitude of effect and the comparative efficacy of other SSRIs remain unclear.

The most detailed investigations of mirtazapine’s effects on sleep in patients with depression involved the objective measure of sleep using sleep studies. Five such trials, ranging in duration from 2 to 12 weeks, met selection criteria and were included in the current review.19,50,52,55,57 Four of the 5 trials were of open-label design and uncontrolled, whereas the remaining investigation was a randomized, double-blind, fluoxetine-controlled study.52 All 5 trials reported significant improvement in sleep parameters from baseline with mirtazapine. Significant improvement from baseline with mirtazapine was most consistent for sleep efficiency (4 of 5 trials),19,50,52,55 total sleep time (3 of 5 studies),19,50,55 and wake time after sleep onset (3 of 5 studies).50,52,57 Of note, REM57 and sleep stages50,57 were significantly improved from baseline in mirtazapine-treated patients in only 1 and 2 of the 5 studies, respectively. In the randomized, double-blind trial with fluoxetine as a comparator, mirtazapine was found to produce significantly greater improvement in total sleep time and sleep latency at 8 weeks.52 A different investigation reported that mirtazapine produced normalization of REM sleep, whereas fluvoxamine did not.58 Taken together, objective sleep studies in patients with depression have demonstrated mirtazapine’s ability to consistently improve total sleep time and sleep efficiency, although mirtazapine’s effects on sleep stages were inconsistent. At the same time, it has been hypothesized that mirtazapine is less likely to interfere with sleep. Polysomnographic recordings of eye movements of nearly 3,000 consecutive patients at a sleep center were evaluated to see the effects of antidepressants and antipsychotics on eye movements in non-REM sleep. Thirty-six percent of patients taking an SSRI had abnormal eye movements compared with 5% of patients taking mirtazapine and 6% of patients taking a TCA.59 Mirtazapine may be a more effective sleep-promoting medication than SSRIs, but the lack of trials directly comparing mirtazapine with a variety of SSRIs substantially hampers any definitive conclusions.

SSRIs and SNRIs are by far the most commonly prescribed medications for MDD. Comparing the sleep-related effects of mirtazapine with these agents provides the most clinically useful information. To summarize, mirtazapine was found to produce significant improvement in sleep vs SSRIs or SNRIs in 4 of the 7 studies, based on subjective sleep assessments,42-44,47,51,52,56 and significant improvement in sleep in the 1 SSRI-controlled trial that used objective sleep measures.52 Among these investigations, the greatest relative benefits associated with mirtazapine involved improvement in sleep latency, total sleep time, and sleep quality.

Are mirtazapine’s sleep effects just a result of its antidepressant efficacy?

The effects of mirtazapine on sleep, based on results from the current review, cannot be explained merely by its antidepressant efficacy. In several of the controlled studies that were reviewed, mirtazapine produced superior effects on sleep despite similar improvement in depressive symptoms. Previous investigators have made similar conclusions regarding comparative antidepressant efficacy. Derived from psychopathology rating scales, the efficacy of mirtazapine generally is considered similar to that of TCAs, SSRIs, and SNRIs in patients with MDD.11,60 More specifically, a meta-analysis of randomized, controlled trials comparing mirtazapine and SSRIs in patients with MDD found efficacy rates for mirtazapine similar to those for SSRIs.61 Analogous findings regarding mirtazapine’s efficacy were reported in a meta-analysis involving randomized, amitriptyline-controlled trials.62 At the same time, several studies suggest that mirtazapine may have a faster onset of action than SSRIs.11,42,43,51,56,60,63-66 Mirtazapine’s onset of action may lead to more rapid improvement in sleep, but it has been proposed that mirtazapine’s benefits for sleep are not merely tied to its faster onset of action.5,44 This is supported by findings in our current review, in which mirtazapine’s beneficial effects on sleep were seen well beyond the first few weeks of therapy, as reported in several studies.42,44,47,52,58

Safety context of mirtazapine’s sleep effects

The current review and previous published studies demonstrate mirtazapine’s beneficial effects on sleep in patients with MDD. Mirtazapine’s ability to improve sleep must be weighed alongside its ability to produce negative effects on sleep, energy, and concentration in some patients. This balance of sleep-related outcomes with mirtazapine must be considered in order to appropriately use the antidepressant in patients with MDD. Using data derived from the trials included in the present review, mirtazapine was associated with rates of somnolence ranging from 12% to 62%,41,49 fatigue ranging from 2% to 36%,20,67 and excessive sedation ranging from 4% to 8%.48,56 A prior assessment of placebo-controlled clinical trials found significantly higher rates of drowsiness in patients who had received mirtazapine compared with placebo (23% vs 14%) and numerically greater rates of excessive sedation (19% vs 5%) and fatigue (16% vs 12%) vs placebo.60 Thus, mirtazapine commonly produces sedation, drowsiness, and fatigue that can be problematic for some patients with MDD.

Mirtazapine’s ability to produce such side effects also must be compared with other commonly prescribed antidepressants to gain a clearer clinical picture. A systematic review of mirtazapine’s adverse effect profile, based on data from randomized, controlled trials, found that mirtazapine use was significantly more likely to lead to fatigue (risk ratio [RR], 1.45; 95% confidence interval [CI], 1.07 to 1.97) or somnolence (RR, 1.62; 95% CI, 1.28 to 2.05) compared with SSRIs. At the same time, it was significantly less likely to cause sleep disturbance (RR, 0.55; 95% CI, 0.00 to 0.46).68 Similar findings were seen in another meta-analysis of SSRI-controlled studies in which mirtazapine patients were more likely to report excessive sleepiness (RR, 1.3; 95% CI, 1.1 to 1.7) and fatigue (RR, 1.5; 95% CI, 1.1 to 2.4) but less likely to complain of insomnia (RR, 0.5; 95% CI, 0.3 to 0.9).61 In a 6-week randomized, double-blind, controlled trial of 150 outpatients with MDD, the efficacy and safety of mirtazapine (mean daily dose = 22 mg) were compared with amitriptyline (mean daily dose = 122 mg) and placebo. Both active treatment groups experienced statistically significant improvement in depression scores compared with placebo but no differences between mirtazapine- and amitriptyline-treated patients. Sedation was reported in 46% of patients in the mirtazapine group, 56% of patients in the amitriptyline group, and 22% of those in the placebo group.69 Similar results were found in another 6-week trial of comparable design.70 Based on these data, clinicians must balance the sleep-promoting effects of mirtazapine with its ability to produce fatigue, somnolence, and sedation. Mirtazapine is much more likely than SSRIs to cause such side effects in patients, whereas rates of fatigue, somnolence, and sedation between mirtazapine and TCAs are comparable.

Mirtazapine, like other antidepressants, has been shown to impair driving performance in healthy subjects.5,71,72 Despite mirtazapine’s widely reported ability to produce sedation, mixed results have been found on measures of cognitive impairment. In a relatively small nonrandomized sample of inpatients with MDD, a driving simulation was used prior to discharge to examine the effects of antidepressant monotherapy on psychomotor function. Patients in the mirtazapine group performed significantly better on global driving ability than those in the TCA, SSRI, or venlafaxine groups. At the same time, nearly 50% of patients in the mirtazapine group were rated as mildly or moderately impaired in their driving ability.73 A different trial investigated actual driving performance and psychomotor performance of 18 healthy patients receiving escitalopram, mirtazapine, or placebo in a crossover fashion. Patients received each of the medications as evening doses for 15 days and were tested during days 2, 9, and 16. Mirtazapine was associated with significantly worse driving performance on day 2 compared with placebo but not during subsequent assessment days. Escitalopram was found to be no different from placebo.72

Although mirtazapine is widely considered a first-line option for the pharmacologic treatment of patients with MDD, it is not for everyone. Mirtazapine’s ability to produce substantial weight gain, although potentially beneficial in patients with poor appetite and substantial weight loss, would likely be inappropriate in depressed patients who are obese or in patients in whom significant weight gain could worsen other medical conditions, such as poorly controlled diabetes or severe osteoarthritis.3,6,10,61,68 Similarly, mirtazapine would not be a rational choice in patients with atypical depression who experience excessive sleep and substantial weight gain. Mirtazapine would be a more appropriate choice in non-obese patients who complain of sleep disturbances associated with their MDD. Mirtazapine’s sleep-promoting effects could be combined with other medications in an effort to improve sleep, but this should be done by using medications with complementary mechanisms of sleep promotion, prescribed in a stepwise fashion in an effort to minimize oversedation and related side effects. The combination of sedating antidepressants may be appropriate in some patients with severe sleep complaints, but caution should be used. Furthermore, the authors do not recommend mirtazapine as a treatment for primary sleep disorders, because in its available formulations there is little to no difference between antidepressant effects and sleep-promoting effects, making it difficult to separate the 2 effects.3,6,10

  CONCLUSIONS

Based on several trials, mirtazapine demonstrates the ability to improve sleep in patients with MDD. Mirtazapine’s effects on sleep appear to be significantly greater than placebo, similar to TCAs, and somewhat similar to SSRIs and SNRIs. Mirtazapine is less likely than SSRIs or SNRIs to worsen sleep in patients with MDD but more likely to produce sedation-related side effects. General subjective measures of sleep used in many of the studies we reviewed found improvements in sleep associated with mirtazapine that did not differentiate themselves from improvements in sleep reported with other antidepressants. More specific measures of sleep consistently reported that mirtazapine produced significant improvement in sleep efficiency, total sleep time, and sleep quality in patients with MDD. In addition, these specific improvements in sleep from baseline in patients treated with mirtazapine were often significantly better than those seen with other antidepressants in the relatively few investigations that combined specific and detailed assessments of sleep along with an active comparator arm. More controlled trials using detailed and objective measures of sleep in patients with MDD would provide greater clarity as to mirtazapine’s effects on sleep. Studies measuring the sleep effects of adding mirtazapine to an existing antidepressant therapy would also provide valuable information. Nonetheless, mirtazapine is a pharmacologic option that combines antidepressant efficacy similar to other antidepressants, along with sleep-enhancing properties better than those of other commonly prescribed antidepressants. At the same time, mirtazapine’s ability to produce sedation-related side effects in patients must be taken into consideration, as well as the fact that an effective antidepressant, regardless of pharmacologic class, may be able to improve sleep in a number of patients as a result of improving depressive symptoms themselves.

DISCLOSURES: The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. The authors completed all work related to the manuscript as part of their regular job duties, and no additional funding was used in the preparation of this manuscript.

ACKNOWLEDGEMENT: The authors would like to thank Jonathan McKinsey, MD, for his assistance with the manuscript.

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CORRESPONDENCE: Christian R. Dolder, PharmD, Associate Professor, Wingate University School of Pharmacy, 515 N. Main Street, Wingate, NC 28174 USA E-MAIL: cdolder@wingate.edu