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 In the treatment of depression, the role of sleep and sleep disturbances is important; it has been suggested that it is the critical factor in the enduring resolution of depressive symptoms. This is based, inter alia, on the following observations. First, mutual relations exist between mood disorder and sleep disorders; for example, depression can induce or be induced by sleep disorders (1–3). Second, sleep disturbances may be worsened during treatment with some antidepressants (4) and may be improved by other antidepressants (5). Third, early relief of sleep disorders, particularly insomnia, may improve compliance with the antidepressant treatment regimen (6), thereby improving overall treatment efficacy. Finally, complete relief from insomnia may improve the patient’s treatment outcome (7,8). Sleep disruptions are a common feature of depressive disorders (9). About 90% of MDD patients report sleep symptoms (7). Objective PSG analysis reveals that depression patients have disrupted sleep continuity, altered REM sleep, and reduced SWS (9). Complaints of persistent sleep symptoms are risk factors for the onset of depression. There is evidence that people with recurrent depression have more sleep abnormalities than do those experiencing a single or initial episode. As well, sleep symptoms are the key diagnostic criteria for MDD. The most frequently reported sleep disorder in depression patients is insomnia; insomnia symptoms are included in all the commonly used symptom-based rating scales for depression. Early relief of insomnia in a depression patient may increase treatment adherence, daytime performance, and overall functioning; complete relief of insomnia may improve prognosis (2,10–12). It has been reported that mirtazapine significantly improves patients’ mood and subjective sleep measurements (13,14). Research in healthy volunteers found that mirtazapine improved sleep quality in normal sleepers (15,16). Only 3 reports exist on the PSG effects of mirtazapine in depression patients. The inconsistent results indicate that mirtazapine decreases sleep latency and WASO and increases total sleep time, sleep efficiency, REM sleep, and SWS (9,10,17). There are no data on SWS in the first sleep cycle, on the ratio of SWS in the first sleep cycle to SWS in the second sleep cycle, and on the first REM sleep episode, although these measurements are important features in the commonly noted sleep markers of depression (2,12,18). This study’s major objective was to further characterize the effects of mirtazapine on PSG sleep, specifically SWS and REM sleep, in patients with MDD. In addition, we analyzed the symptoms, including mood, vital signs, and weight, as well as subjective sleep results. MethodsThis was a longitudinal clinical study with consecutive enrolment of subjects. The research protocol was approved by the Research Ethics Board of the University Health Network. Recruitment took place via referrals from local family practitioners and psychiatrists who were informed about the study’s inclusion and exclusion criteria and research aim. All the included male and female subjects fulfilled DSM-IV criteria (19) for MDD assessed from their psychiatric history and the MINI (20). The MINI is a reliable, short, structured diagnostic interview designed to generate diagnoses congruent with the DSM-IV. The patients were aged 18 years and over; informed consent was obtained. Female subjects of childbearing potential were following an effective birth control method. All subjects scored 17 or higher on the HDRS-17, 1 or higher on the 3 sleep symptom items in the HDRS-17 (21), and 6 or higher on the AIS (22). Subjects’ physical examination, including a brief neurologic examination, showed no clinically significant abnormal findings. They had no known clinically significant abnormal laboratory findings at screening. The study excluded the following: patients who took fluoxetine within 4 weeks, MAOIs within 2 weeks, and all other psychotropic medications and herbal preparations with putative antidepressant and sleep properties within 1 week; those with a history of hypersensitivity to mirtazapine; women who were pregnant or breast feeding; night-shift workers; those who had bipolar mood disorder or psychotic features in the current episode of depression or any psychotic disorder, such as schizophrenia and schizoaffective disorder; those with a history of alcoholism (that is, more than 14 drinks weekly) or drug abuse within the past year; and those who had a clinically significant organic system diseases, such as epilepsy or cardiovascular, hepatic, renal, endocrine, or metabolic disorder. The study duration was 9 weeks (plus or minus 2 days), which included a screening period and a treatment period. The screening period included a primary screening visit, 2 screening nights, and 2 screening days. When subjects were referred, they had a screening visit comprising mood and sleep assessments as well as 2 consecutive PSG recordings (on SN1 and SN2) in the sleep laboratory, followed by daytime data collection that included HDRS-17, BDI-II (23), and AIS measurements; vital signs; and weight. Measurements at SN1–SD1 and SN2–SD2 provided the baseline data. The patients were asked to take one placebo tablet with water on the screening evenings. The primary screening visit and baseline measurements were completed within 1 week. The treatment period started immediately after baseline and lasted 58 days. During this period, one mirtazapine tablet (30 mg) was taken with water every night, 30 minutes prior to lights out. A total of 12 PSG night recordings were performed for each patient. In addition to the baseline session, patients completed 5 more 2-night sessions at Nights 1 and 2, 8 and 9, 15 and 16, 29 and 30, and 57 and 58. Owing to the well-documented first-night effect (24), only the recordings of the second night were analyzed. PSG recordings were carried out in the Sleep Research Unit, Toronto Western Hospital. Subjects arrived at the laboratory at 9 PM, sleep studies commenced with lights-off at 11 PM, and lights-on was at 7 AM. These recordings included an EEG from central (C3–A2 and C4–A1) and occipital (O1–A2 and O2–A1) leads, an EOG (left and right outer canthi), and an EMG (submental). Electrophysiological recordings were made with Nihon Kohden EEG amplifiers (see www.nihonkohden.com); Datalab Windows-based software was used (25). Sleep records were scored in 30-second epochs with the sleep analysis software Sleep View (26). Anterior tibialis EMG recordings were used to rule out periodic limb movement disorder; chest and abdomen leads and a nasal-oral thermistor were added to rule out sleep apnea. PSG parameters included SWS (deep sleep, including Stage 3 and Stage 4 sleep), SWS in the first sleep cycle, SWS in the second sleep cycle, REM latency (that is, time elapsed from sleep onset to the first epoch of REM sleep), REM sleep, the first REM period, REMN, sleep latency (that is, time elapsed from lights-off to the first epoch of any sleep stage), total sleep time (that is, time in all stages of sleep, including REM sleep and non-REM sleep), sleep efficiency (that is, the ratio of all sleep time to total time in bed), WASO, and Stages 1, 2, 3, and 4 sleep. PSG recordings were blindly scored by registered sleep technologists on an epoch-by-epoch basis, according to standard Rechtschaffen and Kales criteria (27). Depressive symptoms were measured with the HDRS-17 and the BDI-II. The HDRS-17 is the most popularly used depression-rating instrument; it includes 3 sleep-related items evaluating the patient’s early, middle, and late insomnia, respectively. The BDI-II is a 21-item, self-report questionnaire measuring depression severity. BDI-II scores range from 0 to 63, with higher values indicating greater severity (23). The AIS evaluated subjective insomnia. This 8-item, self-report questionnaire assesses sleep complaints and identifies possible cases of insomnia. Its first 5 items cover nighttime symptoms, and the remaining 3 items ask for daytime consequences of disturbed sleep (22). The AIS and BDI-II measurements were scheduled at baseline, and on Days 2, 9, 16, 30, and 58, respectively. There was no measurement of the HDRS-17 on day 2, but otherwise, its schedule was the same as that for the AIS and BDI-II. Weight and vital signs, including blood pressure and pause rate, were measured at baseline and on Days 1 and 2, 8 and 9, 15 and 16, 29 and 30, and 57 and 58, respectively. The average of each 2-day session provided the value of each time point. We used rMANOVA including pairwise comparisons with a built-in mechanism to avoid inflation of alpha to analyze the progressive effects of the data. The tests were 2-sided at the 0.05 global significance level. All statistical tests were carried out with the standard SPSS package, Version 12.0 for windows (28). The Huynh-Feldt correction was applied for the repeated measures of the factor that did not meet the sphericity assumption. ResultsSubjects A total of 30 patients were referred and interviewed. We excluded 12 for taking antidepressants or other sleep- affecting medications (n = 5), withdrawal of consent (n = 3), or having an HDRS-17 score lower than 17 (n = 4). One patient discontinued the study because of an increased blood sugar level after he completed the Night–Day 9 assessments. This patient had a history of diabetes, and his blood sugar was well controlled before he was included into the study. Another patient discontinued at Night–Day 16 owing to complaints of feeling significant daytime sleepiness and fatigue. Sixteen patients with MDD (14 women and 2 men) completed the study procedure. The mean age of these patients was 47.1 years, SD 11.6 (range 29 to 60 years). At baseline, their mean value on the HDRS-17 was 23.1, SD 5.2. Of the patients who completed the study, 15 completed all the AIS assessments, and 13 completed all HDRS-17 assessments. All patients (n = 16) completed the data collection on PSG, BDI-II, vital signs, and weight. Sleep Measurements Sleep measurements included objective PSG data and subjective AIS scores. These measurements were analyzed in an ANOVA with time of measurement (that is, baseline compared with nights 2, 9, 16, 30, and 58) as within-subject factors. The rMANOVA results show that the mean effect of time on measurement was significant for SWS, SWS in the first sleep cycle, REM latency, first REM episode, REMN, WASO, and Stage 3 sleep. (see Table 1 and Figure 1)
Figure 1 highlights the effects of mirtazapine on the duration of SWS in the first sleep cycle and the duration of the first REM episode. These are new findings of this study. Table 1 also shows the pairwise comparison results of those measurements with significant finding on repeated measures. Table 1 does not include the pairwise comparison data of SWS in the first sleep cycle and the first REM episode, which are described in Figure 1. The table and the figure show that mirtazapine increased SWS, SWS in the first sleep cycle, REM latency, the first REM episode, and Stage 3 sleep. Simultaneously, it reduced WASO. Figure 2 shows that mirtazapine decreased the mean AIS scores over time.
Mood, Vital Signs, and Weight We used rMANOVA to analyze HDRS-17 scores with 5 time points. The other measurements, including BDI-II, vital signs, and weight, were analyzed with 6 time points. For within-subjects effects, the mean effect of time on measurement was significant for both HDRS-17 and BDI-II (Table 1). These results indicate that mirtazapine significantly decreased the severity of depression. Pairwise comparison results strongly support this conclusion (Table 1). Of the 13 patients who completed HDRS-17 data collection, 3 (23.1%) had scores reduced by 50% or more at Day 9. Patients with a reduction of 50% or more on the HDRS-17 scores numbered 5 (38.5%), 8 (61.5%), and 9 (69.2%) on Days 16, 30, and 58, respectively. Results of rMANOVA indicate that mirtazapine has a significant tendency to increase weight. However, pairwise comparison analysis shows that the differences of the mean values at 6 time points were not significant. (Table 1) Mirtazapine had no significant linear effects over time on SWS duration in the second sleep cycle (F5,75 = 1.897, P = 0.105), on the percentage of REM sleep (F5,75 = 1.738, P = 0.136), on sleep latency (F5,75 = 0.303, P = 0.910), on total sleep time (F3.4,50.7 = 2.480, P = 0.065), on sleep efficiency (F5,75 = 1.586, P = 0.174), on the percentage of Stage 1 sleep (F5,75 = 2.232, P = 0.060), on the percentage of Stage 2 sleep (F5,75 = 1.915, P = 0.102), on systonic blood pressure (F5,75 = 0.283, P = 0.921), on diastolic blood pressure (F4.6,64.5 = 1.112, P = 0.360), or on pulse rate (F5,75 = 1.787, P = 0.126). DiscussionMirtazapine is an effective antidepressant and sleep promoter. It blockades postsynaptic 5-HT2 and 5-HT3 receptors. As well, it is an antagonist of central a2-adrenergic autoreceptors and heteroreceptors. Consequently, mirtazapine enhances noradrenergic and 5-HT1A–mediated serotonergic neurotransmission. In addition, mirtazapine has a high affinity to histamine H1 receptors. It is an antihistaminergic agent (29,30). Mirtazapine increased SWS in the first sleep cycle, increased the first REM episode, and decreased REMN in this group of MDD patients. These new findings provide important information on the effects of mirtazapine on the biological markers of depression. Our data show that mirtazapine also increased SWS, particularly Stage 3 sleep, as well as REM latency, and reduced WASO; these results are consistent with the findings of other investigators (9,10,17). Mirtazapine improved sleep quality in this group of patients. SWS is often decreased in depression, especially in the first sleep cycle, with a relative increase of SWS in the second sleep cycle (9,31). A close relation has been reported between decreased total SWS and recurrence of depression (32). Hatzinger and others showed that diminished SWS persisted in the study group who subsequently had a recurrence of depression (32). To highlight the importance of SWS redistribution, Kupfer postulated the concept of DSR (18), which is the ratio of delta waves in the first sleep cycle compared with those in the second sleep cycle. He found that the DSR was a trait-like marker of depression and a robust predictor of late relapse and recurrence. Patients with a high DSR showed clinical remission that was 5 times longer than those with a low DSR (18). Hatzinger and others reported that the ratio of delta waves in the first sleep cycle to delta waves in the second sleep cycle is an important correlate of depressive vulnerability (32). Healthy subjects with a high genetic load for affective disorders (that is, first-degree relatives of depression patients) exhibited a decreased ratio of SWS in the first sleep cycle to SWS in the second sleep cycle. In our study, mirtazapine administration increased both total SWS and SWS in the first sleep cycle but not SWS in the second sleep cycle. This led to a change in the ratio of SWS in the first sleep cycle to SWS in the second sleep cycle (from 0.81 at baseline to 1.08 on Day 2 and 1.23 on Day 58). Mirtazapine’s augmentation of SWS may be primarily due to the function of 5-HT2A–2C blockade (14). Selective Our results show that mirtazapine increased the duration of REM episodes and decreased the REM episode number. It appears that mirtazapine consolidated these patients’ REM sleep. This study also found that mirtazapine increased REM latency. In actuality, REM latency represents the length of the first non-REM sleep, including SWS (18). Increased SWS in the first sleep cycle may be partly associated with increased REM latency. Mirtazapine administration did not significantly change the percentage of total REM sleep. This is different from the REM sleep effects of SSRIs such as fluoxetine, which typically induce REM suppression (36). This phenomenon may be explained by Schittecatte and others’ study (37), in which 32 drug-free depression patients were challenged with a clonidine REM-suppression test. Then, the patients were treated with fluvoxetine, an SSRI, or mirtazapine. Before treatment, the 2 patient groups showed a significantly blunted REM-sleep response to clonidine. After treatment, the fluvoxatine-treated patients still showed an abnormal REM-sleep response to clonidine. However, the mirtazapine-treated patients showed a normalized REM-sleep response. The authors postulated that mirtazapine’s “REM protection” function might be related to the subsensitivity of a2-adrenergic receptors. The results of our study are compatible with this hypothesis. Sleep discontinuity is the most common complaint in MDD patients. Mirtazapine demonstrated significant reductions in WASO. The effects of mirtazapine in decreasing WASO raise the possibility that this medication may be used to treat depression patients who have insomnia or to treat patients with insomnia who are free of clinical depression (9). After the patients took mirtazapine, their AIS scores decreased progressively and significantly. Compared with baseline, AIS scores decreased by 45.1% by Day 58. The score changes on this subjective sleep questionnaire were highly consistent with changes in PSG measurements. Compared with baseline, the mean HDRS-17 values on Day 9 decreased by 36% (P = 0.001). Over the following weeks, the reduction of the mean HDRS-17 values was continuous. By the end of the study (Day 58), the total reduction was 63.7%, and 69.2% of patients had scores that decreased by 50% or more. The BDI-II score changes were consistent with the changes in HDRS-17 measurements. These results emphasize that mirtazapine relieves depressive symptoms effectively and rapidly. The symptomatological results of this study are consistent with previous research. The antidepressant efficacy of mirtazapine is reported to be comparable or superior to that of amitriptyline, clomipramine, doxepin, fluoxetine, paroxetine, citalopram, trazodone, or venlafaxine, and it is effective at all levels of severity of depressive illness (38–42). Mirtazapine’s antidepressant effect appears to be related to its dual enhancement of central noradrenergic and serotonin 5-HT1 receptor–mediated serotonergic neurotransmission and to its blockade of presynaptic a2-adrenergic receptors and postsynaptic serotonin 5-HT2 and 5-HT3 receptors (42–44). The major limitation of this study is its open design. Placebo response rates in depressive disorder can be high (30% to 40%) (45). The other limitations are that the study sample size was small and the subjects were predominantly women. However, it has been reported in previous studies that placebo responders showed no improvement in PSG features (4,16); as well, improvements in HDRS-17 scores were less robust than noted in the current paper (45,46). The current data support an antidepressant and a sleep-promoting effect of mirtazapine in patients with MDD. Funding and SupportThis study was supported by a grant from Organon Canada Ltd to Dr Colin M Shapiro. AcknowledgementsThe authors thank Ms Nancy MacFarlane for her excellent work on organizing the research patients. References1. Ford DE, Kamerow DB. Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention? JAMA 1989;262:1479–84. 2. Sandor P, Shapiro CM. Sleep patterns in depression and anxiety: theory and pharmacological effects. J Psychosom Res 1994;38(Suppl 1):125–39. 3. Jindal RD, Thase ME. Treatment of insomnia associated with clinical depression. Sleep Med Rev 2004;8:19–30. 4. Dorsey CM, Lukas SE, Cunningham SL. 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A double-blind study comparing the efficacy and tolerability of mirtazapine and doxepin in patients with major depression. Eur Neuropsychopharmacol 1995;5:441–6. 39. Stahl S, Zivkov M, Reinitz PE, Panagides J, Hoff W. Meta-analysis of randomized, double-blind, placebo-controlled, efficacy and safety studies of mirtazapine versus amitriptyline in major depression. Acta Psychiatr Scand Suppl 1997;391:22–30. 40. Gorman JM. Mirtazapine: clinical overview. J Clin Psychiatry 1999;60(Suppl 17):9–13. 41. Benkert O, Szegedi A, Kohnen R. Mirtazapine compared with paroxetine in major depression. J Clin Psychiatry 2000;61:656–63. 42. Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev 2001;7:249–64. 43. Wheatley DP, van Moffaert M, Timmerman L, Kremer CME. Mirtazapine: efficacy and tolerability in comparison with fluoxetine in patients with moderate to severe major depressive disorder. J Clin Psychiatry 1998;59:306–12. 44. Puzantian T. Mirtazapine, an antidepressant. Am J Health Syst Pharm 1998;55:44–9. 45. Brown WA, Dornseif BE, Wernicke JF. Placebo response in depression: a search for predictors. Psychiatry Res 1988;26:259–64. 46. Evans KR, Sills T, Wunderlich GR, McDonald HP. Worsening of depressive symptoms prior to randomization in clinical trials: a possible screen for placebo responders? J Psychiatr Res 2004;38:437–44. Author(s)Manuscript received June 2005, revised, and accepted July 2005. 1. Scientist, Department of Psychiatry, University Health Network, Toronto, Ontario; Clinical Scientist, University of Toronto, Toronto, Ontario. 2. Scientist, Department of Psychiatry, University Health Network, Toronto, Ontario; Staff Scientist, University of Toronto, Toronto, Ontario. 3. Staff Scientist, Department of Psychiatry, University Health Network; Assistant Professor, University of Toronto, Toronto, Ontario. 4. Psychiatrist, Department of Psychiatry, University Health Network, Toronto, Ontario; Lecturer, University of Toronto, Toronto, Ontario. 5. Researcher, Department of Psychiatry, University Health Network, Toronto, Ontario; Research Assistant, University of Toronto, Toronto, Ontario. 6. Clinical Fellow, Department of Psychiatry, University Health Network, Toronto, Ontario; Clinical Fellow, University of Toronto, Toronto, Ontario; Psychiatrist, Institute of Behavioral Sciences, Semmelweis University, Budapest, Hungary. 7. Psychiatrist, Department of Psychiatry, University Health Network, Toronto, Ontario; Staff Psychiatrist, University of Toronto, Toronto, Ontario. 8. Professor and Psychiatrist, Department of Psychiatry, University Health Network, Toronto, Ontario; Professor and Psychiatrist, University of Toronto, Toronto, Ontario Address for correspondence: Dr J Shen, Sleep Research Unit, Department of Psychiatry, Toronto Western Hospital, 399 Bathurst Street, 7M–417, Toronto, ON M5T 2S8 e-mail: jianhua.shen@utoronto.ca
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