467348
2012
TPP332045125312467348Therapeutic Advances in PsychopharmacologyA Baskaran, D Summers
Therapeutic Advances in Psychopharmacology
Original Research
Sleep architecture in ziprasidone-treated bipolar depression: a pilot study Anusha Baskaran, Dave Summers, Stephanie LM Willing, Ruzica Jokic and Roumen Milev
Ther Adv Psychopharmacol (2013) 3(3) 139–149 DOI: 10.1177/ 2045125312467348 © The Author(s), 2012. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Abstract Objectives: This study investigated the effect of ziprasidone augmentation therapy on sleep architecture in bipolar depression. Methods: We conducted a double-blind, randomized, placebo-controlled clinical pilot trial of ziprasidone versus placebo in Diagnostic and Statistical Manual of Mental Disorders, fourth edition bipolar disorder with current major depressive episode. The effects during acute (2–5 days) and continuation treatment (28–31 days) were measured. Main outcomes were sleep architecture variables including rapid eye movement sleep (REM) and slow wave sleep (SWS) measured by polysomnography. Secondary outcomes included subjective sleep quality measures and illness severity measures including the 17-item Hamilton Depression Rating Scale (HAMD-17), Montgomery Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAMA) and Clinical Global Illness Severity (CGI-S) scores. Results: The completer analysis comprised of 14 patients (ziprasidone, N = 8 and placebo, N = 6). Latency to REM, duration of SWS, duration of stage 2 sleep, total sleep time, onset to sleep latency, number of awakenings and overall sleep efficiency significantly improved in ziprasidone-treated participants over placebo. CGI-S and HAMA scores also significantly improved. No significant difference between treatment groups was seen on the HAMD-17, MADRS or in self-reported sleep quality. Increase in SWS duration significantly correlated with improvement in CGI-S, however, this finding did not withstand Bonferroni correction. Conclusion: Adjunctive ziprasidone treatment alters sleep architecture in patients with bipolar depression, which may partially explain its mechanism of action and merits further investigation. Keywords: Atypical antipsychotic, bipolar depression, polysomnography, sleep architecture, ziprasidone, REM, SWS
Introduction Sleep disturbances constitute a core symptom of bipolar disorder (BD). Up to 90% of individuals experiencing a major depressive episode (MDE) complain of sleep disturbance, typically sleeponset insomnia, frequent nocturnal arousals, and early morning awakenings [Tsuno et al. 2005]. Insomnia is a risk factor for the development of MDEs and may precede the onset of depression in those with recurrent illness [Breslau et al. 1996; Ford and Cooper-Patrick, 2001]. Sleep disturbance is also a risk factor for suicide [Liu and Buysse, 2005]. Hence, patient care and treatment should include an assessment focusing on sleep function, as well as appropriate measures to improve and optimize sleep architecture.
Normal sleep architecture can be separated into rapid eye movement (REM) and non-REM (NREM) sleep, which alternate in a cyclic fashion. The first hours of sleep include a high percentage of time spent in the four stages of NREM sleep. Stages 1 and 2 are described as a transition from drowsiness to light sleep, whereas stages 3 and 4 are collectively known as slow wave sleep (SWS). As sleep progresses, more time is spent in the REM stage. This normal sleep architecture is altered in BD. Sleep of patients with bipolar depression is fragmented by REM disinhibition, reduced SWS duration, and impaired sleep continuity [Kupfer, 1995]. REM disinhibition features shortened latency to REM sleep and prolonged total REM duration [Kupfer, 1995].
Correspondence to: Roumen Milev, MD, PhD Department of Psychiatry, Queen’s University, 752 King Street West, Kingston, Ontario, Canada K7L 4X3 [email protected] Anusha Baskaran, MSc Dave Summers, MSc Centre for Neuroscience Studies, Queen’s University, Providence Care, Mental Health Services, Kingston, Ontario, Canada Stephanie LM Willing, BSc Queen’s University, Providence Care, Mental Health Services, Kingston, Ontario, Canada Ruzica Jokic, MD Department of Psychiatry, Queen’s University, Providence Care, Mental Health Services, Kingston, Ontario, Canada
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Therapeutic Advances in Psychopharmacology 3 (3) Impairments in sleep continuity include prolonged sleep latency, and increased number of intermittent arousals and early morning awakenings [Argyropoulos and Wilson, 2005]. The reciprocal interaction model assumes that sleep disturbance in depression is due to dysfunction of the central neurotransmitter systems: acetylcholine (Ach), norepinephrine (NE) and serotonin (5-HT), all of which modulate mood and sleep wakefulness [Hobson et al. 1975]. Ach stimulates REM sleep, whereas NE and 5-HT inhibit it. Depression is strongly associated with an overactive cholinergic system and deficient monoaminergic transmission. This imbalance has been held responsible for disinhibiting REM sleep and may also promote increased wakefulness resulting in reduced sleep continuity and efficiency [Sharpley et al. 2005]. Furthermore, 5-HT receptors, which have been shown to be dysfunctional in depression, play a critical role in regulating SWS and overall sleep continuity [Leonard and Cryan, 2000]. Atypical antipsychotic (AA) medications are often used in augmentation strategies in the treatment of bipolar depression. Large trials investigating the use of olanzapine as an adjunctive treatment with the selective serotonin reuptake inhibitor (SSRI), fluoxetine, have demonstrated beneficial antidepressant effects [Corya et al. 2006; Tohen et al. 2003]. Smaller, open-label studies of patients with BD and MDE have also shown benefits with the use of quetiapine as an adjunctive therapy [Milev et al. 2006; Pathak et al. 2005]. Ziprasidone, one of the newer AAs, has been shown to have beneficial antidepressant effects as a monotherapy treatment in an open-label study of individuals with bipolar depression [Liebowitz et al. 2009]. Ziprasidone is an effective antagonist at the dopamine DA2 and 5-HT2A/2C receptors with high affinity profiles. It is also a full agonist at the 5-HT1A receptor [Seeger et al. 2005]. Furthermore, ziprasidone has been shown to prevent the reuptake of both 5-HT and NE. These properties suggest that ziprasidone may contribute to the normalization of sleep patterns and the restoration of sleep quality in patients with bipolar depression who frequently experience sleep disturbances as part of their illness. To date, however, there has only been one study in which the effect of ziprasidone on sleep architecture has been investigated. In a polysomnographic (PSG) study of 12 healthy men, Cohrs
and colleagues (2005) demonstrated that ziprasidone treatment was associated with significant improvement in sleep continuity and efficiency with reduced REM sleep, and significant increases in REM latency, percentage of stage 2 sleep and SWS. The primary aim of this study was to examine the effects of ziprasidone augmentation treatment on sleep architecture, specifically REM sleep, SWS, sleep continuity, and overall sleep efficiency, in patients with BD experiencing MDE. Secondarily, the effects of ziprasidone augmentation on subjective sleep quality and illness severity were also studied to investigate the correlation between sleep architecture and clinical outcome. It was expected that ziprasidone augmentation would suppress REM sleep, increase SWS, and improve overall sleep continuity and efficiency. If such changes occur and can be related to the improvement of depressive symptomatology, then part of ziprasidone’s antidepressant effect may be explained through its ability to restore sleep architecture. Patients and methods Patients Twenty-seven patients were recruited from a tertiary care mood disorders unit, general practitioner offices, and from advertisements placed in the community. Seven failed baseline screening (four due to subclinical mood symptoms, one due to potentially dangerous liver function abnormalities, one due to history of seizures, and one due to abnormal electrocardiogram) and six withdrew before randomization due to loss of interest in participating. The remaining 14 patients made up our final study sample. Their mean age ± standard deviation (SD) was 44 ±12, ranging from 21 to 58 years. The mean age ± SD of the ziprasidonetreated group and the placebo-treated group was 48 ± 7 years and 40 ± 15 years respectively, with no significant difference between groups (t12 = 1.215, p = 0.248). Treatment groups did not differ in baseline sociodemographic characteristics (Table 1). All patients met Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria for BD, currently experiencing a MDE, confirmed using the Mini International Neuropsychiatric Inventory (MINI) [Sheehan et al. 1998]. At inclusion, all patients had a 17-item Hamilton
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A Baskaran, D Summers et al. Table 1. Sociodemographic characteristics of study participants by treatment. Characteristic Gender Diagnosis Education level Employment status Marital status Children
Men Women BD 1 BD 2 BD NOS High-school diploma or less Completed or some college or technical training Undergraduate degree or more Employed (full-/part-time) Unemployed or disability insurance Student Single Married or cohabiting Separated or divorced None 1 2 3+
Placebo (N = 6)
Ziprasidone (N = 8)
n (%)
n (%)
Between-group p-value
1 (16.67) 5 (83.33) 1 (16.67) 5 (83.33) 0 (0) 3 (50) 2 (33.33)
1 (12.5) 7 (87.5) 2 (25) 3 (37.5) 3 (37.5) 3 (37.5) 4 (50)
0.84 0.45 0.84
1 (16.67)
1 (12.5)
2 (33.33) 4 (66.67)
3 (37.5) 4 (50)
0.81
0 (0) 2 (33.33) 3 (50) 1 (16.67) 1 (16.67) 2 (33.33) 1 (16.67) 2 (33.33)
1 (12.5) 4 (50) 3 (37.5) 1 (12.5) 5 (62.5) 0 (0) 1 (12.5) 2 (25)
0.62 0.37
BD, bipolar disorder; NOS, not otherwise specified
Depression Rating Scale (HAMD-17) score greater than 16 [Hamilton, 1960]. Baseline blood work, electrocardiogram, and physical examination were performed for all patients. Women of child-bearing potential must have had a negative human chorionic gonadotropin test at enrolment, not be nursing, and be willing to use contraception. Exclusion criteria included current or past diagnosis of schizophrenia or dementia, manic/ hypomanic/mixed episode at enrolment defined as a Young Mania Rating Scale (YMRS) score greater than 12 [Young et al. 1978], substance dependence within 3 months prior to enrolment (excluding caffeine or nicotine), imminent risk of suicide or danger to themselves or others, known intolerance to ziprasidone, serious or inadequately treated medical illness, history of seizures, previous enrolment in the study or enrolment in another treatment study within the previous 4 weeks, serum potassium/magnesium/calcium levels outside the normal range, marked liver function abnormalities, serological evidence of human immunodeficiency virus, acute or chronic hepatitis, recent acute myocardial infarction or uncompensated heart failure,
and history of QT prolongation or if taking drugs known to prolong the QT interval. Patients could not be taking any other antipsychotic medication at the time of enrolment or during the study. Further, all medication must have been at a stable dose for 4 weeks prior to enrolment, including benzodiazepines and other sleep aids. Concomitant medications can be seen in Table A1 of Appendix A. Patients who had been administered a depot antipsychotic medication within two dosing intervals of enrolment were also excluded. All patients gave written informed consent to participate in the study, which was approved by the local research ethics board, Health Canada and was registered [ClinicalTrials.gov identifier: NCT00835107]. Intervention Patients were randomly allocated using a randomization table to receive either placebo or ziprasidone. The oral capsule formulation of ziprasidone was dispensed, starting at 40 mg twice daily on day 1 and increased to 60 mg twice daily on day 2. At the second visit (day 2–5),
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Therapeutic Advances in Psychopharmacology 3 (3) subsequent adjustment of dosing by titrating up or down as clinically needed to a maximum of 80 mg twice daily was allowed, based on toleration and efficacy. The median dose of ziprasidone at the end of study was 120 mg/day and the mean was 108.57 mg/day with actual doses ranging from 60 to 120 mg/day. Polysomnographic recordings Objective sleep architecture measurements were obtained from PSG data at defined intervals, including baseline (on the day before administration of study medication), once during days 2–5, and once during days 28–31. Sleep PSGs were set up by a qualified PSG technician and recorded using the MediPalm Personal Recording Device (Braebon Corp., Ogdensburg, NY, USA) while the patient slept at home, as adapted from Gedge and colleagues [Gedge et al. 2010]. Patients were asked to retire and rise at their usual time, and to refrain from alcohol consumption on study nights; however, normal caffeine and nicotine intake was maintained. Recording began at approximately 19:00 h, and ran until the participant rose in the morning. A certified PSG analyst, blinded to study design and treatment status, and different from the technician setting up the PSG equipment, scored each sleep record according to the standardized criteria of Rechtschaffen and Kales using Pursuit Advanced Sleep System software (Braebon Corp.) [Rechtschaffen and Kales, 1968]. Latency to sleep onset was defined as the beginning of the first 2 min that were not scored as awake or movement. Latencies to each sleep stage were calculated to the first 2 continuous min of the stage. The respiratory disturbance index (RDI), which included apneas, hypopneas, and snore arousals for the number of events per hour of sleep, was calculated. Obstructive apneas and hypopneas were scored using the criteria from the American Academy of Sleep Medicine Task Force (1999) and arousals were scored based on the American Sleep Disorders Association (1992) criteria. Sleep efficiency (percentage) was calculated as the total sleep time divided by the total time in bed, multiplied by 100. Clinical measures Patients were clinically assessed at the same time points at which PSG recordings were obtained: baseline, days 2–5, and days 28–31. Each assessment consisted of the HAMD-17 [Hamilton,
1960], the Montgomery Asberg Depression Rating Scale (MADRS) [Montgomery and Asberg, 1979], the Hamilton Anxiety Rating Scale (HAMA) [Hamilton, 1969], YMRS [Young et al. 1978], and the participant-reported Pittsburgh Sleep Quality Index (PSQI) [Buysse et al. 1989], Epworth Sleepiness Scale (ESS) [Johns, 1991], and a visual analogue scale for sleep quality [Dixon and Bird, 1981]. At baseline, the Clinical Global IllnessSeverity scale (CGI-S) [Guy, 1976] was administered. At day 28–31, both the CGI-S and the CGI-Improvement (CGI-I) were administered. Statistical analysis The completer analysis was composed of 14 patients (ziprasidone, N = 8 and placebo, N = 6) who had initiated treatment and had both a baseline and at least one post-baseline PSG measurement. Eight of the 14 patients completed their day 28–31 PSG, while 11 of the 14 patients completed their day 28–31 clinical assessment. Multiple imputation regression analysis was used to approximate missing data for PSG and clinical measures for 6 of the 14 patients who missed their day 28– 31 PSG, and for three who also missed their day 28–31 clinical assessment. In order to detect an improvement in REM sleep of approximately 45% (the published difference in REM sleep between placebo- and ziprasidone-treated healthy volunteers) [Cohrs et al. 2005], 7 patients were needed in each arm, for a total sample size of 14, based on a one-sided normal distribution paired t-test analysis with a significance of 0.05 and 80% power. A sample size of 20 patients was used to allow for patient dropout. Baseline sociodemographic and baseline PSG comparisons between groups were analyzed using two-tailed independent sample t tests. PSG recording and clinical measures (except the CGII) were analyzed using two-way repeated measures analysis of variance (ANOVA). The design included two treatment groups (between subjects) across three different time points (within subjects). The linear component, change from baseline to day 28–31, was examined. The CGI-I was analyzed using a between-group t test. For all PSG and clinical measures, two-tailed distributions were used. To examine the relationship between PSG and clinical measures, first, the change from baseline to the end of the study was calculated for each measure that produced a significant time × group interaction to create standardized scores. Two-tailed Pearson correlations
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A Baskaran, D Summers et al. were then employed to examine the correlation between each set of standardized scores. All calculations were performed in IBM SPSS Statistics version 19.0. Results Polysomnographic measures The ziprasidone and placebo groups did not differ in baseline PSG measures (Table 2). A significant increase in both the latency to REM sleep and duration of SWS was observed for the ziprasidone group compared with the placebo group, whereas duration of REM and latency to SWS were not significantly different (Table 2). Duration of stage 2 sleep also significantly improved in the ziprasidone group compared with the placebo group (Table 2). Significant improvements were observed in various sleep continuity measures, including sleep efficiency, onset to sleep latency, total sleep time, and number of awakenings (Table 2). Table 2 shows the remaining PSG measures for both the ziprasidone- and placebo-treated groups as well as p values for time × group interactions according to two-way repeated measures ANOVA.
baseline and at day 28–31 of the ziprasidone group was 4 ± 1 and 3 ± 1 respectively and for the placebo group was 5 ± 1 and 4 ± 1 respectively. CGI-S at baseline did not significantly differ between groups (t12 = 1.561, p = 0.145). The CGI-I at day 28–31 for both groups was 3 ± 1 and was not significantly different between groups (t12 = 0.498, p = 0.620). Table 3 shows the remaining clinician-administered rating scales as well as p values according to two-way repeated measures ANOVA.
Subjective sleep quality An overall significant improvement in PSQI total score was observed across time [F (1, 12) = 4.917, p = 0.047]. However, there was no significant [F(1, 12) = 0.711, p = 0.416] change in PSQI score from baseline to day 2–5 or day 28–31 with ziprasidone treatment, 12.33 ± 1.66, 11.83 ± 1.24, and 8.97 ± 2.04 respectively compared with treatment with placebo, 11.63 ± 1.43, 11.00 ± 1.07 and 10.11 ± 1.77 respectively. Table 3 shows the remaining self-report rating scale scores for sleep as well as p values according to two-way repeated measures ANOVA.
Correlation between sleep architecture and illness severity The only measures that were included in the correlation analyses were those that produced a significant time × group interaction and these included REM latency, SWS duration, stage 2 duration, sleep efficiency, total sleep time, sleep latency and total number of awakenings for PSG measures, and HAMA and CGI-S for clinical measures, using an α of 0.05. There was a significant correlation between SWS duration and CGI-S score (r = –0.571, p = 0.033). There was no significant correlation between CGI-S and the other PSG measures: REM latency (r = –0.300, p = 0.297), stage 2 duration (r = –0.057, p = 0.846), sleep efficiency (r = 0.019, p = 0.948), total sleep time (r = –0.291, p = 0.312), sleep latency (r = 0.276, p = 0.340), and total number of awakenings (r = 0.096, p = 0.745). There was also no significant correlation between HAMA and the PSG measures: REM latency (r = –0.325, p = 0.256), SWS duration (r = –0.453, p = 0.104), stage 2 duration (r = –0.185, p = 0.526), sleep efficiency (r = –0.194, p = 0.506), total sleep time (r = –0.472, p = 0.089), sleep latency (r = 0.498, p = 0.070), and total number of awakenings (r = 0.209, p = 0.473). No significant correlations between sleep architecture and illness severity were found when using Bonferroni’s adjusted α.
Illness severity An overall significant improvement in total HAMD-17, MADRS, and HAMA scores was observed across time with significant difference between groups observed only for HAMA (Table 3). Two-way repeated measures ANOVA revealed that the ziprasidone group significantly decreased [F(1, 12) = 4.782, p = 0.049] in CGI-S score compared with placebo, and overall, there was a significant improvement in CGI-S across time [F(1, 12) = 19.157, p = 0.001]. The CGI-S at
Discussion In the present study, ziprasidone augmentation demonstrated sleep-consolidating properties by significantly increasing REM latency, SWS duration, stage 2 duration, sleep efficiency, and total sleep time, and by decreasing sleep latency, and number of awakenings. While no significant difference between participants was seen in subjective sleep quality, significant improvements were observed for clinical global severity and anxiety symptoms. Clinical global improvement was also
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39.01 ± 24.91 22.05 ± 3.78 5.58 ± 0.92 36.51 ± 26.87 222.87 ± 27.26 54.78 ± 4.14 66.38 ± 32.43 41.77 ± 16.09 11.84 ± 3.20 140.04 ± 48.31 101.69 ± 17.45 23.71 ± 4.42 402.52 ± 39.72 70.52 ± 31.94 52.63 ± 31.32 89.51 ± 6.84 16.78 ± 2.10 7.15 ± 4.93
Baseline
54.51 ± 28.13 34.08 ± 7.70 8.60 ± 2.33 59.59 ± 31.09 227.57 ± 21.29 58.23 ± 4.35 93.01 ± 26.55 44.75 ± 10.15 12.17 ± 2.69 252.68 ± 39.63 80.10 ± 21.29 20.97 ± 4.64 386.50 ± 27.67 91.12 ± 29.08 54.76 ± 27.16 80.92 ± 5.61 20.17 ± 3.68 8.03 ± 5.35
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48.48 ± 22.83 17.25 ± 2.59 4.68 ± 0.71 47.72 ± 21.05 169.96 ± 38.68 52.26 ± 4.00 58.65 ± 41.59 16.78 ± 18.97 4.16 ± 6.04 67.94 ± 64.66 105.27 ± 17.09 27.40 ± 2.83 330.96 ± 30.50 108.32 ± 30.13 90.66 ± 25.98 70.58 ± 8.51 17.85 ± 1.56 37.97 ± 44.60
Day 28–31 67.23 ± 24.36 26.12 ± 6.67 7.89 ± 2.02 62.16 ± 26.92 199.95 ± 18.44 59.73 ± 3.77 122.71 ± 24.74 38.45 ± 8.79 10.15 ± 2.33 197.65 ± 34.32 84.99 ± 18.44 22.47 ± 4.02 333.29 ± 23.96 136.74 ± 25.18 83.58 ± 23.52 74.14 ± 4.85 21.27 ± 3.18 9.14 ± 7.31
Baseline
Ziprasidone
as % of total sleep time. sleep time/total time in bed × 100; measured as percentage. *Indicates a significant p-value for two-way repeated measures analysis of variance time × group interaction (p < 0.05). ANOVA, analysis of variance; RDI, respiratory disturbance index; REM, rapid eye movement; SWS, slow wave sleep.
‡Total
$Measured
Latency to stage 1 (min) Duration of stage 1 (min) Duration of stage 1 (%)$ Latency to stage 2 (min) Duration of stage 2 (min) Duration of stage 2 (%)$ Latency to SWS (min) Duration of SWS (min) Duration of SWS (%)$ Latency to REM (min) Duration of REM (min) Duration of REM (%)$ Total sleep time (min) Total wake time (min) Sleep onset latency (min) Sleep efficiency‡ No. of awakenings RDI
Day 2–5
Placebo
Selected sleep parameter
101.54 ± 21.58 12.63 ± 3.27 4.23 ± 0.80 109.98 ± 23.27 186.35 ± 23.61 56.73 ± 3.63 141.23 ± 28.09 63.44 ± 13.94 18.39 ± 2.77 223.42 ± 41.84 62.79 ± 15.11 20.64 ± 3.83 325.20 ± 34.40 134.74 ± 27.66 101.98 ± 27.12 69.76 ± 5.93 10.25 ± 1.82 11.59 ± 12.00
Day 2–5
73.70 ± 19.78 12.53 ± 2.24 3.57 ± 0.61 69.21 ± 18.23 263.01 ± 33.50 63.77 ± 3.47 107.05 ± 36.01 52.15 ± 16.42 14.73 ± 5.23 206.26 ± 56.01 65.37 ± 14.80 19.18 ± 2.45 359.65 ± 26.42 104.35 ± 26.10 56.01 ± 22.50 80.75 ± 7.37 7.85 ± 1.35 26.80 ± 27.04
Day 28–31
0.738 0.449 0.823 0.951 0.346 0.799 0.447 0.647 0.581 0.315 0.865 0.811 0.172 0.258 0.438 0.379 0.827 0.761
p value
T-test
0.797 0.67 0.871 0.648 0.03* 0.216 0.771 0.034* 0.08 0.028* 0.22 0.295 0.01* 0.278 0.026* 0.041* 0.037* 0.479
p value
ANOVA
Table 2. Mean ± standard deviation of selected polysomnographic measures at baseline and at each time point during treatment with ziprasidone (N = 8) versus placebo (N = 6).
Therapeutic Advances in Psychopharmacology 3 (3)
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A Baskaran, D Summers et al. Table 3. Mean ± standard deviation of selected clinical measures at baseline and at each time point during treatment with ziprasidone (N = 8) versus placebo (N = 6). Clinical measure
Placebo
Baseline HAMD-17 total MADRS total HAMA total YMRS total ESS total VAS total
23 ± 2 31 ± 3 17 ± 2 5±3 9±5 41 ± 25
Ziprasidone Day 2–5 20 ± 2 22 ± 4 17 ± 6 7±4 7±5 42 ± 31
ANOVA time
Day 28–31
Baseline
Day 2–5
Day 28–31
16 ± 3 24 ± 3 16 ± 5 6±4 10 ± 10 52 ± 30
24 ± 1 33 ± 2 21 ± 5 5±2 10 ± 4 48 ± 16
18 ± 2 19 ± 3 16 ± 4 6±2 10 ± 6 44 ± 22
15 ± 2 18 ± 3 15 ± 9 5±3 6±9 68 ± 38
Time × group
0.001* 0.02* 0.034* 0.231 0.743 0.2
0.711 0.134 0.045* 0.782 0.955 0.704
ESS, Epworth Sleepiness Scale; HAMA, Hamilton Anxiety Rating Scale; HAMD-17, 17-item Hamilton Depression Rating Scale; MADRS, Montgomery Asberg Depression Rating Scale; VAS, visual analogue scale; YMRS, Young Mania Rating Scale. *Indicates a significant p value (p < 0.05).
seen with both treatment groups but with no significant difference between treatment groups. Finally, a significant correlation was observed between increase in SWS duration and improvement in CGI-S score, however, this finding did not withstand Bonferroni correction. To our knowledge, this is the first double-blind randomized controlled study evaluating the effect of ziprasidone augmentation treatment on sleep architecture in bipolar depression. There is only one other similar study identified to date, conducted by Cohrs and colleagues, in which they investigated the effect of ziprasidone treatment on PSG sleep structure and subjective sleep quality in healthy volunteers [Cohrs et al. 2005]. They reported effects on sleep profile, almost opposite to what is known about the sleep of depressed patients. This included improvements in REM sleep, SWS, sleep continuity, and overall sleep efficiency. In general, our data support their findings, as we reported similar improvements. Studies reporting the effect of psychotropic augmentation strategies on sleep architecture in patients with depression are limited. However, similar improvements in sleep following ziprasidone augmentation are also observed with other AAs that have been studied. Adjunctive olanzapine treatment has been shown to improve SWS and overall sleep continuity in SSRI-resistant patients with major depression [Sharpley et al. 2005]. It has been suggested that 5-HT2A/2C blockade properties of olanzapine were responsible for these effects [Sharpley et al. 2005]. Risperidone treatment has been shown to decrease REM sleep and increase stage 2 sleep in treatment-resistant patients with depression [Sharpley et al. 2003].
Recently, quetiapine augmentation in patients with unipolar and bipolar depression has also demonstrated beneficial effects on sleep architecture with decreased REM and increased NREM sleep, specifically during stage 2 [Gedge et al. 2010]. Our study demonstrates that ziprasidone improves REM sleep and increases stage 2 sleep, similar to risperidone and quetiapine, in addition to increasing SWS and sleep continuity, similar to olanzapine. Of particular interest are the findings that ziprasidone augmentation increased REM latency and SWS duration. Depression is associated with sleep fragmentation in the form of REM disinhibition and reduced SWS [Kupfer, 1995]. Although REM disinhibition features both shortened latency to REM sleep and prolonged total REM duration, treatment with ziprasidone only resulted in partial REM suppression. Improved REM latency was seen but suppression of REM duration was not. Although expected, the lack of full REM suppression may be due to the degree of polypharmacy among participants. The use of antidepressants and mood stabilizers may have suppressed REM duration at the onset of treatment and thus further suppression with the addition of ziprasidone may not have been attainable. Improvement in sleep continuity is also an important finding of this study. Impairments in sleep continuity in patients with depression include prolonged sleep latency, and increased number of intermittent arousals and early morning awakenings [Argyropoulos and Wilson, 2005]. Ziprasidone augmentation increased sleep efficiency and total sleep time, and reduced sleep latency and number of awakenings.
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Therapeutic Advances in Psychopharmacology 3 (3) However, a general trend with increasing RDI was observed in both treatment groups. While the increase in the RDI in the control group is puzzling, the increase observed in the ziprasidone group may be a reflection of the sedating properties of ziprasidone either alone, or in combination with the other, varied medication regimens of patients. No significant improvement in self-reported sleep quality was seen and this could be explained by the presence of residual depressive symptoms as they could mask changes in sleep quality shown in self-report questionnaires. Therefore, subjective sleep quality may begin to show greater improvement and differentiation between groups with a longer duration of treatment, and as depressive symptoms are alleviated further. The beneficial effects of ziprasidone treatment on objective sleep architecture may be due to its diverse pharmacological profile. While its most potent antagonism is at the 5-HT2A and DA2 sites, it also has high affinity for 5-HT2C, 5-HT1D, and DA3 receptor subtypes while acting as a full agonist at 5-HT1A [Seeger et al. 2005]. The increase in SWS observed under ziprasidone is most likely mediated through the antagonism of 5-HT2A/2C receptors as receptor blockade at these sites has been shown to enhance SWS [Sharpley et al. 1994]. The partial suppression of REM sleep may be related to ziprasidone’s unique ability to inhibit the reuptake of both 5-HT and NE as termination of REM sleep is normally mediated by monoaminergic REM-off neurons. Ziprasidone’s affinity for the reuptake sites is similar to that of the antidepressant imipramine, a drug that produces comparable changes in REM suppression in patients with depression [Gunasekara et al. 2002]. The increase in REM latency may have also been mediated by 5-HT1A agonism as agonists to postsynaptic receptors have been shown to inhibit REM sleep [Landolt and Wehrle, 2009]. Ziprasidone’s sleep continuity properties might be related to its antihistaminergic and antidopaminergic activity. Active histaminergic cells are wake promoting and reductions in histamine will allow for sleep to occur [Saper et al. 2001]. Furthermore, compounds with DA2 receptor blocking properties have been shown to augment NREM sleep and reduce wakefulness [Monti and Jantos, 2008]. The beneficial effect of ziprasidone on objective sleep quality is probably attributable to its extensive pharmacological profile enabling it to affect
a variety of neurotransmitter systems important for normal sleep structure. Although both groups showed improvements in depressive symptoms, the ziprasidone group did not significantly differ from the placebo group in the total score of the HAMD-17 or the MADRS. This is in contrast to an open-label trial of ziprasidone monotherapy in bipolar depression, in which at 8 weeks post treatment, significant improvement was seen on both of these measures [Liebowitz et al. 2009]. Interestingly, significant improvement was observed on the HAMA and CGI-S. Moreover, correlation analysis demonstrated a significant correlation between increase in the SWS duration and improvement in CGI-S score. This finding is important as it shows a relation between change in sleep architecture and improvement in illness severity. However, this correlation did not withstand Bonferroni correction. Hence, a significant correlation between these two factors is not sufficient to say that ziprasidone’s sleep-consolidating properties are causative of the improvement in overall illness severity. The main limitations of this study are the small sample size and the use of concomitant medications. Participants were taking a variety of concomitant medications, including antidepressants, mood stabilizers, and benzodiazepines, which may affect the key neurotransmitters involved in sleep–wake manipulation. Furthermore, sleep studies such as this acquire PSG data at distinct time points, which may not be representative of the entire time period. Conclusion A close association exists between sleep architectural abnormalities and affective disorders, and patients with bipolar depression who continue to experience sleep disturbances face a high risk of relapse. AAs such as olanzapine, quetiapine, and risperidone, which are often used in augmentation strategies in the treatment of bipolar depression, have been shown to have sleep-consolidating properties. Ziprasidone augmentation in bipolar depression alters sleep architecture and improves overall global illness severity. As far as we are aware, this is the first study to date to have investigated the effects of ziprasidone treatment on both objective and subjective sleep in a clinical population. A
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A Baskaran, D Summers et al. clear correlation was found between change in SWS and overall illness severity. Although this association is not causative, the suggestion that part of ziprasidone’s mechanism of action may be achieved through the restoration of sleep architecture merits further investigation with further randomized investigations with large sample sizes. Acknowledgements The assistance of Dr Meshal Khaled Alaqeel is gratefully acknowledged. We also appreciate the assistance of the staff at the Mood Disorders Research and Treatment Service unit of the Mental Health Services site of the Providence Care Hospital and at the Adult Mental Health Program Intake unit of the Hotel Dieu Hospital in Kingston, Ontario.
Cohrs, S., Meier, A., Neumann, A., Jordan, W., Rüther, E. and Rodenbeck, A. (2005) Improved sleep continuity and increased slow wave sleep and REM latency during ziprasidone treatment: a randomized, controlled, crossover trial of 12 healthy male subjects. J Clin Psychiatry 66: 989–996. Corya, S., Williamson, D., Sanger, T., Briggs, S., Case, M. and Tollefson, G. (2006) A randomized, double-blind comparison of olzanpine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression. Depress Anxiety 1: 1–19. Dixon, J. and Bird, H. (1981) Reproducibility along a 10 cm vertical visual analogue scale. Ann Rheum Dis 40: 87–89. Ford, D. and Cooper-Patrick, L. (2001) Sleep disturbances and mood disorders: an epidemiological perspective. Depress Anxiety 14: 3–6.
Funding This work was supported by an investigator- Gedge, L., Lazowski, L., Murray, D., Jokic, R. initiated research grant from Pfizer Canada as and Milev, R. (2010) Effects of quetiapine on sleep awarded to R. Milev. architecture in patients with unipolar or bipolar Conflict of interest statement R. Milev is on Speaker/Advisory Boards for, or has received research funds from: AstraZeneca, Biovail, BrainCells Inc., Canadian Network for Mood & Anxiety Treatments, Eli Lilly, JanssenOrtho, Lundbeck, Pfizer, Servier, Takeda, Wyeth, Bristol-Myers Squibb and Merck.
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Sharpley, A., Attenburrow, M., Hafizi, S. and Cowen, P. (2005) Olanzapine increases slow wave sleep and sleep continuity in SSRI resistant depressed patients. J Clin Psychiatry 66: 450–454. Sharpley, A., Bhagwagar, Z., Hafizi, S., Whale, W., Gijsman, H. and Cowen, P. (2003) Risperidone augmentation decreases rapid eye movement sleep and decreases wake in treatment-resistant depressed patients. J Clin Psychiatry 64: 192–196. Sharpley, A., Elliott, J., Attenburrow, M. and Cowen, P. (1994) Slow wave sleep in humans: role of 5-HT2A and 5-HT2C receptors. Neuropharmacology 33: 467–471. Sheehan, D., Lecrubier, Y., Sheehan, K., Amorim, P., Janavs, J., Weiller, E. et al. (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl. 20): 22–33. Tohen, M., Vieta, E., Calabrese, J., Ketter, T.A., Sachs, G., Bowden, C. et al. (2003) Efficacy of olanzapine and olanzapine/fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 60: 1079–1088. Tsuno, N., Besset, A. and Ritchie, K. (2005) Sleep and depression. J Clin Psychiatry 66: 1254–1269. Young, R., Biggs, J., Ziegler, V. and Meyer, D. (1978) A rating scale for mania: reliability, validity, and sensitivity. Br J Psychiatry 133: 429–435.
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A Baskaran, D Summers et al. Appendix A In Table A1, we list the concomitant medications of ziprasidone- and placebo-treated groups. Table A1. Concomitant medications of ziprasidone- and placebo-treated groups. Medication
Placebo (N = 6)
Ziprasidone (N = 8)
Total (N = 14)
n
n
n
1 3 0 0 2 1 1 8
0 0 2 1 0 1 1 5
1 3 2 1 2 2 2 13
2 1 2 5
0 3 2 6
2 0 2
1 1 2
2 4 4 10 3 1 4
0 1 1 1 0 1 4
1 0 0 0 1 0 2
1 1 1 1 1 1 6
Antidepressants Amitriptyline Bupropion Citalopram Desvenlafaxine Escitalopram Trazodone Venlafaxine Total Mood stabilizers Lamotrigine Lithium Valproic acid Total Benzodiazepines Clonazepam Lorazepam Total Other Clonidine Concerta Gabapentin Imovane Methadone OxyContin Total
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2012
TPP332045125312467348Therapeutic Advances in PsychopharmacologyA Baskaran, D Summers
Therapeutic Advances in Psychopharmacology
Original Research
Sleep architecture in ziprasidone-treated bipolar depression: a pilot study Anusha Baskaran, Dave Summers, Stephanie LM Willing, Ruzica Jokic and Roumen Milev
Ther Adv Psychopharmacol (2013) 3(3) 139–149 DOI: 10.1177/ 2045125312467348 © The Author(s), 2012. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Abstract Objectives: This study investigated the effect of ziprasidone augmentation therapy on sleep architecture in bipolar depression. Methods: We conducted a double-blind, randomized, placebo-controlled clinical pilot trial of ziprasidone versus placebo in Diagnostic and Statistical Manual of Mental Disorders, fourth edition bipolar disorder with current major depressive episode. The effects during acute (2–5 days) and continuation treatment (28–31 days) were measured. Main outcomes were sleep architecture variables including rapid eye movement sleep (REM) and slow wave sleep (SWS) measured by polysomnography. Secondary outcomes included subjective sleep quality measures and illness severity measures including the 17-item Hamilton Depression Rating Scale (HAMD-17), Montgomery Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAMA) and Clinical Global Illness Severity (CGI-S) scores. Results: The completer analysis comprised of 14 patients (ziprasidone, N = 8 and placebo, N = 6). Latency to REM, duration of SWS, duration of stage 2 sleep, total sleep time, onset to sleep latency, number of awakenings and overall sleep efficiency significantly improved in ziprasidone-treated participants over placebo. CGI-S and HAMA scores also significantly improved. No significant difference between treatment groups was seen on the HAMD-17, MADRS or in self-reported sleep quality. Increase in SWS duration significantly correlated with improvement in CGI-S, however, this finding did not withstand Bonferroni correction. Conclusion: Adjunctive ziprasidone treatment alters sleep architecture in patients with bipolar depression, which may partially explain its mechanism of action and merits further investigation. Keywords: Atypical antipsychotic, bipolar depression, polysomnography, sleep architecture, ziprasidone, REM, SWS
Introduction Sleep disturbances constitute a core symptom of bipolar disorder (BD). Up to 90% of individuals experiencing a major depressive episode (MDE) complain of sleep disturbance, typically sleeponset insomnia, frequent nocturnal arousals, and early morning awakenings [Tsuno et al. 2005]. Insomnia is a risk factor for the development of MDEs and may precede the onset of depression in those with recurrent illness [Breslau et al. 1996; Ford and Cooper-Patrick, 2001]. Sleep disturbance is also a risk factor for suicide [Liu and Buysse, 2005]. Hence, patient care and treatment should include an assessment focusing on sleep function, as well as appropriate measures to improve and optimize sleep architecture.
Normal sleep architecture can be separated into rapid eye movement (REM) and non-REM (NREM) sleep, which alternate in a cyclic fashion. The first hours of sleep include a high percentage of time spent in the four stages of NREM sleep. Stages 1 and 2 are described as a transition from drowsiness to light sleep, whereas stages 3 and 4 are collectively known as slow wave sleep (SWS). As sleep progresses, more time is spent in the REM stage. This normal sleep architecture is altered in BD. Sleep of patients with bipolar depression is fragmented by REM disinhibition, reduced SWS duration, and impaired sleep continuity [Kupfer, 1995]. REM disinhibition features shortened latency to REM sleep and prolonged total REM duration [Kupfer, 1995].
Correspondence to: Roumen Milev, MD, PhD Department of Psychiatry, Queen’s University, 752 King Street West, Kingston, Ontario, Canada K7L 4X3 [email protected] Anusha Baskaran, MSc Dave Summers, MSc Centre for Neuroscience Studies, Queen’s University, Providence Care, Mental Health Services, Kingston, Ontario, Canada Stephanie LM Willing, BSc Queen’s University, Providence Care, Mental Health Services, Kingston, Ontario, Canada Ruzica Jokic, MD Department of Psychiatry, Queen’s University, Providence Care, Mental Health Services, Kingston, Ontario, Canada
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Therapeutic Advances in Psychopharmacology 3 (3) Impairments in sleep continuity include prolonged sleep latency, and increased number of intermittent arousals and early morning awakenings [Argyropoulos and Wilson, 2005]. The reciprocal interaction model assumes that sleep disturbance in depression is due to dysfunction of the central neurotransmitter systems: acetylcholine (Ach), norepinephrine (NE) and serotonin (5-HT), all of which modulate mood and sleep wakefulness [Hobson et al. 1975]. Ach stimulates REM sleep, whereas NE and 5-HT inhibit it. Depression is strongly associated with an overactive cholinergic system and deficient monoaminergic transmission. This imbalance has been held responsible for disinhibiting REM sleep and may also promote increased wakefulness resulting in reduced sleep continuity and efficiency [Sharpley et al. 2005]. Furthermore, 5-HT receptors, which have been shown to be dysfunctional in depression, play a critical role in regulating SWS and overall sleep continuity [Leonard and Cryan, 2000]. Atypical antipsychotic (AA) medications are often used in augmentation strategies in the treatment of bipolar depression. Large trials investigating the use of olanzapine as an adjunctive treatment with the selective serotonin reuptake inhibitor (SSRI), fluoxetine, have demonstrated beneficial antidepressant effects [Corya et al. 2006; Tohen et al. 2003]. Smaller, open-label studies of patients with BD and MDE have also shown benefits with the use of quetiapine as an adjunctive therapy [Milev et al. 2006; Pathak et al. 2005]. Ziprasidone, one of the newer AAs, has been shown to have beneficial antidepressant effects as a monotherapy treatment in an open-label study of individuals with bipolar depression [Liebowitz et al. 2009]. Ziprasidone is an effective antagonist at the dopamine DA2 and 5-HT2A/2C receptors with high affinity profiles. It is also a full agonist at the 5-HT1A receptor [Seeger et al. 2005]. Furthermore, ziprasidone has been shown to prevent the reuptake of both 5-HT and NE. These properties suggest that ziprasidone may contribute to the normalization of sleep patterns and the restoration of sleep quality in patients with bipolar depression who frequently experience sleep disturbances as part of their illness. To date, however, there has only been one study in which the effect of ziprasidone on sleep architecture has been investigated. In a polysomnographic (PSG) study of 12 healthy men, Cohrs
and colleagues (2005) demonstrated that ziprasidone treatment was associated with significant improvement in sleep continuity and efficiency with reduced REM sleep, and significant increases in REM latency, percentage of stage 2 sleep and SWS. The primary aim of this study was to examine the effects of ziprasidone augmentation treatment on sleep architecture, specifically REM sleep, SWS, sleep continuity, and overall sleep efficiency, in patients with BD experiencing MDE. Secondarily, the effects of ziprasidone augmentation on subjective sleep quality and illness severity were also studied to investigate the correlation between sleep architecture and clinical outcome. It was expected that ziprasidone augmentation would suppress REM sleep, increase SWS, and improve overall sleep continuity and efficiency. If such changes occur and can be related to the improvement of depressive symptomatology, then part of ziprasidone’s antidepressant effect may be explained through its ability to restore sleep architecture. Patients and methods Patients Twenty-seven patients were recruited from a tertiary care mood disorders unit, general practitioner offices, and from advertisements placed in the community. Seven failed baseline screening (four due to subclinical mood symptoms, one due to potentially dangerous liver function abnormalities, one due to history of seizures, and one due to abnormal electrocardiogram) and six withdrew before randomization due to loss of interest in participating. The remaining 14 patients made up our final study sample. Their mean age ± standard deviation (SD) was 44 ±12, ranging from 21 to 58 years. The mean age ± SD of the ziprasidonetreated group and the placebo-treated group was 48 ± 7 years and 40 ± 15 years respectively, with no significant difference between groups (t12 = 1.215, p = 0.248). Treatment groups did not differ in baseline sociodemographic characteristics (Table 1). All patients met Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria for BD, currently experiencing a MDE, confirmed using the Mini International Neuropsychiatric Inventory (MINI) [Sheehan et al. 1998]. At inclusion, all patients had a 17-item Hamilton
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A Baskaran, D Summers et al. Table 1. Sociodemographic characteristics of study participants by treatment. Characteristic Gender Diagnosis Education level Employment status Marital status Children
Men Women BD 1 BD 2 BD NOS High-school diploma or less Completed or some college or technical training Undergraduate degree or more Employed (full-/part-time) Unemployed or disability insurance Student Single Married or cohabiting Separated or divorced None 1 2 3+
Placebo (N = 6)
Ziprasidone (N = 8)
n (%)
n (%)
Between-group p-value
1 (16.67) 5 (83.33) 1 (16.67) 5 (83.33) 0 (0) 3 (50) 2 (33.33)
1 (12.5) 7 (87.5) 2 (25) 3 (37.5) 3 (37.5) 3 (37.5) 4 (50)
0.84 0.45 0.84
1 (16.67)
1 (12.5)
2 (33.33) 4 (66.67)
3 (37.5) 4 (50)
0.81
0 (0) 2 (33.33) 3 (50) 1 (16.67) 1 (16.67) 2 (33.33) 1 (16.67) 2 (33.33)
1 (12.5) 4 (50) 3 (37.5) 1 (12.5) 5 (62.5) 0 (0) 1 (12.5) 2 (25)
0.62 0.37
BD, bipolar disorder; NOS, not otherwise specified
Depression Rating Scale (HAMD-17) score greater than 16 [Hamilton, 1960]. Baseline blood work, electrocardiogram, and physical examination were performed for all patients. Women of child-bearing potential must have had a negative human chorionic gonadotropin test at enrolment, not be nursing, and be willing to use contraception. Exclusion criteria included current or past diagnosis of schizophrenia or dementia, manic/ hypomanic/mixed episode at enrolment defined as a Young Mania Rating Scale (YMRS) score greater than 12 [Young et al. 1978], substance dependence within 3 months prior to enrolment (excluding caffeine or nicotine), imminent risk of suicide or danger to themselves or others, known intolerance to ziprasidone, serious or inadequately treated medical illness, history of seizures, previous enrolment in the study or enrolment in another treatment study within the previous 4 weeks, serum potassium/magnesium/calcium levels outside the normal range, marked liver function abnormalities, serological evidence of human immunodeficiency virus, acute or chronic hepatitis, recent acute myocardial infarction or uncompensated heart failure,
and history of QT prolongation or if taking drugs known to prolong the QT interval. Patients could not be taking any other antipsychotic medication at the time of enrolment or during the study. Further, all medication must have been at a stable dose for 4 weeks prior to enrolment, including benzodiazepines and other sleep aids. Concomitant medications can be seen in Table A1 of Appendix A. Patients who had been administered a depot antipsychotic medication within two dosing intervals of enrolment were also excluded. All patients gave written informed consent to participate in the study, which was approved by the local research ethics board, Health Canada and was registered [ClinicalTrials.gov identifier: NCT00835107]. Intervention Patients were randomly allocated using a randomization table to receive either placebo or ziprasidone. The oral capsule formulation of ziprasidone was dispensed, starting at 40 mg twice daily on day 1 and increased to 60 mg twice daily on day 2. At the second visit (day 2–5),
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Therapeutic Advances in Psychopharmacology 3 (3) subsequent adjustment of dosing by titrating up or down as clinically needed to a maximum of 80 mg twice daily was allowed, based on toleration and efficacy. The median dose of ziprasidone at the end of study was 120 mg/day and the mean was 108.57 mg/day with actual doses ranging from 60 to 120 mg/day. Polysomnographic recordings Objective sleep architecture measurements were obtained from PSG data at defined intervals, including baseline (on the day before administration of study medication), once during days 2–5, and once during days 28–31. Sleep PSGs were set up by a qualified PSG technician and recorded using the MediPalm Personal Recording Device (Braebon Corp., Ogdensburg, NY, USA) while the patient slept at home, as adapted from Gedge and colleagues [Gedge et al. 2010]. Patients were asked to retire and rise at their usual time, and to refrain from alcohol consumption on study nights; however, normal caffeine and nicotine intake was maintained. Recording began at approximately 19:00 h, and ran until the participant rose in the morning. A certified PSG analyst, blinded to study design and treatment status, and different from the technician setting up the PSG equipment, scored each sleep record according to the standardized criteria of Rechtschaffen and Kales using Pursuit Advanced Sleep System software (Braebon Corp.) [Rechtschaffen and Kales, 1968]. Latency to sleep onset was defined as the beginning of the first 2 min that were not scored as awake or movement. Latencies to each sleep stage were calculated to the first 2 continuous min of the stage. The respiratory disturbance index (RDI), which included apneas, hypopneas, and snore arousals for the number of events per hour of sleep, was calculated. Obstructive apneas and hypopneas were scored using the criteria from the American Academy of Sleep Medicine Task Force (1999) and arousals were scored based on the American Sleep Disorders Association (1992) criteria. Sleep efficiency (percentage) was calculated as the total sleep time divided by the total time in bed, multiplied by 100. Clinical measures Patients were clinically assessed at the same time points at which PSG recordings were obtained: baseline, days 2–5, and days 28–31. Each assessment consisted of the HAMD-17 [Hamilton,
1960], the Montgomery Asberg Depression Rating Scale (MADRS) [Montgomery and Asberg, 1979], the Hamilton Anxiety Rating Scale (HAMA) [Hamilton, 1969], YMRS [Young et al. 1978], and the participant-reported Pittsburgh Sleep Quality Index (PSQI) [Buysse et al. 1989], Epworth Sleepiness Scale (ESS) [Johns, 1991], and a visual analogue scale for sleep quality [Dixon and Bird, 1981]. At baseline, the Clinical Global IllnessSeverity scale (CGI-S) [Guy, 1976] was administered. At day 28–31, both the CGI-S and the CGI-Improvement (CGI-I) were administered. Statistical analysis The completer analysis was composed of 14 patients (ziprasidone, N = 8 and placebo, N = 6) who had initiated treatment and had both a baseline and at least one post-baseline PSG measurement. Eight of the 14 patients completed their day 28–31 PSG, while 11 of the 14 patients completed their day 28–31 clinical assessment. Multiple imputation regression analysis was used to approximate missing data for PSG and clinical measures for 6 of the 14 patients who missed their day 28– 31 PSG, and for three who also missed their day 28–31 clinical assessment. In order to detect an improvement in REM sleep of approximately 45% (the published difference in REM sleep between placebo- and ziprasidone-treated healthy volunteers) [Cohrs et al. 2005], 7 patients were needed in each arm, for a total sample size of 14, based on a one-sided normal distribution paired t-test analysis with a significance of 0.05 and 80% power. A sample size of 20 patients was used to allow for patient dropout. Baseline sociodemographic and baseline PSG comparisons between groups were analyzed using two-tailed independent sample t tests. PSG recording and clinical measures (except the CGII) were analyzed using two-way repeated measures analysis of variance (ANOVA). The design included two treatment groups (between subjects) across three different time points (within subjects). The linear component, change from baseline to day 28–31, was examined. The CGI-I was analyzed using a between-group t test. For all PSG and clinical measures, two-tailed distributions were used. To examine the relationship between PSG and clinical measures, first, the change from baseline to the end of the study was calculated for each measure that produced a significant time × group interaction to create standardized scores. Two-tailed Pearson correlations
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A Baskaran, D Summers et al. were then employed to examine the correlation between each set of standardized scores. All calculations were performed in IBM SPSS Statistics version 19.0. Results Polysomnographic measures The ziprasidone and placebo groups did not differ in baseline PSG measures (Table 2). A significant increase in both the latency to REM sleep and duration of SWS was observed for the ziprasidone group compared with the placebo group, whereas duration of REM and latency to SWS were not significantly different (Table 2). Duration of stage 2 sleep also significantly improved in the ziprasidone group compared with the placebo group (Table 2). Significant improvements were observed in various sleep continuity measures, including sleep efficiency, onset to sleep latency, total sleep time, and number of awakenings (Table 2). Table 2 shows the remaining PSG measures for both the ziprasidone- and placebo-treated groups as well as p values for time × group interactions according to two-way repeated measures ANOVA.
baseline and at day 28–31 of the ziprasidone group was 4 ± 1 and 3 ± 1 respectively and for the placebo group was 5 ± 1 and 4 ± 1 respectively. CGI-S at baseline did not significantly differ between groups (t12 = 1.561, p = 0.145). The CGI-I at day 28–31 for both groups was 3 ± 1 and was not significantly different between groups (t12 = 0.498, p = 0.620). Table 3 shows the remaining clinician-administered rating scales as well as p values according to two-way repeated measures ANOVA.
Subjective sleep quality An overall significant improvement in PSQI total score was observed across time [F (1, 12) = 4.917, p = 0.047]. However, there was no significant [F(1, 12) = 0.711, p = 0.416] change in PSQI score from baseline to day 2–5 or day 28–31 with ziprasidone treatment, 12.33 ± 1.66, 11.83 ± 1.24, and 8.97 ± 2.04 respectively compared with treatment with placebo, 11.63 ± 1.43, 11.00 ± 1.07 and 10.11 ± 1.77 respectively. Table 3 shows the remaining self-report rating scale scores for sleep as well as p values according to two-way repeated measures ANOVA.
Correlation between sleep architecture and illness severity The only measures that were included in the correlation analyses were those that produced a significant time × group interaction and these included REM latency, SWS duration, stage 2 duration, sleep efficiency, total sleep time, sleep latency and total number of awakenings for PSG measures, and HAMA and CGI-S for clinical measures, using an α of 0.05. There was a significant correlation between SWS duration and CGI-S score (r = –0.571, p = 0.033). There was no significant correlation between CGI-S and the other PSG measures: REM latency (r = –0.300, p = 0.297), stage 2 duration (r = –0.057, p = 0.846), sleep efficiency (r = 0.019, p = 0.948), total sleep time (r = –0.291, p = 0.312), sleep latency (r = 0.276, p = 0.340), and total number of awakenings (r = 0.096, p = 0.745). There was also no significant correlation between HAMA and the PSG measures: REM latency (r = –0.325, p = 0.256), SWS duration (r = –0.453, p = 0.104), stage 2 duration (r = –0.185, p = 0.526), sleep efficiency (r = –0.194, p = 0.506), total sleep time (r = –0.472, p = 0.089), sleep latency (r = 0.498, p = 0.070), and total number of awakenings (r = 0.209, p = 0.473). No significant correlations between sleep architecture and illness severity were found when using Bonferroni’s adjusted α.
Illness severity An overall significant improvement in total HAMD-17, MADRS, and HAMA scores was observed across time with significant difference between groups observed only for HAMA (Table 3). Two-way repeated measures ANOVA revealed that the ziprasidone group significantly decreased [F(1, 12) = 4.782, p = 0.049] in CGI-S score compared with placebo, and overall, there was a significant improvement in CGI-S across time [F(1, 12) = 19.157, p = 0.001]. The CGI-S at
Discussion In the present study, ziprasidone augmentation demonstrated sleep-consolidating properties by significantly increasing REM latency, SWS duration, stage 2 duration, sleep efficiency, and total sleep time, and by decreasing sleep latency, and number of awakenings. While no significant difference between participants was seen in subjective sleep quality, significant improvements were observed for clinical global severity and anxiety symptoms. Clinical global improvement was also
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39.01 ± 24.91 22.05 ± 3.78 5.58 ± 0.92 36.51 ± 26.87 222.87 ± 27.26 54.78 ± 4.14 66.38 ± 32.43 41.77 ± 16.09 11.84 ± 3.20 140.04 ± 48.31 101.69 ± 17.45 23.71 ± 4.42 402.52 ± 39.72 70.52 ± 31.94 52.63 ± 31.32 89.51 ± 6.84 16.78 ± 2.10 7.15 ± 4.93
Baseline
54.51 ± 28.13 34.08 ± 7.70 8.60 ± 2.33 59.59 ± 31.09 227.57 ± 21.29 58.23 ± 4.35 93.01 ± 26.55 44.75 ± 10.15 12.17 ± 2.69 252.68 ± 39.63 80.10 ± 21.29 20.97 ± 4.64 386.50 ± 27.67 91.12 ± 29.08 54.76 ± 27.16 80.92 ± 5.61 20.17 ± 3.68 8.03 ± 5.35
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48.48 ± 22.83 17.25 ± 2.59 4.68 ± 0.71 47.72 ± 21.05 169.96 ± 38.68 52.26 ± 4.00 58.65 ± 41.59 16.78 ± 18.97 4.16 ± 6.04 67.94 ± 64.66 105.27 ± 17.09 27.40 ± 2.83 330.96 ± 30.50 108.32 ± 30.13 90.66 ± 25.98 70.58 ± 8.51 17.85 ± 1.56 37.97 ± 44.60
Day 28–31 67.23 ± 24.36 26.12 ± 6.67 7.89 ± 2.02 62.16 ± 26.92 199.95 ± 18.44 59.73 ± 3.77 122.71 ± 24.74 38.45 ± 8.79 10.15 ± 2.33 197.65 ± 34.32 84.99 ± 18.44 22.47 ± 4.02 333.29 ± 23.96 136.74 ± 25.18 83.58 ± 23.52 74.14 ± 4.85 21.27 ± 3.18 9.14 ± 7.31
Baseline
Ziprasidone
as % of total sleep time. sleep time/total time in bed × 100; measured as percentage. *Indicates a significant p-value for two-way repeated measures analysis of variance time × group interaction (p < 0.05). ANOVA, analysis of variance; RDI, respiratory disturbance index; REM, rapid eye movement; SWS, slow wave sleep.
‡Total
$Measured
Latency to stage 1 (min) Duration of stage 1 (min) Duration of stage 1 (%)$ Latency to stage 2 (min) Duration of stage 2 (min) Duration of stage 2 (%)$ Latency to SWS (min) Duration of SWS (min) Duration of SWS (%)$ Latency to REM (min) Duration of REM (min) Duration of REM (%)$ Total sleep time (min) Total wake time (min) Sleep onset latency (min) Sleep efficiency‡ No. of awakenings RDI
Day 2–5
Placebo
Selected sleep parameter
101.54 ± 21.58 12.63 ± 3.27 4.23 ± 0.80 109.98 ± 23.27 186.35 ± 23.61 56.73 ± 3.63 141.23 ± 28.09 63.44 ± 13.94 18.39 ± 2.77 223.42 ± 41.84 62.79 ± 15.11 20.64 ± 3.83 325.20 ± 34.40 134.74 ± 27.66 101.98 ± 27.12 69.76 ± 5.93 10.25 ± 1.82 11.59 ± 12.00
Day 2–5
73.70 ± 19.78 12.53 ± 2.24 3.57 ± 0.61 69.21 ± 18.23 263.01 ± 33.50 63.77 ± 3.47 107.05 ± 36.01 52.15 ± 16.42 14.73 ± 5.23 206.26 ± 56.01 65.37 ± 14.80 19.18 ± 2.45 359.65 ± 26.42 104.35 ± 26.10 56.01 ± 22.50 80.75 ± 7.37 7.85 ± 1.35 26.80 ± 27.04
Day 28–31
0.738 0.449 0.823 0.951 0.346 0.799 0.447 0.647 0.581 0.315 0.865 0.811 0.172 0.258 0.438 0.379 0.827 0.761
p value
T-test
0.797 0.67 0.871 0.648 0.03* 0.216 0.771 0.034* 0.08 0.028* 0.22 0.295 0.01* 0.278 0.026* 0.041* 0.037* 0.479
p value
ANOVA
Table 2. Mean ± standard deviation of selected polysomnographic measures at baseline and at each time point during treatment with ziprasidone (N = 8) versus placebo (N = 6).
Therapeutic Advances in Psychopharmacology 3 (3)
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A Baskaran, D Summers et al. Table 3. Mean ± standard deviation of selected clinical measures at baseline and at each time point during treatment with ziprasidone (N = 8) versus placebo (N = 6). Clinical measure
Placebo
Baseline HAMD-17 total MADRS total HAMA total YMRS total ESS total VAS total
23 ± 2 31 ± 3 17 ± 2 5±3 9±5 41 ± 25
Ziprasidone Day 2–5 20 ± 2 22 ± 4 17 ± 6 7±4 7±5 42 ± 31
ANOVA time
Day 28–31
Baseline
Day 2–5
Day 28–31
16 ± 3 24 ± 3 16 ± 5 6±4 10 ± 10 52 ± 30
24 ± 1 33 ± 2 21 ± 5 5±2 10 ± 4 48 ± 16
18 ± 2 19 ± 3 16 ± 4 6±2 10 ± 6 44 ± 22
15 ± 2 18 ± 3 15 ± 9 5±3 6±9 68 ± 38
Time × group
0.001* 0.02* 0.034* 0.231 0.743 0.2
0.711 0.134 0.045* 0.782 0.955 0.704
ESS, Epworth Sleepiness Scale; HAMA, Hamilton Anxiety Rating Scale; HAMD-17, 17-item Hamilton Depression Rating Scale; MADRS, Montgomery Asberg Depression Rating Scale; VAS, visual analogue scale; YMRS, Young Mania Rating Scale. *Indicates a significant p value (p < 0.05).
seen with both treatment groups but with no significant difference between treatment groups. Finally, a significant correlation was observed between increase in SWS duration and improvement in CGI-S score, however, this finding did not withstand Bonferroni correction. To our knowledge, this is the first double-blind randomized controlled study evaluating the effect of ziprasidone augmentation treatment on sleep architecture in bipolar depression. There is only one other similar study identified to date, conducted by Cohrs and colleagues, in which they investigated the effect of ziprasidone treatment on PSG sleep structure and subjective sleep quality in healthy volunteers [Cohrs et al. 2005]. They reported effects on sleep profile, almost opposite to what is known about the sleep of depressed patients. This included improvements in REM sleep, SWS, sleep continuity, and overall sleep efficiency. In general, our data support their findings, as we reported similar improvements. Studies reporting the effect of psychotropic augmentation strategies on sleep architecture in patients with depression are limited. However, similar improvements in sleep following ziprasidone augmentation are also observed with other AAs that have been studied. Adjunctive olanzapine treatment has been shown to improve SWS and overall sleep continuity in SSRI-resistant patients with major depression [Sharpley et al. 2005]. It has been suggested that 5-HT2A/2C blockade properties of olanzapine were responsible for these effects [Sharpley et al. 2005]. Risperidone treatment has been shown to decrease REM sleep and increase stage 2 sleep in treatment-resistant patients with depression [Sharpley et al. 2003].
Recently, quetiapine augmentation in patients with unipolar and bipolar depression has also demonstrated beneficial effects on sleep architecture with decreased REM and increased NREM sleep, specifically during stage 2 [Gedge et al. 2010]. Our study demonstrates that ziprasidone improves REM sleep and increases stage 2 sleep, similar to risperidone and quetiapine, in addition to increasing SWS and sleep continuity, similar to olanzapine. Of particular interest are the findings that ziprasidone augmentation increased REM latency and SWS duration. Depression is associated with sleep fragmentation in the form of REM disinhibition and reduced SWS [Kupfer, 1995]. Although REM disinhibition features both shortened latency to REM sleep and prolonged total REM duration, treatment with ziprasidone only resulted in partial REM suppression. Improved REM latency was seen but suppression of REM duration was not. Although expected, the lack of full REM suppression may be due to the degree of polypharmacy among participants. The use of antidepressants and mood stabilizers may have suppressed REM duration at the onset of treatment and thus further suppression with the addition of ziprasidone may not have been attainable. Improvement in sleep continuity is also an important finding of this study. Impairments in sleep continuity in patients with depression include prolonged sleep latency, and increased number of intermittent arousals and early morning awakenings [Argyropoulos and Wilson, 2005]. Ziprasidone augmentation increased sleep efficiency and total sleep time, and reduced sleep latency and number of awakenings.
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Therapeutic Advances in Psychopharmacology 3 (3) However, a general trend with increasing RDI was observed in both treatment groups. While the increase in the RDI in the control group is puzzling, the increase observed in the ziprasidone group may be a reflection of the sedating properties of ziprasidone either alone, or in combination with the other, varied medication regimens of patients. No significant improvement in self-reported sleep quality was seen and this could be explained by the presence of residual depressive symptoms as they could mask changes in sleep quality shown in self-report questionnaires. Therefore, subjective sleep quality may begin to show greater improvement and differentiation between groups with a longer duration of treatment, and as depressive symptoms are alleviated further. The beneficial effects of ziprasidone treatment on objective sleep architecture may be due to its diverse pharmacological profile. While its most potent antagonism is at the 5-HT2A and DA2 sites, it also has high affinity for 5-HT2C, 5-HT1D, and DA3 receptor subtypes while acting as a full agonist at 5-HT1A [Seeger et al. 2005]. The increase in SWS observed under ziprasidone is most likely mediated through the antagonism of 5-HT2A/2C receptors as receptor blockade at these sites has been shown to enhance SWS [Sharpley et al. 1994]. The partial suppression of REM sleep may be related to ziprasidone’s unique ability to inhibit the reuptake of both 5-HT and NE as termination of REM sleep is normally mediated by monoaminergic REM-off neurons. Ziprasidone’s affinity for the reuptake sites is similar to that of the antidepressant imipramine, a drug that produces comparable changes in REM suppression in patients with depression [Gunasekara et al. 2002]. The increase in REM latency may have also been mediated by 5-HT1A agonism as agonists to postsynaptic receptors have been shown to inhibit REM sleep [Landolt and Wehrle, 2009]. Ziprasidone’s sleep continuity properties might be related to its antihistaminergic and antidopaminergic activity. Active histaminergic cells are wake promoting and reductions in histamine will allow for sleep to occur [Saper et al. 2001]. Furthermore, compounds with DA2 receptor blocking properties have been shown to augment NREM sleep and reduce wakefulness [Monti and Jantos, 2008]. The beneficial effect of ziprasidone on objective sleep quality is probably attributable to its extensive pharmacological profile enabling it to affect
a variety of neurotransmitter systems important for normal sleep structure. Although both groups showed improvements in depressive symptoms, the ziprasidone group did not significantly differ from the placebo group in the total score of the HAMD-17 or the MADRS. This is in contrast to an open-label trial of ziprasidone monotherapy in bipolar depression, in which at 8 weeks post treatment, significant improvement was seen on both of these measures [Liebowitz et al. 2009]. Interestingly, significant improvement was observed on the HAMA and CGI-S. Moreover, correlation analysis demonstrated a significant correlation between increase in the SWS duration and improvement in CGI-S score. This finding is important as it shows a relation between change in sleep architecture and improvement in illness severity. However, this correlation did not withstand Bonferroni correction. Hence, a significant correlation between these two factors is not sufficient to say that ziprasidone’s sleep-consolidating properties are causative of the improvement in overall illness severity. The main limitations of this study are the small sample size and the use of concomitant medications. Participants were taking a variety of concomitant medications, including antidepressants, mood stabilizers, and benzodiazepines, which may affect the key neurotransmitters involved in sleep–wake manipulation. Furthermore, sleep studies such as this acquire PSG data at distinct time points, which may not be representative of the entire time period. Conclusion A close association exists between sleep architectural abnormalities and affective disorders, and patients with bipolar depression who continue to experience sleep disturbances face a high risk of relapse. AAs such as olanzapine, quetiapine, and risperidone, which are often used in augmentation strategies in the treatment of bipolar depression, have been shown to have sleep-consolidating properties. Ziprasidone augmentation in bipolar depression alters sleep architecture and improves overall global illness severity. As far as we are aware, this is the first study to date to have investigated the effects of ziprasidone treatment on both objective and subjective sleep in a clinical population. A
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A Baskaran, D Summers et al. clear correlation was found between change in SWS and overall illness severity. Although this association is not causative, the suggestion that part of ziprasidone’s mechanism of action may be achieved through the restoration of sleep architecture merits further investigation with further randomized investigations with large sample sizes. Acknowledgements The assistance of Dr Meshal Khaled Alaqeel is gratefully acknowledged. We also appreciate the assistance of the staff at the Mood Disorders Research and Treatment Service unit of the Mental Health Services site of the Providence Care Hospital and at the Adult Mental Health Program Intake unit of the Hotel Dieu Hospital in Kingston, Ontario.
Cohrs, S., Meier, A., Neumann, A., Jordan, W., Rüther, E. and Rodenbeck, A. (2005) Improved sleep continuity and increased slow wave sleep and REM latency during ziprasidone treatment: a randomized, controlled, crossover trial of 12 healthy male subjects. J Clin Psychiatry 66: 989–996. Corya, S., Williamson, D., Sanger, T., Briggs, S., Case, M. and Tollefson, G. (2006) A randomized, double-blind comparison of olzanpine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression. Depress Anxiety 1: 1–19. Dixon, J. and Bird, H. (1981) Reproducibility along a 10 cm vertical visual analogue scale. Ann Rheum Dis 40: 87–89. Ford, D. and Cooper-Patrick, L. (2001) Sleep disturbances and mood disorders: an epidemiological perspective. Depress Anxiety 14: 3–6.
Funding This work was supported by an investigator- Gedge, L., Lazowski, L., Murray, D., Jokic, R. initiated research grant from Pfizer Canada as and Milev, R. (2010) Effects of quetiapine on sleep awarded to R. Milev. architecture in patients with unipolar or bipolar Conflict of interest statement R. Milev is on Speaker/Advisory Boards for, or has received research funds from: AstraZeneca, Biovail, BrainCells Inc., Canadian Network for Mood & Anxiety Treatments, Eli Lilly, JanssenOrtho, Lundbeck, Pfizer, Servier, Takeda, Wyeth, Bristol-Myers Squibb and Merck.
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A Baskaran, D Summers et al. Appendix A In Table A1, we list the concomitant medications of ziprasidone- and placebo-treated groups. Table A1. Concomitant medications of ziprasidone- and placebo-treated groups. Medication
Placebo (N = 6)
Ziprasidone (N = 8)
Total (N = 14)
n
n
n
1 3 0 0 2 1 1 8
0 0 2 1 0 1 1 5
1 3 2 1 2 2 2 13
2 1 2 5
0 3 2 6
2 0 2
1 1 2
2 4 4 10 3 1 4
0 1 1 1 0 1 4
1 0 0 0 1 0 2
1 1 1 1 1 1 6
Antidepressants Amitriptyline Bupropion Citalopram Desvenlafaxine Escitalopram Trazodone Venlafaxine Total Mood stabilizers Lamotrigine Lithium Valproic acid Total Benzodiazepines Clonazepam Lorazepam Total Other Clonidine Concerta Gabapentin Imovane Methadone OxyContin Total
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