Journal of Affective Disorders 157 (2014) 33–40

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Research report

Effect of quetiapine XR on depressive symptoms and sleep quality compared with lithium in patients with bipolar depression Seog Ju Kim a, Yu Jin Lee b,n, Yu-Jin G. Lee b, Seong-Jin Cho c a

Department of Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea Department of Psychiatry, Center for Sleep and Chronobiology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Republic of Korea c Department of Psychiatry, Gachon University of Medicine and Science, Incheon, Republic of Korea b

art ic l e i nf o

a b s t r a c t

Article history: Received 30 September 2013 Received in revised form 24 December 2013 Accepted 24 December 2013 Available online 2 January 2014

Background: Bipolar depression is one of the most serious psychiatric conditions. In addition, sleep disturbance in bipolar disorder is common, and therapeutic agents restoring sleep disturbances in bipolar disorder patients will be clinically beneficial. In the current study, we compared the effect of quetiapine XR with lithium on depressive symptoms and sleep in bipolar depression patients during 8 weeks of trial. Methods: An open-label, randomized comparison of sleep-activity and depressive symptoms between 8-week quetiapine XR monotherapy and lithium monotherapy for bipolar depression was conducted. Each assessment consisted of HDRS-17, Clinical Global Impression-severity (CGI-S), and self-reported Pittsburgh Sleep Quality Index (PSQI). Actigraphy-measured sleep parameters were assessed. Results: A total of 42 patients (35.7710.9 years; gender: male 15, female 27) with bipolar depression were screened out. Out of 42 patients, six patients were excluded before randomization. After randomization, seven patients were withdrawn. Twenty-nine patients with more than two visits after randomization (lithium group: 17, quetiapine XR group: 12, mean age: 36.1 710.4, gender: male 13, female 16) were included in the final analysis. In both groups, Hamilton Depression Rating Scale (HDRS) scores were significantly decreased at weeks 1, 2, 4, 6, and 8 compared with baseline. Remission rate (HDRS r7) in the quetiapine XR was significantly higher than that of the lithium group. In the quetiapine XR group, PSQI scores at weeks 1, 2, 4, 6, and 8 was significantly decreased compared with baseline. Sleep efficiency at weeks 6 and 8 was significantly increased. WASO at week 8 was significantly decreased. Limitations: First, the present study was conducted with the relatively small number of study subjects. Second, bias could have affected the study results due to its open-label design. Third, study subjects were made up of high proportion of bipolar II disorder patients. Conclusions: Quetiapine XR monotherapy was more effective in treating bipolar depression than lithium. In particular, quetiapine XR treatment improved both subjective and objective sleep quality in patients with bipolar depression. However, relationship between favorable sleep quality and depressive symptom improvement were limited. & 2014 Elsevier B.V. All rights reserved.

Keywords: Quetiapine XR Lithium Sleep Actigraphy Bipolar depression

1. Introduction Bipolar depression is one of the most serious psychiatric conditions. Psychosocial impairment of bipolar depression is comparable to that of mania (Judd et al., 2005). Bipolar depression has also been reported to be associated with a higher suicide risk than other types of depression (Tondo et al., 2003). In addition, bipolar patients experience depressive episodes that are three times longer than manic or hypomanic episodes (Hirschfeld et al.,

n

Corresponding author. Tel.: þ 82 2 2072 2456; fax: þ 82 2 744 7241. E-mail address: [email protected] (Y.J. Lee).

0165-0327/$ - see front matter & 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2013.12.032

2003). However, there are not many treatment options for bipolar depression. Treatment of bipolar depression with traditional antidepressants has a risk of affective switch. Mood stabilizers have shown antidepressant effects in bipolar depression. However, only a small portion of patients with bipolar depression respond to mood stabilizers (Thase and Sachs, 2000). Nowadays, atypical antipsychotics have been suggested as useful strategies against both manic and depressive episodes of bipolar disorder. In addition to dopamine, serotonin, and 2A receptors blockade of other atypical antipsychotics, quetiapine has effects on noradrenalin alpha 2 receptors (Yatham et al., 2005). Because of their biochemical property, quetiapine has been suspected to have stronger antidepressant effects than other atypical antipsychotics

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S.J. Kim et al. / Journal of Affective Disorders 157 (2014) 33–40

(Cookson et al., 2007, Sanford and Keating, 2012). Either monotherapy or combination therapy with quetiapine has been shown to be effective against both manic and depressive episode of bipolar disorder (Sachs et al., 2004; Bowden et al., 2005). A number of placebo-controlled studies have also reported that quetiapine monotherapy for bipolar depression is effective and well-tolerated (Calabrese et al., 2005; Hirschfeld et al., 2006; Thase et al., 2006; Cookson et al., 2007; Endicott et al., 2007). In addition, the antidepressant effect of quetiapine augmentation has been reported to be superior to that of lithium augmentation in treatment-resistant depression (Doree et al., 2007). Besides mood symptoms, circadian disruption has also been reported in bipolar disorder (Jones et al., 2005). Sleep disturbance in bipolar disorder has been reported in mania, depression and even euthymic status (Wehr et al., 1987; Nofzinger et al., 1991; Jackson et al., 2003; Millar et al., 2004). Stabilized activities and sleep patterns are important for reducing relapse risk in patients with bipolar disorder (Klein et al., 1992; Jones, 2001). Therefore, therapeutic agents restoring sleep disturbances in bipolar disorder will be clinically beneficial. Quetiapine has been reported to improve sleep induction and continuity on nocturnal polysomnography in healthy subjects (Cohrs et al., 2004) and subjective sleep quality in bipolar depression (Endicott et al., 2007). Previous studies have reported that the initial sedative effects of quetiapine did not persist for long time and the increase of activity appeared with the maintenance of quetiapine (Baune et al., 2007; Juri et al., 2005). Adjunctive antidepressant therapy with quetiapine for unipolar depression has been reported to improve nighttime sleep (Todder et al., 2006) and increase daytime activity (Baune et al., 2007). Bipolar patients have been reported to generally overestimate (or underestimate) their own sleep and show discrepancy between objective and subjective sleep (Harvey et al., 2005), even though there has been a previous notion of correlation between the estimation of sleep time by actigraphy and by sleep diaries in bipolar patients (Gonzalez et al., 2013). Wrist actigraphy has been known to be a good method for objective measurement of sleep and activity, and sleep parameter estimates from actigraphy have been reported to be correlated with those from polysomnography in bipolar disorder (Kaplan et al., 2012). In addition, wrist actigraphy enables relatively long-term assessment of natural sleep-activity with minimal disruption. However, there have been no prior studies assessing the effect of quetiapine monotherapy on actigraphy-measured sleep and activity in bipolar depression (Todder et al., 2006). Therefore, it would be necessary to investigate the effects of quetiapine on sleep and activity in bipolar depression with more objective methods such as wrist actigraphy. Extended-release (XR) quetiapine is formulated to provide a gradual release of quetiapine, which can allow more stable plasma concentration than with immediate-release (IR) quetiapine (Figueroa et al., 2009). Lower intensity of sedation compared with quetiapine IR has been reported (Datto et al., 2009). In the current study, we assessed the effect of quetiapine XR with lithium on sleep and depressive mood in bipolar depression during 8 weeks of trial. To compare the effect of quetiapine with lithium on nighttime sleep and depressive symptoms in bipolar depression, we assessed changes in actigraphy-measured sleep variables and HDRS during the study period of 8 weeks.

Hospital. Study protocol was informed to consecutive patients aged 18–65 years who met DSM-IV criteria for bipolar I or II disorder and were experiencing currently major depressive episodes. Patients who agreed to screening visit were screened. The diagnosis was confirmed with the Structured Clinical Interview for DSM-IV at the screening visit. The patients were required to have a Hamilton Depression Rating Scale 17-item score [HDRS-17] Z20 and a Young Mania Rating Scale [YMRS] score r12 at the screening visit. Patients who gave verbal and written informed consent prior to initiation of any study procedure were enrolled. Participants were excluded if they had (or a history of) substance or alcohol dependence or medical conditions that would affect absorption, distribution, metabolism and excretion of medications. Pregnant or lactating women or shift workers were also excluded. The study protocol was approved by the Institutional Review Board of Gachon University of Medicine and Science. 2.2. Study design and treatment An open-label, randomized comparison of sleep-activity and depressive symptoms between 8-week quetiapine XR monotherapy and lithium monotherapy for bipolar depression was conducted. The target dose of quetiapine XR was 300 mg/day (fixed dose). A dose of 300 mg/day of quetiapine XR for bipolar depression has been reported to have enough antidepressant efficacy that is comparable to 600 mg/day (Calabrese et al., 2005). Titration of quetiapine XR was initiated with 50 mg, 100 mg at day 3, 200 mg at day 5, and 300 mg (target dose) at day 7. An initial dose of 600 mg was adjusted to the serum level of 0.8–1.2 mmol/L for 2 weeks. Serum lithium level was monitored at weeks 1 and 8, and the level was checked at week 2 only when the serum level at week 1 was not within 0.8–1.2 mmol/L. 2.3. Previous and concomitant medications Before taking study drugs, washout period of previous psychotropic medication was at least four half-lives of any prior psychotropic medications. The use of cytochrome P450 3A4 inhibitors or inducers was not permitted within 14 days prior to enrollment and during the study. Antipsychotics, antidepressants or mood stabilizers other than the study drug were prohibited during the study. Psychotropic, sedative, and hypnotic medications were not permitted during the study. Only lorazepam for severe anxiety was permitted during the wash-out periods. 2.4. Assessments Patients were assessed at six time points, at baseline (before administration of study medication) and at weeks 1, 2, 4, 6, and 8. Each assessment consisted of HDRS-17, Clinical Global Impressionseverity (CGI-S) and self-reported Pittsburgh Sleep Quality Index (PSQI). The incidence of treatment-emergent mania was assessed using the YMRS at each visit. YMRS total score Z12 on consecutive assessments was considered to be a manic or hypomanic switch. For assessment of side effects including extrapyramidal symptoms and secondary restless legs syndrome, Simpson–Angus Rating Scale (SARS) (Simpson and Angus, 1970), Barns-Akathisia Rating Scale (BARS) (Barnes 1989) and Restless Legs Syndrome Rating Scale (RLSRS) (Walters et al., 2003) were administered at each visit.

2. Methods 2.5. Actigraphy 2.1. Subjects Participants were recruited from inpatient clinics and outpatient at the department of psychiatry of Gachon University Gil

Actigraphy is a reliable and valid tool for sleep-activity cycle measurement (Teicher, 1995). Actigraphy can provide objective data unbiased by subjective self-reporting. Patients wore an

S.J. Kim et al. / Journal of Affective Disorders 157 (2014) 33–40

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Table 1 Comparisons of demographic and clinical characteristics between the Quetiapine XR and Lithium group (n¼ 29).

Age Gendera Diagnosisa Number of past mood episodes Baseline HDRS Baseline CGI-S Baseline PSQI Baseline SL (min) Baseline SE (%) Baseline WASO (min) Baseline daytime acitivity (%)

Quetiapine XR (n¼ 12)

Lithium (n¼ 17)

Total

t or χ2

p

39.2 711.9 Male 3 (25.0%) Bipolar II 10 (83.3%) 3.8 72.2 27.8 75.1 5.0 70.9 11.4 7 2.9 15.5 7 11.3 82.0 75.4 50.2 713.9 80.8 78.9

33.9 7 8.9 Male 10 (58.8%) Bipolar II 16 (94.1%) 2.8 72.1 24.17 2.2 4.6 70.9 8.4 73.8 22.4 713.9 80.9 74.8 61.5 7 25.3 81.2 7 8.6

36.1 710.4 Male 13 (44.8%) Bipolar II 26 (89.7%) 3.2 7 2.1 25.6 7 4.1 4.8 7 0.9 9.6 7 3.7 19.4 7 13.1 81.3 7 5.0 56.7 7 21.6 81.0 7 8.5

 1.896 3.254 0.882  1.340  2.732  1.091  2.357 1.415  0.579 1.402 0.119

0.182 0.130 0.367 0.191 0.011n 0.285 0.026n 0.169 0.568 0.173 0.906

Independent t-test. HDRS: Hamilton Depression Rating Scale, CGI-S: Clinical Global Improvement-Severity, PSQI: Pittsburgh Sleep Quality Index, SL: Sleep Latency, SE: Sleep Efficiency, WASO: Wakefulness After Sleep Onset. a n

Chi-square test. po 0.05.

actigraphy (Actiwatch 2, Respironics) on their non-dominant wrist during the study period. The actigraphy was exchanged at weeks 0, 1, 2, 4, and 6. They were asked to remove the actigraphy only during washing or swimming. Sleep variables at each visit from baseline was measured by actigraphy. Sleep efficiency which was the primary outcome in the current study was the percentage of true sleeping time while in bed (Korszun et al., 2002; Todder et al., 2006). Baseline sleep efficiency in the current study represented sleep efficiency before medication (at least 1 week necessary). Wake proportion in the “active” phase on individual actigraphy was considered as part of daytime activity in the current study. 2.6. Statistical analysis For comparisons between groups, an independent t-test with continuous variables and the Fisher exact test with categorical variables were performed. To assess efficacy and changes in sleepwake variables from baseline, the paired t-test was performed in each group. Partial correlation analysis was performed for assessing the relationship between mood and sleep variables. Last observation carried forward methods were used. All the analyses were performed using SPSS for Windows. All statistic methods were two-tailed at the 0.05 level of significance.

3. Results A total of 42 patients (35.7 7 10.9 years; gender: male 15, female 27) with bipolar depression were screened out. Out of 42 patients, six patients were excluded before randomization (three patients: screening failure on HDRS and three patients: withdrawal of the consent). Thirty-six patients (36.5711.2 years; gender: male 13, female 23) were randomized into the lithium monotherapy group or the quetiapine XR monotherapy group. After randomization at visit 2 (week 0), seven patients (one: lithium group and six: quetiapine XR group) were withdrawn. In the lithium group, a patient was withdrawn due to subjective chest discomfort. In the quetiapine XR group, three patients were withdrawn due to sedation, two patients due to dizziness and one patient due to withdrawal of the consent. Twenty-nine patients with more than two visits after randomization (lithium group: 17, quetiapine XR group: 12, mean age: 36.1 710.4, gender: male 13, female 16) were included in the final analysis. Twenty-three patients (lithium group: 12, quetiapine XR group: 11, mean age: 36.47 10.8, gender: male nine, female 14) attended all visits during the study period of 8 weeks. In the

quetiapine XR group, a patient was withdrawn due to suicide attempt at visit 5 (week 4). In the lithium group, one patient was withdrawn due to myalgia at visit 3 (week 1), one patient due to chest discomfort at visit 4 (week 2), one patient due to nausea, one patient due to headache, and one patient due to follow up loss at visit 5 (week 4). During study, there was no patient who showed manic or hypomanic switch measured by YMRS. There was no significant difference between the lithium and quetiapine XR groups in terms of age, sex, diagnosis of bipolar I or II, and the number of past mood episodes (Table 1). 3.1. Mood In the independent t-test, the baseline HDRS score was higher in the quetiapine XR group compared to the lithium group (27.8 75.1 vs. 24.17 2.2, t ¼ 2.732, p¼ 0.011) (Table 1). When the response rate was defined as more than 50% improvement from baseline on the HDRS, there was no significant difference between the two groups in the response rate (quetiapine XR 7/12, 58.3% vs. lithium 6/17, 35.3%, χ2 ¼1.510, p ¼0.274). When remission was defined as a score of equal to or less than 7 on the HDRS, the remission rate in the quetiapine XR group was significantly higher than that of the lithium group (6/12, 50.0% vs. 2/17, 11.8%, χ2 ¼5.148, p ¼0.038) (Fig. 1). In the quetiapine XR group, HDRS scores at weeks 1, 2, 4, 6, and 8 were significantly decreased compared with baseline (t ¼2.790, po 0.001; t ¼3.217, po 0.001; t ¼3.828, po 0.001; t ¼3.820, po 0.001; and t¼ 3.576, p o0.001, respectively). CGI severity scores at weeks 1, 2, 4, 6, and 8 were significantly decreased compared with baseline (t¼ 2.219, p ¼0.027; t¼2.073, p ¼0.007; t¼3.096, p ¼0.002; t¼3.429, p ¼0.002; and t¼ 3.054, p ¼0.001, respectively) (Table 2). In the lithium group, HDRS scores at weeks 1, 2, 4, 6, and 8 were significantly decreased compared with baseline (t ¼2.790, p¼ 0.013; t¼3.217, p ¼ 0.005; t¼3.828, p¼ 0.001; t ¼3.820, p¼ 0.002; and t ¼3.576, p ¼0.003, respectively). CGI severity scores at weeks 1, 4, 6, and 8 were significantly decreased compared with baseline (t¼2.219, p¼ 0.041; t¼3.096, p ¼0.007; t ¼3.429, p¼ 0.003; and t ¼3.054, p ¼0.008, respectively) (Table 3). 3.2. Subjective sleep quality The independent t-test results showed that the baseline PSQI score was higher in the quetiapine XR group compared to the lithium group (11.472.9 vs. 8.4 73.8, t¼  2.357, p ¼0.026).

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In the quetiapine XR group, PSQI scores at weeks 1, 2, 4, 6, and 8 were significantly decreased compared with baseline (t¼6.250, p o0.001; t ¼6.398, p o0.001; t¼8.360, p o0.001; t¼7.036, p o0.001; and t¼6.240, p o0.001, respectively) (Table 4). In the lithium group, PSQI scores at weeks 1, 2, 4, 6, and 8 showed no significant changes from baseline (Table 5).

3.4. Correlation of sleep parameters with depressive symptom After controlling for age and gender, partial correlation analysis of HDRS scores with sleep variables at each week was performed for the quetiapine XR group. At week 4, the HDRS score was positively correlated with WASO (r ¼ 0.736, p¼ 0.024). At week 6, the HDRS score was positively correlated with the PSQI score (r ¼0.786, p ¼0.012) (Table 6).

3.3. Objective sleep variables and daytime activity

3.5. Adverse effects

In the quetiapine XR group, sleep latency at weeks 1, 2, 4, 6, and 8 showed no significant changes from baseline. Sleep efficiency at weeks 6 and 8 was significantly increased compared with baseline (t¼  2.686, p¼0.021 and t¼  3.117, p¼0.010, respectively). WASO at week 8 was significantly decreased compared with baseline (t¼ 2.285, p¼0.043) (Table 4). In the lithium group, there were no significant changes at weeks 1, 2, 4, 6, and 8 from baseline in sleep latency, sleep efficiency, and wakefulness after sleep onset (WASO) (Table 5). In both groups, changes in daytime activity at weeks 1, 2, 4, 6, and 8 from baseline were not significant (Tables 4 and 5).

In the quetiapine XR group, SARS, BARS, and RLSRS scores at the study end point showed no significant change compared with baseline (t¼  0.692, p ¼0.504; t¼ 1.830, p ¼0.095; and t¼0.106, p¼ 0.917, respectively). In the lithium group, SARS, BARS, and RLSRS scores at the study end point showed no significant change compared with baseline (t¼  1.000, p¼ 0.332; t¼1.319, p ¼0.206; and t¼  1.209, p¼ 0.244, respectively).

4. Discussion In the current study, we found that both quetiapine XR monotherapy and lithium monotherapy reduced depressive symptoms. However, the remission rate was higher with quetiapine XR than that with lithium. Significant improvement of subjective and objective sleep quality measured by actigraphy was noted in only quetiapine XR monotherapy group. In the present study, improvement in HDRS score on quetiapine XR was noted from the first week, which was maintained throughout the study duration. This rapid response to bipolar depression was also reported in a prior study with quetiapine XR Table 3 Changes in scores on HDRS and CGI-S from baseline in the lithium group (n¼ 17).

Fig. 1. Comparison of remession rates between the quetiapine XR and lithium group. When remission was defined as a score equal to or less than 7 on the HDRS, the remission rate in the quetiapine XR was significantly higher than that of the lithium group (6/12, 50.0% vs. 2/17, 11.8%, χ2 ¼ 5.148, p ¼0.038).

Baseline

Week 1

Week 2

Week 4

Week 6

Week 8

HDRS t p

24.17 2.2

21.3 7 4.4 2.790 0.013n

19.7 7 6.3 3.217 0.005nn

17.8 7 7.4 3.828 0.001nn

17.6 77.2 3.820 0.002nn

17.17 8.2 3.576 0.003nn

CGI-S t p

4.6 7 0.9

4.4 7 0.9 2.219 0.041n

4.3 7 1.0 2.073 0.055

4.0 7 1.1 3.096 0.007nn

3.9 71.0 3.429 0.003nn

3.9 7 0.9 3.054 0.008nn

Paired t-test at each week compared with baseline. HDRS: Hamilton Depression Rating Scale, CGI-S: Clinical Global ImprovementSeverity. n

p o 0.05. p o 0.01.

nn

Table 2 Changes in scores on HDRS and CGI-S from baseline in the quetiapine XR group (n¼ 12). Baseline

Week 1

Week 2

Week 4

Week 6

Week 8

HDRS t p

27.8 7 5.1

19.6 7 5.5 7.180 o 0.001nnn

17.5 76.7 7.112 o 0.001nnn

15.3 7 7.5 6.163 o0.001nnn

12.4 7 9.0 6.363 o 0.001nnn

11.5 710 6.005 o 0.001nnn

CGI-S t p

5.0 7 0.9

4.4 7 1.1 2.548 0.027n

4.0 71.2 3.371 0.007nn

3.7 7 1.2 4.000 0.002nn

3.1 71.7 3.960 0.002nn

2.9 71.5 4.795 0.001nn

Paired t-test at each week compared with baseline. HDRS: Hamilton Depression Rating Scale, CGI-S: Clinical Global Improvement-Severity. n

po 0.05. p o0.01. nnn p o0.001. nn

S.J. Kim et al. / Journal of Affective Disorders 157 (2014) 33–40

37

Table 4 Changes in self-reported PSQI and actigraphy-measured sleep parameters from baseline in the quetiapine XR group (n¼ 12). Baseline

Week 1

Week 2

Week 4

Week 6

Week 8

PSQI t p

11.4 72.9

6.7 7 3.1 6.250 o 0.001nn

7.2 73.6 6.398 o 0.001nn

5.4 7 2.6 8.360 o 0.001nn

5.4 7 2.8 7.036 o0.001nn

4.8 7 3.6 6.240 o 0.001nn

SL (min) t p

15.5 711.3

18.4 7 12.5  1.126 0.286

18.6 7 17.6  0.896 0.391

24. 57 15.1  1.690 0.122

18.7 7 8.5  0.680 0.510

17.8 7 8.0  0.573 0.578

SE (%) t p

82.0 75.4

83.2 7 4.8  0.924 0.375

83.9 7 6.7  0.970 0.353

78.7 7 18.3 0.577 0.576

87.2 75.7  2.686 0.021n

88.7 7 5.5  3.117 0.010n

WASO (min) t p

50.2 713.9

57.4 725.7  1.458 0.173

51.0 7 25.8  0.116 0.909

54.2 7 16.1  0.678 0.512

52.2 7 13.9  0.399 0.697

39.5 7 11.9 2.285 0.043n

Daytime activity (%) t p

80.8 78.9

81.1 73.5  0.576 0.579

79.7 7 7.9  0.075 0.942

80.0 7 4.4 0.098 0.924

78.8 7 5.1 0.433 0.675

79.7 7 5.0 0.347 0.735

Paired t-test. PSQI: Pittsburgh Sleep Quality Index, SL: Sleep Latency, SE: Sleep Efficiency, WASO: Wakefulness After Sleep Onset. n

po 0.05. p o0.01.

nn

Table 5 Changes in self-reported PSQI and actigraphy-measured sleep parameters from baseline in the lithium group (n¼ 17). Baseline PSQI t p

8.4 73.8

Week 1

Week 2

Week 4

Week 6

Week 8

7.4 73.4 1.263 0.225

6.17 3.7 2.629 0.065

6.9 7 3.2 1.768 0.096

6.7 7 3.2 1.679 0.113

6.1 74.2 1.990 0.064

SL (min) t p

22.4 713.9

20.6 7 13.7  0.146 0.886

26.8 7 13.8  0.777 0.451

22.4 7 14.7  0.285 0.780

19.5 79.1 0.993 0.337

22.8 7 13.2  0.078 0.939

SE (%) t p

80.9 74.8

81.17 5.3  0.134 0.895

80.5 7 5.5 0.370 0.716

81.8 75.6  0.632 0.537

81.5 7 5.0  0.656 0.522

82.4 7 5.4  1.226 0.239

WASO (min) t p

61.5 725.3

54.2 7 16.2 1.414 0.178

61.4 7 25.0 0.031 0.976

61.5 7 34.5 0.001 0.999

60.9 7 34.1 0.108 0.916

86.9 7 107.8  0.973 0.346

Daytime activity (%) t p

81.2 78.6

83.3 7 8.7  1.305 0.212

80.5 7 8.9 0.117 0.908

80.9 7 7.5 0.221 0.829

83.7 7 7.4  1.222 0.240

80.2 7 8.0 0.374 0.713

Paired t-test. PSQI: Pittsburgh Sleep Quality Index, SL: Sleep Latency, SE: Sleep Efficiency, WASO: Wakefulness After Sleep Onset.

300 mg once daily dosage (Suppes et al., 2010) and a review (Pompili et al., 2012). In addition, we found that the remission rate of quetiapine XR by HDRS was higher than that of lithium. Swartz and Thase (2011) suggested that quetiapine had most favorable evidence for acute depression in bipolar II disorder rather than lithium or lamotrigine. The proportion of remitters in the present study was 50.0% in quetiapine XR, which was comparable with 54.1% with quetiapine XR monotherapy (Suppes et al., 2010), 52.9% with quetiapine IR monotherapy (Calabrese et al., 2005) and 42.1% with combined medication in a previous observational study on bipolar depression (Jeong et al., 2013). Previous studies did not show significant superiority of lithium on bipolar depression compared with other mood stabilizers or placebo, and its efficacy in depression has been suggested to be modest (Bhagwagar and Goodwin, 2002; Van Lieshout and MacQueen, 2010; Malhi et al., 2013). In addition, lithium was reported to show a more delayed effect on bipolar depression than that in mania (Heit and Nemeroff, 1998), which is inconsistent

with our results. However, a number of past studies reported the antidepressant efficacy of lithium in unipolar and bipolar depression (Goodwin et al., 1972; Baron et al., 1975; Watanabe et al., 1975; Worrall et al., 1979; Souza and Goodwin, 1991). Since bipolar II depression was reported to have significant improvement in HDRS with lithium treatment (Suppes et al., 2008), it is necessary to consider high portion of bipolar II disorder (89.7%) for the current results with efficacy of lithium. Moreover, the prior notion that lithium showed has better effect in bipolar patients with recurrent episodes (Gershon et al., 2009) may be another explanation for the efficacy of lithium, because the mean number of past mood episodes in the lithium group of the current study was 2.8. The somnolence effect of quetiapine is thought to arise from its 5-HT2 and H1 receptor blockade (Gedge et al., 2010). In the current study, patients in the quetiapine XR group showed significant improvement in subjective sleep quality assessed by PSQI. This improvement was noted from week 1 and continued up to week 8. Favorable outcomes on subjective sleep quality with

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S.J. Kim et al. / Journal of Affective Disorders 157 (2014) 33–40

Table 6 Partial correlation results between HDRS score with sleep variables at each week in the quetiapine XR group (n¼ 12). Baseline HDRS

Week 1 HDRS

Week 2 HDRS

Week 4 HDRS

Week 6 HDRS

Week 8 HDRS

PSQI r  0.283 p 0.429

-0.681 0.063

0.452 0.261

0.107 0.785

SL (min) r 0.506 p 0.136

0.192 0.649

0.155 0.713

0.017 0.966

 0.315 0.409

 0.232 0.518

SE (%) r  0.414 p 0.234

0.107 0.801

 0.543 0.165

0.164 0.674

 0.511 0.160

 0.245 0.495

WASO (min) r 0.462 p 0.179

0.473 0.236

0.598 0.118

0.532 0.141

0.370 0.292

Daytime activity (%) r  0.198 0.102 p 0.584 0.810

 0.435 0.281

 0.665 0.051

 0.309 0.385

0.736 0.024n  0.474 0.197

0.786 0.012n

0.313 0.378

HDRS: Hamilton Depression Rating Scale, PSQI: Pittsburgh Sleep Quality Index, SL: Sleep Latency, SE: Sleep Efficiency, WASO: Wakefulness After Sleep Onset. n

po 0.05.

quetiapine have been consistently reported in previous studies on unipolar depression (Cutler et al., 2009; Weisler et al., 2009; Bortnick et al., 2011; Maneeton et al., 2012), bipolar depression (Calabrese et al., 2005; Vieta et al., 2007; Endicott et al., 2008), and healthy individuals (Cohrs et al., 2004). The sleep-improving effect of quetiapine XR can have its clinical significance in the role of decreasing suicidality in unipolar or bipolar depression (Pompili et al., 2012). However, there have been relatively few studies on objective sleep parameters in quetiapine treatment patients. To the best of our knowledge, this is the first study on quetiapine XR monotherapy on actigraphy-measured sleep and activity in bipolar depression. In the current study, we objectively measured sleep quality including sleep efficiency and found that sleep fragmentation was improved with quetiapine XR. Sleep efficiency measured by actigraphy increased at week 6 and was maintained at week 8. WASO decreased at week 8. In a previous study with healthy individuals, low doses of quetiapine altered the sleep architecture on polysomnography including increases in total sleep time, sleep efficiency and percentage sleep stage 2 (Cohrs et al., 2004). However, a study with unipolar or bipolar depression failed to show alteration of sleep efficiency and sleep continuity on polysomnography with adjunctive low dose quetiapine therapy (Gedge et al., 2010). Moreover, actigaphy-measured sleep parameters in depressed patients were not significantly changed with antidepressant treatment plus quetiapine, but shortened the sleep latency during only the 1st week (Todder et al., 2006). These inconsistencies with previous reports may be caused by differences in the characteristics of study subjects and treatment methods. All participants of the current study were experiencing major depressive episodes in bipolar disorder. In addition, not adjunctive therapy but quetiapine XR or lithium monotherapy was allowed. In the current study, sleep parameters with lithium monotherapy did not show significant improvement compared with baseline. There have been few past studies on the effects of lithium on sleep, but there have been no studies with actigraphy measurement. Lithium increased slow wave sleep in healthy individuals, which was thought to be an effect consistent with reduced brain 5-HT2 receptor function (Friston et al., 1989). In depressed patients, lithium reduced REM sleep, delayed REM latency and increased

slow wave sleep on polysomnography (Billiard, 1987). Comparison of our results with past studies was limited, because of discrepancies in research methods and subjects. In the current study, daytime activity on actigraphy did not show significant change over the study duration in both groups. Few studies on the medication effects on motor activity in bipolar patients have been performed, but it is still poorly understood. Like our result, a previous study reported lack of significant difference between the first and last week of a 4-week study on treatment resistant depression with antidepressant treatment plus quetiapine (Baune et al., 2007). The researchers tried to explain these results by the fast onset of quetiapine with a relatively low change to the end point of the study or the effects of quetiapine on agitation but not on motor activity. In the future, a further study on daytime activity in bipolar depression with a large study population is necessary. To investigate the relationship between improvement in sleep quality in the quetiapine XR group and depressive symptom change, we performed a partial correlation analysis. Only limited correlations of HDRS score with WASO or PSQI score at weeks 4 and 6 respectively were found. This finding is partially consistent with a prior study which reported no significant differences in objective by actigraphy or subjective sleep by PSQI between the clinical improvement and nonimprovement groups with quetiapine treated depression (Todder et al., 2006), even though past studies have reported the relationship between mood symptoms and impaired sleep (Wehr et al., 1987; Jackson et al., 2003). Based on our findings, a hypothesis stating that quetiapine has an antidepressant effect independent of the sleep promoting effect may be feasible. The antidepressant effects of quetiapine are poorly understood and several pathways have been proposed. The effects may be related to antagonism of 5-HT2A receptors in cortical regions, partial agonism of 5-HT1A in the prefrontal cortex in association with increased extracellular dopamine release in the region, or reduced synaptic reuptake of noradrenaline resulting from inhibition of the noradrenaline reuptake transporter by the quetiapine metabolite norquetiapine (Sanford and Keating, 2012). On the other hand, sleep-inducing properties of quetiapine are mainly related with antagonism at H1 receptors, and also with 5HT2receptor blockade (Gedge et al., 2010). A further study on the relationship between the sleep promoting effect and mood improvement will be needed. The current study has several limitations. First, it was conducted with the relatively small number of study subjects. Second, bias could have affected the study results due to its open-label design. Third, study subjects were made up of high proportion of bipolar II disorder patients. In conclusion, quetiapine XR monotherapy was more effective in treating bipolar depression than lithium. In particular, quetiapine XR treatment improved both subjective and objective sleep quality in patients with bipolar depression. However, relationship between favorable sleep quality with depressive symptom improvement were limited.

Role of funding source Funding for this study was provided by AstraZeneca (D1443C00031).

Conflict of interest The authors have indicated no financial conflicts of interest.

References Barnes, T.R., 1989. A rating scale for drug-induced akathisia. Br. J. Psychiatry 154, 672–676.

S.J. Kim et al. / Journal of Affective Disorders 157 (2014) 33–40

Baron, M., Gershon, E.S., Rudy, V., Jonas, W.Z., Buchsbaum, M., 1975. Lithium carbonate response in depression. Prediction by unipolar/bipolar illness, average-evoked response, catechol-O-methyl transferase, and family history. Arch. Gen. Psychiatry 32, 1107–1111. Baune, B.T., Caliskan, S., Todder, D., 2007. Effects of adjunctive antidepressant therapy with quetiapine on clinical outcome, quality of sleep and daytime motor activity in patients with treatment-resistant depression. Hum. Psychopharmacol. 22, 1–9. Bhagwagar, Z., Goodwin, G.M., 2002. The role of lithium in the treatment of bipolar depression. Clin. Neurosci. Res. 2, 222–227. Billiard, M., 1987. Lithium carbonate: effects on sleep patterns of normal and depressed subjects and its use in sleep-wake pathology. Pharmacopsychiatry 20, 195–196. Bortnick, B., El-Khalili, N., Banov, M., Adson, D., Datto, C., Raines, S., Earley, W., Eriksson, H., 2011. Efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in major depressive disorder: a placebo-controlled, randomized study. J. Affect. Disord. 128, 83–94. Bowden, C.L., Grunze, H., Mullen, J., Brecher, M., Paulsson, B., Jones, M., Vagero, M., Svensson, K., 2005. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J. Clin. Psychiatry 66, 111–121. Calabrese, J.R., Keck Jr., P.E., Macfadden, W., Minkwitz, M., Ketter, T.A., Weisler, R.H., Cutler, A.J., McCoy, R., Wilson, E., Mullen, J., 2005. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am. J. Psychiatry 162, 1351–1360. Cohrs, S., Rodenbeck, A., Guan, Z., Pohlmann, K., Jordan, W., Meier, A., Ruther, E., 2004. Sleep-promoting properties of quetiapine in healthy subjects. Psychopharmacology (Berl.) 174, 421–429. Cookson, J., Keck Jr., P.E., Ketter, T.A., Macfadden, W., 2007. Number needed to treat and time to response/remission for quetiapine monotherapy efficacy in acute bipolar depression: evidence from a large, randomized, placebo-controlled study. Int. Clin. Psychopharmacol. 22, 93–100. Cutler, A.J., Montgomery, S.A., Feifel, D., Lazarus, A., Aström, M., Brecher, M., 2009. Extended release quetiapine fumarate monotherapy in major depressive disorder: a placebo- and duloxetine-controlled study. J. Clin. Psychiatry 70, 526–539. Datto, C., Berggren, L., Patel, J.B., Eriksson, H., 2009. Self-reported sedation profile of immediate-release quetiapine fumarate compared with extended-release quetiapine fumarate during dose initiation: a randomized, double-blind, crossover study in healthy adult subjects. Clin. Ther. 31, 492–502. Doree, J.P., Des Rosiers, J., Lew, V., Gendron, A., Elie, R., Stip, E., Tourjman, S.V., 2007. Quetiapine augmentation of treatment-resistant depression: a comparison with lithium. Curr. Med. Res. Opin. 23, 333–341. Endicott, J., Paulsson, B., Gustafsson, U., Schiöler, H., Hassan, M., 2008. Quetiapine monotherapy in the treatment of depressive episodes of bipolar I and II disorder: improvements in quality of life and quality of sleep. J. Affect. Disord. 111, 306–319. Endicott, J., Rajagopalan, K., Minkwitz, M., Macfadden, W., 2007. A randomized, double-blind, placebo-controlled study of quetiapine in the treatment of bipolar I and II depression: improvements in quality of life. Int. Clin. Psychopharmacol. 22, 29–37. Figueroa, C., Brecher, M., Hamer-Maansson, J.E., Winter, H., 2009. Pharmacokinetic profiles of extended release quetiapine fumarate compared with quetiapine immediate release. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 199–204. Friston, K.J., Sharpley, A.L., Solomon, R.A., Cowen, P.J., 1989. Lithium increases slow wave sleep: possible mediation by brain 5-HT2 receptors? Psychopharmacology (Berl.) 98, 139–140. Gedge, L., Lazowski, L., Murray, D., Jokic, R., Milev, R., 2010. Effects of quetiapine on sleep architecture in patients with unipolar or bipolar depression. Neuropsychiatr. Dis. Treat. 6, 501–508. Gershon, S., Chengappa, K.R., Malhi, G.S., 2009. Lithium specificity in bipolar illness: a classic agent for a classic disorder. Bipolar Disord. 11 (Suppl. 2), 34–44. Goodwin, F.K., Murphy, D.L., Dunner, D.L., Bunney Jr., W.E., 1972. Lithium response in unipolar versus bipolar depression. Am. J. Psychiatry 129, 44–47. Gonzalez, R., Tamminga, C., Tohen, M., Suppes, T., 2013. Comparison of objective and subjective assessments of sleep time in subjects with bipolar disorder. J. Affect. Disord. 149, 363–366. Kaplan, K.A., Talbot, L.S., Gruber, J., Harvey, A.G., 2012. Evaluating sleep in bipolar disorder: comparison between actigraphy, polysomnography, and sleep diary. Bipolar Disord. 14, 870–879. Klein, E., Lavie, P., Meiraz, R., Sadeh, A., Lenox, R.H., 1992. Increased motor activity and recurrent manic episodes: predictors of rapid relapse in remitted bipolar disorder patients after lithium discontinuation. Biol. Psychiatry 31, 279–284. Korszun, A., Young, E.A., Engleberg, N.C., Brucksch, C.B., Greden, J.F., Crofford, L.A., 2002. Use of actigraphy for monitoring sleep and activity levels in patients with fibromyalgia and depression. J. Psychosom. Res. 52, 439–443. Harvey, A.G., Schmidt, D.A., Scarna, A., Semler, C.N., Goodwin, G.M., 2005. Sleeprelated functioning in euthymic patients with bipolar disorder, patients with insomnia, and subjects without sleep problems. Am. J. Psychiatry 162, 50–57. Heit, F., Nemeroff, C.B., 1998. Lithium augmentation of antidepressants in treatment-refractory depression. J. Clin. Psychiatry 59, 28–33. Hirschfeld, R.M., Lewis, L., Vornik, L.A., 2003. Perceptions and impact of bipolar disorder: how far have we really come? Results of the national depressive and manic-depressive association 2000 survey of individuals with bipolar disorder. J. Clin. Psychiatry 64, 161–174.

39

Hirschfeld, R.M., Weisler, R.H., Raines, S.R., Macfadden, W., 2006. Quetiapine in the treatment of anxiety in patients with bipolar I or II depression: a secondary analysis from a randomized, double-blind, placebo-controlled study. J. Clin. Psychiatry 67, 355–362. Jackson, A., Cavanagh, J., Scott, J., 2003. A systematic review of manic and depressive prodromes. J. Affect. Disord. 74, 209–217. Jeong, J.H., Bahk, W.M., Woo, Y.S., Seo, H.J., Hong, S.C., Jon, D.I., Min, K.J., Yoon, B.H., 2013. Efficacy of quetiapine in patients with bipolar I and II depression: a multicenter, prospective, open-label, observational study. Neuropsychiatr. Dis. Treat. 9, 197–204. Jones, S.H., 2001. Circadian rhythms, multilevel models of emotion and bipolar disorder—an initial step towards integration? Clin. Psychol. Rev. 21, 1193–1209. Jones, S.H., Hare, D.J., Evershed, K., 2005. Actigraphic assessment of circadian activity and sleep patterns in bipolar disorder. Bipolar Disord. 7, 176–186. Judd, L.L., Akiskal, H.S., Schettler, P.J., Endicott, J., Leon, A.C., Solomon, D.A., Coryell, W., Maser, J.D., Keller, M.B., 2005. Psychosocial disability in the course of bipolar I and II disorders: a prospective, comparative, longitudinal study. Arch. Gen. Psychiatry 62, 1322–1330. Juri, C., Chana, P., Tapia, J., Kunstmann, C., Parrao, T., 2005. Quetiapine for insomnia in Parkinson disease: results from an open-label trial. Clin. Neuropharmacol. 28, 185–187. Malhi, G.S., Tanious, M., Das, P., Coulston, C.M., Berk, M., 2013. Potential mechanisms of action of lithium in bipolar disorder. Current understanding. CNS Drugs 27, 135–153. Maneeton, N., Maneeton, B., Srisurapanont, M., Martin, S.D., 2012. Quetiapine monotherapy in acute phase for major depressive disorder: a meta-analysis of randomized, placebo-controlled trials. BMC Psychiatry 27, 160. Millar, A., Espie, C.A., Scott, J., 2004. The sleep of remitted bipolar outpatients: a controlled naturalistic study using actigraphy. J. Affect. Disord. 80, 145–153. Nofzinger, E.A., Thase, M.E., Reynolds III, C.F., Himmelhoch, J.M., Mallinger, A., Houck, P., Kupfer, D.J., 1991. Hypersomnia in bipolar depression: a comparison with narcolepsy using the multiple sleep latency test. Am. J. Psychiatry 148, 1177–1181. Pompili, M., Rihmer, Z., Gonda, X., Serafini, G., Sher, L., Girardi, P., 2012. Early onset of action and sleep-improving effect are crucial in decreasing suicide risk: the role of quetiapine XR in the treatment of unipolar and bipolar depression. Riv. Psichiatr. 47, 489–497. Sachs, G., Chengappa, K.N., Suppes, T., Mullen, J.A., Brecher, M., Devine, N.A., Sweitzer, D.E., 2004. Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study. Bipolar Disord. 6, 213–223. Sanford, M., Keating, G.M., 2012. Quetiapine: a review of its use in the management of bipolar depression. CNS Drugs 26, 435–460. Simpson, G.M., Angus, J.W., 1970. A rating scale for extrapyramidal side effects. Acta Psychiatr. Scand. 212, 11–19. Souza, F.G., Goodwin, G.M., 1991. Lithium treatment and prophylaxis in unipolar depression: a meta-analysis. Br. J. Psychiatry 158, 666–675. Suppes, T., Datto, C., Minkwitz, M., Nordenhem, A., Walker, C., Darko, D., 2010. Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. J. Affect. Disord. 121, 106–115. Suppes, T., Marangell, L.B., Bernstein, I.H., Kelly, D.I., Fischer, E.G., Zboyan, H.A., Snow, D.E., Martinez, M., Al Jurdi, R., Shivakumar, G., Sureddi, S., Gonzalez, R., 2008. A single blind comparison of lithium and lamotrigine for the treatment of bipolar II depression. J. Affect. Disord. 111, 334–343. Swartz, H.A., Thase, M.E., 2011. Pharmacotherapy for the treatment of acute bipolar II depression: current evidence. J. Clin. Psychiatry 72, 356–366. Teicher, M.H., 1995. Actigraphy and motion analysis: new tools for psychiatry. Harv. Rev. Psychiatry 3, 18–35. Thase, M.E., Macfadden, W., Weisler, R.H., Chang, W., Paulsson, B., Khan, A., Calabrese, J.R., 2006. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study). J. Clin. Psychopharmacol. 26, 600–609. Thase, M.E., Sachs, G.S., 2000. Bipolar depression: pharmacotherapy and related therapeutic strategies. Biol. Psychiatry 48, 558–572. Todder, D., Caliskan, S., Baune, B.T., 2006. Night locomotor activity and quality of sleep in quetiapine-treated patients with depression. J. Clin. Psychopharmacol. 26, 638–642. Tondo, L., Isacsson, G., Baldessarini, R., 2003. Suicidal behaviour in bipolar disorder: risk and prevention. CNS Drugs 17, 491–511. Van Lieshout, R.J., MacQueen, G.M., 2010. Efficacy and acceptability of mood stabilisers in the treatment of acute bipolar depression: systematic review. Br. J. Psychiatry 196, 266–273. Vieta, E., Calabrese, J.R., Goikolea, J.M., Raines, S., Macfadden, W., 2007. BOLDER Study Group, 2007. Quetiapine monotherapy in the treatment of patients with bipolar I or II depression and a rapid-cycling disease course: a randomized, double-blind, placebo-controlled study. Bipolar Disord. 9, 413–425. Walters, A.S., LeBrocq, C., Dhar, A., Hening, W., Rosen, R., Allen, R.P., Trenkwalder, C., 2003. International Restless Legs Syndrome Study Group, 2003. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. 4, 121–132. Watanabe, S., Ishino, H., Otsuki, S., 1975. Double-blind comparison of lithium carbonate and imipramine in treatment of depression. Arch. Gen. Psychiatry 32, 659–668. Wehr, T.A., Sack, D.A., Rosenthal, N.E., 1987. Sleep reduction as a final common pathway in the genesis of mania. Am. J. Psychiatry 144, 201–204. Weisler, R., Joyce, M., McGill, L., Lazarus, A., Szamosi, J., Eriksson, H., 2009. Extended release quetiapine fumarate monotherapy for major depressive disorder:

40

S.J. Kim et al. / Journal of Affective Disorders 157 (2014) 33–40

results of a double-blind, randomized, placebo-controlled study. CNS Spectr. 14, 299–313. Worrall, E.P., Moody, J.P., Peet, M., Dick, P., Smith, A., Chambers, C., Adams, M., Naylor, G.J., 1979. Controlled studies of the acute antidepressant effects of lithium. Br. J. Psychiatry 135, 255–262.

Yatham, L.N., Goldstein, J.M., Vieta, E., Bowden, C.L., Grunze, H., Post, R.M., Suppes, T., Calabrese, J.R., 2005. Atypical antipsychotics in bipolar depression: potential mechanisms of action. J. Clin. Psychiatry 66 (Suppl. 5), 40–48.