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Efficacy of olanzapine in the treatment of bipolar mania with mixed features defined by DSM-5
Journal of Affective Disorders 168 (2014) 136–141
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Research report
Efficacy of olanzapine in the treatment of bipolar mania with mixed features defined by DSM-5 Mauricio Tohen a, Roger S. McIntyre b, Shigenobu Kanba c,d, Shinji Fujikoshi e, Hideaki Katagiri f,n a
University of New Mexico, Health Sciences Center, Department of Psychiatry, Albuquerque, NM, USA University of Toronto, Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Canada c Kyushu University, Department of Neuropsychiatry, Fukuoka, Japan d East Asian Bipolar Forum, Fukuoka, Japan e Eli Lilly Japan K.K., Lilly Research Laboratories, Statistical Science, Kobe, Japan f Eli Lilly Japan K.K., Lilly Research Laboratories, Medical Science, Sannomiya Plaza Building, 7-1-5, Isogamidori, Chuo-ku, Kobe 651-0086, Japan b
art ic l e i nf o
a b s t r a c t
Article history: Received 31 May 2014 Accepted 24 June 2014 Available online 3 July 2014
Background: These analyses compared efficacy of olanzapine in patients with bipolar mania with or without mixed features, as defined in the DSM-5. Methods: Pooled data from 3 placebo-controlled olanzapine studies in patients having bipolar I disorder with manic/mixed episode were analyzed (N¼228 olanzapine; N¼ 219 placebo). Patients were categorized for mixed features by number of concurrent depressive symptoms at baseline (0, 1, and 2 [category A; without mixed features], and Z3 [category B; with mixed features]), as determined by HAM-D17 item score Z1. Depressive symptoms corresponded to 6 HAM-D17 items in the DSM-5 definition of manic episode with mixed features. Primary efficacy was evaluated by changes in the baseline-to-3-week YMRS total score. Results: Patients were categorized into A (N¼322; 72.0%) or B (N¼125; 28.0%). Mean baseline YMRS total scores were 28.1 in category A and 27.8 in category B. Least-squares mean change of YMRS total scores in categories A and B (olanzapine versus placebo) were 11.78 versus 6.86 and 13.21 versus 4.72, respectively. Patients in the olanzapine- compared with placebo-group experienced a greater decrease in YMRS total score for both categories (po0.001). An interaction between mixed features and treatment was seen in YMRS change at a 0.3 significance level (p¼0.175). Limitations: The results are from post-hoc analyses. Conclusions: Olanzapine was efficacious in the treatment of bipolar I mania, in patients both with and without mixed features, defined by DSM-5; however, greater efficacy was observed in patients with mixed features having more severe depressive symptoms. & 2014 Elsevier B.V. All rights reserved.
Keywords: Bipolar Mania Olanzapine Mixed features DSM-5
1. Introduction The longitudinal symptom structure of bipolar disorder is usually comprised of an admixture of manic and depressive symptoms. Patients with mixed episodes in bipolar disorder tend to have poor response and long-term prognosis (Tohen et al., 1990; González-Pinto et al., 2011), longer duration of illness (MartinCarrasco et al., 2012), and impaired function related to the number of episodes (Rosa et al., 2009), when compared with individuals having pure mania or depression. Subsyndromal depressive symptoms, often experienced by patients during manic episodes in bipolar disorder (Bauer et al., 2005; Goldberg et al., 2009; Judd
n
Corresponding author. Tel.: þ 81 78 242 9389; fax: þ81 78 242 9526. E-mail address: [email protected] (H. Katagiri).
http://dx.doi.org/10.1016/j.jad.2014.06.039 0165-0327/& 2014 Elsevier B.V. All rights reserved.
et al., 2012; Gitlin et al., 2011) can interfere with functional recovery after symptomatic recovery from a manic episode (Gitlin et al., 2011). In addition, the presence (Tohen et al., 1990) or emergence (Tohen et al., 2006) of subsyndromal depressive symptoms after recovery from mania increases the risk of relapse especially into depression. In the diagnosis of bipolar I disorder, mixed episode, the previous Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) required patients to meet full criteria for both mania and major depressive disorder. However, in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the new specifier “with mixed features” was introduced, to reflect the “mixed” mood state (Angst, 2013). To be diagnosed with mixed features, a patient must meet the full criteria for 1 mood (i.e., depression, mania, or hypomania) and have 3 or more symptoms of the opposite mood. This addition of the mixed-mood specifier
M. Tohen et al. / Journal of Affective Disorders 168 (2014) 136–141
allows clinicians to diagnose subthreshold expressions of depressionlike symptoms with mania or hypomania as well as subthreshold mania-like symptoms with depression, thereby increasing the possibility of improving treatment selection (Vieta and Valenti, 2013). Olanzapine has demonstrated efficacy in the treatment of manic, mixed, or depressive episodes in bipolar disorders (Katagiri et al., 2012; Tohen et al., 1999, 2000, 2002, 2003, 2012; Zajecka et al., 2002). There is little available evidence to evaluate the efficacy of olanzapine in adult patients with bipolar I disorder having manic episodes with or without mixed features as defined in DSM-5. To better understand how effective olanzapine is in patients with bipolar mania, we assessed whether there were any differences in the efficacy of olanzapine between patients with bipolar mania with and without mixed features.
2. Methods Pooled data were analyzed from 3 randomized placebocontrolled studies (Tohen et al., 1999, 2000; Katagiri et al., 2012), examining the efficacy of olanzapine in patients having bipolar I disorder with a manic/mixed episode (N ¼447). The study protocols (clinical trial registration numbers: 1028, 1729, and NCT00129220) were reviewed by the applicable Ethical Review Boards (ERBs) for the clinical sites, and the ERBs provided written approval of the study protocol and the informed consent forms. All patients provided written informed consent, and the studies were conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki, Good Clinical Practice, and applicable laws and regulations. 2.1. Study populations and study designs Study 1 was a 3-week randomized, double-blind, placebocontrolled parallel group study in patients (18–65 years old) with bipolar disorder, either manic or mixed episode (Tohen et al., 1999). The patients had manic or mixed episodes that lasted Z 2 weeks duration and had a minimum total score of 20 on the Young Mania Rating Scale (YMRS) (Young et al., 1978). Patients were randomly assigned to receive olanzapine (n ¼70) (dose range of 5–20 mg/day) or placebo (n ¼69) in a 1:1 ratio. Study 2 was a 4-week, randomized, double-blind, parallel study, conducted in patients (18–70 years old) with manic or mixed bipolar disorder (Tohen et al., 2000). At screening, patients had a minimum total score Z20 on the YMRS. Patients were randomized to olanzapine (n ¼55) (dose range of 5–20 mg/day) or placebo (n ¼60) in a 1:1 ratio. Study 3 was a randomized, double-blind, parallel-group, placebo- and haloperidol-controlled study that investigated the efficacy of olanzapine in patients (20–65 years old) with bipolar I disorder in a current manic or mixed episode (Katagiri et al., 2012). All patients had YMRS total score Z 20 at baseline. For 3 weeks, patients blindly received either olanzapine (5–20 mg/day; N¼105), haloperidol (2.5–10 mg/day; N¼20), or placebo (N¼99). For the subsequent 3 weeks, the olanzapine and haloperidol groups continued their treatment, while the placebo group switched blindly to olanzapine.
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with mixed features]), measured by HAM-D17 item score Z1 in 6 of the HAM-D17 items corresponding to mixed features defined in the DSM-5. The 6 depressive symptoms that were assessed and their corresponding HAM-D17 item symptoms, represented in parentheses, are the following: prominent dysphoria/depressed mood (i.e., depressive mood), diminished interest/pleasure (i.e., work and activities), psychomotor retardation (i.e., retardation), fatigue/loss of energy (i.e., work and activities/somatic symptoms general), feelings of worthlessness or excessive/inappropriate guilt (i.e., feelings of guilt), and recurrent thoughts of death (i.e., suicide). Rates of response and remission were assessed. Response was defined as a baseline-to-endpoint (3 weeks) reduction of Z 50% in YMRS total score. Percentage reduction (i.e., Z75%, 50% r o75%, 25%r o50%, 0% r o25%, and o0%) was calculated using the change in YMRS total score at 3 weeks from baseline. Remission was defined as a YMRS total score r12 at 3 weeks. 2.3. Statistical analyses These post-hoc analyses were based on the intent-to-treat principle, which comprised all randomized patients who took Z1 dose of olanzapine or placebo and had at least 1 valid postbaseline YMRS assessment. Missing data were imputed using last-observationcarried-forward (LOCF) methodology. A treatment effect for each category of mixed features was assessed using analysis of covariance (ANCOVA) including treatment, baseline as a factor for continuous variable, and Fisher's exact test for binomial variable. Effect size measures including number needed to treat (NNT) were also calculated based on the variable type. The interaction between mixed features and treatment was assessed using ANCOVA, including treatment, baseline, mixed features, and treatment mixed feature as factors for continuous variable, and Breslow–Day test for binomial variable. The significance level of 2-sided 5% was used for the treatment effect, and 30% was used for the interaction effect; no adjustments were conducted for multiplicity.
3. Results 3.1. Demographics The percentage of patients with mixed features measured by the number of baseline HAM-D17 items with scores Z 1 is shown in Fig. 1. The percentages of patients without and with mixed
2.2. Assessments The change in the YMRS (primary) and 17-item Hamilton Depression Rating Scale (HAM-D17) (secondary) total score from baseline to 3 weeks was used as the efficacy endpoint for treatment of mania. Patients were categorized for mixed features by the number of concurrent depressive symptoms at baseline (0, 1, and 2 [patients without mixed features], and Z3 [patients
Fig. 1. Number of patients with mixed features (N ¼ 447). Abbreviation: HAMD17 ¼ 17-item Hamilton Psychiatric Rating Scale for Depression.
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features, as defined by DSM-5, were 72.0% and 28.0%, respectively. These percentages were similar between the olanzapine and placebo groups. Baseline patient demographics and disease characteristics are shown in Table 1. At baseline, in the analysis, there were statistically significant differences (p o0.05) among patients without and with mixed features in HAM-D17 total score, age of onset, mixed episode, rapid-cycling course, and racial origin.
3.2. Change in YMRS scores Patients in the olanzapine group experienced a statistically significantly greater mean decrease in YMRS total score compared with the placebo group in the total population (po 0.001, effect size¼ 0.48) and for patients without mixed features (p o0.001, effect size ¼ 0.40) and patients with mixed features (p o0.001, effect size ¼0.72) (Table 2). There was a significant interaction between mixed features and treatment for mean changes from baseline in YMRS total score (p¼ 0.175).
3.3. Change in HAM-D17 score Patients in the olanzapine group experienced a statistically significantly greater mean decrease in HAM-D17 total score compared with the placebo group in the total population (p ¼0.010, effect size ¼0.25). Olanzapine groups for both categories showed numerically larger decrease than placebo groups. There was a numerically larger effect size in those with mixed features (effect size¼ 0.34) than without mixed features (effect size ¼0.20). There was a significant interaction between mixed features and treatment for mean changes from baseline in HAM-D17 total score (p ¼0.126).
3.4. Response The response rate of the olanzapine group was statistically significantly higher than that of the placebo group in the total population (53.1% versus 36.1%, p o0.001) and the NNT was 6. Response rates for the olanzapine group versus placebo group were 50.3% versus 39.2% (p ¼0.056) for patients without mixed features and 61.0% versus 28.8% (p o0.001) for patients with mixed features. The NNT was 10 and 4 for patients without mixed features and patients with mixed features, respectively. There was a significant interaction between mixed features and treatment for response rate (p ¼0.041) (Fig. 2). 3.5. Remission The remission rate of the olanzapine group was statistically significantly higher than that of the placebo group in the total population (p¼ 0.001) (Fig. 3) and the NNT was 7. Remission rates for the olanzapine group versus placebo group were 45.6% versus 35.9% (p ¼0.089) for patients without mixed features and 57.6% versus 27.3% (p o0.001) for patients with mixed features. The NNT was 11 for patients without mixed features and 4 for patients with mixed features. There was a significant interaction between mixed features and treatment for remission rate (p ¼0.045).
4. Discussion Mixed states are common in bipolar disorder as evidenced by a previous study by Bauer et al. (2005) who reported that clinically significant depressive symptoms, which were defined as Z2 symptoms, occurred in 94.1% of those with (hypo) mania. In another study, self-reported frequency of Z3 depressive symptoms during a manic episode was reported to occur in 39% of patients (Vieta et al., 2014), and prevalence estimations for mixed
Table 1 Baseline patient characteristics by mixed feature categories. Mixed feature categorya
Gender Females, n (%) Males, n (%) Age, mean (SD), years Range YMRS total score, mean (SD) HAM-D17 total score, mean (SD) Age at onset, mean (SD), years Psychotic features, n (%) Mixed episode, n (%) Rapid-cycling course, n (%) Yes No Racial origin, n (%) East Asian African Caucasian Others
0, 1, and 2
Z3
Total
(N¼322)
(N¼ 125)
(N¼447)
169 (52.5) 153 (47.5) 41.5 (11.4) 18–67 28.1 (6.4) 6.0 (4.5) 28.1 (10.6)d 114 (35.4) 27 (8.4)
65 (52.0) 60 (48.0) 39.2 (10.5) 19–66 27.8 (6.0) 17.5 (6.8) 23.7 (11.0)e 54 (43.2) 60 (48.0)
234 (52.3) 213 (47.7) 40.9 (11.2) 18–67 28.0 (6.3) 9.2 (7.4) 26.9 (10.9)f 168 (37.6) 87 (19.5)
45 (14.0) 277 (86.0)
56 (44.8) 69 (55.2)
101 (22.6) 346 (77.4)
o 0.001b
185 (57.5) 24 (7.5) 103 (32.0) 10 (3.1)
19 (15.2) 19 (15.2) 83 (66.4) 4 (3.2)
204 (45.6) 43 (9.6) 186 (41.6) 14 (3.1)
o 0.001b,g
p-value
1.000b 0.054c 0.710c o 0.001c o 0.001c 0.129b o 0.001b
Abbreviations: HAM-D17 ¼ 17-item Hamilton Depression Rating Scale; LOCF ¼ last observation carried forward; N ¼ number of patients with nonmissing baseline value and 3-week value (LOCF) in YMRS total score; n¼number of patients; SD ¼ standard deviation; YMRS ¼Young Mania Rating Scale. a Mixed feature was defined by number of baseline HAM-D17 item (depressed mood, work and activities, somatic symptoms general, feelings of guilt, suicide, retardation subscales) with scores Z 1. b The p-values are from Fisher's exact test. c The p-values are from analysis of variance (ANOVA) model: value ¼mixed feature. d N¼ 320. e N ¼ 124. f N ¼444. g The p-value was calculated based on 2 categories (East Asian versus Others).
c
0.25 1.17 ( 2.07, 0.28) 0.010 Total
Z3
Mixed feature was defined by number of baseline HAM-D17 item (depressed mood, work and activities, somatic symptoms general, feelings of guilt, suicide, retardation subscales) with scores Z 1. Analysis of covariance (ANCOVA) model: change ¼ treatment þbaseline. Analysis of covariance (ANCOVA) model: change ¼ treatment þbaseline þ mixed featureþmixed feature treatment. b
a
0.34 2.29 ( 4.70, 0.11) 0.061
–
0.20 0.74 ( 1.57, 0.09) 0.080 0, 1, and 2 HAM-D17
Total
Z3
Abbreviations: CI ¼confidence interval; HAM-D17 ¼ 17-item Hamilton Psychiatric Rating Scale for Depression; LOCF ¼last observation carried forward; LS Mean ¼least-squares mean; N¼ number of patients with nonmissing baseline value and 3-week value (LOCF) in YMRS total score or HAM-D17 total score; SD ¼standard deviation; SE ¼ standard error; YMRS ¼Young Mania Rating Scale.
–
0.126
0.48 5.93 ( 8.21, 3.65) o0.001
0.72 8.48 ( 12.69, 4.27) o0.001
–
0.759
–
0.175 0.801 0.40 4.93 ( 7.65, 2.20)
6.86 (1.004) 11.78 (0.955) 4.72 (1.459) 13.21 (1.543) 6.22 (0.828) 12.15 (0.811) 0.91 (0.306) 1.65 (0.291) 4.56 (0.838) 6.86 (0.879) 1.91 (0.325) 3.09 (0.318) 6.36 6.46 5.96 6.08 6.24 6.35 4.52 4.56 6.71 6.91 7.49 7.27 27.94 28.22 27.45 28.27 27.79 28.23 5.99 5.99 17.63 17.41 9.48 8.96 153 169 66 59 219 228 152 168 65 59 217 227 YMRS
0, 1, and 2
Placebo Olanzapine Placebo Olanzapine Placebo Olanzapine Placebo Olanzapine Placebo Olanzapine Placebo Olanzapine
Treatment difference
LS mean difference (95% CI)b p-valueb LS mean (SE)b Mean
SD
Change Baseline N Treatment Mixed feature categorya
Table 2 Change in YMRS/HAM-D17 total score at 3 weeks (LOCF) by mixed feature categories.
o0.001
Mixed feature
Effect sizeb
p-valuec
Mixed feature treatment
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episodes were 23.2% according to clinical judgment (Vieta and Morralla, 2010). Despite a difference in methodology, in this analysis, using clinical trials for manic/mixed episodes, 39.1% of patients reported 2 or more depressive symptoms. In this report, we applied Z3 comorbid symptoms as mixed features based on the DSM-5, and 28% of patients met the criterion as “with mixed features”. Though definitions of mixed states are not well established, it is clear that mixed state is common in patients with bipolar disorders. We also observed that patients with mixed features had a younger age of onset (24 years versus 28 years) and a higher percentage of rapid-cycling course (45% versus 14%). Other studies have also reported that mixed depressive patients have an earlier onset of age (Swann et al., 2007, Goldberg et al., 2009) as well as more rapid-cycling (Azorin et al., 2009), compared with patients with nonmixed depression. These findings suggest that a greater illness complexity may be observed in individuals with mixed depressive features. In a previous study that assessed response of olanzapine versus placebo in bipolar I manic patients with dysphoric and nondysphoric mania, YMRS improvement in olanzapine-treated patients in comparison with placebo recipients did not differ between those with and without baseline dysphoria which was defined as HAM-D21 score of 420 (Baker et al., 2003). However, in our study following the DSM-5 definition, olanzapine showed significant improvement, in both patients with and without mixed features, compared with placebo, and olanzapine compared with placebo showed greater improvement in patients with mixed features than in patients without mixed features in terms of the YMRS change. In parallel, similar results were seen in response and remission rates. In addition, although olanzapine did not show statistically significant improvement in depressive symptoms in both populations perhaps due to low statistical power, depressive symptoms did tend to improve, suggesting that olanzapine may also work on depressive symptoms in both populations. This result is consistent with olanzapine efficacy in bipolar depression (Tohen et al., 2003, 2012). Our results suggest that olanzapine may be efficacious not only in patients without mixed features but also in patients with mixed features as defined by DSM-5, and importantly that olanzapine may be more effective in patients with mixed features. This may validate the threshold of 3 depressive symptoms for mixed features defined in DSM-5 in terms of treatment response. In a recent post-hoc analysis of asenapine studies including olanzapine in patients with bipolar I disorder associated with manic/mixed episodes and Z3 depressive features, in olanzapine-treated patients, the Montgomery–Asberg Depression Scale remission (score r12) rate decreased with increasing severity of depressive symptoms among patients with mixed features, demonstrating that increasing depression symptom severity may be associated with poorer outcome (McIntyre et al., 2013). Therefore, further investigation is necessary to get a better understanding of the efficacy of olanzapine and other atypical antipsychotics in patients with bipolar I disorder who have manic episodes with mixed features.
4.1. Limitations Some limitations to these analyses should be considered when interpreting these findings. The generalizability of the results may be impacted by the inclusion and exclusion criteria inherent in any clinical trial. This was a post-hoc analysis and the studies were not designed to examine the influence of mixed features. The current assessment is a proxied definition and is not the precise definition of the exact criteria in the DSM-5 (i.e., the criteria of duration were not considered). The severity of mixed features was not considered.
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Fig. 2. Response rate by mixed feature categories. Mixed feature was defined by number of baseline HAM-D17 item (i.e., depressed mood, work and activities, somatic symptoms general, feelings of guilt, suicide, and retardation subscales) with scores Z 1. Response was defined as patients with a Z 50% reduction in YMRS total score at 3 weeks (LOCF) from baseline. The p-values at the top of paired bar graphs indicate the results of comparing responders in the placebo and olanzapine groups, and are from Fisher's exact test. Interaction p-value is from Breslow–Day test. Abbreviations: HAM-D17 ¼17-item Hamilton Psychiatric Rating Scale for Depression; LOCF ¼last observation carried forward; YMRS¼ Young Mania Rating Scale.
criteria would be beneficial in the selection of treatment of bipolar mania.
Conflict of interest Dr. Tohen has been a consultant or has received honoraria from AstraZeneca, Abbott, Bristol-Meyers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Alkermes, Otsuka, Roche, Lundbeck, Elan, Merck, Pamlab, Alexza, Forest, Sunovion, and Wyeth. Dr. Tohen is a former full-time employee of Eli Lilly (1997–2008). The spouse of Dr. Tohen is a former employee of Eli Lilly (1998–2013). Dr. McIntyre is a consultant and/or has received speaker fees and/or sits on the advisory board and/ or receives research funding from Merck, AstraZeneca, Eli Lilly, Janssen Ortho, Sunovion, Pfizer, Lundbeck, Shire, Forest, Bristol-Meyers Squibb, and Otsuka. Dr. Kanba received grants and research support from GlaxoSmithKline, Pfizer, Tanabe-Mitsubishi, Kyowa-Hakko, Astellas, Meiji, and Otsuka; was a consultant for Eli Lilly, GlaxoSmithKline, Pfizer, Ono, Asahi-kasei, Shionogi, and Otsuka; and received honoraria from Eli Lilly, GlaxoSmithKline, Pfizer, Janssen, Meiji, Kyowa-Hakko, Dainippon-Sumitomo, Otsuka, Eisai, Taisho-Toyama, and Astellas. Drs. Fujikoshi and Katagiri are full-time employees and shareholders of Eli Lilly. Fig. 3. Remission rate by mixed feature categories. Mixed feature was defined by number of baseline HAM-D17 item (i.e., depressed mood, work and activities, somatic symptoms general, feelings of guilt, suicide, and retardation subscales) with scores Z 1. Remission was defined as the patient whose YMRS total score was r 12 at 3 weeks (LOCF). Treatment comparison p-values are from Fisher's exact test. Interaction p-value is from Breslow–Day test. Abbreviations: HAM-D17 ¼ 17-item Hamilton Psychiatric Rating Scale for Depression; LOCF ¼last observation carried forward; YMRS¼ Young Mania Rating Scale.
Role of funding source This manuscript is sponsored by/supported by Eli Lilly and Company.
Acknowledgment We thank Miss Sofue Yamamoto and Deborah D’souza, Ph.D., MBA, who assisted with the preparation of the manuscript, and Angela Lorio, ELS who assisted with the editing of the manuscript.
4.2. Conclusions Olanzapine was efficacious in the treatment of bipolar I mania, in both patients without and with mixed features, which were defined after the DSM-5. However, greater efficacy was seen in patients with mixed features who had more severe depressive symptoms. These results suggest that the DSM-5 mixed feature
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Tohen, M., Waternaux, C.M., Tsuang, M.T., 1990. Outcome in mania. A 4-year prospective follow-up of 75 patients utilizing survival analysis. Arch. Gen. Psychiatry 47, 1106–1111. Tohen, M., Sanger, T.M., McElroy, S.L., Tollefson, G.D., Chengappa, R., Daniel, D.G., Petty, F., Centorrino, F., Wang, R., Grundy, S.L., Greaney, M.G., Jacobs, T.G., David, S.R., Toma, V., 1999. Olanzapine versus placebo in the treatment of acute mania. Am. J. Psychiatry 156, 702–709. Tohen, M., Jacobs, T.G., Grundy, S.L., McElroy, S.L, Banov, M.C., Janicak, P.G., Sanger, T., Risser, R., Zhang, F., Toma, V., Francis, J., Tollefson, G.D., Breier, A., 2000. Efficacy of olanzapine in acute bipolar mania. A double-blind, placebo-controlled study. Arch. Gen. Psychiatry 57, 841–849. Tohen, M., Baker, R.W., Altshuler, L.L., Zarate, C.A., Suppes, T., Ketter, T.A., Milton, D.R., Risser, R., Gilmore, J.A., Breier, A., Tollefson, G.A., 2002. Olanzapine versus divalproex in the treatment of acute mania. Am. J. Psychiatry 159, 1011–1017. Tohen, M., Vieta, E., Calabrese, J., Ketter, T.A., Sachs, G., Bowden, C., Mitchell, P.B., Centorrino, F., Risser, R., Baker, R.W., Evans, A.R., Beymer, K., Dube, S., Tollefson, G.D., Breier, A., 2003. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch. Gen. Psychiatry 60, 1079–1088. Tohen, M., Bowden, C.L., Calabrese, J.R., Lin, D., Forrester, T.D., Sachs, G.S., Koukopoulos, A., Yatham, L., Grunze, H., 2006. Influence of sub-syndromal symptoms after remission from manic or mixed episodes. Br. J. Psychiatry 189, 515–519. Tohen, M., McDonnell, D.P., Case, M., Kanba, S., Ha, K., Fang, Y.R., Katagiri, H., Gomez, J.C., 2012. Randomised, double-blind, placebo-controlled study of olanzapine in patients with bipolar I depression. Br. J. Psychiatry 201, 376–382. Vieta, E., Morralla, C., 2010. Prevalence of mixed mania using 3 definitions. J. Affect. Disord. 125, 61–73. Vieta, E., Valenti, M., 2013. Mixed states in DSM-5: implications for clinical care, education, and research. J. Affect. Disord. 148, 28–36. Vieta, E., Grunze, H., Azorin, J., Fagiolini, A., 2014. Phenomenology of manic episodes according to the presence or absence of depressive features as defined in DSM-5: results from the IMPACT self-reported online survey. J. Affect. Disord. 156, 206–213. Young, R.C., Biggs, J.T., Ziegler, V.E., Meyer., D.A., 1978. A rating scale for mania: reliability, validity and sensitivity. Br J. Psychiatry 133, 429–435. Zajecka, J.M., Weisler, R., Sachs, G., Swann, A.C., Wozniak, P., Sommerville, E.A., 2002. A comparison of the efficacy, safety, and tolerabilty of divalproex sodium and olanzapine in the treatment of bipolar disorder. J. Clin. Psychiatry 63, 1148–1155.
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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
Efficacy of olanzapine in the treatment of bipolar mania with mixed features defined by DSM-5 Mauricio Tohen a, Roger S. McIntyre b, Shigenobu Kanba c,d, Shinji Fujikoshi e, Hideaki Katagiri f,n a
University of New Mexico, Health Sciences Center, Department of Psychiatry, Albuquerque, NM, USA University of Toronto, Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Canada c Kyushu University, Department of Neuropsychiatry, Fukuoka, Japan d East Asian Bipolar Forum, Fukuoka, Japan e Eli Lilly Japan K.K., Lilly Research Laboratories, Statistical Science, Kobe, Japan f Eli Lilly Japan K.K., Lilly Research Laboratories, Medical Science, Sannomiya Plaza Building, 7-1-5, Isogamidori, Chuo-ku, Kobe 651-0086, Japan b
art ic l e i nf o
a b s t r a c t
Article history: Received 31 May 2014 Accepted 24 June 2014 Available online 3 July 2014
Background: These analyses compared efficacy of olanzapine in patients with bipolar mania with or without mixed features, as defined in the DSM-5. Methods: Pooled data from 3 placebo-controlled olanzapine studies in patients having bipolar I disorder with manic/mixed episode were analyzed (N¼228 olanzapine; N¼ 219 placebo). Patients were categorized for mixed features by number of concurrent depressive symptoms at baseline (0, 1, and 2 [category A; without mixed features], and Z3 [category B; with mixed features]), as determined by HAM-D17 item score Z1. Depressive symptoms corresponded to 6 HAM-D17 items in the DSM-5 definition of manic episode with mixed features. Primary efficacy was evaluated by changes in the baseline-to-3-week YMRS total score. Results: Patients were categorized into A (N¼322; 72.0%) or B (N¼125; 28.0%). Mean baseline YMRS total scores were 28.1 in category A and 27.8 in category B. Least-squares mean change of YMRS total scores in categories A and B (olanzapine versus placebo) were 11.78 versus 6.86 and 13.21 versus 4.72, respectively. Patients in the olanzapine- compared with placebo-group experienced a greater decrease in YMRS total score for both categories (po0.001). An interaction between mixed features and treatment was seen in YMRS change at a 0.3 significance level (p¼0.175). Limitations: The results are from post-hoc analyses. Conclusions: Olanzapine was efficacious in the treatment of bipolar I mania, in patients both with and without mixed features, defined by DSM-5; however, greater efficacy was observed in patients with mixed features having more severe depressive symptoms. & 2014 Elsevier B.V. All rights reserved.
Keywords: Bipolar Mania Olanzapine Mixed features DSM-5
1. Introduction The longitudinal symptom structure of bipolar disorder is usually comprised of an admixture of manic and depressive symptoms. Patients with mixed episodes in bipolar disorder tend to have poor response and long-term prognosis (Tohen et al., 1990; González-Pinto et al., 2011), longer duration of illness (MartinCarrasco et al., 2012), and impaired function related to the number of episodes (Rosa et al., 2009), when compared with individuals having pure mania or depression. Subsyndromal depressive symptoms, often experienced by patients during manic episodes in bipolar disorder (Bauer et al., 2005; Goldberg et al., 2009; Judd
n
Corresponding author. Tel.: þ 81 78 242 9389; fax: þ81 78 242 9526. E-mail address: [email protected] (H. Katagiri).
http://dx.doi.org/10.1016/j.jad.2014.06.039 0165-0327/& 2014 Elsevier B.V. All rights reserved.
et al., 2012; Gitlin et al., 2011) can interfere with functional recovery after symptomatic recovery from a manic episode (Gitlin et al., 2011). In addition, the presence (Tohen et al., 1990) or emergence (Tohen et al., 2006) of subsyndromal depressive symptoms after recovery from mania increases the risk of relapse especially into depression. In the diagnosis of bipolar I disorder, mixed episode, the previous Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) required patients to meet full criteria for both mania and major depressive disorder. However, in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the new specifier “with mixed features” was introduced, to reflect the “mixed” mood state (Angst, 2013). To be diagnosed with mixed features, a patient must meet the full criteria for 1 mood (i.e., depression, mania, or hypomania) and have 3 or more symptoms of the opposite mood. This addition of the mixed-mood specifier
M. Tohen et al. / Journal of Affective Disorders 168 (2014) 136–141
allows clinicians to diagnose subthreshold expressions of depressionlike symptoms with mania or hypomania as well as subthreshold mania-like symptoms with depression, thereby increasing the possibility of improving treatment selection (Vieta and Valenti, 2013). Olanzapine has demonstrated efficacy in the treatment of manic, mixed, or depressive episodes in bipolar disorders (Katagiri et al., 2012; Tohen et al., 1999, 2000, 2002, 2003, 2012; Zajecka et al., 2002). There is little available evidence to evaluate the efficacy of olanzapine in adult patients with bipolar I disorder having manic episodes with or without mixed features as defined in DSM-5. To better understand how effective olanzapine is in patients with bipolar mania, we assessed whether there were any differences in the efficacy of olanzapine between patients with bipolar mania with and without mixed features.
2. Methods Pooled data were analyzed from 3 randomized placebocontrolled studies (Tohen et al., 1999, 2000; Katagiri et al., 2012), examining the efficacy of olanzapine in patients having bipolar I disorder with a manic/mixed episode (N ¼447). The study protocols (clinical trial registration numbers: 1028, 1729, and NCT00129220) were reviewed by the applicable Ethical Review Boards (ERBs) for the clinical sites, and the ERBs provided written approval of the study protocol and the informed consent forms. All patients provided written informed consent, and the studies were conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki, Good Clinical Practice, and applicable laws and regulations. 2.1. Study populations and study designs Study 1 was a 3-week randomized, double-blind, placebocontrolled parallel group study in patients (18–65 years old) with bipolar disorder, either manic or mixed episode (Tohen et al., 1999). The patients had manic or mixed episodes that lasted Z 2 weeks duration and had a minimum total score of 20 on the Young Mania Rating Scale (YMRS) (Young et al., 1978). Patients were randomly assigned to receive olanzapine (n ¼70) (dose range of 5–20 mg/day) or placebo (n ¼69) in a 1:1 ratio. Study 2 was a 4-week, randomized, double-blind, parallel study, conducted in patients (18–70 years old) with manic or mixed bipolar disorder (Tohen et al., 2000). At screening, patients had a minimum total score Z20 on the YMRS. Patients were randomized to olanzapine (n ¼55) (dose range of 5–20 mg/day) or placebo (n ¼60) in a 1:1 ratio. Study 3 was a randomized, double-blind, parallel-group, placebo- and haloperidol-controlled study that investigated the efficacy of olanzapine in patients (20–65 years old) with bipolar I disorder in a current manic or mixed episode (Katagiri et al., 2012). All patients had YMRS total score Z 20 at baseline. For 3 weeks, patients blindly received either olanzapine (5–20 mg/day; N¼105), haloperidol (2.5–10 mg/day; N¼20), or placebo (N¼99). For the subsequent 3 weeks, the olanzapine and haloperidol groups continued their treatment, while the placebo group switched blindly to olanzapine.
137
with mixed features]), measured by HAM-D17 item score Z1 in 6 of the HAM-D17 items corresponding to mixed features defined in the DSM-5. The 6 depressive symptoms that were assessed and their corresponding HAM-D17 item symptoms, represented in parentheses, are the following: prominent dysphoria/depressed mood (i.e., depressive mood), diminished interest/pleasure (i.e., work and activities), psychomotor retardation (i.e., retardation), fatigue/loss of energy (i.e., work and activities/somatic symptoms general), feelings of worthlessness or excessive/inappropriate guilt (i.e., feelings of guilt), and recurrent thoughts of death (i.e., suicide). Rates of response and remission were assessed. Response was defined as a baseline-to-endpoint (3 weeks) reduction of Z 50% in YMRS total score. Percentage reduction (i.e., Z75%, 50% r o75%, 25%r o50%, 0% r o25%, and o0%) was calculated using the change in YMRS total score at 3 weeks from baseline. Remission was defined as a YMRS total score r12 at 3 weeks. 2.3. Statistical analyses These post-hoc analyses were based on the intent-to-treat principle, which comprised all randomized patients who took Z1 dose of olanzapine or placebo and had at least 1 valid postbaseline YMRS assessment. Missing data were imputed using last-observationcarried-forward (LOCF) methodology. A treatment effect for each category of mixed features was assessed using analysis of covariance (ANCOVA) including treatment, baseline as a factor for continuous variable, and Fisher's exact test for binomial variable. Effect size measures including number needed to treat (NNT) were also calculated based on the variable type. The interaction between mixed features and treatment was assessed using ANCOVA, including treatment, baseline, mixed features, and treatment mixed feature as factors for continuous variable, and Breslow–Day test for binomial variable. The significance level of 2-sided 5% was used for the treatment effect, and 30% was used for the interaction effect; no adjustments were conducted for multiplicity.
3. Results 3.1. Demographics The percentage of patients with mixed features measured by the number of baseline HAM-D17 items with scores Z 1 is shown in Fig. 1. The percentages of patients without and with mixed
2.2. Assessments The change in the YMRS (primary) and 17-item Hamilton Depression Rating Scale (HAM-D17) (secondary) total score from baseline to 3 weeks was used as the efficacy endpoint for treatment of mania. Patients were categorized for mixed features by the number of concurrent depressive symptoms at baseline (0, 1, and 2 [patients without mixed features], and Z3 [patients
Fig. 1. Number of patients with mixed features (N ¼ 447). Abbreviation: HAMD17 ¼ 17-item Hamilton Psychiatric Rating Scale for Depression.
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features, as defined by DSM-5, were 72.0% and 28.0%, respectively. These percentages were similar between the olanzapine and placebo groups. Baseline patient demographics and disease characteristics are shown in Table 1. At baseline, in the analysis, there were statistically significant differences (p o0.05) among patients without and with mixed features in HAM-D17 total score, age of onset, mixed episode, rapid-cycling course, and racial origin.
3.2. Change in YMRS scores Patients in the olanzapine group experienced a statistically significantly greater mean decrease in YMRS total score compared with the placebo group in the total population (po 0.001, effect size¼ 0.48) and for patients without mixed features (p o0.001, effect size ¼ 0.40) and patients with mixed features (p o0.001, effect size ¼0.72) (Table 2). There was a significant interaction between mixed features and treatment for mean changes from baseline in YMRS total score (p¼ 0.175).
3.3. Change in HAM-D17 score Patients in the olanzapine group experienced a statistically significantly greater mean decrease in HAM-D17 total score compared with the placebo group in the total population (p ¼0.010, effect size ¼0.25). Olanzapine groups for both categories showed numerically larger decrease than placebo groups. There was a numerically larger effect size in those with mixed features (effect size¼ 0.34) than without mixed features (effect size ¼0.20). There was a significant interaction between mixed features and treatment for mean changes from baseline in HAM-D17 total score (p ¼0.126).
3.4. Response The response rate of the olanzapine group was statistically significantly higher than that of the placebo group in the total population (53.1% versus 36.1%, p o0.001) and the NNT was 6. Response rates for the olanzapine group versus placebo group were 50.3% versus 39.2% (p ¼0.056) for patients without mixed features and 61.0% versus 28.8% (p o0.001) for patients with mixed features. The NNT was 10 and 4 for patients without mixed features and patients with mixed features, respectively. There was a significant interaction between mixed features and treatment for response rate (p ¼0.041) (Fig. 2). 3.5. Remission The remission rate of the olanzapine group was statistically significantly higher than that of the placebo group in the total population (p¼ 0.001) (Fig. 3) and the NNT was 7. Remission rates for the olanzapine group versus placebo group were 45.6% versus 35.9% (p ¼0.089) for patients without mixed features and 57.6% versus 27.3% (p o0.001) for patients with mixed features. The NNT was 11 for patients without mixed features and 4 for patients with mixed features. There was a significant interaction between mixed features and treatment for remission rate (p ¼0.045).
4. Discussion Mixed states are common in bipolar disorder as evidenced by a previous study by Bauer et al. (2005) who reported that clinically significant depressive symptoms, which were defined as Z2 symptoms, occurred in 94.1% of those with (hypo) mania. In another study, self-reported frequency of Z3 depressive symptoms during a manic episode was reported to occur in 39% of patients (Vieta et al., 2014), and prevalence estimations for mixed
Table 1 Baseline patient characteristics by mixed feature categories. Mixed feature categorya
Gender Females, n (%) Males, n (%) Age, mean (SD), years Range YMRS total score, mean (SD) HAM-D17 total score, mean (SD) Age at onset, mean (SD), years Psychotic features, n (%) Mixed episode, n (%) Rapid-cycling course, n (%) Yes No Racial origin, n (%) East Asian African Caucasian Others
0, 1, and 2
Z3
Total
(N¼322)
(N¼ 125)
(N¼447)
169 (52.5) 153 (47.5) 41.5 (11.4) 18–67 28.1 (6.4) 6.0 (4.5) 28.1 (10.6)d 114 (35.4) 27 (8.4)
65 (52.0) 60 (48.0) 39.2 (10.5) 19–66 27.8 (6.0) 17.5 (6.8) 23.7 (11.0)e 54 (43.2) 60 (48.0)
234 (52.3) 213 (47.7) 40.9 (11.2) 18–67 28.0 (6.3) 9.2 (7.4) 26.9 (10.9)f 168 (37.6) 87 (19.5)
45 (14.0) 277 (86.0)
56 (44.8) 69 (55.2)
101 (22.6) 346 (77.4)
o 0.001b
185 (57.5) 24 (7.5) 103 (32.0) 10 (3.1)
19 (15.2) 19 (15.2) 83 (66.4) 4 (3.2)
204 (45.6) 43 (9.6) 186 (41.6) 14 (3.1)
o 0.001b,g
p-value
1.000b 0.054c 0.710c o 0.001c o 0.001c 0.129b o 0.001b
Abbreviations: HAM-D17 ¼ 17-item Hamilton Depression Rating Scale; LOCF ¼ last observation carried forward; N ¼ number of patients with nonmissing baseline value and 3-week value (LOCF) in YMRS total score; n¼number of patients; SD ¼ standard deviation; YMRS ¼Young Mania Rating Scale. a Mixed feature was defined by number of baseline HAM-D17 item (depressed mood, work and activities, somatic symptoms general, feelings of guilt, suicide, retardation subscales) with scores Z 1. b The p-values are from Fisher's exact test. c The p-values are from analysis of variance (ANOVA) model: value ¼mixed feature. d N¼ 320. e N ¼ 124. f N ¼444. g The p-value was calculated based on 2 categories (East Asian versus Others).
c
0.25 1.17 ( 2.07, 0.28) 0.010 Total
Z3
Mixed feature was defined by number of baseline HAM-D17 item (depressed mood, work and activities, somatic symptoms general, feelings of guilt, suicide, retardation subscales) with scores Z 1. Analysis of covariance (ANCOVA) model: change ¼ treatment þbaseline. Analysis of covariance (ANCOVA) model: change ¼ treatment þbaseline þ mixed featureþmixed feature treatment. b
a
0.34 2.29 ( 4.70, 0.11) 0.061
–
0.20 0.74 ( 1.57, 0.09) 0.080 0, 1, and 2 HAM-D17
Total
Z3
Abbreviations: CI ¼confidence interval; HAM-D17 ¼ 17-item Hamilton Psychiatric Rating Scale for Depression; LOCF ¼last observation carried forward; LS Mean ¼least-squares mean; N¼ number of patients with nonmissing baseline value and 3-week value (LOCF) in YMRS total score or HAM-D17 total score; SD ¼standard deviation; SE ¼ standard error; YMRS ¼Young Mania Rating Scale.
–
0.126
0.48 5.93 ( 8.21, 3.65) o0.001
0.72 8.48 ( 12.69, 4.27) o0.001
–
0.759
–
0.175 0.801 0.40 4.93 ( 7.65, 2.20)
6.86 (1.004) 11.78 (0.955) 4.72 (1.459) 13.21 (1.543) 6.22 (0.828) 12.15 (0.811) 0.91 (0.306) 1.65 (0.291) 4.56 (0.838) 6.86 (0.879) 1.91 (0.325) 3.09 (0.318) 6.36 6.46 5.96 6.08 6.24 6.35 4.52 4.56 6.71 6.91 7.49 7.27 27.94 28.22 27.45 28.27 27.79 28.23 5.99 5.99 17.63 17.41 9.48 8.96 153 169 66 59 219 228 152 168 65 59 217 227 YMRS
0, 1, and 2
Placebo Olanzapine Placebo Olanzapine Placebo Olanzapine Placebo Olanzapine Placebo Olanzapine Placebo Olanzapine
Treatment difference
LS mean difference (95% CI)b p-valueb LS mean (SE)b Mean
SD
Change Baseline N Treatment Mixed feature categorya
Table 2 Change in YMRS/HAM-D17 total score at 3 weeks (LOCF) by mixed feature categories.
o0.001
Mixed feature
Effect sizeb
p-valuec
Mixed feature treatment
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episodes were 23.2% according to clinical judgment (Vieta and Morralla, 2010). Despite a difference in methodology, in this analysis, using clinical trials for manic/mixed episodes, 39.1% of patients reported 2 or more depressive symptoms. In this report, we applied Z3 comorbid symptoms as mixed features based on the DSM-5, and 28% of patients met the criterion as “with mixed features”. Though definitions of mixed states are not well established, it is clear that mixed state is common in patients with bipolar disorders. We also observed that patients with mixed features had a younger age of onset (24 years versus 28 years) and a higher percentage of rapid-cycling course (45% versus 14%). Other studies have also reported that mixed depressive patients have an earlier onset of age (Swann et al., 2007, Goldberg et al., 2009) as well as more rapid-cycling (Azorin et al., 2009), compared with patients with nonmixed depression. These findings suggest that a greater illness complexity may be observed in individuals with mixed depressive features. In a previous study that assessed response of olanzapine versus placebo in bipolar I manic patients with dysphoric and nondysphoric mania, YMRS improvement in olanzapine-treated patients in comparison with placebo recipients did not differ between those with and without baseline dysphoria which was defined as HAM-D21 score of 420 (Baker et al., 2003). However, in our study following the DSM-5 definition, olanzapine showed significant improvement, in both patients with and without mixed features, compared with placebo, and olanzapine compared with placebo showed greater improvement in patients with mixed features than in patients without mixed features in terms of the YMRS change. In parallel, similar results were seen in response and remission rates. In addition, although olanzapine did not show statistically significant improvement in depressive symptoms in both populations perhaps due to low statistical power, depressive symptoms did tend to improve, suggesting that olanzapine may also work on depressive symptoms in both populations. This result is consistent with olanzapine efficacy in bipolar depression (Tohen et al., 2003, 2012). Our results suggest that olanzapine may be efficacious not only in patients without mixed features but also in patients with mixed features as defined by DSM-5, and importantly that olanzapine may be more effective in patients with mixed features. This may validate the threshold of 3 depressive symptoms for mixed features defined in DSM-5 in terms of treatment response. In a recent post-hoc analysis of asenapine studies including olanzapine in patients with bipolar I disorder associated with manic/mixed episodes and Z3 depressive features, in olanzapine-treated patients, the Montgomery–Asberg Depression Scale remission (score r12) rate decreased with increasing severity of depressive symptoms among patients with mixed features, demonstrating that increasing depression symptom severity may be associated with poorer outcome (McIntyre et al., 2013). Therefore, further investigation is necessary to get a better understanding of the efficacy of olanzapine and other atypical antipsychotics in patients with bipolar I disorder who have manic episodes with mixed features.
4.1. Limitations Some limitations to these analyses should be considered when interpreting these findings. The generalizability of the results may be impacted by the inclusion and exclusion criteria inherent in any clinical trial. This was a post-hoc analysis and the studies were not designed to examine the influence of mixed features. The current assessment is a proxied definition and is not the precise definition of the exact criteria in the DSM-5 (i.e., the criteria of duration were not considered). The severity of mixed features was not considered.
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Fig. 2. Response rate by mixed feature categories. Mixed feature was defined by number of baseline HAM-D17 item (i.e., depressed mood, work and activities, somatic symptoms general, feelings of guilt, suicide, and retardation subscales) with scores Z 1. Response was defined as patients with a Z 50% reduction in YMRS total score at 3 weeks (LOCF) from baseline. The p-values at the top of paired bar graphs indicate the results of comparing responders in the placebo and olanzapine groups, and are from Fisher's exact test. Interaction p-value is from Breslow–Day test. Abbreviations: HAM-D17 ¼17-item Hamilton Psychiatric Rating Scale for Depression; LOCF ¼last observation carried forward; YMRS¼ Young Mania Rating Scale.
criteria would be beneficial in the selection of treatment of bipolar mania.
Conflict of interest Dr. Tohen has been a consultant or has received honoraria from AstraZeneca, Abbott, Bristol-Meyers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Alkermes, Otsuka, Roche, Lundbeck, Elan, Merck, Pamlab, Alexza, Forest, Sunovion, and Wyeth. Dr. Tohen is a former full-time employee of Eli Lilly (1997–2008). The spouse of Dr. Tohen is a former employee of Eli Lilly (1998–2013). Dr. McIntyre is a consultant and/or has received speaker fees and/or sits on the advisory board and/ or receives research funding from Merck, AstraZeneca, Eli Lilly, Janssen Ortho, Sunovion, Pfizer, Lundbeck, Shire, Forest, Bristol-Meyers Squibb, and Otsuka. Dr. Kanba received grants and research support from GlaxoSmithKline, Pfizer, Tanabe-Mitsubishi, Kyowa-Hakko, Astellas, Meiji, and Otsuka; was a consultant for Eli Lilly, GlaxoSmithKline, Pfizer, Ono, Asahi-kasei, Shionogi, and Otsuka; and received honoraria from Eli Lilly, GlaxoSmithKline, Pfizer, Janssen, Meiji, Kyowa-Hakko, Dainippon-Sumitomo, Otsuka, Eisai, Taisho-Toyama, and Astellas. Drs. Fujikoshi and Katagiri are full-time employees and shareholders of Eli Lilly. Fig. 3. Remission rate by mixed feature categories. Mixed feature was defined by number of baseline HAM-D17 item (i.e., depressed mood, work and activities, somatic symptoms general, feelings of guilt, suicide, and retardation subscales) with scores Z 1. Remission was defined as the patient whose YMRS total score was r 12 at 3 weeks (LOCF). Treatment comparison p-values are from Fisher's exact test. Interaction p-value is from Breslow–Day test. Abbreviations: HAM-D17 ¼ 17-item Hamilton Psychiatric Rating Scale for Depression; LOCF ¼last observation carried forward; YMRS¼ Young Mania Rating Scale.
Role of funding source This manuscript is sponsored by/supported by Eli Lilly and Company.
Acknowledgment We thank Miss Sofue Yamamoto and Deborah D’souza, Ph.D., MBA, who assisted with the preparation of the manuscript, and Angela Lorio, ELS who assisted with the editing of the manuscript.
4.2. Conclusions Olanzapine was efficacious in the treatment of bipolar I mania, in both patients without and with mixed features, which were defined after the DSM-5. However, greater efficacy was seen in patients with mixed features who had more severe depressive symptoms. These results suggest that the DSM-5 mixed feature
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