Placebo-controlled trials do not find association of olanzapine with exacerbation of bipolar mania

Journal of Affective Disorders 73 (2003) 147–153 www.elsevier.com / locate / jad

Research report

Placebo-controlled trials do not find association of olanzapine with exacerbation of bipolar mania ´ R. Milton a , Virginia L. Stauffer a , Alan Gelenberg b , Robert W. Baker a , *, Denai Mauricio Tohen a,c a

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Drop Code 4133, Indianapolis, IN 46285, USA b University of Arizona College of Medicine, Tucson, Arizona, USA c McLean Hospital, Harvard Medical School, Belmont, MA, USA Received 23 January 2002; accepted 6 June 2002

Abstract Background: Published case reports describe apparent induction or exacerbation of manic-like symptoms during treatment with the atypical antipsychotics olanzapine and risperidone. To date, such reports are from uncontrolled clinical experience and therefore cannot clarify whether the atypical antipsychotics caused such manic-like states or simply failed to prevent them. Presumably, bipolar patients would be at increased risk for this putative adverse event. Therefore, we evaluated the potential of olanzapine to exacerbate symptoms of mania compared to placebo during treatment of bipolar mania. Methods: Two inpatient, double-blind, randomized trials investigating the efficacy of olanzapine 5–20 mg daily versus placebo for the treatment of acute mania were combined. Two hundred and fifty-four subjects participated (placebo n 5 129; olanzapine n 5 125) in the two studies. Severity of mania was quantified with the 11-item Young-Mania Rating Scale (Y-MRS). In a post-hoc analysis, after double-blind therapy up to 3 weeks, categorical comparison of olanzapine and placebo groups was made for any worsening and worsening by 10 or 20% from baseline Y-MRS scores (LOCF). Results: The percentage of subjects with exacerbation at endpoint were: any worsening, placebo 37.7%, olanzapine 21.8% (P 5 0.005); $ 10% worsening, placebo 24.6%, olanzapine 14.5% (P 5 0.039); $ 20% worsening, placebo 15.6%, olanzapine 8.1% (P 5 0.064). Conclusion: Mania rating scores worsened for some patients during olanzapine therapy. However, this was significantly less common with olanzapine than with placebo. These controlled data suggest that clinical case reports of occurrence of ‘mania’ during treatment with olanzapine, and possibly those with other atypical antipsychotics, reflect exacerbation in the natural history of bipolar illness, rather than an adverse pharmacological effect. Limitations: Post-hoc analysis of pooled data from two different studies.  2002 Elsevier Science B.V. All rights reserved. Keywords: Olanzapine; Mania; Exacerbation; Bipolar disorder

*Corresponding author. Tel.: 1 1-317-433-5392; fax: 1 1-317-433-3410. E-mail address: [email protected] (R.W. Baker). 0165-0327 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved. PII: S0165-0327( 02 )00335-X

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1. Introduction Olanzapine’s efficacy for the treatment of bipolar mania has been demonstrated in placebo- and activecomparator trial (Tohen et al., 1999, 2000, 2001, 2002). However, a number of published case reports paradoxically describe apparent induction or exacerbation of manic symptoms during olanzapine treatment (Benazzi, 1999; Fahy and Fahy, 2000; John et al., 1998; Lindenmayer and Klebanov, 1998; London, 1998; Naruyan and Puranik, 2000; Reeves et al., 1998; Simon et al., 1999). Most described patients with baseline diagnoses of schizophrenia or schizoaffective disorder. Treatment-emergent symptoms suggesting mania included irritability, agitation, euphoria, and grandiosity. Similar case reports tie various psychotropic medications to this putative phenomenon. Antidepressants clearly pose a risk of mania induction or precipitation (Howland, 1996; Stoll et al., 1994; Wehr and Goodwin, 1987); other reports implicate risperidone (Barkin and Paris, 1997; Diaz, 1996; Dwight et al., 1994; Koek and Kessler, 1996; Lane and Lin, 1998; O’Croinin et al., 1995; Schnierow and Graeber, 1996; Tomlinson, 1996; Zolezzi and Badr, 1999), quetiapine (Benazzi, 2001), and gabapentin (Short and Cooke, 1995; Trinka et al., 2000). As they do not control for the natural history of an individual’s illness, anecdotal observations may not distinguish ‘causing’ certain symptoms from failure to prevent those symptoms, which may stimulate erroneous speculations about causality. Controlled clinical trials avoid this confounding factor. To date, the question of olanzapine-associated emergence of manic symptoms has not been assessed in a controlled clinical trial. To test this question, we conducted post-hoc analyses of two placebo-controlled trials of olanzapine for acute mania, a cohort presumably at increased risk for mania exacerbation.

2. Methods

methods and primary results of the studies have been published elsewhere (Tohen et al., 1999, 2000). At enrollment, patients were hospitalized for a manic or mixed episode of bipolar I disorder. Diagnoses were established using the Structured Clinical Instrument for DSM-IV (SCID) (First et al., 1997). A minimum total score of 20 points on the Young-Mania Rating Scale (Y-MRS) (Young et al., 1978) was required at both the screening visit and on the day of randomization (baseline). In addition, patients with mania that emerged during antidepressant-treatment were not included in the study. The present analysis pooled results of those two similarly designed studies. Psychotropic medications were discontinued at least 1 day prior to randomization. Patients received double-blind treatment with olanzapine (flexibly dosed, 5–20 mg / day) or placebo. Limited doses of lorazepam was the only permitted concomitant psychotropic treatment and its use was permitted only during the first 10 days of both studies. The pooled studies differed in two important ways. Firstly, olanzapine starting dose was 10 mg in Study I (Tohen et al., 1999) and 15 mg in Study II (Tohen et al., 2000). Secondly, Study I was 3 weeks in duration, compared to 4 weeks duration for Study II. To circumvent these limitations, study and study-by-treatment interaction were included in the analysis of variance (ANOVA) model for the change in Y-MRS total scores. In addition, the Cochran–Mantel–Haenszel (CMH) test was conducted stratified by study. Further, the pooled analysis considered only results through 3 weeks.

2.2. Assessments Severity of illness was measured by the Y-MRS. Worsening of mania was determined using the change from baseline Y-MRS total score. Dividing the change from baseline score by the baseline score assessed percent of mania worsening. Analyses were also conducted on groups defined by gender and diagnostic subtype. Baseline severity of illness was determined using the median Y-MRS total score.

2.1. Patient population and study design 2.3. Statistical methods Two multi-center double-blind studies conducted at 35 sites in the United States compared olanzapine to placebo for the treatment of acute mania. Detailed

Patients were analyzed on an intent-to-treat, last observation carried forward (LOCF) basis, including

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3.2. Efficacy

all patients with a baseline and at least one postbaseline measurement. The Y-MRS total score was derived from the individual items; if any single item was missing, the total score was treated as missing. Categorical comparisons were assessed using the Cochran–Mantel–Haenszel test. Mean comparisons were evaluated using ANOVA. All P values were based on two-tailed tests with a significance level of 0.05. Since benzodiazepine use was allowed in limited doses and for the first 10 days of the studies, an exploratory analysis was done using the CMH test controlling for both protocol and benzodiazepine use. Benzodiazepine use was dichotomized into those patients who took at least one dose and those who did not.

Olanzapine-treated patients experienced a significantly greater mean improvement in Y-MRS total score compared to the placebo-treated patients (211.8613.2 vs. 2 5.6611.6; F(1,242) 5 15.9, P , 0.001) and this improvement was similar for each study (study-by-treatment interaction; F(1,242) 5 0.38, P 5 0.540). Individual changes ranged from improvement of 46 points to worsening of 23 points; the histogram of Fig. 1 demonstrates the distribution of beginning to endpoint rating change for the two treatment groups.

3.3. Exacerbation of mania Ratings worsened for some patients during treatment, but significantly fewer patients (21.8%) in the olanzapine-treated group experienced any beginning to endpoint (LOCF) Y-MRS total score worsening compared to the placebo treatment group (37.7%; CMH 5 7.8, P 5 0.005). In addition, fewer patients receiving olanzapine worsened by at least 10% (14.5% vs. 24.6%; CMH 5 4.3, P 5 0.039) and at least 20% (8.1% vs. 15.6%; CMH 5 3.4, P 5 0.064). The distribution by treatment group of patients who experienced any worsening during treatment was

3. Results

3.1. Patients All 254 patients from the two studies were included in the pooled analyses. Baseline patient and illness characteristics for each treatment group are summarized in Table 1; there were no statistically significant differences between treatment groups. Table 1 Patient, baseline, and illness characteristics Characteristic

Age Baseline Y-MRS total Baseline CGI-severity

Gender Male Female Ethnicity (% Caucasian) Episode type Mixed Manic Psychotic features Rapid cyclers c a

Olanzapine

Placebo

n

Mean

S.D.

n

125 125 125

39.4 28.7 4.6

11.2 6.7 0.8

129 129 129

n

n

%

N

125

62 63 93

49.6 50.4 74.4

129

36 89 72 44

28.8 71.2 57.6 35.2

P value Mean

S.D.

38.8 28.7 4.7

10.2 6.9 0.9

0.674 a 0.932 a 0.401 a

n

%

P value

67 62 100

51.9 48.1 77.5

0.709 b

37 92 66 46

28.7 71.3 51.2 35.7

0.983 b

Means analyzed using a type III sums of squares analysis of variance (ANOVA). Frequencies analyzed using x 2 -test. c Rapid cycling defined as any patient with four or more manic, depressed, or mixed episodes in the previous year. b

0.561 b

0.303 b 0.939 b

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Fig. 1. Distribution in the change in Y-MRS scores at endpoint. The purple bar represents the olanzapine group (n 5 124) and the gray bar represents placebo group (n 5 122).

similar irrespective of type of mania, presence or absence of psychotic features, presence or absence of rapid cycling, baseline severity of illness, and gender. Visit-wise change from baseline in Y-MRS total score (observed case) analysis was also performed. Fewer patients in the olanzapine treatment group experienced any worsening compared to the placebo treatment group at each week, with a significant difference observed at Week 3 (olanzapine, three out of 82 patients (3.7%); placebo, eight out of 53 patients (15.2%); CMH 5 5.3, P 5 0.021). An exploratory analysis controlling for benzodiazepine use revealed findings similar to those reported above in that significantly fewer patients receiving olanzapine experienced any worsening (CMH 5 7.3, P 5 0.007), and at least 10% worsening (CMH 5 4.0, P 5 0.046) compared to the placebo treatment group. However, while fewer patients worsened at least 20% compared to placebo,

this finding was not statistically significant (CMH 5 3.3, 0.70). One-hundred and ninety-two patients received at least one dose of benzodiazepine during the studies while 54 patients did not.

4. Discussion In this pooled-analysis of two large clinical trials, Young-Mania Rating Scale total scores worsened in some individuals during 3 weeks of treatment for acute mania; such exacerbation was significantly more common among patients receiving placebo than among those treated with olanzapine. This controlled finding counters the anecdotally based suggestion that olanzapine provokes mania. The proposed association of olanzapine with mania induction seems paradoxical, given repeated demonstration of olanzapine’s anti-manic properties (Tohen et al., 1999, 2000, 2001, 2002). However, it

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is conceivable that mean improvement in mania across a population may obscure significant worsening in those individuals who are particularly vulnerable to putative mania provoking effects. This report extends previous analyses by identifying the improvement or worsening of individual patients. It is striking that some patients did worsen substantially, in the extreme case by 23 Y-MRS points during placebo treatment. That some patients worsened during olanzapine treatment confirms that it is not effective for every patient. However, if it has maniainducing properties, one could expect more cases of exacerbation on olanzapine than in placebo-treated patients. This was not observed; in fact, significantly fewer olanzapine-treated patients worsened, concordant with established anti-manic properties. Antidepressant agents are well-linked to accelerated cycling and / or upswing to mania in bipolar patients (Howland, 1996; Stoll et al., 1994) and are associated with mania and / or agitated psychosis in patients previously not diagnosed with bipolar disorder (Peet, 1994; Preda et al., 2001). In a recent review of the published cases of possible induction of mania and hypomania caused by olanzapine or risperidone, Aubry et al. (2000) speculate that antidepressant properties are derived from potent 5HT2A antagonism, an attribute shared by antidepressant agents such as nefazodone or trazodone. However, this overlooks olanzapine’s many differences from these antidepressants. For example, olanzapine lacks their serotonin-reuptake inhibition, perhaps the feature most likely to confer pro-manic effects. Others surmise antidepressant properties from reports of olanzapine’s superiority for co-morbid depressive features in schizophrenia trials versus haloperidol (Tollefson et al., 1998) and risperidone (Tran et al., 1997). However, improvement in co-morbid depressive features may not be demonstrative of classical antidepressant properties. For example, one analysis suggests that olanzapine monotherapy improves the depressive symptom ratings of dysphoric mania (Baker et al., 2000), which primarily reflects improvement in depressive symptoms such as sleep, cognition, insight, and irritability more so than mood. Such a profile may be more likely to lessen than exacerbate manic symptoms. It is possible that certain molecules may have antidepressant properties unencumbered by the liability of provoking mania;

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lithium may be such a compound. We agree with previous proposals that intrinsic anti-manic properties put a ceiling on antidepressant effects, preventing excessive mood-elevation (Calabrese and Rapport, 1999; Ghaemi, 2000; Sachs, 1996). Our report has several limitations. First, it is posthoc and combines two slightly dissimilar trials. Furthermore, the patient population may not optimally test the question; most case reports of manic symptom induction describe patients with schizophrenia, yet the trials reported above enrolled patients with bipolar mania. Therefore, we may overlook effects unique to patients with schizophrenia, or be incorrect in our assumption that a medication that provokes de novo mania will worsen existing mania. Similarly, we cannot rule out the theoretical possibility that olanzapine could trigger a switch from depression into mania. However, a preliminary controlled, albeit small study in treatment-resistant unipolar depression (Shelton et al., 2001) did not find higher rates of switches into mania in patients treated with olanzapine monotherapy or the combination of olanzapine with an antidepressant (fluoxetine) over fluoxetine and placebo. Also, 3 weeks may be too short to evaluate mania exacerbation; however, most reported cases describe symptoms appearing within the first several weeks and even days after changes in treatment (Aubry et al., 2000). Moreover, perhaps outcome varies depending on an individual’s predisposition. In this scenario, the relatively larger number of patients with a better anti-manic response to olanzapine than placebo may mask a vulnerable subgroup whose mania worsens more on olanzapine than it would have on placebo. If there is such a vulnerable subgroup, we could not identify it. Findings were consistent across the diagnostic and gender subgroups. At the least, this confirms that the net clinical impact of olanzapine is reduction of mania. In addition, a controlled trial may minimize an unidentified ‘real-world’ contributor to treatmentemergent mania, e.g., co-morbid substance use. To date, no such controlled data are available for other atypical antipsychotics. However, given our findings, it is prudent to be cautious in accepting anecdotal suggestions that other atypical antipsychotic agents such as risperidone may induce mania. Generalizability of our findings to reports of mania exacerbation with other agents such as novel anticon-

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vulsants remains to be assessed. In any case, there are flaws prevalent in many of the published case reports. In the published case reports, most patients were diagnosed with schizophrenia, not bipolar disorder. The occurrence of mania in these patients raises the possibility that they were misdiagnosed, as medication-induced mania is considered rare outside of bipolar or schizoaffective conditions, even with standard antidepressants. Second, most patients were not treated with concomitant standard mood stabilizers, like lithium or valproate. For those who were, there was no evidence of therapeutic blood levels of those agents reported. Inadequate treatment of bipolar disorder in itself would lead to mood episodes, and in some case reports, standing mood stabilizer treatment was discontinued shortly before the appearance of ‘medication-induced’ mania (Schnierow and Graeber, 1996). Lastly, a number of case reports are inadequately detailed to confirm a manic syndrome that would satisfy DSM-IV criteria. This raises the possibility of a different clinical phenomenon, such as agitation related to the underlying psychotic disturbance, or activation or restlessness related to treatment. These factors underline the need for caution in ascribing causation based on anecdotal observations, as well as potential benefit in further exploring this question in controlled studies of different patient groups and / or different medications.

5. Conclusion Our findings from pooled placebo-controlled studies do not to support anecdotal conjecture of mania-provoking properties of olanzapine. Olanzapine’s net effect is anti-manic; it is likely that uncontrolled reports inadequately consider the mood fluctuation that is part of the natural history of psychiatric illness for some individuals, or due to other environmental factors such as substance abuse. In an uncontrolled setting, spontaneous mood elevation might be misinterpreted as olanzapine causing mania induction or exacerbation. We indeed found that mania worsens in some individuals during olanzapine treatment, but that worsening was significantly less common than in the control group. This controlled study argues for caution in presum-

ing a causative relationship between atypical antipsychotics, in this case olanzapine, and apparent mania induction in uncontrolled clinical reports.

Acknowledgements Appreciation is expressed to Jan Short for editorial assistance with the manuscript. This work was sponsored by Eli Lilly and Company.

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