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Efficacy of ziprasidone in dysphoric mania: Pooled analysis of two double-blind studies
Journal of Affective Disorders 122 (2010) 39–45
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Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d
Research report
Efficacy of ziprasidone in dysphoric mania: Pooled analysis of two double-blind studies S. Stahl a,⁎, I. Lombardo b, A. Loebel b, F.S. Mandel b a b
Department of Psychiatry, UCSD, San Diego, CA, USA Pfizer Inc., New York, NY, USA
a r t i c l e
i n f o
Article history: Received 24 October 2008 Received in revised form 11 June 2009 Accepted 15 June 2009 Available online 17 July 2009 Keywords: Dysphoric mania Dysphoria Bipolar mania Mixed mania Ziprasidone
a b s t r a c t Background: Dysphoric mania is a common and often difficult to treat subset of bipolar mania that is associated with significant depressive symptoms. Objective: This post hoc analysis was designed to evaluate the efficacy of ziprasidone in the treatment of depressive and other symptoms in a cohort of patients with dysphoric mania. Methods: Pooled data were examined from two similarly designed, 3-week placebo-controlled trials in acute bipolar mania. Patients scoring ≥ 2 on at least two items of the extracted Hamilton Rating Scale for Depression (HAM-D) met criteria for dysphoric mania and were included in the post hoc analysis. Changes from baseline in symptom scores were evaluated by a mixed-model analysis of covariance. Results: 179 patients with dysphoric mania were included in the post hoc analysis (ziprasidone, n = 124; placebo, n = 55). Beginning at day 4, HAM-D scores were significantly lower at all visits in patients treated with ziprasidone compared with those treated with placebo (p b 0.05). Ziprasidone-treated patients also demonstrated significant improvements on the Mania Rating Scale and all secondary efficacy measures, and had significantly higher response and remission rates compared with placebo. Limitations: The main limitations are the use of a post hoc analysis and the pooling of two studies with slightly different designs. Conclusion: In this analysis, ziprasidone significantly improved both depressive and manic mood symptoms in patients with dysphoric mania, suggesting that it might be a useful treatment option in this patient population. Further prospective controlled trials are needed to confirm these findings. © 2009 Elsevier B.V. All rights reserved.
1. Introduction The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Text Revision (DSM-IV-TR) diagnostic criteria for mixed mood episodes of bipolar disorder DSM-IV require that patients have both full syndromal mania and depression. However, both DSM-IV and ICBD-10 criteria may be too rigid to capture the full range of mixed manic subtypes (Cassidy et al.,
⁎ Corresponding author. Department of Psychiatry, University of CaliforniaSan Diego,1930 Palomar Point Way, Carlsbad, CA 92008, USA. Tel.: +1760 444 9903; fax: +1 760 931 8517. E-mail address: [email protected] (S. Stahl). 0165-0327/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2009.06.023
2008). In clinical practice, mixed states have a more variable clinical presentation and many patients do not meet full syndromal definitions simultaneously (Akiskal et al., 2000; Akiskal, 2004; Angst and Gamma, 2002; Benazzi, 2008a,b; Clothier et al., 1992; Frye et al., 1996; Hantouche et al., 2006; McElroy et al., 1992; Stahl, 2008). According to Hantouche et al. (2006), the average rate of mixed mania is about 39%, with a wide variation of reported rates in the literature ranging from 5% to 75%. These different presentations of mixed states are fairly common and may have important treatment implications. Although there are currently no agreed and validated criteria for defining the mixed states across the bipolar spectrum from full syndrome mania with some symptoms of depression, to full syndrome depression with some symptoms of mania (Akiskal et
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al., 2000; Akiskal, 2004; Angst and Gamma, 2002; Stahl, 2008), in one subtype, dysphoric mania, patients have subsyndromal depressive symptoms in the presence of mania that are nevertheless clinically relevant (Benazzi, 2008a,b; McElroy et al., 1992). Moreover, studies suggest that a subthreshold level of depression may represent a distinct form of mania accounting for nearly 36% of these patients (Azorin et al; Frye et al., 1996). Bipolar disorder, especially bipolar II disorder, is increasingly being seen as fundamentally a depressive disorder over time (Judd et al., 2002, 2003a,b, 2008a,b; Judd and Akiskal, 2003), and patients may continue to have subsyndromal symptoms of depression not only following a depressive episode, but even during a manic or hypomanic episode. Since the vast majority of studies of psychotropic drug treatments, and all psychotropic drug approvals, for mixed states are for full syndrome mania and depression, this has left a quandary for clinicians as to how best to treat the very common subsyndromal mixed states within the bipolar spectrum (Akiskal et al., 2000; Akiskal, 2004; Angst and Gamma, 2002, Stahl, 2008). The effectiveness of medications shown useful for pure manic episodes is largely unproven in the subset of patients who require effective and simultaneous management of both manic and depressive symptoms. Although there have been studies of valproate and lithium, results are inconsistent. For example, while lithium is an efficacious treatment for mania, it may be less useful for individuals with mixed states (Azorin et al., 2008; Krüger et al., 2005; Prien et al., 1988; Swann et al., 2002, 1997; Thuile et al., 2005). Ziprasidone has been shown to be effective in the treatment of patients with acute manic or mixed episodes associated with bipolar disorder, with significant improvement of manic symptoms (Keck et al., 2003; Potkin et al., 2005). In addition to its anti-manic efficacy, ziprasidone possesses strong affinity at a broad range of serotonin receptors, which might offer additional benefit to the treatment of co-morbid depressive symptoms of patients in a dysphoric mania (Stahl and Shayegan, 2003). The objective of this post hoc analysis is to evaluate the efficacy of ziprasidone in the treatment of depressive and manic symptoms in a cohort of patients with dysphoric mania using previously operationalized criteria (McElroy et al., 1992).
Table 2 Dysphoric mania definition. Full criterion mania plus two or more of the following items with a score of 2 or more at baseline a SADS-CB item Dysphoric mood Worry Self-reproach Negative self-evaluation a
Discouragement Suicidal tendency Feeling of fatigue Loss of interest
McElroy et al. (1992).
Potkin et al., 2005). The two studies differed only in the speed of drug titration (see “Treatments” below). Full inclusion and exclusion criteria for each study have been previously reported in detail (Keck et al., 2003; Potkin et al., 2005). The major entry criteria for each study were a primary diagnosis of bipolar I disorder, current episode manic or mixed criteria (DSM-IV) (American Psychiatric Association, 1994); a Mania Rating Scale (MRS) score of ≥14, with scores of ≥2 on at least four items at screening and baseline; and the onset of the current episode occurring ≤ 3 months before screening. The operationalized diagnostic criteria of McElroy et al. (1992) were used to select the dysphoric mania cohort (Table 2). Patients were required to have a score of ≥2 on at least two of the following eight items on the extracted HAM-D: dysphoric mood, worry, self-reproach, negative selfevaluation, discouragement, suicidal tendency, feeling of fatigue, loss of interest. The pooled data set from the two intent-to-treat studies included 248 manic episode patients plus 151 mixed episode patients; among these patients 181 qualified as dysphoric and 218 as nondysphoric (Table 1). Briefly, the exclusion criteria for each study were an axis I diagnosis of (a) schizophrenia, (b) schizoaffective disorder, or (c) bipolar I disorder, current depressed episode (DSM-IV criteria); substance abuse/dependence during the preceding 2 months; any previous psychotropic drugs not discontinued a minimum of 2 weeks prior to randomization (depending upon drug).
2. Methods 2.1. Subjects Data were pooled from two similarly designed randomized, double-blind, placebo-controlled, 3-week trials of ziprasidone monotherapy for the treatment of patients with acute manic and mixed episodes (Table 1) (Keck et al., 2003; Table 1 Patient disposition for the pooled data set from two studies (Keck et al., 2003; Potkin et al., 2005). Mixed episode patients Manic episode patients (n = 151) (n = 248) Dysphoric patients n = 104 (n = 181) Nondysphoric patients n = 47 (n = 218)
n = 77 n = 171
Dysphoria defined according to McElroy et al. (1992).
Table 3 Baseline characteristics of patients from the dysphoric mania cohort of the pooled studies. Demographics
Ziprasidone (n = 124)
Placebo (n = 55)
Men, n (%) Mean age, years (SD) Patients aged N 65 years, n (%)
54 (43.5) 39.3 (10.5) 1 (0.8)
27 (49.1) 38.2 (11.3) 1 (1.8)
Clinical characteristics, mean scores (SD)
Ziprasidone (n = 123)
Placebo (n = 55)
Extracted HAM-D MRS CGI-S PANSS positive GAF
9.6 (4.6) 24.7 (6.8) 4.6 (0.8) 18.8 (5.1) 40.9 (9.2)
8.7 (4.1) 23.9 (5.7) 4.7 (0.7) 18.5 (5.6) 38.9 (8.0)
SD = standard deviation; HAM-D = Hamilton Depression Rating Scale; MRS = Mania Rating Scale; CGI-S = Clinical Global Impression—Severity; PANSS = Positive and Negative Syndrome Scale; GAF = Global Assessment of Functioning.
S. Stahl et al. / Journal of Affective Disorders 122 (2010) 39–45
2.2. Efficacy assessments Efficacy was assessed using the Schedule for Affective Disorders and Schizophrenia—Change Bipolar Scale (SADSCB) (Endicott and Spitzer, 1978). The SADS-CB consists of the MRS (Endicott and Spitzer, 1978) and its two subscales, the Manic Syndrome Subscale and the Behavior and Ideation Subscale. HAM-D data were extracted from the SADS-CB; the HAM-D (Endicott et al., 1981) was the primary efficacy measure for this analysis. Secondary efficacy measures included Clinical Global Impression—Severity (CGI-S) and Improvement (CGI—I) (Guy, 1976), Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) total score and positive subscale score, and Global Assessment of Functioning (GAF) (Endicott et al., 1976) scores. Efficacy assessments were
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performed at baseline and on days 2, 4, 7, 14 and 21 (or at discontinuation) with the exception of the PANSS and GAF, which were assessed only on days 7, 14 and 21 (Keck et al., 2003; Potkin et al., 2005).
2.3. Safety assessments Safety assessments included monitoring for adverse events (AEs), clinical laboratory tests, vital signs, electrocardiograms, physical examinations, and ratings of movement disorders and extrapyramidal symptoms. Safety assessments were performed at baseline and on days 2, 4, 7, 14 and 21 (or at discontinuation) (Keck et al., 2003; Potkin et al., 2005).
Fig. 1. Least squares (LS) mean change from baseline in (a) extracted Hamilton Depression Rating Scale (HAM-D) and (b) Mania Rating Scale (MRS) scores for patients receiving placebo or ziprasidone. Mean ± standard deviation (SD) baseline HAM-D scores were 9.6 ± 4.6 for ziprasidone and 8.7 ± 4.1 for placebo. Mean ± standard deviation (SD) baseline MRS scores were 24.7 ± 6.8 for ziprasidone and 23.9 ± 5.7 for placebo.
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2.4. Treatments Ziprasidone was initiated at 80 mg/day in both studies. For the first study (Keck et al., 2003), on day 2 the dosage was increased to 160 mg/day and subsequently could be adjusted by up to 40 mg/day, for a dosage within the range of 80– 160 mg/day. For the second study (Potkin et al., 2005), starting on day 2 the dosage could be adjusted by up to 40 mg/ day, for a dosage within the range of 80–160 mg/day. The mean daily dose in the pooled sample of dysphoric subjects was ziprasidone 133.4 ± 34.3 mg/day. 2.5. Data analysis The data used in this post hoc analysis were derived from the pooled intent-to-treat (ITT) dataset from the two studies (Keck et al., 2003; Potkin et al., 2005) and were limited to a cohort of patients meeting criteria for dysphoric mania at baseline. A mixed-model repeated-measures analysis (Mallinckrodt et al., 2001) was used to impute any missing data. The model included main effects for treatment and visit; a treatment× visit interaction term was used to compare the rate of change between the two groups, and baseline and protocol were used as covariates. Least squares mean values were estimated, adjusting for all terms in the model. Response was defined as a ≥50% reduction in MRS score from baseline to endpoint. Remission was defined as an MRS score ≤10 and an extracted HAM-D score ≤8 at study endpoint (last observation carried forward). Treatment group response rates and remission rates were compared using Cochran–Mantel–Haenszel tests, controlling for protocol.
Fig. 2. Responder and remission status at study endpoint. Reponse was defined as a ≥50% reduction in Mania Rating Scale (MRS) score from baseline to endpoint. Remission was defined as MRS ≤ 10 and exrtracted Hamilton Depression Rating Scale (HAM-D) ≤ 8 at study endpoint. Statistical comparisons were performed using a Cochran–Mantel–Haenszel model with treatment center as control variable and a χ2 statistic.
between treatment groups (Table 3). Seventy six of 179 (42%) dysphoric patients were psychotic at baseline. These comprised 51 of 124 (41.1%) and 25 of 55 (45.5%) in the ziprasidone and placebo groups respectively. The mean daily dose of ziprasidone in the pooled sample of dysphoric patients was 133.4 ± 34.3 mg/day. 3.1. Efficacy
The pooled dataset (ITT) from the two studies (Keck et al., 2003; Potkin et al., 2005) consisted of 399 patients, of which 181 met the criteria for dysphoric mania (Tables 1 and 2). Of these 181 dysphoric patients, 124 patients received ziprasidone and 55 were given placebo and were included in the post hoc analysis (Table 3). Baseline demographic and clinical characteristics of the dysphoric mania cohort were similar
Mean improvement in HAM-D score was significantly greater in the ziprasidone group than in the placebo group, beginning on day 2 (p = 0.026) and continuing through study endpoint (p = 0.027) (Fig. 1). Mean improvement in HAM-D score in the ziprasidone group at study endpoint was −4.2 ± 0.7, representing a reduction of 44% from baseline (Fig. 1a). Mean improvements in MRS scores were significantly greater in the ziprasidone group than in the placebo group throughout the study, beginning at day 2 (p b 0.01; Fig. 1b). At 21 days, the effect size was 0.29 (MRS) and 0.21 (HAM-D) using Cohen's d. Mean improvements in CGI-S scores were significantly greater in the ziprasidone group than in the placebo group throughout the study, beginning at day 2 (p b 0.01). From day 7 onward, mean change from baseline in PANSS total score
Table 4 Item analysis of extracted HAM-D components.
Table 5 Adverse events reported in more than 5% of the dysphoric mania cohort.
3. Results
Item a
1 2 3 4 5 6 16 20
Ziprasidone (n = 124)
Placebo (n = 55)
p
Baseline
Change (from baseline to LOCF)
SD
Baseline
Change (from baseline to LOCF)
SD
2.1 2.5 1.9 1.9 1.9 0.4 1.2 1.4
− 0.90 − 0.85 − 0.92 − 0.94 − 0.83 − 0.23 − 0.28 − 0.52
1.28 1.34 1.39 1.54 1.35 0.77 1.43 1.37
2.1 2.3 1.7 1.8 1.9 0.5 1.1 1.2
− 0.22 − 0.40 − 0.47 − 0.25 − 0.38 − 0.22 − 0.29 − 0.24
1.56 1.23 1.23 1.24 1.31 0.98 1.20 1.23
0.0024 0.0370 0.0419 0.0038 0.0401 0.9081 0.9686 0.1844
a 1 = dysphoric mood, 2 = worry, 3 = self-reproach, 4 = negative selfevaluation, 5 = discouragement, 6 = suicidal tendency, 16 = feeling of fatigue, 20 = loss of interest.
Adverse event
Ziprasidone (n = 126)
Dizziness Extrapyramidal symptoms Headache Nausea Muscular hypertonia Agitation Akathisia Dystonia Constipation Tremor Exacerbation of mania Asthenia Abdominal pain
22 20 15 13 13 12 11 10 9 9 2 7 0
(17.5%) a (15.9%) a (11.9%) (10.3%) a (10.3%) a (9.5%) a (8.7%) (7.9%) a (7.1%) (7.1%) (1.6) (5.6%) (0.0%)
Placebo (n = 55) 3 1 5 1 0 1 4 2 3 0 0 2 4
(5.5%) (1.8%) (9.1%) (1.8%) (0.0%) (1.8%) (7.3%) (3.6%) (5.5%) (0.0%) (0.0%) (3.6%) (7.3%)
a Adverse events reported in the ziprasidone group at a frequency at least twice that of the placebo group.
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(p = 0.005) and PANSS positive score (p b 0.001) was significantly greater in the ziprasidone group than in the placebo group at all measured time points. The improvement in GAF score was highly significant at all measured time points (p b 0.001). The results of an item analysis of the SADS-CB items used to operationalize dysphoric mania are shown in Table 4. Items 1 (dysphoric mood), 2 (worry), 3 (self-reproach), 4 (negative self-evaluation) and 5 (discouragement) showed a significant difference between the placebo and ziprasidone groups (with the ziprasidone group always showing the greater of improvement in the item score). There was no difference between the two groups on items 6 (suicidal tendency), 16 (feeling of fatigue) and 20 (loss of interest). In the dysphoric patients, response rates were significantly higher in the ziprasidone group (47.6%) than the placebo group (27.3%) at study endpoint (p = 0.02; Fig. 2). Rates of remission were also significantly higher in the ziprasidone group (42.3%) than the placebo group (21.8%) at study endpoint (p = 0.01; Fig. 2) in the dysphoric patient cohort. In the total patient cohort (including those without dysphoric mania), the remission rates were similar, at 40% for ziprasidone and 26% for placebo (p b 0.01). 3.2. Safety and tolerability Ziprasidone was generally well tolerated. Safety and tolerability data, discontinuation rates and reasons for discontinuation have been reported in more detail previously (Keck et al., 2003; Potkin et al., 2005). The most commonly reported AEs in the dysphoric mania population were dizziness, extrapyramidal symptoms and headache (Table 5). Those AEs that were reported in the ziprasidone group at twice the frequency of those in the placebo group were nausea, agitation, dizziness, dystonia, extrapyramidal symptoms and muscular hypertonia (Table 5). Exacerbation of mania (defined as report of AE or reason for discontinuation: worsening of mania, worsening of disease under study, exacerbation of mania, manic reaction, insufficient clinical response, manic depressive reaction) occurred in 1.6% and none of ziprasidone and placebo subjects, respectively. When exacerbation of mania was defined as a 20% worsening of MRS scores, there was no significant difference (p=0.25) between the placebo (7 patients of 55, 12.7%) and ziprasidone (9 of 124, 7.3%) groups. Equivalent values in the entire cohort (with and without dysphoric mania) were 10.7% and 5.2% in placebo and ziprasidone groups, respectively (pb 0.05). 4. Discussion A phenomenological study of mania suggested that mania can be naturalistically classified into several distinct states, including dysphoric mania (Dilsaver et al., 1999). The treatment of subsyndromal mixed states within the bipolar spectrum (Akiskal et al., 2000; Akiskal, 2004; Angst and Gamma, 2002; Stahl, 2008) is of particular clinical interest since, although very common, these nonetheless fall outside the scope of most psychotropic drug studies. Much of the reason for this is the difficulty in drawing boundaries between states using operational criteria for dysphoric mania (Cassidy et al., 2008). In this post hoc analysis of two pooled, acute, bipolar mania studies, treatment with ziprasidone significantly
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improved both manic and depressive symptoms of patients with dysphoric mania. Depressive symptoms were improved within 4 days of treatment initiation and through to study endpoint, as assessed by the extracted HAM-D, in patients with dysphoric mania. Consistent with the parent studies (Keck et al., 2003; Potkin et al., 2005), improvement was also seen across manic, positive and negative symptom domains and disease severity and function in the dysphoric mania cohort, as assessed by the MRS, PANSS, CGI-S and GAF. The effects of ziprasidone seen here on MRS in dysphoric mania were comparable to those seen in the parent studies of bipolar mania and mixed states (Keck et al., 2003; Potkin et al., 2005). In this analysis, the response rate for the ziprasidone group was nearly twice that for the placebo group in the population with dysphoric mania. The response rates in the dysphoric mania cohort were similar to those in the parent studies (Keck et al., 2003; Potkin et al., 2005), suggesting that ziprasidone is equally effective in the cohort of patients with dysphoric mania and among bipolar mania patients overall. Both analyses are based upon rapid ziprasidone dosing, starting with 80 mg/day and then increasing on day 2 or 3 by up to 40 mg/day, for a dosage within the range of 80–160 mg/day and with a mean daily dose in the pooled sample of dysphoric subjects of 133.4 ± 34.3 mg/day. The results also show that certain components of the SADS-CB operationalization of dysphoric mania (dysphoric mood, worry, self-reproach, negative self-evaluation and discouragement) were responsive to ziprasidone while others, perhaps those reflecting more overt depression symptomatology (suicidal tendency, feeling of fatigue and loss of interest), were not. Ziprasidone was generally as well tolerated in the dysphoric mania cohort as in the wider population. The AEs reported in the dysphoric mania group were essentially the same as for the wider population, with the exception that although somnolence was the most frequently reported AE in the wider population, this did not occur at ≥5% of patients in the dysphoric mania cohort. Few studies exist that have investigated the effects of treatment on depressive symptoms in patients with dysphoric mania or with subsyndromal symptoms of mania mixed with full syndrome depression (Akiskal et al., 2000; Akiskal, 2004; Stahl, 2008). Since dysphoric mania is a discrete clinical entity with distinct outcomes and treatment response (McElroy et al., 1992), it is important to investigate treatment options that can simultaneously improve depressive and manic symptoms. Studies that have examined the effect of divalproex and lithium in a population with dysphoric mania have repeatedly identified a differential, and frequently poorer, treatment response in these patients compared with patients with classic mania, and suggest that treatment of this subtype of mania should differ (Clothier et al., 1992; Swann et al., 2002, 1997; Bowden et al., 2005; Himmelhoch and Garfinkel,1986; Secunda et al., 1985; Freeman et al., 1992). Atypical antipsychotics have not been studied as monotherapy in a dysphoric mania, and only olanzapine has been examined in combination with lithium or divalproex (Gonzalez-Pinto et al., 2002; Baker et al., 2004). To the best of our knowledge, this is the largest analysis to date of the use of an atypical antipsychotic as monotherapy in patients with dysphoric mania. Ziprasidone treatment showed
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significant benefits on depressive and manic symptoms compared with placebo. Nonetheless, we acknowledge that these results are post hoc analyses of studies that were not designed to address dysphoric mania and the results should be taken with that caveat. Moreover, although the two studies had similar patient cohorts, there were differences in the titration speed, which may have a bearing on treatment success and course. In conclusion, this exploratory analysis provides preliminary evidence that ziprasidone can treat the co-occurring symptoms of depression and mania in patients with dysphoric mania. Further prospective studies in this patient population are needed to develop treatment options that target the specific clinical challenges for this patient population, namely treating acute mood symptoms of mania and depression simultaneously. Role of funding source This research was funded by Pfizer. All authors have contributed to the intellectual content of this article, and have reviewed, approved, and accept full responsibility for its contents. Conflict of interest Dr Stahl has received grant support from AstraZeneca, Biovail, BristolMyers Squibb, Cephalon, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Neurocrine, Organon, PamLabs, Pfizer, Sepracor, Shire, Somaxon and Wyeth. He has received honoraria from or is a consultant for Acadia, Amylin, Asahi, AstraZeneca, Avera, Azur Pharma, Biolaunch, Biovail, Bionevia, Boehringer Ingelheim, Bristol-Myers Squibb, Cephalon, CSC Pharma, Cyberonics, Cypress Bioscience, Endo, Eli Lilly, Epix, Fabre Kramer, Forest, GlaxoSmithKline, Jazz, LaboPharm, Lundbeck, Neurocrine Bioscience, Neuromolecular, Neuronetics, Nova Del Pharma, Novartis, Noven, Nuvis, Organon, Otsuka, PamLab, Pfizer, Pierre Fabre, Sanofi Synthelabo, Schering Plough, Sepracor, Servier, Shire, SK Corporation, Solvay, Somaxon, Takeda, Tetragenix, and VandaWyeth. Drs Lombardo, Loebel and Mandel are or were employees of Pfizer Inc.
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Swann, A.C., Bowden, C.L., Morris, D., et al., 1997. Depression during mania. Treatment response to lithium or divalproex. Arch. Gen. Psychiatry 54, 37–42. Swann, A.C., Bowden, C.L., Calabrese, J.R., Dilsaver, S.C., Morris, D.D., 2002. Pattern of response to divalproex, lithium, or placebo in four naturalistic subtypes of mania. Neuropsychopharmacology 26, 530–536. Thuile, J., Even, C., Guelfi, J.D., 2005. Mixed states in bipolar disorders: a review of current therapeutic strategies. Encephale 31, 617–623.
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Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d
Research report
Efficacy of ziprasidone in dysphoric mania: Pooled analysis of two double-blind studies S. Stahl a,⁎, I. Lombardo b, A. Loebel b, F.S. Mandel b a b
Department of Psychiatry, UCSD, San Diego, CA, USA Pfizer Inc., New York, NY, USA
a r t i c l e
i n f o
Article history: Received 24 October 2008 Received in revised form 11 June 2009 Accepted 15 June 2009 Available online 17 July 2009 Keywords: Dysphoric mania Dysphoria Bipolar mania Mixed mania Ziprasidone
a b s t r a c t Background: Dysphoric mania is a common and often difficult to treat subset of bipolar mania that is associated with significant depressive symptoms. Objective: This post hoc analysis was designed to evaluate the efficacy of ziprasidone in the treatment of depressive and other symptoms in a cohort of patients with dysphoric mania. Methods: Pooled data were examined from two similarly designed, 3-week placebo-controlled trials in acute bipolar mania. Patients scoring ≥ 2 on at least two items of the extracted Hamilton Rating Scale for Depression (HAM-D) met criteria for dysphoric mania and were included in the post hoc analysis. Changes from baseline in symptom scores were evaluated by a mixed-model analysis of covariance. Results: 179 patients with dysphoric mania were included in the post hoc analysis (ziprasidone, n = 124; placebo, n = 55). Beginning at day 4, HAM-D scores were significantly lower at all visits in patients treated with ziprasidone compared with those treated with placebo (p b 0.05). Ziprasidone-treated patients also demonstrated significant improvements on the Mania Rating Scale and all secondary efficacy measures, and had significantly higher response and remission rates compared with placebo. Limitations: The main limitations are the use of a post hoc analysis and the pooling of two studies with slightly different designs. Conclusion: In this analysis, ziprasidone significantly improved both depressive and manic mood symptoms in patients with dysphoric mania, suggesting that it might be a useful treatment option in this patient population. Further prospective controlled trials are needed to confirm these findings. © 2009 Elsevier B.V. All rights reserved.
1. Introduction The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Text Revision (DSM-IV-TR) diagnostic criteria for mixed mood episodes of bipolar disorder DSM-IV require that patients have both full syndromal mania and depression. However, both DSM-IV and ICBD-10 criteria may be too rigid to capture the full range of mixed manic subtypes (Cassidy et al.,
⁎ Corresponding author. Department of Psychiatry, University of CaliforniaSan Diego,1930 Palomar Point Way, Carlsbad, CA 92008, USA. Tel.: +1760 444 9903; fax: +1 760 931 8517. E-mail address: [email protected] (S. Stahl). 0165-0327/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2009.06.023
2008). In clinical practice, mixed states have a more variable clinical presentation and many patients do not meet full syndromal definitions simultaneously (Akiskal et al., 2000; Akiskal, 2004; Angst and Gamma, 2002; Benazzi, 2008a,b; Clothier et al., 1992; Frye et al., 1996; Hantouche et al., 2006; McElroy et al., 1992; Stahl, 2008). According to Hantouche et al. (2006), the average rate of mixed mania is about 39%, with a wide variation of reported rates in the literature ranging from 5% to 75%. These different presentations of mixed states are fairly common and may have important treatment implications. Although there are currently no agreed and validated criteria for defining the mixed states across the bipolar spectrum from full syndrome mania with some symptoms of depression, to full syndrome depression with some symptoms of mania (Akiskal et
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al., 2000; Akiskal, 2004; Angst and Gamma, 2002; Stahl, 2008), in one subtype, dysphoric mania, patients have subsyndromal depressive symptoms in the presence of mania that are nevertheless clinically relevant (Benazzi, 2008a,b; McElroy et al., 1992). Moreover, studies suggest that a subthreshold level of depression may represent a distinct form of mania accounting for nearly 36% of these patients (Azorin et al; Frye et al., 1996). Bipolar disorder, especially bipolar II disorder, is increasingly being seen as fundamentally a depressive disorder over time (Judd et al., 2002, 2003a,b, 2008a,b; Judd and Akiskal, 2003), and patients may continue to have subsyndromal symptoms of depression not only following a depressive episode, but even during a manic or hypomanic episode. Since the vast majority of studies of psychotropic drug treatments, and all psychotropic drug approvals, for mixed states are for full syndrome mania and depression, this has left a quandary for clinicians as to how best to treat the very common subsyndromal mixed states within the bipolar spectrum (Akiskal et al., 2000; Akiskal, 2004; Angst and Gamma, 2002, Stahl, 2008). The effectiveness of medications shown useful for pure manic episodes is largely unproven in the subset of patients who require effective and simultaneous management of both manic and depressive symptoms. Although there have been studies of valproate and lithium, results are inconsistent. For example, while lithium is an efficacious treatment for mania, it may be less useful for individuals with mixed states (Azorin et al., 2008; Krüger et al., 2005; Prien et al., 1988; Swann et al., 2002, 1997; Thuile et al., 2005). Ziprasidone has been shown to be effective in the treatment of patients with acute manic or mixed episodes associated with bipolar disorder, with significant improvement of manic symptoms (Keck et al., 2003; Potkin et al., 2005). In addition to its anti-manic efficacy, ziprasidone possesses strong affinity at a broad range of serotonin receptors, which might offer additional benefit to the treatment of co-morbid depressive symptoms of patients in a dysphoric mania (Stahl and Shayegan, 2003). The objective of this post hoc analysis is to evaluate the efficacy of ziprasidone in the treatment of depressive and manic symptoms in a cohort of patients with dysphoric mania using previously operationalized criteria (McElroy et al., 1992).
Table 2 Dysphoric mania definition. Full criterion mania plus two or more of the following items with a score of 2 or more at baseline a SADS-CB item Dysphoric mood Worry Self-reproach Negative self-evaluation a
Discouragement Suicidal tendency Feeling of fatigue Loss of interest
McElroy et al. (1992).
Potkin et al., 2005). The two studies differed only in the speed of drug titration (see “Treatments” below). Full inclusion and exclusion criteria for each study have been previously reported in detail (Keck et al., 2003; Potkin et al., 2005). The major entry criteria for each study were a primary diagnosis of bipolar I disorder, current episode manic or mixed criteria (DSM-IV) (American Psychiatric Association, 1994); a Mania Rating Scale (MRS) score of ≥14, with scores of ≥2 on at least four items at screening and baseline; and the onset of the current episode occurring ≤ 3 months before screening. The operationalized diagnostic criteria of McElroy et al. (1992) were used to select the dysphoric mania cohort (Table 2). Patients were required to have a score of ≥2 on at least two of the following eight items on the extracted HAM-D: dysphoric mood, worry, self-reproach, negative selfevaluation, discouragement, suicidal tendency, feeling of fatigue, loss of interest. The pooled data set from the two intent-to-treat studies included 248 manic episode patients plus 151 mixed episode patients; among these patients 181 qualified as dysphoric and 218 as nondysphoric (Table 1). Briefly, the exclusion criteria for each study were an axis I diagnosis of (a) schizophrenia, (b) schizoaffective disorder, or (c) bipolar I disorder, current depressed episode (DSM-IV criteria); substance abuse/dependence during the preceding 2 months; any previous psychotropic drugs not discontinued a minimum of 2 weeks prior to randomization (depending upon drug).
2. Methods 2.1. Subjects Data were pooled from two similarly designed randomized, double-blind, placebo-controlled, 3-week trials of ziprasidone monotherapy for the treatment of patients with acute manic and mixed episodes (Table 1) (Keck et al., 2003; Table 1 Patient disposition for the pooled data set from two studies (Keck et al., 2003; Potkin et al., 2005). Mixed episode patients Manic episode patients (n = 151) (n = 248) Dysphoric patients n = 104 (n = 181) Nondysphoric patients n = 47 (n = 218)
n = 77 n = 171
Dysphoria defined according to McElroy et al. (1992).
Table 3 Baseline characteristics of patients from the dysphoric mania cohort of the pooled studies. Demographics
Ziprasidone (n = 124)
Placebo (n = 55)
Men, n (%) Mean age, years (SD) Patients aged N 65 years, n (%)
54 (43.5) 39.3 (10.5) 1 (0.8)
27 (49.1) 38.2 (11.3) 1 (1.8)
Clinical characteristics, mean scores (SD)
Ziprasidone (n = 123)
Placebo (n = 55)
Extracted HAM-D MRS CGI-S PANSS positive GAF
9.6 (4.6) 24.7 (6.8) 4.6 (0.8) 18.8 (5.1) 40.9 (9.2)
8.7 (4.1) 23.9 (5.7) 4.7 (0.7) 18.5 (5.6) 38.9 (8.0)
SD = standard deviation; HAM-D = Hamilton Depression Rating Scale; MRS = Mania Rating Scale; CGI-S = Clinical Global Impression—Severity; PANSS = Positive and Negative Syndrome Scale; GAF = Global Assessment of Functioning.
S. Stahl et al. / Journal of Affective Disorders 122 (2010) 39–45
2.2. Efficacy assessments Efficacy was assessed using the Schedule for Affective Disorders and Schizophrenia—Change Bipolar Scale (SADSCB) (Endicott and Spitzer, 1978). The SADS-CB consists of the MRS (Endicott and Spitzer, 1978) and its two subscales, the Manic Syndrome Subscale and the Behavior and Ideation Subscale. HAM-D data were extracted from the SADS-CB; the HAM-D (Endicott et al., 1981) was the primary efficacy measure for this analysis. Secondary efficacy measures included Clinical Global Impression—Severity (CGI-S) and Improvement (CGI—I) (Guy, 1976), Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) total score and positive subscale score, and Global Assessment of Functioning (GAF) (Endicott et al., 1976) scores. Efficacy assessments were
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performed at baseline and on days 2, 4, 7, 14 and 21 (or at discontinuation) with the exception of the PANSS and GAF, which were assessed only on days 7, 14 and 21 (Keck et al., 2003; Potkin et al., 2005).
2.3. Safety assessments Safety assessments included monitoring for adverse events (AEs), clinical laboratory tests, vital signs, electrocardiograms, physical examinations, and ratings of movement disorders and extrapyramidal symptoms. Safety assessments were performed at baseline and on days 2, 4, 7, 14 and 21 (or at discontinuation) (Keck et al., 2003; Potkin et al., 2005).
Fig. 1. Least squares (LS) mean change from baseline in (a) extracted Hamilton Depression Rating Scale (HAM-D) and (b) Mania Rating Scale (MRS) scores for patients receiving placebo or ziprasidone. Mean ± standard deviation (SD) baseline HAM-D scores were 9.6 ± 4.6 for ziprasidone and 8.7 ± 4.1 for placebo. Mean ± standard deviation (SD) baseline MRS scores were 24.7 ± 6.8 for ziprasidone and 23.9 ± 5.7 for placebo.
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2.4. Treatments Ziprasidone was initiated at 80 mg/day in both studies. For the first study (Keck et al., 2003), on day 2 the dosage was increased to 160 mg/day and subsequently could be adjusted by up to 40 mg/day, for a dosage within the range of 80– 160 mg/day. For the second study (Potkin et al., 2005), starting on day 2 the dosage could be adjusted by up to 40 mg/ day, for a dosage within the range of 80–160 mg/day. The mean daily dose in the pooled sample of dysphoric subjects was ziprasidone 133.4 ± 34.3 mg/day. 2.5. Data analysis The data used in this post hoc analysis were derived from the pooled intent-to-treat (ITT) dataset from the two studies (Keck et al., 2003; Potkin et al., 2005) and were limited to a cohort of patients meeting criteria for dysphoric mania at baseline. A mixed-model repeated-measures analysis (Mallinckrodt et al., 2001) was used to impute any missing data. The model included main effects for treatment and visit; a treatment× visit interaction term was used to compare the rate of change between the two groups, and baseline and protocol were used as covariates. Least squares mean values were estimated, adjusting for all terms in the model. Response was defined as a ≥50% reduction in MRS score from baseline to endpoint. Remission was defined as an MRS score ≤10 and an extracted HAM-D score ≤8 at study endpoint (last observation carried forward). Treatment group response rates and remission rates were compared using Cochran–Mantel–Haenszel tests, controlling for protocol.
Fig. 2. Responder and remission status at study endpoint. Reponse was defined as a ≥50% reduction in Mania Rating Scale (MRS) score from baseline to endpoint. Remission was defined as MRS ≤ 10 and exrtracted Hamilton Depression Rating Scale (HAM-D) ≤ 8 at study endpoint. Statistical comparisons were performed using a Cochran–Mantel–Haenszel model with treatment center as control variable and a χ2 statistic.
between treatment groups (Table 3). Seventy six of 179 (42%) dysphoric patients were psychotic at baseline. These comprised 51 of 124 (41.1%) and 25 of 55 (45.5%) in the ziprasidone and placebo groups respectively. The mean daily dose of ziprasidone in the pooled sample of dysphoric patients was 133.4 ± 34.3 mg/day. 3.1. Efficacy
The pooled dataset (ITT) from the two studies (Keck et al., 2003; Potkin et al., 2005) consisted of 399 patients, of which 181 met the criteria for dysphoric mania (Tables 1 and 2). Of these 181 dysphoric patients, 124 patients received ziprasidone and 55 were given placebo and were included in the post hoc analysis (Table 3). Baseline demographic and clinical characteristics of the dysphoric mania cohort were similar
Mean improvement in HAM-D score was significantly greater in the ziprasidone group than in the placebo group, beginning on day 2 (p = 0.026) and continuing through study endpoint (p = 0.027) (Fig. 1). Mean improvement in HAM-D score in the ziprasidone group at study endpoint was −4.2 ± 0.7, representing a reduction of 44% from baseline (Fig. 1a). Mean improvements in MRS scores were significantly greater in the ziprasidone group than in the placebo group throughout the study, beginning at day 2 (p b 0.01; Fig. 1b). At 21 days, the effect size was 0.29 (MRS) and 0.21 (HAM-D) using Cohen's d. Mean improvements in CGI-S scores were significantly greater in the ziprasidone group than in the placebo group throughout the study, beginning at day 2 (p b 0.01). From day 7 onward, mean change from baseline in PANSS total score
Table 4 Item analysis of extracted HAM-D components.
Table 5 Adverse events reported in more than 5% of the dysphoric mania cohort.
3. Results
Item a
1 2 3 4 5 6 16 20
Ziprasidone (n = 124)
Placebo (n = 55)
p
Baseline
Change (from baseline to LOCF)
SD
Baseline
Change (from baseline to LOCF)
SD
2.1 2.5 1.9 1.9 1.9 0.4 1.2 1.4
− 0.90 − 0.85 − 0.92 − 0.94 − 0.83 − 0.23 − 0.28 − 0.52
1.28 1.34 1.39 1.54 1.35 0.77 1.43 1.37
2.1 2.3 1.7 1.8 1.9 0.5 1.1 1.2
− 0.22 − 0.40 − 0.47 − 0.25 − 0.38 − 0.22 − 0.29 − 0.24
1.56 1.23 1.23 1.24 1.31 0.98 1.20 1.23
0.0024 0.0370 0.0419 0.0038 0.0401 0.9081 0.9686 0.1844
a 1 = dysphoric mood, 2 = worry, 3 = self-reproach, 4 = negative selfevaluation, 5 = discouragement, 6 = suicidal tendency, 16 = feeling of fatigue, 20 = loss of interest.
Adverse event
Ziprasidone (n = 126)
Dizziness Extrapyramidal symptoms Headache Nausea Muscular hypertonia Agitation Akathisia Dystonia Constipation Tremor Exacerbation of mania Asthenia Abdominal pain
22 20 15 13 13 12 11 10 9 9 2 7 0
(17.5%) a (15.9%) a (11.9%) (10.3%) a (10.3%) a (9.5%) a (8.7%) (7.9%) a (7.1%) (7.1%) (1.6) (5.6%) (0.0%)
Placebo (n = 55) 3 1 5 1 0 1 4 2 3 0 0 2 4
(5.5%) (1.8%) (9.1%) (1.8%) (0.0%) (1.8%) (7.3%) (3.6%) (5.5%) (0.0%) (0.0%) (3.6%) (7.3%)
a Adverse events reported in the ziprasidone group at a frequency at least twice that of the placebo group.
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(p = 0.005) and PANSS positive score (p b 0.001) was significantly greater in the ziprasidone group than in the placebo group at all measured time points. The improvement in GAF score was highly significant at all measured time points (p b 0.001). The results of an item analysis of the SADS-CB items used to operationalize dysphoric mania are shown in Table 4. Items 1 (dysphoric mood), 2 (worry), 3 (self-reproach), 4 (negative self-evaluation) and 5 (discouragement) showed a significant difference between the placebo and ziprasidone groups (with the ziprasidone group always showing the greater of improvement in the item score). There was no difference between the two groups on items 6 (suicidal tendency), 16 (feeling of fatigue) and 20 (loss of interest). In the dysphoric patients, response rates were significantly higher in the ziprasidone group (47.6%) than the placebo group (27.3%) at study endpoint (p = 0.02; Fig. 2). Rates of remission were also significantly higher in the ziprasidone group (42.3%) than the placebo group (21.8%) at study endpoint (p = 0.01; Fig. 2) in the dysphoric patient cohort. In the total patient cohort (including those without dysphoric mania), the remission rates were similar, at 40% for ziprasidone and 26% for placebo (p b 0.01). 3.2. Safety and tolerability Ziprasidone was generally well tolerated. Safety and tolerability data, discontinuation rates and reasons for discontinuation have been reported in more detail previously (Keck et al., 2003; Potkin et al., 2005). The most commonly reported AEs in the dysphoric mania population were dizziness, extrapyramidal symptoms and headache (Table 5). Those AEs that were reported in the ziprasidone group at twice the frequency of those in the placebo group were nausea, agitation, dizziness, dystonia, extrapyramidal symptoms and muscular hypertonia (Table 5). Exacerbation of mania (defined as report of AE or reason for discontinuation: worsening of mania, worsening of disease under study, exacerbation of mania, manic reaction, insufficient clinical response, manic depressive reaction) occurred in 1.6% and none of ziprasidone and placebo subjects, respectively. When exacerbation of mania was defined as a 20% worsening of MRS scores, there was no significant difference (p=0.25) between the placebo (7 patients of 55, 12.7%) and ziprasidone (9 of 124, 7.3%) groups. Equivalent values in the entire cohort (with and without dysphoric mania) were 10.7% and 5.2% in placebo and ziprasidone groups, respectively (pb 0.05). 4. Discussion A phenomenological study of mania suggested that mania can be naturalistically classified into several distinct states, including dysphoric mania (Dilsaver et al., 1999). The treatment of subsyndromal mixed states within the bipolar spectrum (Akiskal et al., 2000; Akiskal, 2004; Angst and Gamma, 2002; Stahl, 2008) is of particular clinical interest since, although very common, these nonetheless fall outside the scope of most psychotropic drug studies. Much of the reason for this is the difficulty in drawing boundaries between states using operational criteria for dysphoric mania (Cassidy et al., 2008). In this post hoc analysis of two pooled, acute, bipolar mania studies, treatment with ziprasidone significantly
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improved both manic and depressive symptoms of patients with dysphoric mania. Depressive symptoms were improved within 4 days of treatment initiation and through to study endpoint, as assessed by the extracted HAM-D, in patients with dysphoric mania. Consistent with the parent studies (Keck et al., 2003; Potkin et al., 2005), improvement was also seen across manic, positive and negative symptom domains and disease severity and function in the dysphoric mania cohort, as assessed by the MRS, PANSS, CGI-S and GAF. The effects of ziprasidone seen here on MRS in dysphoric mania were comparable to those seen in the parent studies of bipolar mania and mixed states (Keck et al., 2003; Potkin et al., 2005). In this analysis, the response rate for the ziprasidone group was nearly twice that for the placebo group in the population with dysphoric mania. The response rates in the dysphoric mania cohort were similar to those in the parent studies (Keck et al., 2003; Potkin et al., 2005), suggesting that ziprasidone is equally effective in the cohort of patients with dysphoric mania and among bipolar mania patients overall. Both analyses are based upon rapid ziprasidone dosing, starting with 80 mg/day and then increasing on day 2 or 3 by up to 40 mg/day, for a dosage within the range of 80–160 mg/day and with a mean daily dose in the pooled sample of dysphoric subjects of 133.4 ± 34.3 mg/day. The results also show that certain components of the SADS-CB operationalization of dysphoric mania (dysphoric mood, worry, self-reproach, negative self-evaluation and discouragement) were responsive to ziprasidone while others, perhaps those reflecting more overt depression symptomatology (suicidal tendency, feeling of fatigue and loss of interest), were not. Ziprasidone was generally as well tolerated in the dysphoric mania cohort as in the wider population. The AEs reported in the dysphoric mania group were essentially the same as for the wider population, with the exception that although somnolence was the most frequently reported AE in the wider population, this did not occur at ≥5% of patients in the dysphoric mania cohort. Few studies exist that have investigated the effects of treatment on depressive symptoms in patients with dysphoric mania or with subsyndromal symptoms of mania mixed with full syndrome depression (Akiskal et al., 2000; Akiskal, 2004; Stahl, 2008). Since dysphoric mania is a discrete clinical entity with distinct outcomes and treatment response (McElroy et al., 1992), it is important to investigate treatment options that can simultaneously improve depressive and manic symptoms. Studies that have examined the effect of divalproex and lithium in a population with dysphoric mania have repeatedly identified a differential, and frequently poorer, treatment response in these patients compared with patients with classic mania, and suggest that treatment of this subtype of mania should differ (Clothier et al., 1992; Swann et al., 2002, 1997; Bowden et al., 2005; Himmelhoch and Garfinkel,1986; Secunda et al., 1985; Freeman et al., 1992). Atypical antipsychotics have not been studied as monotherapy in a dysphoric mania, and only olanzapine has been examined in combination with lithium or divalproex (Gonzalez-Pinto et al., 2002; Baker et al., 2004). To the best of our knowledge, this is the largest analysis to date of the use of an atypical antipsychotic as monotherapy in patients with dysphoric mania. Ziprasidone treatment showed
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significant benefits on depressive and manic symptoms compared with placebo. Nonetheless, we acknowledge that these results are post hoc analyses of studies that were not designed to address dysphoric mania and the results should be taken with that caveat. Moreover, although the two studies had similar patient cohorts, there were differences in the titration speed, which may have a bearing on treatment success and course. In conclusion, this exploratory analysis provides preliminary evidence that ziprasidone can treat the co-occurring symptoms of depression and mania in patients with dysphoric mania. Further prospective studies in this patient population are needed to develop treatment options that target the specific clinical challenges for this patient population, namely treating acute mood symptoms of mania and depression simultaneously. Role of funding source This research was funded by Pfizer. All authors have contributed to the intellectual content of this article, and have reviewed, approved, and accept full responsibility for its contents. Conflict of interest Dr Stahl has received grant support from AstraZeneca, Biovail, BristolMyers Squibb, Cephalon, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Neurocrine, Organon, PamLabs, Pfizer, Sepracor, Shire, Somaxon and Wyeth. He has received honoraria from or is a consultant for Acadia, Amylin, Asahi, AstraZeneca, Avera, Azur Pharma, Biolaunch, Biovail, Bionevia, Boehringer Ingelheim, Bristol-Myers Squibb, Cephalon, CSC Pharma, Cyberonics, Cypress Bioscience, Endo, Eli Lilly, Epix, Fabre Kramer, Forest, GlaxoSmithKline, Jazz, LaboPharm, Lundbeck, Neurocrine Bioscience, Neuromolecular, Neuronetics, Nova Del Pharma, Novartis, Noven, Nuvis, Organon, Otsuka, PamLab, Pfizer, Pierre Fabre, Sanofi Synthelabo, Schering Plough, Sepracor, Servier, Shire, SK Corporation, Solvay, Somaxon, Takeda, Tetragenix, and VandaWyeth. Drs Lombardo, Loebel and Mandel are or were employees of Pfizer Inc.
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