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Efficacy of olanzapine combined with valproate or lithium in the treatment of dysphoric mania

  • Robert W. Baker (a1) (a2), Eileen Brown (a1), Hagop S. Akiskal (a3), Joseph R. Calabrese (a4), Terence A. Ketter (a5), Leslie M. Schuh (a1), Paula T. Trzepacz (a1) (a2) (a6), John G. Watkin (a1) and Mauricio Tohen (a1) (a7)...

Few controlled studies examine the treatment of depressive features in mania.


To evaluate the efficacy of olanzapine, in combination with lithium or valproate, for treating depressive symptoms associated with mania.


Secondary analysis of a 6-week, double-blind, randomised study of olanzapine (5–20 mg/day) or placebo combined with ongoing valproate or lithium open treatment for 344 patients in mixed or manic episodes. This analysis focused on a dysphoric subgroup with baseline Hamilton Rating Scale for Depression (HRSD) total scores of 20 or over contrasted with non-dysphoric patients.


In the dysphoric subgroup (n=85) mean HRSD total score improvement was significantly greater in olanzapine co-therapy patients than in those receiving placebo plus lithium or valproate (P<0.001). Substantial contributors to this superiority included the HRSD Maier sub-scale (P=0.013) and the suicide item (P=0.001). Total Young Mania Rating Scale improvement was also superior with olanzapine co-therapy.


In patients with acute dysphoric mania, addition of olanzapine to ongoing lithium or valproate monotherapy significantly improved depressive symptom, mania and suicidality ratings.

Corresponding author
Dr Robert Baker, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. Fax: +317 276 7100; e-mail:
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Declaration of interest

JGW, E.B., L.M.S., P.T.T., JGW and M.T. are employees of Eli Lilly and Company.

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Efficacy of olanzapine combined with valproate or lithium in the treatment of dysphoric mania

  • Robert W. Baker (a1) (a2), Eileen Brown (a1), Hagop S. Akiskal (a3), Joseph R. Calabrese (a4), Terence A. Ketter (a5), Leslie M. Schuh (a1), Paula T. Trzepacz (a1) (a2) (a6), John G. Watkin (a1) and Mauricio Tohen (a1) (a7)...
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Olanzapine and dysphoric mania

Muzaffar Husain, SHO in Old Age Psychiatry
17 December 2004

Baker et al’s paper “Efficacy of olanzapine combined with Valproate or Lithium in the treatment of dysphoric mania”(1) made interesting reading. However, on close inspection the essence of this post hoc analysis and conclusions seem forced, and are curiously circular. This is for a number of reasons.

First of all, a significant amount of information about the trial andits participants is simply missing. In the absence of any CONSORT diagram(2), one is left guessing the flow of participants through the trial. This is of additional relevance given the small numbers involved, especially in the dysphoric patient subgroup. Basic questions, like how many of the patients in the dysphoric group actually completed the trial, or indeed if any died, are left unanswered. Details of patients from the source study by Tohen et al(3) (referenced by the authors) fail to remedy this flaw, for lack of specificity to dysphoria.

Secondly, one struggles to understand the rationale for discussing atlength the ‘no baseline dysphoria’ subgroup and indeed even including their data in the analysis. If the study targets the possible efficacy of olanzapine as co-therapy versus placebo in patients with dysphoric mania, what is the purpose of comparing this with non-dysphoric mania? In addition, the ‘non-dysphoric’ patient group is established as so by HRSD scores of less than 20 and then the same HRSD scale is used to map treatment response. In other words, non-dysphoric patients included in thetrial are treated with the intervention and then assessed for dysphoria again. The authors could have kept their eye on the ball by excluding thisamusing contradiction altogether.

Thirdly, it was intriguing to note the discrepancy between the diagnosis of mixed episode by investigators using the DSM-IV criteria and the authors’ use of HRSD scores of 20 and above. This is discussed in the paper and although the authors report that most of the participants in thedysphoria subgroup (85%) did have a diagnosis of a mixed episode, it is noted that as many as 41% of the non-dysphoric patients also had the same diagnosis. If the issue is one of clinical relevance, one would have been better advised to use the clinical diagnosis of mixed episode as a measureof dysphoria than a score on the HRSD, which is a research instrument anyway.

Lastly, but perhaps most glaringly, side effects are not mentioned even once. Were there any reported, or did the authors look for any? Was there any difference in the use of adjunctive medication in the treatment groups? In the absence of such vital information, one would be tempted to be less optimistic about the wonder drug that is olanzapine.

In conclusion, it seems olanzapine presents as something less than a model treatment option for refractory dysphoria, and one would approach the conclusions drawn by Baker et al with caution. The need of the moment is better research design that addresses dysphoric mania directly, rather than as an afterthought.

Conflict of interests: None


1.Baker, R., W., Brown, E., et al (2004) Efficacy of Olanzapine combined with Valproate or lithium in the treatment of dysphoric mania. British Journal of Psychiatry. 185, 472-478.

2.Begg, C., Cho, M., Eastwood, S., et al (1996) Improving the qualityof reporting of randomized controlled trials: the CONSORT statement. JAMA.276: 637-639.

3.Tohen, M., Chengappa, K., N., Suppes, T., et al (2002) Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to Valproate or lithium monotherapy. Archives of General Psychiatry, 59, 62-69.
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Conflict of interest: None Declared

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Olanzapine for dysphoric mania-pragmatic outcomes need reporting

Prakash Hosalli, Specialist Registrar in Psychiatry
17 December 2004

Baker et al (2004) report an interesting post hoc analysis from a randomised double blind, placebo controlled study evaluating the efficacy of olanzapine co-therapy in patients with bipolar disorder who had inadequate responses to valproate or lithium monotherapy (Tohen 2002). Theauthors describe a secondary analysis assessing response among dysphoric and non dysphoric bipolar I patients. />
Authors conclude that olanzapine in combination with either lithium or valproate was effective in improving the severity of depressive symptoms co-existing with acute mania. This conclusion is based on statistically significant difference in mean change in Hamilton Rating Scale for Depression (HRSD). However the authors have not reported the standard deviations for the mean changes in HRSD scores. Hence it is difficult to know if the data is skewed or not. It is possible that a few patients showing large change on the rating scale could have skewed the data. We also found it puzzling that the authors report the magnitude of difference in the HRSD score between combination and monotherapy groups was larger for dysphoric patients. As it is one would naturally expect participants in the non-dysphoric group to have much lower baseline scoresso that there is less of a chance to expect significant reduction. [Mean HRSD baseline score in non-dysphoric group was 10.42(5.27) and in the dysphoric group 25.18 (4.62)]

We are also of the view that reporting study outcomes in terms of mean changes on a rating scale will not provide meaningful information to the clinicians. Reporting results on a dichotomous outcome measure such as‘improved’ and ‘not improved’ on a meaningful cut off point defined a priori would be helpful. Clinicians would be more interested in outcome measures such as complete remission of symptoms, return to premorbid levels of functioning etc. To address the question of whether olanzapine is helpful for patients with dysphoric mania it would be helpful to know how many in the olanzapine add on group actually achieved complete remission and whether there was any statistical difference between groups.It would have been interesting if Baker et al had provided dichotomous outcomes based on the Clinical Global Impressions Severity of Bipolar Disorder scale (CGI-BP) scale as well, as this has been administered during the course of the trial and data should be readily available.

It is not uncommon to come across reporting of various outcome measures and multiple analysis of a randomised controlled trial. But whether that actually adds to the clinical knowledge is questionable. We agree with the authors that it is important to design studies to explore the pharmacological options for dysphoric mania as the available ones are limited. However we need more pragmatic outcome measures which could easily be understood by clinicians and applied in routine practice rather than being lost in minefield of multiple analysis. Systematic reviews likethe one on olanzapine for mania also highlights the lack of pragmatic outcome measures in reporting of randomised controlled studies (Rendell etal 2003). We hope future reports of studies will try to convey more real world applicable outcome measures.


1.Baker, RW., Brown, E., Akiskal, H.S., et al.(2004) Efficacy of olanzapine combined with valproate or lithium in the treatment of dysphoric mania. Br J Psychiatry 2004 185: 472-478.

2.Tohen, M., Chengappa, K. N., Suppes, T., et al (2002) Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Archives of General Psychiatry, 59, 62 -69.

3.Rendell, J.M., Gijsman, H.J., Keck, P., et al (2003) Olanzapine alone or in combination for acute mania. The Cochrane Database of Systematic Reviews 2003, Issue 1 ... More

Conflict of interest: None Declared

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