Psychopharmacology (2014) 231:4417–4418 DOI 10.1007/s00213-014-3773-1

LETTER TO THE EDITOR

Ketamine’s effectiveness in unipolar versus bipolar depression Guillaume Fond & Laurent Boyer

Received: 28 September 2014 / Accepted: 6 October 2014 / Published online: 15 October 2014 # Springer-Verlag Berlin Heidelberg 2014

Dear Dr. Price, We read with great interest the letter of McGuirr and Berlim (2014) in response to our work. We are in agreement with their general comment on improving coordination between working teams to avoid overlapping studies and waste of efforts in data analyses, as also mentioned in the study of Siantis et al. (2013). However, we are doubtful about the relevance of their criticisms on ketamine’s effectiveness in unipolar versus bipolar depression. McGuirr and Berlim, reported “superior efficacy of ketamine in unipolar (SMD=1.07) as compared to bipolar major depression (SMD = 0.68)” meanwhile “the meta-analysis by Fond and colleagues reported ketamine’s superiority in bipolar (SMD = 1.34) rather than unipolar major depression (SMD=0.91)”. We globally do not agree with the statement of McGuirr and Berlim for the following reasons. We did not find or write that ketamine was superior in bipolar rather than unipolar major depression. Subgroup analyses are observational by nature and are not based on randomized comparisons. This should be kept in mind when

G. Fond Pôle de psychiatrie des hôpitaux universitaires H Mondor, DHU Pe-Psy INSERM U955, Eq Psychiatrie Génétique, Fondation FondaMental Fondation de coopération scientifique en santé mentale, Université Paris Est-Créteil, Créteil, France L. Boyer Service hospitalo-universitaire de psychiatrie, Hôpital Sainte-Marguerite, 270 boulevard de Sainte Marguerite, Marseille, France G. Fond (*) Pole de Psychiatrie, Hôpital A. Chenevier, 40 rue de Mesly, Créteil 94010, France e-mail: [email protected]

interpreting subgroup analyses in meta-analysis. Moreover, if the meta-analysis produces a precise estimate of summary effect in each subgroup, the true effects within each subgroup fall within a certain range (i.e., confidence interval). In our meta-analysis, we found a large overlap in effects between the two subgroups, which prevent us of concluding the superiority of ketamine in bipolar depression. As we have written in our article, the correct interpretation is that “ketamine was found to be effective in unipolar major depression as well as in bipolar depression”. Further studies with specific design are now required to compare the efficacy of ketamine in unipolar versus bipolar depression. Finally, McGuirr and Berlim claimed in their publication that ketamine had a superior efficacy in unipolar compared to bipolar major depression (2014). This statement is incorrect because p value was superior to 0.05. Recent works have even suggested using lower level of significance to reduce the rate of nonreproducibility of scientific researches (Johnson 2013). Concerning the differences of SMD between our work and McGuirr and Berlim results, we agree that several factors can explain it, e.g., the methodological differences such as the correlations between pre- and post-ketamine depression scores, the number of studies according the inclusion criteria. For the specific point of Diazgranados et al. study (2010), we did not use the Cohen’s d published by Diazgranados because it was calculated at certain time without considering the difference pre- and posttreatment necessary for the calculation of the SMD. We thus included raw data from the figure published in the article. Concerning the study of Lapidus et al. (2014), it was not published when we started our analysis. Finally, we considered the study of Valentine et al. (2011) as a quasi-experimental and quasi-randomized controlled trial. However, this study

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was rated with the lowest quality score (as mentioned in our Table 3). The quality of studies was then taken into account in sensitivity analyses, without any change in our findings and the clinical message. We hope that further updated meta-analyses will be published in the future, given the increasing number of high quality trials that are published each year on this subject and the remaining unanswered clinical questions that were underlined in our discussion. Acknowledgments We acknowledge Lore Brunel, psychologist, APHP, Fondation Fondamental, Paris, France for editorial assistance. This work was supported by INSERM, Assistance Publique-Hôpitaux de Paris, RTRS Santé Mentale (Fondation Fondamental). This work was supported (in part) by the Investissements d’Avenir program managed by the ANR under reference ANR-11-IDEX-0004-02. We thank all the patients that participated to the studies presented in this article. Conflict of interest No conflicts to disclose.

Psychopharmacology (2014) 231:4417–4418

References Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S et al (2010) A randomized add-on trial of an N-methylD-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 67(8):793–802 Johnson VE (2013) Revised standards for statistical evidence. Proc Natl Acad Sci U S A 110(48):19313–19317 Lapidus KA, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L et al (2014) A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry McGirr A, Berlim MT (2014) A comment on Fond and colleagues’ systematic review and meta-analysis of ketamine in the treatment of depressive disorders (Psychopharmacology 2014). Psychopharmacology (Berl) Siontis KC, Hernandez-Boussard T, Ioannidis JP (2013) Overlapping meta-analyses on the same topic: Survey of published studies. BMJ 347:f4501 Valentine GW, Mason GF, Gomez R, Fasula M, Watzl J, Pittman B et al (2011) The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS. Psychiatry Res 191(2):122–127

Ketamine's effectiveness in unipolar versus bipolar depression.

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