Individualized homeopathic treatment and fluoxetine for moderate to severe depression in peri- and postmenopausal women (HOMDEP-MENOP study): a randomized, double-dummy, double-blind, placebo-controlled trial
Authors: Juan Asbun-Bojalil
Lidia Llanes-González
Leopoldo Aguilar-Faisal
Emma Del Carmen Macías-Cortés
Journal: PLoS ONE (2015)
Discipline: Multidisciplinary
Keywords: Perimenopausal period; homeopathy; depression; clinical trials; efficacy
Affiliations: División de Estudios de Posgrado, Escuela Superior de Medicina, Instituto Politécnico Nacional, Distrito Federal, México; Consulta Externa de Homeopatía, Hospital Juárez de México, Secretaría de Salud, Distrito Federal, México., Unidad de Salud Mental, Hospital Juárez de México, Secretaría de Salud, Distrito Federal, México., División de Estudios de Posgrado, Escuela Superior de Medicina, Instituto Politécnico Nacional, Distrito Federal, México.

Abstract:  Background: Perimenopausal period refers to the interval when women's menstrual cycles become irregular and is characterized by an increased risk of depression. Use of homeopathy to treat depression is widespread but there is a lack of clinical trials about its efficacy in depression in peri- and postmenopausal women. The aim of this study was to assess efficacy and safety of individualized homeopathic treatment versus placebo and fluoxetine versus placebo in peri- and postmenopausal women with moderate to severe depression. Methods/design: A randomized, placebo-controlled, double-blind, double-dummy, superiority, three-arm trial with a 6 week follow-up study was conducted. The study was performed in a public research hospital in Mexico City in the outpatient service of homeopathy. One hundred thirty-three peri- and postmenopausal women diagnosed with major depression according to DSM-IV (moderate to severe intensity) were included. The outcomes were: change in the mean total score among groups on the 17-item Hamilton Rating Scale for Depression, Beck Depression Inventory and Greene Scale, after 6 weeks of treatment, response and remission rates, and safety. Efficacy data were analyzed in the intention-to-treat population (ANOVA with Bonferroni post-hoc test). Results: After a 6-week treatment, homeopathic group was more effective than placebo by 5 points in Hamilton Scale. Response rate was 54.5% and remission rate, 15.9%. There was a significant difference among groups in response rate definition only, but not in remission rate. Fluoxetine-placebo difference was 3.2 points. No differences were observed among groups in the Beck Depression Inventory. Homeopathic group was superior to placebo in Greene Climacteric Scale (8.6 points). Fluoxetine was not different from placebo in Greene Climacteric Scale. Conclusion: Homeopathy and fluoxetine are effective and safe antidepressants for climacteric women. Homeopathy and fluoxetine were significantly different from placebo in response definition only. Homeopathy, but not fluoxetine, improves menopausal symptoms scored by Greene Climacteric Scale. Trial registration: ClinicalTrials.gov NCT01635218. Protocol publication: https://clinicaltrials.gov/ct2/show/NCT01635218 [corrected]. 

Retracted: No

PubPeer comments:
 2020 retraction. https: journals.plos.org plosone article?id=10.1371 journal.pone.0232415 Following the publication and correction of this article [1, 2], questions were raised about the study design and reporting that prompted a full reassessment of the article. This post-publication evaluation involved three senior staff editors, a statistical reviewer, and a member of PLOS ONEu2019s Editorial Board, and identified the following concerns: The individualized homeopathic treatment (IHT) and the decision-making framework for treatment adjustments were not reported in sufficient detail to enable reproducibility of the study or an assessment as to the clinical validity of treatment choices. In response to this issue, the authors provided information in post-publication discussions about the individualized homeopathic consultations and guidance used for homeopathic prescription, and commented that potencies of homeopathic remedies were selected on the basis of homeopathic principles. Citing a 2014 systematic review of clinical trials involving IHT [3], the authors commented that the replicability of IHT has been demonstrated by previous studies that applied the same treatment approach to other medical conditions. They also asserted that the information reported in [1] was sufficient to enable replication by trained IHT practitioners, and that the study was reported per CONSORT criteria and the RedHot supplement to CONSORT for homeopathy clinical trials. The study design did not include sufficient controls to rule out the possibility that observed effects in the IHT groupu2014which received homeopathic remedies at 30C (10u221260) and 200C (10u2212400) dilutionsu2014represent placebo effects rather than responses to the homeopathic treatments. The authors disagreed with this point, provided additional information about the methodology, and asserted that elements of the study design accounted for placebo effects. Insufficient information was provided in the article about the methodology by which diagnoses were made in the study, the reliability of that methodology, and how blinding was achieved during the diagnostic assessments. The article reported that participants were diagnosed according to DSM-IV but did not include details as to how the criteria were applied in practice during the trial. The authors provided additional methodological information in post-publication discussions. The PLOS ONE Editors and the consulted Academic Editor reviewed the information and additional methodological details provided by authors in response to each of these issues. The Editors determined that the additional information provided did not fully address the above concerns, which call into question the reproducibility of the study, the scientific validity and rigor of the study design, and whether conclusions are adequately supported by the results. For these reasons, the PLOS ONE Editors retract this article. We regret that these issues were not identified and addressed prior to the articleu2019s publication. During the post-publication assessment, questions were also raised about whether the 6-week duration of the study and fixed dosing regimen for fluoxetine treatment were sufficient to allow an assessment as to the efficacy of fluoxetine where it was prescribed. The consulted Academic Editor noted that other randomized clinical trials using fluoxetine allow for increasing dosage in case of nonresponse. The Academic Editor also noted that per clinical practice guidelines, trials of antidepressants should generally last 8u201312 weeks [4] and it generally requires 4u20138 weeks of treatment to determine whether a patient is responsive to a particular intervention [5]. The authors noted that trials identified in published systematic reviews [6, 7, 8] used the same duration of fluoxetine treatment as was applied in [1]. The authors further commented that the fluoxetine dose used aligns with starting doses applied in clinical practice [4]. EdCM-C, LL-G, LA-F, and JA-B did not agree with retraction. References 1.Macu00edas-Cortu00e9s EdC, Llanes-Gonzu00e1lez L, Aguilar-Faisal L, Asbun-Bojalil J (2015) Individualized Homeopathic Treatment and Fluoxetine for Moderate to Severe Depression in Peri- and Postmenopausal Women (HOMDEP-MENOP Study): A Randomized, Double-Dummy, Double- Blind, Placebo-Controlled Trial. PLoS ONE 10(3): e0118440. https: doi.org 10.1371 journal.pone.0118440 pmid:25768800 2.The PLOS ONE Staff (2015) Correction: Individualized Homeopathic Treatment and Fluoxetine for Moderate to Severe Depression in Peri- and Postmenopausal Women (HOMDEP-MENOP Study): A Randomized, Double-Dummy, Double-Blind, Placebo-Controlled Trial. PLoS ONE 10(5): e0127719. https: doi.org 10.1371 journal.pone.0127719 pmid:25938465 3.Mathie RT, Lloyd SM, Legg LA, Clausen J, Moss S, Davidson JRT, Ford I. (2014) Randomised placebo-controlled trials of individualised homeopathic treatment: systematic review and meta-analysis. Syst Rev 3: 142. pmid:25480654 4.TMAP, 2008. Texas Medication Algorithm Project. Procedural Manual: Major Depressive Disorder Algorithms. 5.APA, 2010. American Psychiatric Association. Treating Major Depressive Disorder: A Quick Reference Guide. Available online at: https: psychiatryonline.org pb assets raw sitewide practice_guidelines guidelines mddguide.pdf. 6.Naudet F, Maria AS, Falissard B. (2011) Antidepressant Response in Major Depressive Disorder: A Meta-Regression Comparison of Randomized Controlled Trials and Observational Studies. PLoS ONE 6: e20811. pmid:21687681 7.Magni LR, Purgato M, Gastaldon C, Papola D, Furukawa TA, Cipriani A, Barbui C. (2013) Fluoxetine versus other types of pharmacotherapy for depression. Cochrane Database of Systematic Reviews 7: Art. No.: CD004185. pmid:24353997 8. Ren Y, Zhu C, Wu J, Zheng R, Cao H (2015) Comparison between herbal medicine and fluoxetine for depression: a systematic review of randomized controlled trials. Complement Ther Med 23:674u201384. pmid:26365447 , 
 AUTHORSu2019 COMMENTS ON THIS RETRACTION https: journals.plos.org plosone article comment?id=10.1371 annotation 82077eec-9edb-403b-9b02-4d5d77d6dbae We strenuously reject the PLOS ONE Editorsu2019 decision to retract our work, given that all the issues they have raised would usually warrant critique in a systematic review at most, not retraction. Our team answered all points raised during post-publication discussions in extensive detail. In the interests of transparency, accuracy and fairness, the most relevant points are summarized below, so that an objective reader can make up their own mind about the rigour of our study and whether the PLOS ONE Editorsu2019 decision to retract our work is justified: Claim 1 u2013 Insufficient reporting details provided to allow for replication of the treatment used and assessment of the clinical validity of treatment choices. All additional details requested by the Editors were provided i.e. how consultations were conducted; how the choice of medicine for each patient was made according to their clinical indications; and how dosage (either 30C or 200C) was selected according to well-established homeopathic prescribing guidelines. We also clarified that all patients were prescribed 200C, except for five patients who received a 30C prescription at the end of the observation period. Although we understand the Editorsu2019 curiosity regarding these details, our published study provides sufficient detail for those trained in the specific prescribing technique used (u2018Individualized Homeopathic Treatmentu2019 - u2018Classical Homeopathyu2019) to replicate and validate the intervention given. Claim 2 u2013 Our study design was insufficient to rule out placebo effects, so our conclusions were not supported by our data We reject this point of argument entirely. Our study utilized a double blind, double dummy, randomized, placebo-controlled, three-armed study design: a gold-standard study design according to CONSORT and SPIRIT 2013 guidelines. To our knowledge there is no better clinical trial design to account for placebo effects. Furthermore, fluoxetineu2019s efficacy in depression in adults is well established. As our study detected a clinically beneficial, and statistically significant effect of fluoxetine on depressive symptoms compared to the matched placebo, this positive control arm demonstrates that the study design was indeed capable of generating and detecting a predicted beneficial treatment effect beyond placebo. Disturbingly, during the post-publication discussion the PLOS ONE Editors did not explain in what way s they considered our study design to be inadequate. Rather, they simply stated that because the homeopathic treatments included 30C (i.e. 10^-60) and 200C (10^-400) potencies of the homeopathic medicines, any positive effect seen must have been a placebo effect. Whilst homeopathic medicines cannot have a standard pharmacological mode of action based on interaction at the biochemical level, this does not preclude other, as yet poorly understood, modes of action other than placebo. We also explained to the Editors that Individualized Homeopathic Treatment (IHT) has already been shown to provide beneficial clinical effects beyond placebo in a systematic review and meta-analysis of 32 published studies, from 26 independent research teams, from 12 countries using IHT for many conditions within randomized control trials. Mathie et al. 2014 concluded that IHT is up to twice as likely to provide clinical benefit as placebo (OR = 1.98, 95% CI 1.16 to 3.38); this result fully withstands sensitivity analysis and directly undermines the PLOS ONE Editorsu2019 argument. Claim 3 u2013 We did not provide enough information about how patients were diagnosed, and the Editors questioned the reliability of our diagnoses The diagnosis of Major Depressive Disorder (MDD) was made using Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria from the American Psychiatric Association (stated in the Methods section of the article) and we provided a clear checklist of symptoms that were used. Each participant was also assessed at baseline using two long-established, validated, and standardized scales for assessing depression severity (Hamilton Rating Scale for Depression and Beck Depression Inventory). Moreover, according to the eligibility criteria (page 5 of the article) only women with a 17-item Hamilton Rating Scale for Depression score of 14-24 (corresponding to a moderate to severe depression) were included, confirming the MDD diagnosis. The PLOS ONE Editors provided us with no clear reason as to why this was insufficient to address their concerns. Claim 4 u2013 Insufficient information provided as to u2018how blinding was achieved during the diagnostic assessmentsu2019 The precise meaning of this point is unclear, but if the claim is that blinding could have been broken during the study, this speculation is completely incorrect. Blinding was achieved using the most rigorous u2018double dummyu2019 design. All patients in the study received the same treatment experience u2013 a homeopathic consultation, followed by two prescriptions i.e. a homeopathic medicine (verum or placebo) and Fluoxetine (verum or placebo). The clinical assessments at week 0, 4 and 6 were made independently from the prescribing physician, by a psychologist with no training in homeopathy. Finally, as stated in our publication, blinding was broken only once, due to a patient (taking Fluoxetine) experiencing adverse events. We therefore reject this point outright as a reason to retract our study. For further details visit: https: www.HRI-Research.... Dr. Emma Macias-Cortes et al. , 
 #2 AUTHORSu2019 COMMENTS ON THIS RETRACTION For further details visit: https: www.hri-research.org resources homeopathy-the-debate macias-cortes-2015 ,