NHR Apr-Sept 2019: Research Protocol: A double-blind, randomized, placebo-controlled efficacy trial of individualized homeopathic treatment of geriatric depression

A double-blind, randomized, placebo-controlled efficacy trial of individualized homeopathic treatment of geriatric depression


Shubhamoy Ghosh*1, Sk. Jahir Abbas2, Kaushik Deb Das3, Sangita Saha4, Himangshu Hait5, Sukhdeb Maity6, Anamika Basu7, Sk. Swaif Ali8, Munmun Koley9, Subhranil Saha10

  1. Professor and Head, Dept. of Pathology and Microbiology, Mahesh Bhattacharyya Homoeopathic Medical College and Hospital, Govt. of West Bengal
  2. Lecturer, Dept. of Surgery, Mahesh Bhattacharyya Homoeopathic Medical College and Hospital, Govt. of West Bengal
  3. Reader, Dept. of Pharmacy, Midnapore Homoeopathic Medical College and Hospital, Govt. of West Bengal
  4. Reader, Dept. of Organon of Medicine and Homoeopathic Philosophy, The Calcutta Homoeopathic Medical College and Hospital, Govt. of West Bengal
  5. Professor and Head, Dept. of Practice of Medicine, The Calcutta Homoeopathic Medical College and Hospital, Govt. of West Bengal
  6. Junior Research Fellow, Dept. of Pathology and Microbiology, Mahesh Bhattacharyya Homoeopathic Medical College and Hospital, Govt. of West Bengal
  7. Intern, Mahesh Bhattacharyya Homoeopathic Medical College and Hospital, Govt. of West Bengal
  8. Independent Researcher, Champsara, Baidyabati, Hooghly 712222, West Bengal
  9. Independent Researcher, Shibpur, Howrah 711102, West Bengal

*Correspondence: shubhamoy67@gmail.com


ABSTRACT

Background: The use of complementary and alternative medicine (CAM) including homoeopathy is predominantly more popular in older adults; however, scientific research has so far not provided evidences enough to support their efficacy or effective­ness. In this trial, we intend to evaluate the efficacy of individualized homeopathy (IH) in comparison with placebo in treatment of geriatric depression.

Methods/Design: In this prospective, double-blind, randomized, parallel arm, placebo-controlled trial, geriatric patients diagnosed with depression will be randomized in 1:1 ratio to one of the two interventions – IH or identical-looking Placebo. The outcome measure being used is the Geriatric Depression Scale (GDS) and Quality of Life (QoL) questionnaires. The study endpoint is 3 months. Both the outcome scores will be obtained at baseline and after 3 months. The trial will require 140 patients in order to achieve 80% power for the specified endpoint. In accordance with CONSORT/ReDHoT guidelines, all comparative analyses will be conducted on intention-to-treat basis using SPSS.

Discussion: The outcomes from this trial will generate efficacy data of IH in treatment of geriatric depression.

Trial registration: CTRI/2017/03/008078; UTN: U1111-1193-8257

Keywords

Geriatric depression; Homoeopathy; Placebo; Randomized Controlled Trial


 INTRODUCTION

Depression is the most common mental disorder in community settings, and is a major cause of disability across the world. In 1990, it was the fourth commonest cause of loss of disability adjusted life years in the world, and by 2020, it is projected to become the second commonest cause [1]. Apart from the subjective suffering experienced by people who are depressed, the impact on social and occupational functioning, physical health and mortality is substantial. The impact on physical health sets depression alongside all the major chronic and disabling physical illnesses such as diabetes, arthritis and hypertension [2]. A range of therapeutic approaches are available, the most widely used, in developed countries, is antidepressant drugs [3]. Still, there still remain flaws in the treatment of depression with antidepressants, in terms of efficacy, adverse effects, toxicity overdose, non-compliance to treatment and delayed onset of their therapeutic response [4-7]. Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment and, when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance [8, 9]. Unmet needs of the conventional treatment may contribute to the patients’ search for alternatives: depression is one of the leading causes for use of complementary and integrative medicine [10]. Use of homeopathy to treat psychiatric problems is widespread, and the need for more high quality controlled trials has been identified [11, 12]. Meta-analyses and systematic reviews have drawn mixed conclusions as to whether homeopathy is more effective than placebo in general medicine. The database on studies of homeopathy and placebo in psychiatry is limited, but results do not preclude the possibility of some benefit. Homeopathy is also used extensively to treat depression [13]. However, a systematic review of published and unpublished studies in 2005 demonstrated that the evidence for the effectiveness of homeopathy in depression is limited due to lack of clinical trials of high quality [14]. In an epidemiological cohort study in France, patients with anxiety and depression disorder, who chose to consult general practitioners prescribing homeopathy reported less use of psychotropic drugs, and were marginally more likely to experience clinical improvement, than patients managed with conventional care [15]. Recently, results from a randomized, controlled, double-blind trial indicated that individualized homeopathic Q-potencies were non-inferior to the antidepressant fluoxetine in a sample of patients with moderate to severe depression [16]. But in a randomized, partially double-blind, placebo-controlled, four-armed trial, no consistent or clinically relevant results across all outcomes between homeopathic Q-potencies versus placebo and homeopathic versus conventional case taking were observed; although the results were inconclusive, given that recruitment into this trial was very difficult and was terminated early [17]. In an open observational trial, a course of six months of homoeopathic treatment was associated with significant benefits in patients suffering from depressive episodes [18]. One open observational pilot trial revealed promising role of individualized homeopathic medicines in improving symptoms severity and anoscopic scores in piles with moderate to large effect sizes. The authors undertook a cross-sectional validation survey, followed by open, observational trial involving 60 patients suffering from geriatric depression in the geriatric outpatient of Midnapore Homeopathic Medical College & Hospital (MHMC&H), Govt. of West Bengal, India from May 2015 to April 2016 using Geriatric Depression Scale (GDS). After 3 months of treatment, moderate to large effect size was observed and the questionnaire psychometrics appeared satisfactory [19]. However, the issues regarding efficacy of individualized homeopathy in geriatric depression has remained unresolved. To answer that, the authors intended to undertake a multicenter placebo-controlled double-blind randomized efficacy trial of individualized homeopathic treatment of geriatric depression.

Aims and objectives:

  1. To evaluate the efficacy of IH medicines in comparison to placebo in treatment of geriatric depression
  2. To compare the changes in the geriatric depression score (GDS) short form between groups
  3. To compare the changes in the quality of life (QoL) scale score between groups
  4. To ascertain and shortlist the most frequently indicated homoeopathic medicines in treatment of geriatric depression

METHODS / DESIGN

Study design: Prospective, double-blind, randomized, placebo-controlled, two parallel arms trial with a 3 months’ duration for each patient.

Trial registration: The study protocol is registered prospectively in Clinical Trials Registry – India (CTRI) vides reg. no. CTRI/2017/03/008078; secondary identifier UTN: U1111-1193-8257.

Study setting: Outpatients or inpatients of Mahesh Bhattacharyya Homoeopathic Medical College and Hospital (MBHMC&H), Midnapore Homoeopathic Medical College & Hospital (MHMC&H), and The Calcutta Homoeopathic Medical College & Hospital (CHMC&H).

Selection of samples: Absence of any controlled trial of similar design precluded calculation of standardized difference (effect size) and sample size. Keeping alpha error as 0.05, power 80%, and allocation ratio 1:1, and in order to detect a medium effect size (Cohen’s d) of 0.5 by a two-tailed unpaired t test comparing difference between two independent means of two groups, calculated sample size comes to 128 (verum: 64, placebo: 64). Keeping a provision for assumed 10% drop-outs, target sample size becomes 140 (verum: 70, placebo: 70).

Inclusion criteria:

  1. Aged 60-80 years
  2. Both sexes
  3. Suffering from depression [GDS score: ≥ 5]
  4. Providing written informed consent
  5. Literate patients; ability to read English or Bengali

Exclusion criteria:

  1. Patients who are too sick for consultation, unwilling to take part, unable to read, and not giving consent to join the study
  2. Diagnosed cases of unstable mental or psychiatric illness or other uncontrolled or life-threatening illness affecting QoL
  3. Currently receiving standard psychiatric therapy (conventional medication)
  4. Substance abuse and/or dependence
  5. Self-reported immune-compromised state
  6. Undergoing homeopathic treatment for any chronic disease within last 6 months.

Criteria for discontinuing or modifying allocated interventions: Patients can be excluded from further participation within the study or withdraw themselves without having to provide any further reasons. Possible reasons for this therapy dropout are expected to be:

  1. Withdrawal of the patient’s consent
  2. Consumption of drugs or, rather, medications which are not permitted during the duration of the clinical study
  3. Deficient compliance of patients after the evaluation of the examining physician (regular and specified consumption of study medication)
  4. A newly occurring condition which influences the efficacy of the study investigation or is contra-indicative to the intake of study medication or which needs to be treated with a medication which is not permitted as a concurrent medication during the study
  5. Retroactive appraisal of either unfulfilled inclusion criteria or fulfilled exclusion criteria after the decision of the examining physician/leader of the clinical study
  6. Medically necessary transfer of the patient to a different department or hospital during the study phase
  7. Unexpected findings which make the continuation of therapy from an ethical or medical point of view unjustifiable; the decision will be made by the concerned physician

The complete study can be discontinued prematurely if it is perceptible early on that it cannot fulfill the aforementioned inclusion criteria. This includes:

  1. The necessary recruiting numbers cannot be achieved
  2. There are serious violations of the protocol
  3. The documentation is incomplete or was deliberately filled out incorrectly and legal or ethical instructions are not met

Randomization: Permuted block randomization method has been adopted to generate 14 blocks of 10 random numbers [14 × 10 = 140]. Random sequence (1 and 2 for either of medicine or placebo) has been generated by a third party who is not allowed to influence the study in any way. This chart will be made available to the pharmacist in strict confidentiality and will never be disclosed to the patients or doctors under any circumstances. The allocated code will be maintained till the end of the trial.

Blinding: Participants, the principal investigator and the co-investigators, and the outcome assessors will remain blinded to the identity of the two treatment groups until the end of the study. Unblinding of individual participants through the investigator may occur in cases of SAEs.

Intervention:

  • Experimental arm: Indicated homoeopathic medicines will be administered in centesimal potencies and in individualized dosage, as decided appropriate to the case or condition. Each dose consists of 4-6 cane globules no. 20 moistened with the indicated medicine (preserved in 90% v/v ethanol); to be taken orally on clean tongue with empty stomach; dosage and repetition depending upon the individual requirement of the cases. Duration of therapy: 3 months.
  • Comparator arm: Placebo, indistinguishable from verum, will be administered in individualized dosage orally on clean tongue with empty stomach for 6 months. Each placebo dose will consist of 4-6 cane sugar globules no. 20 moistened with 60º OP ethanol. Duration of therapy: 3 months.

The homoeopathic medicines and placebo are provided by HAPCO® as bulk product. Both medicines and placebo are repacked in identical glass bottles and labeled with code, name of medicine and potency. These were dispended according to the randomization list provided to the pharmacist.

Selection of tools:

  1. Standardized data recording proforma
  2. Repertorization software [RADAR®, version 10.0.028 (ck), Archibel 2007, Belgium]
  3. GDS and QoL questionnaires

Brief of procedure: Following preliminary screening using inclusion criteria and detailed screening using specified exclusion criteria, eligible patients will be recruited in the trial. Following that, outcome data (baseline GDS and QoL questionnaire scores) will be obtained. Coded identical containers will be used. Final selection of the single individualized medicine will be based on case taking in adherence with the standard homoeopathic guidelines, analysis and evaluation of symptoms, miasmatic diagnosis, framing symptom totality, repertorization and consultation with Homoeopathic Materia Medica. Individualized dose will be selected on the judgment of susceptibility of the patients. Subsequent prescriptions will be generated according to Kent’s observations, second prescription, and relevant homoeopathic principles and will be recorded in follow-up sheets.

Outcome assessment: Primary – Geriatric depression score [20] (GDS; 15-item short form provided with Yes/No); Secondary – Quality of Life Scale score [21] (QoLS); 16-items provided with 7-point Likert scale).

Data collection: The outcomes will be assessed at baseline and after 3 months. A specially designed Microsoft Office Excel 2007 spread sheet (master chart) will be used for data extraction and shall be subjected to statistical analysis.

Statistical techniques and data analysis: It will follow the intention-to-treat (ITT) approach; i.e. every included patient will enter the final analyses. Missing values will be imputed and replaced. Descriptive data (categorical and continuous) will be presented in terms of absolute values, percentages, mean, standard deviations (sd), confidence intervals (CI), etc. as appropriate. The groups will be checked for comparability of socio-demographic characteristics at baseline. Parametric or non-parametric inferential tests will be used to detect group differences as per normality or non-normality of distribution of data respectively. P values will be set at less than 0.05 two-tailed as statistically significant. SPSS® IBM® Inc., version 20 for Windows shall be used for statistical analysis. Aside from the analysis of all randomized patients, a per-protocol analysis will also be carried out which is supposed to indicate which effect sizes can be reached under optimal circumstances. In the per-protocol sample, all patients will be included who fulfill all study requirements.

Ethical issues: Intercurrent illness, adverse or serious adverse event(s), if any, will be recorded and treated accordingly as per homoeopathic principles irrespective of the allocated codes, or if non-responding, then the patient shall be referred for conventional treatment. Prior to enrolment, each patient will be provided with a patient information sheet in local vernacular Bengali detailing the objectives, methods, risks and benefits of participating, and confidentiality issues. Subsequent to that, written informed consent shall be obtained. Approval is already taken from the institutional ethics committees (IEC) prior to initiation. The study shall be performed under the constant supervision of the IEC. This study is in compliance with the Helsinki Declaration and with the International Conference on Harmonization (ICH) – Good Clinical Practice. Protocol amendments, if necessary will be submitted to the ethics committee and implementation will be done after approval.

Study flow diagram:

DISCUSSION & CONCLUSION

Despite the fact that homoeopathy has a long tradition in the complementary treatment of patients and is part of the medical curriculum in many European universities, there is an ongoing debate on its efficacy, effectiveness and credibility. Thus, more robust clinical studies with clear and relevant endpoints are needed to substantiate the evidence base from primary to critical care. This study examines the efficacy of individualized homoeopathic medicines over placebo in geriatric depression in randomized design and prospectively for the first time toward generating clinical evidence. The use of homoeopathic medicines in depression is quite popular; however, scientific papers are sparse. This is a multi-centric study in three homoeopathy hospitals. The protocol adheres to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement [22] and TIDieR (Template for Intervention Description and Replication) checklist [23]. Reporting of the study results will adhere to the criteria for reporting individualization in homoeopathy [24], the RedHot (homoeopathy specific CONSORT) statement [25] and model validity of homoeopathic treatment (MVHT) [26].

Should the main outcome of the trial be positive, the qualitative element of the study will provide insights into individualized homoeopathic treatment of geriatric depression. Publication of results in a peer-reviewed and indexed scientific journal and presentation at scientific meetings is planned. Due acknowledgement and/or authorship will be given to them who have participated in the proposal development and data analysis at the end of the paper with their specific contribution to the study. Authorship credit shall be based on substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content, and final approval of the version to be published.

Trial status: At the time of initial manuscript submission, recruitment had already started (April 2017); and is ongoing.

Conflict of interest: The authors declare that they have no competing interests.

Funding: We received no funding for the study. Infrastructural support will be given by the study site. Additional costs required for the project will be incurred by the authors themselves.

Authors’ contributions: SG conceived and designed the study and remains the principal investigator. SJA, KDD, SS, and HH are the co-investigators. MK and SS wrote the study protocol and are responsible for statistical analysis. SM, AB and SSA are responsible for data collection, compilation and management. SS drafted the manuscript. All authors reviewed and approved the final manuscript.

Acknowledgements: We are thankful to the patients, pharmacists and staffs for their sincere participation in this ongoing project.

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Cite this article as: Ghosh S, Abbas SJ, Das KD, Saha S, Hait H, Maity S, Basu A, Ali SS, Koley M, Saha S. Protocol: A double-blind, randomized, placebo-controlled efficacy trial of individualized homeopathic treatment of geriatric depression. National Homoeo Recorder 2019;15(2,3):

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