The authors have declared that no competing interests exist.
Conceived and designed the experiments: CMW KL MT RL SK SNW UCA. Analyzed the data: RL. Wrote the paper: UCA CMW. Treated the patients: UCA. Involved in data acquisition and trial management: LS FM. Interpretation of results/substantial scientific contribution/revising manuscript: CMW FM KL MT LS SK RL SNW UCA.
The specific clinical benefit of the homeopathic consultation and of homeopathic remedies in patients with depression has not yet been investigated.
To investigate the 1) specific effect of individualized homeopathic Q-potencies compared to placebo and 2) the effect of an extensive homeopathic case taking (case history I) compared to a shorter, rather conventional one (case history II) in the treatment of acute major depression (moderate episode) after six weeks.
A randomized, partially double-blind, placebo-controlled, four-armed trial using a 2×2 factorial design with a six-week study duration per patient was performed.
A total of 44 from 228 planned patients were randomized (2∶1∶2∶1 randomization: 16 homeopathic Q-potencies/case history I, 7 placebo/case history I, 14 homeopathic Q-potencies/case history II, 7 placebo/case history II). Because of recruitment problems, the study was terminated prior to full recruitment, and was underpowered for the preplanned confirmatory hypothesis testing. Exploratory data analyses showed heterogeneous and inconclusive results with large variance in the sample. The mean difference for the Hamilton-D after 6 weeks was 2.0 (95%CI −1.2;5.2) for Q-potencies vs. placebo and −3.1 (−5.9;−0.2) for case history I vs. case history II. Overall, no consistent or clinically relevant results across all outcomes between homeopathic Q-potencies versus placebo and homeopathic versus conventional case taking were observed. The frequency of adverse events was comparable for all groups.
Although our results are inconclusive, given that recruitment into this trial was very difficult and we had to terminate early, we cannot recommend undertaking a further trial addressing this question in a similar setting.
Prof. Dr. Claudia Witt had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
clinicaltrials.gov identifier
Depression is the most disabling mental disorder in the European Union (EU), affecting almost 7% of the EU population each year
In classical homeopathy, the treatment consists of two main elements: taking case histories and prescribing individually selected homeopathic medicines
Although there is no rationale for a mechanism of highly diluted homeopathic medicines, a relevant proportion of patients seeking a physician providing homeopathic care in Germany (6% of women and 5% of men)
To date, only one full scale study, of which we are aware, on homeopathy for depression has been published
We investigated the 1) specific effect of individualized homeopathic Q-potencies compared to placebo and 2) the effects of an extensive homeopathic case taking (case history I) compared to a shorter, rather conventional one (case history II) in the acute treatment of major depression (moderate episode) after six weeks.
The protocol for this trial and supporting CONSORT checklist are available as supporting information; see
A randomized, partially double-blind, placebo-controlled, four-armed trial using a 2×2 factorial design with a six week study duration per patient was performed. Patients were randomized to one of four groups: 1) homeopathic Q-potencies/case history I, 2) placebo/case history I, 3) homeopathic Q-potencies/case history II and 4) placebo/case history II. The study protocol was published
A block randomization with variable block lengths was carried out using a 2∶1∶2∶1 ratio (exposing a smaller number of participants to placebo) and placed in sequentially numbered, sealed opaque envelopes. The randomization list was generated with SAS/BASE Software (SAS Inc., Cary NC, USA) by a statistician not further involved in the study.
The patients, the whole study team including the psychiatrist, the psychologist who assessed the HAM-D, and the statistician remained blinded to the identity of the four treatment groups until the end of the study. Only the study physician was unmasked for the case history type. The randomization list was kept strictly confidential. Only the study pharmacist and the statistician who generated the randomization list and prepared the envelopes had access to the randomization list. During the study, unblinding was allowed in the case of a patient emergency using sealed emergency envelopes, but this situation did not occur.
Eligible patients included men and women aged between 18 and 65 years diagnosed with major depression by a psychiatrist and rated afterwards as moderately severe (HAM-D 17 to 24) by a psychologist. Patients must not have been taking antidepressants or anxiolytic drugs (with the exception of Lorazepam as rescue medication, maximum dose 1.5 mg/day) at the time of inclusion. Capability and willingness to give informed consent and to comply with the study procedures were also required.
Exclusion criteria included schizophrenia or other psychotic disorders, bipolar affective disorder, schizoaffective disorders, alcohol or other substance abuse, eating disorders, a clinically significant DSM-Axis II (Diagnostic and Statistical Manual of Mental Disorders) disorder at the time of inclusion; severe depression which previously motivated a suicide attempt as defined by the Columbia-Suicide Severity Rating Scale (C-SSRS); suicidal ideation of type 4 or 5 in the C-SSRS
Written informed consent was obtained from all patients. Regulatory approval was received by the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), EudraCT Nr: 2009-017458-11, Submission-Nr.: 4036175. Ethical approval was given by Ethics Committee, Berlin, Landesamt für Gesundheit und Soziales (LaGeSo): ZS EK 15 099/10. This study was in compliance with the Helsinki Declaration and with the ICH-GCP guidelines. Trial registration: clinicaltrials.gov identifier NCT01178255.
Patients were interviewed and treated at the Integrative Medicine outpatient clinic (CHAMP) of the Charité – Universitätsmedizin Berlin, by a medical doctor specialized in homeopathy with 20 years experience in classical homeopathy. The medical doctor was also experienced in case history and analysis under double blind conditions
The particular approaches of each case history differed in the time used for the semi-standardized questionnaire and the onsite patient-doctor interaction. The homeopathic case history (case history I) was a more extensive conversation (60–90 minutes), in which the patient was asked to speak about different aspects in the questionnaire, including stressful live events, development and details of psychological and physical symptoms, and information which was discussed as needed. This was different in the shorter, more conventional case history (case history II). Case history II took around 30 minutes and the same questionnaire as in case history I was read in silence by the attending physician, who asked questions only to elucidate information that was unclear, resembling a rather conventional case taking, conducted by a general physician, when the patient already has a psychiatric diagnosis of depression. The follow-up differed in the time used to assess the remaining symptoms, 10 or 30 minutes, for the conventional or the homeopathic case history, respectively. In the latter case, interpersonal or ongoing stressful life events were also extensively assessed.
The selection of the individualized remedies (case analyses) was carried out after the case history, in the absence of the patient, based on the latest clinical-pharmaceutical protocol developed by Hahnemann, which includes the standardized use of ascending Q-potencies 8
Q-potencies were provided by Dr. Zinsser Arzneimittel, (Freudenstadt, Germany) and were manufactured according to the methodology described by Hahnemann
The standard dose was one drop of the received vial three times per week
For the planned study, the primary endpoint was the mean total depression score using the 17-item version of the Hamilton Depression Rating Scale (HAM-D)
Adverse events were collected during the study and will form part of the secondary endpoint data in determining the safety of homeopathic medicines. Participantś treatment expectations at baseline were also assessed.
For this study we assumed that the verum treatment is better than placebo by 2.7±6.0 (mean ± standard deviation) HAM-D score points after 6 weeks (corresponding to a SMD = 0.45), that type II case history is better than type I by 2.7±6.0 score points (SMD = 0.45), and that both effects do not interact. If so, a Bonferoni-adjusted F-Test (multiple significance level a = 0.05, two-sided) has a power of 83.5% to detect the difference between verum and placebo and a power of 85.0% to detect the difference in case history taking, if 68 patients are included in groups 1 and 3, and 34 patients are included in groups 2 and 4. This led to a total number of 228 patients, if one allows for a 10%drop-out rate per group.
Recruitment started in September 2010 and the study had to be terminated earlier than anticipated (March 2011), because it became clear that the planned recruitment strategy was not feasible. The rate of recruited patients per month was much lower than preplanned: less than 100 patients would have been included by February 2012, the already postponed end of the recruitment phase, as shown in
448 subjects contacted the coordinating study center and were screened by phone. 211 did not meet the eligibility criteria and 176 were not further interested after receiving more information about the study details. 61 patients participated in a screening visit and 44 were randomized. 17 were not included, because 16 did not meet study criteria (13 with mild depressive episode and 3 with a severe depressive episode) and 1 could not comply with study procedures. A total of 37 patients completed the 6-week treatment phase (
Included patients were mainly female (72.7%) and had an average age of 46.5 (SD 10.6) years. The average disease duration was 8.9 (SD 10.0) years. Further baseline data of study population are summarized in
Homeopathic case history | Conventional case history | |||
+ Q-potencies | + Placebo | + Q-potencies | + Placebo | |
Intention-to-treat population | n = 16 | n = 7 | n = 14 | n = 7 |
Gender (n/% female) | 13/81.3% | 4/57.1% | 11/78.6% | 4/57.1% |
Age (mean±sd) | 49.6±9.2 | 45.4±11.2 | 43.1±11.5 | 47.3±11.1 |
Blood pressure (systolic) (mean±sd) | 123.1±17.4 | 123.6±17.9 | 123.6±18.6 | 125.7±23.7 |
Blood pressure (diastolic) (mean±sd) | 75.9±10.5 | 75.7±11.3 | 75.0±10.1 | 78.6±8.9 |
Other relevant diagnoses (n/%): | 8/50.0% | 1/14.3% | 7/50.0% | 4/57.1% |
BMI (kg/m2) | 24.6±7.1 | 23.8±1.9 | 24.6±4.5 | 25.0±5.1 |
Partnership: yes/% | 7/43.8% | 4/57.1% | 5/35.7% | 4/57.1% |
Currently employed: yes/% | 12/75.0% | 5/71.4% | 6/42.9% | 5/71.4% |
Duration of depression (years, mean±sd) | 4.5±4.8 | 6.0±4.8 | 11.5±9.5 | 16.8±16.8 |
HAM-D (total score) (mean±sd) | 19.9±2.8 | 19.0±1.4 | 19.4±2.3 | 19.0±1.8 |
BDI (total score) (mean±sd) | 28.8±8.8 | 28.4±6.6 | 29.5±6.4 | 26.4±8.2 |
SF-12 psychic score (mean±sd) | 35.2±5.1 | 30.9±4.2 | 33.7±6.3 | 33.7±7.4 |
SF-12 physical score (mean±sd) | 34.4±9.0 | 45.6±7.9 | 38.7±8.8 | 44.3±11.0 |
Reasons for participation (n/%): | ||||
curiosity | 5/31.3% | 4/57.1% | 7/50% | 3/42.9% |
contribution to science | 3/18.8% | 2/28.6% | 7/50% | 4/57.1% |
free therapy | 5/31.3% | 3/42.9% | 2/14.3% | 2/28.6% |
improvement of symptoms | 16/100% | 5/71.4% | 14/100% | 4/57.1% |
Appraisal of the effectiveness of homeopathy (n/%): | ||||
very effective | 3/18.8% | 1/14.3% | 1/7.1% | 1/14.3% |
effective | 13/81.3% | 4/57.1% | 11/78.6% | 2/28.6% |
less effective | 0/0.0% | 1/14.3% | 2/14.3% | 3/42.9% |
ineffective | 0/0.0% | 1/14.3% | 0/0.0% | 0/0.0% |
Expectations (n/%): | ||||
cure | 0/0% | 0/0.0% | 1/7.1% | 0/0.0% |
marked improvement | 11/68.8 | 4/57.1% | 11/78.6% | 2/28.6% |
light improvement | 5/31.3% | 2/28.6% | 2/14.3% | 4/57.1% |
no improvement | 0/0.0% | 1/14.3% | 0/0.0% | 1/14.3% |
The following remedies were chosen by the physician: Alumina, Anacardium orientale, Aurum foliatum, Baryta carbonica, Calcarea carbonica, Carbo animalis, Colocynthis, Graphites, Kalium carbonicum, Lycopodium clavatum, Natrum carbonicum, Natrum muriaticum, Nitri acidum, Nux vomica, Phosphorus, Platina, Pulsatilla pratensis, Sepia succus, Silicea terra and Sulphur.
Results are exploratory and were heterogeneous with large variance in the sample (see
Measure | Q-potencies+homeopathic case history (mean ± sd) | Placebo+homeopathic case history (mean ± sd) | Q-potencies+conventional case history (mean ± sd) | Placebo+conventional case history (mean ± sd) |
HAM-D week 2 | 17.1±7.1 | 17.0±3.2 | 13.2±5.7 | 13.0±5.4 |
HAM-D week 4 | 13.7±6.1 | 12.3±3.7 | 11.8±5.0 | 10.1±6.5 |
HAM-D week 6 | 12.5±7.1 | 9.4±2.5 | 14.3±5.7 | 12.8±3.8 |
BDI week 2 | 22.9±11.5 | 23.7±5.1 | 18.3±9.6 | 14.1±9.9 |
BDI week 4 | 18.1±12.0 | 17.0±10.8 | 16.0±8.8 | 12.3±9.9 |
BDI week 6 | 16.1±12.7 | 10.6±6.7 | 14.2±10.5 | 17.5±11.7 |
SF-12 mental summary scoreweek 2 | 36.6±9.7 | 32.6±8.6 | 42.0±8.6 | 39.7±7.3 |
SF-12 mental summary scoreweek 4 | 40.2±12.4 | 42.6±10.7 | 40.1±10.7 | 38.6±6.9 |
SF-12 mental summary scoreweek 6 | 41.8±11.0 | 46.1±10.6 | 41.0±13.6 | 39.6±11.6 |
SF-12 physical summary scoreweek 2 | 41.8±9.5 | 42.4±11.2 | 39.1±7.8 | 42.8±11.8 |
SF-12 physical summary scoreweek 4 | 44.7±10.6 | 43.6±9.2 | 42.7±9.0 | 39.1±13.3 |
SF-12 physical summary scoreweek 6 | 42.8±11.2 | 50.1±6.6 | 45.9±9.0 | 46.3±12.1 |
When calculating differences between groups, no relevant differences were observed between homeopathic medicines and placebo regarding HAM-D (estimated mean scores after 6 weeks 2.0 (95%CI −1.2;5.2) or BDI (after 6 weeks: 0.2 (−5.8;6.2,
Homeopathic Q-potencies vs placebo | Homeopathic (case history I) vs conventional case history (case history II) | |
Measure | Mean differences (95% CI-limits) | |
HAM-D week 2 | −0.1 (−3.5; 3.3) | 3.7 (0.7; 6.8) |
HAM-D week 4 | 1.8 (−1.5; 5.2) | 1.9 (−1.3; 5.2) |
HAM-D week 6 | 2.0 (−1.2; 5.2) | −3.1 (−5.9; −0.2) |
HAM-D weeks 2–6 | 1.3 (−1.5; 4.0) | 0.9 (−1.5; 3.3) |
BDI week 2 | 0.6 (−3.8; 5.0) | 6.3 (1.9; 10.8) |
BDI week 4 | 1.7 (−4.6; 8.0) | 2.8 (−3.6; 9.3) |
BDI week 6 | 0.2 (−5.8; 6.2) | −2.2 (−8.4; 4.0) |
BDI weeks 2–6 | 0.8 (−4.1; 5.7) | 2.3 (−2.8; 7.4) |
SF-12 mental summary score week 2 | 2.7 (−2.7; 8.2) | −6.0 (−11.3; −0.7) |
SF-12 mental summary score week 4 | −0.8 (−6.7; 5.0) | 2.3 (−3.8; 8.4) |
SF-12 mental summary score week 6 | −1.8 (−8.6; 4.9) | 3.9 (−2.4; 10.2) |
SF-12 mental summary score weeks 2–6 | 0.0 (−4.7; 4.7) | 0.1 (−4.5∶4.6) |
SF-12 physical summary score week 2 | 2.8 (−3.1; 8.7) | 1.9 (−3.7; 7.6) |
SF-12 physical summary score week 4 | 7.3 (2.4; 12.2) | 4.0 (−1.1; 9.2) |
SF-12 physical summary score week 6 | 1.1 (−3.7; 5.9) | 1.1 (−3.8; 6.0) |
SF-12 physical summary score weeks 2–6 | 3.7 (−0.2; 7.6) | 2.4 (−1.6; 6.3) |
Response rates (HAM-D reduction >50%) | ||
Response week 2 | 4.47 (1.18; 16.90) | 0.24 (0.08; 0.69) |
Response week 4 | 1.08 (0.24; 4.80) | 0.64 (0.17; 2.46) |
Response week 6 | 0.88 (0.17; 4.58) | 0.81 (0.17; 3.81) |
Response week 2–6 | 1.62 (0.51; 5.18) | 0.50 (0.20; 1.28) |
Remission rates (HAM-D <8) | ||
Remission week 2 | 2.64 (0.77; 9.02) | 0.35 (0.11; 1.08) |
Remission week 4 | 1.49 (0.46, 4.84) | 0.28 (0.09; 0.85) |
Remission week 6 | 3.95 (0.90; 17.45) | 2.27 (0.49; 10.57) |
Remission week 2–6 | 2.49 (1.11; 5.58) | 0.60 (0.28; 1.29) |
Q.potencies vs placebo/homeopathic case history | Q.potencies vs placebo/conventional case history | |
Measure | Odds Ratio (95% CI-limits) | |
Response week 2 | 10.45 (3.48; 31.33) | 1.92 (0.22; 17.08) |
Response week 4 | 1.07 (0.14; 8.18) | 1.09 (0.14; 8.13) |
Response week 6 | 0.76 (0.08; 7.15) | 1.03 (0.10; 10.50) |
Remission week 2 | 4.45 (1.38; 14.39) | 1.56 (0.20; 12.23) |
Remission week 4 | 7.76 (2.14; 28.15) | 0.28 (0.04; 1.80) |
Remission week 6 | 1.40 (0.09; 22.37) | 11.18 (3.13; 39.97) |
The number of patients reporting an Adverse Event (AE) was similar in the homeopathic medicine groups (19/30 = 63.3%) and the placebo groups (9/14 = 64.3%). A mean of 1.23 AE/patient (37/30) was documented in the homeopathic medicine groups and 1.07 (15/14) in the placebo groups. No serious AE (SAE) was reported or observed, nor did any patient report suicide ideation during the study. Reported AE were acne (2×), herpes simplex, eczema (2×), psoriasis (worsening), hyperhidrosis, xerosis, polymorphous light eruption, hypertrichosis, erythema, skin hyperpigmentation, influenza, acute nasopharyngitis (2×), acute laryngitis, otalgia, anxiety, somatoform pain, somatoform autonomic dysfunction, irritability, nightmares, worsening of the depressive episode, exhaustion, narrowing of attention, polyphagia, pseudocyesis, unspecified abdominal pain, acute cystitis, hemorrhoids, tachycardia, cramps, headache, acute gastroenteritis (3×), superficial injuries, rupture of ligaments at ankle and foot level, anterior chest-wall pain, pain in limb, pain localized to upper abdomen, nausea (2×), and ocular pain.
This study was planned for confirmatory statistical hypothesis testing to determine whether homeopathic Q-potencies and/or the type of the homeopathic case history would have a specific effect in the treatment of acute major depression, but because the preplanned sample size was not reached and following a lack of recruitment the trial was underpowered for the primary statistical analyses, data could only be analyzed using exploratory statistical methods.
We are not aware of a prior trial that aimed to evaluate both the specific effect of homeopathic medicines and of a homeopathic case taking in patients with major depression. Advantages were a study protocol that is in accordance with the EMEA (European Medicines Agency) guidelines, which recommends placebo-controlled studies and the duration of six weeks for trials investigating medicines for depression
Furthermore, patient safety played an important role in this study and was reflected by visits every 2 weeks and by the fact that depression severity was limited to a maximum HAM-D score of 24. For more severe depression the benefit of antidepressant over placebo is substantial
Overall, depression seems to be a disease that has high placebo response and the difference between placebo and active treatment seems to be difficult to detect
Interestingly, the results of the homeopathic case taking were less positive than expected. We would have expected a more positive outcome, because according to a systematic review
The small sample is the most important limitation of our study. The study was planned based on the experience of other studies and the evidence that patients seeking a homeopathic physician frequently suffer from depression
With an inclusion/screening rate of 44/448 = 9.8%, far below rates usually observed in conventional studies on depression, (e.g. Zajecka et al.
Being fully aware that recruitment could be difficult when we began our study, we developed a systematic stepwise recruitment strategy that included referrals from colleagues with outpatient practices as well as extensive media presence (e.g. advertisements in the underground and in regional newspapers, and participation in regional television shows on health topics). However, the size of the recruited sample reveals that this recruitment strategy was also not successful.
Although our results are inconclusive, given that recruitment for this trial was very difficult and necessitated early termination of the study, we cannot recommend undertaking a further trial addressing this question in a similar setting.
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We thank Katja Icke for data management, Iris Bartsch and Beatrice Eden for data acquisition.