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eCAM Advance Access published August 17, 2009
Homeopathic Individualized Q-potencies versus Fluoxetine forModerate to Severe Depression: Double-blind, RandomizedNon-inferiority Trial U. C. Adler, N. M. P. Paiva, A. T. Cesar, M. S. Adler, A. Molina, A. E. Padulaand H. M. Calil Faculdade de Medicina de Jundiaı´, Homeopathy Graduation Programme, Department of Psychobiology,Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil Homeopathy is a complementary and integrative medicine used in depression, The aim ofthis study is to investigate the non-inferiority and tolerability of individualized homeopathicmedicines [Quinquagintamillesmial (Q-potencies)] in acute depression, using fluoxetine as activecontrol. Ninety-one outpatients with moderate to severe depression were assigned to receive anindividualized homeopathic medicine or fluoxetine 20 mg day–1 (up to 40 mg day–1) in a pro-spective, randomized, double-blind double-dummy 8-week, single-center trial. Primary efficacymeasure was the analysis of the mean change in the Montgomery & A˚sberg Depression RatingScale (MADRS) depression scores, using a non-inferiority test with margin of 1.45. Secondaryefficacy outcomes were response and remission rates. Tolerability was assessed with the sideeffect rating scale of the Scandinavian Society of Psychopharmacology. Mean MADRS scoresdifferences were not significant at the 4th (P ¼ 0.654) and 8th weeks (P ¼ 0.965) of treatment.
Non-inferiority of homeopathy was indicated because the upper limit of the confidence interval(CI) for mean difference in MADRS change was less than the non-inferiority margin: meandifferences (homeopathy–fluoxetine) were À3.04 (95% CI À6.95, 0.86) and À2.4 (95% CIÀ6.05, 0.77) at 4th and 8th week, respectively. There were no significant differences betweenthe percentages of response or remission rates in both groups. Tolerability: there were nosignificant differences between the side effects rates, although a higher percentage of patientstreated with fluoxetine reported troublesome side effects and there was a trend toward greatertreatment interruption for adverse effects in the fluoxetine group. This study illustrates thefeasibility of randomized controlled double-blind trials of homeopathy in depression and indi-cates the non-inferiority of individualized homeopathic Q-potencies as compared to fluoxetinein acute treatment of outpatients with moderate to severe depression.
Keywords: depression – drug therapy – fluoxetine – homeopathy – integrative andalternative medicine – non-inferiority – Q-potencies – randomized controlled trial – remission –response Depression was the most prevalent (19.2%) of the For reprint and all correspondence: H. M. Calil, Department of chronic diseases assessed by the Brazilian World Health Psychobiology, Universidade Federal de Sa˜o Paulo, R. Napolea˜o de Survey in 2003 (1), including asthma, arthritis, angina Barros, 925 Sa˜o Paulo, SP 04024-002, Brazil. Tel: þ5511-2149-0155;Fax: þ5511-5572-5092; E-mail: [email protected] ß 2009 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work isproperly cited.
There still remain flaws in the treatment of depres- tolerability of individualized homeopathic Q-potencies sion with antidepressants, in terms of efficacy, adverse in adults with acute depression, as compared to fluoxet- effects, non-compliance to treatment and delayed onset ine, in a prospective, randomized, double-blind, double- of their therapeutic response (2–5). Regarding efficacy, response has been defined as a decrease of 50% ormore from baseline score in a rating scale, such as theHamilton Rating Scale for Depression (HAM-D) or the (MADRS), whereas depression scores HAM-D 7 and MADRS 10 are often used to characterize remission Patients referred to the outpatient clinic of Homeopathy (6). Unmet needs of the conventional treatment may con- and Depression of Jundiaı´ Medical School (Faculdade de tribute to the patients’ search for alternatives: depression Medicina de Jundiaı´, Sa˜o Paulo, Brazil), who met DSM- is one of the leading causes for use of complementary and IV criteria for depression (single or recurrent episode) integrative medicine (CIM) in the USA (7), although any following a Structured Clinical Interview—SCID (19) type of CIM has not yet conclusively had its efficacy were included in the study. Capacity and willingness to demonstrated over placebo in that disease (8).
give informed consent and to comply with study proce- Homeopathy is an integrative medicine, also used in depression (9) and recognized as a medical specialty in Exclusion criteria were: psychosis, mania, hypomania Brazil. The classical homeopathy treatment is customized or any other Axis I disorder except panic disorder, per- to the patient. The homeopathic medicine is individually sonality disorders, history of seizures, history of alcohol selected according to the similitude to the patient’s signs or drug abuse 1 year prior to the screening, antidepres- and symptoms, aiming at desensitizing the organism sant use up to 30 days before screening, pregnancy or to the physical and mental alterations induced by disease.
lactation, age 518 years, MADRS score 515, recent sui- Minimal doses used in homeopathy are obtained by cide planning or attempts, although these are symptoms dynamization, the process developed by Hahnemann to of depression, they are also standard exclusion criteria prepare medicines through sequential agitated dilutions, in depression clinical studies, including CAM trials in in relatively small volumes (10). Hahnemann’s dynamiza- tion gained support of physics: thermoluminescence The 91 patients were consecutively recruited between emitted by ‘ultra-high dilutions’ (dynamizations) of lith- ium chloride and sodium chloride was specific of the saltsinitially dissolved, despite their dilution beyond theAvogadro number (11).
With homeopathic dynamized medicines given in such ‘uncommonly small doses’, Hahnemann aimed at achieving A written informed consent was obtained from each ‘a rapid, gentle and permanent restoration of the health’, participant. The study was approved by the Ethic which seemed to him easier to achieve with his last dynamization method known as fifty-millesimal, orQuinquagintamillesimal (Q-potencies), once the medicine is diluted $50 000 times at each step (potency) of the dyna-mizing process (10). Hahnemann’s instructions for the use The study was a prospective, randomized, double-blind, and preparation of these potencies were part of a posthu- double-dummy trial, with fluoxetine as active control.
mous publication (the 6th edition of the Organon), The double-dummy methodology was used once it was unknown by the homeopathic community until the last not possible to make the homeopathic medication (hydroalcoholic solutions of the medicinal globules) and There is no controlled study of the homeopathic use the fluoxetine capsules to look the same, so we created of Q-potencies in depressive disorders and the overall evidence for the efficacy of homeopathy in depression Following inclusion, patients went through a homeo- has been limited due to lack of clinical trials of high quality (14,15). Nevertheless, Q-potencies have been (U.C.A.) and received a prescription of the individualized recently tested in randomized, controlled studies showing homeopathic medicine and fluoxetine. The research therapeutic effects in fibromyalgia and attention deficit pharmacist randomly delivered homeopathy and placebo hyperactivity disorder as compared to placebo (16,17).
or fluoxetine and placebo, according to a randomized We have reported a series of cases of depression treated assignment sequence to either homeopathy or fluoxetine with individualized Q-potencies, stressing the need of controlled studies (18). The present study was a further with the code, 1 or 2, chosen by the study’s senior step, aiming at investigating the non-inferiority and The randomization sequence (one set of 100 non- The homeopath has a medical degree and 20 years unique numbers, ranging from 1 to 2, unsorted) was recorded and sent to the research pharmacist at the Hahnemann in 6th edition of the Organon (29).
start of the study. Only the senior author and thepharmacist had access to the code of the randomizedsequence during the study. After each patient completed the 8-week trial (or in emergency interventions—clinical Improvement was measured by the MADRS, applied worsening, disturbing adverse effects) the pharmacist by a collaborator blind to treatment groups or outcomes.
informed the PI if the individual patient was taking The MADRS scale has been chosen because it has homeopathy or fluoxetine (and the matched placebo) been validated in Brazil and based on evidence that this instrument most accurately reflects treatment inducedchange (21–23).
The primary efficacy measure was mean change in the MADRS scores from baseline to the 4th and 8th weeksof treatment, whereas the secondary efficacy outcomes Subjects at baseline received one of the following were response and remission rates at the same intervals.
Tolerability was assessed with the side effect rating (i) one drop of the prescribed Q-potency, three times scale of the Scandinavian Society of Psychopharmacology a week (on Mondays, Wednesdays and Fridays), (24), applied by a collaborator blind to treatment groups (ii) one hard white gelatine capsule containing 20 mg fluoxetine-hydrochloride daily, in the morning,after breakfast.
(iii) plus their matching placebos. A double-dummy The demographic characteristics and duration of illness technique with matching placebos for each active were compared with Student’s t-test for independent samples. Fisher’s exact test was used for comparison of seemed identical to their corresponding verum marital status and analysis of dropouts between the two A prefixed margin of non-inferiority (Á) of 1.45 was HN-Cristiano Pharmacy, Pinheiros, Sa˜o Paulo, under specified, according to recommendation that Á should be the responsibility of a pharmacist (Cesar, AT). They between one-third and one-half of the advantage of the were supplied in 30 ml bottles, with one globule of the active comparator over placebo and correspond with indicated Q-potency dissolved in 20 ml of a 30% alcohol- minimum difference that would be considered clinically distilled water solvent. Patients began the study on Q2 important (25). The margin of non-inferiority was potency and moved on to higher potencies in order: Q3, assumed based on the mean MADRS-score changes ofthe placebo arm, from a multicenter placebo-controlled Q4, etc. according to medical indications. Placebo bottles clinical study of moderate to severe depression (26).
were filled with the same amount of 30% alcohol.
The non-inferiority analysis included all 91 randomized Capsules of fluoxetine were provided by the High Cost patients, using a ‘full analysis set’ (27), i.e. with all Pharmacy of Jundiai’s public health system, under the observed MADRS scores, but without filling in the miss- ing data. Non-inferiority of homeopathic individualized Lencioni Lovate). As the capsules available at the local medicines over fluoxetine was accepted in a 0.025 level public health system came in yellow–green color, they test, if the upper limit of the 95% confidence interval (CI) were re-encapsulated in white color by another pharma- around the difference of the primary efficacy measures cist (Regina Oliveira), at Pharmaesseˆncia Pharmacy, was situated below the limit of non-inferiority.
Campinas, SP, to match placebo white capsules contain- Analysis of the MADRS scores follow-up was made ing celluloses, kaolin and talcum powder.
with repeated measures analysis of variance (ANOVA), Both treatments were conducted as if the participants with time as within factor and condition as between were receiving active treatment. In case of no response factor, and Bonferroni’s multiple comparisons method.
after 4 weeks of treatment, the patient blindly received: Response and remission rates were analyzed with non- (i) 40 mg of fluoxetine daily (20 mg b.i.d.) or two parametric analysis for longitudinal data. Sample size was not calculated because this trial was a sequence of (ii) a changed homeopathic prescription, or placebo a pilot study, with a smaller sample (n ¼ 59), but already solution. The homeopath was allowed to change sufficient to suggest the non-inferiority of homeopathy to remedy, potency or posology prescriptions.
were also similar in the fluoxetine and homeopathygroups, as shown in Table 2.
This sample consisted of patients with moderate to severe Twenty medicines were used to treat the 48 patients depression, because their mean MADRS depression scores were close to the 31 score cut-off for moderate orientale, Arsenicum album, Aurum foliatum, Baryta car- and severe depression (28). Initially, 284 subjects were bonica, Calcarea carbonica, Carbo animalis, Causticum, screened, 105 of them met the inclusion criteria, 14 out Graphites, Hepar sulphuris calcareum, Kali carbonicum, of them did not attend the first appointment, 91 were randomized and 55 completed the 8-week trial. A detailed muriaticum, Mezereum, Phosphorus, Sepia succus, Silicea flow chart of subject progress through the study is shown terra, Sulphur and Zincum. These medicines were selected according to Hahnemann’s instructions, i.e. matching the There were no significant differences between the pro- characteristic symptoms (the stronger, well-marked and portions of excluded and lost for follow-up patients inthe two groups (P ¼ 0.99), though there was a trend Table 1. Excluded or lost for follow-up patients toward greater treatment interruption for adverse effectsin the fluoxetine group, as can be seen in Table 1.
Almost all patients enrolled in the study were female: 89/91 (98%). One male patient was randomly assigned to each group. There was no significant difference in the marital status (married, single, widow, divorced) between the two groups (P ¼ 0.86). Other baseline characteristics Figure 1. Diagram flow of subjects throughout the study.
peculiar symptoms) of each case to very similar symp- In line with the MADRS mean changes illustrated in toms described by healthy volunteers in homeopathic Fig. 2, the non-inferiority analysis showed that the indi- vidualized homeopathic Q-potencies were not inferior to Regarding concomitant psychoactive medications, in fluoxetine, once the upper limit of the CIs lies to the left the fluoxetine group three patients were taking clonaze- of Á and includes zero (27), as represented by Fig. 3.
pam (1–2.5 mg) and two were on diazepam (5–10 mg).
In the homeopathy group, one patient was using clona-zepam and another one was on diazepam at the begin- ning of the study (same dosage range). No patient referred to this study was on psychotherapy.
response rates on the 4th (63.9 and 65.8%, respectively)and 8th (84.6 and 82.8%, respectively) weeks of treat-ment. Also no significant differences were found for theremission rates, on the 4th (47.2 and 55.3%, respectively, Repeated measures ANOVA were used with time as factor. The results showed significant differences fortime (within factor, P50.001), but not for treatment group (between factor, P ¼ 0.105) interaction (P ¼ 0.749).
There were also no significant differences between the Both treatment groups started with similar depression side effects rates, although a higher percentage of patients mean scores: fluoxetine 28.09 Æ 6.88 (n ¼ 43), homeopathy treated with fluoxetine (21.4%) than those who received 27.21 Æ 6.22 (n ¼ 48, P ¼ 0.988) and improved during the homeopathy (10.7%) reported ‘side effects that interfere 8 weeks of double-blind treatment. The statistical analysisshowed that the differences between the MADRS scoresin the two groups were not significant (as shown inFig. 2), neither at the 4th week—fluoxetine 12.33 Æ 8.52(n ¼ 36), homeopathy 9.29 Æ 8.31 (n ¼ 38, P ¼ 0.654) norat the 8th week—fluoxetine 8.85 Æ 7.48 (n ¼ 26), homeop-athy 6.21 Æ 4.99 (n ¼ 29, P ¼ 0.965).
Table 2. Baseline demographic and clinical characteristics Figure 2. MADRS mean scores at baseline and on 4th and 8th weeks of randomized treatment with fluoxetine or individualized homeopathic Figure 3. Non-inferiority representation of the difference (homeopathy versus fluoxetine) in the mean change of the MADRS scores on the 4th and8th weeks of randomized, double-bind treatment. Error bars indicate two-sided 95% CIs. Tinted area indicates zone of non-inferiority. Deltaindicates the margin of non-inferiority. Mean differences (homeopathy–fluoxetine) were À3.04 (À6.95 to 0.86) and À2.64 (À6.05 to 0.77) atweeks 4th and 8th, respectively.
antidepressant interventions, favoring the hypothesis that ‘the homeopathic consultation is in itself a thera-peutic intervention working independently or synergistic-ally with the prescribed remedy’ (36).
A placebo-arm was not included in the present study because it was not authorized by the National Ethic In this study, depressed outpatients were randomly Council. Although placebo interventions are associated assigned to a double-blind treatment with individualized with mean response or remission rates of $35% (37,38), a placebo effect cannot be ruled out, since the homeopathic Q-potencies were compared with an anti- Q-potencies were not inferior as compared to fluoxetine depressant and ‘it is becoming more and more difficult in treatment of this sample of outpatients with moderate to prove that antidepressants—even well-established anti- depressants—actually work better than placebo in clinical This is the first randomized controlled double-blind trials’ (39). Nevertheless, it also has to be taken into con- trial with a reasonable number of subjects to draw con- clusions about the homeopathic treatment of depression, seems to be smaller in the trials aiming at mild to mod- to the best of our knowledge. In fact, a recent systematic erate depression (40,41) and the present sample consisted review found only two randomized controlled trials of patients suffering from moderate to severe depression.
examining the use of homeopathy to treat depression, Placebo-controlled studies would be recommendable to one of low methodological quality (non-blinded) and the other with recruitment‘s difficulties: eleven partici- Fluoxetine and homeopathy patients showed differ- pants were included and only three completed the ences, although not significant, in exclusion profiles and tolerability. There was trend toward greater treatment The current sample was not recruited by advertisement interruption for adverse effects in the fluoxetine group, and it was not composed by ‘consumers of alternative what is in line with the higher percentage of troublesome medicine’ (33), but by help-seeking patients referred to adverse effects reported by patients receiving fluoxetine.
On the other hand, more patients randomized to hom- Medical School by health care professionals within eopathy than to fluoxetine were excluded due to worsen- the public health system. The predominance of women ing of their depressive symptoms. Possible explanations participants in a proportion greater than normally are that casual differences can occur in small samples, or expected may be partially explained by men’s relatively that homeopathy was not effective in protecting against limited use of public health services in Brazil, a trend that stressful situations or even that the medicines selected has been associated with representation of caring as a were non-homeopathic, i.e. not adequately individualized female task, work-related issues, difficult access to ser- to match the peculiar symptoms of each case. There is vices and lack of services specifically targeting men’s no data about the efficacy of homeopathy in protecting against depression relapse or recurrence, but it’s known The need of individual prescriptions in classical hom- that stressful life events can cause recurrence of depres- eopathy has been considered as ‘a severe obstacle for any sion even in conventionally medicated patients (42).
double-blind trial’ by experienced researchers (17). In The current study has other limitations besides the lack fact, a study design in which the selection of a suitable, of a placebo control, such as dependence on a single individualized homeopathic medicine occurs during the homeopathic practitioner, a relatively small sample and a short period of treatment—the acute phase of depres- the efficacy of homeopathy, but also the efficiency of sion. A multicenter trial could include a larger number of the homeopath in selecting and managing that medicine.
participants, from different homeopathic research centers, A placebo substitution design (with an open-label phase increasing the generalizability of the results. Nevertheless, preceding the randomization) would be recommendable, larger or multicenter trials aiming at repeating these but in depression studies such a design is used for con- results should take in account the need for properly train- tinuation or maintenance trials (35) and not to assess the ing the physicians in the homeopathic methodology used (6th edition of the Organon), as well as the use of high quality, exactly prepared Q-potencies.
MADRS scores differences were neither significant at A recent meta-analysis of homeopathic trials concluded that the results were ‘compatible with the notion that (P ¼ 0.965). There were also no significant differences clinical effects of homeopathy are placebo effects’ (43).
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Received March 7, 2009; accepted July 17, 2009

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