Hindawi Publishing Corporation
Evidence-Based Complementary and Alternative Medicine
Volume 2011, Article ID 520182, 7 pages
FluoxetineforModerate toSevere Depression:
Double-Blind, Randomized Non-InferiorityTrial
U.C.Adler,N.M. P.Paiva, A.T.Cesar,M. S.Adler,A.Molina, A.E.Padula,andH. M.Calil
Faculdade de Medicina de Jundia´ ı, Homeopathy Graduation Programme, Department of Psychobiology,
Universidade Federal de S˜ ao Paulo, R. Napole˜ ao de Barros, 925 S˜ ao Paulo, SP 04024-002, Brazil
Correspondence should be addressed to H. M. Calil, firstname.lastname@example.org
Received 7 March 2009; Accepted 17 July 2009
Copyright © 2011 U. C. Adler et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Homeopathy is a complementary and integrative medicine used in depression, The aim of this study is to investigate the non-
inferiorityandtolerabilityof individualized homeopathicmedicines [Quinquagintamillesmial(Q-potencies)] in acutedepression,
using fluoxetine as active control. Ninety-one outpatients with moderate to severe depression were assigned to receive an
individualized homeopathic medicine or fluoxetine 20mgday−1(up to 40mgday−1) in a prospective, randomized, double-blind
double-dummy 8-week, single-center trial. Primary efficacy measure was the analysis of the mean change in the Montgomery &
˚ Asberg Depression Rating Scale (MADRS) depression scores, using a non-inferiority test with margin of 1.45. Secondary efficacy
outcomes were response and remission rates. Tolerability was assessed with the side effect rating scale of the Scandinavian Society
of Psychopharmacology. Mean MADRS scores differences were not significant at the 4th (P = .654) and 8th weeks (P = .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: mean differences (homeopathy-fluoxetine) were −3.04
(95% CI −6.95, 0.86) and −2.4 (95% CI −6.05, 0.77) at 4th and 8th week, respectively. There were no significant differences
between the percentages of response or remission rates in both groups. Tolerability: there were no significant differences between
the side effects rates, although a higher percentage of patients treated with fluoxetine reported troublesome side effects and there
was a trend toward greater treatment interruption for adverse effects in the fluoxetine group. This study illustrates the feasibility
of randomized controlled double-blind trials of homeopathy in depression and indicates the non-inferiority of individualized
homeopathicQ-potencies as compared to fluoxetine in acute treatment of outpatients with moderate to severe depression.
Depression was the most prevalent (19.2%) of the chronic
diseases assessed by the Brazilian World Health Survey in
2003 , including asthma, arthritis, angina and diabetes.
There still remain flaws in the treatment of depression
with antidepressants, in terms of efficacy, adverse effects,
non-compliance to treatment and delayed onset of their
therapeutic response [2–5]. Regarding efficacy, response has
been defined as a decrease of 50% or more from baseline
score in a rating scale, such as the Hamilton Rating Scale
for Depression (HAM-D) or the Montgomery & ˚Asberg
Depression Rating Scale (MADRS), whereas depression
scores HAM-D ≤ 7 and MADRS ≤ 10 are often used to
characterize remission . Unmet needs of the conventional
treatment may contribute to the patients’ search for alter-
natives: depression is one of the leading causes for use of
complementary and integrative medicine (CIM) in the USA
, although any type of CIM has not yet conclusively had
its efficacy demonstrated over placebo in that disease .
Homeopathy is an integrative medicine, also used in
depression  and recognized as a medical specialty in Bra-
zil. The classical homeopathy treatment is customized to the
patient. The homeopathic medicine is individually selected
according to the similitude to the patient’s signs and symp-
toms, aiming at desensitizing the organism to the physical
and mental alterations induced by disease. Minimal doses
ess developed by Hahnemann to prepare medicines through
2 Evidence-Based Complementary and Alternative Medicine
Hahnemann’s dynamization gained support of physics: ther-
moluminescence emitted by “ultra-high dilutions” (dynami-
of the salts initially dissolved, despite their dilution beyond
the Avogadro number .
With homeopathic dynamized medicines given in such
“uncommonly small doses”, Hahnemann aimed at achieving
“a rapid, gentle and permanent restoration of the health”,
which seemed to him easier to achieve with his last dy-
namization method known asfifty-millesimal, orQuinquag-
intamillesimal (Q-potencies), once the medicine is diluted
∼50000 times at each step (potency) of the dynamiz-
ing process . Hahnemann’s instructions for the use and
preparation of these potencies were part of a posthumous
publication (the 6th edition of the Organon), unknown
by the homeopathic community until the last decades [12,
There is no controlled study of the homeopathic use of
Q-potencies in depressive disorders and the overall evidence
for the efficacy of homeopathy in depression has been
limited due to lack of clinical trials of high quality [14,
15]. Nevertheless, Q-potencies have been recently tested in
randomized, controlled studies showing therapeutic effects
in fibromyalgia and attention deficit hyperactivity disorder
as compared to placebo [16, 17]. We have reported a series of
cases of depression treated with individualized Q-potencies,
stressing the need of controlled studies . The present
study was a further step, aiming at investigating the non-
inferiority and tolerability of individualized homeopathic
Q-potencies in adults with acute depression, as compared
to fluoxetine, in a prospective, randomized, double-blind,
double-dummy parallel trial.
2.1. Patients. Patients referred to the outpatient clinic of
Homeopathy and Depression of Jundia´ ı Medical School
(Faculdade de Medicina de Jundia´ ı, S˜ ao Paulo, Brazil), who
met DSM-IV criteria for depression (single or recurrent
episode) following a Structured Clinical Interview—SCID
 were included in the study. Capacity and willingness to
give informed consent and to comply with study procedures
were also required.
Exclusion criteria were: psychosis, mania, hypomania or
any other Axis I disorder except panic disorder, personality
1 year prior to the screening, antidepressant use up to 30
daysbefore screening, pregnancy orlactation, age< 18 years,
MADRS score < 15, recent suicide planning or attempts,
although these are symptoms of depression, they are also
standard exclusion criteria in depression clinical studies,
including CAM trials in depression .
The 91 patients were consecutively recruited between
February 2006 and September 2008.
2.2. Ethics. A written informed consent was obtained from
each participant. The study was approved by the Ethic Com-
mittees at FMJ and UNIFESP.
2.3. Study Design, Blinding and Randomization. The study
was a prospective, randomized, double-blind, double-dum-
my trial, with fluoxetine as active control. The double-
dummy methodology was used once it was not possible to
ofthemedicinal globules)and thefluoxetinecapsulestolook
the same, so we created a placebo for each medicine.
Following inclusion, patients went through a homeo-
pathic anamnesis with the principal investigator (U.C.A.)
and received a prescription of the individualized homeo-
pathic medicine and fluoxetine. The research pharmacist
randomly delivered homeopathy and placebo or fluoxe-
tine and placebo, according to a randomized assignment
sequence to either homeopathy or fluoxetine group, gener-
ated by http://www.randomizer.org/ and with the code, 1 or
2, chosen by the study’s senior author (H.M.C.).
The randomization sequence (one set of 100 non-unique
numbers, ranging from 1 to 2, unsorted) was recorded and
sent to the research pharmacist at the start of the study.
Only the senior author and the pharmacist had access to
the code of the randomized sequence during the study.
After each patient completed the 8-week trial (or in emer-
gency interventions—clinical worsening, disturbing adverse
effects) the pharmacist informed the PI if the individual
patient was taking homeopathy or fluoxetine (and the
matched placebo) without disclosing the code.
2.4. Study Medications. Subjects at baseline received one of
the following medications:
(i) one drop of the prescribed Q-potency, three times a
week (on Mondays, Wednesdays and Fridays), in the
morning, before breakfast or,
(ii) one hard white gelatine capsule containing 20mg
fluoxetine-hydrochloride daily, in the morning, after
(iii) plustheirmatching placebos.Adouble-dummytech-
nique with matching placebos for each active treat-
ment was applied, thus both placebos seemed identi-
cal to their corresponding verum formulations.
Homeopathic Q-potencies were provided by HN-Cris-
tiano Pharmacy, Pinheiros, S˜ ao Paulo, under the responsi-
bility of a pharmacist (Cesar, AT). They were supplied in
30mL bottles, with one globule of the indicated Q-potency
dissolved in 20mL of a 30% alcohol-distilled water solvent.
Patients began the study on Q2 potency and moved on to
higher potencies in order: Q3, Q4, and so forth, according to
amount of 30% alcohol.
Capsules of fluoxetine were provided by the High Cost
Pharmacy of Jundiai’s public health system, under the re-
sponsibility of a pharmacist (Luciana Teixeira Lencioni
Lovate). As the capsules available at the local public health
in white color by another pharmacist (Regina Oliveira), at
Pharmaessˆ encia Pharmacy, Campinas, SP, to match placebo
white capsulescontaining celluloses, kaolin and talcumpow-
Evidence-Based Complementary and Alternative Medicine3
Both treatments were conducted as if the participants
were receiving active treatment. In case of no response after
4 weeks of treatment, the patient blindly received:
(i) 40mg of fluoxetine daily (20mg b.i.d.) or two place-
bo capsules and
(ii) a changed homeopathic prescription, or placebo so-
lution. The homeopath was allowed to change rem-
edy, potency or posology prescriptions.
The homeopath has a medical degree and 20 years of
experience with the methodology described by Hahnemann
in 6th edition of the Organon .
2.5. Measures. Improvement was measured by the MADRS,
applied by a collaborator blind to treatment groups or out-
comes. The MADRS scale has been chosen because it has
been validated in Brazil and based on evidence that this
instrument most accurately reflects treatment induced
The primary efficacy measure was mean change in the
MADRS scores from baseline to the 4th and 8th weeks of
treatment, whereas the secondary efficacy outcomes were
response and remission rates at the same intervals.
Tolerability was assessed with the side effect rating scale
of the Scandinavian Society of Psychopharmacology ,
applied by a collaborator blind to treatment groups or
2.6.Statistics. The demographiccharacteristics and duration
of illness were compared with Student’s t-test for indepen-
dent samples. Fisher’s exact test was used for comparison
of marital status and analysis of dropouts between the two
A prefixed margin of non-inferiority (Δ) of 1.45 was
specified, according to recommendation that Δ should be
comparator over placebo and correspond with minimum
difference that would be considered clinically important
. The margin of non-inferiority was assumed based on
the mean MADRS-score changes of the placebo arm, from a
multicenter placebo-controlled clinical study of moderate to
severe depression . The non-inferiority analysis included
all 91 randomized patients, using a “full analysis set” ,
that is, with all observed MADRS scores, but without
filling in the missing data. Non-inferiority of homeopathic
individualized medicines over fluoxetine was accepted in a
0.025 level test, if the upper limit of the 95% confidence
interval (CI) around the difference of the primary efficacy
measures was situated below the limit of non-inferiority.
Analysis of the MADRS scores follow-up was made with
repeated measures analysis of variance (ANOVA), with time
aswithin factorandconditionasbetweenfactor, and Bonfer-
roni’s multiple comparisons method. Response and remis-
sion rates were analyzed with non-parametric analysis for
trial was a sequence of a pilot study, with a smaller sample
(n = 59), but already sufficient to suggest the non-inferiority
of homeopathy to fluoxetine.
N = 91
N = 48
N = 43
Excluded due to
N = 3
lost for follow-up
N = 10
Excluded due to
N = 5
of axis I
N = 1
Excluded due to
N = 8
lost for follow-up
N = 8
Excluded due to
N = 1
(N = 29)
(N = 26)
Figure 1: Diagram flow of subjects throughout the study.
Table 1: Excluded or lost for follow-up patients.
Adverse effects3 (6.3)8 (18.6).071
10 (20.8)8 (18.6).79
Worsening5 (10.4)1 (2.3).207
Comorbidity 1 (2.1)a
This sample consisted of patients with moderate to severe
depression, because their mean MADRS depression scores
were close to the 31 score cut-off for moderate and severe
depression . Initially, 284 subjects were screened, 105 of
the 8-week trial. A detailed flow chart of subject progress
through the study is shown in Figure 1.
There were no significant differences between the pro-
portions of excluded and lost for follow-up patients in the
two groups (P = .99), though there was a trend toward
greater treatment interruption for adverse effects in 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 wasno significant differencein themarital
status (married, single, widow, divorced) between the two
groups (P = .86). Other baseline characteristics were also
4 Evidence-Based Complementary and Alternative Medicine
Table 2: Baseline demographic and clinical characteristics.
N = 43
N = 48
11.8 Age (years)
4.8 126.96.36.199 .883
28.1 6.927.2 6.2.523
similar in the fluoxetine and homeopathy groups, as shown
in Table 2.
Twenty medicines were used to treat the 48 patients
randomized tohomeopathy: Alumina, Anacardium orientale,
Arsenicum album, Aurum foliatum, Baryta carbonica, Cal-
carea carbonica, Carbo animalis, Causticum, Graphites, Hepar
sulphuris calcareum, Kali carbonicum, Lycopodium clavatum,
Natrum carbonicum, Natrum muriaticum, Mezereum, Phos-
phorus,Sepia succus,Silicea terra, Sulphur and Zincum.These
medicines were selected according to Hahnemann’s instruc-
tions, that is, matching the characteristic symptoms (the
stronger, well-marked and peculiar symptoms) of each case
to very similar symptoms described by healthy volunteers in
homeopathic drug trials .
Regarding concomitant psychoactive medications, in the
fluoxetine group three patients were taking clonazepam
(1–2.5mg) and two were on diazepam (5–10mg). In the
homeopathy group, one patient was using clonazepam and
another one was on diazepam at the beginning of the study
(same dosagerange).Nopatientreferred tothisstudy wason
3.1. Primary Efficacy Analysis. Repeated measures ANOVA
wereusedwithtimeaswithin factorandtreatment condition
as between factor. The results showed significant differences
for time (within factor, P < .001), but not for treatment
group (between factor, P = .105) interaction (P = .749).
Both treatment groups started with similar depression
mean scores: fluoxetine 28.09 ± 6.88 (n = 43), homeopathy
27.21 ± 6.22 (n = 48, P = .988) and improved during the
8 weeks of double-blind treatment. The statistical analysis
showed that the differences between the MADRS scores in
the two groups were not significant (as shown in Figure 2),
neither at the 4th week—fluoxetine 12.33 ± 8.52 (n = 36),
homeopathy 9.29 ± 8.31 (n = 38, P = .654) nor at the
8th week—fluoxetine 8.85 ± 7.48 (n = 26), homeopathy
6.21 ± 4.99 (n = 29, P = .965).
In line with the MADRS mean changes illustrated
in Figure 2, the non-inferiority analysis showed that the
Mean scores MADRS
Week 0Week 4Week 8
P = .988
P = .654
P = .965
Figure 2: MADRS mean scores at baseline and on 4th and 8th
weeks of randomized treatment with fluoxetine or individualized
homeopathic Q-potencies (ITT population).
fluoxetine, once the upper limit of the CIs lies to the left of Δ
and includes zero , as represented by Figure 3.
3.2. Secondary Efficacy Analysis. Fluoxetine and homeopathy
demonstrated similar response rates on the 4th (63.9 and
65.8%, resp.) and 8th (84.6 and 82.8%, resp.) weeks of
treatment. Also no significant differences were found for the
remission rates, on the 4th (47.2 and 55.3%, resp., P = .422)
and8th(76.9and72.4%,resp.,P = .716)weeksoftreatment.
3.3. Tolerability. There were also no significant differences
between the side effects rates, although a higher percentage
of patients treated with fluoxetine (21.4%) than those who
received homeopathy (10.7%) reported “side effects that
interfere markedly with thepatient’sperformance” (P =
In this study, depressed outpatients were randomly assigned
to a double-blind treatment with individualized homeo-
pathic Q-potencies or fluoxetine. The non-inferiority anal-
ysis indicated that the homeopathic Q-potencies were not
of outpatients with moderate to severe depression.
This is the first randomized controlled double-blind trial
with a reasonable number of subjects to draw conclusions
about the homeopathic treatment of depression, to the best
of our knowledge. In fact, a recent systematic review found
only two randomized controlled trials examining the use of
homeopathy to treat depression, one of low methodological
quality (non-blinded) and the other with recruitment‘s
difficulties: eleven participants were included and only three
completed the study [30–32].
The current sample was not recruited by advertisement
and it was not composed by “consumers of alternative
medicine” , but by help-seeking patients referred to
clinic of Homeopathy and Depression of Jundia´ ı Medical
School by health care professionals within the public health
Evidence-Based Complementary and Alternative Medicine5
4th week: noninferior
8th week: noninferior
H-F = −2.64
H-F = −3.04
Treatment difference (homeopathy minus fluoxetine; mean MADRS scores)
Δ = 1.45
←Favors homeopathy Favors fluoxetine→
Figure 3: Non-inferiority representation of the difference (homeopathy versus fluoxetine) in the mean change of the MADRS scores on
the 4th and 8th weeks of randomized, double-bind treatment. Error bars indicate two-sided 95% CIs. Tinted area indicates zone of non-
inferiority. Delta indicates the margin of non-inferiority. Mean differences (homeopathy-fluoxetine) were −3.04 (−6.95 to 0.86) and −2.64
(−6.05 to 0.77) at weeks 4th and 8th, respectively.
system. The predominance of women participants in a
proportion greater than normally expected may be partially
explained by men’s relatively limited use of public health
services in Brazil, a trend that has been associated with
representation ofcaring as a female task, work-related issues,
difficult access to services and lack of services specifically
targeting men’s health .
The need of individual prescriptions in classical home-
opathy has been considered as “a severe obstacle for any
double-blindtrial” by experienced researchers . In fact, a
study design in which the selection of a suitable, individual-
ized homeopathic medicine occurs during the double-blind
randomized phase evaluates not only the efficacy of home-
opathy, but also the efficiency of the homeopath in selecting
and managing that medicine. A placebo substitution design
(with an open-label phase preceding the randomization)
would be recommendable, but in depression studies such a
design is used for continuation or maintenance trials 
and not to assess the treatment of the acute episode.
Primary efficacymeasure resultsindicatedmeanMADRS
scores differences were neither significant at the 4th week
(P = .654), nor at the 8th week (P = .965). There were
also no significant differencesbetween response or remission
rates in the two treatment groups, which were over 70%
and in some degree superior to those found in primary
care settings for active antidepressant interventions, favoring
the hypothesis that “the homeopathic consultation is in
itself a therapeutic intervention working independently or
synergistically with the prescribed remedy” .
A placebo-arm was not included in the present study
because it was not authorized by the National Ethic Council.
Although placebo interventions are associated with mean
cannot be ruled out, since the homeopathic Q-potencies
were compared with an antidepressant and “it is becoming
more and more difficult to prove that antidepressants—
even well-established antidepressants—actually work better
than placebo in clinical trials” . Nevertheless, it also
has to be taken into consideration that the antidepressant-
placebo difference seems to be smaller in the trials aiming
at mild to moderate depression [40, 41] and the present
sample consisted of patients suffering from moderate to
severe depression. Placebo-controlled studies would be rec-
ommendable to clarify these findings.
Fluoxetine and homeopathy patients showed differences,
although not significant, in exclusion profiles and tolerabil-
ity. There was trend toward greater treatment interruption
for adverse effects in the fluoxetine group, what is in line
with the higher percentage of troublesome adverse effects
reported by patients receiving fluoxetine. On the other
hand, more patients randomized to homeopathy than to
symptoms. Possible explanations are that casual differences
can occur in small samples, or that homeopathy was not
effectivein protecting against stressful situations or eventhat
the medicines selected were non-homeopathic, that is, not
adequatelyindividualized tomatch thepeculiarsymptoms of
each case. There is no data about the efficacy of homeopathy
in protecting against depression relapse or recurrence, but
it’s known that stressful life events can cause recurrence of
depression even in conventionally medicated patients .
The current study has other limitations besides the
lack of a placebo control, such as dependence on a single
homeopathic practitioner, a relatively small sample and a
short period of treatment—the acute phase of depression.
A multicenter trial could include a larger number of
participants, from different homeopathic research centers,
increasing the generalizability of the results. Nevertheless,
larger or multicenter trials aiming at repeating these results
should take in account the need for properly training
the physicians in the homeopathic methodology used (6th
edition of the Organon), as well as the use of high quality,
exactly prepared Q-potencies.
A recent meta-analysis of homeopathic trials concluded
thattheresultswere “compatiblewith thenotion thatclinical
effects of homeopathy are placebo effects” . However,
as demonstrated by L¨ udtke and Rutten, this conclusion was
based on an arbitrarily chosen subset of eight trials, out
of 21 high-quality trials and the results favor homeopathy,
if another threshold to define a “large trial” is used .
Moreover, the homeopathic interventions were grouped in
classical, clinical, complex or isopathy, without any further
6 Evidence-Based Complementary and Alternative Medicine
reference to the specific homeopathic clinical or pharmaceu-
ticalmethodologyused in each oneofthesegroups. Defining
the homeopathic methodology being analyzed would have
been essential to avoid biased or generalized conclusions. In
an analogous way, the efficacy of psychotherapeutic inter-
ventions in depression is assessed within their specific ap-
proaches: behavioral, cognitive-behavior, interpersonal, and
so forth, .
This study, in spite of its limitations, illustrates the feasi-
bility of randomized controlled double-blind trials of home-
opathy for depression and indicates the non-inferiority of
oxetine in the acute treatment of outpatients with moderate
to severe depression. Further studies are needed to confirm
maintenance phases of depression treatment with homeopa-
The authors acknowledge the confidence of the 91 patients,
Jundiai’s Public Health system, specially the pharmacist
Luciana Teixeira Lencioni Lovate for providing fluoxetine,
the pharmacist Regina Oliveira and Pharmaessˆ encia Phar-
macy for reencapsulating fluoxetine and preparing placebo
capsules,HN-Pharmacy fordonating thehigh qualityhome-
opathic Q-potencies and the Faculdade de Medicina de Jun-
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