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
Emma del Carmen Macías-Cortés,
Published: March 13, 2015
Plos – Open Access
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.
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).
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.
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.
Citation: Macías-Cortés EdC, Llanes-González 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. doi:10.1371/journal.pone.0118440
Academic Editor: Yiru Fang, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, CHINA
Received: September 18, 2014; Accepted: January 13, 2015; Published: March 13, 2015
Copyright: © 2015 Macías-Cortés et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Data Availability: Data are available upon request to the Research and Ethics Committee of National Homeopathic Hospital, Mexico City [Dr. Gustavo Aguilar-Velázquez ([email protected])] for researches who meet the criteria for access to confidential data.
Funding: The authors have no support or funding to report.
Competing interests: The authors have declared that no competing interests exist.
Major depression disorder (MDD) is a chronic and frequently disabling disorder. The risk for MDD is approximately 1.5 to 3 times higher in women than in men, with an estimated lifetime prevalence in women of 21.3% [1,2]. It is characterized by sadness, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, feelings of tiredness, and poor concentration. The perimenopausal period refers to the interval when women’s menstrual cycles become irregular, which generally occurs above 40. It is typically marked by intense hormonal fluctuations with a rising concentration of the pituitary gonadotropin follicle-stimulating hormone (FSH) [3,4]. The rising FSH concentration is probably caused by an exponential decline of gonadotropin-sensitive ovarian follicles as menopause approaches . For some women the menopause is a largely uneventful part of life. However, for others is a period of biological vulnerability with remarkable physiologic, psychological, and somatic symptoms such as vasomotor symptoms (hot flashes, night sweats), changes in sexual function, sleep disturbance, among others [5–7]. According to the Stages of Reproductive Aging Workshop (STRAW), transition to menopause is the period that precedes menopause and it is characterized by variations in cycle length (> 7 days different from baseline or two or more skipped cycles and an interval of amenorrhea of sixty or more days). Postmenopausal stage is the period that continues after twelve months or more of amenorrhea .
Recent studies have demonstrated a significant association between menopausal transition and a higher risk for developing depression, with risk rising from early to late perimenopause and decreasing during postmenopause. It has been postulated that during perimenopause the risk for mood disorders may be increased for women with sensitivity to normal hormonal fluctuations . A number of cross-sectional and longitudinal studies have evaluated the relationship between the menopausal transition and an increased risk of depression . The Study of Women’s Health Across the Nation found correlation between the menopausal transition and depressive symptoms . The risk for recurrence of MDD during the perimenopausal period in women with a history of depression has been well documented . Women with a history of depression are up to five times more likely to have a MDD during this time period. Other recent studies have independently demonstrated that transition to menopause was indeed associated with an increased risk for the development of depression, even among women with no previous history of depression [13,14]. Moreover, there are other risk factors that can contribute to worsen depressive symptoms, such as marital concerns, stressful life events, unhealthy lifestyle, among others .
The Diagnostic and Statistical Manual of Mental Disorders, abbreviated as DSM, is the diagnostic tool that serves as a universal authority for psychiatric diagnosis. The DSM-5 was recently published on 2013 . Depression severity can be assessed by the Hamilton Rating Scale of Depression (HRSD) and Beck Depression Inventory (BDI), two well known standardized scales used in trials worldwide. Spanish versions of both scales have been validated [16–19]. Greene Climacteric Scale (GS) is also a standardized scale used in Mexican population . Spanish version has also been validated . It is intended specifically to be a brief and standard measure of core climacteric symptoms or complaints to be used for comparative and replicative purposes across different types of studies whether they are medical, psychological, sociological or epidemiological in nature. Three separate sub-scales measure vasomotor symptoms, somatic symptoms, psychological symptoms, and an additional probe related to sexual function. Psychological symptoms can be further sub-divided to measure anxiety and depression [20, 21].
A number of meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment. Specifically, Kirsch et al published a meta-analyses of clinical trial data submitted to the US Food and Drug Administration (FDA) and revealed a mean drug-placebo difference in improvement scores of 1.8 points, whereas the National Institute for Clinical Excellence (NICE) used a drug-placebo difference of 3 points as a criterion for clinical significance . Moreover, another meta-analyses found that only studies with higher average baseline severity achieved the clinically significant 3-point difference in HRSD scores . By contrast, Gibbons et al published a detailed research synthesis using patient-level longitudinal data from available youth, adult and geriatric placebo controlled RCTs of fluoxetine. The results revealed consistent statistically benefits of treatment, the magnitude of which was greatest in youth and smallest in geriatric subpopulations. Baseline severity did not moderate the effect of treatment .
Homeopathy is delivered across Mexico via public and private healthcare systems to treat menopausal symptoms and depression, among many others diseases. Homeopathy is based on the ‘principle of similars’. Highly diluted preparations of substances that cause symptoms in healthy individuals are used to stimulate healing in patients who have similar symptoms when ill . Individualized homeopathic treatment (IHT) consists of a prescription of an individually selected homeopathic remedy based on the totality of symptoms ascertained after a complete clinical examination of the patient . Nowadays, homeopathic medicines are produced by a standardized methodology. Homeopathic medicines in Centesimal (C) potencies are produced through sequential agitated dilutions. A drop of a parent substance is diluted in 99 drops of ethanol followed by agitation of the solution (1 C). This procedure is repeated in consecutive agitated dilutions (2 C, 3 C, 4 C, and so on).
Observational studies of homeopathic treatment for menopausal symptoms have been conducted. The evidence demonstrates an association between homeopathic treatment and improvement in fatigue, hot flushes, anxiety, depression and quality of life for menopausal women and breast cancer survivors. More homeopathic research is needed specially in the menopausal time period where there is a lack of well-designed RCTs [27, 28]. At moment, although homeopathy is frequently prescribed for psychiatric conditions, the need for more high-quality RCTs has been identified [29, 30]. Meta-analyses and systematic reviews have drawn mixed conclusions as to whether homeopathy is more effective than placebo in general medicine [26, 23–35]. Few RCTs of homeopathy and placebo in psychiatry have been performed. The results are very limited, but do not preclude the possibility of some benefit, as it was found for fibromyalgia .
Adler et al conducted a RCT of individualized homeopathic Q-potencies for moderate to severe depression and found that IHT was non-inferior to fluoxetine, but because of ethical reasons the study did not include a placebo group . Most importantly, although mood symptoms are one of the most common complaints during transition to menopause, to date, there is a lack of RCTs of homeopathic treatment for depression in women at this stage.
The main objective of the HOMDEP-MENOP study was to assess the efficacy and safety of IHT in C-potencies vs placebo; the secondary objective was to assess the efficacy and safety of fluoxetine vs placebo, for moderate to severe depression in women in peri- and postmenopuase.
The protocol was reviewed and approved by Research and Ethics Committee of Hospital Juárez de México (JMH) (Comisión de Ética e Investigación del Hospital Juárez de México) (Approval Number: HJM 2030/12-A), registered in ClinicalTrials.gov (ID: NCT01635218) and published  in http://www.trialsjournal.com/content/14/1/105. This study is in compliance with Helsinki Declaration and with the International Conference of Harmonisation ICH—Good Clinical Practice. Prior to undertaking any study procedures each participant received a verbal and written explanation about study aims, methods, potential hazards, and benefits from investigators. Participants signed a written informed consent at the time of their enrollment. The trial process was reviewed every three months by the institutional board. Participant’s study information was not released outside of the study without written permission of the participant.
A randomized, placebo-controlled, double-blind, double-dummy, superiority, three-arm trial with a six week follow-up study was conducted.
The study was conducted in a public, academic and research hospital in Mexico City, the Hospital Juárez de México (JMH), which belongs to the Ministry of Health (MoH), central authority in charge of the health policies and design programs. The MoH provides health care to people without social security. JMH is a highly academic specialized hospital. Homeopathy is part of the National Health System regularized by the MoH. The outpatient service of homeopathy was established in JMH since 2004 and provides health care for climacteric stage women daily.
The recruitment methods included advertisements through internet, community groups and liaisons with health professionals. Posters with information about the study protocol were pasted at the study site; brochures were distributed among hospital population. Participants were recruited since March 2012 until December 2013.
Five hundred thirty four women seeking care for menopausal complaints or feeling depressive were screened at study site. Participants were recruited from this sample; one hundred thirty three women diagnosed with MDD according to DSM-IV who met the inclusion criteria agreed to participate. The entry criteria included: (1) 40 to 65 years; (2) diagnosed with major depression according to DSM-IV; (3) moderate to severe depression according with 17-item HRSD (14–24 score); (4) no current use of homeopathic treatment for depression or antidepressants or anxiolytic drugs three months prior to study entry; (5) not be currently taking psychotherapy for at least three months before screening; (6) no current use of estrogens or other medications known to affect ovarian function for at least three months before screening; (7) early transition to menopause, defined by a change in cycle length of seven days or longer in either direction from the participant’s own baseline for at least two cycles, or late transition to menopause, defined as three to eleven months of amenorrhea; (8) postmenopausal stage defined by twelve months or more of amenorrhea; (9) capability and willingness to give informed consent and to comply with the study procedures.
Exclusion criteria included: (1) pregnancy or breastfeeding; (2) other psychiatric disorders different from moderate to severe depression (severe depression, schizophrenia, psychotic disorders, bipolar affective disorders, suicide attempt); (3) alcohol or other substance abuse; (4) known allergy to fluoxetine; (5) cancer or hepatic diseases.
Plans to promote participant retention and complete follow-up included: scheduling appointments and contacting patients by telephone calls.
After inclusion, patients were randomly assigned to either one of three groups: (1) individualized homeopathic treatment (IHT) plus fluoxetine dummy-loaded; (2) fluoxetine (20 mg/d) plus IHT dummy-loaded; (3) fluoxetine placebo plus IHT placebo.
The selection of the individualized remedy was carried out after the case history by a certified medical doctor, specialized in homeopathy with 18 years experience in classical homeopathy based on Hahnemann’s methodology described in paragraphs 83–104 of the Organon of Medicine, 6th edition. A complete medical history with clinical examination was done. All patients no matter the group assigned, had a full homeopathic case-taking including the collection of all the facts pertaining to the patient which may help in reaching the totality of the symptoms: past and present physical and emotional symptoms, family environment since childhood, stressful life events, marital satisfaction. The symptoms were organized by hierarchy: mental, general and physical. In first place, the strategy to choose the individualized remedy was based on the most characteristic and clear mental symptoms. Secondly, general symptoms were taken into account. Computerized version of Synthesis Homeopathic Repertory 9.1 (Radar version 10) was used to facilitate the prescription. Only one remedy was prescribed at a time but it could be changed at every follow-up according to patient’s symptoms.
C-potencies were provided by Laboratorio Similia (Mexico City) and were manufactured according to Mexican Homeopathic Pharmacopoeia and Hahnemann’s methodology. Homeopathic medicines are produced through sequential agitated dilutions in Decimal (D), Centesimal (C) or Quinquagintamillesimal (Q or LM) potencies. C-potencies are prepared by diluting a drop of a parent substance in 99 drops of ethanol followed by agitation of the solution (1 C). Then one drop of this solution is diluted in 99 drops of ethanol followed by agitation of the solution (2 C). This procedure is repeated in consecutive agitated dilutions (3 C, 4 C, and so on). In the HOMDEP-MENOP study each individualized homeopathic remedy was prescribed in C-potencies.
Higher initial potencies were tried, only 30 C and 200 C were prescribed. The factors that influenced the selection of the potency included: clarity of mental symptoms, patient’s vitality and sensitivity, nature and kingdom (source) of medicine, chronicity, presence of any pathological disorder. As previously stated, in an IHT the homeopathic doctor selects a remedy based on the specific and most important symptoms the patient has. This individualized prescription also includes the selection of the appropriate potency based on the factors mentioned. Thus, the prescription is individualized in the selection of the remedy and in the appropriate potency required by the patient.
In the HOMDEP-MENOP study, a single dose of the individualized homeopathic remedy selected was dissolved in a 60 ml bottle of 30% alcohol-distilled water. Patients received 10 drops PO two times per day following agitation plus fluoxetine-dummy loaded prescribed PO daily. A double-dummy technique with matching placebos for each active treatment was applied, thus both placebos seemed identical to their corresponding verum formulations. Follow-up visits were at weeks 4 and 6 after the first clinical interview.
Patients in fluoxetine group received 20 mg/d PO plus IHT-dummy loaded. IHT-dummy loaded was repeated at week 4. Capsules of a generic fluoxetine were provided by Laboratorio Similia (Mexico City). Placebo capsules contained sucrose micro globules. Homeopathic placebo bottles were filled with the same amount of 30% alcohol-distilled water. Patients received 10 drops PO of this solution two times per day following agitation. Homeopathic placebo was repeated at week 4. The third group received both fluoxetine and IHT placebos, as previously described.
Some medications were prohibited during the trial: triptans, tramadol, anxiolytic drugs and other serotonergic agents or antidepressants, as well as hormone replacement therapy. Medication for diabetes and hypertension was allowed. Psychotherapy was also forbidden during study duration. Rescue intervention in case of lack of efficacy in the IHT group was fluoxetine 20 mg per day and, in case of placebo, an IHT was prescribed.
Criteria for discontinuing or modifying allocated medications
In case of emergency interventions, clinical worsening or serious adverse events, the pharmacist informed the homeopathic doctor if the individual patient was taking homeopathy, fluoxetine or placebo, without disclosing the code. In these circumstances, the homeopathic doctor reported the adverse events as serious, examined again the patient and suspended the medication. After medication was interrupted, if placebo was taken, an IHT was prescribed for this patient; if the patient was taken IHT, a new IHT was given. Only in case of lack of efficacy in the IHT group, fluoxetine 20 mg per day was prescribed. In case of serious events during fluoxetine treatment, medication was interrupted and an IHT was also prescribed. The participant did not continue furthermore in the original allocated intervention in placebo or fluoxetine groups.
The criteria for discontinuing or modifying allocated interventions included the presence of serious adverse effects observed during fluoxetine treatment. Some adverse events reported in fluoxetine treatment are: lack of interest in sex, sexual dysfunction, nausea, insomnia, somnolence, anorexia, anxiety, asthenia, tremor, allergic skin reactions. If they resulted in interruption of treatment, this was reported.
In case of IHT, if the participant underwent a severe ‘homeopathic aggravation’ (temporary intensification of symptoms before a condition improves), the homeopathic medicine was interrupted and the reaction was lessened by using frequent doses of the same remedy in lower potency. If the participant experimented the appearance of new symptoms different from those which prescription was based, the homeopathic medicine was interrupted, a full homeopathic case-taking was taken again with a new individualized remedy prescription, and these symptoms were reported as adverse events.
Each participant received a report form that enabled to write daily any adverse event or stressful event observed during trial duration. Study participants were retained in the trial whenever possible to enable follow-up data collection and prevent missing data.
Adherence to study medications
To enhance validity data, participants returned the unused capsules and bottles at each follow-up visit. Unused capsules were counted and recorded on the appropriate case report form. Participants were asked about any problems they had taking their study treatment.
The following three measures were used. The primary efficacy outcome was the change from baseline in mean total depression score using the 17-item version of the HRSD at week 4 and 6. Severity of symptoms was assessed by a blinded investigator (clinical psychologist) from the JMH. The secondary outcomes were: change from baseline in mean total depression score using BDI and GS at week 4 and 6; responder rates (response rate: decrease of 50% or more from baseline score; remission rate: 7 or less points in HRSD score). Number and severity of all adverse events and homeopathic aggravations during the study period and fifteen days after final dose were collected in determining the safety of fluoxetine and homeopathic medicines.
Adverse events were defined as any untoward medical occurrence in a subject without regard to the possibility of a causal relationship. Adverse events were collected after participants consent and enrolled in the study and fifteen days after study completion.
Participants were simple randomized in a 1:1:1 ratio using a computer-generated random allocation sequence, by a statistician not further involved in the study. Participants were assigned in sequential order to the treatment groups. The randomization list was kept strictly confidential.
Concealment mechanism and implementation.
The principal investigator enrolled participants. Following inclusion, all patients went through a full homeopathic case-taking and received a prescription of the individualized homeopathic medicine. Only third of them actually received it. The research pharmacist randomly delivered the treatment according the allocation sequence in one of the three groups previously described. The randomization list was sent to the research pharmacist at the beginning of the study.
Participants, the homeopathic doctor, the psychologist, and the statistician remained blinded from the identity of the three treatment groups until the end of the study. The psychologist assessed the severity of the symptoms and kept the HRSD scores strictly confidential in a close envelope every follow-up until the end of the study.
Sample size calculation
Sample size calculation was estimated using G*Power (available at University of Dusseldorf:http://www.psycho.uni-dusseldorf.de/aap/projects/gpower/). The sample size calculation was based on a previous study protocol for a randomized controlled trial of homeopathy for depression published by Adler et al . We assumed that verum treatment is better than placebo by 2.7 (6.0) [(mean (standard deviation)] HRSD score points after six weeks, corresponding an effect size = 0.45 (largest difference between any two groups to be detected/expected within group standard deviation = diff/de). To detect an effect size = 0.45, in a 3-group design (1:1:1), using F-Test, with a 5% risk of type 1 error, and 83% power, 63 patients per group were expected to be required considering also a 10% drop-out rate.
Study data were collected at baseline and every follow-up during the study duration. Data were collected from different sources: medical records, questionnaires (HRSD, BDI, GS) and report forms where participants wrote daily any adverse event.
All data were entered electronically on data sheets designed for the study. Original study forms were entered and kept on files at the JMH. Participants files were stored in numerical order in a secure and accessible place and manner. Participants files will be maintained in storage for a period of five years after completion of the study. All forms related to the study data were kept in locked cabinets. Access to the study data was restricted.
All patients under randomization were included in the primary efficacy population (intention-to-treat population), regardless whether or not they adhered to the treatment protocol or provided complete data sets. Only patients who withdrew their consent to use their personal data were excluded from the analysis. The flow of participants through the trial is presented in a CONSORT diagram.
First, the three groups were compared in order to verify that there are not significant differences among them at baseline to confirm they are comparable after randomization. Demographic characteristics were summarized using means and standard deviation for continuous data (i.e., age) and relative frequencies for qualitative data (i.e., marital status, occupation, menopausal status). The baseline demographic characteristics among groups were compared with the use of chi square test or by one-way independent measures of analysis of variance (ANOVA) as required. Continuous data were represented by means and standard deviation, whereas categorical data were represented by a frequency table.
Data were analyzed with SPSS statistical software (version 17.0). We compared: (1) IHTversus placebo; (2) fluoxetine versus placebo. The main statistical analysis compared primary and secondary outcomes measurements among groups at weeks 4 and 6. The primary outcome (change in mean HRSD score) and secondary outcomes (change in mean BDI and GS scores) among groups at baseline and weeks 4 and 6, were analyzed by one-way ANOVA to provide a statistical test of whether or not the means of the three groups are all equal. The statistical significant ANOVA result (p<0.05) suggests rejecting the global null hypothesis H0(the means are the same across IHT, fluoxetine and placebo groups). Owing to the study is a three-arm trial, adjustment for multiple comparisons was accomplished with Bonferroni method which requires that the p-value for each comparison be less than or equal to 0.05 divided by the total number of study comparisons. This guarantees that the probability of at least one type I error is less than 0.05.
Eta squared [between-groups sum of squares/total sum of squares] was calculated by hand to determine effect size. Responder rates were compared among groups using chi square test. Relative risk and odds ratio with 95% CI, and number needed to treat (NNT) were also determined. Statistical significance was set at p<0.05 level for all analysis. Steps taken in the design and data collection stages were observed carefully in order to prevent missing data, but this was difficult to completely achieve. Missing data were as a result of loss to follow-up and were handled by sensitivity analysis (SA). A multiple imputation technique (MI) was performed using multiple imputed datasets which yield unbiased estimates, and also accounts for the within and between dataset variability. Five imputations were performed in SPSS (version 17.0).
Statistical analysis for repeated measurements was not prespecified in the study protocol. A mixed effect model analysis with random intercept and slope was used to assess the rate of change in HRSD, BDI and GS scores, among groups over the 6-week treatment interval.
All patients who received at least one dose of study drugs were considered in the safety analysis. Adverse events were translated to Medical Dictionary for Regulatory Activities terms (MeDRa terms), quantified, and compared among groups using chi square test.
Fig. 1 describes the CONSORT diagram of women through the study. Five hundred thirty-four women seeking medical care for menopausal complaints were interviewed. Four hundred and one women did not meet inclusion criteria and were excluded. One hundred thirty-three women (24.9%) met inclusion criteria, accepted to participate in the study and were randomized as previously described.
Fig 1. CONSORT flow diagram of study participants through the trial.
Baseline characteristics of participants are summarized in Table 1. There were no significant differences among the three groups with respect to demographic characteristics (age, marital status, occupation, education) and menopausal status. The mean age (SD) in all groups was approximately 49 (5.8) years (p = 0.944). Most of the women included in the three groups were married (65%), housewives (61%), and the highest level of education was elementary school (80%). Fifty-five percent were postmenopausal, whereas 22% were in early transition to menopause and 23% in late transition (p = 0.474).
Table 1. Baseline demographic characteristics and menopausal status of participants.
There were no significant differences among groups with respect to risk factors for depression (Table 2). Sixty-four percent of women had a history of depression (p = 0.857), 73% reported domestic violence (emotional, physical or economic) (p = 0.883), 36% history of sexual abuse in infancy (p = 0.748) and 53% marital dissatisfaction (p = 0.397).
Table 2. Baseline prevalence of risk factors for depression among groups.
Table 3 shows HRSD, BDI and GS scores at baseline, 4 and 6 weeks. No significant differences among the three groups were observed with respect to baseline mean (SD) scores in HRSD, BDI and GS. Mean (SD) baseline score in HRSD was 21.2 (2.7) [95% CI (20.4–22)] in IHT group vs 20.6 (2.9) [95% CI (19.7–21.5)] in fluoxetine group vs 20.7 (3.1) [95% CI (19.8–21.7)] in placebo group [F (2,130) = 0.506, p = 0.604]. Mean (SD) baseline score in BDI was 26.3 (7.2) [95% CI (24.1–28.4)] in IHT group vs 25 (7.8) [95% CI (22.7–27.3)] in fluoxetine groupvs 27 (9.0) [95% CI (24.2–29.8)] in placebo group [F (2,130) = 0.692, p = 0.502]. Mean (SD) baseline score in GS was 35.3 (8.5) [95% CI (32.7–37.9)] in IHT group vs 33.2 (10.1) [95% CI (30.5–36.5)] in fluoxetine group vs 37.9 (11.5) [95% CI (34.3–41.4)] in placebo group [F (2,130) = 2.11, p = 0.125].