By Carrie Decker, ND
Founder and Medical Director, Blessed Thistle, Eugene, OR
Dr. Decker reports no financial relationships relevant to this field of study.
Summary Points
- This randomized, double-dummy, double-blind, placebo-controlled trial compares individualized homeopathy vs. placebo and fluoxetine vs. placebo for the treatment of moderate to severe depression in menopausal women.
- Treatment with both individualized homeopathy or fluoxetine was found to significantly reduce depression severity compared to placebo as measured by the Hamilton Rating Scale of Depression (HRSD).
- The mean reduction in depression severity as per the HRSD was 5 points greater with homeopathy than placebo, while the fluoxetine-placebo difference was 3.2 points.
- Homeopathy, but not fluoxetine, also significantly reduced menopausal symptoms compared to placebo as measured by the Greene Climacteric Scale.
Synopsis: A higher risk of depressive symptoms has been observed in the menopausal transition period. Antidepressant medications are often recommended; however, many meta-analyses have only shown modest benefit of such medications over placebo. This study compares individual homeopathic treatment vs. placebo and the antidepressant medication fluoxetine vs. placebo for the treatment of moderate to severe depression in peri- and postmenopausal women.
Source: Macías-Cortés Edel C, Llanes-Gonzalez L, Aguilar-Faisal L, et al. 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 2015;10:e0118440.
In this double-blind, double-dummy, placebo-controlled trial, 133 women with moderate to severe peri- and postmenopausal depression were randomized to treatment with individualized homeopathic treatment, 20 mg of fluoxetine a day, or a placebo. The study took place at the public, academic, and research Hospital Juárez de Mexico in Mexico City, and participants were recruited by advertisements on the internet, community groups, and posters and brochures posted in the hospital. To be eligible for participation, depression level was required to be classified as moderate to severe using the DSM-IV criteria. Participants were between 40-65 years of age. Additional criteria to be eligible for the study included no use of hormone replacement therapies, homeopathic treatment, medication for depression or anxiety, or psychotherapy for at least three months prior to (and during) the study. Individuals with psychiatric disorders other than moderate to severe depression, including alcohol or substance use disorders, were also excluded from the study. Of the initial 534 individuals who desired to participate in the study, 133 met study criteria and were enrolled.
Individualized homeopathic remedies were prescribed by a certified medical doctor with 18 years of experience in classical homeopathy based on Hahnemann’s methodology. All patients experienced a full homeopathic intake and the most characteristic symptoms were organized by hierarchy. Additional general symptoms were taken into consideration secondarily. Remedy selection was facilitated using the computerized system Radar version 10. Remedies with centisimal (C) potencies of 30 C or 200 C were prescribed, with the potency based on the clarity of symptoms, the patient’s vitality and sensitivity, and chronicity of symptoms. A single dose of the homeopathic remedy was diluted into a 60 mL bottle of 30% alcohol and water solution. Each placebo group received a loaded “dummy” of the placebo therapy: A sucrose-containing capsule was substituted for fluoxetine and/or a homeopathic placebo containing a 30% alcohol-water solution without a remedy. Instructions were provided to all participants to succuss (agitate) the homeopathic solution or placebo prior to dosing 10 drops orally twice daily and participants took one capsule of 20 mg fluoxetine or placebo daily. The final groups received either verum homeopathic with placebo fluoxetine, fluoxetine with dummy-loaded homeopathic placebo, or placebo of both fluoxetine and homeopathic. Compliance was assessed by collection of unused capsules and bottles at follow-up.
Assessment of depression and menopausal symptoms occurred at the intake appointment, and at four- and six-week follow-up. Depression was assessed using both the Hamilton Rating Scale of Depression (HRSD) and the Beck Depression Inventory (BDI), while menopausal symptoms were assessed using the Greene Climacteric Scale (GS). If indicated, an alternate homeopathic remedy or potency was selected at the visit at four weeks, or a rescue intervention in case of the lack of efficacy was provided. Rescue intervention for the homeopathy group was fluoxetine 20 mg per day and homeopathy for individuals given placebo or fluoxetine and the participant did not continue in the original allocated intervention. The pharmacist was not blinded to interventions and, thus, was able to make these substitutions if indicated.
The primary outcome was the change in mean total depression score as measured via the HRSD, and secondary outcomes were change in depression score as measured with the BDI and GS score of menopausal symptoms. No significant difference in baseline scores existed among the groups between any of the parameters assessed or with regard to demographic characteristics and risk factors for depression. In the homeopathy, fluoxetine, and placebo groups, two, seven, and six subjects were lost to follow-up, respectively. The intention-to-treat population included all patients who were randomized, regardless of whether they adhered to treatment or completed the study. Missing data due to loss of follow-up were handled by sensitivity analysis.
At 6 weeks follow-up, the HRSD score was significantly lower in the homeopathic treatment group (mean, 9.9; standard deviation [SD], 3.0; 95% confidence interval [CI], 9.0-10.9) and fluoxetine group (mean, 11.7; SD, 3.7; 95% CI, 10.5-12.9) than the placebo group (mean, 15.0; SD, 3.7; 95% CI, 15.9-18.3) (P = 0.000). The mean HRSD score was not significantly different between the homeopathy group and the fluoxetine group (P = 0.082). No significant difference existed among the three groups with regard to the BDI score; however, this index decreased in all groups. The GS score in the homeopathy group (mean, 18.1; SD, 7.8; 95% CI, 15.7-20.6) was significantly better than the placebo (mean, 26.8; SD, 11.7; 95% CI, 22.8-30.7) (P = 0.002), while the GS score of the fluoxetine group (mean, 23.1; SD, 12.3; 95% CI, 19.2-27.1) was not significantly different from placebo. The mean GS score was not significantly different between the homeopathy group and the fluoxetine group (P = 0.115).
“Homeopathic aggravation” (temporary intensification of symptoms before improving) and new symptoms that occurred during homeopathic treatment were reported as adverse events. There were no serious adverse events in either group. One patient taking fluoxetine had increased anxiety and insomnia. In this case, the pharmacist told the doctor which group she was in and she was given the “rescue” individualized homeopathy treatment; she did not continue in the previously allocated intervention. No one prescribed the homeopathic treatment had an aggravation requiring a rescue intervention or withdrawal from the study. Mild adverse events reported during the study included nausea, constipation, diarrhea, headache, insomnia, anxiety, dizziness, fatigue, and dyspepsia. Frequency of occurrence was not significantly different between groups.
Commentary
An increased rate of depressive symptoms in the menopausal transition period has been observed in many studies.1,2 Factors that may contribute to depression may include disrupted sleep, family history, hormonal changes, lifestyle, and relationships. Meta-analyses of the efficacy of antidepressant medications have shown little benefit relative to placebo for the treatment of depression overall,3 and other treatments such as hormone replacement therapy have been investigated for the treatment of depression in the menopausal transition.4
Many women seek complementary and alternative medical treatment for menopausal symptoms.5,6 However, many of these treatments have not been well studied to determine if an effect exists greater than the placebo effect. Studies surrounding homeopathy in particular are poorly designed, lack a placebo, or have not shown an effect more significant from placebo.7 In addition, homeopathic treatments are often standardized and do not consider the principles inherent to the practice of individualized homeopathic medicine as detailed in Hahnemann’s Organon of Medicine, the gold standard of homeopathic care.8
The National Institute for Health and Clinical Excellence (NICE) has recommended a drug–placebo difference as a 3-point change in depression severity as measured by the HRSD to be considered clinically significant.9 In the current study, the improvement over placebo experienced in the fluoxetine group was 3.2 points while that of the individualized homeopathy was 5 points. A similar double-dummy investigation comparing individualized homeopathy to a control of 20-40 mg of fluoxetine for a general population with moderate-to-severe depression found no significant differences between the percentages of response or remission rates as measured by the Montgomery & Asberg Depression Rating Scale (MADRS) score.10 In both of these studies, significant improvements in either the HRSD or MADRS score were seen in all groups at the various time points.
A comprehensive homeopathic assessment has characteristics much like a psychotherapy session; that is, discussion concerns not only primary symptoms but also contributing factors, concomitant symptoms, and emotional reactions or states. In this study, the medical history included past and present physical and emotional symptoms, family environment since childhood, stressful life events, and marital satisfaction. Thus, even the placebo group experienced a medical intake that was much like an initial psychotherapy appointment, in which there was an extensive discussion of factors that may contribute to their depression and menopausal symptoms. Although this was not considered an intervention and was necessary for the design of the study, it may have contributed to the improvements observed across all categories in the placebo group as well. Short-term dynamic psychotherapy, which in some ways may be similar to a homeopathic interview (depending on practitioner approach), has been studied for the treatment of depression and has been found to be more effective than control.11
A limitation of this study was that although the homeopathic treatment was individualized with consideration for dosage potency and remedy, the medication intervention of fluoxetine was not adjusted. In clinical practice, the dosage of this medication also would have been increased or an alternative medication considered if it was found to be ineffective. Estrogen therapy also has been found to be an effective monotherapy or adjunctive for depression in the menopausal transition, so this also would have been offered as an adjunctive or alternative therapy in a clinical setting.12
A longer duration of study also would be more appropriate given the nature of the complaints of menopause and depression, which both may wax and wane over time. Intention-to-treat analysis was used to consider all individuals randomized to treatment, including dropouts and individuals not adherent to treatment, with missing data handled by sensitivity analysis. However, the authors did not state how the individual who received the rescue homeopathic treatment after an adverse response to fluoxetine was handled in the analysis, other than that she did not continue in the previously allocated intervention (fluoxetine). Although exclusion criteria that limited participants from accessing additional support like psychotherapy was necessary to limit variables in this study, it is likely that in a clinical setting, additional support such as this would be recommended.
Compliance with homeopathic dosing is sometimes difficult for patients, particularly when remedies are required to be taken at multiple times away from food each day, a practice known as “clean mouth” by homeopathic prescribers. Cost of homeopathic treatment vs. antidepressant medication also may vary, depending on region and availability of care. In the study population (Mexico), homeopathy was considered the lower cost intervention, while in many regions of the United States the opposite would be true for people with insurance coverage. When prescribing homeopathic treatment, these factors also should be considered to maximize likelihood of compliance.
Overall, this study shows that individualized homeopathic treatment is as effective as a low dose of fluoxetine for the reduction of moderate-to-severe depression in menopausal women. However, similar to the treatment applied in this study, there should be follow-up within a month and adjustment of therapy if the treatment has not been shown to be effective. Patients also should be informed of the alternatives, such as antidepressants or hormone replacement therapy, so they can make informed choices. Adjunctive therapy such as counseling also should be offered, as there often are many factors contributing to depression and the data for combined psychotherapy and pharmaceutical treatments are convincing.
References
- Weber MT, Maki PM, McDermott MP. Cognition and mood in perimenopause: A systematic review and meta-analysis. J Steroid Biochem Mol Biol 2014;142:90-98.
- Llaneza P, Garcia-Portilla MP, Llaneza-Suarez D, et al. Depressive disorders and the menopause transition. Maturitas 2012;71:120-230.
- Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and antidepressant benefits: A meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 2008;5:e45.
- Rubinow DR, Johnson SL, Schmidt PJ, et al. Efficacy of estradiol in perimenopausal depression: So much promise and so few answers. Depress Anxiety 2015;32:539-549.
- Shou C, Li J, Liu Z. Complementary and alternative medicine in the treatment of menopausal symptoms. Chin J Integr Med 2011;17:883-888.
- Wong VC, Lim CE, Luo X, et al. Current alternative and complementary therapies used in menopause. Gynecol Endocrinol 2009;25:166-174.
- Ernst E. Homeopathy: What does the “best” evidence tell us? Med J Aust 2010;192:458-460.
- Hahnemann S. Organon of Medicine. Germany: W.F. Wakeman; 1833.
- Kirsch I, Moore TJ, Scoboria A, et al. The emperor’s new drugs: An analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prev Treat 2002;5:Article 23. Available at: http://alphachoices.com/repository/assets/pdf/EmperorsNewDrugs.pdf. Accessed March 28, 2016.
- Adler UC, Paiva NM, Cesar AT, et al. Homeopathic individualized Q-potencies versus fluoxetine for moderate to severe depression: Double-blind, randomized non-inferiority trial. Evid Based Complement Alternat Med 2011;2011:520182.
- Driessen E, Hegelmaier LM, Abbass AA, et al. The efficacy of short-term psychodynamic psychotherapy for depression: A meta-analysis update. Clin Psychol Rev 2015;42:1-15.
- Soares CN, Almeida OP, Joffe H, et al. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: A double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 2001;58:529-534.
A higher risk of depressive symptoms has been observed in the menopausal transition period. Antidepressant medications are often recommended; however, many meta-analyses have only shown modest benefit of such medications over placebo. This study compares individual homeopathic treatment vs. placebo and the antidepressant medication fluoxetine vs. placebo for the treatment of moderate to severe depression in peri- and postmenopausal women.
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