Homeopathy 2005; 94(03): 141-144
DOI: 10.1016/j.homp.2005.05.002
Guest Editorial
Georg Thieme Verlag KG Stuttgart · New York

Depression research in homeopathy: Hopeless or hopeful?

Iris R Bell
Further Information

Publication History

Publication Date:
29 December 2017 (online)

Two papers in the current issue examine the important question of whether or not homeopathy is efficacious in the treatment of depression.[ 1,2 ] The Pilkington et al. systematic review found only a few uncontrolled or randomized controlled trial (RCT) studies on the topic and pointed out the need for a great deal more well-designed research with adequate numbers of participants. At the same time, the Katz et al. paper reported discouraging problems in recruitment of adequate numbers of patients from a primary care setting for a feasibility trial. The findings highlight key considerations for homeopathic research in general, as well as for studies on depression in particular.

The implicit and explicit issues include:

  • a continued lack of an adequate base of well-done observational studies using homeopathy in conventionally-defined diagnostic entities to guide design of randomized controlled trials,

  • the difficulty in developing well-organized homeopathic practice-based networks within which to perform large sample outcome studies,

  • the lack of a critical mass of homeopathy researchers,

  • a lack of adequate funding to support high-quality research studies at one or multiple sites within any given country or worldwide, and

  • the unique methodological challenges for homeopathy as a whole system of care in complementary and alternative medicine (CAM) research.[ 3–8 ]

The latter hurdles combine with the better-known, thorny problems already identified in the study of depression therapies from a mainstream psychiatry[ 9,10 ] and psychology[ 11 ] perspective, eg poor patient adherence to treatment and large placebo effects. In real-world practice, some data suggest that improving attitudes towards the treatment intervention (eg drugs) and self-confidence in ability to manage side effects can bolster patient adherence.[ 10 ] The placebo effect issue may be even more complex than poor adherence to resolve, but may lead to innovative approaches to clinical research in homeopathy (see below). Depression is a sufficiently important public health challenge to merit homeopathic study.

Depressive disorders are a worldwide public health problem, affecting approximately 121 million people. In addition to the substantial risk of suicide, the World Health Organization identified depression as the leading cause of disability as measured by years lived with disability, and the fourth leading cause of disability adjusted life years in the year 2000 (http://www.who.int/mental_health/management/depression/definition/en/). Given that fewer than 25% of persons with depression have access to effective treatment and that patient adherence to a conventional drug regimen when they do receive treatment is poor, homeopathy offers a potentially low cost, efficient, safer, and less stigmatizing alternative to conventional pharmaceutical agents or psychotherapeutic interventions. Homeopathic materia medica and case reports document improved mood in numerous individual patients with and without other medical and psychiatric comorbidities.

However, in the contemporary world of evidence-based medicine, patient self-reports and provider impressions are insufficient to sway policy-makers or sceptics.[ 12 ] In contrast with many other serious disorders in which it is possible to show changes in objective laboratory tests, the definition and the assessment of treatment response in clinical depression rely on subjective symptom reports and behavioral observations—and hence prone to human error, bias, expectation, and interpretation.

To complicate matters, depression research has uncovered a remarkably large magnitude placebo effect in most drug studies and has generated an even more remarkable debate over the reality of the presumed efficacy of widely-accepted drugs in depression treatment.[ 9,13,14 ] Widely-quoted statistics highlight that controlled depression drug studies typically show at least 30–50%,[ 15 ] and up to 65–80% rate of placebo response.[ 16 ] If most depressed people respond to placebos, it requires extremely large samples to demonstrate a statistically significant advantage for any active treatment over placebo. On another side of the issue, additional debates recently have arisen over the existence of placebo effects themselves in many different clinical problems.[ 17 ]

Apparently it is very unsettling to the research community that some people might be able to heal themselves under the right conditions,[ 18 ] and that ‘nonspecific’ effects can play a primary role in the process.[ 19 ] In view of this confusing state of affairs, what should policy-makers decide about recommending or expending societal resources on any given treatment for all persons with depression? The answer may be that it is time to re-evaluate some of the fundamental assumptions used in clinical research, at least for homeopathy. Homeopathy involves the clinical diagnosis and treatment of the person as an individual. The right answers for society, ie, for group averages in research trials, may be difficult to determine, and more importantly, inappropriate to apply to a given individual patient.

First, as the Katz et al. note, the high rate of placebo responses in any conventional clinical trial of depression means that homeopathy studies on unselected samples of depressed patients will also require very large sample sizes to achieve appropriate statistical power for detecting a meaningful significant effect on mood beyond that of placebo. Most pilot studies of CAM cannot meet the latter requirement because of funding and recruitment limitations. For the underpowered sample sizes of most early phase CAM research trials, Aickin[ 4 ] has proposed application of the concept of separation tests as opposed to reliance on null hypothesis testing. He points out that null hypothesis testing is most relevant to phase III clinical trials on larger samples (s to 1000s) when the question is, should society adopt this treatment for everyone with the diagnosis? His legal analogy for phase III is ‘proof beyond a reasonable doubt.’ However, many investigators inappropriately ask the same phase III-level question and apply the same null hypothesis standards to phase I and II trials, which are inherently underpowered to address the question. Rather, the more appropriate question for phase I and II trials is, do the data support further research on the intervention? There Aickin's legal analogy is ‘a preponderance of credible evidence.’ Separation tests can provide such credible evidence.

The definition of a responder for separation tests or null hypothesis testing in homeopathic RCTs and observational studies is a related issue. Most trials of homeopathy have implicitly accepted the assumption of conventional drug RCTs that a narrow, disease-focused outcome is the appropriate measure. In contrast, homeopathic philosophy and practice suggest that diagnosis and treatment are directed to the patient as a whole, not to a specific symptom. Therefore, from a patient-centered, whole person healing perspective, global measures of overall health and well-being as well as multidimensional bio-psycho-social-spiritual outcomes,[ 20 ] rather than disease-specific mood ratings alone, should form the basis for evaluation of homeopathy's efficacy and effectiveness in clinical studies of depression.[ 21 ] Using this comprehensive approach, it may also be crucial to consider Aickin's proposal,[ 3 ] as Katz et al. have suggested for homeopathic effectiveness studies in depression, that data analysis be focused on individual patient outcomes rather than on group averages.

Especially in the short-term trials of 12–16 weeks typical of depression research, homeopathy may induce changes in multiple nonmood outcomes, ie, variables that are disease nonspecific. The result could be an apparently negative RCT, a study considered of high quality by conventional meta-analytic standards, but one that is actually prone to Type II error (‘false negative’) from a real-world point of view—if the full scope of possible changes were missed rather than included in the assessment of response vs no response. Similar arguments are emerging in research on acupuncture and Chinese medicine, another major CAM system with patient-centered outcomes.[ 22–24 ] If a CAM system generates global and multiple, multidimensional local changes in the whole person, then it is illogical to evaluate it solely on the basis of a singular, disease-specific outcome.

Second, is it appropriate to assume that homeopathy might be the treatment of choice for everyone with depression from the community or from the primary care population? The data suggest that the answer is no, from the standpoint of patient preference, adherence, and the individual capacity to respond.[ 25,26 ] For instance, the evidence is that people who use CAM, especially CAM systems such as homeopathy or Chinese medicine, are different from nonusers in at least one of the five primary personality traits, openness to experience. A recent analysis of over 3000 respondents in a US community survey on midlife development revealed that openness was a predictor of CAM systems utilization, with an odds ratio of 3.55 (95% confidence interval 1.33–9.44).[ 27 ] In other research studies, the genetically-based personality trait of absorption, which correlates highly with trait openness to experience, predicted not only the number of CAM modalities used in chronic pain and cancer patients,[ 28 ] but also fibromyalgia patients’ decisions to stay with their original random assignment to verum homeopathy or placebo when given the option to switch to the other group under double-blind conditions after 4 months of study participation.[ 29 ] Despite the shared elevation in trait absorption scores, patients who chose to stay on placebo did not respond as well clinically as did patients who chose to stay on verum homeopathy.

Taken together, the personality data suggest that RCTs recruiting participants from a general population pool or even from conventional primary care clinics end up with samples whose baseline characteristics and capacity for choosing and adhering to homeopathic treatment differ at baseline from those in homeopaths’ typical practices. Investigators would need to pre-screen potential study participants for high levels of openness or absorption as an inclusion criterion before enrolling them in an RCT or observational study in order to evaluate the claims of homeopaths in treating depressed patients. Then the question would be, among persons high in trait openness, not necessarily in everyone in the general population, is homeopathy at least as effective as conventional antidepressant drugs and/or more effective than placebo?

Another individual difference trait relevant to the capacity to respond to treatment is executive function. Executive function includes complex problem-solving ability, including the flexibility to shift response set, to inhibit habitual behaviours and redirect attention, and to make goals, plans, and decisions, all regulated by prefrontal cortex.[ 30 ] Previous studies indicate that poorer baseline executive function predicts subsequently poor response to antidepressant drugs in depression,[ 31 ] and to comprehensive multimodal treatment programs for minimal traumatic brain injury[ 32 ] (in which pilot study evidence suggests homeopathy is beneficial[ 33 ]), or for alcohol rehabilitation.[ 34 ] The testable hypothesis that follows is that the more extensive and persistent favorable responses to homeopathy in depressed persons might occur in individuals whose baseline executive function is relatively stronger.

As with trait openness and absorption, an individual difference approach to executive function assessment for the appropriate experimental design of RCTs would lead to a prescreening process. The process would identify the potentially better responders to homeopathy and then test them with active remedies vs placebo, rather than evaluating all persons with depression. With this strategy, statistical power to detect an effect might increase even for a smaller sample study. In parallel, evaluating clinical populations for executive function in observational studies on homeopathy in primary care populations with depression might clarify differences between persons who choose and do not choose homeopathy and who report favourable vs unfavourable outcomes.

Moreover, emerging physiological research indicates that objective biomarkers might differentiate depressed responders to active agents from those to placebo who otherwise exhibit comparable improvements in mood ratings. The prefrontal region of the brain is particularly involved in modulation of executive function. Previous studies have shown that clinical mood responders to verum antidepressants such as fluoxetine exhibit a different pattern of objective electroencephalographic (EEG) changes in prefrontal leads than do placebo responders. The EEG patterns of both medication and placebo responders differ from each other and from those of clinical mood nonresponders to either drugs or placebo.[ 35 ]

Similarly, prefrontal EEG changes on initial treatment with individualized homeopathic remedies identify the subsequently excellent responders with fibromyalgia (ie, patients with both global health improvements and local tender point pain reductions) after 3 months of double-blind treatment.[ 36 ] In the fibromyalgia-homeopathy study, no patients on placebo exhibit comparably excellent global and local responses after 3 months. Excellent responders have significantly greater improvements on emotional, physical, functional, and spiritual rating scales than do lesser responders to active or placebo. The prefrontal EEG data suggest the possibility of adding an objective screening test for the capacity to respond to homeopathic treatment to inclusion criteria for participants in depression treatment RCTs that include comparisons with placebo and/or conventional antidepressant drugs.

In conclusion, the field of complementary and alternative medicine research in general, and homeopathy research on depression in specific, has suffered from not merely from a lack of high-quality RCTs, but also from intense debates over the appropriate RCT designs for nonpharmaceutical studies and a relative paucity of observational data to guide study design. Rather than accepting all of the assumptions and population-based values of conventional, disease-centered mainstream drug research, homeopathy research may advance best by retaining a patient-centered emphasis on the individual, drawn from its own clinical practice. Patient-centered homeopathic research on depression can be rigorous and evidence-based, but will need to emphasize individual differences over group averages in subject recruitment and assessment procedures as well as in data analytic approaches.

 
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