From 120 million people that suffer from depression around the world, less than 25% receive adequate treatment [1]. The estimated global burden of disease from major depression, measured as "disability adjusted life years" (DALY), is rising globally, making depression the leading cause of DALYs in middle and high income countries [2]. The overall prevalence of depressive disorders in five European countries was 8.56%, with a higher prevalence in urban Ireland (12.3%) and urban United Kingdom (UK, 17.1%) [3]. The prevalence can be higher in some age groups. For instance, in Berlin, Germany, the prevalence of lifetime depression in 2008 was almost 20% for women between 18 and 29 years old, 25% for women between 40 and 59 years old and, among men, 12% and 15% for the same age groups, respectively [4]. In the same year, depression was the main reason for work incapacity and for early retirement among women [4]. This might be in spite of current treatments, which do not seem to have any effect on reducing the number of disabled persons per year [5].

According to the S3-Guidelines from the German Society for Psychiatry, Psychotherapy and Neurology, an antidepressant treatment is indicated to patients presenting a moderate episode of major depression [6]. Although antidepressants are the standard pharmacotherapy for major depression, with a significant difference to placebo, the National Institute of Clinical Excellence (NICE) in the UK stresses that the severity of depression at which antidepressants show consistent benefits over placebo is poorly defined, emphasizing that, in general, the more severe the symptoms, the greater the benefit [7]. In moderate depression, for instance, there is evidence suggesting that there is a statistically important difference favouring Serotonin Selective Reuptake Inhibitors (SSRIs) over placebo on reducing depression symptoms as measured by the Hamilton Depression Rating Scale (HAM-D), but the size of this difference is unlikely to be of clinical importance (SMD = -0.28; 95% CI, -0.48 to -0.08) [7] A recent patient-level meta-analysis confirms these guidelines and previous data [8], indicating small antidepressant benefits for patients with mild (SMD -0.11; 95% CI -0.18 to 0.41) or moderate depressive episodes (SMD -0.17; 95% CI-0.08 to 0.43 [9]). Whereas, for patients with severe depression, the difference was with a SMD of 0.47 (95% CI, 0.22 to 0.71), which is very close to 0.50, i.e., a medium effect size [9].

The patient's discontentment with antidepressants is a reason cited for the search for other treatment options [10]. In Ireland, for instance, individuals with a history of depression were much more likely to seek complementary and alternative medicine (CAM) than those who were not depressed [11]. Depression is also one of the most commonly treated complaints at the outpatient clinics of homeopathic hospitals in the UK National Health Service [12].

Homeopathy is based on the 'principle of similars', whereby substances that cause symptoms in healthy individuals are used to stimulate healing in patients who have similar symptoms when ill [13]. These substances are usually administered in extremely high dilutions, making homoeopathy a controversial and strongly debated system. When a single homoeopathic remedy is selected based on a patient's total symptom picture, it is called 'classical' homoeopathy [14].

In classical homeopathy (addressed in this protocol) the treatment consists of two main elements: the case history and the prescription of an individually selected homeopathic remedy. The homeopathic case history aims to ascertain the totality of signs and symptoms of each patient, enabling the selection of an individualized homeopathic medicine. In addition it attempts to understand the patient's background, environment and daily routine. In some recent approaches the patient might fill in a questionnaire prior to the medical consultation, to improve the efficiency of obtaining the case history [15].

Homeopathic medicines are produced through sequential agitated dilutions in Decimal (D), Centesimal (C) or Quinquagintamillesimal (Q or LM) potencies. In this study we will use Q-Potencies which are prepared by grinding the raw material (C1 until C3), followed by consecutive 1:50.000 agitated dilutions. Therefore a Q1 corresponds to a 5 × 10^-10 fraction of the raw material (Q2 = 2.5 × 10^-15, Q3 = 1.25 × 10^-20, Q4 = 6.25 × 10^-24, etc.). To date, there is no clear evidence that homopethic medicines are superior to placebo.

Results from a multi-center observational study with 3981 patients treated with classical homeopathy indicate clinically relevant improvements in the mental aspects of quality of life, after two and eight years of treatment observation [16]. However, it is not clear whether these results can be attributed to the homeopathic treatment itself, or are due to other factors or just placebo effects since the study had no control group. However, according to a recent trial from Brazil [17], classical homeopathy (i.e., the "whole packet": a thorough case history + homeopathic medicines) seems to be, at least, as effective as conventional standard pharmacotherapy. Data from this randomized, controlled, double-blind trial indicated that individualized homeopathic Q-potencies were non-inferior to the antidepressant fluoxetine in a sample of patients with moderate to severe depression. Interestingly responder rates (defined as a decrease of at least 50% from baseline on the Montgomery & Åsberg depression rating scale) of both the homeopathic medicine and fluoxetine groups were higher (homeopathy 84.6%; fluoxetine 82.8%) than those usually found for antidepressants in trials (43-75%) [18]. One might speculate that this higher response rate could be due to the more extensive homeopathic case history in the study that compared homeopathic medicines with fluoxetine. However, neither the specific effect of individualized homeopathic Q-potencies, nor the specific effect of the homeopathic consultation has been investigated for patients with depression.

For the first time this study evaluates both the specific effect of homeopathic medicines and of a homeopathic case taking in patients with depression. The protocol is in accordance with the EMEA (European Medicines Agency) Guidelines, which recommends placebo-controlled studies and the duration of six weeks for trials investigating medicines for depression [26], considering that during antidepressant pharmacotherapy, one must reckon with a delay of several weeks until sufficient antidepressant effects can be seen [27].

It is the first trial on classical homeopathy after the 15^th amendment to the German Medicines Act (Arzneimittelgesetz, AMG) [28]. The study includes all relevant aspects of the CONSORT guidelines for reporting randomized homeopathic trials with parallel groups [29, 30]. For ethical reasons, individuals with a previous suicide attempt or a C-SSRS score of 4 or 5 will be excluded and the occurrence of suicide ideation (with the same C-SSRS severity) will determine the premature termination of the patient's participation in the study. Depression severity will be limited to a maximum HAM-D score of 24, because for more severe depression a treatment with antidepressant is recommended [9].

The need of individual prescriptions in classical homeopathy has been considered as 'a severe obstacle for any double-blind trial' [31]. In fact, the selection of a suitable, individualized homeopathic medicine will not be always accomplished during the six weeks of acute treatment, especially under double-blind conditions. However, from an ethical point of view a longer placebo treatment period is problematic.

This study is an experimental study with a focus on efficacy and not a pragmatic trial with a focus on effectiveness. It is an attempt to deal with the challenges of homeopathic research [32] and the results might be useful information in the current discussion about the evidence on homeopathy.

Q-potencies that will be stored at the Charité Pharmacy (Q2 and Q3). Medicines not listed can optionally be ordered and prescribed, as needed.

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