Effect of an Oral Contraceptive with Chlormadinone Acetate on Depressive Mood Analysis of Data from Four Observational Studies

Background and objective: Many women of reproductive age experience depressive mood symptoms such as sudden mood swings, irritability, nervousness, excitability and anxiety. Although not defined as a disease, these disturbing mental symptoms are associated with a considerable decrease in quality of life. Molecular pharmacology research over the last 20 years has shown that endogenous steroid hormones may interact with the CNS. Some of these hormones, i.e. the sex hormone progesterone and its 3 alpha-reduced metabolites allopregnanolone (3 alpha,5 alpha-tetrahydroprogesterone) and epipregnanolone (3 alpha,5 beta-tetrahydroprogesterone, eltanolone), influence mood-balancing and anxiolytic effects via the gamma-aminobutyric acid receptor A (GABA(A)), a major inhibiting receptor of the CNS. Activation of GABA(A) receptor results in mood balancing, anxiolytic, antiepileptic and sedative actions. When oral contraception is considered, it should be taken into account that the various synthetic progestogens used may differ in their influence on mental state. For instance, there is strong clinical evidence of mood-balancing effects for the progesterone derivative chlormadinone acetate (CMA). The aim of these studies was to describe the clinical effects of CMA in combination with ethinylestradiol on depressive mood symptoms. Methods: Data from four prospective, non-interventional observational studies involving nearly 50 000 women were analysed. The studies documented use of four, six and 12 treatment cycles of the 28-day conventional regimen, as well as providing data on extended cycle regimens. The women in these studies were prescribed CMA 2 mg and ethinylestradiol (EE) 0.03 mg according to gynaecologists' usual practice. Results: Clinical data from the studies confirmed that intake of CMA 2 mg and EE 0.03 mg promotes emotional well-being and reduces mood swings. Improvement in depressive mood was documented after four, six and 12 treatment cyclesof the conventional intake regimen as well as with an extended-cycle regimen of CMA/EE. Conclusion: CMA 2 mg combined with EE 0.3 me improves symptoms of depressive mood. The high structural congruence between the endogenous GABA(A) modulator epipregnanolone and the CMA metabolite M-V suggests a direct GABAergic, mood stabilizing function of CMA. We propose a theoretical concept - the CMA-GABA(A) model - that could explain the positive psychotropic effect of CMA.