Abstract for presentation at 6th World Congress on Stress

Various steroids may be formed by the brain itself without the aid of peripheral sources. Such brain derived steroids are also called neurosteroids or neuroactive steroids. Especially 3alpha-reduced metabolites of progesterone are powerful positive allosteric modulators of GABA_A receptors. These GABA enhancing properties make them interesting candidates for the development of anxiolytic and antistress agents. We could show that such steroids are reduced in major depression and can be normalized by treatment with SSRIs such as fluoxetine. However, studies using non-pharmacological treatment procedures such as partial sleep deprivation, repetitive transcranial magnetic stimulation or electroconvulsive therapy did not reveal any influence of these non-pharmacological treatments on neuroactive steroids. Moreover, the antidepressant mirtazapine shifted these neuroactive steroids to the same direction as SSRIs independently from the clinical response. These data show that the changes in neuroactive steroid composition induced by antidepressants do not reflect clinical improvement in general but rather pharmacological effects of antidepressants on the 3alpha-hydroxysteroid dehydrogenase, a neurosteroidogenic enzyme. We could demonstrate respective effects of mirtazapine using a human recombinant enzyme in an in vitro assay. During experimentally induced panic attacks we noted a pronounced decrease in GABAergic neuroactive steroids in patients with panic disorder but not in normal controls. A first proof of concept study with a neurosteroidogenic compounds yielded positive effects using the CCK-4 challenge paradigm in humans. As such, neuroactive steroids might be promising candidates for treatment of stress and anxiety states in humans.