Neuroactive steroids in affective disorders: target for novel antidepressant or anxiolytic drugs?

In the past decades considerable evidence has emerged that so-called neuroactive steroids do not only act as transcriptional factors in the regulation of gene expression but may also alter neuronal excitability through interactions with specific neurotransmitter receptors such as the GABA(A) receptor. In particular, 3α-reduced neuroactive steroids such as allopregnanolone or allotetrahydrodeoxycorticosterone have been shown to act as positive allosteric modulators of the GABA(A) receptor and to play an important role in the pathophysiology of depression and anxiety. During depression, the concentrations of 3α,5α-tetrahydroprogesterone and 3α,5β-tetrahydroprogesterone are decreased, while the levels of 3β,5α-tetrahydroprogesterone, a stereoisomer of 3α,5α-tetrahydroprogesterone, which may act as an antagonist for GABAergic steroids, are increased. Antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) or mirtazapine apparently have an impact on key enzymes of neurosteroidogenesis and have been shown to normalize the disequilibrium of neuroactive steroids in depression by increasing 3α-reduced pregnane steroids and decreasing 3β,5α-tetrahydroprogesterone. Moreover, 3α-reduced neuroactive steroids have been demonstrated to possess antidepressant- and anxiolytic-like effects both in animal and human studies for themselves. In addition, the translacator protein (18 kDa) (TSPO), previously called peripheral benzodiazepine receptor, is the key element of the mitochondrial import machinery supplying the substrate cholesterol to the first steroidogenic enzyme (P450scc), which transforms cholesterol into pregnenolone, the precursor of all neurosteroids. TSPO ligands increase neurosteroidogenesis and are a target of novel anxiolytic drugs producing anxiolytic effects without causing the side effects normally associated with conventional benzodiazepines such as sedation or tolerance. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.