Targeting neurosteroidogenesis as therapy for PTSD

Posttraumatic stress disorder (PTSD) is a severe condition resulting from exposure to traumatic events, such as combat situations, sexual assault, serious injury or the threat of death. Symptoms include disturbing recurring flashbacks, avoidance or numbing of memories of the event, and hyperarousal, which continue for more than a month after the traumatic event. Reduced cortical GABA (Kugaya et al., 2003) and cebrospinal fluid (CSF) allopregnanolone levels (Rasmusson et al., 2006) that positively and allosterically modulate GABA action at GABAA receptors (Belelli and Lambert, 2005) suggest that in PTSD patients, a perturbation of GABAergic neurotransmission plays a role in the pathogenesis of this disorder. Thus restoring downregulated brain allopregnanolone levels may be beneficial in treating PTSD. There is a general consensus that maladaptive fear responses (i.e., impaired fear extinction) are a core feature of stress-induced PTSD (Myers and Davis, 2007; Maren, 2008). Exaggerated fear responses and impaired extinction learning, or the inability to extinguish fear memories, are often treated with exposure-based therapy (EBT), which involves the exposure of the patient to the feared context without any danger (Joseph and Gray, 2008). This closely approximates the procedure used to simulate and study fear responses and fear extinction learning in PTSD mouse models (Marks, 1979). While psychological therapy has been highly effective both in treating PTSD and in preventing the progression of the event sequelae that leads to consolidation of fear memories, one challenge of PTSD therapy is the spontaneous recovery of fear that often reemerges following successful EBT. For this reason, pharmacological treatment may be advantageous alone or in combination with EBT. Selective serotonin reuptake inhibitors (SSRIs) are currently the drugs of choice in treating PTSD. They are effective in facilitating and restoring the neurobiological changes altered in PTSD patients, and they are devoid of the unwanted side effects that plague the use of benzodiazepines, more importantly, SSRIs are potent therapeutics where benzodiazepines fail to be beneficial. Following the observation that low non-serotonergic doses of fluoxetine and congeners increase allopregnanolone levels as their primary mechanism of action, we suggested that SSRIs acting as selective brain steroidogenic stimulants (SBSSs) can improve dysfunctional emotional behavior and may be of advantage in PTSD treatment. In addition to its use in PTSD, this novel steroidogenic mechanism of action of SSRIs given at low doses offers enormous therapeutic potentials for the treatment of other psychiatric disorders, including anxiety spectrum disorders, premenstrual dysphoria, and probably depression, as these disorders may be caused by a downregulation of neurosteroid biosynthesis (Uzunov et al., 1996; Westenberg, 1996; Guidotti and Costa, 1998; Romeo et al., 1998; Uzunova et al., 1998; Steiner and Pearlstein, 2000; Berton and Nestler, 2006; Pinna et al., 2006a, 2009; Pinna, 2010; Ipser and Stein, 2012; Pinna and Rasmusson, 2012; Lovick, 2013). In vitro studies show that SSRIs may activate 3α-hydroxysteroid dehydrogenase, thereby facilitating the reduction of 5α-dihydroprogesterone into allopregnanolone (Griffin and Mellon, 1999). Nonetheless, the precise neuronal mechanisms involved in the neurosteroidogenic action of SSRIs remain unclear. Drug design welcomed allopregnanolone biosynthesis as a target for novel rapidly acting anxiolytics devoid of sedation, tolerance, and withdrawal liabilities (Rupprecht et al., 2009, 2010; Schule et al., 2011), and, in addition to low doses of SSRIs, selective ligands for the (18 kDa) translocase protein (TSPO), which increase allopregnanolone levels, may be beneficial in anxiety and PTSD (Rupprecht et al., 2009).