STEROIDS and POST-TRAUMATIC STRESS DISORDER

From a biological perspective, stress involves activation of neurobiological systems, forwarded for the preservation of the life. Such stress responses are required for survival, but they can also increase the risk of physical and mental health problems. Post-Traumatic Stress Disorder (PTSD) is an anxiety condition associated with exaggerated stress responses, which appear in people having experienced serious traumas, as physical assaults or severe accidents. The diagnostic criteria for PTSD may be summarized in three clusters of symptoms: a persistent re-experience, a constant avoidance, and continual symptoms of increased arousal. Among the several suggestions about the molecular basis of the disorder, the alterations of hypothalamus-pituitary-adrenal (HPA) axis and immune system have gained the most attention in the scientific setting, during the last year. In PTSD patients, HPA axis increased sensitivity has been demonstrated, in parallel with a strong negative cortisol feedback. Moreover, low cortisol levels have been considered as possible pre-existing conditions that could predispose to PTSD development. Surely, the activation of the HPA axis leads to elevations in the neuroactive steroidosynthesis. In steroidogenesis, one of the most important step is the cholesterol incoming into the mitochondria through a pore formed by the translocator protein (TSPO). Neuroactive steroids enhance GABA neurotransmission and restore homeostasis following stress. It has been discussed a possible role for the neuroactive dehydroepiandrosterone (DHEA) as a mediator of both HPA axis extreme stress adaptation: the neuromodulatory effects of DHEA, and its metabolite DHEAS at GABA and NMDA receptors in the brain may contribute to psychiatric symptoms associated with PTSD. An involvement of the Cyclic adenosine monophosphate Responsive Element Binding (CREB) proteins, which have key roles in the formation of long-term memories, have been suggested in memory deficit and psychiatric disorders. Aim of the present thesis was to inquire the peripheral levels of some biochemical markers in PTSD patients versus healthy controls. In particular, the research explored the levels of peripheral markers, such as steroids, TSPO and CREB proteins. Secondary aim of the thesis was to correlate such biochemical markers to a detailed clinical/symptom characterization of PTSD, and spectrum comorbidity, investigated through specific rating scales (Structured Clinical Interview for DSM-IV axis-I disorders - SCID-I/P; the Impact of Event Scale - IES; the Panic Agoraphobic Spectrum Self Report lifetime version - PAS-S; the MOOD Spectrum-Self Report - MOODS-SR; the Structured Clinical Interview for the Trauma and Loss Spectrum - SCI-TALL). The studies were carried on a sample of 55 subjects: 30 PTSD patients, under naturalistic pharmacological treatment, and 25 healthy controls, without any psychiatric diagnosis, sex and age matched. Ethics of experimentation procedures were reviewed and approved by the Ethical Committee on Human Experimentation of the Azienda Ospedaliero-Universitaria Pisana. The obtained data showed alterations in serum and saliva DHEAS level in PTSD patients. The correlation analyses carried out between steroid ratio and PAS-SR domain scores in controls showed significant correlations, corroborating the role of anxiety comorbidity as risk factors for adverse sequel following exposure to trauma. The lymphomonocytes of civilian trauma victims with diagnosis of PTSD showed to have a significant decrease in mitochondrial TSPO density, according to data obtained in war-related PTSD patients. Moreover, we found a significant correlation between TSPO maximal density and MOODS-SR total manic scores and PAS-SR Stress Sensitivity. In particular, patients with PTSD presenting the highest number of comorbid lifetime manic/hypomanic items showed the lowest TSPO density, supporting the role of bipolar spectrum comorbidity in PTSD and of even subthreshold bipolar comorbidity. Moreover, since intrusive memories and flashbacks are the core of PTSD psychopathology, another aim of this thesis was to investigate the CREB and P-CREB (activated) protein levels in PTSD subjects. In peripheral blood lymphocytes, the CREB protein density has been found altered. The alteration in CREB protein density occurred in PTSD could be at the basis of the memory imbalance. Many researches are yet necessary to deepen the complex neurochemical basis of PTSD psychopathology, but such efforts could help to obtained more specific diagnoses and target therapeutic approches.