Neurosteroids and Self-Reported Pain in Veterans Who Served in the U.S. Military after September 11, 2001

Nearly half of Operation Enduring Freedom / Operation Iraqi Freedom (OEF/OIF) veterans experience continued pain post-deployment. Several investigations report analgesic effects of allopregnanolone and other neurosteroids in animal models, but few data are currently available focusing on neurosteroids in clinical populations. Allopregnanolone positively modulates GABAA receptors and demonstrates pronounced analgesic and anxiolytic effects in rodents, yet studies examining the relationship between pain and allopregnanolone in humans are limited. We thus hypothesized that endogenous allopregnanolone and other neurosteroid levels may be negatively correlated with self-reported pain symptoms in humans

Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia

The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n = 9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change = 10.38) compared with patients receiving placebo (mean change = 2.33), p = 0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (rs = 0.81, p = 0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (rs = 0.74, p = 0.046). In addition, baseline pregnenolone (rs = −0.76, p = 0.037), pregnenolone sulfate (rs = − 0.83, p = 0.015), and allopregnanolone levels (rs = −0.83, p = 0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (rs = 0.74, p <0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia

Posttraumatic Stress Disorder Symptom Network Analysis in U.S. Military Veterans: Examining the Impact of Combat Exposure

Recent work inspired by graph theory has begun to conceptualize mental disorders as networks of interacting symptoms. Posttraumatic stress disorder (PTSD) symptom networks have been investigated in clinical samples meeting full diagnostic criteria, including military veterans, natural disaster survivors, civilian survivors of war, and child sexual abuse survivors. Despite reliable associations across reported networks, more work is needed to compare central symptoms across trauma types. Additionally, individuals without a diagnosis who still experience symptoms, also referred to as subthreshold cases, have not been explored with network analysis in veterans. A sample of 1,050 Iraq/Afghanistan-era U.S. military veterans (851 males, mean age = 36.3, SD = 9.53) meeting current full-criteria PTSD (n = 912) and subthreshold PTSD (n = 138) were assessed with the Structured Clinical Interview for DSM-IV Disorders (SCID). Combat Exposure Scale (CES) scores were used to group the sample meeting full-criteria into high (n = 639) and low (n = 273) combat exposure subgroups. Networks were estimated using regularized partial correlation models in the R-package qgraph, and robustness tests were performed with bootnet. Frequently co-occurring symptom pairs (strong network connections) emerged between two avoidance symptoms, hypervigilance and startle response, loss of interest and detachment, as well as, detachment and restricted affect. These associations replicate findings reported across PTSD trauma types. A symptom network analysis of PTSD in a veteran population found significantly greater overall connectivity in the full-criteria PTSD group as compared to the subthreshold PTSD group. Additionally, novel findings indicate that the association between intrusive thoughts and irritability is a feature of the symptom network of veterans with high levels of combat exposure. Mean node predictability is high for PTSD symptom networks, averaging 51.5% shared variance. With the tools described here and by others, researchers can help refine diagnostic criteria for PTSD, develop more accurate measures for assessing PTSD, and eventually inform therapies that target symptoms with strong network connections to interrupt interconnected symptom complexes and promote functional recovery

Neurosteroid Levels in the Orbital Frontal Cortex of Subjects With PTSD and Controls: A Preliminary Report

Background Neurosteroids mediate stress signaling and have been implicated in the pathogenesis of post-traumatic stress disorder (PTSD) in both preclinical and clinical studies. Compared to controls, subjects with PTSD exhibit altered neurosteroid levels in peripheral blood and cerebrospinal fluid as well as hypoactivity in the medial orbital frontal cortex (mOFC). Therefore, the aim of this study was to compare neurosteroid levels in the mOFC of subjects with PTSD ( n  = 18) and controls ( n  = 35). Methods Gray matter was dissected from fresh-frozen mOFC, and levels of the neurosteroids pregnenolone, allopregnanolone, pregnanolone, epiallopregnanolone, epipregnanolone, tetrahydrodeoxycorticosterone, and androsterone were determined by gas chromatography-tandem mass spectrometry. Results Analyses of unadjusted levels revealed that males with PTSD had significantly decreased levels of allopregnanolone ( p  = 0.03) compared to control males, and females with PTSD had significantly increased levels of pregnenolone ( p  = 0.03) relative to control females. After controlling for age, postmortem interval, and smoking status, results showed that males with PTSD had significantly decreased levels of androsterone ( t 46  = 2.37, p  = 0.02) compared to control males and females with PTSD had significantly increased levels of pregnanolone ( t 46  = −2.25, p  = 0.03) relative to control females. Conclusions To our knowledge, this is the first report of neurosteroid levels in postmortem brain tissue of subjects with PTSD. Although replication is required in other brain regions and a larger cohort of subjects, the results suggest a dysregulation of allopregnanolone and androsterone in males with PTSD and pregnanolone in females with PTSD in the mOFC