Research Fellow Brigham and Women's Hospital and Harvard Medical School Somerville, Massachusetts, United States
Abstract Objective Posttraumatic stress disorder (PTSD) is associated with disrupted metabolism of the neurosteroid progesterone to its metabolites, allopregnanolone and pregnanolone (equipotent stereoisomers), which may lead to lower inhibitory signaling in the brain (Rasmusson et al., 2022). Low allopregnanolone+pregnanolone is associated with more severe PTSD (Kim et al., 2020), anxiety, and depression (Pinna, 2020), but no study has yet considered their impact on dissociation. Similarly, evidence suggests allopregnanolone deficits in schizophrenia may worsen psychotic symptoms (Belvederi Murri et al., 2016). Because trauma and psychosis each disrupt progesterone metabolism and often co-occur (Giannopoulou et al., 2023), individuals with both may experience a "double hit" that worsens symptoms across multiple domains. This project evaluates relationships between progesterone and allopregnanolone concentrations and the severity of PTSD, dissociative, and psychotic symptoms in individuals with trauma-related disorders with and without comorbid psychotic conditions. Understanding these relationships may illuminate shared neurobiological mechanisms underlying trauma, dissociation, and psychosis.
Methods For this pilot study, we recruited participants in four groups (n=10 in each group): individuals with PTSD and no comorbid psychotic disorder, individuals with PTSD and a comorbid psychotic disorder, individuals with psychotic disorders and no PTSD, and healthy controls. We interviewed all participants to assess PTSD, psychotic, and depressive symptom severity. We measured concentrations of resting progesterone and allopregnanolone from participants’ blood plasma using liquid chromatography-mass spectrometry (LC-MS). We used ANOVAs to test for groupwise differences in progesterone or allopregnanolone concentrations. We then conducted Spearman correlations to examine relationships between progesterone or allopregnanolone concentrations and symptom severity (with p< 0.05).
Results Progesterone, allopregnanolone, and their ratio did not differ significantly between groups (p range 0.35–0.72). Healthy controls showed no significant relationships between progesterone or allopregnanolone levels and symptoms, while distinct patterns emerged across clinical groups. In individuals with PTSD alone, higher allopregnanolone levels positively correlated with dissociative amnesia. In contrast, in those with a psychotic disorder and no PTSD, progesterone levels were positively correlated with PTSD-related arousal, depression, and avolition symptoms, while greater conversion of progesterone to allopregnanolone correlated with increased speech poverty but reduced hallucinations and mania severity. The comorbid PTSD and psychotic disorder group showed the most complex pattern, with higher progesterone levels correlating positively with both depersonalization and PTSD arousal symptoms. These participants also showed a positive correlation between allopregnanolone and severity of delusions. However, paradoxically, greater progesterone-to-allopregnanolone metabolism was correlated with reduced severity of PTSD re-experiencing symptoms, as well as dissociative absorption and amnesia.
Conclusion These findings suggest that progesterone metabolism affects symptom severity differently across diagnostic groups, with comorbid PTSD and psychosis showing particularly complex relationships that may reflect a "double hit" of trauma and psychotic pathophysiology on progesterone metabolism. While replication in larger samples is needed, this pilot study extends prior work by linking progesterone metabolism to overlapping symptoms of PTSD, dissociation, and psychosis, highlighting potential shared neurobiological mechanisms.
