sepranolone (UC1010) / Relmada Therapeutics - LARVOL DELTA

Lower Progesterone and Higher Allopregnanolone to Progesterone Ratio in Women with A History of Recurrent Depression WHO Develop Postpartum Depression (ENDO 2026) - "Plasma levels of neuroactive steroids (ALLO, pregnanolone, isoallopregnanolone, epipregnanolone) and progesterone were measured at each visit using gas chromatography mass spectrometry. In women who were psychiatrically-well during pregnancy, progesterone levels were blunted for those who had a history of MDD and developed PPD compared to women with no history of MDD, even if they developed PPD. Results indicate that this blunted progesterone also influences the ratio of ALLO synthesized compared to precursor progesterone."

Clinical • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Postpartum Depression • Psychiatry

Neuroactive Steroid Regulation in Premenstrual Dysphoric Disorder: Cross-Integration of Metabolism, Dysfunction, Neurobiology, and Precision Medicine. (PubMed, Curr Neuropharmacol) - "NAS-targeted therapies, such as Brexanolone and Sepranolone, along with oral contraceptives, also demonstrate therapeutic efficacy. Targeting NAS-related pathways offers promising therapeutic strategies, as exemplified by recent advances in targeted drug development and individualized medicine. This review provides a foundation for precision medicine in PMDD and related psycho-neuroendocrine disorders, promoting future research into mechanism-based diagnostics and treatments."

Journal • CNS Disorders • Depression • Metabolic Disorders • Mood Disorders • Psychiatry • PGR

Updated insight into the pathophysiology of premenstrual dysphoric disorder and therapeutic approaches. (PubMed, J Affect Disord) - "However, several pharmacological and surgical treatment options are available for PMDD, including SSRIs, hormonal therapies, GnRH agonists, SPRMs, sepranolone (UC1010), and, in severe cases, surgical menopause. These therapies seek to mitigate symptoms by correcting hormonal and neurotransmitter abnormalities. This narrative review provides a comprehensive overview of PMDD, encompassing its pathophysiology, etiology, clinical manifestations, epidemiology, prognosis, and current therapeutic strategies."

Journal • Review • CNS Disorders • Depression • Sleep Disorder

Shared neuroendocrine mechanisms in Premenstrual Dysphoric Disorder (PMDD), Postpartum Depression (PPD), and Perimenopausal Affective Disorders: the role of progesterone, allopregnanolone, and cortisol (ISGE 2026) - "Interventions: Pharmacologic modulation of GABAergic tone through neurosteroids (brexanolone, zuranolone) or neurosteroid antagonists (sepranolone). PMDD, PPD, and perimenopausal depression share a unified neuroendocrine mechanism involving ALLO–GABAA receptor dynamics, HPA imbalance, and neuroinflammation. These disorders reflect a continuum of hormonal sensitivity, and neurosteroid-based GABAergic modulation provides a path to emotional stabilization."

CNS Disorders • Depression • Inflammation • Mood Disorders • Postpartum Depression • Psychiatry • BDNF • IL6

Fluorescence-based assay for rapid screening of GABAA receptor modulating steroid antagonists (GAMSA). (PubMed, Anal Biochem) - "Isoallopregnanolone (IsoALLO), a known GAMSA, was the only compound that significantly reduced ALLO-potentiated GABA responses (to 42 ± 3%) without affecting GABA-evoked responses alone. The inhibitory effect of IsoALLO was confirmed using manual patch-clamp recordings in primary rat anterior pituitary cells, which endogenously express GABAA receptors, where it reduced ALLO-potentiated GABA-induced currents by 32 ± 4%. This study validates the first cell-based HTS method for GAMSA identification and demonstrates its utility in distinguishing GAMSA from direct channel blockers or negative allosteric modulators (NAMs) using standard laboratory equipment."

Journal • CNS Disorders • Epilepsy • Hepatic Encephalopathy • Hepatology

Innovations in the management of premenstrual syndrome (PMS) (FIGO 2025) - "Sepranolone (selective allopregnanolone antagonist): Phase II studies demonstrated significant reduction in PMDD symptoms...Shared decision-making is recommended, involving discussion of the patient's treatment preferences and goals, as well as the benefits and risks of available options, to support patients in selecting the most appropriate strategy. Many patients may benefit from a multimodal approach combining several interventions."

CNS Disorders • Gynecology

Brain Metabolism of Allopregnanolone and Isoallopregnanolone in Male Rat Brain. (PubMed, Int J Mol Sci) - "Human plasma contains mostly sulfate/glucuronided steroids (2.4-6% non-sulfate/glucuronided), whereas male rats exhibit much higher free steroid levels (29-56%), likely due to the absence of zona reticularis. These findings highlight tissue-specific enzymatic differences, which may impact neurosteroid regulation and CNS disorders."

Journal • Preclinical • CNS Disorders • Solid Tumor • AKR1C1

The Emerging Role of Neurosteroids: Novel Drugs Brexanalone Sepranolone Zuranolone and Ganaxolone in Mood and Neurological Disorders (APA 2025) - "Description This review investigates the potential of neurosteroids, including brexanolone, zuranolone, sepranolone, and ganaxalone, as therapeutic agents for a range of mood and neurological disorders. Their modulation of the GABA system emerges as a central mechanism of action, emphasizing the importance of GABAergic signaling in these conditions. The path forward entails continued investigation and clinical trials to fully unlock the potential of neurosteroids, offering hope for enhanced treatments in these challenging clinical domains."

Alzheimer's Disease • CNS Disorders • Depression • Epilepsy • Major Depressive Disorder • Mood Disorders • Postpartum Depression • Post-traumatic Stress Disorder • Psychiatry

Levels of neuroactive steroids are elevated in those who develop first-onset depression early in pregnancy. (PubMed, Front Psychiatry) - "Levels of ALLO, pregnanolone (PA), isoallopregnanolone (ISO), epipregnanolone (EPI), and progesterone (P4) were quantified using gas chromatography-mass spectrometry. These results suggest differing NAS-related mechanisms of pathogenesis across clinical phenotypes based on pre-pregnancy history of MDD and timing of PND onset. Future research should account for these factors when investigating NAS and PND."

Journal • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Postpartum Depression • Psychiatry

Neuroactive steroid biosynthesis during pregnancy predicts future postpartum depression: a role for the 3α and/or 3β-HSD neurosteroidogenic enzymes? (PubMed, Neuropsychopharmacology) - "Participants with a one-unit increase in the log isoallopregnanolone/pregnanolone ratio at the third trimester (T3) had higher odds (OR = 1.64, 95% CI: 1.13-2.37, FDR adjusted p = 0.038, C-index = 0.82), and those with a one-unit increase in the log pregnanolone/progesterone ratio at T3 had lower odds (OR = 0.64, 95% CI: 0.47-0.88, FDR adjusted p = 0.036, C-index = 0.82) of developing PPD; those with a one-unit increase in the log progesterone level at T3 had higher odds of developing PPD (OR = 4.00, 95% CI: 1.54-10.37, FDR adjusted p = 0.035, C-index = 0.80). We found key differences in the progesterone metabolic pathway at the third trimester, indicating likely decreased activity/expression of the 3α-HSD enzyme and/or increased activity/expression of 3β-HSD."

Journal • CNS Disorders • Depression • Mood Disorders • Postpartum Depression • Psychiatry

Relmada Therapeutics Acquires Potential Therapy for Tourette Syndrome from Asarina Pharma AB (GlobeNewswire) - "Relmada Therapeutics, Inc...today announced the acquisition of Sepranolone, a Phase 2b ready neurosteroid, from Asarina Pharma AB (Asarina), being developed for the potential treatment of Tourette syndrome (TS) and other compulsive disorders."

M&A • Tourette Syndrome

Premenstrual Dysphoric Disorder: systematic review of alternative treatments (NAMS 2024) - "There was no significant effect observed for myo-inositol, clonidine, magnesium sulfate, quetiapine combined with antidepressants, chromium polynicotinate combined with sertraline, light therapy, or auriculotherapy. However, there was a significant effect observed for massage (one study, high risk of bias), cognitive-behavioral therapy (CBT) (two studies, elevated risk of bias), buserelin (one study, low risk of bias), dutasteride (one study, low risk of bias), acupuncture (one study, elevated risk of bias), sepranolone (one study, low risk of bias), phosphatidylserine (one study, low risk of bias), emotion-focused group therapy (one study, high risk of bias), and homeopathic treatment (one study without blinding and placebo control, high risk of bias). Vitex agnus castus had a similar effect to fluoxetine (one study, some risk of bias)... CBT and physical exercises appear to be effective as complementary treatments for PMDD, but the literature lacks robust evidence...."

Review • CNS Disorders • Depression • Gynecology

The Emerging Role of Neurosteroids: Novel Drugs Brexanalone, Sepranolone, Zuranolone, and Ganaxolone in Mood and Neurological Disorders. (PubMed, Cureus) - "This review investigates the potential of neurosteroids, including brexanolone, zuranolone, sepranolone, and ganaxalone, as therapeutic agents for a range of mood and neurological disorders. Their modulation of the GABA system emerges as a central mechanism of action, emphasizing the importance of GABAergic signaling in these conditions. The path forward entails continued investigation and clinical trials to fully unlock the potential of neurosteroids, offering hope for enhanced treatments in these challenging clinical domains."

Journal • Review • Alzheimer's Disease • CNS Disorders • Depression • Epilepsy • Major Depressive Disorder • Mood Disorders • Movement Disorders • Parkinson's Disease • Postpartum Depression • Post-traumatic Stress Disorder • Psychiatry

NEUROACTIVE STEROIDS FLUCTUATE WITH REGIONAL SPECIFICITY IN THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM ACROSS THE RAT ESTROUS CYCLE. (PubMed, J Steroid Biochem Mol Biol) - "Therefore, we assessed the levels of pregnenolone, progesterone, and its metabolites (i.e., dihydroprogesterone, allopregnanolone and isoallopregnanolone), dehydroepiandrosterone, testosterone and its metabolites (i.e., dihydrotestosterone, 3α-diol and 17β-estradiol) across the rat ovarian cycle to determine whether their plasma fluctuations are similar to those occurring in the central (i.e., hippocampus and cerebral cortex) and peripheral (i.e., sciatic nerve) nervous system. Indeed, with the exception of progesterone, all other neuroactive steroids assessed here showed peculiar regional differences in their pattern of fluctuation in the nervous system during the estrous cycle. These observations may have important diagnostic and therapeutic consequences for neuropathological events influenced by the menstrual cycle."

Journal • Preclinical • CNS Disorders • Mental Retardation • Psychiatry

Associations Between Sleep Quality, Mental Health, and Neuroactive Steroids in Early Pregnancy (ISGE 2024) - "Context : Progesterone-derived neuroactive steroids (NAS) act on the GABA-A receptor to influence mood and sleep...Evidence suggests that depression early in pregnancy is associated with higher ALLO, pregnanolone (PA), and isoallopregnanolone (ISO) levels... NAS do not appear to play a role in the association of sleep quality with depressive and anxiety symptoms early in pregnancy. The association of higher EPI and ISO levels with lower sleep quality in the first but not second trimester suggests heightened sensitivity to surges of these NAS early in pregnancy followed by later adaptation. As negative modulators of the GABAergic system, EPI and ISO may reduce the sedative effects of ALLO, disrupting overall sleep quality."

CNS Disorders • Depression • Mood Disorders • Postpartum Depression • Psychiatry

GABA-ergic Modulators: New Therapeutic Approaches to Premenstrual Dysphoric Disorder. (PubMed, CNS Drugs) - "As part of this discussion, we explore promising findings from early clinical trials of several compounds that stabilize allopregnanolone signaling during the luteal phase, including dutasteride, a 5-alpha reductase inhibitor; isoallopregnanolone, a GABA-A modulating steroid antagonist; and ulipristal acetate, a selective progesterone receptor modulator. We then reflect on the implications of these therapeutic advances, including how they may promote our knowledge of affective regulation more generally. We conclude that these and other studies of PMDD may yield critical insight into the etiopathogenesis of affective disorders, considering that (1) symptoms in PMDD have a predictable onset and offset, allowing for examination of affective state kinetics, and (2) GABAergic interventions in PMDD can be used to better understand the relationship between mood states, network regulation, and the balance between excitatory and inhibitory signaling in the brain."

Journal • Review • CNS Disorders • Depression • Mood Disorders • Psychiatry • PGR

Metabolites of progesterone in pregnancy: Associations with perinatal anxiety. (PubMed, Psychoneuroendocrinology) - "Our exploratory findings indicate that, for pregnant people with anxiety, metabolism is shunted more aggressively toward the endpoint of the progesterone to allopregnanolone metabolic pathway than it is for those without anxiety."

Journal • CNS Disorders • Depression • Mental Retardation • Mood Disorders • Postpartum Depression • Psychiatry • AKR1C2

Isoallopregnanolone Inhibits Estrus Cycle-Dependent Aggressive Behavior. (PubMed, Biomolecules) - "Vehicle treatment in the same animals showed a minimal effect on the diestrus-related aggressive behavior. In conclusion, we showed that ISO can antagonize Steroid-PAM both in α1β2γ2L and α4β3δ GABA-A receptor subtypes and inhibit estrus cycle-dependent aggressive behavior."

Journal • CNS Disorders • Depression

A Study to Explore the Effect of Sepranolone in Tourette Syndrome (clinicaltrials.gov) - P2 | N=26 | Completed | Sponsor: Asarina Pharma | Recruiting ➔ Completed

Trial completion • Movement Disorders • Pediatrics • Tourette Syndrome

Prefrontal allopregnanolone synergizes with D receptor activation to disrupt sensorimotor gating in male Sprague-Dawley rats. (PubMed, Psychopharmacology (Berl)) - "These results suggest that AP enables the detrimental effects of D receptor activation on sensorimotor gating. AP antagonism or glutamatergic modulation counters these effects and may have therapeutic potential for neuropsychiatric disorders characterized by gating deficits."

Journal • Preclinical • CNS Disorders • Mental Retardation • Psychiatry

Alterations in Progesterone Metabolism Underlie Postpartum Depression (SOBP 2023) - "Using a generalized linear mixed-effects model and repeated measures of PPD, adjusting for postpartum week, age, sleep quality, gestational age, and psychiatric medication use, we found, in women who were not depressed at T3, decreased pregnanolone and increased progesterone were associated with PPD and lower pregnanolone to progesterone levels and higher isoallopregnanolone to pregnanolone ratios were associated with PPD. Conclusions A higher level of progesterone and corresponding lower levels of progesterone metabolites in T3 were associated with the later development of PPD, indicating that altered progesterone metabolism may underlie the vulnerability to PPD in some women."

Late-breaking abstract • CNS Disorders • Depression • Mood Disorders • Psychiatry

Neuroactive Steroid Levels in the First Trimester of Pregnancy Are Higher in Those With Perinatal-Emergent Depression (SOBP 2023) - "Linear regression models assessed the association between history of depression and current T1 depression status with T1 levels of 4 NAS: allopregnanolone (ALLO), isoallopregnanolone (ISO), pregnanolone (PA), and epipregnanolone (EPI), covarying for BMI, number of prior pregnancies, Medicaid status, relationship status, and income...Conclusions T1 NAS may be blunted in those with persistent depression pre-pregnancy and in pregnancy, but heightened in those with perinatal-emergent T1 depression. The role of NAS in early perinatal depression may depend on history of depression in low-income women of color."

CNS Disorders • Depression • Mood Disorders • Psychiatry

Emotion-induced brain activation across the menstrual cycle in individuals with premenstrual dysphoric disorder and associations to serum levels of progesterone-derived neurosteroids. (PubMed, Transl Psychiatry) - "Moreover, the endogenous 3β-epimer of ALLO, isoallopregnanolone (ISO), has been shown to alleviate PMDD symptoms through its selective and dose-dependent antagonism of the ALLO effect. Specifically, a positive relationship between ISO/ALLO levels and brain activity was found in PMDD subjects, while the opposite was observed in controls. In conclusion, individuals with PMDD show altered emotion-induced brain responses in the late-luteal phase of the menstrual cycle which may be related to an abnormal response to physiological levels of GABA-active neurosteroids."

Journal • CNS Disorders • Depression

Acute stress impairs sensorimotor gating via the neurosteroid allopregnanolone in the prefrontal cortex. (PubMed, Neurobiol Stress) - "These effects were reversed by isoallopregnanolone (isoAP), an endogenous AP antagonist, and the GABA receptor antagonist bicuculline and mimicked by AP infusions in the medial prefrontal cortex (mPFC)...These results collectively indicate that acute stress impairs PPI by increasing AP content in the mPFC. The confirmation of these mechanisms across distinct animal models and several acute stressors strongly supports the translational value of these findings and warrants future research on the role of AP in information processing."

Journal

A Study to Explore the Effect of Sepranolone in Tourette Syndrome (clinicaltrials.gov) - P2 | N=30 | Recruiting | Sponsor: Asarina Pharma

New P2 trial • Movement Disorders • Pediatrics • Tourette Syndrome