A randomized, double-blind study on efficacy and safety of sepranolone in premenstrual dysphoric disorder

Bäckström, Torbjörn; Ekberg, Karin; Hirschberg, Angelica Lindén; Bixo, Marie; Epperson, C. Neill; Briggs, Paula; Panay, Nick; O’Brien, Shaughn

doi:10.1016/j.psyneuen.2021.105426

Cited by 32 publications

(24 citation statements)

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“…The treatment was effective in reducing mood symptoms and impairment; no statistically significant effects have been detected on the physical symptoms, and no safety concerns were identified 64 . In a subsequent phase IIb randomized, double-blind, placebo-controlled study using sepranolone in two dosages (10 mg or 16 mg) 65 , the placebo effect was 30% higher compared with the phase IIa study 64 . However, an attenuating effect by sepranolone on mood symptoms, impairment, and distress in PMDD women was demonstrated, while no significant improvement on physical symptoms was noted compared with placebo 65 .…”

Section: Neurotransmitters Hormones and Neurosteroidsmentioning

confidence: 93%

“…In a subsequent phase IIb randomized, double-blind, placebo-controlled study using sepranolone in two dosages (10 mg or 16 mg) 65 , the placebo effect was 30% higher compared with the phase IIa study 64 . However, an attenuating effect by sepranolone on mood symptoms, impairment, and distress in PMDD women was demonstrated, while no significant improvement on physical symptoms was noted compared with placebo 65 . Interestingly, the higher dosage (16 mg) of sepranolone appeared less effective than the 10-mg dose, allowing the speculative hypothesis of a possible biphasic dosage-response effect on mood as shown for allopregnanolone plasma concentrations 61 , 66 , 67 .…”

Section: Neurotransmitters Hormones and Neurosteroidsmentioning

confidence: 93%

“…Interestingly, the higher dosage (16 mg) of sepranolone appeared less effective than the 10-mg dose, allowing the speculative hypothesis of a possible biphasic dosage-response effect on mood as shown for allopregnanolone plasma concentrations 61 , 66 , 67 . Therefore, further research is needed to determine whether isoallopregnanolone, which antagonizes the effect of allopregnanolone on the GABA-A receptor, has the potential to become a treatment for PMDD 64 , 65 . The US Food and Drug Administration recently approved allopregnanolone itself (brexanolone) for the treatment of postpartum depression (PPD) 68 , 69 , a disorder extensively associated with PMS/PMDD 70 , 71 in the context of reproductive depression 72 .…”

Section: Neurotransmitters Hormones and Neurosteroidsmentioning

confidence: 99%

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Recent advances in understanding/management of premenstrual dysphoric disorder/premenstrual syndrome

Tiranini¹,

Nappi²

2022

Fac Rev

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Premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) are common disorders of the luteal phase of the menstrual cycle and are characterized by moderate to severe physical, affective, or behavioral symptoms that impair daily activities and quality of life. PMS and PMDD have recently raised great interest in the research community for their considerable global prevalence. The etiology of PMS/PMDD is complex. Ovarian reproductive steroids (estradiol and progesterone) are considered pathogenetic effectors, but the key feature seems to be an altered sensitivity of the GABAergic central inhibitory system to allopregnanolone, a neurosteroid derived from progesterone produced after ovulation. Also, a reduced availability of serotonin seems to be involved. New insights point to a role for genetic and epigenetic modifications of hormonal and neurotransmitter pathways, and inflammation is the potential link between peripheral and neurological integrated responses to stressors. Thus, new therapeutic approaches to PMS/PMDD include inhibition of progesterone receptors in the brain (i.e., with ulipristal acetate), reduced conversion of progesterone to its metabolite allopregnanolone with dutasteride, and possible modulation of the action of allopregnanolone on the brain GABAergic system with sepranolone. Further research is needed to better understand the interaction between peripheral inflammatory molecules (cytokines, interleukins, C-reactive protein, and reactive oxygen species) and the brain neurotransmitter systems in women with PMS/PMDD. If confirmed, neuroinflammation could lead both to develop targeted anti-inflammatory therapies and to define prevention strategies for the associated chronic inflammatory risk in PMS/PMDD. Finally, the observed association between premenstrual disorders and psychological diseases may guide prompt and adequate interventions to achieve a better quality of life.

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Section: Neurotransmitters Hormones and Neurosteroidsmentioning

confidence: 93%

Section: Neurotransmitters Hormones and Neurosteroidsmentioning

confidence: 93%

Section: Neurotransmitters Hormones and Neurosteroidsmentioning

confidence: 99%

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Recent advances in understanding/management of premenstrual dysphoric disorder/premenstrual syndrome

Tiranini¹,

Nappi²

2022

Fac Rev

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“…While Brexanolone must be intravenously administered in a hospital setting, recent data suggest another neuroactive steroid GABA A R PAM drug, Zuranolone, is also effective in reducing PPD symptoms and unlike Brexanolone, can be orally administered ( Deligiannidis et al, 2021 ). Additional GABA-modulating drugs are also under investigation for the treatment of mood dysregulation associated with other times of hormonal change including PMDD ( Bixo et al, 2018 ; Bäckström et al, 2021 ; Schweizer-Schubert et al, 2021 ) and menopausal depression ( Saripalli et al, 2021 ; Schweizer-Schubert et al, 2021 ) but more data are needed.…”

Section: Targeting Gaba Signaling For the Treatment Of Mood Dysregula...mentioning

confidence: 99%

GABA System Modifications During Periods of Hormonal Flux Across the Female Lifespan

Gilfarb

Leuner

2022

Front. Behav. Neurosci.

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The female lifespan is marked by periods of dramatic hormonal fluctuation. Changes in the ovarian hormones estradiol and progesterone, in addition to the progesterone metabolite allopregnanolone, are among the most significant and have been shown to have widespread effects on the brain. This review summarizes current understanding of alterations that occur within the GABA system during the major hormonal transition periods of puberty, the ovarian cycle, pregnancy and the postpartum period, as well as reproductive aging. The functional impacts of altered inhibitory activity during these times are also discussed. Lastly, avenues for future research are identified, which, if pursued, can broaden understanding of the GABA system in the female brain and potentially lead to better treatments for women experiencing changes in brain function at each of these hormonal transition periods.

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“…Positive treatment effects have been shown in response to 5α-reductase inhibitors, which block the conversion of progesterone to ALLO [17]. Moreover, the therapeutic effect of another endogenous neurosteroid, isoallopregnanolone (ISO), has been investigated in PMDD with promising results [18,19]. ISO is also metabolized from progesterone and levels are increased during the luteal phase of the menstrual cycle [20].…”

Section: Introductionmentioning

confidence: 99%

Emotional brain activation across the menstrual cycle in women with premenstrual dysphoric disorder and associations to serum levels of progesterone-derived neurosteroids

Stiernman

Dubol²,

Comasco

et al. 2022

Preprint

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Premenstrual dysphoric disorder (PMDD) is a debilitating disorder characterized by severe mood symptoms in the luteal phase of the menstrual cycle. Allopregnanolone (ALLO), a GABAA-modulating progesterone metabolite, is hypothesized to contribute to the development of PMDD symptoms. On the other hand, the endogenous 3\(\beta\)-epimer of ALLO, isoallopregnanolone (ISO), has been shown to alleviate PMDD symptoms through its selective inhibitory modulation of the ALLO effect. There is preliminary evidence showing altered recruitment of brain regions during emotional processing in PMDD, but whether there is some relation to ALLO or ISO is unknown. In the present study, women with PMDD and asymptomatic controls underwent functional magnetic resonance imaging (fMRI) in the mid-follicular and the late-luteal phase of the menstrual cycle. Brain responses to emotional stimuli were investigated and related to serum levels of ovarian steroids (estradiol, progesterone) and the neurosteroids ALLO, ISO, and their ratio ISO/ALLO. Women with PMDD exhibited greater activity in brain regions which are part of emotion processing networks during the late-luteal phase of the menstrual cycle. Furthermore, activity in key regions of emotional networks - the parahippocampal gyrus and amygdala - was differentially associated to the ratio of ISO/ALLO levels in PMDD and control women. Specifically, positive relationships between ISO/ALLO levels and brain activity were found in PMDD women, while the opposite was observed in controls. In conclusion, women with PMDD show altered emotional brain responses in the late-luteal phase of the menstrual cycle which may be related to an altered response to GABAA-active neurosteroids.

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A randomized, double-blind study on efficacy and safety of sepranolone in premenstrual dysphoric disorder

Cited by 32 publications

References 37 publications

Recent advances in understanding/management of premenstrual dysphoric disorder/premenstrual syndrome

Recent advances in understanding/management of premenstrual dysphoric disorder/premenstrual syndrome

GABA System Modifications During Periods of Hormonal Flux Across the Female Lifespan

Emotional brain activation across the menstrual cycle in women with premenstrual dysphoric disorder and associations to serum levels of progesterone-derived neurosteroids

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