Mood Disorders
Vincenzo Berghella in Maternal-Fetal Evidence Based Guidelines, 2022
Brexanolone, a soluble IV formulation of the neuroactive steroid allopregnanolone, is the first medication approved by the FDA specifically for the treatment of postpartum depression. Allopregnanolone, a progesterone metabolite, is a potent allosteric modulator of GABAa receptors and has been shown to have significant effects on anxiety and depression in animal models. Allopregnanolone levels change in parallel with progesterone, reaching highest concentrations in the third trimester and decreasing abruptly after childbirth [128, 129]. Brexanolone dosing was designed to be comparable to allopregnanolone levels in the third trimester. Brexanolone is administered as a continuous 60-hour infusion, with a gradual decrease in dose until the infusion is stopped, allowing for a slow rather than abrupt decrease in allopregnanolone levels in a population which may be vulnerable to rapid hormonal fluctuation.
Serotonin Metabolism in Functional Somatic Illness
Peter Manu in The Psychopathology of Functional Somatic Syndromes, 2020
Patients with premenstrual syndrome had significantly higher levels of allopregnanolone than those recorded for the control group. The intergroup difference was statistically significant (p < 0.001) both at baseline (2.6 versus 1 ng/mL) and after stressful tasks (2.3 versus 1.2 ng/mL). Compared with the baseline value, the poststress allopregnanolone level increased in 83 percent of the control subjects and 42 percent of the premenstrual syndrome patients. Patients with greater premenstrual anxiety had significantly lower levels of allopregnanolone than the remainder of the group (p < 0.01), and a similar trend was noted for premenstrual irritability (p = 0.08) and depression (p = 0.09). The cortisol levels were lower in the premenstrual group (p < 0.05). A negative correlation between cortisol and allopregnanolone levels was demonstrated for both baseline and poststress conditions in the premenstrual syndrome group (p < 0.05). The findings were interpreted to indicate that premenstrual syndrome is associated with higher levels of allopregnanolone, which inhibit the function of the hypothalamic-pituitary-adrenal axis. They also postulated that the hormone alters the receptor sensitivity of neurotransmitters that modulate the anxiety, irritability, and depression of patients with this condition, but direct evidence for this type of effect was not obtained in the study.
Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Sheryl S. Smith in Neurosteroid Effects in the Central Nervous System, 2003
Allopregnanolone is so far the best-studied neurosteroid in relation to anxiety state. In animal models, the anxiolytic effect of allopregnanolone (Akwa et al., 1999; Bitran et al., 1991; Wieland et al., 1995) has been demonstrated and mainly attributed to its positive modulation of GABAA receptor activity (Bitran et al., 1995; Brot et al., 1997; Smith et al., 1998), but may also implicate the activation of PBR (Bitran et al., 2000). Clinically, there is still no steroidal derivative available for treatment of anxiety disorders. PROG, which is largely metabolized to allopregnanolone after systemic administration, currently remains the best candidate.
The pharmacotherapeutic management of premenstrual dysphoric disorder
Published in Expert Opinion on Pharmacotherapy, 2023
Nancy Ciccone, Maya B. Kovacheff, Benicio N. Frey
Extensive research showing that PMDD symptoms are triggered by hormonal fluctuations, and the fact that five placebo-controlled trials have demonstrated efficacy of OCPs in the management of PMDD, suggests that the use of OCPs should be more in the forefront of options in the management of this condition. Unfortunately, the use of OCPs to treat a mental health condition is also not consistently disseminated in psychiatry or primary care training. While there is some evidence that trials with shorter placebo breaks (four vs seven days) may be more beneficial, quite often experts in the field use off-label continuous daily OCPs with no breaks for 3–4 months with success. This is a real research gap that needs to be addressed by future controlled trials. Similarly, there is a lack of controlled trials using leuprolide in those who did not respond or could not tolerate antidepressants and OCPs, although anecdotal use suggests benefit from leuprolide in severe, treatment-resistant cases. There is a clear need to find alternative treatments for this recurrent condition. Recent preliminary studies targeting neurosteroids, in particular allopregnanolone, are promising. Preclinical studies investigating the mechanisms of action of chasteberry extract can also shed a light of potentially unexplored mechanisms for drug discovery.
Evaluating brexanolone for the treatment of postpartum depression
Published in Expert Opinion on Pharmacotherapy, 2021
Brexanolone is chemically identical to endogenous allopregnanolone and, like allopregnanolone, acts as a positive allosteric modulator of the gamma-aminobutyric acid A receptor (GABAA) in the brain. GABA acts as an inhibitory neurotransmitter, and GABAA receptors are five-unit transmembrane ion channels that are found in intrasynaptic and extra synaptic sites as well as on glial cells. A number of preclinical and clinical studies have implicated reduced neuroactive steroid levels, in particular allopregnanolone, in mood and anxiety disorders (reviewed in [21,22]). For example, in animal models, neuronal levels of allopregnanolone rise during an acute stress, but with chronic stress decrease and correlate with depressive and anxiety-like behaviors [22]. Allopregnanolone levels rise across the course of pregnancy and precipitously drop after delivery, and some [23,24] but not all studies [25] have found that lower levels of allopregnanolone in pregnancy are associated with the development of PPD. Brexanolone is thus thought to target the decreased levels of allopregnanolone following childbirth, which may trigger a depressive episode in susceptible women, thus alleviating their depressive symptoms.
Novel experimental and early investigational drugs for the treatment of bipolar disorder
Published in Expert Opinion on Investigational Drugs, 2021
Mauro Giovanni Carta, Goce Kalcev, Michele Fornaro, Antonio Egidio Nardi
Tamoxifen, a centrally acting inhibitor of protein kinase C shown anti-manic effects in humans [46] against placebo [47]. Also, memantine, an FDA-approved drug for the management of Alzheimer’s disease, may have beneficial effects in the treatment of mania, and cognitive sparing properties in BD, overall [48]. Some psychotropic agents non intended as primary treatments for BD are nonetheless seldom adopted in the clinical management of treatment-resistant mania [8], as the antipsychotic agent clozapine, an agent able to significantly increase pregnenolone levels in the hippocampus and cortex of rats [49]. In addition, the plasma concentration of the progesterone derivative allopregnanolone is elevated in the premenstrual period of euthymic women with BD compared to healthy controls and women with major depressive disorder [50,51]. In contrast, during episodes of depression, the levels of allopregnanolone appeared to be low [52]. This finding is independent from pharmacological therapy status. It is hypnotized that these neurosteroids would act as potential endogenous mood stabilizers [53], thus representing a potential target for novel pharmacotherapy of BD too.
Related Knowledge Centers
- Postpartum Depression
- Progesterone
- Somnolence
- Xerostomia
- Sedation
- Natural Product
- Neurosteroid
- Hormone
- Intravenous Therapy
- Side Effect