Abstract
Nearly forty percent of women with PMDD remain impaired and resistant to first-line agents. This reflects complexity and heterogeneity of etiopathogenesis at the core of PMDD. Some agents, in the pipeline, sound promising that might usher in a new sparkle in the psychopharmacology of PMDD.
Keywords: PMDD, allopregnanolone, psychopharmacology
Premenstrual disorders affect women of reproductive age during the late luteal phase of the menstrual cycle. They basically encompass premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). Both conditions tend to be chronic, recurrent, following a cyclical predictable pattern, and largely impairing. Typically, affective/physical symptom cluster erupts in the 2 weeks leading up to menstruation that remits within a few days of menses onset.1 PMDD has been alarmingly tied to postnatal depression and even suicidality.2 Comorbidities (e.g. PMDD/bipolar mood disorder) or catamanial exacerbation of a primary mood disorder should be explored especially with resistant cases. Neurobiological underpinnings remain complex and elusive. Altered neurotransmitters and hypersensitivity to gonadal hormonal fluctuations lie at the core. This complexity and heterogeneity has been echoed in the psychopharmacotherapy of PMDD where no ‘one-size-fits-all’ treatment exists.
FDA-approved agents for PMDD include SSRIs (fluoxetine and sertraline) and OC drospirenone/ethinyl estradiol. SSRIs are first-line option for severe PMS/PMDD and circa 66% of women are respondent. Dosage is strikingly lower than typical antidepressant range (e.g. fluoxetine 10–20 mg/d). Both continuous and intermittent (whether luteal-phase or symptom-onset) dosing regimens are successful.3 Oral contraceptives combination of 3 mg drospirenone and 20 μg of ethinyl estradiol are commonly taken for 24 days followed by 4 days of inactive pills have been shown effective but coagulopathy remains a risk.
Nonpharmacological options are protean and include CBT, acupuncture and calcium supplements. Herbal remedies abound in literature with a modicum of evidence in favour of chasteberry and gingko.
Interestingly, allopregnanolone fluctuation during luteal phase has been implicated in PMDD in hormonally sensitive women. Allopregnanolone is a neurosteroid, a metabolite of progesterone and a positive allosteric modulator of GABAA.4
Capitalizing on this premise, agents in the pipeline for PMDD including dutasteride, ulipristal acetate, and sepranolone are promising.
Dutasteride, FDA-approved for benign prostatic hyperplasia, is a 5-α reductase inhibitor; the latter catalyzes the rate-limiting step in metabolism of progesterone to allopregnanolone. It is a teratogen with a half-life of 5 weeks. Two double-blind RCTs, cross-over trials, support use of dutasteride where high-dose (2.5 mg/d) outperforms placebo.5
Ulipristal acetate, FDA-approved as emergency contraceptive, is a selective progesterone receptor modulator. It is well tolerated but nausea is common. One double-blind RCT supports use of ulipristal acetate 5 mg/d.6
Sepranolone is an analog of isoallopregnalonone, which antagonizes allopregnanolone. It is administered q other day SQ throughout the luteal phase. It is generally well tolerated. Use is supported by a double-blind RCT.7
Inclusion and recognition of PMDD in DSM-5 was well perceived but there remain many gaps to bridge in our current understanding and treatment of PMDD. Agents, herein described, await replication in larger studies prior to routine use on clinical grounds, but usher in a new sparkle in the psychopharmacotherapy of this oft-times crippling PMDD with around 40% of women remain treatment-resistant to SSRIs/OCPs.
Footnotes
Disclosures
Authors declare no competing interests or financial affiliations.
Contributor Information
Ahmed Naguy, Naguy, MBBch, MSc, Al-Manara CAP Centre, Kuwait Centre for Mental Health (KCMH), Jamal Abdul-Nassir St, Shuwaikh, State of Kuwait..
Adel El-Sheshai, Prof. El-Sheshai, MD, PhD, Senior Professor of Psychiatry, and Consultant Psychiatrist, Alexandria Faculty of Medicine, Egypt..
Sri Haricharan Thiguti, Thiguti, MD, MRCPsych, Consultant General Adult Psychiatrist, UK..
Bibi Alamiri, Alamiri, MD, ABPN, ScD, Al-Manara CAP Centre, Kuwait Centre for Mental Health (KCMH), Jamal Abdul-Nassir St, Shuwaikh, State of Kuwait..
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