One Small Step for PMDD, One Large Step for Affective Disorders

Back to table of contents Previous article Next EditorialsFull AccessOne Small Step for PMDD, One Large Affective DisordersDavid R. Rubinow, M.D.David RubinowSearch more papers by this author, M.D.Published Online:1 Mar 2021https://doi.org/10.1176/appi.ajp.2020.20121793AboutSectionsView articleView PDFView EPUB ToolsAdd favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail View articleMedicine in general, and psychiatry particular, has had a long, ambivalent relationship with women’s mood disorders. From the attribution maladaptive behaviors wandering uterus (hysteria) ascription both toxic therapeutic powers menstrual blood, beliefs about impact reproductive physiology on regulation largely took form superstition, stereotype, ridicule, invective. Despite myriad descriptive reports dating antiquity reproductive-related disorders, their existence was met irrational skepticism: if disorder is not experienced all women, it must exist. Recapitulating misogyny medicine, our nosology refused admit several disorders into hallowed halls DSM long after epidemiological studies clearly demonstrated these U.S. Food Drug Administration approved medication specifically one them, premenstrual dysphoric (PMDD).In month’s issue, Comasco et al. (1) present findings novel approach PMDD. The authors describe 3-month multicenter proof-of-concept randomized placebo-controlled trial ulipristal acetate (UPA) 95 women UPA selective progesterone receptor modulator—functionally, antagonist—that been used treat uterine fibroids. mean improvement symptom severity Daily Record Severity Problems (DRSP), rating scale often relative baseline greater group (43% 41%) compared placebo (27% 22%) at two time points selected analysis. (As disturbs cycle function, test efficacy were 5 days before last bleeds or during week active treatment participant developed amenorrhea.) Significant also seen DRSP subscales (depression anger/irritability) as well remission rates (50% 21%), but physical subscale secondary, cross-sectional measures depression quality life. Given distribution receptors brain regions critical regulation, conclude that blockade subsequent modulators may represent unique effective options These interesting raise three questions.Why World Would Anyone Study (Or Care About) PMDD?PMDD’s prevalence (about 5% women) morbidity (14.5 million disability-adjusted life-years lost annually United States—equivalent major depression) should make evident clinical need (2). Beyond readily apparent need, however, can argue PMDD offers us best opportunity understand variables affective namely, switch different state differential susceptibility regulation.By state, I coherent, replicable, integrated, self-organized assembly thoughts, associations, memories, cognitions, perceptions, ways relating self others (self object relations) (3). States are programs interpreting interacting environment an efficient fashion. We have them rely ability induce change through morning run, evening beer, social events, meditation, sex, drugs, rock ‘n’ roll.Thinking behavior fashion least advantage: draws attention kinetics rather than myopically focusing symptoms. Depression, example, much characterized persistence any its symptoms (which be assembled over 500 reach same diagnosis) (4). model suggests understanding neurobiology better served studying transitions between states—the switch—rather itself, given homeostatic responses obscure source destabilization. importance clue biology illness described Bunney 50 years ago (5), associated neural changes “that precede behavioral changes” called “the Holy Grail bipolar research” (6). Unfortunately, examination process complicated unpredictability (7).This problem solved In timing symptoms—confined luteal (premenstrual) phase—that defines disorder, presence specific symptom. occurs (particularly out) predictability each month, thus lending itself investigation. further inform because linked specific, detectable set physiological processes, cycle. Association obviously does necessarily entail causation. But case does. As reviewed al., ovarian steroids triggering events onset PMDD: suppression prevents symptomatic which then precipitated when blindly reintroduced. Notably, identical manipulations without no effect mood. Unlike accompanying endocrinopathies, do abnormal hormone levels, show response normal steroids.Similar evidence sensitivity imaging (8) even cellular level. lymphoblastoid cell lines from control subjects, Dubey (9) found increased expression 11 13 genes exposure vitro ESC/E(Z) (Extra Sex Combs/Enhancer Zeste) complex pathway. This gene family responsible regulating epigenetics, ultimate mechanism translating environmental signals enduring signals. Thus, depression, considerably farther down road physiologic factors underlying states results stimulus.Why Think That Reproductive Steroids Regulate Behavior?Psychiatry long-standing love affair stress steroid cortisol, relatively little interest precursor, progesterone, cousins, estrogens androgens. Yet, absent powerfully regulate motivational state—sexual attraction/action—the species would die out. Indeed, informational molecules “by design” generate acting centrally integrate wide array peripheral actions, behaviors. Not surprisingly, then, orchestrate virtually every element signaling, including transcription translation, influence system ever implicated etiopathogenesis (from individual neurotransmitter systems neuroplasticity/neuroprotection network function) (10).Progesterone, studied psychiatrists neuroscientists, target adopted prevalent belief 30 unlikely CNS effects because, supposedly, only role antagonize estrogen signaling uterus, substantial. addition already mentioned data supporting administration precipitate Hans Selye, father research, observed 1941 intravenous intramuscular rapidly induced anesthesia, analgesic, anxiolytic, antistress, antiseizure subsequently noted (11). rapid later discovered result metabolite, allopregnanolone, neurosteroid positively modulates GABA activity, increasing synaptic extrasynaptic cortical inhibition (12).The allopregnanolone suggested recent showing prevention appearance either antagonist (sepranolone, isomer allopregnanolone) (13) metabolism dutasteride (14). Since (brexanolone) postpartum (15), why antagonism prevent PMDD? Apart obvious—that same—sepranolone stabilize signaling. such, consistent observations levels (as opposed themselves) important regulatory signals, well-described phenomenon fast-rate feedback ACTH secretion (16) pulsatile frequency-dependent actions gonadotropin hormone-releasing release (17). Prevention variable plausible action negative modulator, blocks ovulation, thereby stabilizing estradiol, allopregnanolone. (Anovulation, unfortunately, compromises study blind disrupting function.)Should Hormonal Therapeutics Be Part Psychiatric Armamentarium?An answer affirmative UPA, brexanolone estradiol perimenopausal (18). added advantage use safety Additionally, since one-third participants taken antidepressants past stopped nonresponse, possible could benefit patients who fail trials SSRI. Further, illustrates potential modulators. compounds, include (and androgen) modulators, display tissue specificity interactions tissue-specific coregulators, conceptually allowing development few off-tissue-target effects.Potential problems blinding notwithstanding, deserve replication heuristic appeal. They join growing body relevance hormones expand footprint class compounds exceptional advancing goals precision medicine. And they underscore ensuring current future attentive reproduction hormones.Departments Psychiatry Medicine, School University North Carolina Chapel Hill.Send correspondence Dr. Rubinow ([email protected]).Dr. received research funding Foundation Hope; he Clinical Advisory Board Sage Therapeutics, company equity interest, previously editorial board member Dialogues Neuroscience.References1 E, Kopp Kallner H, Bixo M, al.: Ulipristal disorder: controlled trial. Am J 2021; 178:256–265Abstract, Google Scholar2 Halbreich U, Borenstein J, Pearlstein T, prevalence, impairment, impact, burden (PMS/PMDD). Psychoneuroendocrinology 2003; 28(suppl 3):1–23Google Scholar3 Putnam FW: Way Are: How Mind Influence Our Identities, Personality, Potential Change. New York, International Psychoanalytic Books, 2016Google Scholar4 Olbert CM, Gala GJ, Tupler LA: Quantifying heterogeneity attributable polythetic diagnostic criteria: theoretical framework empirical application. Abnorm Psychol 2014; 123:452–462Crossref, Medline, Scholar5 WE, Murphy DL, Goodwin FK, “switch process” manic-depressive illness, 1: systematic sequential changes. Arch Gen 1972; 27:295–302Crossref, Scholar6 Blumberg HP: Euthymia, mania: what we know switch? Biol 2012; 71:570–571Crossref, Scholar7 Salvadore G, Quiroz JA, Machado-Vieira R, review. Clin 2010; 71:1488–1501Crossref, Scholar8 Baller EB, Wei SM, Kohn PD, Abnormalities dorsolateral prefrontal function multimodal neuroimaging study. 2013; 170:305–314Link, Scholar9 N, Hoffman JF, Schuebel K, complex, effector steroids, manifests intrinsic difference cells disorder. Mol 2017; 22:1172–1184Crossref, Scholar10 Schiller CE, Johnson SL, Abate AC, behavior. Compr Physiol 2016; 6:1135–1160Crossref, Scholar11 Selye H: Anaesthetic hormones. Proc Soc Exp Med 1941; 46:116–121Crossref, Scholar12 Zorumski CF, Paul Covey DF, Neurosteroids anxiolytics: GABA-A beyond. Neurobiol Stress 2019; 11:100196Crossref, Scholar13 Ekberg Poromaa IS, Treatment GABAA modulating sepranolone (UC1010): 80:46–551Crossref, Scholar14 Martinez PE, DR, Nieman LK, 5?-Reductase phase increase plasma mitigates Neuropsychopharmacology 41:1093–1102Crossref, Scholar15 Meltzer-Brody S, Colquhoun Riesenberg Brexanolone iv, depression: pooled analysis HAM-D sub-items. European 29(suppl 1):S63 (doi: 10.1016/j.euroneuro.2018.11.1040)Crossref, Scholar16 Dallman MF, Yates FE: Dynamic asymmetries corticosteroid path distribution-metabolism-binding elements adrenocortical system. Ann N Y Acad Sci 1969; 156:696–721Crossref, Scholar17 Knobil E: neuroendocrine Recent Prog Horm Res 1980; 36:53–88Medline, Scholar18 Schmidt PJ, Ben Dor Effects withdrawal JAMA 2015; 72:714–726Crossref, Scholar FiguresReferencesCited byDetailsCited ByImproving Outcomes Includes Increasing Diversity WorkforceNed H. Kalin, M.D.1 March 2021 | American Journal Psychiatry, Vol. 178, No. 3 Volume 178Issue 01, 2021Pages 215-217 Metrics KeywordsPremenstrual Dysphoric DisorderDepressive DisordersNeuroendocrinology History Accepted December 2020 Published online 1 print