RCPC, MBA Cla udio N So a re s MD, PhD, F F ina nc ia l disc lo sure s: no ne Ne uro b io lo lo g y o f De pre ssio o n Re se a rc h suppo rt: Que e n’ s Unive rsity, Onta rio Bra in I nstitute a nd Midlife De pre ssio n Professor, Department of Psychiatry Queen’s University School of Medicine Executive Lead, Strategy and New Partnerships De pre ssio n During Me no pa use : L e a rning Ob je c tive s g j An E vo lving Co nc e ptua l F ra me wo rk T o unde rsta nd the c o nc e pts o f c o ntinuum o f risk a nd ‘ windo w o f vulne ra b ility’ fo r midlife de pre ssio n Structural Neurobiology Psychosocial Involutional Empty Nest Regulatory effects T o re c o g nize the ro le o f VMS, Sle e p a nd Anxie ty Melancholia Syndrome of E2 on TPH-2 T o e xplo re ne uro b io lo g y mo de ls fo r de pre ssio n in midlife wo me n - Whe re sho uld we g o ne xt?
De pre ssio n During Me no pause : De pre ssio n During Me no pause I s the re a life time risk o r is this a c o nte xt-re late d pro ble m? • Risk fa c tors • Co ntinuum o f risk/ Windo w o f vulne rability • L e sso ns le arne d fro m e pide mio lo g ic data • T raje c to rie s o ve r time • Co- oc c urre nc e or c a usa lity? So are s CN. Me no pause 2008; 15(2):207-9 • Vaso mo to r Sympto ms • Sle e p • Anxie ty • T he Role of E strog e n • E tio lo g y • Mo dulatio n o f ne uro transmitte rs Me no pause 2010; 17(4):812-14. • T he rape utic value Mo st wo me n will NOT de ve lo p sig nific ant de pre ssive sympto ms during the me no pause transitio n Co ntinuum o f Risk • Pre vio us de pre ssio n(diag no sis and/ o r tre atme nt) • Histo ry o f anxie ty (past, c urre nt) • Pre vio us e xpo sure to trauma, histo ry o f abuse Windo w o f Vulne rability • Pre vio us re pro duc tive -re late d mo o d disturbanc e s (PMS, PPD) • Me no pause -re late d sympto ms – VMS, sle e p, pain • Co nte xt and time -re late d stre ssful life e ve nts So are s CN. Me no pause 2008; 15(2):207-9
F irst-o nse t o f de pre ssio n and time o f me no pause transitio n: T he Harvard Study o f Mo o ds and Cyc le s The Australian Longitudinal Study on Women’s Health Around 11% of the sample • 835 wo me n ( 36-49 ye ars o f ag e ) (N=6,000) showed stable • 3-14 ye ars o f fo llo w up high or increasing • NO histo ry o f de pre ssio n at e nro llme nt depressive symptoms over 8 time Hig he st inc ide nc e o f Continuum of risk’ de pre ssio n 6 previous diagnosis or within two ye ars treatment for depression, into the 4 presence of enduring, me no pause challenging socio-economic transitio n issues 2 0 ‘window of vulnerability’ - high/persistent CES-D -10 -8 -6 -4 -2 0 2 4 6 8 10 Time relative to entry to perimenopause (years) scores among those who experienced a lengthy Harlow BL, MacLehose RF, Soares CN, perimenopause or those with a surgically induced Rate of depression (per 100 person years) in 2 year time Am J Epidemiology, 2013 periods relative to entry to menopause transition menopause Hic ke y M e t al. Me no pause in pre ss De pre ssio n During Me no pause • R isk fac tor s 31% de ve lo pe d • Co ntinuum o f risk/ Windo w o f vulne rability Pe rsiste nt/ re c urre nt • L e sso ns le arne d fro m e pide mio lo g ic data De pre ssio n • T raje c to rie s o ve r time c ontinuum of r isk fac tor s (de pre ssio n [past, • Co-oc c ur r e nc e or c ausality? c urre nt, family], • Vaso mo to r Sympto ms me dic al c o nditio ns) • Sle e p and • Anxie ty c onte xt-r e late d fac tor s (e .g . life stre sso rs • T he R ole of E str oge n • E tio lo g y • Mo dulatio n o f ne uro transmitte rs • T he rape utic value
29 premenopausal women • • 27.3 ± 7.2 years old Non-depressed • GnRHa (leuprolide) 4 weeks Mood, HF, Sleep assessments Wome n with L OW Anxie ty at Base line Anxie ty pe ake d at Pe rime no pause - 4.6% to 13.6% Wome n with HIGH Anxie ty at Base line • 20 subjects (69%) developed HFs T ho se re maine d anxio us o ve r time (16-21%), with sympto ms de c lining afte r • Only 1 subject develop clinical depression me no pause (fro m 71% to 40%) • Association between changes in depressive Vasomotor Symptoms r e main str ongly assoc iate d with Anxie ty ove r symptoms and nighttime HF • Association with sleep changes time (2-3 fold inc r e ase d r isk ) at both gr oups Menopause 2013;20(5) 488-95. J Clin Endocrinol Metab 2016; 101:3847-3855 Ro le o f E stro ge n fo r De pre ssio n during the De pre ssio n During Me no pause Me no pause T ransitio n Gre ate r c hange s, fluc tuatio ns in e stro ge n le ve ls • Risk fac to rs • Co ntinuum o f risk/ Windo w o f vulne rability • L e sso ns le arne d fro m e pide mio lo gic data Vulne rability to de pre ssio n during the • T raje c to rie s o ve r time me no pausal transitio n • Co -o c c urre nc e o r c ausality? • Vaso mo to r Sympto ms Administratio n o f e stro ge n (17 β E stradio l) • Sle e p • Anxie ty Pre se nc e / se ve rity o f mo o d sympto ms during • T he R ole of E str oge n the me no pausal transitio n • E tio lo gy • Mo dulatio n o f ne uro transmitte rs • T he rape utic value So are s CN, e t al. Arc h Ge n Psyc hiatry . 2001;58:529-534. So are s CN. Me no pause 2008; 15(2):207-9.
Effects of Estradiol Withdrawal on Mood in Women with Past Onse t o f De pre ssive Sympto ms a nd Ho rmo ne Cha ng e s Perimenopausal Depression: A Randomized Clinical Trial E stro g e n Withdra wa l c a use d de pre ssive re spo nse Hig h CE S-D sc o re s ONL Y we re a sso c ia te d with I n wo me n with histo ry o f inc re a se d va ria b ility pe rime no pa usa l (within sub je c t) o f de pre ssio n tre a te d le ve ls o f: with E T • E stra dio l (P = .03) • F SH (P<.001) • L H (P = .005) Sc hmidt e t a l. 2015; 72(7):714-726 Freeman, E. W. et al. Arch Gen Psychiatry 2006;63:375-382. E stro g e n-Ba se d T he ra pie s fo r the T re a tme nt o f MDD in E stro g e n-Ba se d T he ra py (T ra nsde rma l 17 β -E 2 ) fo r the Pe rime no pa usa l Wo me n T re a tme nt o f MDD in Pe rime no pa usa l Wo me n Pla c e b o 25 17 β -E 2 20 MADRS Me a n Sc o re s 15 10 5 • Over 2,3000 searches (1997-2014) • 25 RCT on the effects of estrogen therapy on mood 0 • 5 included symptomatic (depressed) women Ba se line We e k 4 We e k 8 We e k 12 Wa sho ut • Only 2 E2 RTCs for perimenopausal depression So a re s CN, e t a l.. 2001;58:529-534.
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