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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,

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SLIDE 1

Ne uro b io lo lo g y o f De pre ssio o n a nd Midlife De pre ssio n

F ina nc ia l disc lo sure s: no ne Re se a rc h suppo rt: Que e n’ s Unive rsity, Onta rio Bra in I nstitute Professor, Department of Psychiatry Queen’s University School of Medicine Executive Lead, Strategy and New Partnerships

Cla udio N So a re s MD, PhD, F RCPC, MBA

L e a rning Ob je c tive s g j

T

  • 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 T

  • re c o g nize the ro le o f VMS, Sle e p a nd Anxie ty

T

  • 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 pa use : An E vo lving Co nc e ptua l F ra me wo rk

Structural Involutional Melancholia Psychosocial Empty Nest Syndrome Neurobiology Regulatory effects

  • f E2 on TPH-2
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SLIDE 2

De pre ssio n During Me no pause

  • 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?
  • 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
  • T

he rape utic value

So are s CN. Me no pause 2008; 15(2):207-9

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?

Me no pause 2010; 17(4):812-14.

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

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SLIDE 3

Harlow BL, MacLehose RF, Soares CN, Am J Epidemiology, 2013

  • 835 wo me n ( 36-49 ye ars o f ag e )
  • 3-14 ye ars o f fo llo w up
  • NO histo ry o f de pre ssio n at e nro llme nt

2 4 6 8

  • 10
  • 8
  • 6
  • 4
  • 2

2 4 6 8 10 Time relative to entry to perimenopause (years)

Rate of depression (per 100 person years) in 2 year time periods relative to entry to menopause transition

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

Hig he st inc ide nc e o f de pre ssio n within two ye ars into the me no pause transitio n

Hic ke y M e t al. Me no pause in pre ss

Around 11% of the sample (N=6,000) showed stable high or increasing depressive symptoms over time The Australian Longitudinal Study on Women’s Health Continuum of risk’ previous diagnosis or treatment for depression, presence of enduring, challenging socio-economic issues ‘window of vulnerability’ - high/persistent CES-D scores among those who experienced a lengthy perimenopause or those with a surgically induced menopause 31% de ve lo pe d Pe rsiste nt/ re c urre nt De pre ssio n

c ontinuum of r isk fac tor s (de pre ssio n [past,

c urre nt, family], me dic al c o nditio ns) and c onte xt-r

e late d fac tor s

(e .g . life stre sso rs

De pre ssio n During Me no pause

  • R

isk fac tor s

  • 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 ur

r e nc e or c ausality?

  • Vaso mo to r Sympto ms
  • Sle e p
  • Anxie ty
  • T

he R

  • le of E

str

  • ge n
  • E

tio lo g y

  • Mo dulatio n o f ne uro transmitte rs
  • T

he rape utic value

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SLIDE 4

J Clin Endocrinol Metab 2016; 101:3847-3855

  • 29 premenopausal women
  • 27.3 ± 7.2 years old
  • Non-depressed

GnRHa (leuprolide) 4 weeks Mood, HF, Sleep assessments

  • 20 subjects (69%) developed HFs
  • Only 1 subject develop clinical depression
  • Association between changes in depressive

symptoms and nighttime HF

  • Association with sleep changes

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

T ho se re maine d anxio us o ve r time (16-21%), with sympto ms de c lining afte r me no pause (fro m 71% to 40%)

Menopause 2013;20(5) 488-95.

Vasomotor Symptoms r e main str

  • ngly assoc iate d with Anxie ty ove r

time (2-3 fold inc r e ase d r isk ) at both gr

  • ups

De pre ssio n During Me no pause

  • 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

  • T

raje c to rie s o ve r time

  • Co -o c c urre nc e o r c ausality?
  • Vaso mo to r Sympto ms
  • Sle e p
  • Anxie ty
  • T

he R

  • le of E

str

  • ge n
  • E

tio lo gy

  • Mo dulatio n o f ne uro transmitte rs
  • T

he rape utic value

Ro le o f E stro ge n fo r De pre ssio n during the Me no pause T ransitio n

Gre ate r c hange s, fluc tuatio ns in e stro ge n le ve ls Vulne rability to de pre ssio n during the me no pausal transitio n Administratio n o f e stro ge n (17 β E stradio l) Pre se nc e / se ve rity o f mo o d sympto ms during the me no pausal transitio n

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.

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SLIDE 5

Freeman, E. W. et al. Arch Gen Psychiatry 2006;63:375-382.

Onse t o f De pre ssive Sympto ms a nd Ho rmo ne Cha ng e s Hig h CE S-D sc o re s we re a sso c ia te d with inc re a se d va ria b ility (within sub je c t) o f le ve ls o f:

  • E

stra dio l (P = .03)

  • F

SH (P<.001)

  • L

H (P = .005) Effects of Estradiol Withdrawal on Mood in Women with Past Perimenopausal Depression: A Randomized Clinical Trial

Sc hmidt e t a l. 2015; 72(7):714-726

E stro g e n Withdra wa l c a use d de pre ssive re spo nse ONL Y I n wo me n with histo ry o f pe rime no pa usa l de pre ssio n tre a te d with E T

  • Over 2,3000 searches (1997-2014)
  • 25 RCT on the effects of estrogen therapy on mood
  • 5 included symptomatic (depressed) women
  • Only 2 E2 RTCs for perimenopausal depression

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 Pe rime no pa usa l Wo me n

So a re s CN, e t a l.. 2001;58:529-534.

Pla c e b o 17β-E

2

5 10 15 20 25 Ba se line We e k 4 We e k 8 We e k 12 Wa sho ut

MADRS Me a n Sc o re s

E stro g e n-Ba se d T he ra py (T ra nsde rma l 17β-E

2) fo r the

T re a tme nt o f MDD in Pe rime no pa usa l Wo me n

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SLIDE 6

To identify early biomarkers for PPD among at-risk women Biomarker panel of 116 transcripts unique to PDD in the third trimester (89% accuracy)

  • controlled for anxiety
  • controlled for lifetime MDD
  • r BPD
  • Replicated in another dataset

Higher numbers of transcripts were linked to estrogen signaling – i.e., dysregulation of estrogen signaling in PPD

E 2 inc r e ase s 5-HT synthe sis and availability De c re a se s a c tivity o f mo no a mine o xida se s (MAO-A a nd MAO-B), ke y e nzyme s invo lve d in 5-HT de g ra da tio n; inc re a se s b o th iso fo rms o f trypto pha n hydro xyla se (T PH-1 a nd T PH-2) E 2 inc r e ase s 5-HT availability in the synaptic c le ft Re g ula te s 5-HT re upta ke fro m the syna ptic c le ft to the pre -syna ptic ne uro n E 2 inc r e ase s 5-HT availability for postsynaptic tr ansmission. Do wn-re g ula te s 5HT

1a a uto -re c e pto rs a nd

up-re g ula te s 5HT

2a re c e pto rs

J Clin Psyc hia try. 2011;72(11):e 1563-9

E xplo ring a E 2 5H-T pa thwa y fo r mo o d re g ula tio n: T he Ac ute T rypto pha n De ple tio n (AT D) Pa ra dig m

AT D ha s b e e n use d to inve stig a te the pa tho physio lo g y o f de pre ssio n a nd the MOA o f a ntide pre ssa nt tre a tme nts

  • ing e stio n o f la rg e ne utra l a mino a c ids (NO trypto pha n)

re sulting in 70-90% re duc tio n in b ra in trypto pha n within 5-7 ho urs.

  • De c line in c e ntra l 5-HT

b e ha vio ra l a nd physio lo g ic a l c o rre la te s. NO E F F E CT HE AL T HY VOL UNT E E RS PAST

MDD

Curre nt MDD Re c e iving no n-5-HT CURRE NT MDD Re c e iving 5-HT

  • b a se d tre a tme nts

MAXIMUM E F F E CT

  • Minuzzi, L

e t a l, NAMS 2013

ATD and fMRI in MDD-remitted subject on E2 treatment

AT D pro c e dure wa s suc c e ssful – 93% re duc tio n in T rp a va ila b ility 6 ho urs a fte r mixture ing e stio n

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SLIDE 7

I mpac t o f T rypto phan De ple tio n o n Sle e p E ffic ie nc y during the Me no pausal T ransitio n while o n E stro g e n T he rapy

NAMS Me e ting , 2016

Effects of ATD in Midlife Women on E2 with Current MDD or Past MDD (euthymic)

Syan, S e t al. Po ste r pre se ntatio n at NAMS 2016

Allo pre g nano lo ne – a pro g e ste ro ne -de rive d ne uro ste ro ids, usually:

  • I

nc re ase s GABA ac tivity thro ug h GABAA re c e pto rs

  • Ne g ative ly mo dulate s the HPA axis to

re turn it to ho me o stasis fo llo wing stre ss

  • E

xe rts anxio lytic and antide pre ssant ac tio ns Which GABAA receptor subunit gene polymorphisms could be associated with an increased risk for perimenopausal depression?

Depr ession in Midlife Women: Unique functional char acter istics, biomar ker s?

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SLIDE 8

Ac tiva tio n o f DL PF C during e mo tio na l c o nflic t re so lutio n De a c tiva tio n o f a myg da la during e xpo sure to fe a rful fa c e s

Pr e c ision Me dic ine :

Po te ntia l Bio ma rke r Ca ndida te s a nd I nte rve ntio ns

Dise a se Bio ma rke r I nte rve ntio n

L ung Ca nc e r E ML 4-AL K Crizo tinib Co ro na ry Arte ry Dise a se CYP2C19 Clo pido g re l (Pla vix) Smo king Ce ssa tio n CYP2A6 Va re nic line Alc o ho l Ab use GRI K 1 T

  • pira ma te

Ja me so n a nd L

  • ng o , Ne w E

ng l J M 2015

*

Bio ma rke rs in Psyc hia try:

Ba rrie rs to pro g re ss

  • L

imite d by Syndr

  • me s/ Disor

de r s

  • Ove rla pping phe no type s a c ro ss diso rde rs
  • He te ro g e ne ity within diso rde rs
  • L

ac k of in-vivo biopsy

  • Suic ide po st mo rte m tissue s
  • Naïve pur

suit of single mar ke r s

  • No Hb A1C
  • R

e tr

  • spe c tive , ge ne r

ic

  • Pa uc ity o f ra ndo miza tio n o n the b a sis o f

ma rke rs

  • F

ailur e to r e plic ate

  • Co mmo n the me a c ro ss a ll a re a s o f me dic ine
  • R

e lative ly small sample s

  • Ne e d Big Da ta to mo ve fo rwa rd
  • 10

UNIVERSITY PARTNERS

9

HEALTH-SCIENCE PARTNERS

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SLIDE 9

CAN-BI ND I nte grate d Platfo rms

Clinical Outcomes

  • Clinician administered scales
  • Patient-reported outcomes
  • Electronic data capture

Molecular Profiling

  • Gene expression
  • SNP analysis
  • GWAS
  • SRM-MS
  • Whole genome miRNA
  • Redox, methylation

Neuroimaging

  • T1-weighted anatomical scan
  • DTI series
  • T2-weighted BOLD EPI series
  • BOLD EPI series during tasks

Data Science

  • Statistical tools coupled with machine

learning tools to create biomarker models EEG

  • Resting state, eyes open
  • Resting state, eyes closed
  • Various functional tasks

M-Health

  • Behavioural Sensing
  • Ecological momentary assessments

Preclinical

  • Rodent anhedonia models
  • Zebrafish high-throughput
  • Pharmacology & electrophysiology

Knowledge Translation

  • Public and provider education
  • Patient Advisory Committee
  • Social media strategy
  • Implementation science
  • Imaging
  • EEG
  • Validate and Retest

Hypothesis generation and testing

Treatment Approaches Cross-platform data collection Data Science Response Biomarkers Reverse translation in animal models

  • Clinical
  • Molecular
  • M-Health
  • Response

Biomarkers

  • Imaging
  • EEG

Cross-platform data collection

  • Clinical
  • Molecular
  • M-Health

Data Science ranslation models ate and Retest

thesis generation and testing

Valida

Hypoth a

CAN-BI ND Appro ac h

Identify key mar ker s that pr edict tr eatment r esponse in the most accur ate and efficient manner using an iter ative pr

  • cess
  • CAN-BIND-1 Partial Dataset: n = 73

Clinical scale: MADRS Method: K-means Clustering

Confirmed 3 Trajectories of Response to Escitalopram

  • Fast responders
  • Slow responders
  • Non-responders
  • Baseline Severity

(MADRS, QIDS) Check for No Predictive Value Clinical inputs: Anxiety Co-morbidity Anhedonia (DARS) Predicts Slow Responders with 72% Accuracy Molecular inputs: Inflammatory Markers Predicts Fast vs. Non-responders with 76% Accuracy

  • Summary o f Mo de l
slide-10
SLIDE 10

Se arc h fo r Bio marke r Pane ls fo r De pre ssio n in Midlife Wo me n

NE W ONSE T

  • f MDD

during Midlife VMS+ Sle e p + Sle e p - VMS - Sle e p + Sle e p - E 2 Re spo nde r Anxie ty - Anxie ty + E 2 No n Re spo nde r