Zong Yi Hu et al- Neurosteroids: Oligodendrocyte mitochondria convert cholesterol to pregnenolone
Pregnenolone Trial in Autism— a...
Transcript of Pregnenolone Trial in Autism— a...
PregnenoloneTrialinAutism—aNeurosteroid Approach
LawrenceFung,M.D.,Ph.D.AttendingPsychiatrist,Autism&DevelopmentalDisabilitiesClinicAttendingPsychiatrist,PediatricNeuropsychopharmacologyClinic
Co-investigator,“RandomizedControlledPilotTrialofPregnenoloneinAutism”Co-investigator,“Cross-SpeciesMulti-ModalNeuroimagingtoInvestigateGABA
PhysiologyinFragileXSyndrome”StanfordUniversitySchoolofMedicine
Neurosteroid ApproachtoTreatASD
Excitation/InhibitionBalance
3
Excitation Inhibition
Hypothesis:Excitation/InhibitionImbalanceinAutism
4
Excitation Inhibition
ModulatingExcitation/InhibitionImbalanceinAutism
5
Excitation Inhibition
ModulatingExcitation/InhibitionImbalanceinAutism
6
Excitation Inhibition
PRE-SYNAPTIC INHIBITORY
NEURON
POST-SYNAPTIC NEURON
GLIAL CELL
GABAA R
GABA
Glu
GABA
GABA-T
Gln
GlnGln
Gln
Glu Glu
Glutam-inase
Mito
chon
drio
n
GABAGABA
GABA GABAGABAGABA
GABA GABA
GABA
GAD GLS
GABA
GABAB R
GABA
GABA GABAGABA
GABAergicSystem
Phasiccurrents
Toniccurrents
GABAGABA
GABA
Extra-synaptic GABAA R
8
2014 November ; 44(11): 2971–2977
9CortisolCorticosterone
11𝛽 hydroxylase
P450c17
EstradiolEstroneAromataseAromatase
NeurosteroidMetabolism
PRE-SYNAPTIC INHIBITORY
NEURON
POST-SYNAPTIC NEURON
GLIAL CELL
GABAA R
GABA
Glu
GABA
GABA-T
Gln
GlnGln
Gln
Glu Glu
GLS
Mito
chon
drio
n
GABAGABA
GABA GABAGABAGABA
GABA GABA
GABA
GAD GLS
GABA
GABAB R
GABA
GABA GABAGABA
GABAergicSystem
Phasiccurrents
Toniccurrents
GABAGABA
GABA
Extra-synaptic GABAA R
Allopregnanolone,THDOC,
Androstanediol
Allopregnanolone,THDOC,Androstanediol
PregnenoloneOpen-LabelTrialinASDAdults
• Studydesign– Open-label– 10malesand2females– Doseadministration:
• Week1&2:50mgtwicedaily• Week3&4:100mgtwicedaily• Week5&6:150mgtwicedaily• Week7&8:200mgtwicedaily• Weeks 9to12:250mgtwicedaily
• Inclusioncriteria– 18–45yearsofage– physicallyhealthymalesand
femaleswhoare– diagnosisofautisticdisorder– CGI-Sgreaterthanorequalto4– stableconcomitantmedicationsfor
atleast2weeks(4weeksifpatienttookfluoxetine)
– noplannedchangesinpsychosocialinterventionsduringtheopen-labelpregnenolone trial
• ExclusionCriteria– DSM-IV-TRdiagnosisof
schizophrenia,schizoaffectivedisorder,orpsychoticdisorderNOS
– prioradequatetrialofpregnenolone
– activemedicalproblemssuchasunstableseizures,orsignificantphysicalillness(e.g.,seriousliverorrenalpathology)
– Pregnancyorsexuallyactivefemales(asdeterminedbyaurinarypregnancytestinthebeginningofthestudy)
– subjectstakingoilorfat-basednutritionalsupplementswouldbeexcludedfromthestudyexcepttheyhadbeenoffthesecompoundsforatleast4weeks
• PrimaryEndpoint:AberrantBehavioralChecklist-Irritability(ABC-I)
11Fungetal.JAutismDevDisord (2014)44(11):2971-7.
AdverseEventsreportedinPregnenoloneOpen-LabelTrialinAdultswithASD
Adverseevents NumberofpatientsreportingAE
Tiredness 1*
diarrhea 1*,1#
depressiveaffect 1*,1#
increasedexcitement/agitation 3#
sleepproblems 1#
drowsiness 1#
anorexia/decreasedappetite 2#
increasedmotor activity 1#
sweating 1#
constipation 1#
tremor 1#
Fungetal.JAutismDevDisord (2014)44(11):2971-7.
*maybemedication-related#remotechancetobemedication-related
Clinical Measures Baseline Week 12a Paired t test Effect size
Mean SD Mean SD t p Cohen’s d Aberrant Behavioral Checklist ABC-Irritability 17.4 7.4 11.2 7.0 2.5 0.028* -0.86 ABC-Lethargy/Social Withdrawal 18.1 8.0 12.8 8.7 2.3 0.046* -0.63 ABC-Stereotypy 9.8 5.5 8.7 6.5 0.7 0.522 -0.18 ABC-Hyperactivity 20.5 16.1 16.1 8.9 1.8 0.098 -0.34 ABC-Inappropriate Speech 5.8 4.3 4.8 4.4 1.0 0.356 -0.23 Short Sensory Profile – Total Score 137.7 21.5 147.6 15.3 -3.2 0.009* 0.53 Social Responsiveness Scale – Total Score 84.9 8.1 84.5 9.2 0.2 0.848 -0.05 Vinelandb – Adaptive Behavior Composite Score 37.3 13.1 42.9 16.5 -1.3 0.224 0.38
* p < 0.05 a Week 12: end of the active treatment phase b Vineland: Vineland Adaptive Behavior Scales
Fungetal.JAutismDevDisord (2014)44(11):2971-7.
Preliminaryevidencefromoneopen-labelstudysuggeststhatPregnenolonemaybehelpfulinreducingirritability,socialwithdrawal,andsensoryaberrationsinadultswithASD.
Plasma Concentrations of Neurosteroids at Baseline and after
a 12-week Treatment of Pregnenolone
14
Neurosteroid Baselineconc(ng/mL) Week12conc(ng/mL) pvaluePregnenolone 1.9±.7 7.0±4.1 .00029Pregnenolonesulfate 28±14 134±104 .0022Progesterone .38±.09 .56±.19 .0067Allopregnanolone .15±.18 1.0±1.0 .0079DHEA 5.5±2.1 7.2±4.3 .21DHEAsulfate 239±134 255±131 .77Estradiol .18±.17 .24±.33 .58Totaltestosterone 2.9±2.2 2.8±1.5 .84Freetestosterone .011±.008 .010±.006 .92Cortisol 101±42 139±61 .088
Fungetal.Presentedin2015AnnualMeetingofAmericanCollegeofNeuropsychopharmacology.
Comparisons of Plasma Concentrations of Neurosteroids between Responders
and Non-responders after a 12-week Treatment of Pregnenolone
15
ABC-I Pregnenolone(ng/mL) Totaltestosterone(ng/mL)
Freetestosterone(ng/mL)
Baseline Change(0-12wk) Baseline Week12 Baseline Week12 Baseline Week12Responders 20.3
±9.112.7±6.0
1.5±0.4
7.0±4.6
2.4±2.3
1.8±1.3
.030±.028
.022±.017
Non-responders 14.5±4.3
14.7±2.3
2.3±0.7
7.0±3.9
3.5±2.1
3.8±0.7
.045±.027
.050±.009
pvalue .18
.0026 .039 .99 .44 .0097 .37 .0054
Fungetal.Presentedin2015AnnualMeetingofAmericanCollegeofNeuropsychopharmacology.
-0.2±5.2
Comparisons of Plasma Concentrations of Neurosteroids between Responders
and Non-responders after a 12-week Treatment of Pregnenolone
16
Fungetal.Presentedin2015AnnualMeetingofAmericanCollegeofNeuropsychopharmacology.
ABC-I Pregnenolone(ng/mL) Totaltestosterone(ng/mL)
Freetestosterone(ng/mL)
Baseline Change(0-12wk) Baseline Week12 Baseline Week12 Baseline Week12Responders 20.3
±9.112.7±6.0
1.5±0.4
7.0±4.6
2.4±2.3
1.8±1.3
.030±.028
.022±.017
Non-responders 14.5±4.3
14.7±2.3
2.3±0.7
7.0±3.9
3.5±2.1
3.8±0.7
.045±.027
.050±.009
pvalue .18
.0026 .039 .99 .44 .0097 .37 .0054
-0.2±5.2
ConclusionstothePREGOpen-labelStudy• PregnenolonewasmodestlyeffectiveandwasoverallsafeandwelltoleratedinindividualswithASD.
• BaselineplasmaPregnenolonelevelswerepredictiveofresponse(reductioninirritability).
• 12weekplasmaTestosteronelevelscorrelatedwithreductioninirritability.
• Thedatasupportfurtherstudiesinexploringpregnenolone’s effectsonreducingirritability,improvingsocialfunctioning(acoresymptomofASD),andattenuatingsensoryabnormalities.– ApilotRandomizedControlledTrialofPregnenoloneisnowfundedbytheSimonsFoundationAutismResearchInitiative
PregnenoloneRCTStudyDesign
19
40participants(age14-21years)withASD
20participantstoreceivePregnenolone
20participantstoreceivePlacebo
20participantstohaveoption toreceivePregnenolone
60mgtwicedailyfor2weeks
90mgtwicedaily for2weeks
150mgtwicedaily for2weeks
210mgtwicedaily for2weeks
250mgtwicedaily for4weeks
Rand
omized
Co
ntrolled
Phase
Ope
n-Labe
lExtension
Phase 60mgtwicedailyfor2weeks
90mgtwicedaily for2weeks
150mgtwicedaily for2weeks
210mgtwicedaily for2weeks
250mgtwicedaily for4weeks
=EEG,eye-tracking,vitalsigns,NSlevels,bloodchemistry,ratingscales=vitalsigns, ratingscales
placebo
placebo
placebo
placebo
placebo
AcknowledgmentsStanfordPsychiatryAntonioHardan,M.D.JenniferPhilips, Ph.D.RobinLibove,B.S.SerenaTanaka,B.S.AzaleaLee,B.S.
FundingSourcesEscherFamilyFundattheSiliconValleyCommunityFoundation
Mosbacher FamilyFund
StanfordBioADD LabWenchao Sun,Ph.D.JayRajadas,Ph.D.DivisionofCardiovascularMedicineFrancoisHaddad,M.D.
21
GABAergicNeuroimaging
22
THANKYOU!