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TODAY, WE'RE HONORED TO HAVE AS
OUR SPEAKER DR. CAROLYN
RODRIGUEZ, ASSOCIATE DEAN FOR
ACADEMIC AFFAIRS AT STANFORD
UNIVERSITY SCHOOL OF MEDICINE,
DIRECTOR OF THE TRANSACTIONAL
THERAPEUTIC PLAN OR PROFESSOR IN
THE DEPARTMENT OF PSYCHE FREE
AND BEHAVIORIAL SCIENCES AT
STANFORD AND A CONSULTATIONAL
LIAISON PSYCHIATRIST FOR THE P A
LO ALTASD O VETERAN'S HEALTHCARE
SYSTEM.
DR. RODRIGUEZ EARNED HER
BACHELORS FROM HARVERDICT
UNIVERSITY AND THEN AS A STUDENT
IN THE INTERDISCIPLINARY HARVARD
MEDICAL SCHOOL, INSTITUTE OF
TECHNOLOGY OF PROGRAM AND HEALTH
SCIENCES AND TECHNOLOGY, SHE
EARNED HEAR Ph.D. IN GENETICS.
SHE COMPLETED INTERNAL MEDICINE
RESIDENCY AND THEN PURSUING A
POST DOCTORAL FELLOWSHIP AT
COLUMBIA AT NEW YORK STATE'S
PSYCHIATRIC INSTITUTE.
AS DIRECTOR OF TRANSLATIONAL
THERAPEUTICS LAB, OBSESSIVE
COMSULSIVE RESEARCH PROGRAM, AND
STANFORD HOARDING RESEARCHERS
PROGRAM, DR. RODRIGUEZ LEADS
STUDIES INVESTIGATING SEVERE
MENTAL DISORDER SAYS.
HER LANDMARK CLINICAL TRIALS
PILOT PROJECT OR NEAR ACTIVE
TREATMENT FOR ILLNESS FOR
RELATED DISORDERS.
HER NIH AND DONOR FUND BEING
MECHANISTIC AND CLINICAL
EFFICACY STUDIES TARGET DPLIEWT
MITTERGIC AND [INDISCERNIBLE],
NONEVASIVE BRAIN STIMULATION,
PSYCHOTHERAPY AND SUICIDE
PREVENTION.
SHE'S ALSO THE AUTHOR OF
HOARDING DISORDER, PUBLISHED
THIS LAST AUGUST BY THE AMERICAN
PSYCHIATRIC ASSOCIATION.
DR. RODRIGUEZ IS DEPUTY DIRECTOR
OF THE AMERICAN JOWNAL OF
PSYCHIATRY, A BOARD MEMBER OF
THE AMERICAN--RESEARCH COUNCIL
FOR AMERICAN PSYCHIATRIC
ASSOCIATION, THE BRAIN AND
BEHAVIOR RESEARCH FOUNDATION
SCIENTIFIC COUNCIL AND AMERICAN
FOUNDATION FOR SUICIDE
PREVENTION ADVISORY GROUPS AND
AS A SCIENTIFIC AND CLINICAL
ADVICERY BOARD MEMBER OF THE
INTERNATIONAL FOUNDATION.
DR. RODRIGUEZ HAS RECEIVED
SEVERAL NATIONAL AWARDS
INCLUDING PRESIDENTIAL EARLY
CAREER AWARD FOR SCIENTIST
ENGINEER WHICH RECOGNIZES
INVESTIGATORS WHO ARE PURSUING
BOLD AND INNOVATIVE PROJECTS AND
CONSIDERED 1 OF THE HIGHEST
HONORS IN SCIENTIFIC RESEARCH.
DR. RODRIGUEZ PRESENTED HER
RESEARCH AT THE 2019 ECONOMIC
FORUM IN DAVOS, AND AT FORTUNE
BRAINSTORM HEALTH THIS PAST
YEAR.
HER WORK HAS BEEN FEATURED ON
NPR, PBS, THE NEW YORK TIMES,
ABC NEWS, NBC NEWS AND NEWS WEEK
AND TIME.COM.
IN ADDITION TO HER NEARLY 80
PEER REVIEWED PUBLICATIONS AND
BOOK CHAPTERS DR. RODRIGUEZ IS A
CONTRIBUTOR TO THE HARVARD
BUSINESS REVIEW AND HUFFING TON
POST TO SHARE SCIENTIFIC FINDING
WITH THE GENERAL PUBLIC.
NOW, PLEASE WELCOME OUR SPEAKER
DR. CAROLYN RODRIGUEZ WHOSE TALK
IS ENTITLED: NOVEL
INTERVENTIONS FOR OBSESSIVE
COMPULSIVE DISORDER.
>> IT'S A PLEASURE
TO BE HERE WITH YOU TODAY AND
SHARE WITH YOU ADVANCES WE'RE
MAKING NEAR NOVEL INTERVENTIONS
FOR OCD.
THIS IS A LIST OF MY FUNDING AND
DISCLOSURES OVER THE PAST 3
YEARS AND I WANTED TO START OFF
BY SHARING WITH YOU THAT IN MY
TRAINING IT HAS ALWAYS BEEN
INCREDIBLY MEANINGFUL TO ME
WANTING TO TRY AND HELP
INDIVIDUALS SUFFERING FROM
SEVERE MENTAL ILLNESS, AND EARLY
IN MY PATH, I MET AN INDIVIDUAL
NAMED JOHN, HIS NAME IS
DISGUISED WHO RIGHT WHEN WE
ENTERED COLLEGE WAS HIT WITH
THIS WALL OF EXCRUCIATING
ANXIETY.
AND HE FELT THAT HE NEEDED TO
WRITE AND REWRITE HIS
ASSIGNMENTS UNTIL THEY WERE,
THEY FELT JUST RIGHT.
HE SPENT HOURS AT NIGHT, COULD
BARELY SLEEP IN THE MORNING HE
WOULD WAKE UP EARLY AND TRY TO
DIFFERENT CLOTHING UNTIL THEY
FELT RIGHT AND THIS-THESE
THOUGHTS AND BEHAVES MADE IT SO
THAT HE WAS LATE TO CLASS, HE
WASN'T ABLE TO FUNCTION, HIS
GIRL BROKE UP WITH HIM AND IT
WAS INCREDIBLY, INCREDIBLY
DISTRESSING FOR HIM.
SO JOHN IS AN INDIVIDUAL WHO HAS
OBSESSIVE COMPULSIVE DISORDER OR
OCD.
ASK THIS IS CHARACTERIZED BY
INTRUSIVE THOUGHTS, IMAGES,
URGES THAT INCREASE ANXIETY AND
COMPULSIONS WHICH ARE BEHAVIORS
THAT CAN BE MENTAL OR PHYSICAL
ACTS THAT DECREASE THIS ANXIETY.
AND THIS DISORDER IS PREVALENT,
IT'S COMMON.
IT HAS A HIGH PROPORTION OF
CASES THAT ARE SEVERE AND 1 OF
THE--1 OF THE FACTS THAT REALLY
COMPELLED ME TO STUDY OCD IS
THAT IT TAKES ON AVERAGE 14
YEARS FROM AN INDIVIDUAL BEING
DIAGNOSED, HAVING THE SYMPTOMS
OF OCD TO THEN BEING DIAGNOSED
AND HAVING FIRST LINE TREATMENT
SO IT CAN BE A VERY HIDDEN
DISORDER AND IT'S IMPORTANT TO
KNOW THAT EVEN THOUGH SOME OF
THE MEDIA ABOUT OCD IS SORT OF
FOCUSED ON CONTAMINATION AND
HAND WASHING, THERE'S ALSO A LOT
OF DIFFERENT KINDS OF THEMES IN
OCD INCLUDING THOSE OF HARM.
SO PEOPLE CAN HAVE INTRUSIVE
THOUGHTS THAT THEY'VE RUN
SOMEBODY OVER WHEN THEY HAVEN'T
AND THEY WILL FEEL COMPELLED TO
GO BACK TO THE SITE WHERE THEY
HAD THIS THOUGHT AND CHECK TO
SEE IF THEY'VE HEARD ANYONE.
THEY WILL GO HOME AND CHECK THE
NEWS TO SEE IF THERE'S ANY
REPORTS OF ACCIDENTS AND AS YOU
CAN IMAGINE, THIS REALLY IS
DISRUPTING FOR PEOPLE'S TIME,
FOR THEIR SCHEDULE, FOR THEIR
ENERGY AND ALSO 1 OF THE THEMES
THAT IS NOT BROUGHT TO LIGHT
VERY OFTEN IS TABOO THOUGHTS OR
THEY CAN BE MENTAL RITUALS LIKE
A PRAYER OR PHRASE OR COUNTING
OR THEY CAN BE PHYSICAL ACTS TO
NEUTRALIZE THAT ANXIETY.
ONE MEMORABLE INDIVIDUAL HAD AN
ENTRUCIVE THOUGHT OF THE WORD
JOHN, INCREASED HIS ANXIETY AND
I HAD THINK IN HIS MIND TO HAVE
THAT ANXIETY GO AWAY.
THE STANDARD TREATMENTS FOR OCD
INCLUDE MEDICATIONS AS SEROTONIN
INHIBIT UPTAKE, THINGS LIKE
SSRI, SO THINGS LIKE PROZACH,
AND ON THE BEHAVIORIAL SIDE,
BEHAVIORIAL THERAPY WITH
COGNITIVE RESPONSE.
AND THIS IS AN EFFECTIVE THERAPY
WHERE YOU TRY AND DISRUPT THE
LINK BETWEEN A PERSON FEELING
LIKE THEY HAVE THIS INTRUSIVE
THOUGHT THAT CAUSES ANXIETY AND
THEY THEY HAVE TO DO THE
COMPULSIONS TO DECREASE THE
ANXIETY.
BUT THE OCD IS STRONG AND WE TRY
TO DISRUPT THAT THOUGHT AND THE
ANXIETY GO DOWN AND INDIVIDUALS
EXPOSE THEMSELVES FROM LEAST TO
HIGHEST FEAR.
AND TOGETHER THESE 21st LINE
TREATMENTS CAN HELP
APPROXIMATELY HALF OF
INDIVIDUALS WITH OBSESSIVE
COMPULSIVE DISORDER BUT HALF OF
INDIVIDUALS WILL NOT BE HELPED
AND THAT'S REALLY WHERE MY FOCUS
OF MY RESEARCH IS AND WHERE
THE--YOU KNOW WHERE WE GOT TO
WITH JOHN.
SO I WOULD LIKE TO REVIEW, JUST
A LITTLE BIT ABOUT SOME OF THE
FIRST LINE PHARMAICOLOGICAL
TREATMENTS FOR THOSE WHO OF YOU
WHO SEE INDIVIDUALS WITH OCD.
THIS IS A LIST OF THOSE
INHIBITORS AND CLOMIPRAMINE IS 1
OF THE FIRST TREATMENTS.
PEOPLE USUALLY START WITH THE
SSRIs, BECAUSE THEY HAVE LESS
SIDE EFFECTED PROFILE.
BUT ON AVERAGE 40-60% OF
INDIVIDUALS WILL HAVE AN AVERAGE
OF 20-40% SYMPTOM REDUCTION WITH
1 OF THESE FIRST LINE TREATMENTS
AND SO IT WILL DECREASE THE
SYMPTOMS BUT KNOCK IT OUT
COMPLETELY.
THE OTHER THING IS THAT THE
DOSES FOR THESE MEDICATIONS ARE
MUCH HIGHER FOR OCD THAN MAJOR
DEPRESSION?
THEY NEED TO BE GIVEN AT LONGER
DOSE.
SO EVIDENCE SHOW THAT HIGHER
SSRI PRODUCE A GREATER MAGNITUDE
OF SYMPTOM OF RELIEF AND YOU
WANT TO CONTINUE THIS FOR 8-12
WEEKS INCLUDING 4-6 WEEKS AT A
MAXIMALLY TOLERATED DOSE.
THIS IS A LOT LONGER THAN
DEPRESSION WHERE YOU COULD SEE
AN EFFECT ON SOMETHING LIKE IN
THE ORDER OF 2 WEEKS.
LOWER DOSES AND GRADUAL
TITRATION MAY BE NEEDED FOR
PATIENTS WITH OCCURRING ANXIETY
DISORDERS, THE ELDERLY OR IF
SIDE EFFECTS ARE A CONCERN.
IF THE FIRST SSRI DOESN'T WORK,
SWITCH TO DIFFERENT, IS SRI OR
SWITCH TO CLOMIPRAMINE, OR
AUGMENT A DOPAMINE BLOCKER OR
TWITCH TO EFEXPECTATIONS OR OR
REMERON, OR TRY CBT.
REGARDING BLOCKERS, RESPIRRA
DONE HAS BEEN TRIED IN STUDIES.
THIS IS WORKED IN PATIENTS WITH
TICK DISORDER, ABILIFY, HAVE HAD
GOOD RESULTS BUT SEROQUELL AND
ZYPREXA'RE MIXED BUT THE OTHERS
THERE'S BEEN NO STUDY IN OCD.
THIRD LINE TREATMENTS INCLUDE
USING A DIFFERENT DOPAMINE
BLOCKER OR MAYBE A THIRD OR
FOURTH SSRI AND THEY MAY HAVE A
BENEFIT AND THERE'S A PERCENTAGE
OF PEOPLE WHO WILL RESPOND.
ADDING THE MEDICATIONS THAT ARE
DPLIEWT MATE MODULATORS THESE
ARE THINGS LIKE LAMANTIEN OR
OTHERS.
OR SWITCHING TO DUG DRUGS THAT
HAVE AT LEAST 1 RANDOMIZED
CONTROL TRIAL AND SOME EVIDENCE
INCLUDING DEMETHAMPHETAMINE,
MORPHINE, TRAUMA DOLL OR
ONDANSETRON.
SO CAN YOU GO TO AN INTENSIVE
RESIDENTIAL TREATMENT OR HAVE A
PARTIAL HOSPITALIZATION.
ONE THING TO NOTE IS THAT
MONOTHERAPY WITH THINGS LIKE
BENZODIAPINES ARE NOT WELL
SUPPORTED.
THERE'S NO EVIDENCE OF BENEFIT
FROM LITHIUM.
BENZOs MAY BE HELPFUL FOR
ANXIETY AND SLEEP BUT DON'T
ADDRESS THE CORE OF OCD
SYMPTOMS.
IN NEUROLEAPTICS 1 THING TO BE
CAUTIOUS OF IS THAT THESE DRUGS
THIS, DRUG CLASS CLOZAPINE CAN
TRIGGER OR EXACERBATE OCD
SYMPTOMS.
NEXT IS NEURO MODULATIONS,
THERE'S 2 FORMS, NONINVASIVE AND
INVASIVE.
SO FOR NONINVASIVE, FDA HAS
APPROVED A DEEP TMS DEVICE WITH
THE HELMET COIL AND ALSO THE FDA
HAS APPROVED COMPASSIONATE USE
OF DEEP BRAIN STIMULATION FOR
OCD.
AND AS I MENTIONED MY LAB IS
INTERESTED IN THOSE FOLKS WHO
ARE INTERESTED IN HELPING IN
FIRST LINE TREATMENTS AND IN
ADDITION TO TRIALLY TRYING TO
IDENTIFY DRUGS, WE WANT TO TRY
AND UNDERSTAND IF THEY CAN WORK
RAPID LOAMACYY ON SYMPTOMS AS
YOU SAW, 8 TO 12 WEEK SYSTEM A
LONG TIME FOR PATIENTS TO WAIT
TO GET BETTER.
WE REALLY WANT TO BE ABLE TO DO
IT RAPIDLY.
AND THE OTHER IS HOW DO WE USE
THESE DRUGS IF THEY DO HAVE
RAPID EFFECTS, HOW DO WE USE
THEM AS PROBES TO UNDERSTAND THE
UNDERLYING MECHANISMS OF
BEHAVIOR.
SO HOW DOES, YOU KNOW FROM THE
RECEPTOR LEVEL, LOOKING AT
GLUTAMATE RECEPTORS, HOW THOSE
IN NEURONS, HOW THOSE BUILD
CIRCUITS IN OCD, THERE'S A
REPETITIVE, THOUGHT TO BE A
RAPID FIRING--FIRING RAPID HYPER
STIMULATED CIRCUIT INVOLVING THE
CORTEX STRIATUM AND THIS WILL
MUSIN ADDITION TO OTHER CIRCUITS
IN THE BRAIN AND ALSO HOW DO
THOSE CIRCUITS, HYPER ACTIVE
CIRCUITS THEN BUILD INTO SIGNALS
OR NEURAL NETWORKS, SO THAT
YOU--HOW IS THE NETWORK FIRE
NOTHING A SYMPHONY IN ORDER TO
BE ABLE TO ELICIT THESE KINDS OF
BEHAVIORS THAT WE SEE.
AND FINALLY, CAN UNDERSTANDING
MECHANISM IMPROVE PRECISION FOR
OUR DIAGNOSIS AND FOR MONITORING
AND FOLLOWING BENEFITS OF
PATIENTS.
SO I WILL HEIGHT LIGHT FOR YOU
AN APPROACH WE'RE USE NOTHING
TRANSLATIONAL THERAPEUTIC
APPROACH.
I WAS REALLY INSPIRED AND I WILL
TELL YOU ABOUT THIS ABOUT
AN ANIMAL MODEL FOR COMPULSE OF
BEHAVIORS.
THAT LED TO WANTING TO TEST OUT
NOVEL COMPOUNDS, THAT COULD BE
USED IN HUMAN TRIALS OF OCD, AND
THEN I'LL DESCRIBE A LITTLE BIT
BACK TRANSLATION WE'VE BEEN
DOING TO SEE IF THOSE COMPOUNDS
CAN HAVE EFFECTS IN THE ANIMAL
MODEL TO REFINE THE ANIMAL
MODELS.
SO FIRST EARLY IN MY TRAINING, I
SAW THAT DRUGS IS A FAMILY OF
PROTEINS AND WHEN THEY'RE
DISRUPTED, AT GLUTEMITTERGIC
SYNAPSES, GLUTAMATE AS YOU KNOW
MAY KNOW IS THE EXCITATORY
NEUROTRANSMITTER IN THE BRAIN,
THOSE--THAT DISRUPTION ELICITS
IN THIS ANIMAL MODEL, EXCESSIVE
GROOMING AND ANXIETY LIKE
BELAIEVERS AND CORTICO STRIATUM
DEFINITES AND WHEN YOU
REINTRODUCE THAT PROTEIN
EXPRESSION INTO THE TRIAT UMKC,
YOU SEE A SUSSESSION OF THESE
COMPULSIVE BEHAVIORS AND SO THIS
LINE OF EVIDENCE IN ADDITION TO
STUDIES OF GLUTAMATE MODULATORS
IN OCD, THAT SEEM TO WHEN ADDED
TO AN SSRI HAVE BENEFIT IN
REDUCING OCD SYMPTOMS MAY BE
REALLY INTERESTED IN GLUTAMATE
SYSTEM.
AND AROUND THE TIME THAT I WAS,
YOU KNOW STARTING IN RESEARCH,
KETAMINE HAD JUST BEEN
IDENTIFIED AS A RAPID ACTING
COME POUND THAT DECREASED
DEPRESSION IN STUDY BY BERM AN
ET AL, AND IT SEEMED TO ME TO
MAKE SENSE TO TRY THIS IN OCD.
AND WHAT WE DID IS WE TOOK A
SMALL PILOT STUDY, THOSE
RANDOMIDED TO IV KETA MEAN OR IV
SALIVA--SALIVAINE, WE ASKED THEM
ON A SCALE OF 0-10, WHAT ARE THE
SYMPTOMS LIKE OVER THE COURSE OF
1 WEEK.
AND WHEN WE DELIVERED A 0.5 MIX
PER KG INFUSION OF KETAMINE,
WHICH S&P LOW DOSE AND IT
DOESN'T PRODUCE ANESTHESIA,
AFTER THAT WE SAW THESE REALLY
DRAMATIC AND VAST WITHIN HOURS
DECREASE IN OCD SYMPTOMS.
AND THOSE EFFECTS AMAZING 3
PERSISTED LONG PAST KETAMINE'S
VERY RAPID METABOLISM IN THE
BODY.
AND THEN, FINALLY, WE WERE JUST
BLOWN AWAY THAT THESE EFFECTS
PERSISTED IN THE NEXT COUPLE
DAYS.
THE OTHER THING THAT WAS REALLY
EXCITING WAS THAT NONE OF THESE
INDIVIDUALS WERE ON MEDICATION
AT THE TIME AND THEY DIDN'T HAVE
DEPRESSION AT THE TIME.
SO REALLY FOCUSED ON JUST OCD
SYMPTOMS.
AND THIS IS THE FIRST TIME THAT
THESE RAPID EFFECTS HAD BEEN
DEMONSTRATED IN A NOVEL PATHWAY,
1 THAT DIDN'T INVOLVE SRIs.
WE ALSO ASKED AT 1 WEEK, SO
USING THIS STANDARD MEASUREMENT
FOR RESPONSE, THE YALE BROWN
OBSESSIVE COMPULSIVE SCALE, WAS
THERE AT LEAST A 35% REDUCTION
IN THE SCORE?
AND 1 WEEK OUT HALF OF THE
INDIVIDUALS THAT GOT IV KETAMINE
WERE MET CRITERIA FOR RESPONSE
AND NONE OF THE SALINE DID.
SO JOHN FELT LIKE HE WAS HAVING
A VACATION FROM HIS OCD.
HERE'S QUOTES FROM THE
PARTICIPANTS, BUT WHAT'S REALLY
STRIKING IS THAT THEY CAN'T,
LIKE THE LAST 1, I TRIED TO HAVE
OCD THOUGHTS BUT I COULDN'T.
ONE OF THE DOWN SIDES OF
KETAMINE IS FEELINGS OF
DISASSOCIATION, FEELING OF
FLOATING, UNREALITY AND
INDIVIDUALS CAN FEEL DIZZINESS
AND NAUSEA, CONSISTENT WITH
OTHER STUDIES IN DEPRESSION,
THERE'S MILD INCREASES IN BLOOD
PRESSURE AND HEART RATE AND ALSO
ANOTHER DOWN SIDE IS THAT PEOPLE
CAN'T DRIVE FOR THE NEXT 24
HOURS.
SO IN SUMMARY, THIS IS A FIRST
STUDY SHOWING KETAMINE CAN
DECREASE INTRUSIVE THOUGHTS IN
THE ABSENCE OF SSRIs AND
GLUTAMATE MODULATION MAY BE A
RAPID ACTING TARGET IF ARE OCD.
AND THERE ARE REASONS FOR
CAUTION, SO THE EFFECTS ARE
TRANSIENT.
THERE ARE CLINICS OUT THERE THAT
ARE DELIVERING IT BUT IT CAN BE
COSTLY.
IT'S NOT FDA APPROVED FOR OCD,
THE SIDE EFFECTS I DESCRIBED AND
ALSO A DRUG OF ABUSE, IT'S
CALLED SPECIAL K, WE ARE VERY
CAREFUL TO SCREEN PEOPLE WHO
HAVE A HISTORY OF DRUG ABUSE FOR
OUR STUDIES.
BUT CAUTION IS STILL NEEDED.
SO I'VE TURNED OUT TO 1 OF THE
THINGS WE'RE REALLY INTERESTED
IN AND KETAMINE IS ACTING
THROUGH THE GLUTAMATE SYSTEM,
HOW CAN WE UNDERSTAND THE
MECHANISM.
SO DOES KETAMINE CHANGE LEVELS
OF DPLIEWT MATE?
AND YOU CAN ACTUALLY STUDY THIS
IN THE HUMAN BRAIN USING
SOMETHING CALLED MAGNETIC
RESONANCE SPECTROSCOPY.
SO PARTNERING WITH
[INDISCERNIBLE] AT CORNELL AND
BLAIR SIMPSON ANDULARY
[INDISCERNIBLE] AT COLUMBIA, WE
WERE ABLE TO LOOK AT A SPECIFIC
AREA OF THE BRAIN AND ASK
WHETHER, DPLIEWT MATE AND GLUTEA
MINE TOGETHER CALLED GLX CHANGE
IN KETAMINE.
AND WE CAN ALSO ASK IF GABBA IS
CHANGED, SO GABBA IS AN
INHIBITORY COMPOUND.
AND YOU CAN DO THIS WORK IN THE
SCANNER AND INNED WHEN WE WERE
GIVING THE INFUSIONS TO THE
PATIENTS IN THE SCANNER, WE WERE
ABLE TO COLLECT THIS DATA AND
USE A J-PRESS EDITING APPROACH
TO EXAMINE THESE PEAKS.
AND 1 OF THE FUN THINGS ABOUT
SCIENCE THAT WILL SURPRISE YOU
AND WE DIDN'T SEE ANY CHANGES IN
GLX BUT WE DID SEE ELEVATION AND
THE INHIBITORY COMPOUND GABBA,
WHICH WAS QUITE INTERESTING AND
WE ACTUALLY, THE STUDY WAS
CONDUCT INDEED PARALLEL WITH THE
VERY SIMILAR STUDY DESIGN IN
INDIVIDUALS WITH DEPRESSION.
AND THE IN DEPRESSION
INDIVIDUALS HAD INCREASE IN BOTH
GLX AND GABA, SO THERE MAY BE
KETAMINE EFFECTS IN OCD RELATIVE
TO DEPRESSION BUT AGAIN THIS
NEEDS REPLICATION IN A LARGER
SAMPLE.
SO GOING FROM THE ANIMAL MODEL
SET BACK, 3, TO THINKING IT AS A
CANDIDATE AND TESTING IT IN OCD,
WE WANTED TO GO BACK NOW TO THE
ANIMAL MODEL THAT INSPIRED ME
AND WE PARTNERED WITH LISA
[INDISCERNIBLE] AND GWEN DAVIS
AS A STUDENT IN
DR. [INDISCERNIBLE]'S LAB AT
UCSF TO ACTUALLY DO KIND OF A
CLINICAL TRIAL IN MICE.
WE GAVE THESE ANIMALS HAD BASE
LINE GROOMING DEFICITS AND WE
INJECTED THEM WITH EITHER
KETAMINE OR SALINE ON DAY 0 EXPW
WE CAN ACTUALLY LOOK AT GROOMING
BOUTS 1 HOUR, 1 DAY, 3 DAYS, 7
DAYS AT THE SAME TIME WE DID THE
CLINICAL STUDY.
AND WE WANTED TO ASK
SPECIFICALLY DOES THIS AFFECT
THE FRONTAL TRIAT OLDER PEOPLE
PROJECTION IN THE CIRCUIT WE
THINK IS IMPORTANT FOR OCD.
AND SO THE FIRST THING WE WANTED
TO DO IS YOU SEE HERE IN THE
PURPLE BARS IS THIS IS THE SAPP
A P3 KNOCKOUT MICE.
YOU CAN SEE THE NUMBER OF
GROOMING BOUTS AND ELEVATED
RIGHT HERE.
COMPARED TO WILD-TYPE MICE.
AND THEN, THE INDIVIDUALS WITH
THE DASH BARS ARE THE 1S THAT
GOT THE KETAMINE AND THEN YOU
CAN SEE THE RESPONSE GOING DOWN.
SO THIS IS ANOTHER PICTURE.
SO IN THE KNOCKOUT MICE THIS, IS
THE GROOMING, STAYS UP ABOVE
THIS BAR BUT THEN WHEN YOU GET
KETAMINE, IT COMES DOWN AND THE
WILD-TYPE, THERE ISN'T MUCH
DIFFERENCE BETWEEN THE SALINE
AND KETAMINE AND THEN
DR. [INDISCERNIBLE] IS HER TEAM
WERE ABLE TO USE WOBDERFUL TOOLS
CALLED OPTOGENETICS IN WHICH YOU
INTRODUCE THIS MOLECULE INTO
NEURONS AND BASICALLY WITH LIGHT
TURN ON AND OFF DIFFERENT KINDS
OF CELL POPULATIONS.
AND SO THE FITTER PART OF THE
EXPERIMENT, SHE USED CANETTA
MINE TO SHOW INCREASED ACTIVITY
AND THE PREFRONTAL NEURONS AND
THOSE ARE THE 1S THAT ARE
PROJECTING THE 1S IN THE
KNOCKOUT MICE AND THEN OPTICAL
IMAGES O GENETICALLY, SHE
MIMICKED THIS INCREASE IN THE
FRONTAL TRIAT OLDER PEOPLE
ACTIVITY AND IT SHOWED REDUCED
COMPULSIVE GROOMING BEHAVIOR IN
THE KNOCKOUT MICE.
AND THEN CONVERSELY IF YOU
INHIBIT THE CIRCUIT IN THE
WILD-TYPE MICE, IT INCREASED
GROOMING.
AND THEN, SHE WAS ABLE TO SHOW
THAT KETAMINE BLOCKED
EXACERBATION OF GROOMING IF THE
KNOCKOUT MICE CAUSED BY OPTICAL
IMAGES O GENETICALLY INHIBITING
THE FRONTAL TRIATAL ACTIVITY.
SO WE'RE REALLY EXCITED THIS
EXPERIENCE CEMETERY THAT
KETAMINE INCREASES ACTIVITY IN
THE FRONTAL STRIATAL CIRCUIT
THAT POSITIVELY CONTROLS
GROOMING BEHAVIOR.
THIS IS SOMETHING YOU CAN'T DO
IN HUMANS BUT THIS IS THE
BEAUTIFUL THING ABOUT WORKING IN
ANIMAL MODELS, YOU CAN ACTUALLY
LOOK AT CAUSALITY AND THIS
SUGGESTS THAT THE CIRCUIT MAY BE
IMPORTANT FOR KETAMINE'S
THERAPEUTIC EFFECTS ON OCD.
SO WITH THIS, YOU KNOW FEELING,
YOU KNOW HAPPY ABOUT THESE
RESULTS AND HAVING THIS SORT OF
TRANSLATIONAL MODEL TO WORK
WITH, WE TURN BACK TO SEEING IF
THERE ARE OTHER APPROACHES THAT
DON'T HAVE THE SIDE EFFECTS CAN
KETAMINE.
SO CARLOS [INDISCERNIBLE] AT NIH
AND HIS TEAM DEVELOPED A
METABOLITE OF KETAMINE CALLED
RRHNK AND IT WAS STUDIED IN
ANIMAL MODELS OF DEPRESSION AND
IS NOW UNDERGOING PHASE 2 STUDY
AND IT'S SHOWING VERY PROMISING
EARLY RESULTS THAT IT CAN HAVE
ANTIDEPRESSANT EFFECTS WITHOUT
SOME OF THE SIDE EEIVETS OF
KETAMINE.
AND SO WE'RE VERY FORTUNATE TO
BE ABLE TO DO ALSO A PHASE 2
STUDY IN PARALLEL WITH OCD.
AND THEN FINALLY WITH NIH
FUNDING BE ABLE TO DO A STUDY
LOOKING AT A STRONGER CONTROL
INSTEAD OF SALINE LIKE THE PILOT
STUDY.
WE'RE ABLE TO ELECTRIC AT AN
ACTIVE COMPARITTOR MEDAZALAM,
WHICH MIMIC THE WOOZINESS AND
FLOATY FEELING OF KETAMINE.
AND ALSO LOOK AT BIOMARKERS OF
RESPONSE EXPANDING NOT ONLY
MAGNETIC RESONANCE MICROSOPEN
MEETINGY BUT LOOKING AT FMRI TO
LOOK AT CIRCUITS INVOLVED AND
EEG TO LOOK AT NETWORK AND
SYNCHRONY TO UNDERSTAND WHERE IS
KETAMINE ACTING AND THERE ARE
ANY BIOMARKERS OF WHO RESPONDS
TO THIS.
SO I WILL BE PRESENTING THE TOP
LINE RESULTS AT ECNP THIS COMING
DECEMBER AND SO STAY TUNED THERE
WILL BE A LOT OF WONDERFUL DATA
AND RESULTS THAT COME OUT OF
THIS STUDY.
SO TURNING NEXT TO MECHANISMS OF
KETAMINE, 1 OF THE THINGS WE
FIND IS THAT THERE'S THIS KIND
OF EUPHORIC FEETING FOR KETAMINE
IN THE BEGINNING AND THERE ARE
ALSO LOCKER LASTING EFFECTS, SO
WE WANTED TO TRY AND UNDERSTAND,
IS THIS KIND OF RUSHED THIS
EUPHORIA, IS THAT, YOU KNOW
AFFECTING THE OPIOID SYSTEM.
AS YOU KNOW KETAMINE IS ALSO A
DRUG OF ABUSE.
SO IN ORDER TO TEST THIS OUT, I
PARTNERED WITH ALAN CANNED WHAT,
AND NOLAN WILLIAMS AND
[INDISCERNIBLE] TO LOOK AT
WHETHER WE COULD USE MALTREKS
OWN WHICH IS AN OPIOID RECEPTOR
ANTAGONIST TO BLOCK, TO SEE IF
WE COULD BLOCK THIS EFFECT
ACROSS 2 CONDITIONS.
AND SO INDIVIDUALS WERE
RANDOMIZED TO EITHER GET
KETAMINE PLUS NALTREKS OWN OR
KETAMINE PLUS MA SEEB O AND THEN
THEY WERE ADDRESSED WITH THE
DEPRESSION SCALE AS LISTED HERE,
THE GREATER THE NUMBER, THE
GREATER THE DEPRESSIVE EFFECTS,
OVER THE COURSE OF A WEEK AND
THEN TO ANOTHER ADDITIONAL WEEK
AFTER AND WHAT YOU CAN SEE HERE
IS THAT KETAMINE PLUS NALTREXONE
BLOCKED THE EABT DEPRESS ANT
EFFECTS WHERE JUST KETAMINE
ALONE YOU GET THE NICE ROBUST
EFFECT.
AND THAT THE ANTAGONIST, 10UATE
THE ANTIDEPRESSANT EFFECT BUT
NOT THE DISASSOCIATATIVE
SYMPTOMS.
SO IN SUMMARY, THE OPIOID SYSTEM
ACTIVATION IS CRITICAL FOR
KETAMINE'S ANTIDEPRESSANT
EFFECTS AND 1 OF THE QUESTIONS
IS HOW DO WE
RECOGNIZE--RECONCILE THIS WITH
THE PRIOR RESEARCH IN GLUTAMATE.
SO, YOU KNOW 1 POTENTIAL
HYPOTHESIS BUT AGAIN NEEDS LOTS
OF FOLKS IN THE FIELD TO FURTHER
RESEARCH THIS, IS THAT THE
INITIAL EUPHORIC EVENTS AND
EFFECT MAY BE CATALYZED THROUGH
THE OPIOID SYSTEM BUT THEN
THERE'S A PERIOD OF TIME WHERE
THOSE EFFECTS REMAIN AND SO THAT
MAY BE WHERE THE GLUTAMATE
SYSTEM IS IMPORTANT IN DRIVING
THE TRANSIENT MAINTENANCE OF
ANTIDEPRESSANT RESPONSE THROUGH
MODULATION OF BRAIN PLASTICITY
AND CONNOR LISTED AND COLLEAGUES
HAVE INDEED SHOWN THAT DENDRITIC
SPINES ARE IMPACTED BY KETAMINE
AND PLAY A ROLE IN THE
ANTIDEPRESSANT RESPONSE.
WHAT'S REALLY EXCITING TO BE
ABLE TO STUDY AND HAVE OTHER
PEOPLE CONTRIBUTE TO OUR
UNDERSTANDING OF THE KETAMINE'S
MECHANISM OF ACTION.
ONE AREA THAT IS NOT YET
STUDIED, IS WHY THIS REVERSES?
SO KETAMINE'S EFFECTS ARE
TRANSIENT.
AND SO WHAT HAPPENS TO THE
GLUTAMATE SYSTEM THAT ALLOWS IT
TO SUSTAIN BUT THEN WHERE IS IT
HAPPENING THAT HAVE YOU THIS
SORT OF OFF EFFECT.
AND CAN WE DESIGN NEW TREATMENTS
TO TRY AND CONTINUE THE EFFECTS
OF KETAMINE.
NEXT I WILL SPEAK ABOUT WORK
WE'RE DOING WITH
NEUROMODDULATION AND IT'S VERY
EXCITING AND WANT TO SHARE WITH
YOU.
SO AGAIN BEING MINDFUL AS A
CLINICIAN AND WANTING TO DO
THINGS THAT HAVE MAXIMUM
BENEFIT, RAPID AND HAVE LOW SIDE
EFFECT PROFILE, NONINVASIVE
NEUROMODDULATION IS REALLY
EXCITING DIRECTION.
AND SO, WE PARTNERED WITH NOLAN
WILLIAMS, KEEP KEITH
[INDISCERNIBLE] DRS. COLE,
[INDISCERNIBLE] AND LEEAN
WILLIAMS IN ORDER TO DO A
MULTIMODAL COLLABORATION TO TEST
WHETHER ACCELERATED DATA
BIFORTS, SO THIS IS SOMETHING
THAT NOLAN WILLIAMS AND
[INDISCERNIBLE] AN APPROACH
THEY'VE PATENTED COULD THAT BE
APPLIED TO OBSESSIVE COMPULSIVE
DISORDER.
SO THEIR EARLY WORK IN
DEPRESSION WAS REALLY
INSPIRATIONAL.
SO AS I MENTIONED, FDA HAS
APPROVED REPETITIVE TMS USING A
DEEP TMS APPROACH WITH AN H7
COIL, THE TARGET IS THE
PREMEDIAL CORTEX WITH THE
FRONTAL CORTEX BILATERALLY AND
WHAT YOU SEE HERE IS ESSENTIALLY
THE RECIPE FOR HOW THOSE DOSES
ARE DELIVERED.
SO IT'S 5 DAYS A WEEK, 20
MINUTES PER SESSION.
IT TAKES PLACE OVER 6 WEEKS, AND
PATENTS HUNDRED PULSES AND SO,
IN THIS METHODOLOGY, THEY USE
PERSONALIZED TREATMENT
PROVOCATION.
SO THEY WILL DO THE HIERARCHY
THAT I HAD MENTIONED AND TRY AND
HIT A CERTAIN LEVEL OF ANXIOUS
TO KIND OF GET THE CIRCUIT
ONLINE.
AND SO 1 OF THE MOST PROMISING
OPTIMIZATIONS FOR TRANSCRANIAL
MAGNETIC STIMULATION IS TRYING
TO SEE IF WE CAN REDUCE THE
SESSION TIME, THE DURATION,
INCREASING THE DOSE JUST LIKE WE
DO WITH MEDICATIONS, AND SEEING
IF TARGET PERSONALIZATION IS
SOMETHING THAT CAN BE HELPFUL.
SO 1 OF THE THINGS ABOUT BETA
STIMULATION IS NOT ONLY DOES IT
MIMIC NATURAL BRAIN RHYTHMS AND
IT'S AN EFFECTIVE STIMULATION
METHOD FOR THE CORTEX BUT IT
ALSO REDUCES THE TIME OF
TREATMENT WHILE KEEPING A
SIMILAR EFFICACY TO TRADITIONAL
RTMS, SO THAT'S WONDERFUL TO
HEAR, RIGHT?
IT DECREASES PATIENT BURDEN AND
THE RISKS ARE MINIMAL TO
PATIENTS.
AND THIS CARTOON HERE ON THE
RIGHT JUST SHOWS THAT DIFFERENT
KINDS OF STIMULATION THAT YOU DO
IN THE BRAIN CAN BE EXCITATORY
OR INHIBITORY AND WE CHOSE A
MODIFIED CONTINUOUS DATA BIFORT
WITH SPACED APPLICATION THAT IS
INHIBITORY IN NATURE.
AGAIN, THIS ALLOWS US TO
DECREASE THE TIME FROM 20
MINUTES TO AROUND 2 MINUTES.
AND IT ACTUALLY DRAMATICALLY
ALSO SHRINKS THE TREATMENT
DURATION SO INSTEAD OF DOING 6
WEEKS OR 3-4 WEEKS, OUR NEW
PROTOCOL THAT WE'RE DESIGNING
WERE ABLE TO DO IN 5 DAYS.
AND SIMILARLY, BECAUSE OF THE
DATA BURST STIMULATION, CAN YOU
HAVE EVEN MORE DOSE, SO INSTEAD
OF THE BRAIN SWEEP DEVICE,EE CAN
GET NEARLY 90,000 PULSES IN.
IS SO WE WERE ABLE TO USE A
PERSONALIZED TARGET APPROACH, SO
HIERARCHICAL CLUSTERING
ALGORITHM CAN BE APPLIED TO EACH
PARTICIPANTS RESTING STATE SCAN
TO IDENTIFY THOSE PERSONALIZED
SUBREGIONS.
SO IN PHASE 1, WE BRING THE
INDIVIDUAL INTO THE INNER
IMAGING FACILITY.
AND WE APPLY AN 8 MINUTE RESTING
STATE SEQUENCE, AND THEN YOU CAN
DO AN ANALYSIS, SO WE SELECT THE
RIGHT FRONTAL POLE SUBUNIT
SHOWING THE GREATEST
CONNECTIVITY ACROSS ALL THE
VENTRAL STRIATUM SUBUNITS AND
THEN PHASE 2, IS REGISTRATION
AND STIMULATION, SO THIS
IS--THIS IS IN THE SCANNER SO
THIS IS MY ACTUAL BRAIN HERE AND
LOOKING AT THE LOCALITE
NEURONAVIGATION SYSTEM TO
POSITION THE COIL AND THIS
SYSTEM ALLOWS YOU TO KIND OF
POSITION TO REGISTER WHERE IS
THE SITE YOU WANT TO STIMULATE
AND ACTUALLY POSITION THE COIL
OVER THAT PERSONALIZED TARGET.
SO THIS WAS AGAIN OUR FIRST
FORAY OPEN LABEL, MEAN ITS
DOESN'T HAVE A RANDOMIZED
CONTROL ARM OF 7 INDIVIDUALS
JUST SO SEE, COULD WE DO 5
CONSECUTIVE DAYS OF AN
ACCELERATED COURSE OF THE THETA
BUST STIMULATION TO THE RIGHT
FRONTAL POLE AND HIT UP TO
90,000 TOTAL PULSES AND JUST
SEE, IS THIS SOMETHING THAT CAN
BE OF BENEFIT TO INDIVIDUALS.
AND I WAS REALLY HEARTENED AND
THE TEAM WAS HEARTENED TO SEE IF
YOU LOOK AT THE OBSESSIVE
COMPULSIVE RATINGS SCALE WHICH I
USED BEFORE, THE HIGHER THE
NUMBER, THE MORE THE SYMPTOMS AT
DAY 0 AND AT DAY 7, SO AFTER THE
5 SESSIONS WE WERE ABLE TO SEE
75% REDUCTION IN SYMPTOMS, 63,
IT WAS VERY DRAMATIC AND WHAT'S
INTERESTING THEN IF WE SEE,
WHAT'S THE DURABILITY OF THE
EFFECT, SO WE LOOK AT, YOU KNOW
2 WEEKS OUT, 3 WEEKS OUT, 4
WEEKS OUT, THE FIRST INDIVIDUAL
HERE HAD A REMARKABLE DURABILITY
OF THE EFFECT, AND NO LONGER
MEETS CRITERIA FOR SYMPTOMATIC
OCD SYMPTOMS.
SOME INDIVIDUALS THOUGH,
DIDN'T--DIDN'T HAVE ANY EFFECTS
AND SOME HAD EFFECTS THAT TOOK A
WHILE AND SOME HAD EFFECTS THAT
STARTED IMMEDIATELY BUT THEN
WENT AWAY.
LOOKING AT THE SIDE EEIVETS IT
WAS REALLY WONDERFUL TO SEE
THERE WERE VERY FEW.
SO IT WAS REMARKABLY WELL
TOLERATED HEADACHE RESOLVE
INDEED 1-3 DAYS POST SIMULATION
START.
AND FATIGUE RESOLVED IN 1-3
DAYS.
AND AS A CLINICIAN THIS IS WHAT
WE WANT TO SEE.
THERE WERE NO SERIOUS ADVERSE
EVENTS.
SO AGAIN THE CAVEAT IS A VERY
SMALL OPEN LABEL PILOT BUT WE
WANTED TO SEE IF WE COULD JUST
EXPLORE AND GET A SIGNAL OR
BIOMARKERS OF COGNITIVE CONTROL.
SO I MENTIONED THAT IN OCD,
THERE'S THIS KIND OF HYPER
ACTIVE CIRCUIT, AND 1 OF THE
HYPOTHESIS IS THAT WITHOUT A
STOP SIGNAL, SO WITHOUT HAVING
THE COGNITIVE CONTROL MACHINERY
TO STOP THOSE THOUGHTS, THAT'S
WHAT'S SORT OF BOMBARDING
PATIENTS LIKE JOHN WITH THESE
THOUGHTS.
AND SO, WHAT WE LOOKED AT IS A
TASK THAT ACTUALLY ALLOWS YOU TO
LOOK AT COGNITIVE CONTROL AND WE
SHOWED THAT RESPONDERS SHOWED
GREATER DECREASE IN DORSAL
LATERAL PREFRONTAL CORTEX DURING
THE COGNITIVE CONTROL TASK
FOLLOWING THE PROTOCOL.
AND SO IN SUMMARY, WE SAW ROBUST
AND RAPID, SO 5 OUT OF 7 OF
THOSE INDIVIDUALS, 71% AT LEAST
50% REDUCTION WITHIN 7-14 DAYS.
IT WAS--SUSTAINED IN THE SUBSET,
SO 3 OUT OF 5 HAD THESE EFFECTS
THAT LASTED UP TO 4 WEEKS.
AGAIN, SORT OF THINKING ABOUT
THINGS IN TRANSLATION AND
CLINICAL APPLICATION, IT WAS
WONDERFUL IT WAS NONINVASIVE, IT
HAD MINIMAL AND TRANSIENT SIDE
EFFECTS.
AND AGAIN, BIG CAVEAT THIS NEEDS
TO BE REPLICATED AND SNEEDS A
SHAM CONTROL BUT HEARTENING TO
SEE AND THERE ARE MORE QUESTIONS
TO EXPLORE.
SO WHY DO SOME BUT NOT ALL
PATIENTS RESPOND?
AND WHY DO SOME HAVE PEAK
RESPONSES AT DIFFERENT TIMES AND
OTHERS HAVE MORE DURABLE
RESPONSE.
SO I JUST WANT TO SAY THAT THIS
IS WHAT REALLY--THAT REALLY
DRIVES AND MOTIVATES ME, SO
JOHN, WAS ABLE YOU KNOW AFTER
DOING THE KETAMINE STUDY,
REDUCES SYMPTOMS, HE WAS ABLE TO
DO COGNITIVE BEHAVIORIAL THERAPY
WITH EXPOSURE AND RESPONSE
PREVENTION AND CONTINUE WITH
MAINTENANCE TO DO WELL, WAS ABLE
TO GO BACK TO COLLEGE, ABLE TO
GRADUATE, AND THAT'S REALLY WHY
I DO THIS WORK.
ALSO IT TAKES A VILLAGE TO DO
CLINICAL RESEARCH STUDIES AND BE
IN TRANSLATIONAL TEAMS SO I'M
INCREDIBLY GRATEFUL FOR OUR
RESEARCH TEAM AND ALL OF OUR
COLLABORATORS THAT HAVE
MENTIONED AS WE'VE GONE ALONG IN
THE PRESENTATION.
CONTACT US IF YOU KNOW, WE'RE AT
STANFORD AND THE BAY AREA.
IF YOU KNOW OF SOMEBODY WHO MAY
BE INTERESTED IN PARTICIPATING
RESEARCH STUDY FOR OCD, PLEASE
E-MAIL US AT OCDRESEARCH
@STANFORD PASSPORT EDU.
I ALSO MENTIONED THE RESEARCH
AND HERING DISORDER SO E-MAIL US
AT CLUTTERHELP @STANFORD.EDU.
AND WE TRY TO HELP PEOPLE WITH
CARE, EVEN IF YOU'RE NOT
ELIGIBLE FOR RESEARCH STUDIES WE
ARE WELL CONNECTED WITH OCD
FOLKS THROUGHOUT THE UNITED
STATES SO FEEL FREE TO USE US AS
A RESOURCE IN THAT WAY.
AND FINALLY WE'RE REALLY
INTERESTED IN RESEARCH
COLLABORATIONS.
WE WOULD LOVE TO TRANSLATE
DISCOVERIES INTO NEW TREATMENTS
AND SO IF YOU'RE INTERESTED IN
BEING PART OF THIS RESEARCH WORK
OR PARTNERING WITH US, WE
DEFINITELY WELCOME THAT.
SO THAT'S IT.
THANK YOU SO MUCH.
I WILL TAKE QUESTIONS NOW AND I
WILL STOP SHARING MY SCREEN.
>> THANK YOU DR. RODRIGUEZ FOR
YOUR PASSION AND SHARING YOUR
WORK IN WHAT IS OBVIOUSLY A VERY
DIFFICULT DISEASE OR SPECTRUM OF
DISEASES.
A COUPLE QUESTIONS HAVE COME IN.
FIRST OF ALL CAN YOU TELL US
MORE ABOUT THE ROLE OF THE
PREFRONTAL CORTEX IN THE EMILY
CIBOL SYSTEM IN OCD?
YEAH.
>> YEAH, HAPPY TO DO THAT.
SO THERE'S CONVERGING MINDS OF
EVIDENCE THAT THERE IS A HYPER
ACTIVE LOOP CONSISTING OF THE
ORBITAL FRONTAL CORTEX WHICH IS
IMPORTANT FOR GENERATING
THOUGHTS, THE STRIATUM WHICH IS
IMPORTANT FOR GENERATING ABOUT
HAIEVERS AND LOOPING DOWN TO THE
THALAMUS WHICH IS A RELAY
STATION BACK TO THE ORBITAL
FRONTAL CORTEX AND IF YOU LOOK
AT NEURAL IMAGING STUDIES, THIS
REGION TENDS TO BE HYPER ACTIVE.
AND SO, THAT IS 1 OF THE MAIN
SORT OF TOPICS OF INVESTIGATION.
HOWEVER, IN THE OCD FIELD, SO
THIS WAS KIND OF LIKE THE FIRST
CIRCUIT THAT WAS HIGHLIGHTED BUT
THERE ARE A LOT OF REALLY
INTERESTING LINES AND THREADS OF
RESEARCH LOOKING AT OTHER LOOPS
AND OTHER AREAS, SO LOOKING AT
THINGS LIKE HABIT AND GOAL
DIRECTED ACTIVITY AND MANY MORE,
SO, REALLY I'VE KIND OF
SIMPLIFIED AND WE CAN FOCUS ON
THIS 1 BUT OCD IS COMPLICATED,
IT'S HETEROGEANIOUS AS WELL SO
THAT'S WHY IT'S IMPORTANT TO
HAVE RESEARCH AND SORT OF
PRECISION AND BIOMARKERS TO
FIGURE OUT WHO HAS THESE SORT OF
UNDERLYING CIRCUIT CHANGES AND
WHO MIGHT NOT.
SO WHO MAY BENEFIT FROM WHAT
TYPE OF THERAPY OR NOT.
RIGHT NOW WE KNOW 1 SIZE DOESN'T
FIT ALL.
>> ALONG THOSE LINES, ACTUALLY,
DO YOU HAVE ANY THOUGHTS ON WHY
DRUGS WORK IN SOME PATES AND WHY
CBT WILL WORK IN OTHERS?
>> THERE'S ONGOING RESEARCH.
I KNOW IF YOU LOOK AT CLINICAL
TRIALS .GOV, THERE'S A LOT OF
STUDIES LOOKINGA THE THIS, SO
WHY, YOU KNOW WE DON'T KNOW, 1
OF THE GREAT MYSTERIES, I DON'T
KNOW IF YOU'VE SEEN THE RECENT
PRESSES THAT SEROTONIN AND ITS
LINKS TO NEUROPATHOLOGY AND
PARTICULARLY IN OCD HAVEN'T BEEN
ESTABLISHED SO THERE ISN'T SORT
OF LIKE THE SMOKING--THE END ALL
BE ALL THAT SEROTONIN IS
DEFINITELY LINKED WITH OCD AND
EVEN THOUGH SEROTONIN WORKS,
SEROTONIN MODULATION WORKS FOR
OCD WE HAVEN'T PIECED TOGETHER
THE THREADS OF THAT.
SO THERE'S ACTUALLY A LITTLE BIT
MORE EVIDENCE FOR GLUTAMATE
MODULATION FOR OCD.
SO, I THINK IT'S IMPORTANT TO
UNDERSTAND THOSE NEUROBIOLOGICAL
AND CHEMICAL MECHANISMS BUT JUST
COMPLETELY ANECDOTALLY WHEN
WE--WHEN WE DID A STUDY LOOKING
AT A SINGLE INFUSION OF KETAMINE
AND THEN PARTNERING IT, THAT
WITH COGNITIVE BEHAVIORIAL
THERAPY, THE RESPONSES WERE
DIFFERENT FOR EACH OF THE
INDIVIDUALS, SOME PEOPLE HAVE
VARIABLE RESPONSE TO KETAMINE,
SOME PEOPLE HAD VARIABLE
RESPONSE TO EXPOSE AND YOU ARE
RESPONSE PREVENTION.
AND IT MAY BE THAT THERE ARE A
NUMBER OF DEFICITS THAT CAN LEAD
TO OCD AND 1 OF THE THINGS THAT
COGNITIVE BEHAVIORIAL THERAPY
RELIES ON OR WE THINK IT DOES IS
EXTINCTION LEARNING SO THE
ABILITY TO LEARN THAT ANXIETY
GOES DOWN OVER TIME BUT WHAT IF
THE UNDERLYING NEUROBIOLOGY OF
THAT IS SOMEHOW BROKEN OR
DAMAGED?
THOSE PEOPLE MAY NOT BENEFIT
FROM COGNITIVE BEHAVIORIAL
THERAPY, SO THESE TYPES OF
STUDIES THAT SORT OF CAREFULLY
LOOK AT MULTIPLE HYPOTHESIS AT
THE SAME TIME AND BY O MARKERS
OF RESPONSE MAY HELP US GET TO
THIS QUESTION.
>> THANK YOU.
>> AND THAT GETS TO ANOTHER
QUESTION AS FAR AS A
MULTIPRONGED APPROACH TO OCD.
REGARDING KETAMINE MEDICATION
AND THE RAPID EMELIORATION OF
OCD SYMPTOMS IN THAT STUDY WHERE
CONSURRENT MEDICATION IS USED
AND IF SO HOW DID THAT AFFECT
DURABILITY TO THE RESPONSE?
>> SAY THE FIRST PART AGAIN?
>> YEAH, SO WITH THE REGARDING
KETAMINE INFUSION AND RAPID
EMELIORATION OF THE OCD SYMPTOMS
WHERE CONCURRENT MEDICATIONS
CONTINUED OR--
>> YEAH, YES, SO IN THAT STUDY
AND TO GIVE BACKGROUND.
SO THERE'S ALSO A STUDY DONE, AN
OPEN LABEL STUDY BY A GROUP AT
YALE, MICHAEL--LED BY MICHAEL
BLOCK AND THEY DID AN OPEN LABEL
STUDY OF IN-PATIENT WHO IS HAD
OCD AND MAJOR DEPRESSION.
AND WHAT THEY FOUND IS THAT
KETAMINE DECREASED DEPRESSIVE
SYMPTOMS BUT NOT THE OCD
SYMPTOMS THAT MUCH BUT WHAT'S
INTERESTING IN THAT STUDY IS
THAT PEOPLE WERE ON CONCOMITANT
MEDICATIONS SO AT THE SAME TIME
THEY WERE TAKING SRIs, TAKING
GLUTAMATE MODULATORS AND THE
EFFECTS WERE NOT ROBUST.
AND SO I'VE ALWAYS HAD THIS
HYPOTHESIS ON WHAT LED TO THE
STUDY IS THAT I WONDERED IF
THOSE DRUGS THAT THEY WERE
TAKING WERE ACTUALLY INTERFERING
WITH THE RESPONSE.
SO THAT'S WHY THAT STUDY WAS
DONE AS CLEAN AS POSSIBLE SO
PEOPLE WERE NOT ON ANY KIND OF
MEDICATIONS AND WE WERE ABLE TO
SEE THAT ROBUST RESPONSE AND
THEN IN THE STUDY, THE LARGER
NIH FUNDED STUDY, ALSO WE DID
NOT HAVE PATIENTS WHO HAD OR
WERE ON CONCOMITANT MEDICATIONS
AND DID NOT HAVE DEPRESSION AS
WELL.
--I OFTEN GET THE QUESTION OF
SHOULD I DO KETAMINE?
SHOULD I BE ON MEDICATIONS OR
NOT ON MEDICATIONS?
THESE ARE SORT OF 2 PARALLEL
QUESTIONS, RIGHT?
SO BOTH THE YALE GROUP AND OUR
GROUP, IT'S IMPORTANT TO STUDY
BOTH OF THESE PHENOMENON.
IN OUR STUDY WE'RE USING AT THE
TIMA MINE ALSO AS A PROBE, A
BRAIN FUNCTION AS WELL SO IT'S
IMPORTANT TO GET THE MOST ROBUST
RESPONSE.
>> WOULD USING THE CONCURRENT
MEDICATIONS OR IF THEY WERE
ADDED WOULD THAT AFFECT THE
DURABILITY OF THE RESPONSE, YOU
THINK?
>> I'M NOT SURE, IT'S AN OPEN
QUESTION, SO, IN THIS STUDY, WE
BASICALLY JUST STUDIED
INDIVIDUALS WHO WERE NOT ON
MEDICATION BUT WE HAVEN'T DONE A
STUDY TO SEE LIKE, IF YOU THEN
ADD MEDICATIONS BACK ON TOP OF
IT, OR REPEATED INFUSIONS OF
KETAMINE OR ADDING ON EXPOSURE
AND RESPONSE PREVENTION, SO THAT
WOULD BE--THAT WOULD BE AN
INTERESTING QUESTION, OPEN
QUESTION.
>> WONDERFUL.
ANOTHER QUESTION, SO SOME OF
YOUR WORK HAS BEEN IN HOARDING
DISORDER, WHAT'S THE DIFFERENCE
BETWEEN OCD AND HOARDING
DISORDER?
>> YEAH, SO WITH HOARDING
DISONNEREDDER WHAT'S INTERESTING
IS HISTORICALLY BECAUSE OF THE
YALE-BROWN OBSESSIVE COMPULSIVE
CHECK LIST, LIKE THE WAY YOU
OBSESS OBSESSIONS AND COMPUGZS
AND YOU LOOKA AT THESE THEMES
AND 1 OF THE THEMES WAS HOARDING
ISSUES HOARDING SYMPTOMS SO
WANTING TO KEEP ITEMS.
AND SO HISTORICALLY THAT SORT OF
BECAME PART OF 1 OF THE SUBTYPES
OF OCD AND YET, MY MENTORS AND
SENIOR FOLKS IN THE OCD FIELD
ACTUALLY EXCLUDED PEOPLE THAT
HAD THESE SYMPTOMS FROM CLINICAL
TRIALS BECAUSE THEY HAVE THIS
INIF YOUITION THAT IT WAS A
LITTLE BIT DIFFERENT AND INDEED,
HOARDING DISORDER HAS BECOME A
NEW DIAGNOSIS IN THE DSM 5 AS OF
2013 AND IT'S PHENOMENAL
LOGICALLY DIFFERENT SO YOU KNOW,
OCD YOU HAVE INTRUSIVE THOUGHTS
THAT CAUSE ANXIETY, PEOPLE WITH
HOARDING DISORDER ARE REALLY
ATTACHED TO THEIR ITEMS AND IT'S
NOT EXPERIENCES INTRUSIVE OR
DISTRESSING, THEY ARE ARE
ATTACHED TO THEIR ITEMS.
EXCUSE ME.
AND 1 OF THE OTHER KEY
CHARACTERISTICS OF HOARDING
DISORDER IS WANTING TO ACQUIRE
ITEMS SO THERE'S A LOT GOING IN,
NOT A LOT GOING OUT AND IT
RESULTS IN CLUSTER THAT
IMPAIRING LIVING SPACES SO YOU
OFTEN SEE PEOPLE WHO HAVE, YOU
KNOW THEIR BEDS, YOU KNOW, 1 OF
THE KEY THINGS WE HAVE TO SEE IS
LIKE THEY CAN'T SLEEP IN THEIR
BEDS, PEOPLE ARE JUST REALLY
HAVE A LOT OF ITEMS IN THEIR BED
OR THEY CAN'T USE THEIR KITCHEN
FOR COOKING BECAUSE THEY HAVE
THINGS INSIDE OF THE OVEN OR ON
TOP OF THE OVEN WHICH CAN ALSO
BE A HUGE FIRE HAZARD AS WELL.
SO IT'S DIFFERENT AND ALSO
THERE'S BEEN A LOT OF LITERATURE
THAT'S COME OUT, RANDY FROST AND
[INDISCERNIBLE] WERE SOME OF THE
FIRST TO SORT OF IDENTIFY
HOARDING DISORDER AND DO THE
COGNITIVE MODEL BUT SINCE THEN,
A LOT OF DIFFERENT GROUPS HAVE
SHOWN DIFFERENT NEUROBIOLOGICAL
UNDERPINNINGS OF OCD AND
HOARDING.
>> I HOPE THAT DOESN'T APPLY TO
KITCHEN JUNK DRAWERS BECAUSE
THEN I MIGHT ACTUALLY HAVE THAT.
>> YEAH, I GET THAT--I JUST WANT
TO ADDRESS THAT FOR A MOMENT
BECAUSE I GET THAT A LOT BECAUSE
PEOPLE SEE HOARDING, HOARDING
DISORDER REFLECTED IN THEMSELVES
IN TERMS OF CLUTTER BUT IT'S
SOMETHING THAT ATTACHMENT TO
ITEMS IS SOMETHING THAT AFFECTS
ALL OF US.
AND PEOPLE WITH HOARDING
DISORDER ARE NO DIFFERENT THAN
PEOPLE WHEN ON DON'T IN TERMS OF
THEIR ASH TACHMENT TO ITEMS
RIGHT?
LIKE WE HANG ON TO THINGS
BECAUSE MAYBE THEY'RE USEFUL OR
MAYBE THEY'RE AESTHETICALLY
BEAUTIFUL, OR WE THINK THAT WE
WILL USE IT 1 DAY.
SO THAT'S THE KITCHEN RIGHT?
LIKE MAYBE I'LL USE THIS
SOMETIME BUT PEOPLE WITH
HOARDING DISORDER HAVE THAT
ATTACHMENT TO THE EXTREME SO
EVERY OBJECT IS IMBUED WITH
MEANING AND SIS 95 CANC AND SOME
OF THE PEOPLE WITH HOARDING
DISORDER TEND TO BE THE MOST
CREATIVE WAYS AS WELL BECAUSE
THEY CAN THINK OF DIFFERENT USES
FOR SOMETHING NWITH REGARDS TO
THAT, YOU KNOW IN PARTICULAR
WITH SENIOR CITIZEN AND HOARDING
DO HAVE YOU ANY COMMENTS ON
THAT?
>> YEAH, SO THERE'S BEAUTIFUL
WORK COMES OUT OF UCSD LOOKING
AT MODIFICATIONS FOR HOARDING
DISORDER TREATMENTS FOR OLDER
ADULTS AND AT THE VA AND WHAT'S
INTERESTING IS THAT THEY'RE
PAIRING COGNITIVE BEHAVIORERAL
THERAPY FOR HOARDING DISORDER
AND AND THIS IS TACKLING
THOUGHTS ABOUT HOARDING DISORDER
IN WAYS THAT MODIFY IT FOR OLDER
ADULT ANDS THEY HAVE COG FIELD
FUNCTIONSATIVE IMPAIRMENT,
CALENDARING, SORTING ORGANIZING,
THESE EXECUTIVE FUNCTIONING
SKILLS AND THEY'RE SEEING REALLY
BEAUTIFUL EFFECTS ON THAT.
THANK YOU FOR THE QUESTION.
>> PSYCHEDELICS HAVE RECEIVED
RENEWED ATTENTION IN
THERAPEUTICS IS THERE ANY ROLE
OF PSYCHEDELICS IN OCD?
>> OH RYES.
THIS IS A QUESTION I GET A LOT
AND 1 OF THE THINGS I WILL SAY
IS THAT, WELL, MAYBE I WILL
SHARE SOME SLIDES ABOUT IT
IT'S IMPORTANT FOR ME TO MAKE
SHOULDURE THAT WHEN PEOPLE ASK
ME ABOUT PSYCHEDELICS IT TOUCHES
ON THE WORK I DO IN KETAMINE.
SO, PSYCHEDELICS IS ACTUALLY A
VERY BROAD TERM AND THERE ARE
DIFFERENT CLASSES THAT SOMETIMES
GET SORT OF ALL PUT INTO THE
CATEGORY OF PSYCHEDELICS BUT
CLASSICAL PSYCHEDELICS ARE
THOUGHT TO BE THINGS THAT AFFECT
THE SEROTONIN TO A RECEPTOR AND
THEN ATYPICAL PSYCHEDELICS AND
INTACT O GENS, DISSOCKIA
TIFFANIESTHETICS AND
CANNABINOIDS GET IF THERE BUT
THEY HAVE DIFFERENT EFFECT ON
COGNITION AND EMOTION AND SOCIAL
RELATEDNESS.
AND SO INTACT O GENS FOR
EXAMPLE, IT'S CALLED A MATH O
GENERATED AND THESE ARE THINGS
LIKE MDMA, SO PEOPLE FEEL LIKE
EMPATHY BUT I'M PART OF THE
AMERICAN PSYCHIATRIC ASSOCIATION
COUNCIL ON RESEARCH AND 1 OF THE
WORK PRODUCTS THAT WE HAVE BEEN
FOCUSING ON IS TRYING TO EDUCATE
ON WHAT'S THE STATUS OF RESEARCH
FOR PSYCHEDELICS AND MENTAL
HEALTH AND IMPATHOGENS AND THESE
OTHER CLASSES.
APPROVAL OF A BAND NEW THERAPY
WHICH MEANS BEFORE FDA APPROVAL
THEY ARE GIVING THE GREEN LIGHT
FOR IT TO BE STUDIED MORE.
AND SIMILARLY WITH SILO SIGNIN
IN THE TREATMENT OF DEPRESSION,
IT'S GOT THIS BREAK THROUGH
THERAPY DESIGNATION AND THEY'RE
ALSO PROMISING DATA ON IOWASCA
BUT TO DATE THERE'S INSUFFICIENT
DATA OF FDA APPROVAL OF ANY
PSYCHEDELIC COMPOUND FOR ROUTINE
USE IN PSYCHIATRIC DISORDERSA
THE THIS TIME SO IF YOU HAVE 1
TAKE AWAY IN TERMS OF
PSYCHEDELICS AND MENTAL HELT, WE
DON'T HAVE ENOUGH EVIDENCE TO
DATE.
SO CERTAINLY THAT'S
DISPROPORTIONATE WITH THE HYPE
YOU MAY BE SEEING IN NEWS MEDIA
OUTLETS AND OTHER PLACES.
AND THEN, SPECIFICALLY IN TERMS
OF THIS CATEGORY OF CLASSICAL
PSYCHEDELICS, SILO SIGNIN AND
OCD HAS HAD SOME INITIAL
PROMISING CASE REPORTS IN AN
OPEN LABEL STUDY AND THERE'S A
GROUP AT YALE STUDYING SILO
SIGNIN GETTING PROMISING RESULTS
AND NOW LEADING ON TO A LARGER
MULTISITE STUDY PARTNERING WITH
INDUSTRY.
AND I'VE BEEN REALLY INTERESTED
IN MDMA FOR OCD AND THIS IS
AGAIN, THIS IS INDUCES PRO
SOCIAL EFFECTS AND FEELINGS OF
INTROSPECTION AND CONNECTION
WITH OTHERS.
SO I'M REALLY EXCITED THAT WE'VE
BEEN FUNDED NOW TO DO A PILOT
STUDY OF MDMA AND OCD.
AND THE IDEA HERE IS THAT YOU
KNOW, YOU KNOW COULD MDMA,
EXPOSURE AND RESPONSE PREVENTION
IS REALLY WONDERFUL THERAPY
ABOUT YOU IT'S REALLY HARD TO DO
SOMETHING THAT IS YOUR GREATEST
FEAR RIGHT?
AND SO, CBT IS TYPICALLY LIMITED
BY DROP OUT SO COULD WE PARTNER
MDMA WITH OCD IN ORDER TO GET
PEOPLE TO BE ABLE TO ENGAGE MORE
WITH THIS VERY EFFECTIVE THERAPY
OR COULD MD MA EVEN BY ITSELF BE
HELPFUL FOR OCD?
WE KNOW MDA IS KNOWN TO MODIFY
SOCIAL CUES AND INCREASE
ACTIVITY IN THE NUCLEUS SERIES
POINTS CUM BENS WHICH IS
IMPLICATED IN OCD.
SO WE'RE REALLY EXCITED ABOUT
THAT WORK.
SO THANK YOU FOR ASKING.
>> THANK YOU.
AND THE FINAL QUESTION WE HAVE
HERE GOOD TO WRAP UP WITH ARE
THERE ANY NEW FDA APPROVED OCD
MEDICATIONS ON THE HORIZON?
>> YEAH, I KNOW WE'RE
PARTICIPATING IN A PHASE 3 STUDY
OF A DRUG CALLED TRIUZOL E, IT'S
AN INDUSTRY SPONSORED STUDY AND
WE PARTICIPATE INDEED THE PHASE
2 STUDY, SO THIS IS A GLUTAMATE
MODULATING DRUG THAT IS BUILDING
ON WORK WITH [INDISCERNIBLE], SO
IT HAS A MOETY THAT HAS BETTER
METRICS TAB O--IT IS METABOLIZED
BETTER THROUGH AND HAS LESS
LIVER SIDE EFFECTS THAN THE
ORIGINAL COMPOUND.
AND YOU CAN ALSO TAKE IT 1 TIENL
A DAY, SO WITH THESE KIND OF
CHEMICAL IMPROVEMENTS, NOW
THEY'RE STUDYING IT, THE PHASE 2
STUDY, WAS PRESENTED AND HAD
PROMISING ENOUGH FINDINGS THAT
THEY WENT ON TO THIS LARGER
PHASE 3 STUDY, AND SO, THAT IS
THE DRUG THAT I SEE THAT IS THE
CLOSEST TO FDA APPROVAL SO IF
THEY GET GOOD RESULTS FROM THIS
PHASE 3 STUDY, THEN IT WILL BE
THE FIRST DRUG APPROVED SINCE
THE 1990S FDA APPROVED FOR OCD.
SO THAT'S REALLY EXCITING AND,
YEAH, THANK YOU FOR THAT
QUESTION.
I'M JUST REALLY EXCITED FOR THE
HORIZON AND HOPE FOR THE FIELD
AND FOR THOSE PEOPLE WHO ARE
JUST EARLY ON MAYBE GOT
DIAGNOSED WITH OCD, THERE'S A
WHOLE WORLD OF THINGS, FIRST
LINE TREATMENTS THAT HAVE
INCREDIBLE RESEARCH, PIONEERING
NEW TREATMENTS THAT ARE, YOU
KNOW WE'RE COLLECTING DATA ON
AND SO THERE'S A LOT OF HOPE OUT
THERE.
>> WONDERFUL.
WELL DR. RODRIGUEZ, THANK YOU
VERY MUCH FOR SHARING YOUR WORK
AND OFFERING US SOME DEEPER
INSIGHTS INTO OCD, ON HOARDING,
ALSO ABOUT MY KITCHEN DRAW WHICH
IS REASSURING AS WELL?
MINE TOO!
YOU ARE NOT ALONE, SIR.
YEAH.
>> WELL, THANK YOU AGAIN AND TOO
THE NIH COMMUNITY.
WE WOULD LIKE TO WISH ALL OF YOU
A WONDERFUL AFTERNOON.
>> I JUST WANT TO MAKE A PLUG
FOR THE INTERNATIONAL OCD
FOUNDATION, NONPROFIT GROUP CAN
ANSWER A LOT OF QUESTIONS AND
LINKS TO CARE SO INTERNATIONAL
OCD FOUNDATION.
THANK YOU SO MUCH.