GOOD MORNING, EVERYONE, AND
WELCOME TO WHAT I THINK IS THE
PENULTIMATE EVENT OF THIS YEAR'S
RESEARCH FESTIVAL AND WHAT A
FESTIVAL IT HAS BEEN. I THANK
ALL OF YOU FOR BEING HERE AND I
MUST THANK BEFORE I SAY ANYTHING
ELSE THE CHEN FAMILY FOR BEING
WITH US AND FOR DR. CHEN WHO I
FEEL I KNOW PERSONALLY WHO I
JUST MET BECAUSE HIS PHOTOGRAPH
SITS VERY SQUARELY ABOVE MY DESK
AND SO YOU HAVE BEEN WITHOUT
KNOWING IT, DR. CHEN, YOU'VE
BEEN WATCHING OVER ME FOR THE
YEAR THAT I'VE BEEN THE DDIR SO
I THANK YOU VERY, VERY MUCH FOR
THAT. SO I WILL BEGIN BY
TELLING YOU A LITTLE BIT ABOUT
DR. CHEN. IT'S A LITTLE LIKE
BRINGING COALS TO NEWCASTLE
BECAUSE I SUSPECT MANY OF YOU IN
THE AUDIENCE KNOW HIM MUCH
BETTER THAN I. AND THEN I WILL
INTRODUCE THIS MORNING'S
SPEAKER. SO DR. CHEN RECEIVED
HIS PH.D. IN PHARMACOLOGY FROM
THE UNIVERSITY OF ROCHESTER. HE
HAD A VERY DISTINGUISHED CAREER.
HE WAS IN A PUBLICATION THAT
DESCRIBED THE ANALYTICAL
TECHNIQUE FOR DETERMINATION OF
INCOVER -- INORGANIC PHOSPHATE.
HE SERVED UNDER EIGHT DIRECTORS.
YOU SHOULD GET AN AWARD FOR D
DIP -- DIPLOMACY. THAT HAS TO
BE UNIQUE. HE SERVED IN MANY
ROLES AT THE NIH, HELD POSITIONS
AT THE NATIONAL HEART INSTITUTE,
THE DIVISION OF RESEARCH GRANTS.
THE NATIONAL INSTITUTE OF
GENERAL MEDICAL SCIENCES AND THE
OFFICE OF THE DIRECTOR. THEY
RANGED FROM BEING AN
INVESTIGATOR TO BEING ASSOCIATE
DIRECTOR FOR INTRAMURAL AFFAIRS
AND ACTING DEPUTY DIRECTOR FOR
SCIENCE FOR TWO YEARS. AS A
SCIENCE ADMINISTRATOR, HE REALLY
WAS KNOWN FOR HIS INNOVATION AND
FOR HIS CREATIVITY. HIS ABILITY
TO CREATIVELY SOLVE PROBLEMS AND
ISSUES. HE CAME UP WITH NOVEL
PAY AND PERSONNEL SYSTEMS FOR
SCIENTIFIC RESEARCHERS. AND
PROGRAMS FOR THE TRAINING OF
FOREIGN SCIENTISTS. AT NIH. IN
1986, DR. CHEN ESTABLISHED NIH'S
FIRST OFFICE OF TECHNOLOGY
TRANSFER. AND IT WAS THERE THAT
HE IMPLEMENTED MANY, MANY
INNOVATIVE SOLUTIONS TO THE
INTERACTION BETWEEN NIH AS A
GOVERNMENT AGENCY AND INDUSTRY
OUTSIDE OF OUR FOUR WALLS.
THINGS LIKE THE CRAY DA, THE
COOPERATIVE RESEARCH AND
DEVELOPMENT AGREEMENT REALLY HAD
ITS ORIGINS WITH DR. CHEN AND I
WOULD BET THAT MANY PEOPLE IN
THE AUDIENCE HAVE TAKEN
ADVANTAGE OF THIS SYNERGY
BETWEEN NIH AND INDUSTRY. HE
WAS KNOWN TO NIHERS FOR MANY,
MANY GENERATIONS AS A TRUSTED
AND COMPASSIONATE COUNSEL AND N
VERY DIVERSE AREAS
HE HAS EARNED THE RESPECT, THE
AD ADMIRATION BOTH HERE AT NIH
AND ACROSS THE UNITED STATES.
SO A WORD ABOUT OUR SPEAKER
TODAY. DR. CARLOS ZARATE IS NIH
DISTINGUISHED INVESTIGATOR AND
CHIEF OF THE SECTION ON
NEUROBIOLOGY AND TREATMENT OF
MOOD DISORDERS. WE'VE HAD 38
PATENT APPLICATIONS WHICH
RESULTED IN 19 PATENTS. I WILL
FOCUS ONLY ON ONE WHICH IS THE
STORY OF KETAMINE, HOW IT BECAME
TO BE KNOWN AS SPRA VAT TO
WHICH IS LICENSED IN 70
COUNTRIES SO THIS IS AN OUTLINE
OF TODAY'S TALK WHAT IS
DEPRESSION? A BRIEF HISTORY OF
PHARMACOLOGICAL TREATMENTS FOR
DEPRESSION AND SUICIDE. NEXT
GENERATION TREATMENTS FOR
DEPRESSION AND SUICIDE WITH A
FOCUS ON KETAMINE DEVELOPMENT
AND IMPLEMENTATION.
UNDERSTANDING KETAMINE'S
MECHANISM OF ACTION AS A GATEWAY
TO BETTER THERAPEUTICS IN THE
FUTURE OF RAPID ACTING AND
AGENTS FOR SUICIDE. SO WHAT IS
DEPRESSION? WE COMMONLY SEE A
CHECKLIST OF IF YOU HAVE THESE
MANY SYMPTOMS YOU HAVE
DEPRESSION AND HERE IT IS
ILLUSTRATED IN THIS FIGURE IT
EFFECTS ABOUT 4% OF THE POP
HAITIAN -- POPULATION WHICH IS
ABOUT 280 MILLION. IN A YEAR
THERE'S 9,000 THAT COMMIT
SUICIDE.
THERE ARE VICTIMS REQUIRE AT
LEAST ONE OF TWO SYMPTOMS.
DEPRESSED MOOD OR APATHY AND
LOST OF INTEREST WHAT WE REFER
TO ANNA DONE YA AND FOUR OUT OF
THESE FOLLOWING SYMPTOMS.
CHANGES IN WEIGHT. PSYCHO MOTOR
AGITATION, SAY KPSYCHO MOTOR
RETARDATION, EXECUTIVE FUNCTION
WHERE YOU HAVE PROBLEMS WITH
MEMORY, ATTENTION, CONCENTRATION
AND OF COURSE SUICIDAL IDEATION
WHICH CAN UNFORTUNATELY RESULT
IN SUICIDE. SO THIS IS KIND OF
WHAT WE KNOW AND IF YOU START
DOING THE MATH HERE YOU CAN FIND
THAT THERE ARE HUNDREDS OF WAYS
TO MAKE CRITERIA FOR MAJOR
DEPRESSSIVE DISORDER. WE'RE
TALKING ABOUT, THIS IS A
HETEROGENOUS CONDITION. WE
DON'T TALK ABOUT ONE DEPRESSION
BUT HUNDREDS OF DEPRESSIONS AND
WHAT NOW IS COMMONLY KNOWN AS
THAT DEPRESSION HAS SOME CORE
FEATURES. WHICH IS PROBLEMS NOT
ONLY WITH MOOD BUT BEHAVIOR,
CIRCADIAN RHYTHMS AND ACTIVITY
LEVELS THAT RESULT IN
SIGNIFICANT IMPAIRMENT AND
FUNCTION AND THOSE ARE SOME KEY
CONCEPTS THAT ARE BEING EXPLORED
IN TODAY'S RESEARCH BUT RATHER
THAN GOING THROUGH A CHECKLIST
WE SHOULD HEAR IT FROM ONE OF
OUR PATIENTS WHO I INTERVIEWED
IF THIS WORKS, AT THE WHITE
HOUSE MENTAL HEALTH EVENT LAST
YEAR AND THIS WAS FROM THE
OFFICE OF SCIENCE AND
TECHNOLOGY. IN AS A FOCUS ON
THE DISCOVERY AND THE RESEARCH
THAT HAD BEEN KNOWN IN KETAMINE
RESISTANT DEPRESSION. THIS IS
MICHELE WHO HAS SUFFERED FROM
LIFELONG DEPRESSION.
>> WELL I GUESS JUST TO START
OUT WHERE I HEADED WITH THIS
DEPRESSION IS THAT MY OLDEST SON
PASSED AWAY IN JULY OF 2020 AND
OF COURSE I EXPERIENCED SHOCK
AND INTENSE GRIEF AND THEN
WITHIN A SHORT WHILE I WAS VERY
DEPRESSED AND I JUST FELT
EXTREMELY SAD AND WORTHLESS I
DIDN'T HAVE ANY ENERGY. I FELT
EXTREMELY HOPELESS AND JUST
EMPTY AND I DIDN'T THINK I'D
EVER FEEL OKAY AGAIN. I LOST
INTEREST IN EVERYTHING.
INCLUDING MY FAMILY, FRIENDS,
AND HOBBIES AND, YOU KNOW, EVEN
THE BLUE SKY AND THE SUN. YOU
NAME IT, NOTHING WAS PLEASURABLE
ANYMORE. I WAS HAVING A LOT OF
DIFFICULTY SLEEPING. TROUBLE
THINKING. AND REMEMBERING AND
CONCENTRATING WHICH ALSO
IMPACTED MY WORK. AND THEN IT
GOT SO SEVERE I STARTED HAVING
THOUGHTS OF SUICIDES. OR
THOUGHTS OF SUICIDE AND SOME
PLANS IN PLACE.
>> CARLOS: THIS IS UNFORTUNATE
BUT WHAT WE DEAL WITH ON A DAILY
BASIS. AND WE CAN DO BETTER.
SO LET ME GO TO THE NEXT TOPIC
IS A BRIEF HISTORY OF THE
PHARMACOLOGICAL TREATMENTS FOR
DEPRESSION AND SUICIDE. SO WE
HAVE OVER 36 DIFFERENT
ANTIDEPRESSANTS. WHY DO WE NEED
ANOTHER? AND LET SUMMARIZE THIS
BRIEFLY. IT HAD A VERSE EFFECTS
WE TALKED ABOUT MICHELE, OUR
PATIENT, TALKED ABOUT SYMPTOMS
BUT IT COMES DOWN TO THE
DISRUPTION TO PERSONAL FAMILY
AND SOCIETAL IMPAIRMENT AS WELL
AND SO BEYOND THE SYMPTOMS YOU
ALSO HAVE A RISK OF SUICIDAL
BEHAVIOR AND ALTHOUGH WE HAVE
THREE DOZEN ANTIDEPRESSANTS,
THEY'RE ASSOCIATED WITH LOW
REMISSION RATES. MEANING,
SIGNIFICANT IMPROVEMENT, 30-40%
HAVE TRD OR TREATMENT RESISTANT
DEPRESSION MEANS YOU FILL
MULTIPLE DIFFERENT TREATMENTS
AND MICHELE HAS FILLED MANY T
TYPES AND TALK THERAPIES AND THE
NEXT IS THE LAG OF THERAPEUTIC
DEPRESSION AND TARGET THE
SUICIDAL THINKING. SO THIS
FIGURE SHOWS THE MAJOR
DEPRESSIVE EPISODE AND WHAT
HAPPENS IS WHEN WE INITIATE
TREATMENT WITH OUR CONVENTIONAL,
OR TARGETING OF SEROTONIN YOU
HAVE AN ANT ANTIDEPREZZIVE
EFFECT.
IT TAKES 14 WEEKS IF NOT LONGER
AND REMEMBER, NOT EVERYONE GETS
BETTER AND YOU ASK YOUR
PATIENTS, HANG IN THERE, THINGS
WILL GET BETTER.
THEY HAVE A DISRUPTION IN THEIR
SOCIAL LIFE AND ARE AT RISK FOR
SUICIDE SO NEXT GENERATION
TREATMENTS AND THIS IS NOW A
REALITY HAVE AN ONSET WITHIN
HOURS. OR A FEW DAYS AT MOST.
AND THEY'RE MORE EFFECTIVE THAN
THE PREVIOUS VERSION OF
ANTIDEPRESSANTS AND THAT IS WHAT
I'M GOING TO TALK ABOUT BUT
FIRST WE NEED TO TALK ABOUT THE
LONG AND WINDING JOURNEY OR ROAD
TO IMPROVE THERAPEUTICS AND THIS
IS WHERE THINGS STARTED. SO WE
HAVE HERE THE BY SERENDIPITY
DISCOVERY, I WON'T HAVE TIME TO
GO INTO THAT BUT THE MONOAMINE
SEROTONIN WERE FOUND TO HAVE
THERAPEUTIC EFFECTS AND THIS WAS
WONDERFUL NEWS. PEOPLE STARTED
INVESTIGATING IT LATER ON THE
ROLLOUT SIP GNATTIC AND PSYCHO
TROPIC ACTIONS AND DISEASE WAS
IDENTIFIED.
AND IN 1987, AN SSRI FLUOXETINE,
ALSO KNOWN AS PROZAC LED TO
MILLIONS OF PEOPLE RECEIVING
TREATMENT FOR DEPRESSION. AND
THAT'S A GOOD THING. BUT WHAT
HAPPENED WAS, AND THIS IS WHAT I
REFER TO AS THE TITLE ME TOO
DRUGS IS SEVERAL DIFFERENT
CLASSES OF ANTIDEPRESSANTS EACH
IN GENERAL WITH COMPARABLE
EFFICACY TO THE PREVIOUS CLASS
MAY BE BETTER TOLERATED IN TERMS
OF SIDE EFFECTS BUT THEY WERE
NOT BETTER THAN THE OLDER
VERSIONS AND SO FOR LITERALLY
SIX DECADES WE HAD WHAT WE CALL
ME TOO DRUGS OR COPYCAT DRUGS.
AND IT WASN'T THAT THE TRY WAS
NOT -- THEY WERE TRYING REALLY
HARD TO COME UP WITH NEW TARGETS
BUT THEY DID NOT RESULT IN ANY
NEW TREATMENT SO LET ME MOVE
ONTO THE NEXT PART OF THE STORY
WHICH IS NEXT GENERATION
TREATMENTS FOR DEPRESSION AND
SUICIDE WITH A FOCUS ON
KETAMINE. NOW, HERE, THE STORY
WAS THAT EVERYBODY WAS
INTERESTED IN COMING UP WITH NEW
VERSIONS AND IT STARTED BECOMING
APPARENT. INDUSTRY STARTED
LEAVING PSYCHIATRIC DRUG
DEVELOPMENT AND THE TITLES OF
THESE PIECES WERE -- IS PHARMA
RUNNING OUT OF BRAINY IDEAS.
YOU CAN SEE THE MEDICINE CAP
NET. ONLY A FEW MEDICINES
THERE. THE DRUG DEAD LOCK
PHARMA COMPANIES QUITTING.
AND THEY PREFERRED TO MOVE TO
OTHER INFECTIOUS DISEASE WHICH
WERE HIGHER PERCENTAGE RATES AND
IN THE MARKET. THESE ARE THE
CHALLENGES OF THE NEUROSCIENCE
MARKET AND THIS IS A FUNNEL YOU
PUT 10,000 MOLECULES, COMPOUNDS
AND AT THE END IF YOU'RE
FORTUNATE YOU COME OUT WITH ONE
THE COST VARY FROM STUDY TO
STUDY BUT IT'S QUITE
SUBSTANTIAL. HERE YOU CAN SEE
THE PRECLINICAL DEVELOPMENT.
PHASE ONE STUDIES. PHASE TWO.
AND WHEN YOU TRANSITION FROM ONE
TO 2A TO A LITTLE BIT LATER WE
REFER TO THIS AS THE VALLEY OF
DEATH WHERE INDUSTRY GETS OUT OF
BECAUSE IT'S TOO RISKY TO PURSUE
AND THAT HAS BEEN A CONCERN.
INTRAMURAL RESEARCH DOES FILL
THAT VOID AND I WILL TALK ABOUT
THAT IN A MINUTE BUT THIS IS THE
CLINICAL APPROVAL SUCCESS RATE
AND YOU CAN SEE THE INFECTIOUS
DISEASE FROM ONCOLOGY WHERE YOU
HAVE CLEAR TARGETS FOR
PSYCHIATRY IT'S A BIT NEBULOUS
WE RELY ON CRITERIA. AND SO WE
HAVE THE LOWEST APPROVAL SUCCESS
RATE IN CNS DISORDERS UNDER 8%.
SO THIS IS WHY SOME OF THE
REASONS THAT HAVE BEEN MENTIONED
OR SUGGESTED WHY WE DON'T GET
BETTER TREATMENTS FOR
PSYCHIATRY. SHEER COMPLEXITY OF
THE DISEASES, HIGHER -- BRAIN
FUNCTION IS HARD OR VERY
CHALLENGING TO MODEL CLINICALLY.
WE TALKED ABOUT HETEROGENOUS
CONDITIONS, HUNDREDS OF
DEPRESSION AND SO IT'S HARD TO
STRATIFY, COME UP WITH ENRICHED
SUBGROUPS. ATTRITION IN LATER
STATEMENTS -- STAGES OF THE
DEVELOPMENT AND GENETICS AND
PAYER PRESSURES AS WELL AND
THESE ARE THE REASONS THAT THE
INDUSTRY LEFT PSYCHIATRY.
COMING UP WITH SOME TARGET, THIS
WAS WORK IN AND A PAPER BY PHIL
SKOAL NICK AND PLEASE REFER TO
IT IF YOU HAVE TIME TO READ IT.
THIS IS HOW WE COME UP WITH SOME
NEW TARGETS. AN ESCAPABLE
STRESS IS A PRECLINICAL TARGET
THAT HAD BEEN EARLIER LINKED TO
DEPRESSION. THAT MEANS I
MENTIONED EARLIER SIR RAH TO
ANYONE LINKED TO DEPRESSION.
AND LATER ON IF YOU GIVE CHRONIC
TREATMENT THAT AFFECTS SEROTONIN
THEY HAVE ANTIDEPRESSANT LIKE
PROPERTIES AND PRECLINICAL MODEL
AND ALSO LATER ON DISCOVERY WAS
IN THE STRESS LED TO LTP
IMPAIRMENT AND THAT'S A MEASURE
OF PLASTICITY AND THEN THE
INVOLVEMENT OF RECEPTORS,
KETAMINE, NNDA RECEPTORS WAS
INVOLVED IN LONG-TERM PROTEN
SHAGS AND WORK BY PHIL
PSYCHOLOGICAL NICK IDENTIFIED
THAT THEY HAVE ANTIDEPRESSANT
LIKE PROPERTIES.
FANTASTIC. BUT WHAT HAPPENED
WAS NEARLY A DECADE WENT BY, NOT
MUCH HAPPENED AND I'M GOING TO
GET A LITTLE BIT BY AND HERE'S
THE GROUP BY PHIL THAT LED TO
THIS IMPORTANT BODY OF WORK
HIGHLIGHTED IN THE GREEN. A
DECADE PASSED BY WHERE INITIAL
REPORT I WILL TALK ABOUT BY BOB
BERMAN IN THE YEAR 2000 AND YOUR
GROUP IN 2006 AND THAT WILL BE
THE REST OF MY TALK.
LET ME TALK ABOUT THE KETAMINE
DRUG, AND IT'S USE. SO, CALVIN
STEPHENS WAS -- SYNTHESIZED A
BETTER VERSION OF PCP WHICH WAS
KETAMINE, KETAMINE ALSO AFFECTS
MNDA RECEPTORS. IT WAS BELIEVED
THAT PCP WOULD BE AN EFFECTIVE
ANESTHETIC AGENT BUT IT LASTED A
LONG TIME. DAYS IF NOT LONGER
AND SO SYNTHESIZE THAT AND
SOMEONE WHO PASSED AWAY WAS
INVOLVED IN THE CLINICAL
DEVELOPMENT OF THIS AND IT WAS
DESCRIBED AS A DISASSOCIATE
ANESTHETIC WHICH MEANS YOUR MIND
AND BODY ARE DISCONNECTED THERE
ONE ANOTHER AND THE ADVANTAGE OF
KETAMINE COMPARED TO OTHER
AGENTS DID NOT CAUSE CNS
DEPRESSION SO IN 1970 THE FDA
APPROVES A KETAMINE AS AN
ANESTHETIC AGENT AND IT BECAME
KNOWN AS THE BUDDY DRUG IN THE
VIETNAM WAR. WHY? BECAUSE IF
YOU HAD A BUDDY NEXT TO YOU WHO
HAD TO TREAT YOUR PAIN, YOUR
INJURY, GIVE KETAMINE AND YOU
WOULD NOT HAVE TO WORRY SO MUCH
ABOUT CNS DEPRESSION COMPARED TO
MORPHINE OR OTHER TYPES OF DRUGS
AND SO THE ERA STARTED WHERE
JOHN LILLY AND OTHERS, YOU
PROBABLY KNOW ABOUT THAT,
STARTED USING IT IN THE
COMMUNITY TO EXPERIMENT IN IT
AND ALSO A COMBINATION OF
THERAPY AND IT'S SUMMARIZE THIS
HAD THE KETAMINE PAPERS AND EVEN
THERE'S PORTRAITS THAT DEPICT
THIS TIME WHERE YOU CAN SEE
HERE, THIS IS REFERRED BY --
THIS IS A PAINTING BY MARISSA
BASSET AS THE KET XHEEN TIGER.
YOU CAN SEE HERE THAT THIS IS
THE UNIVERSE, THIS IS THE K
HOLE, WHAT A CERTAIN EXPERIENCE
EVERYTHING AROUND YOU IS YOU
DON'T SEE.
YOU JUST FOCUS ON THE TUNNEL.
AND THIS IS YOUR BRAIN ON THE
DRUG AND THE TWO HERE HAVE
EFFECTS ON THE BRAIN AND ONE IS
THE UNITY OF CONNECTION WITH THE
UNIVERSE. AND THAT, YOU KNOW,
BY DOSES, THE RIGHT DOSE OF
KETAMINE YOU CAN CONTROL THE
TIGER AND THAT WAS BELIEVED TO
BE THE CASE. NOW LET'S LOOK AT
THERE VERY GENERAL OVERVIEW OF
THE RAPID ACTING -- THE
DEVELOPMENT OF THE RAPID ACTING
ANTIDEPRESSANT KETAMINE FOR
SEVERE DEPRESSION AND IT WAS
DESCRIBED THAT KETAMINE AND PCP
WERE A RECEPTOR ANTAGONIST. AND
THEN YALE HAD BEEN STUDYING
KETAMINE FOR OVER A DECADE AS A
MODEL FOR PSYCHOSIS AND FOR
ADDICTION AND THEY WERE LOOKING
AT COGNITION AND ALL OF A SUDDEN
THEY FOUND IN SEVEN PATIENTS,
STORY STARTED WITH SEVEN
PATIENTS THAT THEY GOT BETTER IN
A FEW HOURS. SO THAT IS RAPID
AND PRESENT EFFECTS BUT THIS IS
MAJOR DEPRESSION AND I'M GOING
TO GET INTO THAT -- THE
DIFFERENCE WITH TREATMENT
RESISTANT DEPRESSION SO IN THE
YEAR 2000 DENNIS AND -- WHO IS
NOW DEAN OF DEANS AT MOUNT SINAI
AND ANOTHER WHO WAS WITH THEM
CREATED THE MOOD DISORDERS
PROGRAM AND I WAS HIRED IN THE
YEAR 2000 AND I CAME AS A STAFF
CLINICIAN AND THEY SAID YOU HAVE
A RESEARCH UNIT AND CAN DO WHAT
YOU WANT AND TRY TO COME UP WITH
BETTER TREATMENTS AND SO I WAS
DELIGHTED TO LEAVE WHERE I WAS
AND COME TO THE NIH AND THE
WARREN MAGNUS SON CLINICAL
CENTER. I'VE BEEN IN TWO
CLINICAL CENTERS.
WE'VE BEEN DOING THIS RESEARCH
FOR CLOSE TO TWO DECADES WE
SAID, LET'S DECIDE DO WE GO ON
THE MONOALLERGIC PATHWAY LOOKING
AT EPINEPHRINE OR DO WE GO IN A
NEW DIRECTION.
WE SAID LET'S GO IN A NEW
DIRECTION AFTER THE PLASTICITY
AND GLUTAMATE. THIS IS A
PICTURE OF THE BAG, THE SALINE
SOLUTION, WHY DO YOU PRESENT
THIS AT A DISTINGUISHED LECTURE?
IT'S THE FIRST BAG OF THE FIRST
SUBJECT THAT WENT INTO KETAMINE
SO YOU GIVE THE -- YOU PUT IT IN
THERE AND THE SOLUTION AND WHAT
HAPPENS IS THAT THE REST IS
HISTORY. SO 2006, WE PUBLISHED
THE FIRST PREPARE TREATMENT
RESISTANT DEPRESSION WE KNFOCUS
ON THIS, MAINLY FOR ETHICAL
REASONS, AND THE OTHER BIG NEED
FOR TREATMENT RESISTANT
DEPRESSION TREATMENTS. AND THE
OTHERS THAT THERE HAD BEEN MANY,
MANY REPORTS OF RAPID ACTING
AGENTS IN DEPRESSION. THE
PROBLEM IS THAT THERE'S A HIGH
PLACEBO EFFECT AND SO YOU HAVE
TO SHOW THAT IT'S -- YOU'RE
REALLY GETTING IT AT A LARGE
EFFECT SIZE HERE. WE CONNECT
THE RESEARCH ON THREE WEST IN
THE OLDER BUILDING AND IN THE
SOUTHEAST NORTH SIDE. AFTER
THAT AND WE DID THREE
INDEPENDENT CONTROLLED STUDIES
HERE INTRAMURALLY AND THERE HAD
BEEN UNTIL 2013 NO INDEPENDENT
REPLICATION IN A CONTROL STUDY.
CASE SERIES, YES BUT NOT CONTROL
STUDY AND THAT WAS DONE -- AND A
TWO SITE STUDY WHICH I WILL
REVIEW BRIEFLY AND THEN OF
COURSE IN 2019 YOU CAN SEE IT
GOES FROM THE BAG, SALINE
INFUSION TO INTRANASAL
ADMINISTRATION. KNOWN AS BRO
HAVE AED DO. SO WHAT ARE THE
CHALLENGES IN THE BEGINNING OF
STUDYING KETAMINE AND LET ME
WALK YOU BACK IN THAT IN TIME
BUT FIRST OF ALL YOU HAVE THIS
CARTOON, KETAMINE BINDS TO THE
PCP SITE, SORRY, HERE. WITHIN
THE PROTEIN WHICH IS HARD TO SEE
FROM HERE AT LEAST AND YOU HAVE
IN RED OR ORANGE YOU HAVE S
KETAMINE THAT BINDS WITHIN ITS
POCKET. TO TWO AMINO ACIDS, ONE
IS AT THE RECEPTOR WHICH IS 646
AND AT THE GLYCINE SITE 616 IS
THE OTHER AMINO ACID AND
BELIEVED TO TRIGGER THE DOWN
CASCADE EFFECTS OF KETAMINE.
IT'S CLASSIFIED AS A
DISSOCIATIVE ANESTHETIC, AHA
LEWIS -- HALLUCINOGEN. AND TWO
THINGS OF THE BIOAVAILABILITY
ONE IS 100% IF YOU GIVE IT
INTRAVENOUS AND INTRANASAL IT'S
ABOUT HALF OF THAT. AND WE'LL
COME MORE TO THEM LATER ON NOW
THE INTERESTING PART IS HOW WE
GOT THERE. SO RESEARCH, LET'S
TALK ABOUT SOME OF THE HURDLES
WHY DON'T WE PURSUE OTHER
TARGETS BACK THEN BECAUSE THIS
IS TOO COMPLEX, SEROTONIN,
DOPAMINE, IT HAD BEEN ABANDONED
RESEARCH. NOTHING WENT ON FOR A
YEAR EVEN AFTER THE BERMAN
STUDIED IT WAS FINISHED IN THE
LATE 1990S, ALMOST A DECADE HAD
GONE BY AND YOU WILL SEE WHY.
THE CONCERN OF COURSE IS SAFETY,
SAFETY, SAFETY WE WERE
DEVELOPING A NEW PROGRAM AND THE
LAST THING IS TO DEVELOP
SOMETHING CONTROVERSIAL. WILL
THIS JUST BE AN INTERESTING
DISCOVERY OR IS THERE A REAL
PATH TO THE CLINIC? THE NEXT
CHALLENGE WOULD BE
ADMINISTRATIVE. IT'S AN
ANESTHETIC AGENT. AND YOU HAVE
PATIENTS WHO ARE SEVERELY
MENTALLY ILL AND SUFFER. THE
TRAINING OF STAFF, WE ADMINISTER
PSYCHOTHERAPY, TALK THERAPY AND
MAYBE PILLS BUT WE DON'T GET
MUCH INTO OTHER TYPES OF
INTERVENTION UNTIL RECENTLY OF
COURSE. THE LEGAL ASPECTS OF
IT. FAILURE MODES, EFFECTS,
ANALYSIS. THIS WAS PRIOR TO THE
DEVELOPMENT OF THAT BUT IT'S A
SYSTEM OF TRYING TO IDENTIFY
WHERE THINGS COULD GO WRONG AND
THERE'S SO MANY AREAS THAT COULD
HAVE GONE WRONG. CULTURE. THE
UNIT THAT I TOOK OVER WAS DOING
A LOT OF PSYCHOTHERAPY BACK
THEN. SOME MEDICATION
CHALLENGES BUT NOTHING TO THIS
DEGREE AND THEN OF COURSE
THERE'S THE ETHICAL. OUR
PATIENTS SUFFER ALREADY. YOU
HEARD FROM MICHELE SO DO WE WANT
TO GIVE OUR PATIENTS OR EVEN IN
A TANGENT MANNER DISSOCIATIVE
SIDE EFFECTS. THERE'S A RISK OF
MISUSE OR ABUSE, RIGHT? AND WE
WERE STUDYING UNMEDICATED
SUBJECTS. THAT WAS THE PLAN
BECAUSE WE WANTED TO UNDERSTAND
BIOLOGY OF THE BRAIN AND
MEDICATIONS AND PLACEBO
COMPARISON. IT HAS BEEN VIEWED
IN THE COMMUNITY THAT IT'S GOOD
TO GIVE PLACEBO IF IT'S
EFFECTIVE. BUT WHAT? THERE ARE
FEW IF ANY. THE MAIN
LIMITATIONS AND THAT LEADS TO
ANOTHER DRUG WE'RE DEVELOPING IS
IT'S AN ANESTHETIC, THE
DISSOCIATIVE SIDE EFFECTS AND
THE MISUSE POTENTIAL SO FOR
ETHICAL REASONS IN OUR FIRST
STUDY, WE STUDIED AN INDIVIDUAL
WHO FAILED OVER SIX
ANTIDEPRESSANTS AND
ANTICONVULSIVE THERAPY AND MANY
HAD PREVIOUS SUICIDE ATTEMPTS
AND HERE IS QUESTION IS IF WE
GIVE ONE DOSE WHICH TARGETS THE
RECEPTOR WILL THAT BRING ABOUT
THE EFFECTS. AND THE ANSWER WAS
YES, BACK THEN. SO HERE IS THE
DEPRESSION RATE OF SKILL ORANGE
IS KETAMINE, THIS MEANS GREATER
IMPROVEMENT. YOU CAN SEE
SIGNIFICANCE AS EARLY AS A
COUPLE OF HOURS WITH ONE
ADMINISTRATION LASTING ONE WEEK
WITH ONE INFUSION AN INDIVIDUAL
WHO WERE RESISTANT IN TREATMENT
FOR DEPRESSION. THE RESPONSE
RATE MEANS YOU'RE 50% BETTER
THAN WHEN YOU STARTED AND YOU
GET 62-65%. THAT'S GOOD. BUT
IT'S AT 8-10-12 WEEKS AND IN
INDIVIDUALS WHO ARE NOT FOR
TREATMENT RESISTANT FOR
DEPRESSION. IN THE PATH YOU CAN
SEE IT TAKES A LOCK TIME -- LONG
TIME.
AND YOU CAN SEE THERE'S SOME
SUPERIOR WITHIN HOURS AND THAT
WAS, WOW, ROBUST. AND
RELATIVELY SUSTAINED
ANTIDEPRESSANT EFFECT. SO WE
WERE LIKE, VERY IMPRESSED EARLY
ON BUT AGAIN THIS IS ONE STUDY.
AND MICHELE DESCRIBES HER
EXPERIENCE.
>> SO IT WAS AMAZING, IT WAS
LIKE, LIKE THE LIGHTS WERE
TURNED ON AGAIN. AND WHAT I
MEAN BY THAT IS, YOU KNOW, I
COULD SEE COLORS AGAIN, THE SKY
WAS BLUE AND THE GRASS WAS GREEN
AND PEOPLE SEEMED ALIVE AGAIN
AND I FELT ALIVE AGAIN. AND
BEFORE THAT, IT WAS TOTALLY
ABSENT.
>> CARLOS: AND SO THAT WAS
REALLY REWARDING TO SEE THAT IN
OUR EARLIER PATIENTS AND STILL
TO THIS DAY. NEVER GOES AWAY
THAT FEELING. SO OBVIOUSLY THIS
LED TO A LOT EARLY ON MEDIA
EXPOSURE AND IN TIME, SCIENCE
HAD BEEN DEEMED ONE OF THE MOST
IMPORTANT DISCOVERIES IN 50
YEARS. THERE HAD NOT BEEN MUCH
ACCOMPLISHED IN THOSE DRUGS. WE
SAID ALL THAT IS INTERESTING BUT
HOW DO WE GET IT TO OUR PATIENTS
AND THAT IS THE REAL CHALLENGE
AND THE ANSWER, YOU KNOW, IS
SUMMARIZED HERE BUT IT'S MUCH
MORE THAN THIS BY DOING CLINICAL
TRANSLATIONAL WORK STRENGTHENING
OUR PARTNERSHIPS IN THE OFFICE
OF TECHNOLOGY TRANSFER AND
THAT'S BEEN IMPORTANT IN THE
REST OF THE JOURNEY. SO WE
CONTINUE TO TRY TO EXPLORE AND
REPLICATE THE STUDIES BECAUSE
FRANKLY VERY FEW BELIEVED THAT
EARLY ON AND DEPUTY, CLINICAL
DIRECTOR OF NIHHH DID THE FIRST
STUDY SHOWING THE DEPRESSION
SCORES, AND RED IS KETAMINE AND
BIPOLAR DEPRESSION WITHIN
MINUTES LASTING THE GOOD PART OF
THE WE WEEK VERY SIMILAR TO THE
OTHER STUDY.
AND THE NEXT REPLICATION STUDY
AS WELL. WE'RE UP TO THREE
CONTROLLED STUDIES AND THEY LOOK
VERY SIMILAR TO EACH OTHER
SUGGESTS A TRUE BIOLOGIC EFFECT.
WHAT THE TARGET IS REMAINS TO BE
DETERMINED BUT THAT WAS
INTRIGUING THAN THE YOUNG LAD
WHO WAS A PREDOC AT THE TIME
LOOKED AT ANNA DONE YA AS
IDENTIFIED BY A LACK OF PLEASURE
AND YOU HAVE LOSS OF PLEASURE
THE HIGHER THE NUMBER AND IT
IMPROVES AS YOU GO DOWN. IT
STARTS IN TWO HOURS AND LASTS
TWO WEEKS AND MORE IMPORTANT IS
A RELATIONSHIP BETWEEN THE
IMPROVEMENT AND CHANGES IN
GLUCOSE METABOLISM WITH PET
IMAGING IN THE STRAY TAMM
SUGGEST THAT'S PART OF THE
REWARD SUGGESTING HERE'S A PANEL
AREA OR CIRCUIT OR REGION THAT
MIGHT BE IMPLICATED IN THE
PROPERTIES AND THEN IN 2013,
MOVED FROM SALINE TO BEN SEW DYE
DIAZ PEOPLE AND PRETTY SIMILAR
ONSET AND OFFSET AND THERE'S
SOMETHING THERE AND IT SEEMS TO
BE PURSUED IN A MORE SYSTEMATIC
FASHION. THE NEXT AREA,
SUICIDE. WHERE THERE'S ALREADY
48,000 SUICIDES PER YEAR, 12
MILLION THINK OF SUICIDE. AND
THERE'S A MILLION PER YEAR AND
THAT'S ONE DEATH EVERY 11
MINUTES. AND SO, IN EARLIER
WORK, WE AND OTHERS IDENTIFIED
KETAMINE AS HAVING EFFECTS ON
SUICIDAL IDEATION, HIGHER NUMBER
GREATER THOUGHTS OF SUICIDE AND
RED IS THE HIGH RISK GROUP AND
YOU BRING THEM DOWN IMPROVEMENT
WITHIN 40 MINUTES AND WITH AN
INFUSION LASTING ZEN SEVEN
DAYS.
WHICH GIVES YOU TIME TO TRANSFER
PEOPLE BACK TO THEIR HOME OR GET
TREATMENT WITH THEIR PROVIDERS
IN THE COMMUNITY. AND SO, OTHER
SIGHTS REPLICATED AND
META-ANALYSIS THAT THE ONSET WAS
IN AN HOUR OR A DAY LASTING ONE
WEEK. SO REPLICATION,
REPLICATION, IMPORTANCE OF DRUG
DISCOVERY AND DEVELOPMENT. AND
SO LET'S HEAR BACK FROM MICHELE
AND HER EXPERIENCE MONTHS AFTER
KETAMINE AND SPECIFICALLY THE
FOCUS.
>> THINGS ARE GOING REALLY WELL
NOW, I'M FEELING SO MUCH BETTER
AND I HAVE AN INTEREST IN THINGS
AGAIN IN LIFE I'M BUSY PLANNING
FOR MY FUTURE INSTEAD OF
SUICIDE. I HAVEN'T HAD ANY
SUICIDAL THOUGHTS SINCE
COMPLETING THE STUDY. I
PROBABLY WILL ALWAYS STRUGGLE
WITH THE UPS AND DOWNS OF GRIEF
BUT THAT I CAN GO THROUGH AND
HANDLE THOSE WAVES IT'S JUST THE
DEEPEST HELPLESS DARK DESPAIR OF
DEPRESSION WHICH IS SO, SO
DIFFICULT TO HANDLE.
>> CARLOS: AND SO EFFICACY IS
ESTABLISHED AND ONE GOES
TOEFKTIVENESS. HOW DOES IT
BEHAVE IN THE REAL WORLD.
AND THE STUDY WAS RECENTLY
PUBLISHED THE MOST EFFECTIVE
TREATMENT IS ELECTROCONVULSIVE
THERAPY AND HERE 400 ARE
RANDOMIZED IN A NON INFERIOR
DESIGN WHICH MEANS YOU SHOW
YOU'RE AS GOOD AS THE BEST
TREATMENT AVAILABLE. AND FOR
DEPRESSION SCALES SHOW THAT
KETAMINE INTRAVENOUSLY IS
COMPARABLE TO TCT AND IN SIX
MONTHS SHOW ITS NON INFERIOR SO
IT SUGGESTS THIS IS ANOTHER
PHARMACOLOGICAL OPTION FOR
DEPRESSION IN THE COMMUNITY SO
WITH THIS BODY OF WORK WE SAY,
WOW, DO WE HAVE A PATH TO THE
MARKET IN HERE IT'S A
PARTNERSHIP BETWEEN ACADEMIA,
GOVERNMENT INDUSTRY WITH SOME OF
THE PEOPLE ALREADY MENTIONED.
THAT WE GOT TOGETHER, AND WE
SAY, LET'S TRY TO GET THIS TO
THE MARKET. SO KEEP IN MIND NOW
RECEIVING KETAMINE IS COMPOSED
OF TWO ANTI HERS. R AND S SO
WHICH ONE DO YOU CHOOSE? DO YOU
DEVELOP R OR DO YOU DEVELOP S
AND FOR A LONG STORY S WAS
DECIDED BECAUSE IT WAS THE MOST
POTENT RECEPTOR ANTAGONIST
COMPARED TO R. AND SO GOING
BACK TO OUR TRAINEES HAVE BEEN
WONDERFUL AND SPEARHEADED MOST
OF THIS WORK IS JAZZ WHO WAS A
RESEARCH FELLOW AND WENT TO
JANSON AND HELPED DEVELOP AND
WAS A LARGE PART OF THESE
STUDIES AND A LARGE PART WAS
DOES KETAMINE HAVE THESE
EFFECTS. OR DO YOU NEED A
COMBINATION? YOU CAN SEE HERE
TWO DOSES, .2 MILLIGRAMS, .4
DECREASES THE DEPRESSION SCORES,
STAY WELL FOR SEVEN DAYS SO
PRETTY SIMILAR TO THE PREVIOUS
STUDIES I MENTIONED THE NEXT
QUESTION IS, OKAY, WE HAVE
INTRAVENOUS KETAMINE BUT IT
REQUIRES NURSING,
ANESTHESIOLOGIST, THE
MONITORING, IT'S NOT PRACTICAL
FOR PSYCHIATRISTS OR
NURSE-PRACTITIONERS IN THE
COMMUNITY. THE FOCUS WAS TO
COME UP WITH INTRANASAL. THE
CHALLENGE IS 50% BIOAVAILABILITY
BUT WITH MUCH WORK IT WAS
APPROVED BY THE FOOD AND DRUG
ADMINISTRATION FOR TWO
INDICATIONS FOR ADULTS WITH
MAJOR DEPRESSION WHO HAVE
SUICIDAL IDEATION HERE IS THE
DEVICE THAT WAS CREATED. THE
TIP, YOU INSERT THE NOSE AREA,
THEN YOU HAVE THE GREEN DOTS
MEANS THAT THERE IS DRUG AND A
28 MILLIGRAMS EACH AND SO ON AND
SO FORTH. THIS IS HOW IT IS
ADMINISTERED BUT HAS TO BE
MONITORED BY SOMEONE WHO IS
TRAINED. WE DO NOT GIVE IT TO
THE COMMUNITY. THIS IS A
RELAPSE STUDY. TIME TO RELAPSE
WHERE YOU SEE HERE IF YOU -- SO,
INDIVIDUALS WHO HAVE DEPRESSION
ARE TREATED UNTIL THEY REMIT.
AND THEN THEY ARE RANDOMIZED TO
EITHER CONTINUE S KETAMINE OR
COME OFF OF IT ON TOP OF A NEWLY
STARTED ANTIDEPRESSANT AND YOU
SEE HERE THE NUMBER OF RELAPSES
IS ALMOST HALF OF THAT IF YOU
COME OFF OF IT. AND THESE
INDIVIDUALS ARE FOLLOWED FOR
MANY WEEKS OUT SO THIS IS ONE OF
THE PIVOTAL STUDIES THAT LED TO
FDA APPROVAL NOW THE FUTURE
RAPID ACTING ANTIDEPRESSANTS FOR
DEPRESSION AND SUICIDE, WE AT
THE INTRAMURAL PROGRAM 7
SOUTHEAST HERE, DO A MULTISCALE
APPROACH WHERE WE INTEGRATE A
WIDE RANGE OF CLINICAL
BEHAVIORAL OTHER TECHNOLOGIES
AND HAVE STRONG BASIC SCIENCE
COLLABORATION TO GET INFORMATION
GOING FROM THE MECHANISM OF
KETAMINE TAALL THE WAY TO BEHAVR
GOING THROUGH CIRCUITS. AND WE
HAVE LONG ENTER -- WE --
EXTRAMURAL COLLABORATORS THAT DO
THIS ON THE PRECLINICAL SIDE TO
GET A MECHANISM IN ON OUR SIDE.
WE INTEGRATE LOOKING AT
DIFFERENT TECHNOLOGIES,
ELECTROPHYSIOLOGY, DIFFERENT
TYPES OF IMAGE INSTRUCTIONAL AND
FUNCTIONAL TO GET AT HOW
KETAMINE MIGHT WORK SO THE STORY
OF KETAMINE LED TO A SURGE IN
FUNDING FOR CLINICAL STUDIES.
SUB GENERAL PREFRONTAL CORTEX
ABNORMALITIES HAVE BEEN REPORTED
WHERE YOU SEE HERE INDIVIDUAL
WITH MOOD DISORDERS BIPOLAR AND
DEPRESSION HAVE REGIONAL
REDUCTIONS IN GRAY MATTER AND
YOU SEE HERE DECREASE GLUCOSE
METABOLISM IN THE SAME REGION SO
THIS WAS INTERESTING TO THE
FIELD BECAUSE SUGGESTED THAT
THERE ARE REDUCTION IN THE
NUMBER, SIZE AND NEURONS AND
SUGGESTED THAT THERE IS ANATOMY
AND FUNCTION THAT IS DISTURBED
HERE. SO THIS LED TO OTHER
THEORIES SUCH AS DEPRESSION IS A
DISORDER OF IMPAIRED RESILIENCE
AND NEUROPLASTICITY AND THEN
WORK BY THE LATE AND NOW
DECEASED RON D. WHO CAME UP WITH
A KETAMINE INCREASE IN SPINE,
THESE ARE DENDRITES IN SPINES
UNDER CONTROLLED CONDITIONS.
AND THEN WHAT STRESS YOU CAN SEE
REDUCTION IN NUMBER SIGNS IN
SYNAPSES AND CIRCUITS AND THEN
EVENTUALLY KETAMINE INCREASED IN
THE SPINE. THIS WAS LIKE, WOW.
WORK OUT OF A LAB SHOWED HERE
THAT ACTUALLY IN RED IS STRESS.
AND KETAMINE RESTORES THEM
RATHER THAN PRODUCE NEW SPINES
SO THIS MAY BE IMPORTANT MORE
FOR THE SUSTAINED ANTIDEPRESSIVE
EFFECTS OF KETAMINE HOW DO WE
PUT THESE MECHANISMS TOGETHER?
MOOD DISORDERS ARE DISORDERS OF
PLASTICITY, EFFECTIVE SYNAPSES
AND CIRCUITS. YOU CAN SEE HERE
THE SPINES. THERE'S TWO
THEORIES ON HOW KETAMINE MIGHT
WORK. OR TWO SCHOOLS OF
THOUGHT. KETAMINE BLOCKS THE
RECEPTORS, INCREASES IN PROTEIN
SYNTHESIS WHICH LEADS TO THE
INCREASE IN SPINES, RESTORING
SPINES IN CIRCUITS. THE OTHER
THEORY THAT IS MORE INDIRECT,
YOU BLOCK AN MDMA RECEPTORS, YOU
DECREASE, GATHER EFFECTS THAT
LEADS TO EXCITATION OF CELLS,
EVOKED RELEASE OF GLUTAMATE
ACTIVATES, THAT'S THE
TRANSMITTER ACTIVATES RECEPTORS
IN MACHINERY THAT LEADS TO
PROTEIN SYNTHESIS, AND CIRCUITS.
NOW THIS IS INTERESTING BUT WE
SAID, WELL, IF YOU BLOCK
RECEPTORS YOU HAVE WHAT, MAYBE
ANESTHETIC EFFECTS AND REDUCED
POTENTIAL SO WHY NOT PRODUCE
THIS EVOKED RELEASE WITH ANOTHER
MECHANISM AND SO WE HAVE THE SON
OF KETAMINE WHICH IS HYDROXY NOR
KETAMINE WHICH DOES NOT BLOCK
BUT DOES PRODUCE THE EVOKED
RELEASE OF GLUTAMATE AND
ACTIVATES THIS MACHINERY
NECESSARY FOR INCREASED SPINES
RESTORING SYNAPSES IN THE
CIRCUITS.
I'M GOING TO SKIP THIS THIS THE
INTEREST OF TIME. HERE WE SHOW
THIS IS ANOTHER WAY OF
MEASURING. THIS IS DEG 30-50
HERTZ WHERE ONCE YOU ACTIVATE
RECEPTORS, YOU PRODUCE INCREASES
IN GAMMA POWER. IF YOU TREAT
WITH AN AMP ANTAGONIST YOU BLOCK
THE EFFECTS OF KETAMINE BUT YOU
ALSO BLOCK GAMMA POWER AND THIS
WAS OF INTEREST BECAUSE OF THE
BIOMARKER WE CAN USE IN RODENTS
AND IN HUMANS. IN HERE YOU SEE
THAT WE SEE INCREASES IN GAMMA
POWER WITH THE METABOLITE
HYDROXY FAMILIAR KETAMINE THAT
WE'RE INTERESTED IN. SO THIS IS
ONE EXAMPLE OF THE STUDY THAT
WE'RE DOING. I DON'T HAVE TIME
TO GO INTO DETAIL HERE BUT THIS
IS TO TRY TO GET AT MECHANISM WE
DO PHARMACODYNAMIC IMAGING,
STUDIES GETTING KETAMINE AND MRI
AND EEG AND THEN HIGH OR LOW
DOSE. WE OBTAIN MANY DIFFERENT
PLEASURES. WE GET MRI AND THESE
ARE WONDERFUL STAFF THAT DO ALL
THE WORK AND ARE MENTIONED
THERE. SO THE GROWING
PHARMACOLOGICAL LANDSCAPE FOR
NEXT GENERATION TREATMENT. THIS
IS AN UGLY FIGURE FROM THE PAGE
MAKER THAT I USED IN THIS PAPER
BACK THEN AND WE HAD THE
PRESYNAPTIC NEURON. WE HAD
KETAMINE AS A POTENTIAL DRUG TO
TEST. AND THIS IS FOR
ALZHEIMER'S DISEASE WHICH WE
DIDN'T FIND IN ANY PRESENT
PROPERTIES AND SO AFTER TWENTY
YEARS OF WORK HERE YOU CAN SEE
HIGH THE FIGURE LOOKS MUCH
BETTER, YOU HAVE IN THIS COLOR
REDDISH PINK, YOU HAVE ALL THE
NEW DRUG TARGETS AND NEW DRUGS
SO IT'S QUITE INTERESTING. BUT
ONE OVER HERE IS THAT THE NMDA
RECEPTOR, MANY DRUG TARGETS HAVE
UNFORTUNATELY NOT PANNED OUT AND
MANY OF THE TRIALS WE DID AND
OTHERS. THERE'S A LONG STORY TO
THAT BUT WE WERE INTERESTED IN
THE METABOLITE OF KETAMINE WHICH
DOES NOT AFFECT AT THERAPEUTIC
RELEVANT CONCENTRATIONS OF THE
RECEPTOR AND SO VERY BRIEF
HISTORY OF HYDROXY NOR KEET
MEAN. SO HERE THE THE
METABOLISM GOES INTO NOR
KETAMINE AND TO A HYDROXY NOR
KETAMINE AND RS STAY WITHIN RS.
SO YOU START BY REVIEWING
ORIGINAL PAPERS.
READING WHAT'S THERE THIS THE
LITERATURE AND WE WERE, LIKE,
OH, THIS IS TERRIBLE. WE SAID,
LIKE, NOR KETAMINE IS THE ACTIVE
METABOLITE IN HYDROXY NOR
KETAMINES AND YOU SAY, OH, END
OF REVIEW BUT IT COMES TO
INACTIVE FOR WHAT? FOR
ANESTHESIA BUT NOT DEPRESSION SO
WE DECIDED TO PURSUE THAT.
AND IF YOU REMEMBER THIS FIGURE
HERE, YOU HAVE A RAPID ONSET OF
ANTIDEPRESSANT EFFECTS. THE
SIDE EFFECTS LAST VERY SHORTLY
THE HALF LIFE OF KETAMINE IS
ONLY A COUPLE OF HOURS AND SO
WHY IS THE EFFECT LASTING ONE TO
TWO WEEKS IN THAT'S UNHEARD OF.
USUALLY YOU HAVE A DRUG. YOU
HAVE AN EFFECT AND IT GOES AWAY
IN PSYCHIATRY AND WE WONDERED
MAYBE THERE'S METABOLITES. I
TOLD YOU A LITTLE BIT ABOUT THE
HISTORY AND THIS HAS WORKED WITH
IRVING AND WE THOUGHT MAYBE IT'S
A PRODRUG. THIS IS HARD TO
STUDY BECAUSE YOU GIVE KETAMINE
AND WITHIN MINUTES IN RATS AND
IN HUMANS YOU HAVE 24
METABOLITES SO HOW DO YOU KNOW
WHAT DOES WHAT? AND THIS IS THE
STORY. WE IDENTIFIED IN OUR
PATIENTS AND I BRIEFER LY BRIEY
SHOWED YOU THE CLINICAL DATA.
AND THERE'S THIS KETAMINE
METABOLITES. AND LONG PROCESS
WE IDENTIFIED 12R 6H IN K THAT
WE DECIDED TO MOVE FORWARD. SO
HERE THE STORY IS HIGH DO WE
SEPARATE THE WEED FROM THE CHAT
TO KNOW WHAT IS RELEVANT AND NOT
RELEVANT.
SO WE INJECT KETAMINE TO A
RODENT. WE GET 24 METABOLITES
AND WITHIN A VERY SHORT PERIOD
OF TIME, YOU CAN THEN DECIDE IS
IT RESPONSIBLE, THE SIDE
EFFECTS. HOW DO YOU DECREASE
METABOLISM? SO YOU STRENGTHEN
CARBON SIX. YOU DETERIORATE IT
AND YOU CAUSE D2 OR KETAMINE AND
YOU COME ONE A NEW COMPOUND THAT
IS PHARMACOLOGICALLY SIMILAR TO
GLYCEMIC KETAMINE BUT WHEN YOU
TEST IT AND YOU SHOW THAT THE
METABOLISM IS BLOCKED AND WHEN
YOU TEST IT IN RODENTS IT
DOESN'T HAVE SUSTAINED EFFECTS
BUT IT DOES HAVE THE ABUSE
POTENTIAL IN SIDE EFFECTS.
INTERESTING SO THEN WE TAKE OUR
DRUG TO OUR 6RHR AND WE INJECT
IT IN MICE AND YOU FIND IT DOES
HAVE RAPID EFFECTS BUT DOES
INDUCE ANESTHETIC EFFECTS. AND
ACTIVATES THE RECEPTOR AS I
MENTIONED IMPORTANT TO THE
CASCADES. AND IT INCREASES
GAMMA POWER. WHICH COULD BE AN
IMPORTANT BIOMARKER HERE IN THE
STUDY. HERE WE SHOW THAT HNK
INCREASES GAMMA POWER WE SHOW IT
HAPPENS IN HUMANS SO IT'S A
CROSS SPECIES BIOMARKER WE CAN
USE IN DRUG DISCOVERY AND
DEVELOPMENT SO VERY BRIEFLY THE
SUMMARY OF THE STORY WE HAVE THE
NATURE PAPER THAT SHOWS ALL THE
EXPERIMENTS THAT I JUST
SUMMARIZED AND IT'S BEEN
REPLICATED IN OVER 30 PLUS OTHER
PAPERS VERY BRIEFLY THAT LED TO
THE KEY INNOVATION. TOXICOLOGY,
WE ESTABLISHED THAT IT WAS SAFE
AND PRODUCED ONLY LEGIONS CAUSED
BY THE ANTAGONIST. PRECLINICAL
PHASE ONE AND PHASE TWO STUDY
SUGGESTED SAFE. THE STUDIES IN
HUMANS DOES NOT SHOW IT PRODUCES
DISSOCIATIVE SIDE EFFECTS AND WE
ARE ABOUT TO START STUDIES IN
THE FALL WITH HYDROXY NOR
KETAMINE AND TREATMENT RESISTANT
DEPRESSION.
SO I'M GOING TO CONCLUDE HERE
SHOWING THAT KETAMINE, I HOPE I
CONVINCED YOU THAT KETAMINE DOES
HAVE BROAD THERAPEUTIC EFFECTS
AND SUICIDE AND ANXIETY. NOT
EVERYBODY RESPONDS TO KETAMINE I
WANT TO MAKE THAT CLEAR. BUT
WHEN YOU DO RESPOND, IT SEEMS TO
LAST. WORK BY COLLABORATORS,
ACADEMIA, INDUSTRY GOVERNMENT
HAS LED TO APPROVAL BY THE EMA
OF KETAMINE FOR TWO INDICATIONS
FOR TREATMENT RESISTANT
DEPRESSION AND SUICIDAL
IDEATION. WE THINK THAT
METABOLISM OF KETAMINE TO
HYDROXY NOR KETAMINE IS KEY AND
IMPORTANT TO ITS THERAPEUTIC
EFFECTS. WE CAN ONLY DO SO MUCH
IN PRECLINICAL STUDIES. WE HAVE
TO TEST THIS IN OUR DEPRESSED
PATIENTS TO SEE IF THIS IS THE
CASE AND IT IS UNDER DEVELOPMENT
BY MULTIPLES OF THE IMPORTANCE
OF PARTNERSHIPS IS CRITICAL SO
HERE THERE'S SO MANY TO
ACKNOWLEDGE. FIRST OF ALL ALL
THIS WONDERFUL WORK WAS DONE AT
THE CLINICAL CENTER. WOULD NOT
BE POSSIBLE WITHOUT THE SUPPORT
OF ALL THE WONDERFUL STAFF AND
THE NURSES: I'D LIKE TO THANK
THEM OUR TRAINEES. OUR
WONDERFUL 7 SOUTHEAST NURSES WHO
HAVE BEEN PART OF THE JOURNEY
FOR TWO DECADES. INTRAMURAL AND
EXTRAMURAL COLLABORATORS HERE IS
OUR STAFF AND MORE IMPORTANTLY,
AND AS IMPORTANTLY, I'D LIKE TO
THANK THE HNKERS, WE CALL
OURSELF, WE HAD WEEKLY MEETINGS
GOING BACK TO THE 2015 OR '14
AND IF YOU REMEMBER THAT VALLEY
OF DEATH WE SUPPORT EACH OTHER
TO TRY TO GET THROUGH THIS
PERIOD OF TIME. WE ARE WORKING
HARD. AND I'D LIKE TO THANK
TODD GOULD, PATRICK MORRIS FOR
THEIR COLLABORATION AND MOST
IMPORTANTLY, THANKS TO OUR
PATIENTS SUCH AS MICHELE, TO THE
FAMILIES, WHO HELPED SUPPORT OUR
RESEARCH SO. I WOULD LIKE TO
STOP THERE AND THANK YOU FOR
YOUR ATTENTION. .
>> ANYONE QUESTIONS, FEEL FREE
TO GO TO THE MICS.
>> CARLOS: ANY QUESTIONS OR
COMMENTS.
>> AUDIENCE: ABOUT 104 PATIENTS
IN A RANDOM IDEAS CLINICAL
CONTROL TRIAL.
WHICH SHOWED ALSO RAPID ONSET
AGAINST MAJOR DEPRESS I DISORDER
AND WHAT I'M WONDERING IS IF YOU
COMMENT ON THE FUTURE OF NATURAL
PRODUCTS LIKE SILL LA SAY BEN
PERHAPS IN CONJUNCTION WITH
KETAMINE THERAPY.
>> CARLOS: THANK YOU FOR THE
QUESTION. SEVERAL POINTS, ONE
IS THAT PSYCHEDELIC RESEARCH HAS
GONE ON FOR MANY, MANY DECADES
BUT IT SEEMED IN -- THERE HAVE
BEEN, YOU KNOW, STUDIES IN, YOU
KNOW, A THOUSAND STUDIES IN THE
PAST AND MANY 40,000 PATIENTS
EXPOSED TO PSYCHEDELICS AND, YOU
KNOW, FOR MANY REASONS THE LAW
AND IT BECAME A CONTROLLED
SUBSTANCE THAT KIND OF WENT AWAY
BUT IT SEEMS TO ME THAT THE
RESULTS OF THE KETAMINE DID
RESURRECT THIS IN LARGE PART
THAT IT WAS OKAY TO HAVE A DRUG
THAT PRODUCES DISSOCIATIVE SIDE
EFFECTS. I DON'T MEAN OKAY THAT
IT'S A GOOD THING BUT THAT MEANS
THAT YOU CAN HAVE A GREATER
THRESHOLD FOR TESTING OTHER
TYPES OF PRODUCTS THAT EFFECTS
THIS. AND THAT WAS VERY
IMPORTANT. THE OTHER IS THAT,
THE RECENT STUDIES, UNTIL
RECENTLY, THE STUDY YOU
MENTIONED, THE WORLD LITERATURE
HAD ONLY BEEN ABOUT 257 PATIENTS
RANDOMIZED ON THIS. AND YET,
THE AMOUNT OF ATTENTION IS
INCREDIBLE. I MEAN, IT'S TAKEN
OFF, 75 VENTURE CAPITALIST.
BILLIONS OF DOLLARS INVESTED AND
I CERTAINLY BELIEVE, YOU KNOW,
THAT IT'S IMPORTANT TO CONTINUE
TO UNDERSTAND IT BUT IT'S REALLY
TAKEN OFF VERY QUICKLY AND
THERE'S ALWAYS MY CONCERN
SOMETHING COULD GO WRONG AND YOU
COULD ARGUE THAT THE RESEARCH WE
TOOK WAS SLOW. IT TOOK A LONG
TIME. I WOULD ARGUE THAT WAS
APPROPRIATE UNDER THE ETHICAL
CONSIDERATIONS, THE SIDE
EFFECTS, THE MISUSE POTENTIAL,
AND THINGS THAT COULD GO WRONG
IN THIS SLOW AND DELIBERATE WAS
BENEFICIAL TO THE FIELD. AND SO
I THINK THAT WHAT I WOULD SAY
THAT THESE ARE INTRIGUING AND
INTERESTING RESULTS BUT WE HAVE
TO BE CAREFUL.
>> AUDIENCE: THANK YOU.
>> CARLOS: YES, NEXT QUESTION.
>> AUDIENCE: YOU SAID WITH THE
SPROE HAVE A DO YOU HAD SEVEN
DAYS OF EFFECTIVENESS SO HOW
MANY DOSAGE DO YOU HAVE TO GET
TO A REMISSION?
>> CARLOS: YEAH, SO, RIGHT NOW
THE WAY -- THERE'S A -- AN ACUTE
DOSING STRATEGY WHICH IS YOU
GIVE -- AND IT'S VERY SIMILAR
FOR THE INTRAVENOUS KETAMINE YOU
GET TWO INFUSIONS A WEEK FOR TWO
WEEKS SO THAT'S FOUR INFUSION.
SOME MIGHT GO ANOTHER WEEK AND
THEN YOU GO TO ONE INFUSION A
WEEK AND TRY TO COME UP WITH
THAT SWEET POINT FOR THAT
INDIVIDUAL. AND SO NOW THERE IS
DATA WITH SPRO HAVE A DO IN
TERMS OF SAFETY AND EFFICACY FOR
SIX AND A HALF YEARS SO THERE
IS -- IT'S OPEN LABEL DATA.
IT'S NOT CONTROLLED. SO THAT'S
GENERALLY HOW YOU PRESCRIBE IT.
>> AUDIENCE: SO YOU'RE SAYING
THAT SOME PEOPLE ARE ON, LET'S
SAY MONTHLY FOR SIX AND A HALF
YEARS OR THEY OBTAIN A REMISSION
OR WHAT DO YOU MEAN?
>> CARLOS: WHAT IS GENERALLY
TRIED IS WE TRY TO FOCUS ON
USING THE EXISTING MEDICATIONS
AND NOT TO GIVE IT CONTINUOUSLY.
YOU TRY WITH THAT, IF NOT
ANOTHER CLASS, AND IF NOT SOME
PEOPLE MIGHT NEED IT FOR LONGER
PERIODS OF TIME SO WE TRY TO
WORK ON THAT BECAUSE THERE IS
STILL NOT A LOT OF LONG-TERM
SAFETY DATA WITH SPRO HAVE A DO
OR S KETAMINE WE NEED A LARGER
AND LONGER TERM STUDY TO REALLY
KNOW WHAT THE EFFECT IS. SO WE
ALWAYS TRY WITH EXISTING
TREATMENTS AND BUILD UP TO GET
INTO THAT POINT WE WOULD NEED IT
MONTHLY BUT IF YOU DON'T MIND IT
WITHIN ONE MONTH I TRY SOMETHING
ELSE.
>> LET ME SLIP IN AT LEAST ONE
QUESTION OVER HERE. HI. FROM
ONLINE, JUST BEFORE WE GO THERE
SO FROM OUR COLLEAGUES AT NCBI,
IF ONLY R KETAMINE IS
METABOLIZED BY 2R 6R-HNK HOW
DOES IT EXPLAIN THE LASTING
EFFECTS OF S KETAMINE?
>> CARLOS: ONE IS IMPORTANT
BECAUSE OF THE TIME IS IN OUR
NATURE PAPER. WE STUDIED THE
TWO PATH, THE S AND THE R. SO
THERE'S ALSO 2S HYDROXY NOR
KETAMINE WE ALSO FOUND THAT 2 S.
WHAT WE DID FIND IS THAT THE 2S
HAS MISUSE POTENTIAL. SO IT'S
NOT DISSIMILAR FROM S KETAMINE
AND HAS THE SIDE EFFECTS OF
KETAMINE THAT IS THE MODELS THAT
OCCUR IN HUMANS AND WE WENT WITH
THE DRUG THAT WAS BETTER
TOLERATED. DID NOT HAVE THE
ABUSE POTENTIAL AND THAT WE
COULD DEVELOP AND SO THAT WAS
THE REASON. IT'S POSITIVE THERE
MIGHT BE OTHER METABOLITES WITH
OTHER EFFECTS. THAT'S A GOOD
QUESTION.
>> AUDIENCE: GOOD MORNING
DR. ZOO RAH ZARATE.
SOMETHING THAT STOOD OUT IS THAT
KETAMINE LIKES YOU SAID, AS GOOD
AS OR BETTER IN TREATMENT THAN
ECT AND I THINK THAT -- I MEAN
FROM MY UNDERSTANDING ECT IS A
PRETTY INTENSE TREATMENT I
WANTED TO KNOW AND I COMMEND YOU
FOR TAKING AS LONG AS YOU DID
BECAUSE IT IS -- IT IS FOR A
TREATMENT RESISTANT DEPRESSION
R. THE SIDE EFFECTS OF KETAMINE
AS SEVERE AS THOSE OF ECT? IN
MY EXPERIENCE OF SEEING FATIGUE,
BRAIN FOG, AFTER TREATMENT. AND
IF SO, WOULD THAT DEPEND ON THE
METHOD OF ADMINISTRATION WHETHER
IV OR NASALLY?
>> CARLOS: THANK YOU FOR THAT
QUESTION. KEEP IN MIND THAT
WHAT I HOPE I SAID WAS THAT IT
IS AS EFFECTIVE I DIDN'T SAY IT
WAS SUPERIOR EVEN THOUGH YOU MAY
HAVE NOTICED THE NUMBERS TENDED
TO FAVOR KETAMINE. BUT IS WHAT
WE REFER TO AS A NON INFERIOR
DESIGN SO IT'S NOT POWER TO SHOW
THAT ONE IS BETTER THAN THE
OTHER. THAT'S ONE POINT. ECT
IS A VERY EFFECTIVE TREATMENT
BUT THE INDIVIDUALS WERE MAINLY
OUTPATIENTS WITH NON PSYCHOTIC
DEPRESSION. IN INDIVIDUALS WHO
HAVE PSYCHOSIS IMPAIRED REALITY
TESTING AND INPATIENTS MIGHT
BENEFIT MORE FROM ECT WE DO NOT
KNOW. THOSE STUDIES HAVE TO BE
DONE. THE SIDE EFFECTS ARE
DIFFERENT. ONE CANNOT GENERALLY
SAY ONE IS BETTER THAN OTHER SO
DO YOU PREFER TO HAVE MORE
MEMORY IMPAIRMENT OR PREFER TO
HAVE MORE DISSOCIATIVE SIDE
EFFECTS WHICH ARE TRANSITORY,
KEEP IN MIND AND THE RISK OF
ABUSE POTENTIAL. A LOT OF THIS
HAS TO DO WITH SAFETY AND IT'S A
PERSONAL CHOICE. SO WHAT MORE
AND MORE PROFESSIONALS ARE DOING
IS THEY ARE REFERRED FOR ECT
BECAUSE THEY HAVE REALLY BAD
DEPRESSION. AND SAY, WELL,
WHY -- AND FOR THEM, THEY REALLY
DEPEND ON THEIR MEMORY AND THEIR
CONCENTRATION EXECUTIVE FUNCTION
WHY NOT TRY KETAMINE ONE OR TWO
DOSES BEFORE I DECIDE TO GO TO
ECT? SO IT'S REALLY ALL THE
MEDICATIONS IS BASED -- THE SIDE
EFFECTS ARE BASED UPON YOUR
INDIVIDUAL PREFERENCE.
>> AUDIENCE: I SEE. THANK YOU.
>> AUDIENCE: HI, GOOD MORNING,
THANK YOU FOR THE TALK. I HAD A
QUICK QUESTION FROM ALL YOUR
EXPERIENCE AND ESPECIALLY
CONSIDERING WHAT YOU SAW WITH
HYDROXY NOR KETAMINE DO YOU
THINK THAT THE ACTUAL MENTAL
EPISODES OF DISASSOCIATION HAVE
ANYTHING THERAPEUTIC BENEFIT
THAT COME FROM DRUGS OF KETAMINE
OR OTHER TYPES OF HALLUCINOGENIC
TYPE COMPOUNDS?
>> CARLOS: WE TAKEN ADVANTAGE OF
THE DATA WE'VE COMMITTED OVER
THE YEARS. WE LOOKED AT THAT IN
108 INDIVIDUALS WHO RECEIVED
KETAMINE UNDER THE SAME
CONDITIONS AND NOTICED THAT THE
VARIANCE, THE RELATIONSHIP OF
DISASSOCIATION WITH RESPONSE WAS
ABOUT 12-14-16%. SO IT'S STILL
IMPORTANT BUT THERE ARE OTHER
FACTORS THAT ARE IMPLICATED IN
THE RESPONSE. THE OTHER IS WE
HAD THOSE WHO RESPONDED AND
OTHERS DID NOT RESPOND AND SOME
WHO -- SORRY, ANY DISASSOCIATION
WHO RESPONDED. AND SO AFTER
REVIEWING ALL THE LITERATURE,
AND LOOKING AT DIFFERENT STUDIES
AND I THINK EVEN SPRO HAVE AED
DO HAS LOOKED AT THAT.
THEY DON'T FIND A STRONG
RELATIONSHIP BETWEEN
DISASSOCIATION AND THEIR PUT
IMEFFECTS. ONE WOULD HAVE TO
DESIGN THE SPECIFIC STUDY TO
TEST THAT QUESTION AND TO MY
KNOWLEDGE IS ONGOING AT THIS
STAGE.
THAT DOES NOT MEAN, FOR EXAMPLE,
THAT YOU CAN TAKE THIS LESSON
AND APPLY TO THE PSYCHEDELICS,
RIGHT? BECAUSE THAT WOULD BE
ANOTHER QUESTION, YOU KNOW,
WELL, IF DISASSOCIATION IS NOT
IMPORTANT THAT PROBABLY MEANS WE
DON'T NEED THESE SIDE EFFECTS ON
THE PSYCHEDELICS BUT THESE ARE
SEPARATE DRUGS, SEPARATE
COMPOUNDS, SEPARATE TARGETS AND
THOSE QUESTIONS HAVE TO BE
LOOKED AT. I THINK. THANK YOU.
>> TAKE ONE LAST QUESTION THEN,
PLEASE.
>> AUDIENCE: THANK YOU VERY MUCH
DR. ZARATE FOR YOUR GREAT
PRESENTATION. SO I JUST WANT TO
ASK, IF YOU DETERMINE THE
BINDING POCKET FOR HNK AND IF IT
IS THE SAME ONE THAT IS USED BY
KETAMINE, TO BIND INTO THE
RECEPTOR AND THE SECOND QUESTION
REGARDING THIS ONE, IF YOU HAVE
DETERMINED WHETHER THERE ARE BUY
INS, YES GENOMIC BUY INS THAT
YOU CAN REPORT NOW THAT COULD
RESULT IN THAT ME TOO DRUG LATER
O
ON:
>> CARLOS: WHAT WE KNOW IS THAT
THIS IS WITH S KETAMINE AND NDA
AN IT'S AIST -- ANTAGONIST.
THAT DOESN'T MEAN IT'S
FUNCTIONAL HI RESPONSIBLE FOR
THE ANTIDEPRESSANT EFFECTS.
KETAMINE HAS A LOT OF DIFFERENT
TARGETS. AND HYDROXY NOR
KETAMINE WE KNOW THAT REALLY
DOES NOT BLOCK AN NMDA. YOU
REALLY HAVE TO PUSH IT TO GET
ANYWHERE NEAR AN NMDA ANTAGONISM
SO WE DON'T SEE THAT AND THE
SECOND PART OF THE QUESTION.
AND WE STILL DON'T KNOW WHAT THE
TARGET MIGHT BE OF HNK.
>> AUDIENCE: OKAY. GOT IT.
PERFECT. THANK YOU.
>> CARLOS: WELL THANK YOU.
>> OKAY, I'D LIKE TO THANK YOU
FOR COMING HERE TODAY.
>> AUDIENCE: (APPLAUSE).
>> I JUST WANT TO THANK DR.
DR. ZARATE REALLY FOR A
MAGNIFICENT EXAMPLE FOR
EVERYTHING THAT NIH STANDS FOR
THE DISCOVERY OF BASIC SCIENCE
OF BIOLOGIC SYSTEMS AND THE
APPLICATION OF THOSE DISCOVERIES
TO THE RELIEF OF SUFFERING IN
PATIENTS. SO THANK YOU SO MUCH.
AUDIENCE: (APPLAUSE).