>> WELCOME TO THE 14th VIRTUAL SESSION IN THE 20th YEAR OF DEMYSTIFYING MEDICINE. USING THE BROOKLYN BRIDGE AS A LOGO, WE CONTINUE OUR COURSE IN BRIDGE BUILDING. THE COURSE IS INTENDED TO BRIDGE EXCITING DEVELOPMENTS IN MEDICINE WITH ADVANCES IN THE BASIC BIOLOGICAL AND ENGINEERING SCIENCES. THE GOAL IS TO EXCITE AS WELL AS INFORM, STUDENTS, FELLOWS, INVESTIGATORS AND PROGRAM PLANNERS, IN ADDITION, WE SEEK TO LINK SPEAKERS IN ATTENDEES WHO OFTEN DO NOT READILY COMMUNICATE THEIR KNOWLEDGE OF SCIENCE WITH EACH OTHER. USUALLY THE TOPICS INVOLVE A SPECIFIC DISEASE--CLINICIAN SCIENTISTS AND THE BASIC SCIENTISTS TODAY'S PROGRAM BRIDGES 3 MAJOR CRITICAL RELATED GLOBAL HEALTH ISSUES, THE COVID-19 PANDEMIC, DEPRESSION AND SUICIDE. DEPRESSION, SUICIDE AND COVID-19 ARE WORLD WIDE AND MANY, MANY QUESTIONS COME TO MIND: WHAT IS THE EFFECT OF COVID ON DEPRESSION AND SUICIDE? WHAT PSYCHOLOGIC AND SOCIOLOGIC PROCESSES AND BASIC NEURAL BIOLOGIC AND GENETIC MECHANISMS ARE INVOLVED? ARE THERE ANY CLUES WHICH ARE DERIVED FROM CLINICAL MANIFESTATIONS, DIAGNOSIS OR PATHOLOGY? RECALL THAT BEFORE FUNCTIONAL IMAGING OF THE BRAIN ADDICTION WAS NOT CONSIDERED A NEURAL BIOLOGIC DISEASE. IS THIS TRUE FOR SUICIDE? IF SUICIDE IS DEPRESSION ARE RESPONSES TO UNCONTROLLABLE STRESS, IS THERE A SPECIFIC NEURAL BIOLOGY FOR THIS TRANSITION AND WHY ARE THE PUBLISHED FREQUENCIES AND SUICIDE IN DIFFERENT COUNTRIES SO VARIED, FROM SOMETHING LIKE 23 PER HUNDRED THOUSAND IN EASTERN EUROPE TO .5 PER HUNDRED THOUSAND IN CARIBBEAN COUNTRIES. AND SOME DATA INDICATE THAT AMONG THE 800,000 DEATHS PER YEAR FROM SUICIDE, MEN ARE 3 TIMES MORE LIKELY THAN WOMEN TO TAKE THEIR LIVES. IN AN EFFORT TO ADDRESS THESE AND MANY OTHER QUESTIONS MULTIPLE LEVELS, ALL LEVELS OF SOCIETY AND SCIENCE PARTICIPATE, GOVERNMENTS, STRUGGLE TO PREVENT THE UNDERLYING SOCIOECONOMIC FACTORS, NEUROBIOLOGIST SEEK NEURAL MECH INFORMS AND PREDICTORS, PHARMACOLOGISTS SEARCH FOR THERAPEUTIC DRUGS, AND THERAPISTS STRIVE TO IDENTIFY UNDERLYING PSYCHOPATHOLOGY. ALL OF THESE CHALLENGES APPEAR TO BE AUGMENTED BY THE COVID-19 PANDEMIC. ARE PEOPLE WITH SUBSTANCE ABUSE PARTICULARLY VULNERABLE TO COVID-19 AND ITS ADVERSE HEALTH OUTCOMES. IF SO, WHY, AND HOW? AND AT THE BOTTOM OF THE LINE IS FINALLY, ARE ADVANCES IN NEUROBIOLOGY BEING TRANSLATED INTO BETTER TREATMENT OF PATIENTS? WE ARE FORTUNATE TO HAVE 2 WORLD EXPERTS HERE AT THE NIH, EXPERTS IN THIS SPECIFIC TOPIC OF TODAY'S COURSE. OUR FIRST SPEAKER IS NORA VOLKOW, WHO'S DIRECTOR OF THE NATIONAL INSTITUTE ON DRUG ABUSE. NIDA, SUPPORTS MOST OF THE WORLD'S RESEARCH ON THE HEALTH ASPECTS OF DRUG USE AND ADDICTION. HER RESEARCH DEMONSTRATED THAT DRUG ADDICTION IS A DISEASE OF THE BRAIN AND THAT WAS BASED ON PIONEERING PROPERTIES OF ABUSABLE DRUGS AS WELL AND SHE'S MADE MAJOR CONTRIBUTIONS TO THE NEURAL BIOLOGY OF OBESITY, ADHD AND AGING NORA GRADUATED FROM MEDICAL SCHOOL IN MEXICO WHERE SHE RECEIVED AN AWARD FOR THE BEST MEDICAL STUDENT OF HER GENERATION. SINCE THEN AT EVERY STEP IN HER CAREER, HER LEADERSHIP AND CONTRIBUTIONS HAVE RESULTED IN 1 AWARD AFTER ANOTHER, FOR EXAMPLE, HER PSYCHIATRIC RESIDENCY AT NEW YORK HOSPITAL WAS ASSOCIATED WITH AN AWARD WHERE SHE WAS 1 OF THE 10 OUTSTANDING PSYCHIATRIC RESIDENTS IN THE ENTIRE COUNTRY. MEEOF THE--MOST OF HER PROFESSIONAL LIFE WAS SPENT AT THE DEPARTMENT OF ENERGY'S BROOK HAVEN NATIONAL LABORATORY IN UPTON, NEW YORK WHERE SHE WAS DIRECTOR OF NUCLEAR MEDICINE, CHAIRMAN OF THE MEDICAL DEPARTMENT AND ALSO PROFESSOR OF PSYCHIATRY AND ASSOCIATE DEAN AT THE NEW YORK STATE MEDICAL SCHOOL AT STONY BROOK. SHE CAME TO NIH IN 2003. HER WORK IS OUTSTANDING AND RESULTED IN AWARDS INCLUDING THE OUTSTANDING--FOR OUTSTANDING GOVERNMENT SERVICE, THE FRENCH INSTITUTE OF HEALTH AND MEDICAL RESEARCH, THE CARNEGIE PRIZE IN MIND AND BRAIN SCIENCES AND ELECTION TO THE NATIONAL ACADEMY OF MEDICINE AND THE ASSOCIATION OF AMERICAN PHYSICIANS. NORA'S 1 OF THE MOST WIDELY KNOWN SCIENTISTS MAINLY THROUGH HER EXTRAORDINARY EFFORTS TO COMMUNICATE SCIENCE AND THE PROBLEMS OF ADDICTION TO THE PUBLIC. THIS EFFORT HAS BEEN RECOGNIZED WIDELY AND IN A WAY HIGHLIGHTED BY VIRTUALLY ALL THE MAJOR MAGAZINES OF OUR TIMES WHO HAVE CONDUCTED VARIOUS SURVEYS LIKE AND HAVE DESIGNATED HER FOR EXAMPLE, AMONG THE TOP HUNDRED PEOPLE WHO SHAPE OUR WORLD, AMONG THE HUNDRED MOST POWERFUL WOMEN AND THE 1 I LIKE FROM FORTUNE MAGAZINE, 1 OF 34 LEADERS WHO ARE CHANGING HEALTHCARE. SHE'S BEEN IN THE FOREFRONT OF TACKLING THE OPIOID EPIDEMIC AND MORE RECENTLY ITS RELATIONSHIP TO THE COVID-19 PANDEMIC. THE TITLE OF HER TALK IS OPIOID ARK DICTION AND OTHER SUBSTANCE ABUSE IN THE ERA OF COVID-19. NOW OR SECOND SPEAKER IS CARLOS ZARANTE, WHO IS AN NIH DISTINGUISHED INVESTIGATOR AND CHIEF OF EXPERIMENTAL THERAPEUTICS AND PATHOPHYSIOLOGY AT THE NATIONAL INSTITUTE OF MENTAL HEALTH. AND HE'S ALSO A CLINICAL PROFESSOR OF PSYCHIATRY AT GEORGE WASHINGTON UNIVERSITY. AFTER A FELLOWSHIP IN CLINICAL-PSYCHOPHARMACOLOGY AT THE MCCLAIN HOSPITAL AT HARVARD MEDICAL SCHOOL, HE BECAME DIRECTOR OF THE BIPOLAR AND PSYCHOTIC DISORDERS GROUP THERE AND LATER AT THE UNIVERSITY OF MASSACHUSETTS AND IN 2001 CAME TO NIH AND NATIONAL INSTITUTE OF MENTAL HEALTH AS CHIEF OF THE MOOD DISORDERS RESEARCH UNIT AND THE EXPERIMENTAL THERAPEUTICS PATHOPHYSIOLOGY BRANCH. CARLOS, TOO, HAS RECEIVED MANY ACHIEVEMENTS AND AWARDS, AT HARVARD, FROM THE AMERICAN PSYCHIATRIC ASSOCIATION, THE NIH DIRECTORS' AWARD AND THE BRAIN BEHAVIOR RESEARCH FOUNDATION AWARD FOR BIPOLAR MOOD DISORDER RESEARCH. HIS RESEARCH FOCUSES ON DEVELOPING NOVEL MEDICATIONS FOR TREATMENT OF RESISTANT DEPRESSION, BIPOLAR DISORDERS AND MOOD DISORDERS IN ADULTS. AND HE'S PIONEERED THE USE OF KETA MINE TO TREAT DEPRESSION AND REDUCE SUICIDAL IMPULSES. HIS TALK IS ENTITLED RISK AND RESILIENCE FOR DEPRESSION AND SUICIDE IN THE TIME OF COVID-19. WE WILL HAVE A QUESTION AND ANSWER PERIOD AFTER EACH PRESENTATION AND SO, NOW IT'S A PLEASURE TO HAVE OUR FIRST SPEAKER DR. NORA VOLKOW. >> GOOD AFTERNOON, EVERYONE AND WYNN, THANK YOU VERY MUCH FOR THE KIND INTRODUCTION AND FOR GIVING ME THE OPPORTUNITY TO MEET WITH ALL OF YOU VIRTUALLY, THIS, AMID THESE CHALLENGING TIMES. AND I THINK IT IS DRUG TAKING REFLECTS THE SUFFERING THAT IS NOT NECESSARILY IDENTIFIED AS 1 OF THE IMPORTANT RELEVANT FACTORS THAT'S DRIVING DRUG TAKING IN GENERAL. IN GENERAL AS A SOCIETY WE VIEW DRUG TAKING AS THE DESIRE TO HAVE A GOOD TIME, AND WHILE THIS MAY BE CORRECT FOR MANY PEOPLE WHEN IT INITIALLY HAPPENS IT'S SELF-LIMITING AND THESE INDIVIDUALS IN THOSE INDIVIDUALS THAT ACTUALLY HAVE AN UNDERLYING STRESS OR DEPRESSION OR CHALLENGES OR VERY ADVERSE UPBRINGING THAT DRUGS CAN TRIGGER ADDICTION WITH ALL OF ITS VERY ADVERSE CONSEQUENCES. AND THUS IT IS NOT SURPRISING THAT THE CO MORBIDITY BETWEEN DEPRESSION AND ADDICTION IS EXTREMELY HIGH AND INDEED WE KNOW THAT THERE IS ACTUALLY MORE OF AN SUSCEPTION TO DO NOT HAVE UNDERLYING ANXIETY OR UNDERLYING DEPRESSION DISORDER AND THIS OF COURSE BECOMES VERY RELEVANT AS WE AIM FOR TREATMENTS FOR IF WE WANT TO BE SUCCESSFUL IN TREATING INDIVIDUALS WITH SUBSTANCE USE DISORDERS OR IF WE WANT TO PREVENT SUBSTANCE USE, WE NEED TO ADDRESS THE MENTAL ILLNESS NEEDS OF THOSE SUFFERING FROM THESE DISEASES. NOW I WAS ASKED TO ACTUALLY--SO I WILL NOW SHARE MY SCREEN AND I WILL START BY THE SLIDES THAT INDICATE THAT I DO NOT HAVE ANY FINANCIAL DISCLOSURES TO DECLARE. I ALSO WAS ASKED TO GIVE 3 LEARNING OBJECTIVES WHICH BASICALLY, IN MY PERSPECTIVE WAS TO TRY TO GIVE YOU AN OVERALL PERSPECTIVE ABOUT WHAT ARE THE CHALLENGES WE FACE FOR THE OPIOID CRISIS IN THE UNITED STATES WHEN IT INTERSECTED WITH COVID-19 AND WHAT ARE SOME OF THE OPPORTUNITIES THAT WE HAVE TO MITIGATE THESE ADVERSE ACTIONS. NOW I MUST ALSO ASK IF YOU CAN SEE THE SLIDES AND PEOPLE ARE GOING TO THE FIRST SLIDE OF DATA? CAN YOU SEE MY SLIDES, GUYS? >> YES. >> GOOD. NOW WE HAVE BEEN BATTLING IN THE UNITED STATES, THE WORSE ADDICTION EPIDEMIC THAT WE HAVE EVER ENCOUNTERED FOR THE PAST 2 DECADES. THIS WAS AN EPIDEMIC THAT WAS TRIGGERED BY THE OVERPRESCRIPTION AND FREEDOM OF VERY LAXED PRESCRIPTION OF OPIOID MEDICATIONS THAT RESULTED IN A VERY LARGE NUMBER OF INDIVIDUALS EXPOSED TO OPIOIDS THAT SHOULD NOT BE EXPOSED TO OPIOIDS AND THE DIVERSION OF THESE DRUGS AND THIS IS EXACTLY WHERE THE WHOLE OPIOID CRISIS STARTED, THE OVERPRESCRIPTION WHICH YOU SEE IN THIS LINE OF OPIOID MEDICATIONS THAT HAD BEEN ACTUALLY AROUND SINCE THE BEGINNING OF 2000 AND IT WASN'T UNTIL 2011 THAT THE--WE ALL BECAME TOGETHER TO ACTUALLY ADDRESS THE NEED TO MODIFY THOSE PRACTICES, AND BACK AS WE SAW THE NEW GUIDELINES AND PROPERLY HOW TO USE OPIOIDS BUT ALSO ON LIMITING THE DISPENSING OF THESE DRUGS AND HIGHER OVERSIGHT. WE SOMETIMES COORDINATE THESE CONSEQUENCES BY NOT GIVING ACCESS TO THESE MEDICATIONS TO PATIENTS WITH SEVERE PAIN CONDITIONS THAT WOULD BENEFIT FROM THEM. SO THESE LED AGAIN TO AN INSTANCE OF A LEVELING TO INCREASE IN OVERDOSE DEATH THAT HAVE BEEN HAPPENING SINCE 2000. UNFORTUNATELY, AMID THE INCREASES IN DEATHS FROM PRESCRIPTION OPIOIDS, IS IT TARTED A NUMBER OF DEATHS ASSOCIATED WITH HEROIN STARTED TO RISE AND YOU SEE THAT VERY CLEARLY, CONSIST WENT A TIME WHEN THE AGENCY START TO COME UP WITH NEW GUIDELINES AND OVERSIGHT OF PRESCRIPTION OF OPIOIDS AS PEOPLE HAVE BECOME ADDICTED TO THE PRESCRINGZ OPIOIDS AND IT WAS HARDER TO GET ACCESS TO THEM, THEN YOU SAW SHIFTING OF INDIVIDUALS TO THE USE OF HEROIN, AND THAT, THAT IS WHY YOU SEE IN PARALLEL IN 2010,-2011, AN INCREASE IN THE NUMBER OF DEATHS FROM HEROIN. NOW THERE HAVE BEEN IN ADDITION TO THE CHANGING PRESCRIPTION FACTISS VERY SIGNIFICANT INTERVENTIONS TO MINIMIZE THE ACCESS TO HEROIN. DESPITE THIS AND ACTUALLY THIS HAS BEEN BENEFICIAL FOR PLATEAUING THE EFFECTS OF HEROIN OVERDOSES, WHERE WE HAVE NOT BEEN ABLE TO SEE A DECREASE IN THE MORTALITY OF THE PEOPLE OVERDOSING IN THE UNITED STATES, AND THIS IS DUE TO 2 PHENOMENA. ONE OF THEM IS THIS RED LINE HERE, THAT REFLECTS THE INCREASED ACCESS OF SYNTHETIC OPIOIDS AND ASSOCIATED WITH THE HIGHER MORTALITY RATE AND ON THE 1 HAND AND ON THE OTHER HAND THE INCREASE IN MORTALITY IN STIMULANT DRUGS AND THAT MEANS COCAINE AND METHAMPHETAMINES. AND I WANT YOU TO KNOW HOW STEEPLY THE RISE OF DEATHS ARE ASSOCIATE WIDE THESE 2 DRUGS WHICH AGAIN HIGHLIGHTS THE URGENCY TO CONTROL THEM AND THIS IS WHERE WE WERE. IN 2019 BEFORE COVID PANDEMIC HIT US, WE HAVE BEEN UNABLE AS A COUNTRY TO DECREASE THE MORTALITY ASSOCIATED WITH OPIOID OVERDOSES, DESPITE MULTIPLE--I MEAN INTERVENTIONS FOR MULTIPLE AGENCIES, THE CHALLENGES THAT NOW REMAIN, IT'S CLEAR IF WE CONTROL PRESCRIPTION OPIOIDS OR EVEN IF WE CONTROL HEROIN, THAT IS NOT SUFFICIENT TO CONTROL THE OPIOID OVERDOSE DEATHS. SO AMIDST THIS, WHAT HAPPENED WITH THE COVID PANDEMIC? ONE OF THE THINGS WE RAPIDLY REALIZE, SO MARCH CAME ALONG AND EVERYONE WAS AWARE THAT THE PROSPECT WAS QUITE, QUITE, THREATENING, WAS THAT WE DID NOT REALLY HAVE AN INFRASTRUCTURE TO PROVIDE US WITH TIMELY DATA OF WHAT WAS GOING ON IN THE OPIOID CRISIS AND WHILE BEFORE THE COVID PANDEMIC, YOU ACTUALLY HAD AN ENORMOUS AMOUNT OF ATTENTION FROM THE MEDIA ON UNDERSTANDING HOW DIFFERENT AREAS IN THE COUNTRY WERE BEING AFFECTED BY THE OVERDOSE MORTALITY, WHEN COVID CAME AROUND, ALL OF THAT WOULD DISAPPEAR FOR THE MOST PART, EVEN THOUGH OF COURSE, THE OPIOID EPIDEMIC HAD NOT DISAPPEAR, IT WAS JUST HIDING BELOW THE SURFACE OF THAT GIGANTIC TSUNAMI THAT WAS BROUGHT BY COVID-19. IN THESE CIRCUMSTANCES, THE LACK OF TIMELY DATA BECAME FRUSTRATING BECAUSE WE COULDN'T UNDERSTAND WHAT PEOPLE WERE FACING. ONE OF THE FOCUSES ON THE BEGENERATEDDING WHERE I WAS VERY OPTIMISTIC WAS WHEN WE WERE CLOSING THE BORDERS, 1 OF THE POSSIBILITIES WAS THAT THAT WOULD MAKE ACCESS TO DRUGS, LIKE FENTANYL OR HEROIN, HARD TORE COME ABOUT AND THEREFORE THAT WE MAY SEE A DECREASE IN THE MORTALITY FROM OVERDOSES BECAUSE DRUGS WERE NOT AVAILABLE. UNFORTUNATELY, NOW WE KNOW THAT WAS NOT THE CASE, AND DRUG SEIZURES ACROSS THE UNITED STATES, WHILE THEY MAY HAVE GONE DOWN SLIGHTLY IN MARCH, APRIL, THEY RAPIDLY REBOUNDED IN MAY AND JUNE AND AS OF NOW, THERE IS NO EVIDENCE THAT ACCESS OF DRUGS HAS DECREASED ACROSS THE UNITED STATES TO THE COVID PANDEMIC. WHAT HAS BECOME CLEAR IS THAT THE TYPE OF DRUGS THAT IS NOW BECOMING MORE WIDELY AVAILABLE IS MUCH MORE DANGEROUS THAN WHAT WE MAY HAVE ALREADY HAVE BEFORE COVID PANDEMIC. WHAT DO I MEAN BY THAT? LOOKING AT DATA DERIVE FRIDAY LABORATORIES THAT MAKE SURE THE CONTENT OF DRUGS IN PATIENTS THAT ARE REFER FOR TREATMENT BECAUSE OF A SUBSTANCE USE DISORDER THE LABORATORIES CAN ACTUALLY TRACK THE CHANGES IN THE POSITIVE URINES FOR THE DIFFERENT TYPES OF DRUGS BETWEEN 2019 BEFORE THE COVID PANDEMIC AND DURING THE COVID PANDEMIC AND THIS IS DATA FROM SUCH LAB RAARE TOYS, THIS IS MILLENNIAL HEALTH AND THIS IS QUEST AND SEE MARCH IS WHEN THEY CALLED THE DECLARATION OF COVID-19 A NATIONAL EMERGENCY IN THE UNITED STATES AND YOU CAN SEE THE NUMBERS BEFORE AND AFTER THE DECLARATION OF THE EMERGENCY AND THIS IS PERCENT CHANGE COMPARED TO THE 12 MONTHS PRIOR. YOU CAN SEE THE SIGNIFICANT RISE IN THESE PARTICULAR ORANGE HERE THAT REFLECTS AN INCREASE IN THE POSITIVE NUMBER OF NEURONS FOR FENTANYL WHICH AGAIN IS 1 OF THE MOST POTENT THINTHETIC OPIOIDS AVAILABLE RIGHT NOW IN THE BLACK MARKET. NOT AS MUCH AS CARFENTANYL THAT IS SO DEADLY THAT HAS LIMITED HIS OVERALL DISTRIBUTION IN THE UNITED STATES, BUT FENTANYL AGAIN, I RATE THE RATE, VERY USEFUL FOR SURGICAL PROCEDURES, EXTREMELY ADDICTIVE AND VERY, VERY LETHAL. THERE'S ALSO AN INCREASE IN THE NUMBER OF POSITIVE URINES 20% FOR METHAMILLIO FET MINES THAT MEANS MAISHTS TAKEN--THEY ARE RESPONDING FOR PATIENTS RESPONDING TO METHAMPHETAMINES, AND A 12% IN COCAINE AND 12% IN THE PATIENTS WITH HEROIN. THIS IS THE QUEST DATA IT SHOWS IT DIFFERENTLY. WHAT IT'S SHOWING YOU IS THE POSITIVITY FOR FENTANYL BEFORE THE COVID IN GREEN AND DURING COVID IN PURPLE. WHETHER IT IS A MALE OR A FEMALE, YOU CAN SEE SIGNIFICANTLY HIGHER NUMBER OF INDIVIDUALS TESTING POSITIVE FOR FENTANYL DURING THAT COVID PANDEMIC BEFORE, AND THAT IS ALSO OBSERVED ACROSS ALL OF THE AGE OF INDIVIDUALS WHOSE URINES WERE TESTED FOR DRUG CONTENT, INDEED INDICATING 1 OF THE THINGS WE HAVE OBSERVED DURING THE COVID PANDEMIC IS AN INCREASE IN POSITIVITY FOR EXTREMELY DANGEROUS DRUGS, FENTANYL AND METHAMPHETAMINE BEING THE MOST TOXIC DRUGS THAT HUMANS USE. SIMILARLY, WE ARE TRYING TO GET OUR HANDS IN TERMS OF TIMELY DATA WHAT'S GOING ON IN THE COVID PANDEMIC. THAT DATA REFLECTS DRUG USE, BUT WE WANTED TO ALSO UNDERSTAND WHAT ABOUT THE MORTALITY, WE ALREADY WERE RECORDING 76,000 DEATHS ANNUALLY OR MORE FROM OVERDOSES AND THE QUESTION WAS HOW DO THOSE PATTERNS OF DRUG USE INFLUENCE MORTALITY DATA AND THIS IS ACTUALLY DATA THAT IS COMING TRADITIONAL DATA FROM THE CDC, THAT GOES UP TO AUGUST 2020 SO IT'S NOT COVERING THE WHOLE COVID PERIOD AND THIS IS BECAUSE IT TAKES A CERTAIN AMOUNT OF TIME, AT LEAST 6 MONTHS TO ORBTIANYL THE DATA TO OVERDOSES AND CHARACTERIZE THEM AS OVERDOSES AND BASED ON THESE DATA THAT GOES UP TO OUR AUGUST 2020 AND COMPARE IT WITH 12 MONTHS THAT PRECEDE AUGUST 2019, YOU CAN ACTUALLY SEE ACROSS THE UNITED STATES, 27% INCREASE IN MORTALITY DURING THIS PERIOD. AND IF YOU LOOK AT THE TYPE OF DRUGS THAT ARE DRIVING THESE MORTALITY, AGAIN, YOU SEE THESE PATTERN OF PRESENCE AND ACCESS OF MORE DANGEROUS DRUGS, SYNTHETIC OPIOIDS, FENTANYL, THE NUMBER OF OVERDOSE DEATHS ASSOCIATED WITH FENTANYL INCREASED MORE THAN 50%. AND THE NUMBER OF THOSE DEAD ASSOCIATED WITH FENTANYL INCREASED MORE THAN 40% AND THIS IN TURN IS ULTIMATELY WHAT--IT'S IN FRONT OF US FOR CHALLENGES. WHY, WHY IS THAT SO, WHY IS THE ACCESS TO THESE DRUGS ACTUALLY SO AND 1 OF THEM IS THE PROPHET, IF YOU ARE SOMEONE THAT IS DEALING WITH DRUGS, WITH FENTANYL ARE MUCH GREATER THAN THEY ARE WITH HEROIN. YOU DON'T HAVE TO CULTIVATE THE PLAN, THE CARRYING OF FENTANYL BECAUSE OF HIGH POTENCY REQUIRES MUCH LOWER VOLUMES TO CROSS THE BORDERS THAN IF YOU WERE DOING IT FOR HEROIN. SIMILARLY, METHAMPHETAMINE IS A DRUG THAT SYNTHITIZED AND THE SYNTHESIS IS NOT DIFFICULT AND IT CAN BE DONE IN RELATIVELY SMALL LIKE HOUSE LIKE LABORATORIES THAT MAKE ITS VERY CHEAP TO PRODUCE WITH HIGH MARGINS OF GAINS. SO WHAT WE'RE OBSERVING NOW IS ANOTHER PROBLEM THAT HAS STARTED BEFORE THE COVID PANDEMIC OR HAS JUST GOTTEN WORSE IS THAT DRUG DEALERS ARE DILUTING OTHER DRUGS LIKE COCAINE OR EVEN METHAMPHETAMINE OR HEROIN IN FENTANYL. WHY? BECAUSE BY DILUTING IT AND LACING IT, YOU CAN ACTUALLY PUT MUCH LESS OF THE DRUG THAT ORIGINALLY THEY ARE CALIFORNIAING AND TILL GET A VERY POTENT PSYCHOACTIVE DRUG AND THIS IS WHAT WE'RE OBSERVING ACROSS ALL OF THE COUNTRY. IN FACT, 50% OF ALL DEATHS FROM METHAMPET MINE REFLECT METHAMPHETAMINE WITH FENTANYL AND IN MANY INSTASS INDIVIDUALS DO NOT WANT TO TAKE FENTANYL, THEY ARE AFRAID OF FENTANYL BUT EERKT THEY CAN NOT AFFORD TO GET THE DRUG THAT IS FREE OF FENTANYL OR ACTUALLY DO NOT HAVE A MEANS TO ACTUALLY EVALUATE IF THE DRUGS THAT THEY ARE TAKING CONTAINS OR NOT FENTANYL. IF YOU ARE A PERSON ADDICTED TO STIMULANTS WHETHER IT IS COCAINE OR METHAMPHETAMINE AND YOU DO NOT KNOW THAT YOUR DRUGS THAT YOU ARE BUYING IS LACE WIDE FENTANYL, YOUR RISK MUCH OVERDOSES ARE EVEN HIGHER. WHY? BECAUSE IF YOU ARE A REGULAR USER OF OPIOIDS, YOU ACTUALLY BECOME TOLERANT TO THE RESPIRATORY DEPRESS ANT EFFECTS OF OPIOIDS WHICH IS ULTIMATELY WHICH DRIVES THE MORTALITY. --VERY LIKELY LEAD TO OVERDOSE AND MORTALITY. SO WHAT WE ARE UNDERSTANDING IS THAT THE COVID-19 HAS FACILITATED THE BLACK MARKET FOR THE DISTRIBUTION OF INCREASINGLY MORE LETHAL DRUGS AMONG WHICH IS FENTANYL AND METHAMPHETAMINE. NOW THE OTHER QUESTION THAT IS RELEVANT IS THIS IS WHAT'S HAPPENING WITH RESPECT TO THE OVERDOSE FATALITIES, BUT AGAIN DURING THE COVID PANDEMIC WE HAVE SEEN THE SIGNIFICANT RISE IN MORTALITY ASSOCIATED WITH AN INFECTION, WE HAVE ALSO SEEN THE NEGATIVE CONSEQUENCES OF GETTING INFECTED. THE QUESTION THERE OF COURSE WAS TO WHAT EXTENT ACTUALLY WE ARE AFFECTING NEGATIVELY AFFECTING WITH COVID THE PATIENTS WITH THE SUBSTANCE USE DISORDER. AND WHAT WE KNOW BASED ON THE ELECTRONIC RECORDS, THIS IS A STORY WE ANALYZE ON THE CLOSE TO A HUNDRED MILLION ELECTRONIC PATIENTS WITH ELECTRONIC CARE RECORDS THAT HAS SINCE BEEN REPLICATED BY OTHERS, IS THAT IF YOU HAVE A SUBSTANCE USE DISORDER, WHETHER IT IS AN ALCOHOL USE DISORDER OR COCAINE USE DISORDER, CANNABIS, OPIOID USE DISORDER OR TOBACCO, NICOTINE USE DISORDER YOUR RATIO ARE GETTING INFECTED IS SIGNIFICANTLY HIGHER THAN IF YOU HAVE DO NOT HAVE A SUBSTANCE USE DISORDER, OVER ALL IN AVERAGE IT'S CLOSE TO 8.7 FOR AN INDIVIDUAL THAT HAS A SUBSTANCE USE DISORDER IN A HISTORY OR A PRESENT OF A SUBSTANCE USE DISORDER TO GET INFECTED AND THESE ADJUSTED ODDS RATIOS ARE HIGHEST FOR OPIOID USE DISORDERS BUT ALL ARE SIGNIFICANTLY HIGHER ALONG ALL OF THESE TYPES OF DRUGS WHETHER IT'S LEGAL OR ILLEGAL, IT DOES NOT MAKE A DIFFERENCE. AND THE OTHER ISSUE THAT IS VERY CONCERNING IS FOR INDIVIDUALS THAT HAVE A SUBSTANCE USE DISORDER IF THEY GET INFECTED WITH COVID, THE LIKELIHOOD OF NEGATIVE OUTCOMES IS MUCH HIGHER AND THE OUTCOMES THAT YOU SEE IN THE RIGHT PANEL IS THE RISK, THE RATE OF DEATH IF YOU GET COVID-19 THERE WAS DATA THAT IS REPORTED AFTER APRIL 2020 IN THE UNITED STATES FOR THE GENERAL POPULATION HERE AND FOR INDIVIDUALS WITH SUBSTANCE USE DISORDER HERE. SO THIS IS THE PERCENTAGE OF PEOPLE THAT ARE INFECTED DIE, AND THE RATES OF MORTALITY AS YOU RECALL ARE MUCH HIGHER THAN THE 1 WHAT'S VERMEN INFECTED CURRENTLY, 2 FACTORS ACCOUNT FOR THAT. ONE OF THEM THE MOST VULNERABLE ELDERLY INDIVIDUALS BECOMING INFECTED BUT ALSO WE DIDN'T NOT KNOW HOW TO MANAGE THE DISEASE SO AS OF NOW, THE RATES ARE MUCH LOWER. BUT AT THAT TIME IT WAS CLEAR ALSO THAT THERE WERE DISPARITIES IN THE MORTALITY OBSERVED WITH COVID, THAT THE MORTALITY WAS HIGHER, WITH AFRICAN AMERICANS IN BLUE THAN IT WAS AMONG CAUCASIANS, AND THIS DISPARITY WHAT IS STRIKING IS THAT THIS IS A GENERAL POPULATION, CAN YOU SEE THE MUCH HIGHER RISK OF MORTALITY, YOU HAVE A SUBSTANCE USE DISORDER AND THIS MORTALITY IN THE CASE OF AFRICAN AMERICAN IS ALMOST 80% HIGHER IN AN ALREADY MUCH HIGHER MORTALITY THAN WITH THE CAUCASIAN, IN THIS THE CAUCASIAN THERE'S A MORE SIGNIFICANT RISE IN THE MORTALITY RATES INDICATING INDEED THAT HAVING A SUBSTANCE USE DISORDER IS ACTUALLY A FACT OR THAT MAKES YOU VULNERABLE ON THE 1 HAND INFECTION, BUT ON THE OTHER 1 IF YOU GET INFECTED, TOO MUCH WORSE OUTCOMES AND HIGHLIGHTING THIS POPULATION, THESE PATIENTS WITH SUBSTANCE USE DISORDER IS 1 OF THE VULNERABLE TARGET GROUPS WHICH ACTUALLY THERE WERE IMPLICATIONS THAT THEY DESERVE INTERVENTIONS TO ACTUALLY MINIMIZE THEIR LIKELIHOOD OF INFECTION INCLUDING ACCESSIBLE VACCINES AS WELL AS INTERVENTIONS TO PROTECT THEM BY OTHER MEANS. WHY IS THAT SO? WELL, IT'S NOT DIFFICULT TO IMAGINE, PEOPLE THAT TAKE DRUGS, DRUGS NOT ONLY AFFECT THE BRAIN AND THE REWARD CENTERS BUT UNFORTUNATELY, THEY HAVE A VARIETY OF NEGATIVE HISTOLOGICAL EFFECTS. MOST OF ALL OF THE DRUGS ARE USED AND IN FACT, I WOULD SAY, BASICALLY OF CALL THE DRUGS THAT HAVE ADDICTIVE POTENTIAL, ALL OF THEM NEGATIVELY AFFECT CARDIAC FUNCTION. MANY OF THEM NEGATIVELY EFFECT PULL MONITORARY FUNCTION AND MANY OF THEM ALSO AFFECT THE IMMUNE SYSTEM AND METABOLISM. IN EARLY STAGES OF THE COVID PANDEMIC WERE ASSOCIATED WITH HIGHER RISK OF INFECTION AND WORSE OUTCOMES. THEY DO IT DIFFERENTLY. IT'S VERY EASY TO UNDERSTAND WHY SOMEONE THAT SMOKES CIGARETTES WOULD BE AT HIGHER RISK OF INFECTION AND NEGATIVE OUTCOMES. WHY? BECAUSE OF THE NEGATIVE EFFECTS OF THE TOBACCO ON PULL MONITORARY FUNCTION. SIMILARLY, THEY THINK WHETHER IT IS NICOTINE OR THC IS NOW RECOGNIZED AS ACTUALLY A FACTOR THAT CONTRIBUTES TO DAMAGE TO PULL MONITORARY FUNCTION AND IN 2019 IT OPENED OUR EYES WHEN STUDIES START TO REPORT ACUTE PULL MONITORARY FAILURE ASSOCIATE WIDE VAPING, IN THE PAST WHETHER WE THOUGHT, THIS WAS IN A WAY TO THE CERTAIN EXTENT THE SURPRISE BECAUSE WE THOUGHT THAT VAPING WAS A SAFE MEANS TO ACTUALLY TAKE IN DRUGS. OPIOIDS, OPIOIDS BASICALLY DEPRESS RESPERRATION AND INTERFERE WITH TRANSFER OFOX NE--NIH TO THE PULMONARY SYSTEM, AND THEY WOULD INCREASE THE RISK FOR INFECTION THAT TARGETS THE PULMONARY SYSTEM, AND WHETHER IT'S COCAINE OR METHAMPHETAMINES, THESE 2 DRUGS ARE POTENT VASE O CONSTRICTING AGENTS THAT DECREASE THE CIRCULATION TO THE TISSUES INCLUDING THE LUNGS AND THE HEART WHICH AGAIN EXPLAINS WHY THEY HAVE NEGATIVE CONSEQUENCES. AND ULTIMATELY, MARIJUANA EVEN THOUGH IT IS NOT APPEAR TO BE AS HARMFUL TO PULMONARY FUNCTION AS TOBACCO IT'S STILL ASSOCIATE WIDE IMPAIRNLT IN PULMONARY FUNCTION AS WELL AS IMPAIRMENT IN CARDIAC ACTIVITY AND HEALTH. BUT IT'S NOT JUST WHEN YOU THINK ABOUT THESE VULNERABILITY OF INDIVIDUALS WITH SUBSTANCE USE DISORDERS THAT RELATES TO THE PHARMACOLOGICAL EFFECTS OF THE DRUGS IN OUR PHYSIOLOGY, BUT IMPORTANTLY, THE SOCIAL STRUCTURE OF FACTORS OF HOW ACCESS TO SOCIETY WE ADDRESS THE TREATMENT OR MORE TO SAY, THAT CRIMINALIZATION OF INDIVIDUALS WITH SUBSTANCE USE DISORDERS. AND THAT'S WHY IN RED, I PUT AMONG THE MOST IMPORTANT SOCIAL STRUCTURAL FACTORS THAT ARE CONTRIBUTING TO THEIR INCREASED RISK FOR COVID AND DEATH FROM COVID IS STIGMA. STIGMA HAS LED, AGAIN, TO THE DISSCRIM NATION AGAINST INDIVIDUALS WITH SUBSTANCE USE DISORDER IN GENERAL. IT'S 1 OF THE BIG CHALLENGES WE HAVE, PATIENTS THAT HAVE A SUBSTANCE USE DISORDER THAT MAY START ACTUALLY MAY HAVE DIABETES OR HYPER TENSION DO NOT SEEK TREATMENT BECAUSE THEY DON'T WANT TO BE DISCRIMINATED IN THE HEALTHCARE SYSTEM OR MISTREATED. SO VERY NATURAL, NORMAL RESPONSE FOR THE SAME REASON 1 OF THE CHALLENGES THAT WE HAVE IN BRINGING THEM TO TREAT YOURSELF FOR SUBSTANCE USE DISORDER SYSTEM TO MAKE THEM FEEL COMFORTABLE AND ACCEPTED. AND AGAIN, 1 OF THE BIG TARGET AREAS TO IMPROVE OUTCOME OVER ALL AMONG THESE PATIENTS IS TO ADDRESS STIGMA AND IN THIS RESPECT IT IS ALSO AN IMPORTANT ISSUE RELATED TO MENTAL ILLNESS. ACCESS TO OPIOID MISUSE EDMEDICATIONS BECAME VERY, VERY DIFFICULT BECAUSE THE METHADONE CLINICS WERE NOT PROPERLY STAFFED, THE STAFF GOT SICK, THE CONGLOMERATE IN THE CLINIC FACILITATED TRANSMISSION SO MANY OF THESE METHADONE CLINICS HAD TO CLOSE THEIR DOORS: THERE WAS A CLOSING OF COMMUNITY SUPPORT PROGRAMS, SUCH AS SYRINGE EXCHANGE PROGRAMS AND AS A RESULT OF THAT, WE KNOW THERE WAS A RECENT OUTBREAK OF HIV CASES DUE TO THE FACT THAT NO LONGER PATIENTS WERE ABLE TO ACCESS SAFE SYRINGES, THE SOCIAL DISTANCE REMOVED SOCIAL SUPPORT THAT IS SO NECESSARY TO HELPING TO SUSTAIN MAISHTS TO HELP THEM ACHIEVE RECOVERY AND IMPORTANTLY IF YOU ARE OVER THOSE THINGS WITH OPIOIDS, CAN YOU REVERSE IT IF YOU CAN GIVE NALOXOFNE. OR IF YOU ARE ISOLATED UNDER TAKING DRUGS OPIOIDS BY YOURSELF AND NO 1 OBSERVES YOU, NO 1 CAN REVERSE THAT OVERDOSE. INCARCERATION. WE INCARCERATE MANY INDIVIDUALS WITH SUBSTANCE USE DISORDERS, THEY'RE OVERREPRESENTED. I JUST TOOK THIS JUST TO ILLUSTRATEOT 1 HAND HOW CROWDED THESE CONDITIONS ARE, BUT ALSO IT JUST STRUCK ME WHEN I WAS PUTTING IT THERE, BASICALLY WHAT I HAD SEEN IN OTHER JAILS WHERE I VISIT THEM, IS BASICALLY THE HIGH PREVALENCE OF ARCS FRIC AN AMERICAN WHICH AGAIN, HAS BEEN 1 OF I WOULD SAY MOST EMBARRASSING--FOR PEOPLE THAT ARE BLACK AS WELL AS INDIVIDUALS WITH SUBSTANCE USE DISORDER AND IN THESE CONDITIONS IT HAS BEEN KNOWN FOR MANY, MANY YEARS THAT INFECTIONS RAPIDLY SPREAD. SO THIS WAS THE SOCIAL STRUCTURE OF FACTORS THAT ARE LIKELY TO HAVE CONTRIBUTED TO THE HIGH RISK OF INFECTION TO THE HIGH RISK OF MORTALITY. SO HOW HAS THE HEALTHCARE SYSTEM, TREATMENT PROGRAM RESPONDED TO THESE CHALLENGES. OT 1 HAND WE KNEW THAT 1 OF THE MOST POWERFUL INTERVENTIONS THAT WE HAVE FOR PREVENTING OVERDOSE DEATHS ON HELPING PEOPLE ACHIEVE RECOVERY ON THE 1 HAND IS THE MEDICATIONS TO TREAT OPIOID USE DISORDER WHETHEROOSE METHADONE, BUPRENORPHINE OR NALTREXONE, THESE MED KAIGDZINGS SIGNIFICANTLY REDUCE THE LIKELIHOOD OF DYING FROM AN OVERDOSE, APPROXIMATELY SEIVET%. AND IF YOU ADMINISTER IT RAPIDLY, CAN YOU ACTUALLY REVERSE THAT OVERDOSE SO THE NATIONAL ACADEMY OF SCIENCES HAD IN A REPORT IN 2019 HIGHLIGHTING THAT 1 OF THE THE OPIOID CRISIS WAS TO MAKE THESE MEDICATIONS MUCH MORE WIDELY AVAILABLE. WITH COVID-19 THIS BECAME A CHALLENGE BECAUSE THE HEALTHCARE SYSTEM, WHICH IS INVOLVED IN THE PRESCRIPTION OF BUPRENORPHINE OR NALTREXONE, DID NOT HAVE THE CAPACITY TO ACCOMMODATE FOR THOSE IN NEED AS WE WERE DELIVERING THE TREATMENT BEFORE COVID. SIMILARLY, I WILL SHOW YOU THE PICTURES OF THE METHADONE CLINICS WERE NOT ACTUALLY ORGANIZED TO BE ABLE TO ADDRESS THE COVID PANDEMIC, THE SECURITY. AND THEN IT BECOMES HARDER TO ADMINISTER NALOXONE, NOW THERE WERE 2 CHANGES. AND AGAIN SOMETIMES WHEN YOU HAVE A TRAGEDY OF PROPORTIONS LIKE THAT OF THE COVID PANDEMIC, IT SIEMS FORCES US TO CHANGE THOSE PRACTICES THAT HAVE BEEN HISTORICALLY THERE, EVEN THOUGH THE DATA SHOW THAT THEY'RE NOT THE BEST WAY OF CONDUCTING TREATMENT WITHED HAVES WITH SUBSTANCE USE DISORDER, AND THOSE PRACTICES RELATE TO BOTH METHADONE AND BUPRENORPHINE. IN THE UNITED STATES, IS OTHER COUNTRY, NOT ALL OF THEM BUT IN THE UNITED STATES, IF YOU WANT TO BE TREATED WITH METHADONE FROM AN OPIOID USE DISORDY HAVE TO GO TO A METHADONE CLINIC AND YOU HAVE TO GO IN A DAILY BASIS. THIS WAY THE BURDEN FOR ANYONE THAT IS ADDICTED TO OPIOIDS BUT IT'S EVEN WORSE IN SITUATIONS WHERE THE METHADONE CLINIC IS FAR AWAY, IT'S ALSO VERY CHALLENGING WHERE PEOPLE ARE TRYING TO ACHIEVE SOABRIETY AND SUSTAIN A JOB THAT THEY HAVE TO PRESENT THEMSELVES ON SAY DAILY BASIS AND MAKE THAT DECISION ON A DAILY BASIS FOR METHADONE CLINIC. IT WAS CLEAR THIS WAS GOING TO BE CONTAINABLE AND IT WOULD BE VERY, VERY DIFFICULT FOR PATIENTS TO ACCESS THEIR TREATMENT. SO VERY RAPIDLY, THE COVID PROMOTED CHANGES THAT MADE ACCESS TO METHADONE MUCH EASIER. SAMHSA ON MARCH 16th CHANGED PRACTICES TO ALLOW PATIENTS TO TAKE 28 DAYS HOME OF METHADONE. IN COMPLIANCE WITH THE TREATMENT AND FOR THOSE UNDER QUARANTINE, THEY BASICALLY ALSO ALLOW A SURROGATE WHICH WAS IN THE PAST NOT POSSIBLE TO TAKE HOME THAT METHADONE TO THE PATIENTS OR ANOTHER PRACTICE THAT WAS NOT VERY AVAILABLE DOOR STEP DELIVERY. IT STILL REQUIRES IN-PERSON VISIT FOR THE FIRST DOSE BUT OVERALL THESE FAST CHANGES OF SA AMHSA ALLOWED FOR THEM TO OFFER THE DIFFICULT EXTENT OF GETTING METHADONE TREATMENT. ANOTHER CHANGE THAT HAPPENED AS IT RELATES TO BUPRENORPHINE WAS WHAT THE SITUATION WAS BEFORE COVID, THAT IF YOU WANTED TO BE TREATED WITH BUPRENORPHINE, YOU HAD TO BE PHYSICALLY PRESENT IN THE PRESENCE OF A PHYSICIAN WHO IS WAIVER OR WHOSE WAIVERRED TO PROVIDE BUPRENORPHINE. YOU HAVE TO BE PHYSICALLY PRESENT. THAT HAD ALWAYS BEEN SEEN AS A CHALLENGE BECAUSE THERE ARE NOT SUFFICIENT CLIN IPGZ THAT ARE WAIVERRED TO PROVIDE BUPRENORPHINE AND SOME AREAS, RURAL AREAS WHERE IT MAY TAKE 2 OR 3 HOURS FOR SOMEONE TO SEE THOSE PROVIDERS. IN THIS SITUATION, THAT THE DEA MADE CHANGES ALLOWING IN MARCH, MARCH 17, 2020 TO ENABLE PRESCRIPTION OF BUPRENORPHINE THROUGH TELEHEALTH AND THAT MADE IT SO MUCH MORE ACCESSIBLE BECAUSE YOU CAN GET BY AN OUT OF STATE CLINICIAN, IT DOESN'T NEED TO BE SOMEONE IN YOUR OWN STATE. AND AGAIN, IN RURAL AREAS WHERE THOSE CLINICIANS ARE NOT AVAILABLE AND AS A RESULT OF THAT, OVERALL, THERE APPEARS TO HAVE BEEN FILLED IN SOME OF THE STATES A REDUCED NUMBER OF PEOPLE THAT WERE INITIATED ON METHADONE OR BUPRENORPHINE, BUT OVER ALL, IF YOU WERE ALREADY ON THESE MEDICATIONS, THE LIKELIHOOD THAT YOU AT A IN TREATMENT WAS ACTUALLY ENORMOUSLY FACILITATED BY THESE CHANGES. OTHER ASPECTS THAT WE SAW IN VERY CREATIVE AND I WOULD SAY POSITIVE EXCHANGES IN THE WAY THAT WE PRACTICE TREATMENT FOR SUBSTANCE USE DISORDERS WAS THE FACILITATION OF GIVING ACCESS TO TREATMENT TO TELEHEALTH AND THIS WAS NOT JUST TO PROVIDE TREATMENT, INITIATION AND BUPRENORPHINE, BUT TO PROVIDE SUPPORT, TREATMENT, FOR CO MORBID CONDITIONS THAT ARE SO VERY FREQUENTLY--FREQUENT AMONG INDIVIDUALS WITH SUBSTANCE USE DISORDER IN GENERAL AND IN PARTICULAR WITH INDIVIDUALS WITH OPIOID USE DISORDER, IN WHICH CASE FOR EXAMPLE, AS I MENTIONED DURING INTRODUCTION OF OUR MY TALK, THE CO MORBIDITY WITH MOOD DISORDERS, SPECIFICALLY WITH DEPRESSION AND SUICIDALLITY IS VERY HIGH. SUCCESS TO TELEHEALTH, MAYBE POSSIBLE, MUCH MORE ACCESSIBLE TO HEALTH PATIENTS, ACTUALLY AT A IN RECOVERY. IT WAS ALSO VERY DRAMATIC CHANGE IN JUSTICE SETTINGS, JUSTICE SETTINGS IN OUR COUNTRY OVERALL HAVE BEEN VERY, VERY CONSERVATIVE AND VERY RELUCTANT TO IMPLEMENT MEDICATIONS FOR OPIOID USE DISORDER. IN PARTICULAR METHADONE AND BUPRENORPHINE BECAUSE OF THE FEAR THESE WILL BE DIVERTED AND MISUSED. AND ALSO BECAUSE THE SETTINGS DO NOT HAVE THE MEDICAL CAPACITY THAT IS NECESSARY THAT IS ABLE TO PROVIDE THESE MEDICATIONS AND OVERALL THESE SETTINGS HAVE BEEN VERY CLOSE AND RELUCTANT TO BRING TELEHEALTH INTO THEIR FACILITY. THAT CHANGED RAPIDLY CAN COVID AND THROUGHOUT THE COUNTRY, MANY JAILS AND PRISONS HAVE ACTUALLY NOW TAKEN ADVANTAGE AND INCORPORATED THE USE OF TELEHEALTH, NOT JUST TO INITIATE IN THE MEDICATION TREATMENT FOR OPIOID USE DISORDERS BUT ALSO TO SUPPORT PSYCHOTHERAPEUTIC INTERVENTIONS AS WELL AS GROUP TREATMENT PROGRAMS. ANOTHER ISSUE THAT HAPPENED IN--WITH THE COVID PANDEMIC IS BECAUSE PRISONS AND JAILS ARE PLACES WHERE INFECTIONS HAD--CAN BE PASSED AROUND VERY, VERY RAPIDLY, RELEASE NONVIOLENT OFFENDERS IN THE COMMUNITY, MANY OF THEM WITH SUBSTANCE USE DISORDER ANDS THEY ALSO DECREASED THEIR SENSES BY ALSO DECREASING THE NUMBER OF ADMISSIONS INTO PRISONS AND JAILS DURING THE COVID PANDEMIC IN AS MUCH EAR MANY OF PATIENTS WITH SUBSTANCE USE DISORDER IN AND REVOLVE THROUGH THE JUSTICE SYSTEM, THE EXTENT TO WHICH WE HAVE NOW THE OPPORTUNITY TO SHOW THAT THESE PRACTICES OF INCARCERATING INDIVIDUALS WITH SUBSTANCE USE DISORDER WITHOUT VIOLENT OFFENSES INSTEAD OF PROVIDING THEM TREATMENT COULD ACTUALLY VERY LIKELY LEAD TO MUCH BETTER OUTCOMES AND MORE HUMAN TREATMENT OF INDIVIDUALS THAT ARE ALREADY VERY VULNERABLE FOR MANY OTHER REASONS. SO AS WE LOOK AT WHAT LIES AHEAD FOR ALL OF US, WE KNOW THAT WE WILL OVERCOME THE COVID PANDEMIC, WE WILL OVERCOME IT BECAUSE WE HAVE REALLY SOME EXTRAORDINARY REMARKABLE EFFECTIVE VACCINE. BUT THE PROBLEMS WE'RE SEEING SURGING DURING COVID IN TERMS OF THE PATTERN OF DRUG USE IS NOT GOING TO CHANGE AND IF ANYTHING, WE CAN PREDICT THAT MORE AND MORE SYNTHETIC DRUGS WILL BE THE MAIN STAY FOR ABUSE IN THIS COUNTRY AND OTHERS BECAUSE OF THE HIGH PROFIT MARGINS THAT THEY BRING TO THE DRUG DEALERS, THERE ARE MANY CHALLENGES BECAUSE THESE DRUGS ARE NEW TO US. SO WHILE WE KNOW MEDICATIONS FOR OPIOID USE DISORDER IS EFFECTIVE IN TREATING OPIOID USE DISORDER IN GENERAL WE HAVE MUCH MORE LIMITED INFORMATION IN INDIVIDUALS WITH FENTANYL WHO USE A FENTANYL USE DISORDER BUT WE ALSO KNOW THEY ARE MUCH MORE LIKELY TO RELAPSE, WE ALSO KNOW THEY ARE MUCH HARD TORE INITTIAIT INTO DRUG TREATMENT. SIMILARLY, FOR FENTANYL DRIVEN OVERDOSES WE KNOW THAT NALOXONE WORKS BUT YOU HAVE TO GIVE REPEATED DOSES BECAUSE THE TIME, THE HALF LIFE OF DURATION OF FENTANYL IS MUCH LONGER THAN THAT OF NALOXONE, BUT THEN AGAIN THIS OFFERS AN OPPORTUNITY IN TERMS OF RESEARCH FOR DEVELOPING INTERVENTIONS THAT ARE LIKELY TO BE EASIER FOR PATIENTS WITH FENTANYL USE DISORDER AND THAT MAY BE MORE EFFECTIVE. INCREASINGLY CONTRIBUTING TO THE OVERDOSE DEATHS, WE HAVE NO FDA APPROVED MEDICATION, OF COURSE, THESE GUYS MADE IT 1 OF OUR PRIORITIES IN EMERGING ITS OF DEVELOPING NEW INTERVENTIONS THAT CAN IMPROVE THE OUTCOMES ON INDIVIDUALS WITH METHAMPHETAMINE USE DISORDERS AND THERE ARE SOME PROMISING PRODUCTS THAT ARE CURRENTLY BEING EVALUATED. BUT IMPORTANTLY SINCE WE DO NOT HAVE MEDICATIONS THAT CAN BE USEFUL, THERE ARE BEHAVIORIAL INTERVENTIONS THAT CAN HELP INDIVIDUALS WITH METHAMPHETAMINE USE DISORDER BUT IT ALSO BRINGS TO LIFE THAT TO US WE'RE ADDRESSING THE OPIOID CRISIS, WE ARE ADDRESSING THESE CRISIS, NOT JUST OPIOIDS, THE NOTION OF PREVENTION BECOMES SO VERY IMPORTANT. AND THIS IN THE CONTEXT OF WHERE ACTUALLY THE PRESENTATION MADE IN OPENING THESE, OUR TALKS ABOUT HOW ADVERSE ENVIRONMENTS MAKE PEOPLE MORE VULNERABLE TO DRUG TAKING, HOW STRESSED PLACES SUCH AN IMPORTANT ROLE IN MENTAL ILLNESS AND DRUG TAKING, I CANNOT THINK OF ANY, AGAIN, ANY OTHER PERIOD WHILE I'VE BEEN ALIVE OF GREATER STRESS AS A POPULATION GLOBAL LEVEL THAN WHAT WE ARE LIVING CURRENTLY WITH THE COVID PANDEMIC. THUS, IT IS NOT SURPRISING THAT THE DATA FOR THE UNITED STATES, WE HAVE SEEN AN INCREASE IN ALCOHOL COMSUMPTION, THIS IS CHANGES IN ALCOHOL SALES IN STEALS AND ONLINE, THESE IT INCREASING IN STORES OVERALL I MUCH HIGHER NUMBER OF ALCOHOL SALES REFLECTING HIGHER USE OF CONTROL BY INDIVIDUALS IN OUR COUNTRY. THIS IS DATA FOR TAXINGS MADE OUT OF SELLING THE CANNABIS AND YOU CAN SEE THE SIGNIFICANT RISE IN THE SALE OF CANNABIS ACROSS THE UNITED STATES INDICATE WHAG WE ALL KNOW ALL ALONG THAT IN SITUATIONS OF STRESS AND UNCERTAINTY, 1 OF THE MECHANISMS OF COPING IS THE USE OF SUBSTANCES AND THIS IS FOR ILLEGAL DRUG, THIS 1 TO THE RIGHT FOR ILLEGAL DRUG ACCORDING TO SOME STATES AND AN ILLEGAL DRUG ACCORDING TO THE FEDERAL GOVERNMENT. SO AS WE LOOK AT THAT, AND AS WE LOOK INTO THE FUTURE AND WE KNOW THAT THE MOST IMPORTANT INTERVENTION WE CAN DO IS PREVENTION. IT BEHOOVES US TO UNDERSTAND HOW A STRESS OVER ALL IS AFFECTING US, WE ALREADY SEE IT IN THE COMSUMPTION OF MORE DRUGS, WE ALSO HAD TO KEEP OUR EYES IN CHILDREN AND ADOLESCENTS. WHY, BECAUSE IT IS IN THEM THAT PREVENTION, INTERVENTIONS ARE LIKE LIE TO HAVE THE HIGHEST EFFECT, BOLDLY PREVENTING SUBSIDIARY STANCE USE DISORDER AND IMPROVING MENTAL HEGHT OUTCOMES AND WE KNOW FOR THEM THE COVID PANDEMIC HAS BEEN PARTICULARLY STRESSFUL, NOT ONLY AND IN A WAY THAT THEY AND CHANGED DRAMATICALLY AND THE UNSUPPORTS ABOUT THERE FUTURE AND USED IN THE PREVALENCE OF SOCIETY, DISORDERS AND DEPRESSION AMONG TEENAGERS. THOSE ARE A KEY AREA OF PRIORITY IS TO UNDERSTAND WHAT ARE THE CONSEQUENCES OF COVID IN THE WELL BEING OF THESE TEENAGERS AND WHAT ARE THE INTERVENTIONS WE CAN DO TO MAXIMIZE THEIR SUCCESS IN PROTECTING THEM FROM TAKING DRUGS AND IMPROVING THE HEALTH OUTCOME. THIS SLIDE ACTUALLY SHOWS 2 EVENTS THAT WE HAVE TO KEEP OUR EYES ON. ON THE RIGHT WOO HAVE KNOWN THAT POVERTY, CERTAINLY GLOBALLY AND IN THE UNITED STATES, WITH THE PACKAGES THAT HAVE BEEN GIVEN TO ACCESSERATE THE ECONOMY HAVE BEEN ABLE TO BUFFER TO A CERTAIN EXTENT THE NEGATIVE CONQUENCE OF THE ECONOMY IN OUR COUNTRY, NONETHELESS THE LOSS OF JAWS HAS BEEN IN PARTICULARLY STRESSFUL AND AS WE LOOK AT THE NEGATIVE EFFECTS OF POVERTY OVERALL, IN SUBSTANCE USE CONTRIBUTING TO SUBSTANCE USE AND MENTAL HEALTH. WE REALIZE THE POVERTY RATES ARE HIGHER FOR CHILDREN AND WOMEN AND THAT THIS IS A BIG CHALLENGE THAT WE HAVE TO LOOK INTO AND TO THE LEFT IS CONSEQUENCES OF SOCIAL ISOLATION. TO THE EXTENT THAT WE CAN NO LONGER INTERACT WITH 1 ANOTHER, WHICH IS 1 OF THE MOST POWERFUL REINFORCERS, UNLESS OF COURSE YOU ARE DISCRIMINATED IN WHICH CASE SOCIAL ISHT ACTIONS CAN BE VERY ADVERSE. IN IS DATA I THINK I HAD PRESENTED BEFORE IN A MEETING IN 1 OF THE DEMYSTIFYING MEETINGS BECAUSE IT IS SO VERY ELOQUENTLY ADDRESSES, HOW IMPORTANT WE ARE TO EACH OTHER, THIS IS A THAT ALLOW THE ANIMAL TO PRESS FOR THE DRUG WHETHER IT'S METHAN FEET MEAN OR PRESS FOR A SOCIAL INTERACTION THAT WHEN YOU GIVE THAT ANIMAL, THAT OPPORTUNITY, THE CHOICE OF SOCIAL INTERACTION, THEY DON'T TAKE HEROIN, THEY PRESS THE LEVER FOR THE SOCIAL INTERACTION, IT'S THEN THAT THIS SOCIAL INTERACTION IS ACTUALLY PENALIZED WHEN YOU WERE DISCRIMINATED, WHEN YOU WERE MISTREATED, WHEN YOU ARE IGNORED THAT THEN THE DRUG INTAKE TAKES PLACE, AND SOCIAL INTERACTIONS THEN. I JUST WANT TO SAY THAT AT THE END OF MY PRESENTATION, THAT AS WE LOOK AT SUBSTANCE USE DISORDERS WE DISMISS THEM LIKE DISMISS THEM IN THE PAST LIKE BASICALLY SOMEONE THAT DOES NOT HAVE POOR MORAL JUDGMENT OR CRIMINAL BEHAVIOR, RECOGNIZING THAT THE USE OF DRUG SYSTEM DRIVEN BY SOCIAL STRESSORS THAT CREATE PAIN IN A SENSE OF INADEQUACIES THAT LEADS SOMEONE TO TRY TO ESCAPE IT IF WE IGNORE THAT VALID AND RELIABLE BASIC CONSEQUENCE OF DRIVER OF DRUG TAKING, WE WILL BE CHASING OUR TAILS IN TERMS OF PREVENTING SUBSTANCE USE DISORDERS. WE NEED TO CREATE SOCIAL SYSTEMS THAT PROVIDE SOCIAL SUPPORT THAT IT'S MEANINGFUL THAT CAN PROTECT EVERYONE, SO THAT WE CAN ACHIEVE MENTAL HEALTH AND PROSPERITY. THANK YOU VERY MUCH FOR GIVING ME THIS OPPORTUNITY TO SPEAK WITH ALL OF YOU. THANKS A LOT. >> THANK YOU VERY, VERY MUCH NORA, FOR CERTAINLY A VERY EXCITING AND PROVOCATIVE AND DEPRESSING ON ON 1 HAND AND CHALLENGING ON THE RECOLLECT. THERE HAVE BEEN SEVERAL QUESTIONS THAT HAVE COME IN, SEVERAL PEOPLE HAVE ASKED WHY DO YOU THINK THAT METHADONE USE IS ASSOCIATED WITH OVERDOSES AS WELL AS SUICIDE? >> YEAH, VERY IMPORTANT QUESTION AND AGAIN, HOW FROM THE PERSPECTIVE ON ON NEURAL BIOLOGY, THE NEUROCIRCUITRY OF ADDICTION ACTUALLY AND DEPRESSION HAS TREMENDOUS OVERLAPS AND WE KNOW THAT 1 OF THE PHYSIOLOGICAL SYSTEMS THAT REGULATES MOODS IS THE OPIOID RECEPTOR SYSTEM, THE OPIOID RECEPTOR SYSTEM FOR THE REWARDING EFFECT HAS BEEN SHOWN TO HAVE EABT KEPRESS ANT EFFECTS SO YOU STIMULATE THOSE RECEPTORS, YOU ACTUALLY IN PATIENTINGS WITH DEPRESSION AND YOU CAN ACTUALLY IMPROVE WHILE DEPRESSIVE SYMPTOMS. DURING WITHDRAWAL, THOUGH, THERE IS DYSPHORIA STARTS TO EMERGE AND THE GREATER THE KRONISSITY WITH OPIOID TAKING THE GREATER THE SENSITIVITY OF THAT THE DEPRESSIVE EFFECTS THAT APPEAR TO REFLECT IN THE 1 PART THE DOWN REGULATION OF SIGNALING TO THE NEW OPIOID RECEPTOR AND THE UPREGULATION OF THE SIGNALING TO ANOTHER OPIOID RECEPTOR FOR STIMULATION IS ASSOCIATED WITH DYSPHORIA IN THE RECEPTOR SYSTEM. SO WHEN WE'RE LOOKING IF ARE XCH, THAT ARE THE MECHANISMS UNDERLYING BENEFITS AND YOU WILL BE HEARING FROM DR. ZARANTE, OF KETA MEAN, THERE IS ALREADY DATA TO INDICATE THAT PERHAPS SOME OF THOSE MECHANISMS ARE DRIVEN BY CHANGES IN THE OPIOID RECEPTOR SYSTEM. SO YES, THEY ARE VERY MUCH INTERMINGLE BECAUSE THESE SYSTEMS OPIOID RECEPTOR SYSTEM MOVES AND STRESSY REACTIVITY AND IT'S IMPORTANT FOR DEPRESSION AND ALSO QUITE IMPORTANT FOR SUICIDALLITY. >> YOU SAID THERE'S ALSO AN INQUIRY WONDERING WHETHER WE HAVE ANY IDEA FROM A QUANTITATIVE STANDPOINT HOW MUCH FENTANYL COMES IN THROUGH DARK CHANNELS, THE INTERNET AND WHAT NOT AS COMPARED TO WHAT'S PRODUCED LOCALLY. >> THE DATA SEEMS TO INDICATE, BASICALLY THE FENTANYL THAT IS RESPONSIBLE FOR THE OVERDOSES AND THE PROBLEMS IN THE COUNTRY IS BASICALLY ILLICITLY MANUFACTURED FENTANYL. MOST OF IT UNTIL RECENTLY WAS COMING FROM CHINA, BUT OTHER COUNTRIES MAY BE PRODUCING IT, BUT IT'S NOT LIST MANUFACTURED FENTANYL, IT'S NOT THE 1 THAT'S UTILIZED FOR BREAK OUT PAIN OR SURGICAL PROCEDURES. >> SO, IT'S ALSO CURIOUS THAT CURRENTS AND AVAILABILITY OF THINGS LIKE METHADONE CLINIC OR ANY PROGRAM DEALING WITH REGULATION OF DISTRIBUTION OF DRUGS AND MORE IMPORTANTLY UPON FROM THE STANDPOINT OF TREATMENT, ARE THESE STATES RESPONSIBILITIES OR FEDERAL OR BOTH. >> THEY ARE BOTH, THEY ARE DIFFERENCES IN THE STATES ULTIMATELY REGULATE THE METHADONE CLINIC BUT OVERALL THIS IS A [INDISCERNIBLE] TO CERTAIN GUIDELINES THEY HAVE TO FOLLOW AND THE SAME THING WITH BUPRENORPHINE, I MEAN THE STATES DETERMINE THE EXTENT TO WHICH MEDICAID IS GOING TO BE COVERING FOR BUPRENORPHINE, IT ALSO DETERMINES WHAT ARE THE REQUIREMENTS IN ORDER TO GET APPROVAL TO USE BUPRENORPHINE FOR HOW LONG SO THERE IS TREMENDOUS DIFFERENCES IN--IN TERMS OF HOW THE STATES ARE MAKING THESE MED KAIGDZS AVAILABLE, AND THE THINGS WE CAN DO AND AND LET'S MAKE IT AS ACCESSIBLE BUT EVEN THEN IT VARIES BY STATE AND 1 PRESCRIPTION AMONTH OF NALOXONE, BUT THE PROBLEM IS WHEN YOU ARE OVERDOSING WITH FENTANYL, YOU CAN GET 1 OR MORE 2 SHOTS WHICH IS WHAT 1 PRESCRIPTION WILL GIVE YOU, SO WHAT WREE HEARD FROM PATIENTS, ACTUALLY COMMENTING IS THAT THEY DON'T HAVE SUFFICIENT NALOXONE, BECAUSE THEY USE IT ALREADY. SO THESE ARE STATE PRACTICES THAT IN SOME INSTANCES MAKE IT HARDER FOR PATIENTS TO GET THEIR MEDICATIONS. >> SO WHAT ARURE --ARE YOUR THOUGHTS OF THE GEOGRAPHIC EXPWRIEWKS OF SUICIDE AND ALSO THE GENDER DISTRIBUTION? ARE THOSE DATA REAL? AND WHAT ARE YOUR THOUGHTS ABOUT THE MECHANISM OF THAT BECAUSE MANY OF THEM ARE TIED IN WITH DRUGS. >> YEAH, THANKS FOR ASKING THAT QUESTION BECAUSE WITH WE ARE SPEAKING FOR EXAMPLE, 88,000 OVERDOSE DEATHS IN 20 THAT'S THE ESTIMATED NUMBER, BASICALLY, THESE ARE THE DEATHS THAT ARE BEING REPORTED OF OVERDOSES. WHETHER IT IS INTENTIONAL OR UNINTENTIONAL, IS NOT COMPLETELY CLEAR AND IT IS ESTIMATED THE QUESTION IS TO WHAT EXTENT SOME OF THOSE OVERDOSES WERE INTENTIONAL, INTENTIONAL SORT OF SAYS THAT WELL, I DON'T WANT TO LIVE ANYMORE, I'M GOING TO TAKE A HIGHER DOSE SO I CAN DIE BECAUSE YOU KNOW YOU THAT CAN YOU DIE, BUT ALSO PERHAPS, YOU KNOW SOME INSTANCES EVEN IF IT'S NOT SO CLEAR, STARTS WITH THE NOTION OF PEOPLE TAKING RISK BECAUSE AT THE END OF THE DAY, THEY DON'T REALLY CARE IF THEY ARE GOING TO WAKE UP OR NOT. SOPHISTICATEDY WE DO HA KNOW THAT PERHAPS AT LEAST, THERE--PERHAPS THE PERCENT OF THOSE OVERDOSES MAY HAVE AN INTENTIONAL SUICIDE COMPONENT THAT IS CONSCIOUS OR EVEN IF IT'S NOT FULLY CONSCIOUS THAT THERE IS A SUICIDALLITY COMPONENT AND AGAIN HILIGHTING THE POINT THAT WAS MADE BEFORE ABOUT WHY IS IT THAT PATIENTS WITH METHADONE SUFFER FREQUENTLY SUFFER FROM DEPRESSION? AND THE ASSOCIATION, TOO, I MEAN THE COMMON ASSOCIATION WESTBOUND BOTH OF THEM SO GUESS, 1 OF THE REASONS WHY PEOPLE AVOID DO ING WHEN YOU ARE ADDICTED TO DRUGS AND THIS MAY BE EVEN WORSE FOR OPIOIDS IS SUICIDE AND AGAIN, NOW, AS TO THE QUESTION ABOUT WHAT ARE THE DIFFERENCES, THERE ARE INTERESTING DIFFERENCES IN THAT OVERALL WE'VE BEEN MONITORING THE INCREASES IN INTENTIONAL VERSUS UNINTENTIONAL OVERDOSES IN THE USES AND INTENTIONAL OVERDOSES HAVE ACTUALLY BEEN INN CREASING PARTICULARLY AMONG WOMEN MORE THAN MEN. AND EVEN THOUGH SUICIDES ARE HIGHER AMONG MEN, WE KNOW THAT MEN TEND TO USE FIREARMS TO KILL THEMSELVES. WRASSE WOMEN MAY BE FAVORING MORE THE OVERDOSES, SO INTERESTINGLY FOR INTENTIONAL OVERDOSES, THE INCREASES HAVE BEEN HIGHER IN WOMEN AMONG MEN WHICH IS DIFFERENT WHAT WE TYPICALLY SEE FOR SUICIDES THEMSELVES. WHAT ARE YOUR THOUGHTS ABOUT THE NEURAL BIOLOGY--SEVERE DEPRESSION. I GUESS WITH DRUGS IT'S A LOT EASIER BUT THE TRANSITION TO SUICIDE IS THERE SOME SORT OF NEURAL BIOLOGY THAT IS DETECTABLE TO EVEN IBDICATE RISK? OR IS SUICIDE AN INDEPENDENT EVENT? CAN YOU ELABORATE ON THAT? >> YES, WHEN I--THIS HAS BEEN A QUESTION THAT HAUNTED SO MANY PEOPLE IF YOU COULD PREDICT WHO WAS GOING TO COMMIT SUICIDE AND WITH THAT ARTIFICIAL INTELLIGENCE AND MACHINE LEARNING THIS IS 1 OF THE FIRST TARGETED PROGRAMS BECAUSE WHEN YOU ACTUALLY WHEN PEOPLE ARE GOING TO COMMIT SUICIDE,--IT'S NOT LIKE THERE WAS 1 TRANSLATIONAL RESEARCH JECT WREE IN THE WAY THAT PEOPLE ARE ACTUALLY GOING TO WORK THE WORST COMMITTING SUICIDE BUT 1 PROBLEM IS THAT PEOPLE ISOLATE THEMSELVES AND THAT IS A FACTOR THAT CONTRIBUTES. WHEN YOU HAVE A SUICIDE THAT IS LINKED WITH DRUG TAKING FOR EXAMPLE, AND THIS IS SOMETHING THAT WE HAVE BEEN--AND OTHERS HAVE BEEN IMPORTANT WITH THE USE OF CANNABIS, THERA IS IN SOME INSTANCE AN INCREASE RISKER OF SUICIDALLITY EVEN THOUGH IT'S NOT ASSOCIATE WIDE AN INCREASED RISK FOR DEPRESSION SO YOU CAN ALSO HAVE SUICIDES THAT ARE DRIVEN BY AN IMPULSIVE, AN IMPULSIVITY THAT IS TRIGGERED BY DRUG TAKING OR THAT ALSO MAY BE DRIVEN BY PARANOIA THAT LEADS YOU TO BASICALLY TOO TAKE YOUR OWN LIFE. SO I AM NOT AN EXPERT IN TERMS OF THAT NEURAL CIRCUITRY THAT RELATES TO SUICIDE BEHAVIOR, WHERE WE ARE. WHAT I CAN SAY IS THAT THERE IS CLEARLY AN OVERLAP IN THAT THE POSITIVE REWARD SYSTEMS THAT MAKE US FEEL GOOD THOSE FUNCTION MUCH LESS BOTH IN DEPRESSION AND FUNCTION MUCH LESS IN THE INDIVIDUALS WITH SUBSTANCE USE DISORDERS. OT OTHER HAND, THAT SYSTEM THAT IS THERE FOR A REASON, FOR US TO FEEL ANXIOUS, DEPRESSED, THE OPPOSITE OF HAPPINESS, THAT SYSTEM ALSO IS RELEVANT BECAUSE IN CERTAIN INSTANCES IT CAN PROTECT US FROM DOING THINGS THAT COULD BE VERY HARMFUL AND THAT--THAT SENSITIVITY TO NEGATIVE REINFORCERS IS ACTUALLY INCREASED IN PATIENTS WITH DEPRESSION, BUT IT'S NOT NECESSARILY INCREASED IN INDIVIDUALS AT ALL LEVELS CONSISTENTLY WITH ADDICTION, AND IN ADDICTION THERE IS AN INCREASED SENSITIVITY OR STRESSORS BUT ON THE OTHER HAND, THE THREAT OF A NEGATIVE EVENT HAPPENING TO YOU IN THE FUTURE, LOSES ITS POWER. I MEAN THE PERSON THAT'S ADDICTED IS VERY MUCH DRIVEN BY WHAT HAPPENS RIGHT NOW AS OPPOSED TO PROJECTING THEMSELVES INTO THE FUTURE. AND THAT IS AGAIN, WHETHER IT'S GOING TO BE JUST WHOLE IS A MONTH FROM NOW YOU WILL FEEL BETTER OR IF YOU DON'T DO THIS, YOU WILL END UP IN JAIL 1 MONTH FROM NOW, THAT PROJECTION OF YOURSELF INTO THE FUTURE IS DISRUPTED IN PEOPLE THAT ARE ADDICTED. >> SO WHAT IS THE CURRENT STATUS OF THE NATIONAL EFFORT TO ATTACK THE FENTANYL AND METHAMPHETAMINE CRISIS? >> THERE THERE ARE 2 ELEMENTS TO IT, 1 OF THEM IS WHAT CAN YOU DO IN ORDER TO MAKE BASICALLY THESE DRUGS LESS ACCESSIBLE, THAT IS 1 ELEMENT THAT WAS KNOWN ALL ALONG. THAT ACCESSIBLE DOES DRIVE FROM TAKING SO IF IT'S VERY, VERY DIFFICULT TO GET A DRUG YOU'RE MORE LESS LIKELY TO BE CONSUMING IT BECAUSE IT'S NOT AVAILABLE AND THE PRICES ARE HIGHER BUT THEN A VERY IMPORTANT INTERVENTION IS WHAT CAN YOU DO TO ACTUALLY PROVIEDMAN RESILIENCE OF TO PEOPLE WHO SO THAT WHEN THEY ENCOUNT THEY'RE DRUG, THEY DON'T CONSUME. AND THAT HAS TO START AGAIN WITH A NOTION OF THE FAIR DESCRIPTION ON EDUCATION OF WHAT DRUGS ARE DOING AND WHY, WHAT ARE CONSEQUENCES IF YOU TAKE THEM. WE'RE VERY IMPORTANT, THIS IS SOMETHING WE TEND TO NEGLECT. WHEN YOU JUST SORT OF SAY TO A PERSON, DON'T TAKE THIS DRUG BECAUSE IT'S GOING TO HAVE HARMFUL EFFECTS, PARTICULARLY IF YOU ARE DEALING WITH A DEAN AGER OR A CHILD TO WHOM THE CENTER FOR EXCELLENCE ON AGINGS ARE MORE LIKELY TO BE NEGATIVE, YOU NEED TO PROVIDE THEM IF ALTERNATIVES, IT'S NOT JUST DON'T DO IT BUT ACTUALLY THE OPPORTUNITY, GIVE THAT PERSON THE OPPORTUNITY OF ALTERNATIVE REINFORCERS, JUST LIKE I SHOWED THE SLIDE AT THE END THAT IT IS THE CHOICE BETWEEN A SOCIAL INTERACTION OR THE DRUG--FOR THE DRUG, EVERY SINGLE INVESTIGATORS HAVE SHOWN THAT THEY WILL PRESS THE LEVER FOR A DRUG AND I THINK THAT VERY SIMPLE LESSON SHOULD PERMEATE TO US THAT WE NEED TO PROVIDE SYSTEMS WHERE PEOPLE HAVE ALTERNATIVE CHOICES. WE SPEAK A LOT ABOUT THE FREEDOM, OH LET THE FREEDOM PERSON TAKE DRUG WHEN IS THEY WANT, IF YOU ARE GOING TO GIVE THAT FREEDOM, GIVE THEM WITH THE KNOWLEDGE ABOUT WHAT DRUGS DO, BUT ALSO GIVE THEM WITH ALTERNATIVE CHOICES ON BEHAVIORS WHERE THEY CAN ACTUALLY HAVE REINFORCING EFFECTS, DON'T JUST MAKE THIS OR THAT, MAKE THEM ACCESSIBLE TO A PERSON, SO, BECAUSE AS YOU SEE, I MEAN THIS IS NOT JUST 1 STORY. I MEAN--IT IS CONSISTENTLY SHOWN. YOU GIVE ANIMALS VERY SIMPLE RODENTS MUCH LESS COMPLEX THAN US, ENVIRONMENTS WITH COMPLEXITY WHERE THEY CAN EXPLORE, WHERE THEY CAN INTERACT WITH 1 ANOTHER AND THEY DON'T ATTEND TO FAVOR DRUGS. DRUGSBECAME A FAVORITE CHOICE OR WHEN HAVE YOU AGAIN A CONDITION THAT MAKES YOU VULNERABLE TO THEM LIKE DEPRESSION. >> LISTEN, I WANT TO THANK YOU FOR YOUR TIME AND THE EXCELLENT PRESENTATION. YOU'VE GIVEN ALL OF US MUCH TO APPRECIATE AND THINK ABOUT. SO THANK YOU. >> THANK YOU VERY MUCH. OKAY, DR. ZARATE, YOU'RE ON. >> GOOD AFTERNOON, I AM DELIGHTED TO BE PART OF THIS WORK IN DEMYSTIFYING MEDICINE, MY TOPIC IS ON RISK AND RESILIENCE FOR DEPRESSION AND SUICIDE IN THE TIME OF COVID. AS I WAS PLANNING THIS TALK, I WAS GOING TO FOCUS PREDOMINANTLYOT NEUROBIOLOGY IN NEXT GENERATION TREATMENTS FOR MOOD DISORDERS BUT WE HAVE COVID NOW AND IT WOULD BE IMPORTANT TO KNOW WHAT IS HAPPENING WITH COVID IN TERMS OF MENTAL HEALTH, DEPRESSION, ANXIETY, AND HOW DOES IT IMPACT CLINICAL CARE AND RESEARCH? SO WHEN I WILL PRESENT AND SPRINKLE IN AREAS WHERE COVID MIGHT AFFECT THESE METRICS. THIS IS MY DISCLOSURE AND I AM LISTED ON THE PATENT TO THE KETAMINE AND ITS METABOLITES IN DEPRESSION. IN TRANSLATIONAL RESEARCH RENAL CANCER THEY--THE SIS, I HAVE COVID BECAUSE IT DOES HAVE IMPACT, THE SECOND TO BECOME FAMILIAR WITH THE PROGNOSIS AND OUTCOME OF DEPRESSION AND SUICIDE. AND THE THIRD IS TO UNDERSTAND MANAGEMENT OF SUICIDE DEPRESSION ESPECIALLY IN THE TIME OF COVID. DEPRESSION IS A MAJOR CAUSE OF MORBIDITY, MORTALITY AND WE SEE THAT APPROXIMATELY 10% SUFFER FROM MOOD DISORDER IS IT 16 MILLION FOLKS SUFFER FROM MAJOR DEPRESSIVE DISORDER, 30-40% HAVE WHAT WE REFER TO AS TREATMENT RESISTANT STEPHANIE PREGZ MEANS THEY FAIL 2 ADEQUATE ANTIDEPRESSANT TRIALS, THERE ARE 1 MILLION DEATHS FROM SUICIDE WORLD WIDE EACH YEAR AND THAT OF COURSE HAS CHANGED IN THE SINCE THE PANDEMIC AND IT ALSO CAUSES DISTURBANCES IN CIRCADIAN RHYTHMS AND ACTIVITY LEVELS WITH SIGNIFICANT IMPAIRMENT AND FUNCTION. TREATMENT RESISTANT DEPRESSION, COMPARED TO NONTREATMENT RESISTANT DEPRESSION IS ASSOCIATED WITH GREATER MEDICAL AND PSYCHIATRIC CO MORBIDITY, GREATER NUMBER OF HOSPITALIZATIONS AND AND DEPRESSION IS ABOUT 30-35%. AND PEOPLE WHO HAVE TREATMENT RESISTANT DEPRESSION, LIVE ON AN AVERAGE 13 YEARS LESS THAN INDIVIDUALS WITHOUT TREATMENT RESISTANT DEPRESSION. NOW WHEN TALKING ABOUT MAJOR DEPRESSIVE DISORDER, THERE ARE CRITERIA ON THE TOP, YOU SEE DEPRESSED MOOD, YOU HAVE TO HAVE AT LEAST--1 OF THESE 2, DEPRESSED MOOD OR APATHY OR LOSS OF INTEREST, IN THE BOTTOM YOU HAVE TO HAVE AT LEAST 4 OR MORE OF THESE, WHICH IS CHANGES IN WEIGHT OR APPETITE, SLEEP DISTURBANCES OR SLEEPING TOO MUCH OR TOO LITTLE, PSYCHOMOTOR AGSTATION OR FATIGUE AND EXECUTIVE DYSFUNCTION, WHICH IS INABILITY TO MAKE DECISIONS AND THEN THERE'S SUICIDAL IDEATION, INDIVIDUALS NEED TO HAVE THE SYMPTOMS MORE DAYS THAN NOT IN AT LEAST A 2 WEEK PERIOD OF TIME. SO IN THE--DURING THIS PANDEMIC, 3 QUESTIONS ARISE, 1 IS--HAS THE PANDEMIC HAD AN IMPACT ON DEPRESSIVE SYMPTOMS, SECOND, WHAT IS THE IMPACT OF THE PANDEMIC ON INDIVIDUALS WITH A HISTORY OF DEPRESSION DIAGNOSIS, AND 3 HAS THE PANDEMIC HAD AN EFFECT ON SUICIDE RATES. THIS IS THE IMPACT ON MENTAL HEALTH, A STUDY DONE BY THE CENTERS FOR DISEASE CONTROL, CDC REPORTED IN THE MORBIDITY AND MORTALITY WEEKLY REPORT, THESE DATA REPRESENT MENTAL HEALTH SUBSTANCE USE AND SUICIDAL ADATION DURING COVID AND THIS IS DURING THE MONTH OF JUNE OF 2020. OVERALL WE SEE THAT 40% OF U.S. ADULTS ARE STRUGGLING WITH THE MENTAL HEALTH OR STUB STANCE USE PROBLEMS. WE SEE AT THE TOP OF THE LIST ANXIETY AND DEPRESSIVE SYMPTOMS OF ABOUT ONE-THIRD, 26% STRESSOR OR TRAUMA RELATED DISORDER SYMPTOMS, ABOUT 13% HAVE STARTED OR INCREASED SUBSTANCE USE, WE HEARD THAT FROM DR. VOLKOW, AND THEN 11% HAVE SERIOUSLY CONSIDERED SUICIDE. SO WE DO SEE IMPACTS OF COVID ON MENTAL HEALTH EVEN IN INDIVIDUALS WITHOUT PSYCHIATRIC DISORDERS. SO SUICIDE CONTINUES TO BE MAJOR PUBLIC HEALTH CONCERN, THIS FIGURE BY THE NATIONAL VITAL STATISTICS SYSTEM, REPORTS THE DEATH RATES FROM SUICIDE AND INDIVIDUALS 10-24 YEARS OLD IN THE UNITED STATES BETWEEN THE YEAR 2000-2017. WE SEE IN THE YEAR 2000, HOMICIDE IS MUCH MORE COMMON THAN SUICIDE BUT AT THE YEAR 2007 WE SEE A STEADY INCREASE IN SUICIDE RATES OVER TIME AND IT SURPASSES HOMICIDE READYINGS IN THE YEAR OF 2010. SO NOW WE SEE GREATER SUICIDE RATES THAN WE SEE HOMICIDE RATES AND I WILL TALK ABOUT THE EFFECTS OF COVID NOW. SO IN TERMS OF SUICIDE, IN 2019, ABOUT 47,000 INDIVIDUALS HAVE SUICIDE, DIED FROM SUICIDE, THAT REPRESENTS ABOUT 1 DEATH EVERY 11 INMUTES TOWARDS THE RIGHT, WE CAN SEE THAT ABOUT 12 MILLION INDIVIDUALS SERIOUSLY THOUGHT ABOUT SUICIDE, ABOUT 3 AND HALF MILLION HAVE MADE A SUICIDE PLAN AND 1 AND HALF MILLION ATTEMPTED SUICIDE. SO OF COURSE IT'S IMPORTANT TO KEEP IN MIND AND MONITOR, ENCOURAGE YOUR FAMILY AND MEMBERS TO SEEK TREATMENT IF THEY HAVE PROMINENT DEPRESSIVE SIM TOMS OR EVEN SUICIDAL THINKING. SO WE HAVE SEEN STEADY INCREASES FOR 13 YEARS IN THE SUICIDE RATES, BUT ACTUALLY, AND IN THE NEXT IF YOU SLIDES WE'VE SEEN A DECLINE IN SUICIDE RATES IN 2019, FOR BOTH GENDERS BUT IT'S BEEN INCONSISTENT ACROSS RACIAL GROUPS. NOW THESE ARE DATA FROM 2020 PUBLISHED IN MARCH OF 2021, AND THESE ARE THE NUMBER OF DEATHS FOR LEADING CAUSE, AND LEADING CAUSES OF DEATH IN THE UNITED STATES BETWEEN 2015 AND 2020. THE TOP CAUSES OF DEATH ARE HEART DISEASE, CANCER AND UNINTENTIONAL INJURIES. 345,000 MORE DEATHS BECAUSE--WHAT ABOUT SUICIDE? HERE IN THE BOTTOM WE SEE TOWARDS THE RIGHT THE NUMBER OF SUICIDES IN 2019 WAS ABOUT 47,000 AND IT HAS DECREASED TO 44,000 IN 2020. SO THE SUICIDE RATES HAVE DECLINED ABOUT 6% COMPARED TO THE PREVIOUS YEAR. SO WE ACTUALLY SEE A CONSISTENT NUMBER OF SUICIDES OR ACTUALLY A DECREASE IN THE NUMBER OF SUICIDES. UNFORTUNATELY, THERE SEEMS TO BE SOME RACIAL DISPARITIES, ALTHOUGH THERE'S NO SYSTEMIC INFORMATION AT THE U.S. LEVEL, AT THE STATE LEVEL IN MARYLAND WE SEE RACIAL DIFFERENCES IN THE SUICIDE RATES. HERE WE SEE A TOTAL, FOR 289 IN 2017 AND IN THE AVERAGE IN 2017 TO 2019, ABOUT 280. THAT REPRESENTS A DECREASE IN SUICIDE RATES AMONG ALL, BUT IF YOU LOOK AT THE FIGURE HERE, IT'S HARD TO ACTUALLY SEE IN THE BLACK LINE AFRICAN AMERICANS HAVE A SIGNIFICANT INCREASE IN SUICIDE RATES ABOUT A DOUBLING BETWEEN MARCH 5, TWEBT 20 AND MAY SEVENTH AND THEN IT REMAINS FAIRLY STEADY THEREAFTER. WHEREAS IN WHITE INDIVIDUALS WE SEE A STEADY DECREASE OVER TIME. NOW IT'S IMPORTANT TO KEEP IN MIND THAT THESE NUMBERS IN SUICIDE NEED TO BE ADJUSTED, THEY TEND TO BE DELAYED BY 6 MONTHS, SO IT WILL PROBABLY BE LIKELY, WE WILL SEE CHANGES IN THESE PATTERNS IN THE MONTHS AND YEARS TO COME. NOW TO RESPOND TO THE 3 QUESTIONS I POSED ON IMPACT OF COVID ON ANXIETY, STRESS, AND PDSD SYMPTOMS HAS THE PANDEMIC HAD AN IMPACT ON THE DEPRESSIVE SYMPTOMS AND THE ANSWER IS YES WHETHER HAVE YOU PSYCHIATRIC DISORDERS OR NOT. AND THE SECOND IS HAS THE PANDEMIC HAD AN IMPACT ON HADDISTRY OF DEPRESSION, AND THE ANSWER IS YES, AND THE THIRD WAS HAS THE PANDEMIC HAD AN EFFECT ON SUICIDE RATES, WE RATHER THAN SAYING NO, WE SAY NOT YET BECAUSE IT'S LIKELY IT WILL HAVE AN IMPACT. THERE'S THIS HONEYMOON PHASE WHERE IT TAKES A WHILE FOR THE SUICIDE RATES TO CHANGE AFTER A TRAGEDY OR TRAUMA OR SOME OTHER EVENT. IN TERMS OF MANAGE MGHT TREATMENT OPTIONS WE HAVE PSYCHOSOCIAL OPTIONS, FARM ONICOLOGICAL OPTIONS AND NEURAL STIMULATION, SO AS A LEFT, WE SEE THESE ARE THE PSYCHOSOCIAL INTERVENTIONS, EXERCISE OWGMENTATION, MINDFULNESS, COGNITIVE BEHAVIORIAL THERAPY, BEHAVIORIAL ACTIVATION, AND OTHER TYPES OF THERAPY, IN TERMS OF PHARMACOLOGICAL, WE HAVE THE STANDARD ANTIDEPRESSANTS WHICH ARE GENERALLY BASED ON SERIES POINTSA TONERGIC AND WE USE THESE PSYCHE COTTIC DRUGS, THE MOOD STABILIZIZER LEATHIUM, KETAMINE, AND ON THE RIGHT WE HAVE STIMULATION THERAPY WHICH IS CONSIST OF THE ELECTRIC COMPULSIVE STIMULATION AND NEUROSTIMMULATION AND OTHER TYPES OF TREATMENTS. NOW THESE ARE THE EFFECTS SIZES BASED ON THESE TREATMENTS IN COMBINATION OR AUGMENTATION, WE SEE THOSE TREEPTS THAT HAVE THE LARGEST EFFECT SIZE IN DEPRESSION AND TREATMENT RESISTANT DEPRESSION ARE THOSE THAT AFFECT THE GLUTAMATERGIC TARGETS SUCH AS THE NMDA RECEPTOR, THE ATYPICAL PSYCHOTIC DRUGS, WE SEE A WIDE CONFIDENCE INTERIA VALENTINEDS BY PSYCHOTHERAPIES THEY HAVE MOT BEEN SYSTEMATICALLY PROVEN TO BE EFFECTIVE IN TREATMENT RESISTANT DEPRESSION, ALTHOUGH THIS IS A META-ANALYSIS THAT SUGGESTS THAT PERHAPS INDIVIDUALS TO BENEFIT FROM PSYCHOLOGICAL THERAPIES. STHOW AS I MENTIONED WE HAVE TO DO BETTER IN TERMS OF EXERCISE, DIET, NUTRITION SO HOW HAS THAT IMPACTED OUR PATIENTS? HERE THAT REPRESENTS A LONGITUDINAL DATA SET OF 700 COLLEGE STUDENTS BEFORE THE PANDEMIC, ONCE THE PANDEMIC STARTED THEY DID A SECOND WAVE AND FOLLOWED UP ON DATA THAT INCLUDED CLINICAL AND BIOMETRIC DATA, HERE WE SEE THE SCORE CALLED THE CES DEPRESSION SCALE, BASE LINE 2019 IN BLUE, RED THE END OF 2019, AND YOU SEE THAT IT'S BEEN FAIRLY STEADY IN 2019. THE SCORES, A SCORE OF 16 OR GREATER REPRESENTS DEPRESSION. IN 2020 THE BASE LINE WAS COMPARABLE TO THAT OF 2019 AND SIBLGHT% INCREASE IN THE SCORES OF DEPRESSION, SUGGESTING AN INCREASE IN DEPRESSIVE SYMPTOMS AS I MENTIONED. WHAT ABOUT SCREEN TIME AND SOCIAL INTERACTION, HERE IN THE Y-AXIS WE SEE HOURS, WE SEE BASE LINE IN FEBRUARY IN BLUE, AND APRIL AND RED, AND THEN BY 2020 WE SEE A SIGNIFICANT INCREASE FROM ABOUT 2 HOURS SCREEN TIME TO OVER 5 HOURS. AND THAT IS TOWARD WORK, AND WE SEE 2019 WAS FAIRLY CONSISTENT AND PLATBUT BY APRIL OF 2020, WE SEE DECREASED BY 20, BY 30 MINUTES ON SOCIAL INTERACTION SO SPENDING LESS TIME WITH OTHER INDIVIDUALINGS. WHAT ABOUT PHYSICAL ACTIVITY AND SLEEP, AS I MENTIONED VERY IMPORTANT FOR MAINTAINING OR DEEXPRESSIVE SYMPTOMS, USING FIT BIT, BIOMETTICS WE SEE THE STEPS, THE AVERAGE STEPS RECOMMENDED IS ABOUT 10,000 FOR DAY IN BLUE, TWEBT 19, IN RED, WE SEE 2020 A SIGNIFICANT DECREASE TO ABOUT 5000. IN TERMS OF PHYSICAL ACTIVITY, USUALLY IT'S ABOUT 4 AND HALF HOURS A DAY, THAT WAS IN 2019. WE SEE A SIGNIFICANT DECREASE IN UNDER 3 HOURS IN PHYSICAL ACTIVITY IN 2020. SLEEP DURATION, WE ARE SPENDING MORE TIME AWAY AND THIS REPRESENTS 3 MONTHS DATA BETWEEN FEBRUARY AND APRIL. WE SEE IN RED, 2020 COMPARED TO BLUE 2019. AN INCREASE SLEEP DURATION SIGNIFICANT INCREASES. IN TERMS OF WEAK TIME, WE SEE THERE ARE DIFFERENT, IN RED TWEBT 20 WE SEE THAT MOST INDIVIDUALS ARE NOW WAKING UP BETWEEN 9:30 AND 10. YOU CAN SEE THIS MIGHT AFFECT MOOD, MIGHT AFFECT PHYSICAL ACTIVITY AND CIRCADIAN RHYTHMS AND ALSO HAS IMPACT ON CARE AND CLINICAL RESEARCH. NOW WE TEND TO SEE DEPRESSION AS MORE OF A MOOD OR A BRAIN DISORDER BUT ALSO AS A SYSTEMIC MEDICAL ILLNESS. TOWARDS THE LEFT WE SEE IF YOU HAVE DEPRESSION, YOU HAVE INCREASED RATES OF MANY OTHER MEDICAL CONDITIONS YOU HAVE INCREASED RATES OF DEPRESSION, MIGRAINES, CORTISOL, INCREASES OR DESREGUTION, DISREGULATION OUT OF THE IMMUNE SYSTEM, IMPAIRMENTS IN THE CARDIOVASCULAR SYSTEM, IF I HAD A MY O CARDIAL INFARCTION AND I HAVE DEPRESSION, I AM AT 3 AND HALFTIMES GREATER RISK OF DYING JUST BECAUSE OF THE FACTOR OF HAVING CO MORBID DEPRESSION, WE SEE GRITTER INCREASES IN THIS ADIPOST TISSUE, BODY MASS INDEX AND DECREASES IN BONE DENSITY, OSTEO PENIA, MORE COMMON IN WOMEN WITH DEPRESSION THAN WITHOUT DEPRESSION. AND OF COURSE THERE ARE ENVIRONMENTAL IMPACTORS THAT AFFECT BODY AND HEALTH. TOWARDS THE RIGHT THERE ARE IMPAIRNLTS ON SLEEP ON MANY DIFFERENT PARAMETERS AND, ARCHITECTURE AND ON SYNAPTIC AND OTHER FORMS OF PLAOF THE ISOTOPEIT WHICH I WILL TALK ABOUT IN A MINUTE. HERE WE SEE THAT THE DEPRESSION HAS RESILIENCE IN NEUROPLASTICKITY. TOWARDS THE RIGHT WE SEE THE SPINES AND CIRCUITS OF THOSE INDIVIDUALS AND SYNAPSES OF HEALTHY INDIVIDUALS OR THOSE TREATED WITH MOOD DISORDERS. WE SEE ABUNDANT SPINES AND INSTACT STICKER UTRS AND ABUNDANT BRANCHES AND RAMIFICATIONS HOWEVER, TOWARDS THE LEFT IN THOSE WITH SEVERE RECURRENT DISORDERS, YOU SEE SHIVELING OR ATROPHY REDUCTIONS IN BRAIN VOLUME AND INDUCTION AND STARTS LOOKING LIKE A 3 IN WINTER DEPRIVED OF THE MANY OF THE BRANCHES AND LEAVES. SIDERS THE MIDDLE THIS IS A NEXT GENERATION OF FOCUS IN MAJOR PART ON THE GLUTAMATERGIC SYSTEM, DEVELOPING MEDICATIONS SUCH AS KETAMINE OR DERIVATIVES WHICH ARE ALSO PLASTICITY ENHANCERS AND I WILL TALK ABOUT THAT IN THE NEXT FEW SLIDES. NOW WE TALK ABOUT A FACTOR INVOLVED IN DEPRESSION IS STRESS, ENVIRONMENT WHICH LEADS TO INFLAMMATION, DISTURBANCES IN T-CELLS, MONOCYTE MACROPHAGES WHICH AFFECT THE MONA MEAN METABOLISM, GLUTAMATE METABOLISM AFFECTS EFFECTIVE CIRCUITS AND SYNAPSES AND DECREASE IN PLASTICITY FACTORS THAT MAINTAIN NEURONS. NOW HOW DOES THIS IN FACT--HOW IS THIS IN THE COVID ERA, WELL, WITH THE COVID VIRUS, THERE HAVE BEEN--WE ARE SEEING INCREASES IN INFLAMMATION, IMMUNE REACTIONS, INCREASES IN COAGULATION, AND SO THIS IS IMPACTING THOSE WHO PERHAPS HAVE A MENTAL DISSEREDDER AND MAKING THINGS MUCH WORSE AND WE WILL HAVE TO CONSIDER STUDYING THAT OR FACTOR THAT INTO OUR STUDIES. NOW I HOPE I'VE MADE A CASE WHERE WE NEED NOVEL THERAPEUTICS FOR TREATMENT FOR DEPRESSION AND SUICIDE. WE HAVE ADVERSE EFFECTS FROM DEPRESSION, DISRUPTION TO PERSONAL AND FAMILY AND SOCIAL LIFE. OCCUPATIONAL IMPAIRMENT AND RISK FOR SUICIDAL BEHAVIOR AND WE HAVE PROBLEMS WITH OUR CURRENT ANTIDEPRESSANTS, LOWER EMISSION RATES, MANY HAVE TREATMENT RESISTANT DEPRESSION AND A LAG OF ONSET OF ANTIDEPRESSANTS AND SUICIDE. THE DEPRESSIVE EPISODE FROM AN INDIVIDUAL WHO IS EUTHYMIC, TO WHEN THEY DEVELOP DEPRESSION. AND WHAT WE FIND HERE AND INITIATE TREATMENT WITH OUR MONOMINERGIC TREATMENT, IS A CONSIDERABLE LACK OF 10-14 WEEKS, IN THE MEAN TIME, IN THE INDIVIDUALS CONTINUE WITH DISRUPTION TO THEIR LIFE ANDAT RISK FOR SUICIDAL BEHAVIOR, THIS IS IN MY MIND UNACCEPTABLE AND WE FLEED TO DREP TREATMENTS THAT WORK IN THE FEW HOURS OR DAYS AND THIS IS NOW POSSIBLE FOR EXAMPLE, WITH KETA MINE AND CERTAIN DERIVATIVES. NOW OF COURSE WE HAVE TO MOVE INTO BETTER THERAPEUTIC AND THERE'S A NEED TO IDENTIFY CELLULAR AND MOLECULAR TARGETS. KETAMINE IS NOT AN NMDA RECEPTOR ANTAGONIST, IT BLOCKS THE SITE WITHIN THE NMDA RECEPTOR AND IT HAS MANY DIFFERENT NAMES. VITAMIN K, KETA LORA RODRIGUEZ, IT IS A ANESTHETIC PRODUCES PSYCHOIMMUNE DYSFUNCTIONETTIC PROPERS AND HAS COMMON USES IN MEDICINE FOR DIAGNOSTIC AND SURGICAL PROCEDURES UNFORTUNATELY BECAUSE OF THE SIDE EFFECT PROFILE, IT IS ABUSED IN TERMS OF VIABILITY, IT'S NOT WELL ABSORBED ORALLY, IMPOSSIBLE TO BUILD RAINATEALLY IT'S ABOUT 25-50% AND INTRAVENOUSLY OF COURSE IS 100%. WHEN YOU TAKE KETAMINE, YOU EXPERIENCE PSYCHOLOGICAL SYMPTOMS DECREASE IN AWARENESS OF ENVIRONMENT, SEDATION, DREAM LIKE STATES, YOU HAVE DISASSOCIATION WHERE YOUR MIND AND BODY IS DISCONNECTED ONLY DURING THE TIME OF THE KETA MEAN INFUSION AND WE HAVE INCREASES IN BLOOD PRESSURE AND HEART RATE. NOW WHEN WE WERE STUDYING KETAMINE MANY YEARS AGO, BECAUSE OF THE ETHICS AND THE SIDE EFFECTS WE STUDIED INDIVIDUALS WHO WERE TREATMENT RESIST APT DEPRESSION, MEANING YOU HAD FAILED OVER 5 ANTIDEPRESSANT TREATMENTS AND 50% HAD PREVIOUS SUICIDE ATTEMPTS SO THERE WERE NO OTHER REASONABLE ALTERNATIVE FOR THESE PATIENTS AT THE TIME. SO THE QUESTION WE POSED WAS WHETHER A SINGLE INFUSION OF KETAMINE LEADS TO RAPID ANTIDEPRESSIVE EFFECTS AND THE ANSWER IS YES, YOU SEE THE DEPRESSION SCORES GOING UP, GREATER SEVERE MITRAL ERITY, HERE IN THE X-AXIS OF TIME AND MINUTES AND DAYS AND WE SEE WITH 1 INFUSION RAPID ONSET WITHIN HOURS, AS OPPOSED TO WEEKS WITH 1 INFUSION, INDIVIDUALS WITH TREATMENT RESISTING DEPRESSION AND AND WE CAN SEE HERE WITHIN HOURS OR 1 DAY AACHIEWF WHEN WHAT YOU DO WITH INDIVIDUALS TAKING A PILL EVERY DAY FOR 6-8 WEEKS, SO WE SEE RAPID ROBUST AND RELATIVELY SUSTAINED AND DEPRESSIVE EFFECTS. NOW DETAILSA MEAN IN ADDITION TO HELPING WITH DEPRESSION SEEMS TO HAVE CENTER FOR EXCELLENCE ON AGINGS ON OTHER SYSTEMS. HERE AS I REPORTED WE'VE SEEN ONSET WITHIN 1 HOURS WITH 1 INFUSION LASTING ABOUT 1 WEEK OR LONGER WITH 1 SINGLE ADMINISTRATION. SO TO THE RIGHT REPRESENTS DISASSOCIATIVE SYMPTOM THAT LAST DURING AN INFUSION OF KETAMINE WHICH IS 40 MINUTES BUT WE SEE IN IMPROVEMENTS IN SUICIDE IDEATION AND ANTIANXIETY EFFECTS IMPROVEMENTS IN ANADONIA AND PTSD SYMPTOMS AND IMPROVEMENTS IN QUALITY OF LIFE AND FUNCTION. NOW THERE ARE NOW 3 MAJOR PHARMACOLOGICAL PRESENCES AND THOSE MODULATORS TO PUT A PROTOTYPE IS KETA MEAN, SECOND GROUP ARESTER SOIDS WHERE WE HAVE BREXANOLONE, WHICH IS A GABA MODULATOR IS APPROVED FOR POSTPARTUM DEPRESSION AND TOWARDS BOTTOM WE HAVE A NEW GROUP OF GREGS, SILO SIGNIN AND SEEM TO HAVE RAPID ACTIVE--RECEPTORS PEER HERE WOO HAVE THE OPIOIDS WHICH DR. VOLKOW TALKED ABOUT, YOU HAVE SEROTONEIN IN MDA RECEPTORS. THE CASCADES ARE DIFFERENT FOR THESE DIFFERENT RECEPTORS AND THESE DIFFERENT DRUGS BUT THEY SEEM TO HAVE COMMON OVERLAPPING TARGETS ON NETWORKT RECONFIGURURATION MORE DOWN STREAM THAT INCLUDES SPINE, TURNOVER, INCREASES IN NEUROTROUGHINS, PROTEIN TRANSCRIPTION, CYTOSKELETAL REGULATION AND NEUROGENESIS. NOW IN EMERGING ITS OF MOOD DISORDERS, THIS IS PRESYNAPTIC AND POST SYNAPTIC NEURON, WE SLEEP APNEA AND OBESITY THE KETA MEAN, 1 THEOR SETHAT THE MECHANISMS BY BINDING TO NMDA RECEPTORS ON GABA URNLG INCREASE IN BODY INTERNEURONS, WHEN THAT HAPPENS IT DECREASES INHIBITION, THUS PRODUCING EXCITATION OF PER MIDDLE CELLS AND EVOKED RELEASE OF GLUTAMATE SO THIS IS SO CALLED GLUTAMATE BURST, ACTIVATES AMP O RECEPTORS VERY IMPORTANT IN PLASTICITY MECHANISM AND A SERIOUS OF INTRA CELLULAR SIGNALING CASCADE, CHANGES THAT ULTIMATELY LEAD TO AN REINTEGRATED SERVICES CREASE IN SPINES AND EFFECTS OF SYNAPSES IS CIRCUITS WHICH ARE SHRIVELED AND ATROPHIED IN DEPRESSION AS I MENTIONED. NOW THE PROBLEM I MENTIONED BEFORE IS THAT KETAMINE BLOCKS NMDA RECEPTOR WHICH MIGHT BE RESPONSIBLE FOR SIDE EFFECTS AND ABUSE POTENTIAL SO CAN WE GO MORE DOWN STREAM PRODUCING THIS EVOKED RELEASE OF GIEWTA MATE WITHOUT BLOCKING THE NMDA RECEPTORS SO WE CONSERVE THE EFFICACY WITHOUT THE SIDE EFFECT PROFILE AND THERE SEEMED TO BE OTHER TARGETS AND NGLUR 2, GABA A RECEPTOR MODULATORS, AND THEN WE HAVE THE SON OF KETAMINE WHICH IS 2 R-6 R HYDROXY KETAMINE WHICH WE'RE DEVELOPING INTRA MIEWRALLY AND HOPEFULLY WILL BE TESTED ON OUR RESEARCH UNIT BY THE END OF THE YEAR T. SEEMS TO BE DEVOID OF THE SIDE EFFECTS AND ABUSE TO TENTIAL OF KETAMINE. ALL THESE DRUGS HAVE IN COMMON IS A PROPERTY OF AMPA ACTIVATION BECAUSE WHEN YOU PRETREAT MICE WITH AN AMPAAN TAGANIST, YOU ABOLISH THE PROPERTIES YOU SLEEP APNEA AND OBESITYY SUGGESTING THE THROUGH PUT TO THE MECHANISMS OF KETAMINE. NOW, THIS EXCITATION AND HIB THORSITION BOUNCED FOR GABA AND MEDDLE CELLS THERE SEEMS TO BE A MARKER FOR THIS WHICH IS THE GAMMA POWER THAT YOU WILL OBLIGATIONS STAIN ON EEG 30-50 HRTZ AND THIS REPRESENTS NEURONAL SYNCHRONIZATION AND COULD BE A POTENTIAL CROSS SPECIES BIOMARKER BECAUSE YOU SEE THESE CHANGES IN RODENTS AND ALSO IN HUMANS. SO KEEP IN MIND THAT WE HAVE NOW A RAPID ACTIVE ANTIDEPRESSANT EFFECT, CAN WE TAKE ADVANTAGE OF THIS AND STUDY ITS MECHANISM USING MULTISCALE SYSTEMS BIOLOGY APPROACH TO BETTER UNDERSTAND ITS MECHANISM FOR AN ANTIDEPRESS EXPANT ANTISUICIDE IDEATION EFFECTS SO THAT WE CAN OBLIGATIONS STAIN INFORMATION AT DIFFERENT LEVELS OF BIOLOGY GOING FROM BEHAVIOR TO PHYSIOLOGY, CIRCUIT CELLS AND OF COURSE MOLECULES. AND WE USE DIFFERENT TECHNOLOGIES ON OUR PATIENTS, POLYSOM NOGRAPHY, MRS, MAGNET INCREASE IN BODY ENCEPHALOGRAPHY, WE LOOK THEA THE STRUCTURE, BRAIN CIRCUITS, IN RELATIONSHIP TO TREATMENT RESPONSE. ONE EXAMPLE IS DEFAULT MODE NOTEBOOK WORK, THESE ARE THE TRIPLE NETWORK IS IMPLICATED IN DEPRESSION. THESE ARE THE 3 NETWORKS THIS IS THE DEFAULT MODE NETWORK INVOLVED IN SELF-REFERENTIAL MENTAL ACTIVITY. TOWARDS THE RIGHT THE CENTRAL EXECUTIVE NETWORK, WE SEE THAT INDIVIDUALS HAVE IMPAIRMENTS IN COGNITION AS I MENTIONED, DECISION IMPAIRMENT, AND THEN THE SALIENTS NETWORK THAT SWITCHES BACK AND FORTH, IT'S BELIEVED THAT IN DEPRESSION TOWARDS THE LEFT HERE, WE SLEEP APNEA AND OBESITYY THAT THE DEFAULT MODE NETWORK OR DMN IS INCREASED OR IMPLICATED ILLUMINATION. TOWARDS THE BOTTOM RIGHT WE SEE IN HEALTHY VOLUNTEER SUBJECTS WE LOOK AT THE GERONTOLOGYSTS FAULT NETWORK AND TREATMENT WITH KETA MINE AND WE SEE THERE'S A DECREASE IN THE DEFAULT NETWORK SO SUGGESTING YOU COULD REVERSE WHAT HAPPENS IN DEPRESSION WITH KETAMINE, SO WE PURSUED A STUDY WITH THIS IN DEPRESSED PATIENTS, LOOKING AT RESTING STATE FUNCTIONAL CONNECTIVITY, WHERE INDIVIDUALS RECEIVE 1 INFUSION OF KETAMINE OR PLACEBO AND THEN THEY ACROSSED 2 WEEKS LATER TO THE OTHER TREATMENT CONDITION. AND WHAT YOU FIND HERE IS EACH INDIVIDUAL OBTAINED 5 SCANS, 1 AT BASE LINE, SCORE CHANGES, INDIVIDUALS AT BASE LINE HAVE DEPRESSION SCORE OF ABOUT 33, WITH KETA MEAN WE SEE SIGNIFICANT DECREASE BY DAY 2, AND DEPRESSION SCORES AND AS I MENTIONED BEFORE, THE EFFECTS SEEM TO WEAR OFF BY THE END OF 1 WEEK AND RETURN TO BASE LINE BY DAY 10-14. WHEREAS IN GREEN, THERE ARE NO SIGNIFICANT CHANGES IN PLACEBO. NOW, WHAT IS OF INTEREST HERE IS THAT WE ALSO STUDIED HEALTHY CONTROL INDIVIDUALS AND I WILL SHOW YOU THE DIFFERENCE BETWEEN PATIENTS AND INDIVIDUALS HEALTHY SUBJECTS WHO RECEIVED KETA MEAN. AT BASE LINE THIS REPRESENTS HYPER ACTIVATION OF INSURVEYS LA, THE DIFFERENCE BETWEEN DEPRESSED AND HEALTHY CONTROL SUBJECTS. AT THE PEEK OF KETAMINE'S ANTIDEPRESSIVE EFFECT YOU SEE NO LONGER AFFECTIVATION SO THAT DIFFERENCE IS WIPED OUT SUGGESTS NORMALIZATION AND YOU CAN SEE IF THE DEPRESSIVE SYMPTOMS RETURN, THERE'S A RETURN OF THE HYPER ACTIVATION, SO THERE IS A VERY NICE NEAT RELATIONSHIP OF CHANGE AND DEPRESSIVE SYMPTOMS IMPROVEMENT WITH NEUROIMAGING MARKER. NOW 1 OF THE CARDINAL SYMPTOMS I MENTIONED OF DEPRESSION, IS ANADONIA, THE LACK OF PLEASURE OR INTEREST, AS I MENTIONED. TOWARDS THE RIGHT YOU SEE THE SHOT OF THIS IS A MEASURE OF ANADONIC SYMPTOMS OR PLEASURE, WE SEE KETAMINE IN RED, BRINGS DOWN THE SCORE SO SUGGESTING IT IMPROVES LACK OF PLEASURE AND ADONIA LASTING OVER 1 WEEK. SO HERE AND I HE POSED A FOLLOWING QUESTION DOES KETAMINE AFFECT CORTICAL STRAIGHTAL CIRCUITS? WHY IS THAT? WHAT DR. VOLKOW MENTIONED IN PLEASURE OR REWARD OR ADVERSIVE CONDITIONING SO THAT WAS THE QUESTION POSED AND THIS STUDY WE HAD 33 UNMEDICATED PATIENTS WITH TREATMENT RESISTANT DEPRESSION AND 25 HEALTHY CONTROLS. RECEIVED KETAMINE ORE PLACEBO 1 INFUSION AND ACTIVE WEEKS CROSSED OVER TO THE TREATMENT CONDITION, THE RESTING SCAN WAS DAY 2 AFTER EACH TREATMENT CONDITION, SPECIFICALLY WE LOOKED AT EMOTIONAL COGNITIVE AND RHETORIC PROCESSES, LOOKING AT 4 Cs THAT ARE INVOLVED IN THOSE PROCESSES, DORSAL KAWD QUAIT, VENTRAL STRIATUM, VENTRAL ROSTRAL PUTAMEN, DORSAL KAWDAL PUTAMEN. AND ONCE AGAIN I WILL TALK ABOUT THE GLOBAL DIFFERENCES IN WHOLE BRAIN FUNCTIONAL CONNECTIVITY, IN THESE 4 STRAIGHTAL CIRCUITS BETWEEN HEALTHY CONTROL SUBJECTS AND DEPRESSED SUBJECTS. IN GREEN IS PLACEBO AND KET KETAMINE IS ORANGE. TOWARDS THE LEFT WE SAW HEALTHY CONTROL SUBJECTS AND IN RIGHT WE SEE TREATMENT RESISTANT DEPRESSION ACROSS THE 4 SEATS. IF YOU LOOK ACROSS THE 40 DIFFERENT FIGURES, YOU SEE AN INCREASE IN THE ORANGE PLOT, SUGGESTING INCREASES IN FUNCTIONAL CONNECTIVITY IN DEPRESSED SUBJEKS WHEREAS IN HEALTHY CONTROL SUBJEBS WHEN THEY SEE KETAMINE, THEY HAVE THE OPPOSITE PATTERN, YOU HAVE A DECREASE IN FUNCTIONAL CONNECTIVITY AND THESE 4 SEEDS, SUGGESTING HOMEIO STATIC MECHANISM THAT PLAGUED AND SEEN IN HEALTHY CONTROL SUBJEBS TO RECEIVE KETAMINE IS A TEMPORARY INCREASE IN DEPRESSIVE OR ANADONIC SYMPTOMS WHEREAS IN TREATMENT RESISTANT SYMPTOMS WE HAVE IMPROVEMENT IN DEPRESSION AND ANADONIA. TOWARDS THE BOTTOM WE SEE THE RELATIONSHIP OR CORRELATION BETWEEN IMPROVEMENTS IN DEPRESSION AND THESE 4, INCREASED CONNECTIVITY, A VERY NICE RELATIONSHIP SHOWING WITH VENTRAL STRIATUM, A LOT OF PREFRONTAL CORDEPRESSIVE SYMPTOMS AND ALSO AN IMPROVEMENT IN ANADONIA REWARD OR PLEASURE, SO SUGGESTING THAT CORTICAL CIRCUITS ARE IMPORTANT IN DEPRESSION AND IN ANADONIA ESPECIALLY IN THE MECHANISM OF TREATMENT RESPONSE TO KETAMINE. NOW GETTING INTO THE LAST COUPLE OF SLIDES TO BE ON TIME. WE ARE DEPRIVATIONING NOVEL THERAPEUTICS TOWARD DEPRESSION AND TREATMENT FOR SUICIDE USING A MULTIMODAL APPROACH, I JUST PROVIDED A FEW--A FEW OF OUR STUDIES IN THE INTEREST OF TIME, SO WE ARE OBLIGATIONS STAINING INFORMATION AT THE CELLULAR MOLECULAR LEVEL, USING EXTRAMURAL PRECLINICAL DATA AND ALSO INTRAMURAL PRECLINICAL DATA AND WE FUELED THE INFORMATION WITH PROOF OF CONCEPT STUDIES AND THE--VICE VERSA AND WE ALSO OBLIGATIONS STAINED INFORMATION AND THE AT CIRCUITS AND SYSTEMS FOR BIOLOGICAL MEASURES TO ENHANCE OUR UNDERSTANDING OF DISEASE AND MECHANISM AND TREATMENT RESPONSE? THEN FINALLY THE THIRD LEVEL OF INFORMATION PROVIDED BY THE STUDIES WERE OBTAINING INFORMATION ON BIOLOGICAL SUBGROUPS. WHY IS THAT IMPORTANT? BECAUSE DEPRESSION IS QUITE HETEROGENEOUS ROW GENIUS, THERE ARE MANY DIFFERENT DEPRESSIONS, MANY CAUSE OF DEPRESSION, AND WHAT WE'RE TRYING TO DO IS ENRICHED HOMOGEANOUS SUBTYPES OF DEPRESSION THAT WE CAN TARGET WITH MORE SPECIFIC THERAPEUTICS. SO IN SUMMARY DEPRESSION IS A SYSTEMIC MEDICAL ILLNESS AND ALSO BRAIN DISORDER, THERE IS EVIDENCE OF DEPRESS ANT SYMPTOMATOLOGY DURING THE PANDEMIC BUT WE HAVEN'T SEEN THE LONG-TERM CONSEQUENCES ESPECIALLY IN REGARD TO SUICIDE, SUICIDE IS A CONCERN DURING THIS PERIOD OF STRESS AND ISOLATION, THE CURRENT DATA SUGGESTS THAT THE OVERALL SITES ARE MAINTAINED OR DECREASED SLIGHTLY BUT AGAIN WE WILL HAVE TO SEE IN THE MONTHS AND YEARS TO COME THE EFFECTS OF COVID ON SUICIDE RATES. SO WITH THAT I WOULD LIKE TO STOP HERE AND THANK YOU FOR YOUR ATTENTION. >> THANK YOU VERY MUCH. THIS IS REALLY VERY EXCITING TO REELZ THAT THE--REALIZE THAT THE TRANSITION INTO NEUROBASE AND CELLULAR TECHNOLOGY IS BEING APPLIEDED IN THIS CHALLENGING ENTITY. WE'VE HAD SEVERAL QUESTIONS AND PEOPLE HAVE ASKED WHETHER KET KETAMINE IS ADDICTIVE. >> YES, SO, KETAMINE IS--BESIDES THE SIDE EFFECTS I'VE MENTIONED DISASSOCIATION, IT IS A DRUG OF ABUSE COMMONLY IN--MORE COMMON IN ASIAN COUNTRIES BUT IT IS A DRUG OF ABUSE. I FAILED TO MENTION THAT KETAMINE'S RESEARCH OVER THIS PAST DECADE PLUS HAS LED TO THE FDA APPROVAL OF A FORM OF KETAMINE CALLED SPROVADO, IT'S AN INTRA NAISAL FORM AS KETAMINE, KETAMINE IS RECEIVING IT AND IT HAS AN R-ISOMERAND AN S-ANTIMER, AND S-KETAMINE HAS BEEN DEVELOPED FOR INTRA NAISAL USE. IT IS NOW FDA APPROVED BUT IT CAN ONLY BE ADMINISTERED IN THE CLINICS OR UNDER MEDICAL SUPERVISION, YOU CANNOT TAKE IT HOME. SO A PATIENT WHO HAS QUALIFIED TREATMENT RESISTANT DEPRESSION, FAILED 2 ANTIDEPRESSANT TRIALS CAN GO FOR PEOPLE WHO ARE SPECIFICALLY TRAINED PHYSICIANS AND EVEN THE PHARMACY, THEY CAN RECEIVE IT THERE AND THEY GO HOME, THEY CANNOT TAKE IT HOME AND SO, THAT IS A RISK OF MITIGATION STRATEGY THAT IS BETWEEN JOHNSON AND JOHNSON AND THE FDA AND IT IS IN PART TO ADDRESS THAT RISK OF ABUSE THAT I JUST MENTIONED. SEPARATE THAN THAT, WE CONTINUED SO THAT IS WONDERFUL FOR OUR PATIENTS WHO HAVE FAILED TO RESPOND TO MANY TREATMENTS. YOU GO THROUGH THE DECISION TREE, ALGORITHMS, YOU TRY WHAT IS MEDICINE AND YOU GET TO KETAMINE AND THAT MIGHT HELP THEM. WE IS OTHERS ARE TRYING TO FIND THE NEXT FORM OF KETAMINE IS UNDERSTAND THIS MECHANISM AS I EXPLAINED. ONE OF THE SONS OF KETAMINE IS HYDROXY NORKETAMINE AND WE ARE DEVELOPING AT LEAST IN PRECLINICAL MODELS HAS NOT SHOWN TO HAVE THAT ABUSE POTENTIAL I MENTIONED OR THE DISASSOCIATIVE SIDE EFFECTS AND RIGHT NOW IT'S UNDERGOING PHASE 1 STUDIES AT DUKE AND WE ANTICIPATE IN OUR RESEARCH UNIT AT THE BEGINNING OF THE YEAR AND LEAD TO IMPROVE MENTSS IN THE DEPRESSION HOMES AND NOT HAVE THE SIDE EFFECT THAT KETAMINE PRODUCES. >> NATHAN ASKED CHANGE THE AMPA AS FAR AS NEURAL PLASTICITY? >> YEAH, THAT'S A VERY GOOD QUESTION. SO IN TERMS OF NEUROSTIMMULATION, LET'S SAY FOR EXAMPLE, THE ECT ELECTROCOMPULSIVE THERAPY WHICH IS ALSO A RAPID ACTING TREATMENT, ECT, AND ALSO SLEEP DEPRIVATION, 1 NIGHT OF PROFOUND PARTIAL OR TOTAL SLEEP DIVERSION, I MEAN IN 33 HOURS OR MORE, LEADS TO A RAPID ANTIDEPRESSANT EFFECT OF SLEEP DEPRIVATION, THE PROBLEM IS WHEN YOU GET RESTORATIVE SLEEP AND ANTIDEPRESSIVE RESISTANT THERAPY AND OTHERS TO LEAD TO AMPA ACTIVATION AND THE ANSWER IS YES, AND SO, THAT SEEMS TO BE MORE COMMON UPSTREAM MECHANISM FOR WHAT THE PRECISE MECHANISMS AND ECT, IS THE SLEEP DEPRIVATION, AND THE ACTIVATION SEEMS TO BE A COMMON PROPERTY. >> WHAT IS YOUR VIEW ABOUT IF WHEN A NOVICE LIKE A LIVER DOCTOR LOOKS IN THE INTERNET AND I'M LOOKING FOR STUDIES OF NEURAL BIOLOGY AND BIOCHEMISTRY, PATHOLOGY, ANYTHING, THAT IS SPECIFICALLY ASSOCIATED WITH SUICIDE. AND 1 FINDS A HUGE AMOUNT OF LITERATURE OF THE PATHOLOGY OF THE BRAIN AND ALL DIFFERENT RAMIFICATIONS FOR CONVENTIONAL STAINS TO MORE SOPHISTICATED ELECTRON MICROSCOPY AND SO FORTH, AND A WIDE VARIETY OF CLAIMS OF DIFFERENCES IN THE BRAIN OF PEOPLE WHO COMMITTED SUICIDE, 1 OF THE 1S THAT STANDS OUT IN MY MIND IS THIS WHOLE QUESTION OF WHETHER THE HYPOTHALAMUS IS ACTUALLY CONSIDERABLY SMALLER AND MAYBE DEPRESSED PEOPLE OR IN SUICIDAL PEOPLE, WHAT IS YOUR INTERPRETATION OF THIS KIND OF EXPERIMENTAL APPROACH AND GRANTED, IT'S A DIFFICULT PROBLEM BUT DO YOU THINK THAT IT'S LEADING US IN THE RIGHT DIRECTION? >> WELL, YEAH, YOU MENTIONED, THERE HAS BEEN VERY ELEGANT WORK BY [INDISCERNIBLE] LOOKING AT SUICIDE AND OTHERS, I MEAN, TO GIVE CREDIT OVER THE YEARS AND THEY HAVE IMPLICATED PROBLEMS WITH SEROTONIN, NEUROTRANSMITTER, DOPA MEAN, HYPE OR THALAMIC OR HP A X, YOU MENTIONED CORTISOL AT THE THYROID LEVEL HAS BEEN MENTIONED AND THEN GOING INTO THE CIRCUIT LEVEL. NOW I THINK 1 OF THE LIMITATIONS IS IN TERMS OF THE STUDY OF SUICIDE, FIRST OF ALL, THE SUICIDE IS NOT A COMMON EVENT EVEN THOUGH WE HAVE THE SUICIDAL BEHAVIOR, THE ATTEMPT AND SUICIDAL [INDISCERNIBLE] IS MUCH MORE COMMON. AND THE ISSUE OR THE ETHICS THAT SURROUND THE STUDY OF SUICIDE, SO AS I MAY HAVE MENTIONED MANY OF OUR STUDIES, MANY OF THE STUDIES THAT ARE DONE ARE PATIENTS WHO USE SUBSTANCES, ALCOHOL OR OVERDOSE, THEY MAY BE TAKING ANTIDEPRESSANTS AND THOSE ARE CONFOUNDERS IN ON THE NEURAL BIOLOGY AND SUICIDE AND DEPRESSION AND ANY RESULTS YOU GET ARE AFFECTED BY THOSE FACTORS I MENTIONED SO, IN OUR STUDIES WITH DEPRESSION, GET IN THAT NEURAL BIOLOGY, IT'S NOT UNIMHON EACH WITH OUR PATIENTS WITH SEVERE DEPRESSION, WE TAKE THEM OFF THEIR MEDICATIONS THUS REMOVING POETIC TEBTIAL CONFOUNDERS, OF COURSE, WE DO THIS SAFELY ON AN INPATIENT RESEARCH UNIT WITH CLOSE MONITORING BUT WHAT IS THE ETHICS OF STUDYING AN INDIVIDUAL WHO JUST HAD A SERIOUS SUICIDE ATTEMPT. IS IT ETHICAL TO DEPRIVE THEM OF THEIR MEDICATIONS OR TALK THERAPY AND THOSE ARE CONFOUNDERS. SO WHAT MANY RESEARCH GROUPS HAVE DONE IS STUDY INDIVIDUALS WITH WHO TEMENTED YOUICIDE OR HAD SUICIDAL IDEATION IN REAL--WITH MEDICATIONS OR THE CONFOUNDERS OF CONTROL OR OTHER SUBSTANCES AND TRY TO INTERPRET RESULTS BASED ON IT, THIS IS WHERE WE GET A DIVERSITY OF DIFFERENT STUDY RESULTS. NOW, THE APPROACH WE HAVE TAKEN AND OTHER GROUPS AS WELL IS, WE HAVE--OUR PATIENT WHO IS HAD A RECENT SUICIDE ATTEMPT, THIS IS A STUDY THAT'S LED BY DR. ELIZABETH BALLARD IN MY RESEARCH GROUP, FROM SUBURBAN HOSPITAL WHERE THEY RECENTLY HAD A SUICIDE ATTEMPT AND WITHIN HOURS OR A FEW DAYS, WE ADMIT THEM ON [INDISCERNIBLE] OUR RESEARCH UNIT WHERE WE APPLY THE MULTIMODAL MENTIONEDS SO IT'S 72 HOURS, VERY INTENSE AND VERY PROXIMAL TO THE SUICIDE ATTEMPT. PRIOR STUDIES BECAUSE OF THE COMPLEXITY OF THE ATTEMPT OR THE SUICIDAL THINKING HAVE COMPARED INDIVIDUALS BRAINS WITH SUICIDE ATTEMPT THAT I DATION ATTEMPT, VERSUS--THIS EARLIER SO HOW DO WE KNOW THIS HAS ANYTHING TO DO WITH THE NEUROBIOLOGY SAY OF SUICIDE. SO WHAT WE ARE DOING IS IN MORE REALTIME OR CLOSER TO THE EVENT, OR AN INDIVIDUALS WHO HAVE CURRENT SUICIDATION STUDY AND BRAINS AND THE OTHER ORGAN SYSTEMS I MENTIONED, WHICH DO CONTRIBUTE TO THE PSYCHOSOCIAL STRESS AND ENVIRONMENT IN THE CONTEXT OF THE RECENT ATTEMPT. >> IS THERE AN ANIMAL MODEL FOR SUICIDE? >> THERE IS NO ANIMAL MODEL TO DATE FOR SUICIDE, WHAT DR. VOLKOW MENTIONED AND SHE IS CORRECT THAT THERE ARE I GUESS DIFFERENT--WHAT WE CALL DIFFERENT PHENOTYPES, THERE ARE INDIVIDUALS WHO ARE--WILL PLAN VERY CAREFULLY THEIR SUICIDE ATTEMPT AND THEN ATTEMPT SUICIDE OR BE SUCCESSFUL IN THEIR SUICIDE. THERE ARE INDIVIDUALS WHO TEND TO BE VERY IMPULSIVE ATTEMPTS AND THEY MAY NOT THINK MORE THAN A FEW MINUTES, MAY HAVE HAD A BAD NEWS, BREAK UP AND MAY HARM THEMSELVES AND TAKEN--THEY'S WHAT WE REFER TO AS IMPULSIVITY AND WHAT INVESTIGATORS ARE USING IS STUDYING THE CONSTRUCT OF IMPULSIVITY IN THE INTERPHASE WITH THE SUICIDE ATTEMPT, AS A POETIC ATTENTIAL PROXY AND SO, IN TERMS OF ANIMAL MODELS, THERE ARE ANIMAL MODELS OF IMPULSIVITY IN THOSE LITHIUM WHICH IS A MEDICATION USED FOR BIPOLAR DISORDER, HAS MOOD STABILIZING EFFECTS AND ALSO HAS ANTISUICIDAL PROPERTIES AND SO IN THESE ANIMAL MODEL SUICIDE SEEMS TO HAVE AN EFFECT AND SO INVESTIGATORS ARE INFERRING THAT THOSE CHANGES MIGHT BE RELEVANT TO WHAT HAPPENS IN THE HUMAN BRAIN. WE DO NOT KNOW. THERE ARE HUMAN DISEASES LIKE LESH NEHAN WHICH ARE ARE IN CHILDREN WITH DEVELOPMENT AT DESORDERS AND SEVERELY DISRUPTIVE WHERE THEY HAVE INCREASES IN URIC ACID, HYPER--INCREASED IN URIC ACID AND MEDICATIONS ANTIPSYCHOTIC DRUGS THAT DECREASES OR LEATHIUM DECREASES THE URIC ACID AND THEY SEEM TO HAVE BEHAVIOR, SO DOES THAT MEAN THAT SUICIDE HAS TO DO WITH CHANGES IN THE PURINE SYSTEM OR URIC ACID NO, BUT WITH THE CONSTRUCT OF IMPULSIVITY AND THESE ARE LARGELY INDIRECT WAYS OF STUDYING SUICIDE. >> IS DEPRESSION MORE COMMON WHEN THE CIRCADIAN RHYTHM IS DISRUPTED WHEN A PERSON BECOMES A NIGHT WORKER? >> VERY GOOD QUESTION. SO WE DO FIND THAT THERE IS A LINK BETWEEN TIS DURBANCE IN THE CIRCADIAN RHYTHM AND DEPRESSION AND ALSO THERE'S A LINK WITH CIRCADIAN DISTURBANCES WHAT WE REFER TO AS MOOD DISORDERS SO THERE IS WORK ON NAAND THERE'S CERTAIN MEDICATIONS FOR EXAMPLE, LITHIUM STABILIZES CIRCADIAN RHYTHMS IN BOTH PRECLINICAL MODELS AND MOSTLY IN HUMANS AND SUGGEST THAT MAYBE THAT IS A MECHANISM FOR WHY PEOPLE HAVE CHANGES IN MOOD SYMPTOMS, BIPOLAR, MANIAS AND DEPRESSION, BUT IN TERMS OF YES, THERE SEEMS TO BE INCREASED RATES OF THAT, BUT THERE'S NOT A DIRECT RELATIONSHIP, SOME WORK SUGGESTS THAT THE ACTIVITY LEVELS DRIVE, THE MOOD CHANGES, RATHER THAN THE OTHER WAY AROUND. SO CIRCADIAN RHYTHM IS IMPORTANT AND PROUDLY INVOLVED IN 1 OF THE MANY MECHANISMS AND DEPRESSION OR WOB OF THE SUBTYPES BUT IS SOMETHING WE NEED TO UNDERSTAND TO BETTER UNDERSTAND THE NEUROBIOLOGY OF THE DEPRESSION. >> IS IT A FACTOR IN LONG DISTANCE AIRPLANE PILOTINGS? >> THAT'S A GOOD QUESTION BUT KEEP IN MIND THAT THE INDIVIDUAL SAYS HAVE WHAT WE CALL AN ALL MEDICINE, ALL BIOLOGICAL PROCESS HEMEIO STATIC MECHANISMS AND THERE'S THIS PLAY, OF THE I DIDN'T THINK AND THE YANG THAT GOES ON IN ALL ORGAN SYSTEMS AND ONCE SOMEBODY HAS DONE THAT CONSISTENTLY OVER TIME, THERE'S SYSTEM READJUSTS, AND SO INDIVIDUALS WHO PROBABLY DON'T HAVE A RISK OF DEPRESSION, MAYBE DON'T HAVE HIGH GENETIC LOADING AND DON'T HAVE OTHER OF THE FACTORS IMPORTANT IN METHODS OF DEPRESSION CAN ADJUST WITH IT. BUT WE DO KNOW THAT FOR PATIENTS WITH BIPOLAR DISORDER, CHANGE IN TIME ZONES AFFECTING SLEEP MIGHT PRECIPITATE A HYPOMANIC OR MANIC EPISODE OR DISRUPT THE MOOD EPISODES OF PATIENTS WITH BIPOLAR DISORDER SO THAT'S SOMETHING THAT CLINICIANS ARE VERY AWARE OF. WE REGULARLY JUST-- >> EDMOND ASKED WHAT DO YOU THINK OF RAPID KETAMINE FOR ENHANCING AND PROLONGING THE EFFECTS? >> YEAH, THAT'S--SO I EXPLAINED IN 1 OF THE FIGURES INTRA CELLULARLY IN TERMS OF MECHANISM, WHEN YOU ACTIVATASMA RECEPTOR IT IS A TARGET CALLED MTOR OR MAMMALIAN TARGETED RAP O MICE O SIGN, NOW KNOWN AS MECHANISTICALLY RAPID AND AND IT IS ACTIVATED BY KETAMINE AND WHEN YOU GIVE IT, YOU BLOCK THE EFFECTS OF KETAMINE, KIND OF THICISMULAR TO THASM O BLOCKER, BLOCK THE EFFECTS OF KETAMINE, THIS GOES MORE DOWN STREAM WITHIN THE CELL, YOU GET RAP O MICEIN AND ANTAGONIST, AND BLOCK THE EFFECTS OF KETAMINE SUGGESTING MTOR ACTIVATING WAS IMPORTANT NOW THAT WAS ALL BASED ON PRECLINICAL DATA BY VERY ELEGANT WORK BY MANY LABS BY RON [INDISCERNIBLE] AT YALE WHO RECEIPTLY PASSED AWAY BUT HE DID MUCH OF THE PIONEERING WORK IN THAT AREA, SO VERY IMPORTANT TO TRANSLATE PRECLINICAL FINDINGS INTO HUMAN STUDIES BECAUSE SOMETIMES YOU FIND THE OPPOSITE IN THE PRECLINICAL VERSUS HUMAN SO INVESTIGATORS AT YALE CONDUCTED A STUDY WHERE THEY ADMINISTERED RAP O MICEIN BEFORE GIVING KETAMINE IN SUBJEBS WITH TREATMENT RESISTANT DEPRESSION, SO THEIR HYPOTHESIS WAS IF I GIVE RAP O MICEIN I SHOULD BE ABLE TO BLOCK KETAMINE. BUT INSTEAD WHAT THEY FOUND WAS THE OPPOSITE. THEY FOUND IT THAT THERE--THE EFFECTS OF KETAMINE SEEMED TO BE PROLONGED FOR SEVERAL WEEKS, BEYOND WHAT YOU WOULD GET WITH A SINGLE ADMINISTRATION, SO, SOME HAVE ARGUED, YOU KNOW, WE DON'T HAVE PROBABLY MUCH TIME TO GO INTO THE DIFFERENT REASONS FOR THAT, BUT SOME HAVE ALSO MENTION SAID THAT RAP O MICEIN HAS INDEPENDENT EFFECTS IN INFLAMMATION AND SO IT COULD BE SOME OTHER MECHANISM THAT WAS INVOLVED AS I SHOWED YOU I BELIEVE A FIGURE THAT INFLAMMATION, PROINFLAMMATORY EFFECTS HAPPEN IN A PERSON THAT'S ADDRESSED IN SOME WAY. SO I THINK THIS STUDY WILL HAVE TO BE DONE IN--IT WILL HAVE TO BE REPLICATED SO IT'S A BIT PREMATURE TO SEE THE LONG-TERM EFFECTS OF KETAMINE, THE ONLY THING THAT HAS BEEN CONSISTENTLY TO THIS DATE SHOWN TO MAINTAIN CONTREATMENT OF KETAMINE IS REPEAT TREATMENT OF KETAMINE. WHEN YOU DO SO, CAN YOU KEEP, CAN YOU DECREASE THE DEPRESSIVE SYMPTOMS AND KEEP IT AT BAY FOR LONGER PERIODS OF TIME. WITH TIME OF COURSE IN MANY PATIENTS CAN YOU SPREAD OUT THE INFUSIONS AND EEIVETTUALLY RELY ON STANDARD TREATMENTS BUT WE STILL DO NOT KNOW LONG-TERM TREATMENT STRATEGIES TO REPLACE KETAMINE, MANY GROUPS ARE STILL LOOKING FOR WHAT MIGHT BE THE BEST OPTIONS OUT THERE. >> OKAY, SO 1 LAST QUESTION, CAROL ASKS HOW CAN THE INFORMATION ABOUT KETAMINE BE MORE WIDELY SHARED WITH PSYCHIATRISTS, SPECIFICALLY BEING MORE WIDELY ACCESSIBLE AS A FORM OF TREATMENT AND HOSPITALS ACROSS THE UNITED STATES? IS IT AVAILABLE BROADLY? >> THERE ISN'T MUCH INFORMATION BUT IF SHE WOULD LIKE TO CONTACT ME, I WOULD BE DELIGHTED TO PROVIDE MORE INFORMATION. BUT SHE IS CORRECT, THERE IS A LOT OF INFORMATION ON THE WEB AND THE KEY IS TO SORT WHAT IS MORE RELIABLE VERSUS NOT. THERE ARE MANY KETAMINE CLINICS AROUND THE COUNTRY BUT I THINK IT'S VERY IMPORTANT TO SPEAK IF YOU'RE IN TREATMENT WITH YOUR PHYSICIAN OR PHYSICIANS AT UNIVERSITIES THAT SPECIALIZE IN THE USE OF KETAMINE. SO MAKE SURE THAT ALL TREATMENT OPTIONS HAVE BEEN CONSIDERED INCLUDING TALK THERAPIES, STANDARD MEDICATIONS, KETAMINE IS AVAILABLE BUT IT HAS SOMEWHAT GREATER RISKS AND IT SHOULD BE USED ONLY IN THOSE WHO ARE WHAT WE CALL TREATMENT RESISTANT. >> ALL RIGHT. WELL, LISTEN CARLOS, WE WANT TO THANK YOU VERY, VERY MUCH. THIS IS VERY EXCITING AND CONTINUE THE GOOD WORK. IT'S WONDERFUL. >> THANK YOU VERY HAVING ME.