Institute For Psychiatric Neuroscience

TO CARRY OUT AND SUPPORT RESEARCH RELATED TO OBSESSIVE COMPULSIVE DISORDER OCD AND DEPRESSION.

OCD AND DEPRESSION ARE EMOTIONALLY DEVASTATING PSYCHIATRIC DISORDERS WITH SIGNIFICANT SOCIAL AND ECONOMIC COSTS. AN ESTIMATED 5 TO 6 MILLION PEOPLE IN THE UNITED STATES WILL SUFFER FROM OCD DURING THEIR LIFETIME. THE WORLD HEALTH ORGANIZATION HAS SAID THAT OCD IS AMONG THE 10 MOST DISABLING CONDITIONS IN THE WORLD. ONE PROBLEM IS THAT THE MEDICATIONS USED TO TREAT OCD CAN TAKE UP TO TWELVE WEEKS TO EXERT THEIR EFFECT, AND ONLY 30 PERCENT OF PATIENTS WILL RESPOND TO THEIR FIRST MEDICATION TRIAL. THIS MEANS THAT THOSE WHO DO NOT RESPOND MUST WAIT ANOTHER 12 WEEKS TO SEE IF THE SECOND MEDICATION HAS ANY BENEFIT. IT IS NOT UNCOMMON FOR PATIENTS TO HAVE 3-4 MEDICATION TRIALS TO FIND A TREATMENT THAT WORKS. PATIENTS WITH EXTREME SYMPTOMS MAY GIVE UP AND TAKE THEIR LIVES. IN FACT, 14-17 PERCENT OF OCD PATIENTS WILL ATTEMPT SUICIDE IN THEIR LIFETIME. AN ESTIMATED 17-20 MILLION AMERICAN ADULTS WILL SUFFER FROM DEPRESSION EACH YEAR. SEVERELY DEPRESSED PATIENTS HAVE HIGH SUICIDE RATES. SUICIDE IS THE FIFTH LEADING CAUSE OF DEATH AMONG ADULT MALES, AND THE THIRD LEADING CAUSE OF DEATH FOR ALL YOUNG PEOPLE AGES 15-24. ONE REASON FOR THESE HIGH SUICIDE RATES IS THAT SIGNIFICANT PERCENTAGES OF PATIENTS WITH OCD OR DEPRESSION WILL NOT RESPOND TO TREATMENTS, IN PART, BECAUSE WE DO NOT UNDERSTAND WHAT REALLY CAUSES THESE DISORDERS. THE IFPN HAS FUNDED RESEARCH RELATED TO THE NEUROBIOLOGY OF DEPRESSION IN THE PAST, AND MAINTAINS AN IN-HOUSE RESEARCH LABORATORY PROGRAM COMPLETING STUDIES ON THE NEUROBIOLOGY OF OCD THAT ORIGINATED AT VANDERBILT UNIVERSITY MEDICAL CENTER. OUR IN-HOUSE RESEARCH HAS BEEN A CONTINUATION WORK CARRIED OUT BY THE FOUNDER THAT WAS FUNDED THROUGH THE DEPARTMENT OF PSYCHIATRY AT VANDERBILT UNIVERSITY MEDICAL CENTER. WHILE SCIENTISTS ARE AWARE THAT A SPECIFIC CIRCUIT IN THE BRAIN INVOLVING THE PREFRONTAL CORTEX MAY BE INVOLVED IN PATHOPHYSIOLOGY OF OCD, WE DO NOT UNDERSTAND WHY THIS CIRCUIT IS ABERRANT, WHY MEDICATIONS THAT BLOCK THE INACTIVATION OF A NEUROTRANSMITTER CALLED SEROTONIN (KNOWN AS SELECTIVE SEROTONIN REUPTAKE INHIBITORS OR SSRIS), ARE EFFECTIVE IN THE TREATMENT OF OCD, OR WHY PATIENTS MUST TAKE THESE MEDICATIONS FOR UP TO 12 WEEKS TO GET BENEFIT FROM THEM. WE HAVE BEEN ATTEMPTING TO DETERMINE HOW THESE MEDICATIONS AFFECT THE OCD CIRCUIT USING AN ANIMAL MODEL IN WHICH WE STIMULATE SEROTONIN SIGNALING IN THE BRAIN. WE DETERMINE HOW CELLS IN THE EMOTIONAL PREFRONTAL CORTEX RESPOND TO INCREASED SEROTONIN STIMULATION, BY STAINING BRAIN SECTIONS FOR A PROTEIN THAT TELLS US WHICH CELLS IN THE PREFRONTAL CORTEX HAVE BEEN ACTIVATED BY THAT STIMULATION. WE THEN DETERMINE HOW THAT ACTIVATION IS CHANGED AFTER SHORT- OR LONG-TERM SSRI TREATMENT. WE FOUND THAT LONG TERM BUT NOT SHORT-TERM SSRI TREATMENT DAMPENS THE PREFRONTAL NEURONAL ACTIVATION. WE ARE CONTINUING OUR ANALYSES OF DATA FROM THESE EXPERIMENTS. WE ARE ALSO DETERMINING HOW DIFFERENT CELL TYPES IN THE PREFRONTAL CORTEX RESPOND TO SEROTONIN STIMULATION, AND HOW THOSE RESPONSES ARE ALTERED BY SSRI TREATMENTS. WE HAVE FOUND THAT SEROTONIN AFFECTS THE PROCESSING NEURONS WITHIN THE PREFRONTAL CORTEX DIFFERENTLY THAN THEY AFFECT NEURONS THAT PROJECT FROM THE PREFRONTAL CORTEX TO OTHER BRAIN REGIONS. OUR STUDIES, IN CONJUNCTION WITH THE WORK OF OTHERS, COULD POTENTIALLY LEAD TO TARGETED DRUG TREATMENTS THAT DIRECTLY NORMALIZE ACTIVITY IN THE OCD CIRCUIT, MEANING THAT PATIENTS WOULD NO LONGER HAVE TO SUFFER WHILE WAITING FOR THEIR SSRI TREATMENTS TO HAVE AN EFFECT. SUCH TARGETED MEDICATIONS COULD GREATLY IMPROVE THE TREATMENT AND QUALITY OF LIFE FOR THOSE SUFFERING FROM OCD. WE HAVE COMPLETED THE EXPERIMENTAL WORK FOR THESE STUDIES AND ARE IN THE PROCESS OF ANALYSING DATA FROM THE EXPERIMENTS. WITH THE WORK OF THE IFPN LABORATORY COMPLETE, WE HAVE CLOSED THE LABORATORY AND TERMINATED ALL LABORATORY PERSONNEL. THE WORK OF THIS PROGRAM CONTINUES IN THE ANALYSIS OF THE DATA GENERATED, AND IN THE REQUIREMENT FOR ADMINISTRATIVE AND LEGAL EXPENSES.

WE PREVIOUSLY MADE GRANTS TO VANDERBILT UNIVERSITY TO SUPPORT THE WORK OF THE BLAKELY LABORATORY AT VANDERBILT MEDICAL SCHOOL'S CENTER FOR MOLECULAR NEUROBIOLOGY. IN COLLABORATION THAT LAB, WE EXPLORED THE ROLE OF CHEMICALS CALLED CYTOKINES IN DEPRESSION. CYTOKINES ARE PRO-INFLAMMATORY MOLECULES THAT ARE RELEASED BY THE IMMUNE SYSTEM IN RESPONSE TO INFECTION. NUMEROUS LABORATORIES HAVE FOUND AN ASSOCIATION BETWEEN BRAIN CYTOKINES AND DEPRESSIVE ILLNESS, AND IT HAS RECENTLY BEEN FOUND THAT BLOCKING ONE CYTOKINE RECEPTOR IN THE BRAIN WILL PROTECT ANIMALS FROM DEPRESSIVE-LIKE SYMPOTMS INDUCED BY CHRONIC UNCONTROLLABLE STRESS. IT IS THOUGHT THAT SSRIS REDUCE FEELINGS OF DEPRESSION BY BLOCKING THE TRANSPORTER THAT INACTIVATES SEROTONIN, LEADING TO GREATER SEROTININ STIMULATION IN THE BRAIN. AT THE VANDERBILT CENTER FOR MOLECULAR NEUROBIOLOGY WE SHOWED THAT PROINFLAMMATORY CYTOKINES IN THE BRAIN HAVE THE OPPOSITE EFFECT. THEY INCREASE SEROTNIN INACTIVATION BY THE TRANSPORTER, LOWERING SEROTONIN AND INDUCING DEPRESSIVE-LIKE BEHAVIORS IN ANIMAL MODELS. WHEN THE INTRACELLULAR PATHWAY BY WHICH CYTOKINES ACTIVATE THE TRANSPORTER WAS BLOCKED, THE ANIMALS NO LONGER SHOWED DEPRESSIVE-LIKE SYMPTOMS. THESE STUDIES AND OTHERS SUPPORTED BY GRANTS FROM THE IFPN SUGGEST THAT REDUCED SEROTONIN LEVELS, TRIGGERED BY CYTOKINES IN THE BRAIN, COULD CAUSE DEPRESSION. IF SO, TARGETED ANTI-CYTOKINE TREATMENTS MIGHT LEAD TO IMPROVED TREATMENT AND EVEN PREVENTION OF SEVERE DEPRESSIVE ILLNESS. WORK RELATED TO OUR FINDINGS HAS RESULTED IN THE PUBLICATION OF NUMEROUS PAPERS. THE BLAKELY LAB, NOW AT FLORIDA ATLANTIC UNIVERSITY, HAS CONTINUED THE WORK THAT WE STARTED AT VANDERBILT, WITH OUR INITIAL SUPPORT. THEY HAVE SUBMITTED A PAPER SHOWING THAT A VIRUS-LIKE MOLECULE THAT CAUSES THE RELEASE OF CYTOKINES IN THE BRAIN, INDUCES A RAPID INCREASE IN SEROTONIN INACTIVATION IN LIVING MICE AND INDUCES A DEPRESSIVE-LIKE STATE THAT IS BLOCKED BY AN INHIBITOR OF THE INTRACELLULAR INFLAMMATORY PATHWAY. REVIEWERS HAVE ASKED THAT ADDITIONAL STUDIES BE COMPLETED BEFORE THIS PAPER IS RESUBMITTED FOR PUBLICATION. THE RESUBMISSION HAS BEEN DELAYED BECAUSE THE BLAKELY LAB HAS HAD DIFFICULTY REPLICATING THE ORIGINAL EXPERIMENTAL PARADIGM AT THE NEW FLORIDA LOCATION. THE LAB HAS UNDERTAKEN NEW STUDIES RELATED TO THIS WORK, FUNDED BY LAST YEARS GRANT FROM THE IFPN. THAT WORK IS ONGOING AT THIS TIME. NO GRANTS WERE MADE TO THIS PROJECT THIS FISCAL YEAR.