Project Grant R61HL167909

A SELECTIVE SEROTONIN REUPTAKE INHIBITOR FOR ASTHMA PATIENTS WITH FREQUENT EXACERBATIONS - PROJECT SUMMARY/ABSTRACT ASTHMA PREVALENCE HAS INCREASED IN RECENT YEARS WITH 8.4% OF ADULTS DIAGNOSED WITH ASTHMA. ASTHMA CAN BE A LIFELONG DISEASE. THESE RATES INCREASE WITH AGE, ARE 60% HIGHER IN WOMEN THAN MEN AND ARE ESPECIALLY HIGH IN AFRICAN AMERICANS. THUS, ADULT ASTHMA IS A MAJOR HEALTH CONCERN. RATES OF UNCONTROLLED ASTHMA ALSO INCREASE WITH AGE AND ARE HIGHER IN WOMEN AND IN MINORITIES, ESPECIALLY HISPANICS. TEXAS, WHERE THE PROPOSED STUDY WILL TAKE PLACE, HAS THE THIRD HIGHEST RATE OF UNCONTROLLED ASTHMA; THEREFORE, MORE EFFECTIVE TREATMENTS FOR ADULT ASTHMA ARE NEEDED. ASTHMA PATIENTS WITH FREQUENT EXACERBATIONS DESPITE APPROPRIATE TREATMENT POSE A PARTICULAR CHALLENGE. NEW TREATMENTS ARE NEEDED TO IMPROVE ASTHMA CONTROL IN THIS SUBPOPULATION. OUR PILOT DATA FROM THREE PRELIMINARY STUDIES SUGGEST THAT THE SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS) CITALOPRAM AND ESCITALOPRAM, AS COMPARED TO PLACEBO, IMPROVE ASTHMA CONTROL AND DECREASE ASTHMA EXACERBATIONS IN DEPRESSED PEOPLE WITH VERY FREQUENT EXACERBATIONS. EFFECT SIZES FOR EXACERBATIONS WERE MUCH GREATER THAN FOR DEPRESSION IMPROVEMENT. IN ADDITION, BASELINE DEPRESSIVE SYMPTOM SEVERITY DID NOT PREDICT ASTHMA IMPROVEMENT. THUS, THE ASTHMA EFFECT DID NOT APPEAR TO BE RELATED TO DEPRESSION IMPROVEMENT. THESE CLINICAL TRIAL FINDINGS WERE SUPPORTED BY AN ELECTRONIC MEDICAL RECORD ANALYSIS SUGGESTING PATIENTS WITH ASTHMA, WHO DID NOT HAVE A DEPRESSION DIAGNOSIS, SHOWED REDUCTIONS IN PREDNISONE USE AFTER RECEIVING SSRIS. SSRIS MIGHT IMPROVE ASTHMA CONTROL THROUGH EFFECTS ON SUBCLINICAL ANXIETY AND DEPRESSIVE SYMPTOMS OR PSYCHOLOGICAL TRIGGERS OF ASTHMA OR INDEPENDENT OF EMOTIONS THROUGH ANTI-INFLAMMATORY EFFECTS. IN VITRO STUDIES SUGGEST SSRIS REDUCE THE FREQUENCY OF IL-4- AND IL-2-PRODUCING CELLS TRIGGERED BY CD3 STIMULATION AND POTENTIATE GLUCOCORTICOID RECEPTOR-MEDIATED GENE TRANSCRIPTION, SUGGESTING THEY MIGHT ENHANCE THE EFFECTS OF INHALED STEROIDS. SSRIS ALSO DECREASE IL-6 LEVELS, WHICH ARE ELEVATED WITH ASTHMA. IN ANIMAL MODELS OF ALLERGIC ASTHMA, SSRIS REDUCE BRONCHIAL INFLAMMATION WITH DECREASES IN MACROPHAGES, LYMPHOCYTES, NEUTROPHILS AND EOSINOPHILS IN BRONCHOALVEOLAR LAVAGE FLUID. A SINGLE-SITE INVESTIGATOR-INITIATED CLINICAL TRIAL (R61/R33) IS PROPOSED TO EXAMINE ESCITALOPRAM COMPARED TO PLACEBO IN ADULTS WITH ASTHMA REQUIRING FREQUENT STEROID BURSTS BUT WITHOUT CURRENT MAJOR DEPRESSIVE DISORDER. A MILESTONE-DRIVEN R61 START-UP PHASE OF LESS THAN ONE YEAR WILL SET THE STAGE FOR THE R33 PHASE 24-WEEK, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF ESCITALOPRAM IN 105 MEN AND WOMEN WITH MODERATE TO SEVERE PERSISTENT ASTHMA WHO, DESPITE TREATMENT WITH MEDIUM-HIGH DOSE INHALED CORTICOSTEROIDS AND LONG-ACTING BETA AGONIST THERAPY, HAD 3 ASTHMA EXACERBATIONS IN THE PAST YEAR. NEED FOR STEROID BURSTS (PRIMARY OUTCOME) AND ASTHMA CONTROL, AS WELL AS FUNCTIONING, QUALITY OF LIFE, SERUM IL-6 LEVELS AND EXHALED NITRIC OXIDE, WILL BE ASSESSED. EFFECTS ON MOOD AND ANXIETY WILL BE EXPLORED AND THEIR INFLUENCE ON ASTHMA CONTROL ASSESSED. AN EXPERIENCED INVESTIGATIVE TEAM WITH A LONG HISTORY OF COLLABORATION AND EXPERTISE IN ASTHMA, SSRIS, CLINICAL TRIALS AND STATISTICAL ANALYSIS WILL CONDUCT THE STUDY.