The proposed research is designed to identify neurobiologic abnormalities in patients with agoraphobia with panic attacks (APA), and obsessive compulsive disorder (OCD), and the therapeutic mechanisms related to antipanic and antiobsessional efficacy.
The specific aims of the studies in the APA patients are: (1) Extend the results of previous work which have identified abnormalities in the regulation of noradrenergic (NA) function in APA patients by determining in the same patient and healthy subject the biochemical, behavioral and cardiovascular responses to the alpha-2 receptor agonist, clonidine, and the alpha-2 receptor antagonist, yohimbine. (2) Evaluate NA function beyond the receptor level to further assess possible mechanisms of NA dysfunction in APA patients. Platelet high and low affinity alpha-2 receptor binding will be measured by (-)- epinephrine displacement studies of [H3] yohimbine binding. Alpha-2 adrenergic receptor effector coupling mechanisms will be evaluated by measuring stimulated and inhibited adenylate cyclase activity in platelet membranes and alterations in intracellular cyclic AMP production intact platelets. (3) Drug effects on NA function in relation to antipanic efficacy will be studied by repeating the yohimbine and clonidine tests and the platelet assays during desipramine and placebo treatment. (4) Determination of whether abnormal NA function is a state or trait related phenomena will be studied by repeating the yohimbine and clonidine tests and the platelet assays in remitted patients three months following drug discontinuation.
The specific aims i n the studies of OCD patients are: (1) Extend the preliminary findings that an abnormality in serotonin (5HT) function may exist in OCD patients by determining the behavioral and biochemical effects of the 5HT precursor tryptophan, 5HT1B receptor agonist m-chlorophenylpiperazone, and the 5HT1A receptor agonist, Gepirone, in OCD patients and health subjects. (2) Extend the findings that the 5HT reuptake inhibitor, fluvoxamine, is efficacious in the treatment of OCD patients by evaluating fluvoxamine in a double blind placebo controlled parallel group design. The tests of 5HT function will be repeated during the fluvoxamine and placebo treatment to determine if alterations in 5HT function are related to treatment outcome.
