CSF 5-HIAA, the main metabolite of serotonin (5-HT), has been shown repeatedly to be decreased in suicide attempters (SA-often considered a form of self-aggression) and in individuals manifesting violent behavior. This suggests the presence of a disturbaNce of overall 5-HT metabolism in aggression/impulse disordered patients. CSF studies, although yielding important information, are difficult to perform in psychiatric patients, especially on a repeated basis. In addition, they provide data only about the metabolism of the 5-HT system but not about functional aspects of neuronal function (e.g. receptor sensitivity). Neuroendocrine challenge tests are advantageous in that they are less cumbersome to perform, easily repeatable and potentially offer more function-oriented data. To date, however, serotonergic challenge studies have yielded conflicting data due to the use of non-specific challenge agents. We have been employing a neuroendocrine challenge paradigm with m- chlorophenylpiperazine (MCPP), a selective 5-HT receptor agonist, which we believe offers promise. Since MCPP is relatively specific for 5-HT receptors, the procedure allows us to test the state of these receptors in specific CNS neurons (i.e. the hypothalamic- pituitary axis), thus yielding a more refined understanding of 5- HT neuronal function. Employing po MCPP in normal controls we previously established that MCPP is stimulatory for cortisol release and identified a threshold dose (0.25 mg/kg). We then were then able to demonstrate supersensitivity of 5-HT receptors in panic disorder. We now propose to employ the MCPP challenge paradigm in SA in order to further explore the status of the 5-HT receptor in recent SA and to investigate the relationship between aggression regulation and dysfunction of the serotonergic system. Forty recent SA will be given placebo or 0.25 mg/kg MCPP po. Cortisol, prolactin and MCPP levels will be drawn eery 30 min. In addition to a diagnostic evaluation, a detailed psychological inventory will be administered within one week prior to the challenges in order to obtain measures of the extent of inwardly and outwardly directed aggression, impulsivity, depression and anxiety. Subsequent course will be established for one year by telephone follow-up. The following hypotheses will be tested: 1. SA will demonstrate supersensitivity of 5-HT receptors as demonstrated by increased cortisol and prolactin release after MCPP challenge. 2. The effect will be most pronounced in patients demonstrating the greatest degree of aggression dysregulation (whether inwardly or outwardly directed) and/or anxiety as measured by psychometric tests. 3. 5-HT disturbances are nosologically non-specific and will be related to the psychological dimensions across diagnoses. 4. The challenge test will have predictive value in that those patients demonstrating supersensitivity will subsequently have the most repeat or successful suicide attempts in the ensuring year.
