Psychopharmacology 2002 159 266 274 DOI 10 1007 s002130100915 O R I G I N A L I N V E S T I G AT I O N Don R Cherek Scott D Lane Cynthia J Pietras Joel L Steinberg Effects of chronic paroxetine administration on measures of aggressive and impulsive responses of adult males with a history of conduct disorder Received 21 March 2001 Accepted 10 August 2001 Published online 12 October 2001 Springer Verlag 2001 Abstract Rationale The role of serotonin in human aggression and impulsivity was evaluated by administering paroxetine or placebo for 3 weeks and comparing the effects on laboratory measures of aggression and impulsivity among male subjects with a history of conduct disorder Methods Twelve male subjects with a history of criminal behavior participated in experimental sessions which measured aggressive and impulsive responses Six subjects were assigned to placebo treatment and six subjects to placebo and paroxetine treatment Aggression was measured using the point subtraction aggression paradigm PSAP which provides subjects with an aggressive and monetary reinforced response options Impulsive responses were measured using a paradigm that gives subjects choices between small rewards after short delays versus larger rewards after longer delays Results Chronic administration of paroxetine 20 mg day for 21 days produced significant decreases in impulsive responses Decreases in aggressive responses were evident only at the end of paroxetine treatment Decreases in impulsive and aggressive responses could not be attributed to a non specific sedative action because monetary reinforced responses were not decreased as has been observed following CNS sedation Conclusions Inhibition of serotonin reuptake by paroxetine is the possible mechanism for reductions in aggressive and impulsive responses These results support other data linking serotonin function and aggression and impulsivity Keywords Aggression Impulsivity Serotonin Paroxetine D R Cherek S D Lane C J Pietras J L Steinberg Human Psychopharmacology Laboratory Department of Psychiatry and Behavioral Science University of Texas Houston Health Science Center 1300 Moursund Street Houston TX 77030 3497 USA e mail don r cherek uth tmc edu Tel 1 713 5002797 Fax 1 713 5002618 Introduction A large number of scientific articles support a relationship between serotonin 5 HT and human impulsive and aggressive behavior Linnoila et al 1983 Virkkunen et al 1989 Studies in non human species have also linked reduced 5 HT levels to aggressive and impulsive behavior e g Higley et al 1996 Pharmacological manipulation of the 5 HT system through tryptophan depletion or supplementation resulted in changes in predicted directions in self reported mood hostility Cleare and Bond 1995 and laboratory measures of aggression Bjork et al 1999 Assessments of 5 HT response through challenge agents have revealed blunted 5 HT response in children with conduct disorder Stoff et al 1992 and personality disordered individuals reporting high levels of aggression and impulsivity Moss et al 1990 A number of studies with non human subjects have established a relationship between 5 HT and laboratory measures of impulsivity Decreases in impulsive behavior have been reported following administration of 5 HT reuptake inhibitors 5 HT agonists Soubrie 1986 and 5 HT releasing agents Poulos et al 1996 Lesioning of 5 HT pathways produced decreased impulse control Ho et al 1998 Collectively these investigations suggest that reduced 5 HT plays a role in impulsive and aggressive behavior Serotonin reuptake inhibitors SSRIs such as fluoxetine have been found to decrease aggression in several species of animals see review by Fuller 1996 Some investigators have suggested that patients with impulse and or aggression disorders may respond favorably to SSRIs e g Boyer 1992 Many clinicians have reported a reduction in anger outbursts among depressed affect labile and post traumatic stress disorder patients treated with fluoxetine Rosenbaum et al 1993 Fluoxetine compared to placebo treatment reduced self report measures of irritability and aggression among personality disordered participants Coccaro and Kavoussi 1997 Critical to understanding the biology of impulsive aggressive behavior is accurate measurement of these be 267 haviors In the present study we describe a laboratorybased procedure in which subjects were exposed to tests of both impulsive and aggressive responding in the same experimental day The impulsivity component involved a well documented delay of gratification task Mazur 1987 Logue 1995 in which subjects chose between a small reward available after a short delay and a larger reward available only after a longer delay This procedure has demonstrated sensitivity in detecting impulsiveness in populations with impulse control difficulties Logue 1995 and in measuring drug effects on impulsive behavior Cherek and Lane 2000 The aggressive responding component employed the point subtraction aggression paradigm PSAP Cherek 1992 The external validity of this procedure has been established in studies demonstrating differences between violent and non violent individuals Cherek et al 1997 The present investigation assessed the effects of paroxetine a 5 HT reuptake inhibitor on aggressive and impulsive behavior of individuals with a history of antisocial behavior We postulated that in accord with previous human studies increasing 5 HT activity in the CNS would produce decreases in aggressive and impulsive responding An earlier study with d l fenfluramine which releases 5 HT and dopamine reported significant decreases in aggressive and impulsive responses among a group of CD male subjects Cherek and Lane 1999 The present experiment would allow us to contrast the results of chronic 5 HT reuptake inhibition with our previous studies using 5 HT releasing agents Materials and methods DSM IV SCID P a standardized psychiatric interview First et al 1996 Subjects were excluded for any axis I disorder except past substance abuse or dependence The SCID II Structured Clinical Interview was also used to determine if subjects met criteria for childhood conduct disorder by 15 years of age The final sample included 12 subjects with a history of conduct disorder Six were assigned to placebo and six were assigned to paroxetine treatment Extraneous drug use Collecting a urine sample and expired air sample each day the subjects came into the laboratory monitored recent alcohol and drug use The alcohol