Considerable evidence implicates serotonergic dysfunction in the neurobiol-ogy of impulsivity. While the complexity of neurotransmitter systems demands cautious interpretation, there is evidence of decreased serotonergic tone in impulsive disorders in contrast to increased serotonergic tone found in compulsive disorders. Serotonergic (5-HT) function may be measured by cerebrospinal fluid (CSF) metabolites of 5-HT (5-hydroxyindoleacetic acid: 5-HIAA), by responses to serotonergic probes (m-CPP and others), and by treatment outcome to serotonin reuptake blockers (fluoxetine, clomipramine, fluvoxamine and others). Patients with impulsive aggressive (Linnoila, Virkkunen, Scheinen et al. 1983) and violent suicidal (Asberg, Traskin, Thoren, 1976) behavior have decreased levels of cerebrospinal fluid metabolites of 5-HT (CSF 5HIAA). Patients successfully completing violent suicide also have decreased 5-HT receptors in the frontal cortex (Arora, Meltzer, 1989). In 22 violent offenders, psychopathic features on the PCL-R were associated with low CSF-5HIAA (Soderstrom et al, 2001). On the other hand, elevated CSF 5-HIAA has been demonstrated in a subgroup of OCD patients (Insel, Mueller, Alterman et al. 1985) as well as corresponding decreases following successful treatment with clomipramine (Thoren, Asberg, Bertilsson et al. 1980). Other compulsive disorders such as anorexia nervosa (Kaye, Gwirstman, George et al. 1991) demonstrate increased 5-HIAA overall or in subgroups of patients responsive to 5-HT reuptake blockers.
Acute challenges with serotonergic agents have provided further evidence of 5-HT involvement in impulsivity. Moreover, there is preliminary evidence that impulsive and compulsive disorders may demonstrate opposing behavioral responses to serotonergic challenge. In response to 5-HT agonists such as m-CPP, patients with impulsive disorders, such as impulsive personality disorders (Hollander, Stein, DeCaria et al. 1994) and pathological gambling (DeCaria, Stein, Cohen et al. 1993) for the most part do not show a dysphoric response, but often have a euphoric or a "high" response to m-CPP. On the other hand, compulsive disorder such as OCD (Hollander et al, 1992a; Zohar et al, 1987) and restrictive eating disorders (Buttinger, Holllander, Walsh, 1990) show increased negative affect and increased obsessional thoughts and compulsive urges in response to challenge with 5-HT agonists.
In response to 5-HT reuptake blockers, compulsive disorders such as OCD, anorexia nervosa, and body dysmorphic disorder, show clear cut improvement with chronic treatment. In fact, the hyperfrontality demonstrated in OCD has been shown to be reduced following chronic 5-HT reuptake blocker treatment and this is associated with decreased harm avoidance (Hoehn-Saric et al, 1991). As serotonin reuptake inhibitors function to stimulate 5-HT activity, symptoms may initially worsen following acute administration with high doses (Hollander et al, 1992b). Chronic treatment with these agents, however, may work to desensitize or down-regulate 5-HT receptors over time (Zohar et al, 1988; Hollander et al, 1991a). Open pilot work in impulsive personality disorders shows some improvement early on (Coccaro et al, 1990) but this effect may wear off with time and long term follow-up studies are needed. It has been postulated that acute administration of 5-HT reup-take blockers might worsen compulsive but improve impulsive disorders, whereas chronic administration of these agents might improve compulsive but ultimately worsen impulsive disorders (Cohen et al, 1997).
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