Increased serotonin 2A receptor availability in the orbitofrontal cortex of physically aggressive personality disordered patients

Abstract

Background: Impulsive physical aggression is a common and problematic feature of many personality disorders. The serotonergic system is known to be involved in the pathophysiology of aggression, and multiple lines of evidence have implicated the serotonin 2A receptor (5-HT(2A)R). We sought to examine the role of the 5-HT(2A)R in impulsive aggression specifically in the orbitofrontal cortex (OFC), given that our own studies and an extensive literature indicate that serotonergic disturbances in the OFC are linked to aggression. We have previously hypothesized that increased 5-HT(2A)R function in the OFC is a state phenomenon that promotes impulsive aggression.

Methods: Serotonin 2A receptor availability was measured with positron emission tomography and the selective 5-HT(2A)R antagonist radioligand [(11)C]MDL100907 in two groups of impulsively aggressive personality disordered patients-14 with current physical aggression, and 15 without current physical aggression-and 25 healthy control subjects. Clinical ratings of various symptom dimensions were also obtained.

Results: Orbitofrontal 5-HT(2A)R availability was greater in patients with current physical aggression compared with patients without current physical aggression and healthy control subjects; no differences in OFC 5-HT(2A)R availability were observed between patients without current physical aggression and healthy control subjects. No significant differences in 5-HT(2A)R availability were observed in other brain regions examined. Among both groups of impulsively aggressive personality disordered patients combined, OFC 5-HT(2A)R availability was correlated, specifically, with a state measure of impulsive aggression.

Conclusions: These findings are consistent with our previously described model in which impulsive aggression is related to dynamic changes in 5-HT(2A)R function in the OFC.

Figures

Figure 1

[11C]MDL100907 BPND (adjusted for age and age x group) in the orbitofrontal cortex (OFC) of intermittent explosive disorder-integrated research criteria (IED-IR) groups with and without current physical aggression and healthy controls. The mean BPND for each group is depicted by the horizontal line. BPND was significantly greater in IED-IR patients with current physical aggression compared to those without current physical aggression and healthy controls. IED-IR patients without current physical aggression did not differ significantly from healthy controls. Gray circles represent the 5 patients without current physical aggression who only met criteria for verbal, but never physical, IED-IR.

Figure 2

The relation between [11C]MDL100907 BPND (adjusted for age and age x group) in the orbitofrontal cortex (OFC)of both intermittent explosive disorder-integrated research criteria (IED-IR) groups combined and the Global Irritability subscale of the Overt Aggression Scale-Modified (OAS-M; a measure of state aggression). A positive association (r = .48, p = .009) was found between BPND and this state measure of aggression. Black circles = IED-IR patients with current physical aggression; gray circles = IED-IR patients without current physical aggression.