A polymorphism in tryptophan hydroxylase and irritable aggression in personality disorders

As decreased serotonergic activity has been associated with irritable or impulsive aggression in patients with personality disorders, and there is evidence to suggest a partially heritable basis for irritable aggression, it is logical to investigate the possibility of genetic differences in the determinants of serotonergic activity. A biallelic polymorphism in the gene for tryptophan hydroxylase (TPH), the rate limiting enzyme in the synthesis of serotonin, has been identified using the single strand conformational polymorphism method. The “L” allele has been associated with reduced CSF 5-HIAA and a history of suicide attempt in a cohort of Finnish alcoholic offenders (Nielsen et al 1994). We assessed TPH genotype in a sample of 40 Caucasian patients with personality disorder, investigating a possible association between allelic status and degree of impulsive aggression as measured by the Buss-Durkee Hostility Inventory (BDHI). We also developed new criteria for impulsivity which identify the extremes of highly impulsive and non-impulsive patients. Twenty-one male patients with the “LL” genotype had significantly higher total BDHI scores (45.3±9.8) compared to males with the “UL” or “UU” genotypes (32.9±13.5; t=2.38, df=19; p<0.03) and scored significantly higher on the BDHI irritability subscale. As in previous studies, the BDHI assault plus irritability subscales correlated negatively with the prolactin response to fenfluramine (r0.70, n=16, p<0.01) in the 16 patients who had the fenfluramine challenge; patients with “LL” genotype demonstrated a nonsignificantly lower prolactin response to fenfluramine compared to those with “UL” or “UU” genotypes (9.36±5.0 vs. 12.0±10.5; n=17; t=0.67; df=15; p=ns). Females with the “LL” genotype did not demonstrate higher BDHI scores or a blunted prolactin response to fenfluramine. Although the gene for TPH is autosomal, this gender difference may be accounted for by gender specific phenotypic expression of the genotype. Although the sample size was too small for meaningful analysis, utilizing our newly developed impulsiveness criteria, all men identified as highly impulsive had the “LL” genotype (n=3) and non-impulsive men had the “UL” genotype (n=4). Also, a strong negative correlation, though not significant, was observed between impulsive criteria and prolactin response to fenfluramine (r0.83, n=4, p=ns) in the subset of patients with fenfluramine challenge. These findings suggest preliminarily that in male personality disorder patients impulsive aggression may be linked to TPH genotype.