Association between violent suicidal behavior and the low activity allele of the serotonin transporter gene

Abstract

There is compelling evidence that serotonin system dysfunction is associated with certain behavioral disorders, such as suicidal behavior and impulsive aggression. A functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was recently identified and the presence of the short allele found to be associated with a lower level of expression of the gene, lower levels of 5-HT uptake, suicidal behavior and anxiety-related traits. We genotyped 51 West European Caucasians who had made violent suicide attempts and 139 controls of the same ethnic origin, with no history of suicidal behavior. The frequencies of the S allele and the SS genotype were significantly higher in the violent suicide attempters than in the controls. The odds ratio for the SS genotype vs the LL genotype was 3.63 (95% CI (1.27-10.40)). This suggests that a change in expression of the gene encoding the 5-HT transporter may be involved in violent suicidal behavior. Molecular Psychiatry (2001) 6, 338-341. Since the seminal studies by Asberg and collaborators in the mid 1970s, 1 most studies have shown that impulsive aggression and suicidal behavior are correlated with low levels of 5-HT transmission.2 This association is stronger for more severe phenotypes: lethal and/or violent suicidal behavior and violent aggressive behavior.3-5 The magnitude and duration of serotonergic activity is believed to be regulated mainly by the human serotonin transporter (5-HTT), which controls the uptake of serotonin from the synaptic junction.6,7 The human 5-HTT is in a presynaptic location and Lesch et al 7 have demonstrated that it is identical in platelets and in the brain. Conflicting results have been obtained in studies of the platelet 5-HT transporter in individuals with suicidal behavior. Some studies have shown a decrease in the number of 5-HT transporter recognition sites in such individuals, as shown by the radiolabeled ligand-binding technique, and in the amount of 5-HT transporter protein, as shown by 5-HT uptake measurements. 8,9 Despite differences in the results obtained, probably due to differences in the ligands used, studies of radioligand binding in the brainstem of individuals who have committed suicide and in platelets have provided evidence that there is a negative association between serotonin dysfunction and impulsive aggression and violent or suicidal behavior. [8][9][10][11] Coccaro et al 11 studied patients with personality disorders and found a negative correlation between aggression and tritiated paroxetine binding to platelet serotonin transporter sites. Roy 9 recently reported that the affinity of the serotonin uptake protein for serotonin is lower in depressed patients displaying suicidal behavior than in depressed patients who have never attempted suicide and in controls. This lower affinity for serotonin was also found to have predictive value for subsequent suicide attempts and suicides during a 5-year follow-up period.Pharmacological studies have also provided evidence that the serotonin transport...

Antidepressant-induced mania, rapid cycling and the serotonin transporter gene polymorphism

“…Indeed, it has been reported that SSRIs induce AIM in a dose-dependent manner. 12 Several independent associations have been reported between the 's' allele and anxiety disorders, violent suicidal behavior, [13][14][15] seasonal affective disorder 16 and rapid cycling (this study). These results, together with the association reported by Mundo et al 8 and the association between the 's' allele and rapid cycling (this study), suggest that there is an association between the 5-HTTLPR 's' allele and a pattern of affective instability.…”

Serotonin Transporter: A Potential Substrate in the Biology of Suicide

“…This finding was supported by another group who found that subjects with the ll genotype had significantly higher scores on Beck's Hopelessness Scale and Beck's Scale for Suicide Ideation than subjects with either the ls or ss genotype (Russ et al, 2000). In contrast, three other groups of researchers observed an association between the s allele and violent suicidal behavior, while a fourth found a link between the s allele and the number of lifetime suicide attempts and lethality of the suicidal behavior (Bellivier et al, 2000;Bondy et al, 2000;Gorwood et al, 2000;Courtet et al, 2001).…”

“…Seven of these studies failed to demonstrate any link between suicidal behavior and SERT genotype or 5-HTTLPR allele frequency (Ohara et al, 1998;Chong et al, 2000;Geijer et al, 2000;Ho et al, 2000;Mann et al, 2000;Fitch et al, 2001;Rujescu et al, 2001). The remaining seven studies all found some association, albeit with differing results (Du et al, 1999;Bellivier et al, 2000;Bondy et al, 2000;Gorwood et al, 2000;Russ et al, 2000;Courtet et al, 2001;Baca-Garcia et al, 2002). One study demonstrated a higher frequency of the l allele in depressed suicide victims compared to nonsuicidal controls (Du et al, 1999).…”

“…Although these studies have yielded conflicting results, it is impressive that the four studies that found an association between suicidal behavior or lethality of the behavior and the s form of the 5-HTTLPR were uniform in identifying a subset of attempters or completers that had a similar characteristicFthe use of violent or highly lethal means (Bellivier et al, 2000;Bondy et al, 2000;Gorwood et al, 2000;Courtet et al, 2001). Only one study that distinguished between violent and nonviolent attempters failed to demonstrate any associations (Rujescu et al, 2001).…”

Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder

“…[17][18][19][20] These polymorphisms and a 3ЈUTR SNP have been studied in several neuropsychiatric disorders and personality quantitative trait loci (QTLs), including response to antidepressant treatment. [21][22][23][24] A series of transmission/disequilibrium test (TDT) studies using 5-HTTLPR and VNTR to determine whether SLC6A4 contributes to susceptibility to autistic disorder failed to reveal any consistent evidence of transmission of an allele or haplotype. [25][26][27][28][29][30] Using the TDT, evidence of preferential transmission of the short variant of 5-HTTLPR was found by Cook and colleagues 25 and preferential transmission of the long allele was reported by others.…”