Serotonin Transporter Gene May Be Involved in Short- Term Risk of Subsequent Suicide Attempts Philippe Courtet, Marie-Christine Picot, Frank Bellivier, Stephane Torres, Fabrice Jollant, Ce ´ cile Michelon, Didier Castelnau, Bernard Astruc, Catherine Buresi, and Alain Malafosse Background: In the first year following a suicide attempt, patients are at high risk for reattempt and for completed suicide. We aim to determine the predictive value of two serotonin-related genes, the tryptophan hydroxylase (TPH) and serotonin transporter (5-HTTLPR) genes that have been involved in the susceptibility to suicidal behavior. Methods: After a one-year follow-up study of 103 patients hospitalized after a suicide attempt, patients have been genotyped for both the A218C TPH and the functional S/L 5-HTTLPR polymorphisms. Results: Patients who reattempted suicide during the follow-up period had significantly higher frequencies of the S allele and the SS genotype. The odds ratio for the SS genotype vs. the LL genotype was 6.5 (95% CI [1.18 –35.84]). No difference was observed for TPH gene. Patients carrying the SS genotype were more impulsive. However, multivariate analysis suggested an independent effect of both the SS genotype and impulsivity on the risk of repeated suicide attempts. Conclusions: These results suggest that the 5-HTTLPR SS genotype is associated with further suicide attempts among patients who have previously attempted suicide. Biol Psychiatry 2004;55:46 –51 © 2004 Society of Biological Psychiatry Key Words: Serotonin transporter, tryptophan hydroxylase, sui- cidal behavior, repetition, polymorphism, association study, impulsivity T he prevention of suicide and the reduction of nonfatal suicidal behavior is part of the World Health Organiza- tion’s Health-for-All Policy (World Health Organization 1999). Thus, suicide prevention strategies should focus in priority on high-risk subjects, which means that we need to improve their recognition. A previous suicide attempt is the best predictor of a future suicide or suicide attempt (Beck et al 1975; Beck and Steer 1989; Leon et al 1990; Hawton et al 1998), and subsequent attempts are generally more severe (Malone et al 1995). Indeed, in a recent systematic literature review, Owens et al (2002) estimated that the median rates of nonfatal repetition were about 16% at 1 year and 23% in studies lasting longer than 4 years. The rates of repeated suicide attempts were even higher in several studies, reaching 40% during follow-up periods of 3 to 8 years (Rygnestad 1988; Brauns and Berzewski 1988; Johnsson-Fridell et al 1996). For subsequent suicide, the median rates were about 2% at 1-year follow-up, increasing to 7% in the studies lasting over 9 years. Patients who attempted suicide are well-known consumers of psychiatric resources and are at a high risk of actually committing suicide (Rissmiller et al 1994). The lack of information concerning which preventive strate- gies are effective is probably related at least partly to the difficulty involved in identifying the subjects who should benefit from them. In a large-scale survey in the United Kingdom, where 24% of all suicide cases had been in contact with the mental health services within the 12 months before their death, most people who committed suicide had been estimated by the clinicians to be at no or low risk at the time of the final service contact (Appleby et al 1999). Despite the substantial risks of eventual suicide in subjects who have already attempted to commit suicide, clinicians lack robust predictors that can be used to quantify this risk. Although further efforts may identify clinical profiles of more value as predictors, a search for relevant biological measures is clearly warranted. A large amount of data from studies in biological psychiatry led Mann (1998) to suggest that the serotonin (5-HT) dysfunction is related to the diathesis for suicidal behavior. Since the seminal studies by Asberg et al (1976), follow-up studies have suggested that low cerebrospinal fluid (CSF) 5-hydroxyindole acetic acid (5-HIAA) levels are a predictor of future suicide attempts and suicide completion and are associated with a substantial increase in short-term suicide risk in suicide attempters (Traskman et al 1981; Roy et al 1989; Nordstro ¨m et al 1994). Roy (1999) reported that the low affinity of the platelets serotonin uptake protein for serotonin has a predictive value for subsequent suicidal behavior during a 5-year follow-up period. Impulsive aggression is closely related to lifetime suicidal behavior and is also associated with a serotonergic dysfunction (Mann et al 1999; Placidi et al 2001). People who make repetitive suicide attempts often have dramatic or impulsive personality traits (Paris 1996), and impulsivity is the component of borderline personality disorder that best correlates with repetitive suicide attempts (Brodsky et al 1997). The level of serotonergic system activity is probably a genet- ically determined trait, and one mechanism by which genetic factors may affect the risk of suicide (Brent et al 1996) is by reducing serotonergic function (Mann 1998). Personality traits related to impulsive aggression are probably caused by genetic factors (Coccaro et al 1994, 1997) and involved in the transmis- sion of suicidal behavior in families (Brent et al 1996). Thus, impulsivity may be an intermediate phenotype associated with the serotonergic genes involved in vulnerability to suicidal behavior and to repetitive suicide attempts. We showed that two major serotonin-related candidate genes, one encoding tryptophan hydroxylase (TPH), the rate-limiting enzyme of serotonin synthesis, and the other encoding the From the Department of Psychological Medicine and Psychiatry (PC, FJ, DC, BA), Lapeyronie Hospital , Institut National de la Sante ´ et de la Recherche Me ´ dicale E 0361 (PC, ST, FJ, AM), La Colombie ` re Hospital, Department of Biostatistics (M-CP, CM), Arnaud de Villeneuve Hospital, and University Department of Psychiatry (ST), La Colombie ` re Hospital, Montpellier, France; University Department of Psychiatry (FB), Ho ˆ pital Henri Mondor, Assistance Publique-Ho ˆ pitaux de Paris, and INSERM U513 (FB), Faculte ´ de Me ´decine de Cre ´teil, Cre ´ teil France; and Department of Psychiatry (CB, AM), Geneva University Hospital, Geneva, Switzerland. Address reprint requests to Dr. Philippe Courtet, Department of Psycholog- ical Medicine and Psychiatry, Lapeyronie Hospital, Centre Hospitalier Universitaire Montpellier, 34295 Cedex 5, France. Received April 30, 2003; revised July 21, 2003; accepted July 29, 2003. BIOL PSYCHIATRY 2004;55:46 –51 0006-3223/04/$30.00 doi:10.1016/j.biopsych.2003.07.004 © 2004 Society of Biological Psychiatry