Posttraumatic stress disorder (PTSD) is a chronic anxiety disorder that follows exposure to extreme events. A large twin study of Vietnam veterans had demonstrated a significant genetic contribution to chronic PTSD upon exposure to combat.1,2 The underlying genes, however, have not been described. Given previous findings of abnormal dopamine (DA) function in PTSD, and given the putative effect of dopamine neurotransmission in shaping the responses to stress in animals, this study examined the association of the dopamine transporter (DAT) SLC6A3 3Ј variable number tandem repeat (VNTR) polymorphism with PTSD. The study evaluated 102 chronic PTSD patients and 104 carefully-documented trauma survivors (TS) who did not develop PTSD. Significant excess of 9 repeat allele was observed among PTSD patients (43% vs 30.5% in TS controls; 2 = 6.3, df = 1, P = 0.012). An excess of 9 repeat homozygous genotype was also observed in PTSD (20.43% in PTSD vs 9.47% in TS controls; 2 = 6.11, df = 2, P Ͻ 0.047). These findings suggest that genetically determined changes in dopaminergic reactivity may contribute to the occurrence of PTSD among trauma survivors. Molecular Psychiatry (2002) 7, 903-907. doi:10.1038/ sj.mp.4001085 Post-traumatic stress disorder (PTSD) is an extreme and sustained maladaptive response to stressful events. The disorder consists of symptoms of intrusive recall, avoidance of cues reminding of the traumatic event and hyper-arousal. These symptoms may persist for years, and are often associated with significant disability and distress. The etiology of PTSD is complex and multifactorial.3 Importantly, exposure to a traumatic event does not fully explain the occurrence of the disorder. 4 Exposure, in fact, triggers a cascade of biological events that ultimately lead to the occurrence of chronic PTSD.5 Individuals with prior vulnerability are at higher risk for developing PTSD upon exposure to a traumatic event. Inherited vulnerability is among the better researched vulnerability factors, as follows:True et al, 1 studied 4042 twin pairs from the Vietnam Twin Registry and found that inherited factors accounted for up to 32% of the variance of PTSD symptoms, above and beyond the contribution of trauma intensity. Xiang et al, 2 examined 3304 twin pairs of the Vietnam Twin Registry and similarly found 35.3%, inherited liability to develop PTSD upon combat exposure, 20% of which pertained specifically to PTSD and an additional 15.3% were common to both PTSD and substance dependence. Other studies 6 have shown an aggregation of anxiety disorders in families of PTSD patients.The molecular basis of the above-mentioned vulnerability is hardly known at this point. Two association studies evaluated the Taq-I RFLP site near the D2 dopamine receptor (DRD2) gene in PTSD. The first study 7 compared 37 drug and alcohol addicts with PTSD with 19 addicts without PTSD and found higher frequency of the A1 allele among the former. The second study 8 failed to replicate this finding in a sample of 52 PTSD patients and 82 normal con...

These findings support a small but significant contribution of the HT2CR and DRD3 to susceptibility to TD, which is additive in nature.

Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers.1 Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal effects profile of atypical antipsychotic drugs.2 We examined the association of three polymorphisms in the 5-HT2A receptor gene (HTR2A) with TD susceptibility-T102C 3 and his452tyr 4 in the coding region and A-1438G 5 in the promoter-in matched schizophrenia patients with (n = 59, SCZ-TD-Y) and without TD (n = 62, SCZ-TD-N) and normal control subjects (n = 96). The T102C and the A-1438G polymorphisms are in complete linkage disequilibrium but not his452tyr. Tardive dyskinesia (TD) is an idiopathic, often irreversible, involuntary movement disorder reported in 20% of patients following prolonged exposure to dopamine receptor antagonist drugs.1 The determinants of risk for TD remain largely undefined. A few studies provide indirect basic and clinical evidence implicating a genetic component in idiosyncratic extrapyramidal reactions to antipsychotic drugs. [7][8][9][10] We and others previously demonstrated an association between TD and a serine to glycine polymorphism (ser9gly) in exon 1 of the dopamine D3 receptor gene (DRD3). 11-14The 5-HT2A receptor is a site of action for atypical antipsychotic agents and has been implicated in their added efficacy as well as their reduced extrapyramidal side effects profile.2 Atypical antipsychotic agents such as clozapine 15,16 and olanzapine, 17 have been shown to induce much lower rates of TD than conventional antipsychotic drugs and this has been attributed to a protective effect of their high 5-HT2 receptor blocking activity relative to D2 receptor blockade. 17 The 5-HT2A receptor is distributed in striatal brain areas that modulate motor activity 18 and has been shown to interact with dopaminergic neurotransmission in brain regions relevant to antipsychotic drug action.19 Rodent studies suggest that high occupation of 5-HT2A receptors with lower D2 receptor occupancy might be involved in the absence of up-regulation of D2 receptors after treatment with atypical antipsychotic drugs. 20 This may be relevant to the documented lower rates of TD with atypical agents, given the classical hypothesis implicating D2 receptor supersensitivity with pathogenesis of druginduced TD.21 Furthermore, pretreatment with atypical antipsychotic agents has been shown to reduce repetitive jaw movements in a rat model for TD 22 and 5-HT2A receptor antagonists have been shown to attenuate apomorphine-induced stereotypic oral movements in rats. 23 Finally, long-term elevations in 5-HT2A receptor binding and mRNA expression in neostriatal regions have been documented in response to ontogenetic loss of dopamine neurons following 6 hydroxydopamine administration, 24

Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers. Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal side effect profile of atypical antipsychotic drugs. We evaluated candidate dopamine and serotonin genes for association with drug-induced TD. We examined three polymorphisms in the dopamine D2 receptor gene (DRD2), two sites in the 3' region of the dopamine transporter (DAT) gene, two sites in the promoter and coding region of the dopamine D4 (DRD4) receptor gene, as well as polymorphic sites in the serotonin 6 receptor gene, the serotonin transporter gene and the tryptophan hydroxylase gene, for association with TD susceptibility. Schizophrenic patients with (n=59) and without TD (n=63), matched for antipsychotic drug exposure and other relevant variables, were studied. No significant associations were found. Within the limitations imposed by the size of the clinical sample, these findings suggest that the above polymorphic loci do not contribute significantly to risk for TD. Further examination of loci that yielded positive results at a trend level and investigation of other candidate genetic loci coding for antipsychotic drug targets is warranted.

Keywords: attention deficit hyperactivity disorder; ADHD; interleukin-1 receptor antagonist gene; transmission disequilibrium test