Serotonin Transporter Polymorphism in Major Depressive Disorder (MDD), Psychiatric Disorders, and in MDD in Response to Stressful Life Events: Causes and Treatment with Antidepressant

Results

Polymorphism of 5-HTTLPR, MDD, or MDD associated with stressful life events enclosed those due to cancer disease. The first association between 5-HTTLPR and major depression was reported by Lesch et al. (1), who examined 505 lymphoblastoid cell line, finding a significant relationship between subject with S allele (S/S or S/L) and neuroticism factor (anxiety and depressive symptoms and traits). Subsequently, Caspi et al. examined 867 individuals. The study focused on stressful life events which occurred between the ages of 21 and 26. The authors reported a more significant association (p=0.02) between homozygous S/S subjects (n=435; 51%) than heterozygous subjects (n=147; 17%) and depression, with respect to L/L subject (n=265; 31%). Homozygous S/S subjects experienced the majority depressive symptoms in the 5 years preceding their assessment at age 26 (16). The correlation between the potential relevance of the polymorphism in the promoter region of the 5-HTTLPR gene, and the risk of suffering MDD in 70 white European psychiatric outpatients with MDD and 142 healthy volunteers (HV) was studied by Dorado et al. in 2007 (17). They found that the frequency of subjects with the 5-HTTLPR-S allele was higher (p<0.01; odds ratio=2.03) in MDD patients than in HV. These authors suggested that there is a greater risk of MDD for individuals carrying the 5-HTTLPR-S allele (17). In a article by Kendler et al. 2005, whether stressful life events could lead to the onset of depression and whether this could be somewhat favored by the presence of short allele in the promoter region of the 5-HTT gene were examined. They enrolled 549 subjects, male and female, with established episode of major depression and generalized anxiety syndrome (GAS) such as anxiety, nervousness, feelings of being worried, and muscles felt tense, in the last year. The results of this work emphasized that individuals with 2 short alleles (homozygous SS) at the 5-HTT locus were more sensitive to the effects of depression associated with the effects of stressful life events (SLEs) than were those with heterozygous (SL) or 2 homozygous long alleles (homozygous LL), (p<0.01). This suggests that the variation at the 5-HTT locus moderates the sensitivity of individuals to the depressogenic effects of SLEs largely producing an increase sensitivity to the impact of mild stressors in SS individuals (18). A recent meta-analysis by Kiyohara et al. 2010, reported a summary frequencies of the SS allele of 5-HTTLPR among Caucasian and Asians, based on the random effects model, as 42% and 40.5% respectively. Besides the distribution of the S allele, there was a significant difference between Asians and Caucasian (p<0.001), and the SS genotype of was significantly associated with an increased risk of MDD among the Caucasian population (19). The effect of stressful life events on depressive symptoms in young adults was found to be significantly stronger among SS or SL subjects than among LL subjects, as reported by Wurtman. Neuroimaging studies showed that those with the SS or SL alleles exhibited a greater activation of the amygdala in response to fearful stimuli than those with LL. It has been reported recently that mutations in the gene that controls serotonin synthesis in the human brain (tryptophan hydroxylase) also predispose these individuals to mood disturbances. It may be asked whether people who lack a psychiatric history should be advised to avoid stressful environments if they are found to carry the SS or SL alleles (20). In contrast with this is a study by Chorbov et al. in which 247 young adult female twins from Missouri were examined with the aim of determining whether the 5-HTT polymorphism interacts with the effect of adverse life events to increase the risk for developing depression; They found that L allele was associated with a statistically significant (p>0.0001) increase in MDD (21). Some authors, however have focused their attention on another aspect of the onset of depressive syndrome, that which occurs following a diagnosis of cancer. Cancer patients who survive this serious disease may develop major depression when they become aware of having cancer. Schillani et al. observed a series of 53 consecutive early breast cancer patients and 73 consecutive terminally ill patients who were affected by different types of advanced cancer. The authors analyzed the correlations between SERT polymorphism and mental adjustment to cancer, by assessing Mini–Mac Hopelessness–Helplessness (HH) scores in relation to 5-HTTLPR polymorphism in two groups of cancer patients. Their results showed a significant correlation between HH scores in depression and early breast cancer patients carrying the L/L variant only (22). The results concerning this aspect, are in contrast with what has been described by others authors, because in this work L allele to be associated with a depressive illness after cancer. On the others hand, Grassi et al. 2010 did not find a possible association between 5-HTTPRL polymorphism in conjunction with life events and depression in diagnosed breast cancer (23).

Polymorphism of 5-HTTLPR in suicidal behaviour and borderline personality disorder. Several lines of evidence suggest that suicidal behaviour such as others psychopathologies have a genetic component. Evidence of genetic involvement comes from studies of family history of suicide (24), and more definitively from twin and adoption studies (25). Aggressive and impulsive traits, alcoholism and substance abuse are also associated with serotonergic abnormalities, all of which carry an elevated risk of suicide. (26). It is therefore noteworthy that the 5-HTTLPR genotype is associated, in some but not all studies, with harm avoidance temperament, alcoholism, anxiety or impulsive traits (27).

However the literature concerning the association between the 5-HTTLPR polymorphism and suicidal behaviour is conflicting, and has reported both negative and positive findings. A meta-analyses carried out by Anguelova et al, examined 12 studies comprising a total of 1599 subjects and found that there was a significant association between the 5-HTTLPR polymorphism with low expressing S allele and suicidal behaviour (28-30). These findings have been confirmed in two meta-analyses of Lin et al. and by Li et al. In the first, a series of 379 patients, it was found that the genotypes carrying the S allele were significantly more frequent in these attempting suicide than in those not (p=.004). Additionally, the S allele was associated with violent suicide (p=0.0001) but not with nonviolent suicide (p=1.00; 31). In the second study, the authors examined 39 studies and suggested that there was a significant association between the 5-HTTLPR polymorphism and suicidal behaviour with a value of 0.0068 (overall odds ratio=0.88 (45% CI 0.8, 0.97), thus supporting the involvement of 5-HTT in the pathogenesis of suicidal behavior (32). One potential pathways by which the 5-HTTLPR genes are related to impulsivity, aggression and suicide is through observed alterations in amygdala function as the amygdalae, along with the prefrontal cortex and orbital cortex, play an important role in the emergence of violent behaviour via faulty regulation of negative emotions (33). Others studies of these attempting suicide found association between the 5-HTTLPR polymorphism and suicide attempts (34-36). Neves et al. examined 351 patients and found that those who carried the S allele made violent suicide attempts more frequently (χ²=20.2; p=0.0001) and made more suicide attempts (t = 2.6; P = 0.01) than those with L/L genotype. However, although they were not able to show an association between the S allele bipolardDisorder (BPD). On the other hand, in people with comitted suicide in whom the diagnosis was made post-mortem, there does not appear to be an association between suicide and 5-HTTLPR (37-39). Among patients (n=166) who had previously attempted suicide the frequency of S/S genotype in those who attempted non-violent suicide were not statistically different to those in the controls (n=139) (40).

Polymorphism of 5-HTTLPR and non-psychiatric disorders. Recurrent aphthous stomatitis (RAS) is the most common oral mucosal disease, characterized by periodic painful, single or multiple ulcers that heal spontaneously.

Netto Victoria et al. investigated 5-HTTLPR polymorphism in patients with RAS compared with control subjects. They examined 69 patients affected by minor or major form of RAS, and 70 healthy subjects, finding a significant increase in the genotype of SS (p=0.05) in the group patients with respect to healthy individuals. They suggest that patients with RAS have a tendency to exhibit polymorphism associated with anxiety-related traits (41).

Polymorphism of 5-HTTLPR and antidepressant response. 5-HTT is the site of primary action for selective serotonin reuptake inhibitors (SSRIs). Several reports have demonstrated that the L/L allele polymorphism in 5-HTTLPR is associated with better selective SSRIs. The citalopram, fluvoxamine, paroxetine and setraline have revolutionized the treatment of major depressive disordered because of their favourable side-effects profiles (42). The primary mode of action for SSRIs is by binding to serotonin transporter, inhibiting its capacity to transport serotonin and thus modulating serotonergic activity. It has been determined that in terms of transcriptional activity, the L variant in the 5-HTTLPR has more than twice that of the S allele, with important difference in 5-HTT RNA synthesis. (43). YU et al. tested the hypothesis that the 5-HTTLPR polymorphism is associated with SSRI antidepressant response by evaluating total and cluster depressive symptoms in 121 Chinese patients diagnosed with major depression. These authors reported that patients with the L/L genotype had a significantly better responses to fluoxetine (20-60 mg/day) for 4 weeks when compared with S/S carriers (p=0.002). (44)

A study by Zanardi et al. of 58 depressed Italian patients receiving paroxetine showe that patients with L/L and L/S genotype, improved to a greater degree than those with S/S between 2 and 4 weeks of treatment (45). A blinded placebo-controlled study by Smeraldi et al. concerning pindolol augmentation in 102 patients not responding to fluvoxamine found that the L allele carriers (S/L and L/L) had a better response to fluvoxamine plus placebo than those with S/S (46).

Pharmacogenetic data concerning SSRIs are available, indicating that their effects are more pronounced in patients with depressive mood disorders carrying the L/L 5-HTTLPR polymorphism in comparison with those carrying at least one S allele (47, 48). Response to fluvoxamine plus pindolol did not vary by genotype. An opposing conclusion was provided by the work of Kraft et al., in a study which included 1914 subjects treated with citalopram (20-60 mg/day) for 12 weeks. This study did not find an association between any of the 5-HTTLPR polymorphism and response to citalopram (49). This date is also supported by the work of the Hu et al. (50).