Monoamine Metabolites Level in CSF is Related to the 5-HTT Gene Polymorphism in Treatment-Resistant Depression

Abstract

The serotonin (5-hydroxytryptamine) transporter (5-HTT) is considered to affect the pathogenesis of mood disorders. Large number of genetic association studies between 5-HTT functional polymorphisms and vulnerability of mood disorders and therapeutic response to antidepressants has been carried out. We investigated the influence of 5-HTT-linked polymorphic region (5-HTTLPR) and 5-HTT 17 bp variable number of tandem repeat polymorphism (5-HTTVNTR) polymorphisms on concentrations of monoamine metabolites in cerebrospinal fluid (CSF) among treatment-resistant patients with mood disorders. Subjects were 119 Swedish patients with persistent mood disorders and 141 healthy subjects. In 112 of these patients, we measured 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol in CSF. Genotyping for 5-HTT polymorphisms from genomic DNA was carried out by PCR. There was no significant difference in allele/genotype frequency between patients and healthy subjects. In patients with mood disorders, we found significant difference in mean 5-HIAA concentration between 5-HTTLPR genotypes (p ¼ 0.03). Although the 5-HIAA concentration showed a tendency to be higher in short (S) carriers than in non-S carriers of the 5-HTTLPR in patients (p ¼ 0.06), when considering patients with major depressive disorder (MDD), the 5-HIAA concentration was significantly higher among S carriers than among non-S carriers (p ¼ 0.02). Moreover, the 5-HIAA concentration was higher in S/S subjects compared to long (L)/L (p ¼ 0.0001) and L/S (p ¼ 0.002) subjects in patients with MDD. Similarly, there was higher HVA concentration in S/S subjects compared to L/L (p ¼ 0.002) and L/S subjects (p ¼ 0.002). There was no effect of 5-HTTVNTR. Our findings show that the 5-HTTLPR polymorphism affects 5-HIAA and HVA concentrations among treatment-resistant patients with mood disorders.

Elevated Brain Serotonin Turnover in Patients With Depression

“…Our finding of elevated internal jugular 5-HIAA overflow in depressed patients carrying the s allele of the 5-HTT gene is in agreement with the recent findings by Kishida and colleagues, 62 who observed elevated 5-HIAA levels in the CSF of patients with MDD carrying the s allele. While it has been observed that 5-HTT expression and serotonin uptake are impaired with the presence of the short-form haplotype, 21,30 studies in postmortem brain tissue demonstrated no relationship between 5-HTT binding potential and genotype in suicide victims.…”

VNTRseek—a computational tool to detect tandem repeat variants in high-throughput sequencing data

“…Examples for minisatellite loci include two distinct VNTRs in the serotonin transporter gene (5-HTT, also SLC6A4) which have been linked to phenotype in a variety of populations: HTTLPR, a 20–23 bp TR in the promoter, which occurs as 14 copies and 16 copies, and STin2, a 17 bp TR in the second intron, which occurs as 9, 10 and 12 copies. HTTLPR variants have been associated with depression (10), bipolar disorder (11), symptoms of Alzheimer's disease (12) and may act through a decrease in transcriptional activity of the gene in patients with the shorter allele (13). STin2 has been associated with schizophrenia (14), depression (15), symptoms of Alzheimer's disease (12,16) and treatment outcome in alcohol dependent patients (17).…”

Association of MAOA gene functional promoter polymorphism with CSF dopamine turnover and atypical depression

“…Specifically, the long 5-HTTLPR allele was associated with the melancholic subtype of major depression and the short 5-HTTLPR allele with AD [49,50]. From the current patient sample with persistent mood disorders, we previously reported no significant influence of the 5HTTLPR on CSF-HVA but a tendency on CSF 5-HIAA (P = 0.06) [51]. However, in the subset of patients with the major depressive disorder, the CSF 5-HIAA and HVA concentrations were significantly higher in short-allele carriers than in nonshort-allele carriers of the 5-HTTLPR [51].…”

“…From the current patient sample with persistent mood disorders, we previously reported no significant influence of the 5HTTLPR on CSF-HVA but a tendency on CSF 5-HIAA (P = 0.06) [51]. However, in the subset of patients with the major depressive disorder, the CSF 5-HIAA and HVA concentrations were significantly higher in short-allele carriers than in nonshort-allele carriers of the 5-HTTLPR [51]. In this study, we found no significant effect of 5HTTLPR with susceptibility to AD.…”