Klotho Gene and Selective Serotonin Reuptake Inhibitors: Response to Treatment in Late-Life Major Depressive Disorder

Abstract Klotho protein, encoded by the Klotho gene (KL) at locus 13q12, is an antiaging hormone-like protein playing a pivotal role in cell metabolism homeostasis and associated to longevity and age-related diseases. In particular, altered cell metabolism in central nervous system may influence the behavior of serotoninergic neurons. The role of KL in the response to treatment with selective serotonin reuptake inhibitors (SSRIs) in late-life depressive syndromes and late-life major depressive disorder (MDD) is unclear. We genotyped three single-nucleotide polymorphisms (SNPs) of KL in 329 older patients with diagnosis of late-life MDD, treated with SSRIs and evaluated with the Hamilton Rating Scale for Depression 21-items (HRSD-21) at baseline and after 6 months. A reduction ≥50 and <10 % in HDRS-21 score was considered as response or nonresponse to therapy, respectively, and the values of reduction between 10 and 49 % as poor responders. After 6 months of SSRI treatment, 176 patients responded, 54 patients did not respond and 99 patients showed a poor response. Ordinal logistic models showed a significant association between mutation of SNP rs1207568 and responders and, similarly, for each unitary risk allele increase overlapping results were found. Conversely, a significantly higher frequency of the minor genotype of SNP rs9536314 was found in nonresponders. Considering the pre-post differences of HRSD-21 scores as a continue variable, we confirmed a significant improvement of depressive symptoms after treatment in patients carrying at least one minor allele at rs1207568 and a worse response in patients homozygous for the minor allele at rs9536314. Our results were the first that suggested a possible role of KL in the complex pathway of SSRI response in late-life MDD.