5-HTTLPR Polymorphism of Serotonin Transporter and Effects of Sertraline in Terminally Ill Cancer Patients: Report of Eleven Cases

Abstract

Depression is difficult to detect in cancer patients, though its determination offers an opportunity to relieve patients' suffering in palliative care. Selective serotonin reuptake inhibitors (SSRIs) are the treatment of choice for mood disorders, but they show a highly variable response. The short allelic variants "s/s" and "s/l" of the 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene has been consistently associated with a poorer response to SSRIs. The aim of this study has therefore been to examine depression, anxiety and mental adaptation to cancer in terminally ill and depressed cancer patients, in relation to treatment with sertraline and to the 5-HTTLPR genetic polymorphism. Eleven consecutive depressed patients with different forms of advanced cancer who were admitted to the Hospice of the Casa di Cura "Pineta del Carso" (Trieste, Italy) were treated with sertraline for two weeks and their response was determined and related to 5-HTTLPR. Sertraline significantly reduced the average depression and anxiety subscale scores of HADS, as well as the scores of the subscales of Mini-MAC. When the effects of sertraline were analyzed in relation to the 5-HTTLPR polymorphism, only patients with the "l/l" allelic variant had significantly lower scores of HADS anxiety, Mini-MAC hopelessness-helplessness and anxious preoccupation, and a higher score for the fighting spirit of Mini-MAC; the depression score was significantly reduced in patients with both allelic variants. These data indicate that sertraline is effective after two weeks of treatment in terminally ill cancer patients, acting not only on depression but also on anxiety and mental adaptation to cancer. Moreover, the effect of sertraline significantly depended on the genetic polymorphism of the serotonin transporter, being more pronounced in patients carrying the "l/l" genetic variant; these findings seem to encourage the examination of a larger sample of patients.

Serotonin Transporter 5-HTTLPR Polymorphism and Response to Citalopram in Terminally ill Cancer Patients: Report of Twenty-One Cases

“…The results of this study are consistent with the preliminary results obtained by the authors in palliative care, which showed that the effects of the SSRI sertraline were dependent on the 5-HTTLPR polymorphism 26 . Moreover, these results are in general agreement with the pharmacogenetics of citalopram as a drug endowed with antidepressant, as well as anxiolytic, properties 27 , and indicate that citalopram exerts a significant therapeutic action not only in depressed patients without concomitant somatic illness but also in terminally ill cancer patients.…”

Pharmacogenetics of escitalopram and mental adaptation to cancer in palliative care: Report of 18 cases

“…When depression is treated with drugs, SSRI antidepressants are the most frequently used agents [10][11][12][13][14] . The effects of the treatment with SSRIs has been shown to depend on pharmacogenetics, in particular on the polymorphism of the gene coding for the serotonin transporter (SERT, 5-HTT) [15][16][17][18][19][20] , which is the molecular target of SSRI's action.…”

“…The patients were genotyped for 5-HTTLPR polymorphism by analysis of genomic DNA obtained from buccal mucosa cells with standard procedures (Master-Amp TM buccal swab brushes, Epicentre Biotechnologies; GenElute TM Blood genomic DNA kit, Sigma). Polymerase chain reaction (PCR) and electrophoretic analysis were performed using conventional techniques that have been described in detail elsewhere [12][13][14] .…”

Functional Characterization of Liver Enhancers That Regulate Drug-Associated Transporters

“…Thus far, the majority of identified drug‐associated nucleotide variants are protein coding; however, these account for only a fraction of the interindividual pharmacogenetic differences seen in patient populations. With several promoter variants linked to variability in drug response 4 , 5 , 6 , 7 , 8 , 9 and association studies linking noncoding single‐nucleotide polymorphisms (SNPs) to ADE susceptibility and altered drug response, 10 it is likely that nucleotide variants in regulatory elements, such as enhancers, could also contribute to differences in drug response.…”

“…Removal of SLC22A1 in mice correlated with reduced uptake of metformin in hepatocytes, with heterozygous mice exhibiting intermediate levels, 8 pointing to the importance of proper regulation of transporter expression. In addition, nucleotide variations in promoter sequences are thought to influence drug response by altering the transcription of transporters 4 , 5 , 6 , 7 , 18 , 19 . More recently, it has been shown, using allelic imbalance, that differences in gene regulatory elements can lead to tissue‐specific expression differences in a drug‐associated protein, UGT2B15 20 .…”