Serotonin transporter 5-HTTLPR polymorphism and response to citalopram in terminally ill cancer patients: report of twenty-one cases

The aim of this study was to examine the effects of the SSRI antidepressant drug citalopram on anxiety, depression and mental adjustment to cancer in terminally ill cancer patients, considering also the 5-HTTLPR genetic polymorphism. A group of twenty-one consecutive patients admitted to the hospice of the Casa di Cura Pineta del Carso (Trieste, Italy) with different types of advanced cancer, who were clinically judged to require treatment with an antidepressive drug, was treated with citalopram for two weeks. The response was determined and related to 5-HTTLPR. Citalopram significantly reduced the scores on the depression and anxiety subscales of the Hospital Anxiety and Depression Scale (HADS).When the effects of citalopram were analyzed in relation to the 5-HTTLPR polymorphism, the HADS depression score was significantly decreased only in patients with the “l/l” allelic variant of the serotonin transporter conferring high functional activity, while the score of the Mini- MAC fatalism scale was significantly increased in patients carrying at least one “s” allele. These preliminary findings seem to indicate that two weeks of treatment with citalopram are effective in reducing depressive symptoms in terminally ill cancer patients. Moreover, the effects of citalopram on fatalism as a strategy of mental adaptation to cancer, and on depressive symptoms depend on the allelic variants of the 5-HTTLPR genotype of the patients. These results seem to encourage the examination of a larger patient sample and of different treatment schedules, as well as a more thorough characterization of fatalism as a coping strategy in cancer patients

5-HTTLPR polymorphism of serotonin transporter and effects of sertraline in terminally ill cancer patients: report of eleven case

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 patient

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

Aims and Background: In palliative care, few data are available on the diagnosis and treatment of mood disorders and of difficulties of mental adaptation to cancer for patients in the advanced phases of the disease. SSRI antidepressants are the treatment of choice; the 5-HTTLPR genetic polymorphism of the serotonin transporter (SERT) has been shown in psychiatry to significantly determine the therapeutic response and incidence of adverse effects. The aim of the present investigation has been therefore that to examine the effects of the SSRI antidepressant escitalopram also considering 5-HTTLPR on depression, anxiety and mental adaptation to cancer in palliative care. Methods: 18 consecutive depressed patients with different forms of advanced tumours, which were admitted to the Hospice Ass 6, of S. Vito al Tagliamento (Pordenone, Italy), were genotyped for the “s” and “l” variants of 5-HTTLPR and were treated with escitalopram: their response after two weeks of treatment was psychometrically evaluated. Results: The treatment with escitalopram significantly decreased the scores of anxiety of the Hospital Anxiety and Depression Scale (HADS) (p= 0.006), and of anxious preoccupation (p= 0.007) and hopelessness-helplessness (p= 0.017) of the Mini Mental Adjustment to Cancer (Mini-MAC) scale. When patients were stratified for the SERT genotype, HADS anxiety was significantly decreased in patients carrying the “s/s” and “s/l” variants (p= 0.024), whereas subjects with “l/l” genotype displayed a significant reduction of Mini-MAC anxious preoccupation (p= 0.018). Conclusions: The data presented indicate that the use of SSRI antidepressants is effective in the palliative care of cancer patients, and their action is exerted, in addition to depression, also on the mental adaptation to the disease. These results encourage the deeper examination of a larger cohort of patients, and the significant contribution of pharmacogenetics indicates the possibility of a personalized treatment with SSRIs in palliative care

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies

Frontotemporal dementia and its subtypes: A genome-wide association study

Background: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402

Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population