Further evidence for a possible association between serotonin transporter gene and lithium prophylaxis in mood disorders

Serretti, Alessandro; Malitas, Petros; Mandelli, Laura; Lorenzi, Cristina; Ploia, Cristina; Alevizos, B.; Nikolaou, Chryssoula; Boufidou, Fotini; Christodoulou, G.N.; Smeraldi, Enrico

doi:10.1038/sj.tpj.6500252

Cited by 51 publications

(23 citation statements)

References 86 publications

(82 reference statements)

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“…Furthermore, there is a 5Ј promoter variant, termed the 5HTTLPR, also correlated with genetic predisposition to similar neurological conditions as the intron 2 VNTR (Heils et al, 1996(Heils et al, , 1998. The 5HTTLPR has been associated with lithium response (Serretti et al, 2004;Rybakowski et al, 2005), although as yet the intron 2 VNTR has not been examined for lithium response. The 5HTTLPR contains DNA motifs consistent with its binding to CTCF among other transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Differential Regulation of the Serotonin Transporter Gene by Lithium Is Mediated by Transcription Factors, CCCTC Binding Protein and Y-Box Binding Protein 1, through the Polymorphic Intron 2 Variable Number Tandem Repeat

Roberts

Scott²,

Howard³

et al. 2007

J. Neurosci.

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The serotoninergic pathways are possible targets for the action of lithium, a therapeutic agent for treatment of bipolar affective disorders. This study aimed to investigate the molecular mechanisms regulating human serotonin transporter gene (SLC6A4) expression by lithium and, specifically, the role of the variable number tandem repeat (VNTR) polymorphic region in intron 2, which is potentially a predisposing genetic factor for bipolar affective disorders. We demonstrated that addition of lithium to human JAr cells led to changes in the levels of SLC6A4 mRNA and protein. Additional investigations revealed that the intron 2 VNTR domain was a potential target for mediation of a transcriptional response to lithium. Properties of two transcription factors, CCCTC binding protein (CTCF) and Y-box binding protein 1 (YB-1), previously shown to be involved in the regulation of SLC6A4 VNTR, were found to be modulated by LiCl. Thus, levels of CTCF and YB-1 mRNA and protein were altered in vivo in response to LiCl. Furthermore, CTCF and YB-1 showed differential binding to the polymorphic alleles of the VNTR on exposure to LiCl. Our data suggest a model in which differential binding of CTCF and YB-1 to the allelic variants of the intron 2 VNTR can be regulated by lithium and in part result in differential and even aberrant expression of SLC6A4. Our study of the regulation of the SLC6A4 VNTR by lithium may improve the understanding of psychiatric disorders and enable the development of novel therapies for conditions such as bipolar affective disorder to target only the at-risk allele.

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Section: Discussionmentioning

confidence: 99%

Differential Regulation of the Serotonin Transporter Gene by Lithium Is Mediated by Transcription Factors, CCCTC Binding Protein and Y-Box Binding Protein 1, through the Polymorphic Intron 2 Variable Number Tandem Repeat

Roberts

Scott²,

Howard³

et al. 2007

J. Neurosci.

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“…For instance, polymorphisms in the SLC6A4 gene were associated with antidepressant response or remission [28,68,76,81,88,91]. Similar SLC6A4 variants have shown an association with lithium treatment outcomes in patients with BPD [75,102].…”

Section: Lithium Treatment For Bipolar Disordermentioning

confidence: 99%

“…Pharmacogenomic studies that aimed to identify genetic variants associated with lithium treatment responses, efficacy, tolerability, and safety in patients with BPD have identified novel SNPs located in protein coding genes. Candidate gene studies have reported several polymorphisms associated with lithium treatment response located in the 5-HTT [101,102], [74], and CACNG2 [103] genes (see Table 2). …”

Section: Lithium Treatment For Bipolar Disordermentioning

confidence: 99%

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Pharmacogenomics in the treatment of mood disorders: Strategies and Opportunities for personalized psychiatry

2017

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Personalized medicine (personalized psychiatry in a specific setting) is a new model towards individualized care, in which knowledge from genomics and other omic pillars (microbiome, epigenomes, proteome, and metabolome) will be combined with clinical data to guide efforts to new drug development and targeted prescription of the existing treatment options. In this review, we summarize pharmacogenomic studies in mood disorders that may lay the foundation towards personalized psychiatry. In addition, we have discussed the possible strategies to integrate data from omic pillars as a future path to personalized psychiatry. So far, the progress of uncovering single nucleotide polymorphisms (SNPs) underpinning treatment efficacy in mood disorders (e.g., SNPs associated with selective serotonin re-uptake inhibitors or lithium treatment response in patients with bipolar disorder and major depressive disorder) are encouraging, but not adequate. Genetic studies have pointed to a number of SNPs located at candidate genes that possibly influence response to; (a) antidepressants COMT, HTR2A, HTR1A, CNR1, SLC6A4, NPY, MAOA, IL1B, GRIK4, BDNF, GNB3, FKBP5, CYP2D6, CYP2C19, and ABCB1 and (b) mood stabilizers (lithium) 5-HTT, TPH, DRD1, FYN, INPP1, CREB1, BDNF, GSK3β, ARNTL, TIM, DPB, NR3C1, BCR, XBP1, and CACNG2. We suggest three alternative and complementary strategies to implement knowledge gained from pharmacogenomic studies. The first strategy can be to implement diagnostic, therapeutic, or prognostic genetic testing based on candidate genes or gene products. The second alternative is an integrative analysis (systems genomics approach) to combine omics data obtained from the different pillars of omics investigation, including genomics, epigenomes, proteomics, metabolomics and microbiomes. The main goal of system genomics is an identification and understanding of biological pathways, networks, and modules underlying drug-response. The third strategy aims to the development of multivariable diagnostic or prognostic algorithms (tools) combining individual's genomic information (polygenic score) with other predictors (e.g., omics pillars, neuroimaging, and clinical characteristics) to finally predict therapeutic outcomes. An integration of molecular science with that of traditional clinical practice is the way forward to drug discoveries and novel therapeutic approaches and to characterize psychiatric disorders leading to a better predictive, preventive, and personalized medicine (PPPM) in psychiatry. With future advances in the omics technology and methodological developments for data integration, the goal of PPPM in psychiatry is promising.

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“…However, an association between the functional polymorphism in the upstream regulatory region of the 5HT transporter gene and the prophylactic efficacy of lithium in Italian patients has been demonstrated previously [25] . In another study, the L/L variant was related to the development of manic episodes within 3 years and a better response of L/S carriers, but could not support a decreased effi cacy of the treatment in patients with the S/S genotype [26] . In a European multicenter study, no association was found between the 5HTTLPR polymorphism and the primary psychiatric diagnosis or phenotypic traits [27] .…”

Section: Introductionmentioning

confidence: 99%

Allelic Isoforms and Decrease in Serotonin Transporter mRNA in Lymphocytes of Patients with Major Depression

Lima

Mata

Urbina

2005

Neuroimmunomodulation

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Serotonin transporter, measured by the specific binding of [³H]paroxetine, has been reported to be reduced in circulating lymphocytes of patients with major depression. Due to this observation, the objective of the present report was to determine the levels of serotonin transporter mRNA in lymphocytes obtained from 29 major depression patients (4 men, age 33.10 ± 1.63 years) and from 30 subjects included as a control group (4 men, age 37.54 ± 2.18 years) using RT-PCR. The patients were diagnosed according to the criteria of the American Psychiatric Association, and had a severity of depression of 32.68 ± 1.55 determined by the Hamilton Rating Scale for Depression. The DNA was submitted to polymerase chain reaction with primers for the 5′ regulatory region of human serotonin transporter, which could show the long and the short allelic forms of the transporter gene for the 5HTTLPR polymorphism. Semiquantitative analysis was performed using β-actin as internal and external standard. Control subjects presented the two allelic forms in 9.09% and depressed patients in 8.69%. The long variant was present in 73% of controls and in 60% of patients, without significant differences. There was a significant reduction in mRNA in depressed patients expressing the long allele. The number of immunofluorescent lymphocytes, labeled with a specific antibody against serotonin transporter, was reduced in the patients, as well as CD3+ lymphocytes. Serotonin and 5-hydroxyindoleacetic acid in platelet-poor plasma or lymphocytes did not differ between depressed patients and controls. The reduction in lymphocyte serotonin transporter described in major depression might be due to a decrease in the level of its mRNA and in the number of cells expressing it. These observations might implicate that functional modifications are associated with nervous-immune interactions in depression.

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Further evidence for a possible association between serotonin transporter gene and lithium prophylaxis in mood disorders

Cited by 51 publications

References 86 publications

Differential Regulation of the Serotonin Transporter Gene by Lithium Is Mediated by Transcription Factors, CCCTC Binding Protein and Y-Box Binding Protein 1, through the Polymorphic Intron 2 Variable Number Tandem Repeat

Differential Regulation of the Serotonin Transporter Gene by Lithium Is Mediated by Transcription Factors, CCCTC Binding Protein and Y-Box Binding Protein 1, through the Polymorphic Intron 2 Variable Number Tandem Repeat

Pharmacogenomics in the treatment of mood disorders: Strategies and Opportunities for personalized psychiatry

Allelic Isoforms and Decrease in Serotonin Transporter mRNA in Lymphocytes of Patients with Major Depression

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