Study of the association of serotonin transporter triallelic 5-HTTLPR and STin2 VNTR polymorphisms with lithium prophylaxis response in bipolar disorder

Tharoor, Hema; Kotambail, Ananthapadmanabha; Jain, Sanjeev; Sharma, Podila Satya Venkata Narasimha; Satyamoorthy, Kapaettu

doi:10.1097/ypg.0b013e32835d6fad

Cited by 23 publications

(8 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, another group found a contradictory result indicating that the short variant was associated with a non-response to lithium among bipolar disorder patients (Rybakowski et al, 2005b). While these studies showed some kind of association between 5-HTTLPR variants and lithium response albeit contradictory, two later studies failed to find any significant associations (Michelon et al, 2006; Manchia et al, 2009a; Tharoor et al, 2013). …”

Section: Neurotransmitter Systems and Lithiummentioning

confidence: 97%

Molecular actions and clinical pharmacogenetics of lithium therapy

Can

Schulze

Gould

2014

Pharmacology Biochemistry and Behavior

101

View full text Add to dashboard Cite

Mood disorders, including bipolar disorder and depression, are relatively common human diseases for which pharmacological treatment options are often not optimal. Among existing pharmacological agents and mood stabilizers used for the treatment of mood disorders, lithium has a unique clinical profile. Lithium has efficacy in the treatment of bipolar disorder generally, and in particular mania, while also being useful in the adjunct treatment of refractory depression. In addition to antimanic and adjunct antidepressant efficacy, lithium is also proven effective in the reduction of suicide and suicidal behaviors. However, only a subset of patients manifests beneficial responses to lithium therapy and the underlying genetic factors of response are not exactly known. Here we discuss preclinical research suggesting mechanisms likely to underlie lithium’s therapeutic actions including direct targets inositol monophosphatase and glycogen synthase kinase-3 (GSK-3) among others, as well as indirect actions including modulation of neurotrophic and neurotransmitter systems and circadian function. We follow with a discussion of current knowledge related to the pharmacogenetic underpinnings of effective lithium therapy in patients within this context. Progress in elucidation of genetic factors that may be involved in human response to lithium pharmacology has been slow, and there is still limited conclusive evidence for the role of a particular genetic factor. However, the development of new approaches such as genome-wide association studies (GWAS), and increased use of genetic testing and improved identification of mood disorder patients sub-groups will lead to improved elucidation of relevant genetic factors in the future.

show abstract

Section: Neurotransmitter Systems and Lithiummentioning

confidence: 97%

Molecular actions and clinical pharmacogenetics of lithium therapy

Can

Schulze

Gould

2014

Pharmacology Biochemistry and Behavior

101

View full text Add to dashboard Cite

show abstract

“…Effects of 5‐HTT polymorphisms are seen in response to treatments other than antidepressants; Tharoor et al . reported an association of STin2 polymorphism and its combined effect with 5‐HTTLPR variants with lithium response in treatment of bipolar disorder.…”

Section: The Serotonin Systemmentioning

confidence: 99%

Pharmacogenomics in psychiatry: the relevance of receptor and transporter polymorphisms

Reynolds

McGowan

Dalton

2014

Brit J Clinical Pharma

View full text Add to dashboard Cite

The treatment of severe mental illness, and of psychiatric disorders in general, is limited in its efficacy and tolerability. There appear to be substantial interindividual differences in response to psychiatric drug treatments that are generally far greater than the differences between individual drugs; likewise, the occurrence of adverse effects also varies profoundly between individuals. These differences are thought to reflect, at least in part, genetic variability. The action of psychiatric drugs primarily involves effects on synaptic neurotransmission; the genes for neurotransmitter receptors and transporters have provided strong candidates in pharmacogenetic research in psychiatry. This paper reviews some aspects of the pharmacogenetics of neurotransmitter receptors and transporters in the treatment of psychiatric disorders. A focus on serotonin, catecholamines and amino acid transmitter systems reflects the direction of research efforts, while relevant results from some genome-wide association studies are also presented. There are many inconsistencies, particularly between candidate gene and genome-wide association studies. However, some consistency is seen in candidate gene studies supporting established pharmacological mechanisms of antipsychotic and antidepressant response with associations of functional genetic polymorphisms in, respectively, the dopamine D 2 receptor and serotonin transporter and receptors. More recently identified effects of genes related to amino acid neurotransmission on the outcome of treatment of schizophrenia, bipolar illness or depression reflect the growing understanding of the roles of glutamate and γ-aminobutyric acid dysfunction in severe mental illness. A complete understanding of psychiatric pharmacogenomics will also need to take into account epigenetic factors, such as DNA methylation, that influence individual responses to drugs.

show abstract

“…Some of these studies showed no significant association with lithium response for the following gene variants: BDNF gene, G196A/ Val66Met (Masui et al, 2006;Michelon et al, 2006;Wang et al, 2014) and rs10835210, rs11030101, rs11030102, rs12273363, rs2030324, rs2049045, rs6265", rs7103411, rs962369, and rs988748 (Drago et al, 2010); SLC6A4 gene, s/s, s/l, and l/l (Serretti et al, 2004;Masoliver et al, 2006;Michelon et al, 2006;Manchia et al, 2009); and GSK3β gene, rs3755557 (-1727A/T) (Michelon et al, 2006;Numajiri et al, 2012;Iwahashi et al, 2014), rs334558 (-50T/C) (Szczepankiewicz et al, 2006;Iwahashi et al, 2014), and rs11921360-A (Mitjans et al, 2015). On the other hand, other studies did find an association of the following variants of GSK3β, BDNF, and SLC6A4 with lithium response in patients with BD: GSK3β gene, rs334558 (−50T/C) (Adli et al, 2007;Benedetti et al, 2012;Numajiri et al, 2012;Lin et al, 2013;Mitjans et al, 2015, 3), rs6438552 (McCarthy et al, 2011, rs3755557 (-1727A/T) (Iwahashi et al, 2014), rs1732170-rs1192136 (Mitjans et al, 2015); BDNF gene, Val66Met rs6265 (Rybakowski et al, 2005;Dmitrzak-Weglarz et al, 2008;Rybakowski et al, 2012;Wang et al, 2012;Wang et al, 2014) and rs988748 (Dmitrzak-Weglarz et al, 2008); and SLC6A4 gene, l/l and s/s (Serretti et al, 2001;Benedetti et al, 2012), s allele and 10 repeat allele of STin2 (STin2.10) (Tharoor et al, 2013), and ins/del 44 pz (Rybakowski et al, 2012).…”

Section: Candidate-gene Association Studiesmentioning

confidence: 99%

The Genetics of Response to and Side Effects of Lithium Treatment in Bipolar Disorder: Future Research Perspectives

et al. 2021

View full text Add to dashboard Cite

Although the mood stabilizer lithium is a first-line treatment in bipolar disorder, a substantial number of patients do not benefit from it and experience side effects. No clinical tool is available for predicting lithium response or the occurrence of side effects in everyday clinical practice. Multiple genetic research efforts have been performed in this field because lithium response and side effects are considered to be multifactorial endophenotypes. Available results from linkage and segregation, candidate-gene, and genome-wide association studies indicate a role of genetic factors in determining response and side effects. For example, candidate-gene studies often report GSK3β, brain-derived neurotrophic factor, and SLC6A4 as being involved in lithium response, and the latest genome-wide association study found a genome-wide significant association of treatment response with a locus on chromosome 21 coding for two long non-coding RNAs. Although research results are promising, they are limited mainly by a lack of replicability and, despite the collaboration of consortia, insufficient sample sizes. The need for larger sample sizes and “multi-omics” approaches is apparent, and such approaches are crucial for choosing the best treatment options for patients with bipolar disorder. In this article, we delineate the mechanisms of action of lithium and summarize the results of genetic research on lithium response and side effects.

show abstract

Study of the association of serotonin transporter triallelic 5-HTTLPR and STin2 VNTR polymorphisms with lithium prophylaxis response in bipolar disorder

Cited by 23 publications

References 22 publications

Molecular actions and clinical pharmacogenetics of lithium therapy

Molecular actions and clinical pharmacogenetics of lithium therapy

Pharmacogenomics in psychiatry: the relevance of receptor and transporter polymorphisms

The Genetics of Response to and Side Effects of Lithium Treatment in Bipolar Disorder: Future Research Perspectives

Contact Info

Product

Resources

About