Haplotype Analysis of GSK-3β Gene Polymorphisms in Bipolar Disorder Lithium Responders and Nonresponders

Iwahashi, Kazuhiko; Nishizawa, Daisuke; Narita, Shin; Numajiri, Maki; Murayama, Ohoshi; Yoshihara, Eiji; Onozawa, Yuya; Nagahori, Kaoru; Fukamauchi, Fumihiko; Ikeda, Kazutaka; Ishigooka, Jun

doi:10.1097/wnf.0000000000000039

Cited by 34 publications

(12 citation statements)

References 19 publications

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“…In the search for new drug targets, glycogen synthase 3 (GSK-3) has taken center stage for its known involvement in several pathways linked to both BD and diabetes mellitus (Gould et al 2004 ; Ronai et al 2014 ; Huang et al 2014 ; Iwahashi et al 2014 ). In the rat, lithium, a standard treatment for BD, reduces the enzyme’s activity in the hippocampus and improves memory and learning (Qu et al 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Bipolar disorder and diabetes mellitus: evidence for disease-modifying effects and treatment implications

Charles

Lambert

Kerner

2016

Int J Bipolar Disord

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Background: Bipolar disorder refers to a group of chronic psychiatric disorders of mood and energy levels. While dramatic psychiatric symptoms dominate the acute phase of the diseases, the chronic course is often determined by an increasing burden of co-occurring medical conditions. High rates of diabetes mellitus in patients with bipolar disorder are particularly striking, yet unexplained. Treatment and lifestyle factors could play a significant role, and some studies also suggest shared pathophysiology and risk factors. Objective:In this systematic literature review, we explored data around the relationship between bipolar disorder and diabetes mellitus in recently published population-based cohort studies with special focus on the elderly. Methods:A systematic search in the PubMed database for the combined terms "bipolar disorder" AND "elderly" AND "diabetes" in papers published between January 2009 and December 2015 revealed 117 publications; 7 studies were large cohort studies, and therefore, were included in our review. Results:We found that age-and gender-adjusted risk for diabetes mellitus was increased in patients with bipolar disorder and vice versa (odds ratio range between 1.7 and 3.2). Discussion:Our results in large population-based cohort studies are consistent with the results of smaller studies and chart reviews. Even though it is likely that heterogeneous risk factors may play a role in diabetes mellitus and in bipolar disorder, growing evidence from cell culture experiments and animal studies suggests shared disease mechanisms. Furthermore, disease-modifying effects of bipolar disorder and diabetes mellitus on each other appear to be substantial, impacting both treatment response and outcomes. Conclusions:The risk of diabetes mellitus in patients with bipolar disorder is increased. Our findings add to the growing literature on this topic. Increasing evidence for shared disease mechanisms suggests new disease models that could explain the results of our study. A better understanding of the complex relationship between bipolar disorder and diabetes mellitus could lead to novel therapeutic approaches and improved outcomes.

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Section: Discussionmentioning

confidence: 99%

Bipolar disorder and diabetes mellitus: evidence for disease-modifying effects and treatment implications

Charles

Lambert

Kerner

2016

Int J Bipolar Disord

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“…Lithium is considered to influence numerous neuroprotective pathways through increasing phosphorylated GSK3β and inhibiting its action, ameliorating the effects of excitotoxicity [ 82 ]. Previous studies have reported treatment response to lithium to be predicted by GSK3β gene expression and phosphorylation [ 83 , 84 ], and lithium induced increases in phosphorylated GSK3β to be correlated with symptom improvement [ 82 ]. Brain-derived neurotrophic factor (BDNF) is well known for its involvement in neuronal maturation, differentiation and survival, synaptic plasticity, and long-term memory consolidation, and is highly expressed in the cerebral cortex and hippocampus [ 85 ].…”

Section: Therapeutic Mechanisms Of Lithiummentioning

confidence: 99%

An Oldie but Goodie: Lithium in the Treatment of Bipolar Disorder through Neuroprotective and Neurotrophic Mechanisms

Won

Kim

2017

IJMS

162

113

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Lithium has been used for the treatment of bipolar disorder (BD) for the last sixty or more years, and recent studies with more reliable designs and updated guidelines have recommended lithium to be the treatment of choice for acute manic, mixed and depressive episodes of BD, along with long-term prophylaxis. Lithium’s specific mechanism of action in mood regulation is progressively being clarified, such as the direct inhibition on glycogen synthase kinase 3β, and its various effects on neurotrophic factors, neurotransmitters, oxidative metabolism, apoptosis, second messenger systems, and biological systems are also being revealed. Furthermore, lithium has been proposed to exert its treatment effects through mechanisms associated with neuronal plasticity. In this review, we have overviewed the clinical aspects of lithium use for BD, and have focused on the neuroprotective and neurotrophic effects of lithium.

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“…By comparing Tables 2 , 3 one can see that the genes GSK3β , BDNF , and SLC6A4 (serotonin transporter) seem to be involved bilaterally in poor and good response to lithium in different studies. 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: Pharmacogenetic Studies In Bipolar Disordermentioning

confidence: 99%

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

et al. 2021

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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.

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Haplotype Analysis of GSK-3β Gene Polymorphisms in Bipolar Disorder Lithium Responders and Nonresponders

Cited by 34 publications

References 19 publications

Bipolar disorder and diabetes mellitus: evidence for disease-modifying effects and treatment implications

Bipolar disorder and diabetes mellitus: evidence for disease-modifying effects and treatment implications

An Oldie but Goodie: Lithium in the Treatment of Bipolar Disorder through Neuroprotective and Neurotrophic Mechanisms

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

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