Glycogen synthase kinase‐3β in patients with bipolar I disorder: results from a prospective study

Jacoby, Anne Sophie; Munkholm, Klaus; Vinberg, Maj; Joaquim, Helena Gp; Talib, Leda Leme; Gattaz, Wagner F.; Kessing, Lars Vedel

doi:10.1111/bdi.12400

Cited by 11 publications

(7 citation statements)

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“…Observations in patients indirectly link the GSK3 β activity status with the bipolar phase cycling: a longitudinal study monitored at several time points the blood levels of inactivated GSK3 β, finding a correlation between higher inactivation and the predominance of depressive phases, as opposed to manic phases, where GSK3 β was mostly active. Interestingly, euthymic phases were associated with average levels of inactive-GSK3 β, that however were still lower than those observed in control subjects [70]. This observation is supported by other investigations, linking low activation levels of GSK3 β with depression phases of bipolar disorders, however low GSK3 β activity does not seem to be related with affective traits in healthy controls [71].…”

Section: Methodssupporting

confidence: 53%

Putative Mechanisms of Action and Clinical Use of Lithium in Children and Adolescents: A Critical Review

Pisano

Pozzi

Catone

et al. 2019

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Section: Methodssupporting

confidence: 53%

Putative Mechanisms of Action and Clinical Use of Lithium in Children and Adolescents: A Critical Review

Pisano

Pozzi

Catone

et al. 2019

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“…We have in two longitudinal studies with repeated assessments of patients with bipolar disorder during affective states (manic/mixed, depressive and euthymic) and healthy control individuals found that brain-derived neurotrophic factor (BDNF), 39 increased oxidative DNA and RNA damage 40 41 and decreased mRNA expression of the PTGDS gene encoding the prostaglandin D synthase enzyme 42 are markers related to the illness trait in bipolar disorder. The level of the cytokines IL-6 and IL-18 (interleukin) was related to manic episodes only and the activity of GSK-3beta varied with affective states, 43 suggesting that these may be state markers. 44 These results have contributed to the research area of biomarkers in bipolar disorder, moving the area closer towards identifying clinically applicable biomarkers.…”

Section: Methods and Analysismentioning

confidence: 99%

The Bipolar Illness Onset study: research protocol for the BIO cohort study

Munkholm²,

et al. 2017

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IntroductionBipolar disorder is an often disabling mental illness with a lifetime prevalence of 1%–2%, a high risk of recurrence of manic and depressive episodes, a lifelong elevated risk of suicide and a substantial heritability. The course of illness is frequently characterised by progressive shortening of interepisode intervals with each recurrence and increasing cognitive dysfunction in a subset of individuals with this condition. Clinically, diagnostic boundaries between bipolar disorder and other psychiatric disorders such as unipolar depression are unclear although pharmacological and psychological treatment strategies differ substantially. Patients with bipolar disorder are often misdiagnosed and the mean delay between onset and diagnosis is 5–10 years. Although the risk of relapse of depression and mania is high it is for most patients impossible to predict and consequently prevent upcoming episodes in an individual tailored way. The identification of objective biomarkers can both inform bipolar disorder diagnosis and provide biological targets for the development of new and personalised treatments. Accurate diagnosis of bipolar disorder in its early stages could help prevent the long-term detrimental effects of the illness.The present Bipolar Illness Onset study aims to identify (1) a composite blood-based biomarker, (2) a composite electronic smartphone-based biomarker and (3) a neurocognitive and neuroimaging-based signature for bipolar disorder.Methods and analysisThe study will include 300 patients with newly diagnosed/first-episode bipolar disorder, 200 of their healthy siblings or offspring and 100 healthy individuals without a family history of affective disorder. All participants will be followed longitudinally with repeated blood samples and other biological tissues, self-monitored and automatically generated smartphone data, neuropsychological tests and a subset of the cohort with neuroimaging during a 5 to 10-year study period.Ethics and disseminationThe study has been approved by the Local Ethical Committee (H-7-2014-007) and the data agency, Capital Region of Copenhagen (RHP-2015-023), and the findings will be widely disseminated at international conferences and meetings including conferences for the International Society for Bipolar Disorders and the World Federation of Societies for Biological Psychiatry and in scientific peer-reviewed papers.Trial registration numberNCT02888262.

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“…Recently, a paper by Jacoby et al . titled ‘Glycogen synthase kinase‐3β in patients with bipolar I disorder–results from a prospective study’ was published in Bipolar Disorders .…”

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confidence: 99%

“…The strength of the study by Jacoby et al . is its prospective and longitudinal nature, with the authors obtaining samples from the same individuals at different time points.…”

mentioning

confidence: 99%

Whether lithium inhibits glycogen synthase kinase (GSK)‐3β activity in vivo in humans is still an open question

Agam

Azab

2016

Bipolar Disorders

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Recently, a paper by Jacoby et al. 1 titled 'Glycogen synthase kinase-3β in patients with bipolar I disorder-results from a prospective study' was published in Bipolar Disorders. Glycogen synthase kinase (GSK)-3β is a kinase ubiquitously abundant in mammalian tissues, in general, and in the brain, in particular. 2,3 GSK-3β regulates the activity of multiple proteins involved in regulation of gene expression, apoptosis, survival pathways, inflammation, autophagy and neuronal plasticity. 2,4-7 Klein and Melton 8 and Stambolic et al. 9 have demonstrated that lithium inhibits GSK-3β in vitro at therapeutically relevant concentrations.Subsequently, in vivo studies in animals also found that lithium inhibits GSK-3β activity. 10-13 Following these findings it has been hypothesized that chronic lithium treatment inhibits GSK-3β activity in vivo in humans and that this inhibition mediates the beneficial therapeutic effects of the drug.A major mechanism controlling GSK-3β activity is phosphorylation on its serine (Ser) 9 residue resulting in inhibition of the catalytic activity. 5,14 Thus, phosphorylated-Ser-9-GSK-3β (P-Ser-9-GSK-3β) protein levels are regarded as an indirect measure of the inhibited fraction of GSK-3β. Other indirect measures of GSK-3β activity use β-catenin or phosphorylated tau protein levels. 9,14 GSK-3β phosphorylates a myriad of proteins, in most cases resulting in inactivation of the downstream target. To be phosphorylated by GSK-3β many of its substrates require a 'priming' pre-phosphorylation step, an additional regulatory mechanism of GSK-3β activity. 5Lithium-induced inhibition of GSK-3β is obviously an important pharmacological aspect of this mood stabilizer. However, whether lithium inhibits GSK-3β activity in vivo in humans is a crucial question to which an unequivocal answer has not yet been obtained. Multiple human studies used P-Ser9-GSK-3β protein levels as a measure of GSK-3β activity. This approach might introduce bias since changes in P-Ser9-GSK-3β levels per se may merely reflect changes in total GSK-3β, while the percentage of the phosphorylated form out of the total amount of the enzyme is unaltered. The assessment of the P-Ser9-GSK-3β/total GSK-3β protein level ratio overcomes this specific limitation. Yet, it has to be kept in mind that even the P-Ser9-GSK-3β/total GSK-3β ratio is not a direct measure of the in vivo activity of the enzyme. In a recent seminal review by Beurel et al.,15 the authors indicate that the serine-phosphorylation inhibitory mechanism does not cause absolute inhibition of GSK-3β activity and that increased serine-9 phosphorylation of GSK-3β does not inhibit GSK-3β in the β-catenin destruction complex. These points suggest that relying solely on the determination of the P-Ser-9 GSK-3β/total GSK-3β ratio or β-catenin levels as indirect measures of the extent of the in vivo inhibition of GSK-3β activity by lithium might be misleading. Yet, multiple studies that examined

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Glycogen synthase kinase‐3β in patients with bipolar I disorder: results from a prospective study

Abstract: The activity of GSK-3β is altered in euthymic bipolar disorder compared with healthy control subjects and varies with affective states.

Cited by 11 publications

References 35 publications

Putative Mechanisms of Action and Clinical Use of Lithium in Children and Adolescents: A Critical Review

Putative Mechanisms of Action and Clinical Use of Lithium in Children and Adolescents: A Critical Review

The Bipolar Illness Onset study: research protocol for the BIO cohort study

Whether lithium inhibits glycogen synthase kinase (GSK)‐3β activity in vivo in humans is still an open question

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