A reduced risk of stroke with lithium exposure in bipolar disorder: a population‐based retrospective cohort study

Cui, Lan; Liu, Chia Chien; Lin, Ching Heng; Lan, Tzuo Yun; McInnis, Melvin G.; Chan, Chin Hong; Lan, Tsuo-Hung

doi:10.1111/bdi.12336

Cited by 46 publications

(50 citation statements)

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“…Therefore, patients at risk for stroke with unfortunate collateral status (thus portending poor outcome) could particularly profit from a lithium treatment at low concentrations via a generally improved endothelium-dependent vessel relaxation capacity. This might be speculative, but on the other hand, the lithium-augmented cerebrovascular relaxation capacity may party explain, why continuous lithium treatment can reduce the risk for stroke (Lan et al, 2015) or may improve neurologic recovery after cortical stroke (Mohammadianinejad et al, 2014) potentially caused by various beneficiary effects on neurons (Doeppner et al, 2016; Vosahlikova and Svoboda, 2016), or platelets (Barry et al, 2003) including the direct ones on vascular and cerebrovascular endothelium (Afsharimani et al, 2007; Rahimzadeh-Rofouyi et al, 2007; Bosche et al, 2013, 2016), as presented here. Directly or secondarily impaired endothelial barrier after ischemia and hemorrhages followed by vasogenic edema formation (Stokum et al, 2016) were known to be highly relevant for clinical outcome of various types of stroke (Hacke et al, 1996; Bosche et al, 2003; Macdonald, 2014; Wijdicks et al, 2014; Urday et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have also identified protective effects of lithium in cardiovascular and cerebrovascular diseases (Gold et al, 2011; Chiu and Chuang, 2012). This protective effect was highlighted by two recent clinical studies demonstrating that prolonged lithium treatment reduces the risk of ischemic stroke in bipolar disorder patients (Lan et al, 2015), and improves neurological recovery after cortical stroke (Mohammadianinejad et al, 2014). Stroke and thromboembolism risk depend not only on cerebral but also on general endothelial functioning.…”

Section: Introductionmentioning

confidence: 95%

“…In light of the clinical effectiveness of lithium in stroke, we have recently examined lithium-endothelium interactions (Bosche et al, 2013, 2016). Lithium treatment (Rajkowska, 2000; Lan et al, 2015) may be effective in both ischemic and hemorrhagic stroke, and even traumatic brain injury (Leeds et al, 2014; Gao et al, 2016) by improving disturbances in endothelial functions, such as: vascular or cerebrovascular autoregulation of blood flow, vasorelaxation capacity, and dynamic endothelial barrier permeability (Bosche et al, 2003, 2009, 2010; Gündüz et al, 2003; Butcher et al, 2004; Dohmen et al, 2007; Meisel et al, 2012; Renú et al, 2015; Helbok et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

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Low-Dose Lithium Stabilizes Human Endothelial Barrier by Decreasing MLC Phosphorylation and Universally Augments Cholinergic Vasorelaxation Capacity in a Direct Manner

et al. 2016

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Lithium at serum concentrations up to 1 mmol/L has been used in patients suffering from bipolar disorder for decades and has recently been shown to reduce the risk for ischemic stroke in these patients. The risk for stroke and thromboembolism depend not only on cerebral but also on general endothelial function and health; the entire endothelium as an organ is therefore pathophysiologically relevant. Regardless, the knowledge about the direct impact of lithium on endothelial function remains poor. We conducted an experimental study using lithium as pharmacologic pretreatment for murine, porcine and human vascular endothelium. We predominantly investigated endothelial vasorelaxation capacities in addition to human basal and dynamic (thrombin-/PAR-1 receptor agonist-impaired) barrier functioning including myosin light chain (MLC) phosphorylation (MLC-P). Low-dose therapeutic lithium concentrations (0.4 mmol/L) significantly augment the cholinergic endothelium-dependent vasorelaxation capacities of cerebral and thoracic arteries, independently of central and autonomic nerve system influences. Similar concentrations of lithium (0.2–0.4 mmol/L) significantly stabilized the dynamic thrombin-induced and PAR-1 receptor agonist-induced permeability of human endothelium, while even the basal permeability appeared to be stabilized. The lithium-attenuated dynamic permeability was mediated by a reduced endothelial MLC-P known to be followed by a lessening of endothelial cell contraction and paracellular gap formation. The well-known lithium-associated inhibition of inositol monophosphatase/glycogen synthase kinase-3-β signaling-pathways involving intracellular calcium concentrations in neurons seems to similarly occur in endothelial cells, too, but with different down-stream effects such as MLC-P reduction. This is the first study discovering low-dose lithium as a drug directly stabilizing human endothelium and ubiquitously augmenting cholinergic endothelium-mediated vasorelaxation. Our findings have translational and potentially clinical impact on cardiovascular and cerebrovascular disease associated with inflammation explaining why lithium can reduce, e.g., the risk for stroke. However, further clinical studies are warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Low-Dose Lithium Stabilizes Human Endothelial Barrier by Decreasing MLC Phosphorylation and Universally Augments Cholinergic Vasorelaxation Capacity in a Direct Manner

et al. 2016

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“…The reduced risk was also correlated with a higher dose, longer treatment duration and a higher rate of exposure to lithium 794. In the second study, in a sample of 4729 patients diagnosed with BD, lithium exposure was associated with a reduced risk of cancer, compared to a group prescribed anticonvulsant medications.…”

Section: Specific Populationsmentioning

confidence: 91%

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

et al. 2018

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The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously published treatment guidelines for bipolar disorder in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. The last two updates were published in collaboration with the International Society for Bipolar Disorders (ISBD). These 2018 CANMAT and ISBD Bipolar Treatment Guidelines represent the significant advances in the field since the last full edition was published in 2005, including updates to diagnosis and management as well as new research into pharmacological and psychological treatments. These advances have been translated into clear and easy to use recommendations for first, second, and third‐ line treatments, with consideration given to levels of evidence for efficacy, clinical support based on experience, and consensus ratings of safety, tolerability, and treatment‐emergent switch risk. New to these guidelines, hierarchical rankings were created for first and second‐ line treatments recommended for acute mania, acute depression, and maintenance treatment in bipolar I disorder. Created by considering the impact of each treatment across all phases of illness, this hierarchy will further assist clinicians in making evidence‐based treatment decisions. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination are recommended as first‐line treatments for acute mania. First‐line options for bipolar I depression include quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine. While medications that have been shown to be effective for the acute phase should generally be continued for the maintenance phase in bipolar I disorder, there are some exceptions (such as with antidepressants); and available data suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole monotherapy or combination treatments should be considered first‐line for those initiating or switching treatment during the maintenance phase. In addition to addressing issues in bipolar I disorder, these guidelines also provide an overview of, and recommendations for, clinical management of bipolar II disorder, as well as advice on specific populations, such as women at various stages of the reproductive cycle, children and adolescents, and older adults. There are also discussions on the impact of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. Finally, an overview of issues related to safety and monitoring is provided. The CANMAT and ISBD groups hope that these guidelines become a valuable tool for practitioners across the globe.

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“…In einer ergänzenden Übersichtsarbeit, die auf kontrollierten klinischen Studien basiert, konnten für Lithium positive Effekte auf kognitive Funktionen beim amnestischen Typ der leichten kognitiven Störung sowie bei der Alzheimer-Demenz dargestellt werden [32]. In einer populationsbasierten Kohortenstudie zeigte sich zudem, dass Lithium offensichtlich das bei Bipolaren Störungen erhöhte Schlaganfallrisiko senkt, wobei die Risikoreduktion mit der Dauer und Dosis der Lithiumtherapie positiv korrelierte [33]. Bei insgesamt sehr spärlicher Datenlage scheint Lithium dagegen am ehesten keinen positiven Effekt auf andere neurodegenerative Erkrankungen wie Morbus Parkinson, Multisystematrophie, Amyotrophe Lateralsklerose und Morbus Huntington auszuüben [31,32].…”

Section: Neuroprotektionunclassified

Update – Lithium in der Phasenprophylaxe Bipolarer Störungen

Petzold

Bauer

Severus

2018

Fortschr Neurol Psychiatr

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ZusammenfassungLithium ist der Goldstandard in der Phasenprophylaxe Bipolarer Störungen und das einzige Medikament für das es eine überzeugende suizidpräventive Wirkung bei affektiven Erkrankungen gibt. Unter Berücksichtigung eines regelmäßigen Monitorings ist Lithium eine zumeist gut verträgliche und sichere Phasenprophylaxe, die nach sorgfältiger Risiko-Nutzen-Abwägung auch eine off-label Therapieoption in Schwangerschaft und Stillzeit darstellt. Darüber hinaus gibt es Hinweise, dass Lithium neuroprotektiv wirken mag und möglicherweise das Risiko für eine Alzheimer-Demenz und Schlaganfälle senken kann. Perspektivisch könnten Biomarker zur Verfügung stehen, mit denen man das Ansprechen auf Lithium voraussagen kann und damit personalisiertere Therapien entwickeln könnte.

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A reduced risk of stroke with lithium exposure in bipolar disorder: a population‐based retrospective cohort study

Abstract: Lithium use was significantly related to a reduced risk of stroke in patients with bipolar disorder.

Cited by 46 publications

References 45 publications

Low-Dose Lithium Stabilizes Human Endothelial Barrier by Decreasing MLC Phosphorylation and Universally Augments Cholinergic Vasorelaxation Capacity in a Direct Manner

Low-Dose Lithium Stabilizes Human Endothelial Barrier by Decreasing MLC Phosphorylation and Universally Augments Cholinergic Vasorelaxation Capacity in a Direct Manner

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

Update – Lithium in der Phasenprophylaxe Bipolarer Störungen

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