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Letter to the Editor

Dose-Dependent Effect of Lithium on Cognition in Mild Cognitive Impairment

Roberto Lozano, PhD; Reyes Marí­n, MD; and Maria-Jesús Santacruz, BSc

Published: June 24, 2015

See reply by Miskowiak et al and article by Miskowiak et al

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To the Editor: Miskowiak et al1 showed that recombinant human erythropoietin (rhEPO) has the potential to treat cognitive dysfunction in bipolar disorder patients. Specifically, they found that rhEPO enhanced both sustained attention and speed of complex information processing across learning, attention, and executive function in bipolar disorder patients with moderate to severe cognitive problems. However, an important potential confound was not considered: patients were allowed to continue taking antidepressant or mood-stabilizing drugs.2

The mood-stabilizing drug lithium has dose-dependent effects on cognition in amnestic mild cognitive impairment from 150 mg to 600 mg.3 These effects may be due to activation of a critical pathway involving mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF), as demonstrated in animal models.4 This pathway mediates brain plasticity, including hippocampal-dependent learning and memory. By contrast, doses > 1 g/d may have neurotoxic effects, including cognitive slowing and decreased astrogliogenesis, via inhibition of signal transducer and activator of transcription 3 (STAT3).5 This cognitive slowing can be observed in working memory tasks, including executive attention and short-term memory.

In addition to its effects in bipolar disorder patients, rhEPO could improve cognitive ability in patients with neurodegenerative disease6-8 via the mTOR/BDNF signaling pathway9,10 and could protect astroglia11 via the Janus kinase 2 (JAK2)/STAT3 pathway.12,13 Thus, lithium and rhEPO would have similar effects through mTOR/BDNF, but would exert opposing effects on STAT3 because rhEPO protects astroglia while lithium inhibits astrogliogenesis. Consequently, inclusion of lithium-treated patients could be a confounder in studies of rhEPO for cognitive dysfunction in bipolar disorder patients.

It is important to consider whether the results obtained by Miskowiak et al may have been affected by exposure of patients to lithium salts prior to or during the study. Explicit data regarding lithium exposure should be reported for each study group, including regimen and treatment duration. Analysis of these data would determine whether rhEPO and lithium have independent effects in bipolar disorder or whether the beneficial effect attributed to rhEPO may be at least partially due to lithium or an interaction between rhEPO and lithium.


1. Miskowiak KW, Ehrenreich H, Christensen EM, et al. Recombinant human erythropoietin to target cognitive dysfunction in bipolar disorder: a double-blind, randomized, placebo-controlled phase 2 trial. J Clin Psychiatry. 2014;75(12):1347-1355. PubMed doi:10.4088/JCP.13m08839

2. Miskowiak KW, Vinberg M, Harmer CJ, et al. Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder. Trials. 2010;11(1):97. PubMed doi:10.1186/1745-6215-11-97

3. Nunes MA, Viel TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Curr Alzheimer Res. 2013;10(1):104-107. PubMed

4. Chiu CT, Scheuing L, Liu G, et al. The mood stabilizer lithium potentiates the antidepressant-like effects and ameliorates oxidative stress induced by acute ketamine in a mouse model of stress [published online ahead of print December 28, 2014]. Int J Neuropsychopharmacol. PubMed doi:10.1093/ijnp/pyu102

5. Zhu Z, Kremer P, Tadmori I, et al. Lithium suppresses astrogliogenesis by neural stem and progenitor cells by inhibiting STAT3 pathway independently of glycogen synthase kinase 3 beta. PLoS ONE. 2011;6(9):e23341. PubMed doi:10.1371/journal.pone.0023341

6. Rainville C, Amieva H, Lafont S, et al. Executive function deficits in patients with dementia of the Alzheimer’s type: a study with a Tower of London task. Arch Clin Neuropsychol. 2002;17(6):513-530. PubMed doi:10.1093/arclin/17.6.513

7. Stopford CL, Thompson JC, Neary D, et al. Working memory, attention, and executive function in Alzheimer’s disease and frontotemporal dementia. Cortex. 2012;48(4):429-446. PubMed doi:10.1016/j.cortex.2010.12.002

8. Nunes PV, Forlenza OV, Gattaz WF. Lithium and risk for Alzheimer’s disease in elderly patients with bipolar disorder. Br J Psychiatry. 2007;190(4):359-360. PubMed doi:10.1192/bjp.bp.106.029868

9. Xiong Y, Mahmood A, Meng Y, et al. Delayed administration of erythropoietin reducing hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome following traumatic brain injury in rats: comparison of treatment with single and triple dose. J Neurosurg. 2010;113(3):598-608. PubMed doi:10.3171/2009.9.JNS09844

10. Yan HC, Cao X, Gao TM, et al. Promoting adult hippocampal neurogenesis: a novel strategy for antidepressant drug screening. Curr Med Chem. 2011;18(28):4359-4367. PubMed doi:10.2174/092986711797200471

11. Liu J, Narasimhan P, Song YS, et al. Epo protects SOD2-deficient mouse astrocytes from damage by oxidative stress. Glia. 2006;53(4):360-365. PubMed doi:10.1002/glia.20289

12. Zhao J, Li G, Zhang Y, et al. The potential role of JAK2/STAT3 pathway on the anti-apoptotic effect of recombinant human erythropoietin (rhEPO) after experimental traumatic brain injury of rats. Cytokine. 2011;56(2):343-350. PubMed doi:10.1016/j.cyto.2011.07.018

13. Lopez TV, Lappin TR, Maxwell P, et al. Autocrine/paracrine erythropoietin signalling promotes JAK/STAT-dependent proliferation of human cervical cancer cells. Int J Cancer. 2011;129(11):2566-2576. PubMed doi:10.1002/ijc.25935

Roberto Lozano, PhD

Reyes Marí­n, MD

Maria-Jesús Santacruz, BSc

Author affiliations: Department of Pharmacy (Dr Lozano) and Department of Psychiatry (Dr Marí­n and Ms Santacruz), Hospital Real Nuestra Señora de Gracia, Zaragoza, Spain.

Potential conflicts of interest: None reported.

Acknowledgments: The authors express their gratitude to BioMed Proofreading LLC for the copyediting of this letter.

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