Lithium Mechanism of Action

Peter Forster Basic Science, Bipolar Treatment, Psychobiology 2 Comments

Understanding the lithium mechanism of action may allow us to predict which bipolar patients will respond to the medication (and which will not) and may shape our understanding of the causes of bipolar disorder itself. Research at the University of California, San Diego could lead to just these kind of breakthroughs in the next few years.

In the first of a series of journal articles published by these researchers, they used induced pluripotent stem-call (iPSC) technology to take fibroblasts from the skin of patients with bipolar disorder who were either lithium responsive (3 patients) or lithium non-responsive (3 patients) and create cells that functioned similarly to hippocampal neuron cells. In testing these cells they identified several unique features of the cells.

lithium mechanism of action studies

  1. Bipolar hippocampal cells of all the bipolar patients were hyperexcitable
  2. Mitochondria from these cells were unusually small
  3. Hyperactivity was selectively reversed only in bipolar responsive patients when these cells were bathed in a therapeutic (1.0 mEq/L) solution of lithium

In a follow-up study published in 2017, the same researchers examined hippocampal induced pluripotent stem cells (iPSC’s) from 19 individuals, including those with lithium-responsive (LR) bipolar and non-lithium-responsive (NR) bipolar patients, as well as those with no neuropsychiatric disorder and those with other neurological and psychiatric disorders.

They looked first at bipolar iPSC’s to identify proteins that were expressed differently in lithium responsive (LR) cells bathed in lithium. They found 15 proteins whose expression was altered by lithium. The genes encoding 4 of the 15 proteins had previously been found to be associated with bipolar disorder. One of these four, collapsin response mediator protein 2 (CRMP2) ws of particular interest because it plays a key role in neuron development.

They used two sophisticated analysis tools to examine previous research on metabolic pathways affected by lithium treatment. 4 pathways were identified and CRMP2 was involved in all 4 pathways.

CRMP2 is very active as the brain develops, and plays a key role in axon development in part by its effects on microtubule formation. In adults, CRMP2 is downregulated except in areas, such as the hippocampus, involved with brain plasticity, neurogenesis, or regeneration.

As a result, CRMP2 has already been the focus of active research as a target for medications to treat Alzheimer’s and Parkinson’s disease.

Focusing on CRMP2, they found that in hippocampal iPSC’s from bipolar patients, CRMP2 was inactivated. In those cells from lithium responsive patients, lithium exposure reversed this inactivation, but lithium had no effect on CRMP2 inactivation in lithium non-responsive patients.

In further research, they found that the inactivation of CRMP2 appeared to be due to a change in the phosphorylation of CRMP2 at a specific site (phosphorylation at this site inactivated CRMP2).

In summary, the research suggests that CRMP2 regulation may play a key role in lithium responsive bipolar disorder (approximately 1/3rd of all bipolar patients are lithium responsive).

The next move for the team is to start screening existing drugs to see if they can find any molecules that target this same pathway, but with fewer side effects or more success than lithium.

References

Kim Y, Santos R, Gage FH, Marchetto MC. Molecular Mechanisms of Bipolar
Disorder: Progress Made and Future Challenges. Front Cell Neurosci. 2017 Feb
14;11:30. doi: 10.3389/fncel.2017.00030. eCollection 2017. Review. PubMed PMID:
28261061; PubMed Central PMCID: PMC5306135.

Mertens J, Wang QW, Kim Y, Yu DX, Pham S, Yang B, Zheng Y, Diffenderfer KE,
Zhang J, Soltani S, Eames T, Schafer ST, Boyer L, Marchetto MC, Nurnberger JI,
Calabrese JR, Ødegaard KJ, McCarthy MJ, Zandi PP, Alda M, Nievergelt CM;
Pharmacogenomics of Bipolar Disorder Study, Mi S, Brennand KJ, Kelsoe JR, Gage
FH, Yao J. Differential responses to lithium in hyperexcitable neurons from
patients with bipolar disorder. Nature. 2015 Nov 5;527(7576):95-9. doi:
10.1038/nature15526. Epub 2015 Oct 28. Erratum in: Nature. 2016 Feb
11;530(7589):242.PubMed PMID: 26524527; PubMed Central PMCID: PMC4742055.

Stern S, Santos R, Marchetto MC, Mendes AP, Rouleau GA, Biesmans S, Wang QW,
Yao J, Charnay P, Bang AG, Alda M, Gage FH. Neurons derived from patients with
bipolar disorder divide into intrinsically different sub-populations of neurons,
predicting the patients’ responsiveness to lithium. Mol Psychiatry. 2017 Feb 28.
doi: 10.1038/mp.2016.260. [Epub ahead of print] PubMed PMID: 28242870.

Tobe BTD, Crain AM, Winquist AM, Calabrese B, Makihara H, Zhao WN, Lalonde J,
Nakamura H, Konopaske G, Sidor M, Pernia CD, Yamashita N, Wada M, Inoue Y,
Nakamura F, Sheridan SD, Logan RW, Brandel M, Wu D, Hunsberger J, Dorsett L,
Duerr C, Basa RCB, McCarthy MJ, Udeshi ND, Mertins P, Carr SA, Rouleau GA,
Mastrangelo L, Li J, Gutierrez GJ, Brill LM, Venizelos N, Chen G, Nye JS, Manji
H, Price JH, McClung CA, Akiskal HS, Alda M, Chuang DM, Coyle JT, Liu Y, Teng YD,
Ohshima T, Mikoshiba K, Sidman RL, Halpain S, Haggarty SJ, Goshima Y, Snyder EY.
Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory
set-point for a cytoskeletal modulator in bipolar pathogenesis. Proc Natl Acad
Sci U S A. 2017 May 30;114(22):E4462-E4471. doi: 10.1073/pnas.1700111114. Epub
2017 May 12. PubMed PMID: 28500272; PubMed Central PMCID: PMC5465887.

For More Information

Lithium

Lithium and Genes

Lithium Benefits for Health – NYT Article

  • Greg Marlow

    Consider the effect of lithium on blood calcium levels as the mechanism of its action. Increased blood calcium levels caused by lithium reduce the excitability of neurons.

    • Peter Forster

      Thank you for your comment. There certainly is reason to consider the relationship between lithium, calcium, and neuronal excitability.