How does lithium work?

Ah, lithium; it’s been our gold-standard treatment for bipolar disorder for many years, and can work for people who have failed other drug trials. It is also one of the only drugs known to decrease the risk of suicide1. But how does it work?

It’s a bit more complicated to understand than, for example, an SSRI (which, ultimately, increases serotonin in the synapse, through a fairly intelligible mechanism of stopping reuptake). Despite knowing since 1949 that lithium was an effective treatment for bipolar disorder, we still don’t fully understand its mechanism of action.

There are a lot of signalling pathways in the brain.

One of the difficulties in determining this is that lithium goes everywhere in your body. Within the brain, it can cause an absurd number of changes through numerous signalling pathways. Like other drugs, it can cross the brain-blood barrier (an important quality for psychiatric medications, since they target the brain) but, uniquely among psych meds, it can also enter your intracellular space — hiding inside your cells, instead of just floating around in your blood.

It is excreted by the kidneys in urine, although it is also known to be excreted in human sweat and tears2. (I’ve had hyper-salty tears caused by lithium every so often.)

Lithium appears to increase the concentration of some neurotransmitters (potentially serotonin and GABA) while moderating the effects of dopamine and norepinephrine through its effects on voltage-gated channels3. This action causes a broad cascade of effects throughout the entire brain that restores balance in people with bipolar disorder. Lithium can get into any cell in your body, and it goes inside your neurons (brain cells) too. This is how it affects voltage-gated channels and moderates the activity of all neurotransmitters.

Although we usually call it a mood stabilizer, it’s not related to any other drug we put in this class, since it is not an anticonvulsant. Lithium is probably most accurately classified as a neuroprotective drug4, like memantine (a drug typically used for Alzheimer’s disease). There is even some speculation that memantine could augment the effect of lithium, due to its similar mechanism of action, but specific to the NMDA receptors.

A key point to understanding the pharmacodynamics of lithium is that lithium, in the human body, can use the same transporters as sodium. It fits where sodium should go — therefore, it exits cells through active transport systems designed for sodium, but at about half the speed of sodium. The similarity of lithium and sodium explains why lithium is excreted by the kidneys and not metabolized by the liver.

a) lithium salts; b) sodium salts

This is also why activated charcoal will not absorb lithium. Your body sees it as a metallic salt (it has a positive charge), and metals (or charged ions) are not attracted to charcoal. In addition, the similarity of sodium and lithium creates a sort of sodium-lithium ecosystem in your body; if you maintain a steady dose of lithium but drastically reduce your intake of sodium, your lithium levels can rise to toxicity.

References

  1. Kessing, L. V., Søndergård, L., Kvist, K., & Andersen, P. K. (2005). Suicide risk in patients treated with lithium. Archives of General Psychiatry, 62(8), 860–866. https://doi.org/10.1001/archpsyc.62.8.860
  2. Fraunfelder, F. T., Fraunfelder, F. W., & Jefferson, J. W. (1992). The effects of lithium on the human visual system. Cutaneous and Ocular Toxicology, 11(2), 97–169. https://doi.org/10.3109/15569529209042704
  3. Lenox, Robert H., H. C.-G. (2000). Overview of the Mechanism of Action of Lithium in the Brain: Fifty-Year Update. 61.
  4. Gray, J. D., & Mcewen, B. S. (2013). Lithium’s role in neural plasticity and its implications for mood disorders. Acta Psychiatrica Scandinavica, 128(5), 347–361. https://doi.org/10.1111/acps.12139

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