Lithium – the First Mood Stabilizer

Lithium has been used for more than a half century as a mood stabilizer for people with bipolar and as augmentation agent for people with unipolar major depression.

It is one of the most effective mood stabilizers we have. It prevents and treats both manic and depressive episodes, although its effect on acute depression is somewhat slower than its effect on mania.

It is also one of the best studied “augmentation” agents for people who fail to respond to an antidepressant alone for the treatment of unipolar depression.

Despite this long history of use and research, we know more about what lithium does than we do about how it does it.

In addition to its clinical uses, we know that lithium has clear anti-suicide effects and it appears to prevent the loss of grey matter that often occurs to older patients with bipolar.

Lithium’s Effects

Excitatory Neurotoxicity

Excitatory neurotransmitters are toxic at high levels

We do know that lithium seems to dampen excitatory neurotransmission, and this may explain its effects on neuron preservation, since high levels of excitatory neurotransmitters are known to damage neurons. It has also been shown to reduce the oxidative stress that often accompanies manic or depressive episodes. And it increases brain derived neurotrophic factor, which increases neurite growth.

It is remarkable that a simple natural molecule, not that much different from table salt, has effects on so many different processes.

The picture below summarizes lithium’s effects on psychological Lithium's range of effectsstates (such as depression and mania), on cognition (where it seems to reduce somewhat the process of jumping from thought to thought that can make it so hard for someone who is manic to stay focused), on neuroprotection, on neurotransmitters and on the second messenger systems that connect neurotransmitters that are outside the cell to actions within the cell.

Lithium – Indications

Lithium is particularly useful in these situations:

  • A patient with bipolar disorder who has a family member with a positive response to lithium.
  • A patient whose moods involve gradually increasing mania which “switches” into a depression (mood crash) and then a gradual coming out of depression (“MDI” pattern).
  • Patients with frequent unipolar (depression only) episodes who have had an inadequate response to an antidepressant.
  • Patients at risk of adverse effects from atypical antipsychotics (concerned about weight gain or the possibility of developing diabetes).

Lithium – Contraindications

These factors may suggest caution in taking lithium:

  • Factors that make it hard to get needed lab studies done (lithium must be monitored carefully with blood tests done at least twice a year).
  • Difficulty taking medications as directed (lithium should not be abruptly discontinued, nor should it ever be taken at higher doses than prescribed).
  • Risk of dehydration (anything that makes it hard for someone to remain adequately hydrated increases the risk of toxicity from lithium).
  • Kidney disease.
  • Patients who have mostly depressive episodes and who only have energized (hypomanic or manic episodes) as the result of a “switch” out of depression into mania or hypomania (“DMI” pattern).

Lithium – Risks

Lithium side effects tend to fall into two groups – more common but relatively easily managed adverse effects and rare but more severe side effects.

More common but relatively easily managed side effects include –

  • A dose related, usually mild, tremor. This problem, since it is dose related, usually is only of concern in someone who ends up needing higher than usual doses of the medicine. It responds well to the addition of propranolol.
  • GI side effects of either queasy stomach or loose stools. This side effect tends to be short term, but if it persists it usually responds to changing the type of lithium prescribed.
  • Reduction in thyroid function. This occurs in perhaps a quarter of patients on lithium long term. Lithium interferes with the thyroid gland’s response to signals from the brain to produce more thyroid hormone. Monitoring for this effect is part of the reason blood tests are necessary. If it takes place, it is pretty easy to prescribe levothyroxine, which boosts your thyroid hormone levels back to normal.

Rare side effects include –

  • A gradual (over decades) reduction in kidney function that we watch for carefully, and if it develops, we switch to a different medication.
  • An extremely rare kidney toxicity that comes on suddenly and is similar to the liver toxicities from medications (like Tylenol) that are metabolized by the liver.

Lithium is not usually associated with significant weight gain unless a patient develops hypothyroidism. For more on the topic of lithium and weight gain see this blog post.

For more information

Lithium Prevents Suicide

Lithium Long Term Risks

Lithium and Weight Gain

Lithium and Kidney Damage

Early Lithium Treatment for Bipolar; Better Outcomes?

Lithium Benefits for Health

Lithium Thyroid Effects

Lithium Mechanism of Action


Malhi GS, Tanious M, Das P, Coulston CM, Berk M. Potential mechanisms of action of lithium in bipolar disorder. Current understanding. CNS Drugs. 2013 Feb;27(2):135-53. doi: 10.1007/s40263-013-0039-0. Review. PubMed PMID: 23371914.