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Day # 52: Lithium (part 1) -> Mechanism, Evidence, and Indications.

Welcome back to the current theme of bipolar disorder. So far in this theme we have covered clinical criteria, epidemiology, tips on the clinical interview, the mental status exam, medical workup, psychotherapy, medication algorithms, and bipolar depression. For the next few days we are going to go into detail about the specific drugs used to treat bipolar disorder. We already discussed antipsychotics during the antipsychotic theme. Today will be part 1 of our discussion about lithium. After that we will cover the other mood stabilizers to include valproic acid, lamotrigine, carbamazepine, and topiramate.


•Lithium is an element (atomic number 3) that is special in many ways. In its most natural form it is a light and soft metal - so soft that it can be cut with a kitchen knife.


  • The use of lithium in psychiatry goes back to the mid 1800's.

  • In the late 1800's the danish psychiatrist Frederik Lange made explicit reference to lithium in the treatment of melancholic depression, ultimately treating 35 patients with lithium carbonate.

  • Early work, however, was soon forgotten and the reintroduction of lithium to psychiatry occurred in 1949 by John Cade for the treatment of mania.

  • The United States admitted lithium to the marketplace in 1970 (the 50th country to do so).

Mechanism of Action

  • The mechanism is complex, not fully understood, and challenging to study due to chemical similarity with the sodium ion.

  • Distributes in the central nervous system.

  • Alters intracellular signaling through second messenger systems.

    • Inhibits the enzyme inositol monophosphate, thus decreasing the cellular concentration of the second messenger, inositol triphosphate (IP3) resulting in mood stabilization.

    • Lithium also inhibits glycogen synthase kinase (GSK-3) which is a component of intracellular signaling pathways.

      • Also, likely promotes neurogenesis in the hippocampus.

      • There is variable evidence of decreased norepinephrine and dopamine and increased serotonin and GABA.


Bipolar mania

  • Approved for treatment of acute mania/hypomania and maintenance.

  • May be the most effective drug to prevent future manic episodes and protects against suicide and self-harm. 1

  • Acute mania: takes days to 1 week for effect, consider antipsychotic adjunct +/- benzodiazepines.

  • Maintenance: monotherapy effective and tolerated for longer duration compared with other mood stabilizers/antipsychotics.

  • Often the drug of choice for classic bipolar disorder (euphoric mania).

  • Probably less effective than atypical antipsychotics for severe, excited, disturbed, hyperactive, or psychotic patients with mania.

  • Patients with rapid-cycling and mixed state types of bipolar disorder generally do less well on lithium.

Bipolar depression 2

  • Not FDA approved (off-label)

  • Evidence for bipolar depression is small and the quality of the studies have been questioned, however existing data shows it is probably effective.

  • Also some data for prophylaxis of depressive episodes but more robust data on prevention of mania.

  • Strong support with reduction of completed suicides and all-cause mortality.

Unipolar depression 3, 4

  • Lithium is used an augmenting agent in treatment resistant depression.

  • Lithium augmentation is well supported in the literature and is recommended by the NICE guidelines.

  • There are some interesting studies that show certain factors can be used to predict success with lithium and include psychomotor retardation, weight loss, family history of MDD, and more than one prior episode.

Cyclothymia 5

  • Treatment of cyclothymia is controversial with conflicting studies regarding effectiveness of antidepressants, however TCA's show some positive benefit.

  • A few studies show mild to moderate efficacy of mood stabilizers, especially lithium.

  • Valproate and lamotrigine also show benefit.

Suicidality 6

  • Robust evidence that lithium treatment decreases suicide and all-cause mortality in patients with bipolar disorder and unipolar depression.

  • There is also evidence of decreased suicidality/violence in communities with sub therapeutic levels of lithium in the drinking water.

  • It is the only mood stabilizer show to decrease suicidality.

Aggression 7

  • Evidence for decreased impulsive, aggressive, and self-mutilating behaviors in bipolar disorder, ADHD, intellectual disability, conduct disorder, and inmates with personality pathology.

  • There is also evidence of decreased suicidality/violence in communities with sub therapeutic levels of lithium in the drinking water.


  • Syndrome of inappropriate antidiuretic hormone secretion (SIADH): this is a condition in which the body makes too much antidiuretic hormone (ADH) which leads the kidney/body to retain too much water. Lithium can result in the opposite of this (nephrogenic diabetes insipidus), so it can combat SIADH in some patients.

  • Increase neutrophil count: As discussed here, clozapine can lead to agranulocytosis which is a severe and dangerous drop in the white blood cell count. This is not routinely done, but lithium can cause a leukocytosis and can be used to increase the absolute neutrophil account in patients receiving clozapine.


Lithium is an effective treatment for bipolar disorder and other conditions but there are a lot of considerations to be made. Today we discussed mechanism of action and indications for lithium. Next lesson we will discuss drug levels, interactions, and other important clinical monitoring for patient's taking lithium.

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