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Genomind Drug Spotlight: Lithium

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The use of lithium as a mood stabilizer for bipolar disorder dates back almost 70 years ago.1 In contrast to other mood stabilizers, lithium has many unique effects. For example, it exerts anti-suicidal action, possesses immunomodulatory features, and has been shown to have neuroprotective properties.3-4  As discussed in The Management of Bipolar Disorder with a Focus on Pharmacogenetics, lithium is regarded as a first-line treatment for the following indications related to bipolar:2

1) Acute mania

2) Prevention of any mood episode

3) Prevention of depression

4) Prevention of mania

5) Maintenance phase

However, there seems to be a decline in lithium use in the U.S over the last decades.3-4 Some proposed reasons for this decline include the active promoting of second-generation antipsychotics and the overestimation of potential side effects compared to other mood stabilizing agents .1,4 Many researchers believe the reputation for adverse effects of lithium is unearned.3-4 Most of lithium’s common side effects can be managed effectively with nonpharmacologic and pharmacologic strategies.5

The Management of Lithium’s Common Side Effects:4-6

Side Effect Incidence Onset Correlated with Levels Strategies for Risk Reduction or Treatment
Nausea 10-20% Early in treatment Yes (especially peak levels)
  • Use a sustained release formulation
  • Take lithium after meals
Diarrhea ~10% First 6 months Yes (levels >0.8 mEq/L are associated with higher rates)
  • Assess for lithium toxicity
  • Using an immediate-release formulation may reduce the incidence
Tremor 4-65% Any time point but often decreases with time (only present in 4% of patients who took lithium for 1-2 years) Yes
  • Keep lithium levels in the low-medium range
  • Evaluate the patient’s regimen for other agents that could exacerbate the tremor, such as bupropion, second generation antipsychotics, or caffeine.
  • Use of beta blockers, such as propranolol may help lithium tremor
  • High-dose vitamin B6 has also been shown to help lithium tremor and could be considered when natural approaches are preferred.


50-70% in long-term patients Duration of treatment is a risk factor Yes
  • Keep lithium levels as low as feasible
  • Avoid toxicity episodes
  • Once-daily lithium was associated with lower urine volume and lower urinary frequency
  • Amiloride may be used to manage polyuria
Weight gain ~1/3 patients will gain 4-10 lbs Most weight gain occurs within the first 1-2 years of treatment Mixed
  • Encourage patients to drink low or noncaloric drinks to treat their thirst
  • Encourage general diet and exercise strategies
  • For those taking multiple medications, consider switching from a treatment with high weight gain liability (e.g. olanzapine or quetiapine) to another with less weight gain risk

Lithium and Kidney Function

In a study of 312 patients with bipolar disorder who received lithium carbonate for 8-48 (mean 18) years, the lowering of GFR amounted to a decline of around 30% more than that associated with aging alone. No patient developed end-stage renal failure. Risk factors for declining GFR included low baseline GFR, higher serum levels, longer duration of treatment, medical comorbidity, and older age (starting treatment after 40 years of age).3

In order to minimize the risk of significant renal damage, providers should 1) monitor serum creatinine (SCr) and GFR at baseline and regularly during lithium maintenance treatment at intervals of every 6 months to 1 year; 2) keep mean lithium levels within the low therapeutic range when possible; and 3) consider once-daily dosing at bedtime. Consultation with a nephrologist is appropriate when SCr continues to rise despite these efforts.5

Lithium and Thyroid Function

In a study of 98 patients with bipolar disorder receiving lithium for at least 3 years and 39 subjects who never received lithium, the concentration of TSH was significantly higher in the patients receiving lithium. However, the frequency of hypothyroidism was similar in both groups (24% vs.18%). Subjects who developed hypothyroidism were treated with levothyroxine.4

Because of the risk of hypothyroidism, thyroid function should be checked at baseline, monitored after 3-6 months initially, and then every 6-12 months. Lithium should not be withheld as an option in those with hypothyroidism and does not need to be discontinued if hypothyroidism develops, as patients can be treated successfully with thyroid hormone supplementation.5

In Conclusion

There are several clinical factors associated with the prophylactic efficacy of lithium, including a family history of positive response to lithium, low psychiatric comorbidity, mania-depression episode sequences, a hyperthymic temperament, and a low number of hospitalizations in the pre-lithium period.7

However, despite our knowledge of these clinical factors and the strong evidence for its use in the treatment of bipolar disorder, lithium remains underutilized. Many clinicians may be under the impression that there are more contraindications to lithium use than there really are. Hopefully by using effective strategies to manage side effects, providers can feel more confident in safely prescribing this potentially life-saving medication.

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  1. Volkmann C, Bschor T, Kohler S. Lithium treatment over the lifespan in bipolar disorders. Front. Psychiatry. 2020;11:377.
  2. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorder (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disorder. 2018;20(2):97-170.
  3. Post RM. The new news about lithium: an underutilized treatment in the United States. Neuropsychopharmacology. 2018;43(5):1174-1179.
  4. Rybakowski JK. Challenging the negative perception of lithium and optimizing its long-term administration. Front. Mol. Neurosci. 2018;11:349.
  5. Gitlin M. Lithium side effects and toxicity: prevalence and management strategies. Int J Bipolar Disord. 2016;4(1):27.
  6. Canning JE, Burton S, Hall B. Lithium and valproate-induced tremors. Mental Health Clinician. 2012;1(7):174-176.
  7. Rybakowski JK. Factors associated with lithium efficacy in bipolar disorder. Harv Rev Psychiatry. 2014;22(6):353-357.

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