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Am Fam Physician. 2022;106(3):249-250

This clinical content conforms to AAFP criteria for CME.

Author disclosure: No relevant financial relationships.

Clinical Question

Is lamotrigine (Lamictal) as effective and safe as lithium for the maintenance treatment of bipolar disorder?

Evidence-Based Answer

Compared with placebo, lamotrigine reduces the recurrence of manic symptoms at one year and the need for additional psychotropics necessitated by worsening clinical symptoms. (Strength of Recommendation [SOR]: B, inconsistent or limited-quality patient-oriented evidence.) The adverse effect profile of lamotrigine is similar to that of placebo.1 (SOR: B, inconsistent or limited-quality patient-oriented evidence.)

Compared with lithium, lamotrigine is similarly effective at treating recurrences of depressive episodes and any episode requiring additional psychotropic therapy, but it is less effective at reducing the recurrence of manic episodes at one year. (SOR: B, inconsistent or limited-quality patient-oriented evidence.) Patients using lamotrigine have fewer reported adverse effects and withdrawals from treatment compared with those using lithium.1 (SOR: A, consistent, good-quality patient-oriented evidence.)

Practice Pointers

Worldwide, the prevalence of bipolar disorder is 2.4%. People with bipolar disorder are at increased risk of suicide compared with individuals who have other types of mental illness.2,3 Lithium has historically been the standard maintenance treatment for bipolar disorder. The authors of this review studied the effectiveness and adverse effect profile of lamotrigine compared with placebo or lithium.

This Cochrane review involved 11 randomized controlled trials and 2,314 participants.1 Studies were included if lamotrigine was used as monotherapy, and daily dosages ranged from 100 mg to 500 mg. Among the studies that provided location, most occurred in the United States and other high-income countries. The primary outcomes were manic episodes (defined as a score of 15 or more on the Young Mania Rating Scale), depressive episodes (defined as a score of 15 or more on the Montgomery-Åsberg Depression Rating Scale or 14 or more on the Hamilton Depression Rating Scale), worsening clinical symptoms requiring an additional psychiatric medication, active suicidal behavior, withdrawal from treatment for any reason, and adverse effects. The authors attempted to study hospitalizations for any mood episodes, but none of the studies reported this outcome.

Compared with placebo, lamotrigine was more effective at reducing the recurrence of manic episodes at one year (number needed to treat [NNT] = 8; 95% CI, 6 to 17). Lamotrigine was also more effective than placebo at reducing clinical symptoms requiring additional psychotropic medication (NNT = 11; 95% CI, 6 to 56). No differences were noted in the recurrence of depressive episodes at one year or in short-term (less than six months) or long-term (six to 12 months) adverse effects in patients treated with lamotrigine compared with placebo. Fewer study participants receiving lamotrigine stopped taking their medication after six to 12 months of treatment (relative risk = 0.88; 95% CI, 0.78 to 0.99).

Among the effectiveness outcomes studied, lamotrigine and lithium had a similar recurrence of depressive symptoms, recurrence of clinical symptoms requiring additional psychotropic therapy, recurrence of manic symptoms using the Young Mania Rating Scale, and active suicidal behavior. However, lamotrigine was less effective in reducing the recurrence of manic episodes at one year among studies using an assessor's judgment instead of a rating scale. Lamotrigine had lower rates of adverse effects after six to 12 months of treatment compared with lithium. Although the review did not describe which specific adverse effects were reported, common adverse effects of lithium include cognitive slowing, diabetes insipidus, diarrhea, hypothyroidism, nausea, polyuria, sedation, thirst, tremor, and weight gain. This review found that rates of adverse effects were similar between the lamotrigine and placebo groups; common adverse effects of lamotrigine included nausea, dizziness, skin rash, dry mouth, pancytopenia, leukopenia, and thrombocytopenia.4

Lamotrigine is an anticonvulsant approved by the U.S. Food and Drug Administration for the maintenance treatment of bipolar disorder. It is not effective for treating acute bipolar mania or hypomania. Given the reduced adverse effect profile compared with lithium, lamotrigine may be an appropriate monotherapy during the maintenance phase of bipolar disorder. When initiating lamotrigine, physicians should slowly increase the dosage to reduce the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. The recommended starting dosage is 25 mg by mouth daily; the dosage may be titrated up over six weeks to a maintenance dosage. If a rash develops, the patient should be advised to stop treatment immediately.4

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These are summaries of reviews from the Cochrane Library.

This series is coordinated by Corey D. Fogleman, MD, assistant medical editor.

A collection of Cochrane for Clinicians published in AFP is available at

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