Lamotrigine and Anger/Irritability
Lamotrigine can paradoxically induce anger and irritability in some patients, though this is an uncommon side effect, and when it occurs, dose reduction or discontinuation typically resolves the symptoms.
Evidence for Lamotrigine-Induced Anger
The most compelling evidence comes from case reports documenting severe anger reactions:
Two cases of major depressive disorder developed anger with murderous impulses on lamotrigine, with one patient experiencing symptoms at 125 mg/day (resolved with dose reduction to 75 mg/day) and another at just 25 mg/day (resolved immediately upon discontinuation) 1.
In pediatric autism spectrum disorder trials, lamotrigine was associated with insomnia and hyperactivity as side effects in children ages 3-11 years, though irritability was not specifically reported 2, 3, 4.
Lamotrigine has been reported to cause onset or exacerbation of aggressive or violent behavior in intellectually disabled patients with epilepsy 1.
Comparative Evidence: Lamotrigine Actually Reduces Anger
Paradoxically, the highest quality comparative trial shows the opposite effect:
In a randomized, double-blind study of 268 adults with partial epilepsy, lamotrigine significantly improved anger-hostility scores compared to levetiracetam (mean change -2.0 vs -0.3, p=0.024) over 20 weeks 5.
This improvement was consistently observed throughout treatment and extended to other mood symptoms including depression, fatigue, and confusion 5.
Clinical Management Algorithm
When a patient on lamotrigine develops anger or irritability:
First, rule out bipolar disorder progression: If the patient has bipolar disorder, irritability more likely represents an emerging manic/hypomanic episode requiring additional intervention rather than a lamotrigine side effect, as lamotrigine has limited efficacy for preventing manic episodes 3, 6.
Consider medication withdrawal: If the patient is on multiple medications, particularly SSRIs, anxiety and irritability may represent withdrawal syndrome from other agents, not lamotrigine 4.
Assess timing and dose relationship: Lamotrigine-induced anger typically emerges during dose escalation and resolves with dose reduction or discontinuation 1.
If lamotrigine is the culprit:
Important Caveats
This is a rare but serious adverse effect that clinicians must recognize, even though lamotrigine generally improves mood symptoms in most patients 1, 7.
Psychiatric side effects of lamotrigine can include affective switches, psychotic episodes, and hallucinations, so vigilance is warranted 7.
The risk appears present even at low doses (as low as 25 mg/day in reported cases) 1.