In a patient with chronic schizophrenia taking bupropion (Wellbutrin) and lamotrigine, who has persistent bilateral hand, foot, and head tremor with a vibrating sensation after a stressful event, is the tremor drug‑induced, specifically due to lamotrigine?

Drug-Induced Tremor in a Patient on Bupropion and Lamotrigine

This is most likely lamotrigine-induced tremor, which occurs in 4-25% of patients and characteristically presents as intention tremor with cerebellar involvement, though bupropion can also contribute through enhanced physiological tremor mechanisms. 1, 2

Primary Suspect: Lamotrigine

Lamotrigine is the more likely culprit given the clinical presentation of progressive tremor involving multiple body parts (hands, feet, head) with a sensation of body vibration. 1

Evidence Supporting Lamotrigine as the Cause:

• Lamotrigine induces tremor in 4-10% of patients by clinical assessment, but accelerometry detects pathological tremor in up to 25% of patients on lamotrigine monotherapy 1
• The tremor mechanism involves cerebellar pathways, manifesting as intention tremor with increased intensity in both postural and intentional positions 1
• Lamotrigine-induced tremor shows characteristic quantitative features: significantly higher tremor intensity and lower frequency dispersion compared to controls, particularly in postural and intentional positions 1
• The progressive nature and multi-site involvement (hands, feet, head) fits the pattern of lamotrigine-induced tremor 1

Bupropion's Contribution:

While bupropion can cause tremor through enhancement of physiological tremor (likely via central mechanisms affecting norepinephrine and dopamine), it typically produces a different pattern than what is described here. 2 However, the combination of both medications may have additive or synergistic effects on tremor generation. 3

Critical Diagnostic Considerations

Rule Out Serotonin Syndrome First:

Before attributing tremor solely to medication side effects, you must exclude serotonin syndrome, particularly given the stress-related exacerbation. 4

Key features that would indicate serotonin syndrome (which this patient does NOT clearly have based on the description):

• Clinical triad: mental status changes, autonomic hyperactivity, AND neuromuscular abnormalities 4
• Hyperreflexia and clonus (most diagnostic features) 4
• Autonomic instability: hyperthermia (>38°C), tachycardia, hypertension, diaphoresis 4
• Rapid onset within 6-24 hours of medication change 4

This patient's presentation does NOT fit serotonin syndrome because: neither bupropion nor lamotrigine are serotonergic agents, there is no mention of the diagnostic triad, and the tremor has been progressive over years rather than acute onset. 5, 4

Recommended Diagnostic Workup

Laboratory Testing (Targeted, Not Routine):

Order tests based on specific clinical indicators, as routine laboratory testing in psychiatric patients has low yield (1.4-1.8% clinically meaningful results). 6

Essential tests:

• Thyroid function (TSH, free T4) to exclude hyperthyroidism or hypothyroidism as tremor causes 6
• Basic metabolic panel to assess renal function and electrolytes 6
• Lamotrigine level if available, to assess for toxicity (though tremor can occur at therapeutic levels) 1

Consider if clinically indicated:

• Liver function tests (both medications are hepatically metabolized) 6
• Calcium and magnesium if metabolic derangement suspected 6

Neuroimaging:

Brain MRI is NOT routinely indicated for isolated tremor in patients on known tremorogenic medications unless there are focal neurological signs, asymmetric tremor, rapid progression, or features suggesting structural disease. 6, 7

However, given the progressive nature and multi-site involvement, consider MRI to evaluate for:

• Structural causes and neurodegenerative changes 7
• Atrophy patterns suggesting parkinsonism (though resting tremor is not described here) 7

Management Algorithm

Step 1: Determine Tremor Severity and Functional Impact

If tremor causes significant functional disability, active intervention is warranted. 8

Step 2: Medication Adjustment Strategy

Primary approach: Reduce or discontinue lamotrigine (if clinically feasible given the indication for use):

• Lamotrigine-induced tremor typically resolves once the medication is discontinued, though persistent tremor (tardive tremor) may occur in some cases 3
• If lamotrigine is being used for mood stabilization in schizophrenia (off-label), consider alternative mood stabilizers with lower tremor risk 5
• Carbamazepine and valproate are generally not associated with severe tremor, though valproate can cause tremor in some patients 5

If lamotrigine cannot be discontinued:

• Reduce to the lowest effective dose 3
• Risk factors for drug-induced tremor include high doses and immediate-release preparations 3

Regarding bupropion:

• Consider whether the antidepressant effect is still needed
• If discontinuation is not feasible, dose reduction may help 2

Step 3: Symptomatic Tremor Treatment (If Medication Adjustment Insufficient)

If tremor persists despite medication adjustment or if psychiatric medications cannot be changed:

First-line pharmacological treatment:

• Propranolol (starting 20-40 mg twice daily, titrating up to 120-320 mg/day in divided doses) OR
• Primidone (starting 12.5-25 mg at bedtime, titrating slowly to 62.5-750 mg/day in divided doses) 8, 9

These medications improve tremor in approximately 50% of patients. 8, 9

Important considerations:

• Primidone requires 2-3 months for full effect, so allow adequate trial period before concluding inefficacy 7
• If propranolol causes side effects, alternative beta-blockers (atenolol, metoprolol) can be tried 8
• Propranolol and primidone can be used in combination if monotherapy provides inadequate control 8, 9

Second-line options if first-line agents fail:

• Benzodiazepines (clonazepam), particularly if stress/anxiety exacerbates tremor 8, 9
• Gabapentin or topiramate 8, 9

Step 4: Stress Management

Since stress worsens the tremor, address this component:

• Benzodiazepines can be used during periods when stress-related tremor causes functional disability 8
• Consider cognitive-behavioral therapy or other stress-reduction interventions

Common Pitfalls to Avoid

1. Do not assume all tremor in psychiatric patients is benign - always rule out metabolic causes, particularly thyroid dysfunction 6

2. Do not overlook the possibility of multiple contributing factors - polypharmacy is a risk factor for drug-induced tremor 3

3. Do not abruptly discontinue lamotrigine - taper gradually to avoid seizure risk (even in non-epileptic patients) and potential withdrawal symptoms

4. Do not use anticholinergic agents (like benztropine) for this type of tremor - they are ineffective for drug-induced postural/intention tremor and may worsen cognitive function in schizophrenia patients 5

5. Monitor for beta-blocker adverse effects if propranolol is initiated, especially in this population: excessive heart rate reduction, dizziness, hypotension, lethargy, and depression 7

Prognosis

Drug-induced tremor usually resolves once the offending medication is discontinued, though the timeline varies and some patients may develop persistent tremor. 3 Given the years-long duration in this case, there may be some persistent component even after medication adjustment, making symptomatic treatment more important.