Can zonisamide be used to treat tremor in Parkinson's disease patients who are not adequately controlled with levodopa, and what is the appropriate dosing regimen?

Zonisamide for Parkinson's Disease Tremor

Zonisamide is NOT recommended as a primary treatment for tremor in Parkinson's disease, as the FDA-approved indication is only for adjunctive therapy in partial seizures, not for PD tremor 1. While some evidence suggests potential benefit for motor symptoms in PD, the data specifically for tremor control is insufficient and contradictory.

Current Evidence Status

FDA Approval and Labeling

Zonisamide is FDA-approved exclusively as adjunctive therapy for partial seizures in adults over age 16 1. There is no FDA approval for Parkinson's disease or tremor in any jurisdiction outside Japan. The drug label provides no guidance on PD tremor management.

Research Evidence on Tremor

The most recent and relevant tremor-specific study 2 from 2022 showed:

• No significant improvement in UPDRS tremor scores with zonisamide 25 mg versus placebo (p=0.164)
• Only a "positive trend" was observed, which is clinically insufficient
• The study concluded that larger trials are needed to confirm any benefit

This directly contradicts the use of zonisamide specifically for tremor control.

Evidence for General Motor Symptoms

Earlier Japanese studies 3, 4 demonstrated improvement in overall motor function (UPDRS Part III) at doses of 25-50 mg/day as adjunctive therapy with levodopa. However, these studies:

• Did not specifically target tremor as a primary outcome
• Showed general motor improvement, not tremor-specific benefits
• Were conducted in Japanese populations with limited generalizability

A 2024 study 5 showed improvement in bradykinesia and tremor with 25 mg zonisamide, but this was secondary to overall motor improvement in advanced PD with wearing-off phenomena.

Clinical Guideline Recommendations

The 2024 EAN/MDS-ES guidelines 6 make NO mention of zonisamide for PD tremor management. Instead, the guidelines emphasize:

• STN-DBS (subthalamic nucleus deep brain stimulation) is the only intervention reported to control dopamine-resistant tremor
• Levodopa optimization remains first-line for tremor responsive to dopaminergic therapy
• For invasive options: STN-DBS or GPi-DBS for younger patients; STN-MRgFUS or VIM-MRgFUS for elderly patients with predominantly unilateral tremor

The guidelines note that "although some literature studies report an antitremor effect of LCIG and CAI, there is limited evidence for these treatment options in orally insufficiently treated PD tremor" 6. Zonisamide is not even mentioned in this context.

Practical Clinical Algorithm

For PD Tremor Not Controlled by Levodopa:

1. First: Optimize levodopa dosing - ensure adequate dosing and timing

2. Second: Consider adding dopamine agonists if not already prescribed

3. Third: Evaluate for surgical candidacy:

   • Age <60 years → STN-DBS or GPi-DBS
   • Age >60 years with unilateral tremor → Consider STN-MRgFUS or VIM-MRgFUS
   • Multimorbid patients ineligible for DBS → VIM-MRgFUS

4. Adjunctive pharmacological options (based on general PD literature 7):

   • Propranolol for resting and action tremor
   • Anticholinergics (only in young, cognitively intact patients)
   • Clozapine (limited by adverse effects)

If Considering Zonisamide Off-Label:

This should only be attempted when:

• Patient has failed levodopa optimization
• Patient is not a surgical candidate
• Primary goal is general motor symptom improvement, NOT tremor-specific control
• Patient has wearing-off phenomena

Dosing regimen (extrapolated from PD motor studies, not tremor-specific):

• Start: 25 mg once daily 3, 5
• Can increase to 50 mg daily if tolerated and insufficient response
• Maximum studied dose: 100 mg daily (higher adverse event rate) 3
• Allow 2 weeks at each dose for steady-state assessment 1

Critical Caveats

⚠️ Off-label use: Any use in PD is off-label in most countries outside Japan

⚠️ Tremor-specific evidence is negative: The only RCT specifically examining tremor 2 showed no significant benefit

⚠️ Drug interactions: Enzyme-inducing AEDs (phenytoin, carbamazepine, phenobarbital) reduce zonisamide half-life from 46 hours to 27-38 hours 1. Dose adjustment may be needed.

⚠️ Carbonic anhydrase inhibition: Avoid combining with topiramate, acetazolamide, or dichlorphenamide due to increased risk of metabolic acidosis and kidney stones 1

⚠️ Renal/hepatic impairment: Requires slower titration and closer monitoring 1

Bottom Line

Do not use zonisamide as a tremor-specific treatment in Parkinson's disease. The evidence does not support this indication. If tremor is inadequately controlled by levodopa, pursue surgical options (DBS or MRgFUS) per current guidelines 6. Zonisamide may have a limited role for general motor symptom improvement in advanced PD with wearing-off, but this is distinct from tremor control and remains off-label use.