Side Effects of Zonisamide in Parkinson's Disease
Zonisamide is generally well tolerated at the recommended 25-50 mg/day dosage for Parkinson's disease, with the most common side effects being drowsiness, loss of appetite, dizziness, and problems with concentration or memory. 1
Most Common Side Effects
The FDA-approved labeling identifies the following most frequent adverse reactions: 1
- Drowsiness/sedation - occurs commonly and may persist during initial treatment weeks 1
- Loss of appetite - frequently reported gastrointestinal effect 1
- Dizziness - can affect balance and coordination 1
- Problems with concentration or memory - cognitive effects that warrant monitoring 1
- Trouble with walking and coordination - particularly relevant in Parkinson's patients already experiencing motor symptoms 1
- Agitation or irritability - mood-related effects 1
Serious Side Effects Requiring Immediate Attention
Psychiatric and Behavioral Effects
Zonisamide carries significant CNS toxicity risks that require vigilant monitoring: 1
- New or worsening depression 1
- Suicidal thoughts or behavior - requires immediate psychiatric evaluation 1
- Sudden changes in mood or behavior 1
- Loss of contact with reality, sometimes with hallucinations (hearing voices or seeing things that aren't there) 1
Metabolic Complications
- Metabolic acidosis (too much acid in the blood) - particularly concerning in patients with pre-existing kidney problems or those on ketogenic diets 1
- Kidney stones - manifesting as back pain, stomach pain, or blood in urine; adequate hydration is essential to minimize this risk 1
Bone Health Concerns
- Weakening of bones (osteomalacia, osteopenia, or osteoporosis) - long-term consideration 1
Critical Timing Considerations
Side effects can occur at any time but are most likely during the first several weeks after starting zonisamide, making close monitoring essential during treatment initiation. 1
Special Considerations When Transitioning from Amantadine
Overlapping CNS Toxicity Profile
When transitioning from amantadine to zonisamide, clinicians must recognize that both medications carry significant CNS toxicity risks that could be additive if overlapped: 2
- Amantadine causes CNS side effects in approximately 13% of patients, including nervousness, anxiety, insomnia, difficulty concentrating, and lightheadedness 3
- Serious amantadine toxicity includes marked behavioral changes, delirium, hallucinations, agitation, and seizures, particularly at plasma concentrations >3000 ng/mL 4
- Elderly patients are at highest risk for severe CNS toxicity with amantadine, especially those with renal insufficiency, seizure disorders, or psychiatric history 5, 6
Practical Transition Algorithm
- Verify renal function before initiating zonisamide, as both drugs have renal considerations 5, 6
- Consider tapering amantadine gradually rather than abrupt discontinuation to avoid withdrawal effects 6
- Monitor closely for additive CNS effects during any overlap period, particularly confusion, hallucinations, and agitation 5, 2
- Start zonisamide at 25 mg/day (the recommended and evidence-based dosage) after amantadine is reduced or discontinued 7, 8
Efficacy Context
Despite these side effects, zonisamide at 25-50 mg/day significantly improves motor function (UPDRS Part III scores) and reduces daily "OFF" time without increasing disabling dyskinesia in randomized controlled trials. 7, 8 The overall incidence of adverse events at the 25 mg/day dosage was not significantly different from placebo in phase IIb/III trials. 8
Key Safety Precautions
- Avoid alcohol and sedating medications until individual response is known, as zonisamide can potentiate sedation 1
- Do not drive or operate heavy machinery until effects are established 1
- Maintain adequate hydration to reduce kidney stone risk 1
- Never stop abruptly without medical supervision, as sudden discontinuation can cause serious problems including status epilepticus 1
- Use effective birth control in women of childbearing potential, as zonisamide may harm unborn babies 1