This presentation reviews the current evidence favoring the use of Zonisamide in Idiopathic Parkinson disease

1. Zonisamide:
A review of current evidence
in Parkinson’s Disease
Dr Pramod Krishnan, MD (Int Med), DM Neurology (NIMHANS)
Fellowship in Epilepsy (SCTIMST) (LMU, Munich)
World Sleep Federation Certified Sleep Medicine Specialist.
Consultant Neurologist and Epileptologist
Head of the Department of Neurology,
Manipal Hospital, Bengaluru.

2. Zonisamide in disorders other than epilepsy
• Psychiatric diseases
• Migraine
• Neuropathic pain
• Parkinson’s disease
• Impulse control disorders
• Essential tremor

3. Mechanism of action
• It has Na+ channel blocking activity.
• It reduces the transient inward T-type calcium current.
• It enhances GABA mediated neuronal inhibition by modulating
the GABA-a receptor.
• It reduces glutamate release.
• It is a carbonic anhydrase inhibitor.
• Biphasic, dose dependent effect of ZSN on serotonin and
dopamine release: low dose increases intra and extracellular
dopamine; supratherapeutic doses reduce dopamine release.
Okada M, et al. Effects of zonisamide on dopaminergic system. Epilepsy Res 1995;22:193-205

4. Mechanism of action in Parkinson’s Disease: Summary of animal studies
Inhibition of Dopamine quinone formation
Increased viability of neurons by anti apoptotic effect
Prevention of dopaminergic cell damage and prevention of TH depletion and prevention of
microglial proliferation
Increase in number and area of Tyrosine hydroxylase positive neurons. Increased Dopamine
turnover. Increased number of S100b positive neurons
Increase in extracellular Dopamine in striatum at higher doses but not at lower doses
Biphasic effect on release of DA and 5HT from nerve terminals
Prevents caspase-3 activation
Lower caspase-3 and intracellular Ca2+ levels in ZNS group
No increase in Dopamine turnover but has MAO-B inhibiting activity
Increase in Dopamine turnover but no MAO-B inhibiting action
Protects against mitochondrial impairment

6. Zonisamide in Parkinson’s disease
• In 2001, a patient with epilepsy and PD reported significant
improvement in both with ZSN 300 mg/day.
• A case series of 10 patients confirmed the same, with benefit noted
within 1 week of therapy and sustained throughout treatment.
• Approved in Japan for PD in 2009.

7. • 9 patients (7 M, 2 F) with advanced PD, with average age of 57 years, and average
disease duration of 9.7 years.
• 2 patients had poor response to levo dopa and did not have any motor fluctuation.
• ZSN 50- 200 mg once or twice a day along with their usual PD medicines.
• Study duration was 12 weeks.

8. Results
• The cardinal symptoms of PD showed improvement, and motor
fluctuation all but disappeared in 5 patients.
• The UPDRS (II) of ‘off’ time, UPDRS (III), Yahr stage of ‘off’
time and duration of ‘off’ time significantly improved.
• The mean UPDRS (II) and Yahr stage of ‘off’ time improved and,
the mean ‘off’ time was shortened.
• These effects appeared within 3–7 days and were maintained for
more than 1 year.
• Two patients whose responses to levodopa were poor also had poor
responses to ZNS.

10. Effect on tremors
• A study of 9 patients of PD with tremors not improving with
adequate dose of Levo dopa.
• Addition of ZSN reduced the degree of tremor in 7 out of 9
patients (p < 0.0017).
• 1 patient reported sleepiness and 2 patients had a transient loss of
appetite, but all the patients completed the 8 week study.
• The final dose of ZNS was 100 mg/day in the majority of the
patients.
Nakanishi I, Kohomoto J, Miwa H, Kondo T. Effect of zonisamide on resting tremor resistant
to antiparkinsonian medication. No To Shinkei 2003;55:685-9.

11. • To study efficacy, safety and tolerability of daily doses of 25, 50, and 100 mg of ZNS.
• 347 pts; 12 week study, ZSN added to patients with insufficient response to L-Dopa.
• The primary endpoint was change from baseline in the total score of UPDRS Part III.
Results:
• Significant improvement in the primary endpoint in 25 and 50-mg groups vs placebo.
• Duration of “off ” time was significantly reduced in 50 and 100 mg groups vs placebo.
• Dyskinesia was not increased in ZNS groups.
• The incidence of adverse effects was similar between the 25-mg, 50-mg, and placebo
groups but higher in the 100-mg group
NEUROLOGY 2007; 68: 45–50

13. Adverse effects associated with zonisamide treatment with an incidence of > 5%.
Data is presented as percentage.
NEUROLOGY 2007; 68: 45–50
The authors suggested that the primary mechanism of action of ZNS in PD is to
increase dopamine synthesis.

14. ZSN in Impulse control disorders
• 15 patients with PD with ICDs of atleast I year duration not
improving with reduction of either levodopa or dopamine agonists.
• Initiated on 25 mg/day, and titrated to 200 mg/day, as tolerated.
• Clinical Global Impression and Barratt Impulsiveness Scale was used.
• Motor impairment was assessed by UPDRS.
• Marked reduction in the severity of impulsive behaviours and global
impulsiveness (mean change from baseline −5.8 to −4.8,
respectively).
• UPDRS changed only marginally. ZNS was well tolerated.
Bermejo PE, Ruiz-Huete C, Anciones B. Zonisamide in managing impulse control disorders in
Parkinson’s disease. J Neurol 2010; 257: 1682-5.

15. • Phase 2, placebo-controlled, randomized, double-blind study of ZSN 25 or
50 mg /day or placebo for 12 weeks.
• Outpatients diagnosed with probable DLB were eligible for inclusion.
• Primary endpoint was change from baseline in UPDRS III total score at
week 12.
• Cognitive function, behavioral and psychological symptoms of dementia
(BPSD), caregiver burden, other UPDRS parts as secondary endpoints.

16. Results
• 158 patients with DLB received the study drug.
• 21 discontinued during treatment and 137 completed treatment.
• Improvement in UPDRS part 3 total score at week 12 was greater
in the ZSN 50 mg group compared with placebo (p=0.003).
• ZSN did not worsen cognitive function, BPSD, or caregiver
burden.
• Overall incidence of adverse events was higher in the ZSN 50 mg
than the 25 mg and placebo groups (65.3%, 43.1%, and 50.0%,
respectively).

17. Change from baseline in UPDRS part 3 total score at week 12 (last observation
carried forward)

18. Conclusion: Class I evidence that ZSN (adjunctive to levodopa) improved
parkinsonism accompanying DLB without worsening cognitive function or
psychiatric symptoms.
*p < 0.05; **p < 0.001 (vs placebo)

19. Adverse events

20. • 9157 patients were included. ZSN use was associated with a lower risk of dementia,
insomnia, and gastric ulcers than 3 of 7 other classes without levodopa (p < .05).
• There may be a potential clinical impact of ZSN on some of the PD-relevant
symptoms.

21. • 300 mg Levo dopa with 25 mg ZSN per day.
• Marked improvement in freezing of gait, and he could walk by himself within a
month of initiation of treatment with ZSN.
• His psychotic symptoms remained stable.
• Six months later, the “off-time” periods were reduced.
• 10 months after ZSN initiation, improvement in gait freezing persisted, and he
could cycle. His UPDRS scores markedly improved.
Neurology and Clinical Neuroscience 2 (2014) 201–203

22. • DAT-SPECT is used as a possible biomarker for progressive evaluation of
presynaptic dopaminergic dysfunction in the nigrostriatal pathway of PD patients.
• 15 patients aged > 40 years, with HY stage 2 or 3 received ZSN 25 to 50 mg/d.
• DAT-SPECT was done at study entry and after 1.2 years.

23. Results
• HY stage, UPDRS parts I–IV, and tremor score from baseline to
endpoint was similar between ZNS and non-ZNS groups.
• ZNS significantly improved wearing off and inhibited
development of dyskinesia.
• The SBR decreased significantly at the endpoint in the non-ZNS
group compared to the baseline (P < 0.001), but not in ZNS group.
• The SBR decline rate decreased significantly in the ZNS group
compared to the non-ZNS group (P < 0.01).
• ZNS was an independent preventive factor for SBR reduction
(OR=0.913; 95% confidence interval [CI]=0.847–0.984; P=.0168).

24. Role of ZSN in PD
The Movement Disorder Society Evidence‐Based Medicine Review
Update: Treatments for the motor symptoms of Parkinson's disease
2011.
• “Zonisamide is effective as a symptomatic adjunct to levodopa,
with the practice implication that it is clinically useful.”
• It was also concluded that “use of zonisamide in PD for any other
indication (apart from the use with levodopa for the control of
motor symptoms) is investigational”.

25. Role of ZSN in PD
International Parkinson and Movement Disorder Society Evidence-
Based Medicine Review: Update on Treatments for the Motor
Symptoms of Parkinson’s Disease, 2018.
• Zonisamide is efficacious and clinically useful as:
1. Symptomatic adjunct therapy in early or stable PD patients.
2. Motor fluctuations.

26. Conclusion
• ZSN improves motor function in PD, as an adjunct to Levodopa.
• ZSN reduces motor fluctuation and tremors.
• It is useful in impulse control disorders as adjunct to Levodopa.
• It does not worsen dyskinesia, cognition.
• Improves motor symptoms in DLBD without affecting cognition.
• ZSN has multiple mechanisms of action in PD.
• ZSN 25 to 50 mg/day is the effective dose.
• ZSN is well tolerated and the benefit is sustained.

27. THANK YOU