Pharmacological management of dementia with Lewy bodies with a focus on zonisamide for treating parkinsonism

ABSTRACT

Introduction

Dementia with Lewy bodies (DLB) has no approved symptomatic or disease-modifying treatments in the US and Europe, despite being the second most common cause of neurodegenerative dementia.

Areas covered

Herein, the authors briefly review the DLB drug development pipeline, providing a summary of the current pharmacological intervention studies. They then focus on the anticonvulsant zonisamide, a benzisoxazole derivative with a sulfonamide group and look at its value for treating parkinsonism in DLB.

Expert opinion

Several new compounds are being tested in DLB, the most innovative being those aimed at decreasing brain accumulation of α-synuclein. Unfortunately, new drug testing is challenging in terms of consistent diagnostic criteria and lack of reliable biomarkers. Few randomized controlled trials (RCTs) are well-designed, with enough power to detect significant drug effects. Levodopa monotherapy can treat the parkinsonism in DLB, but it can cause agitation or visual hallucination worsening. Two Phase II/III RCTs of DLB patients recently reported a statistically significant improvement in motor function in those receiving zonisamide as an adjunctive treatment to levodopa. New biomarker strategies and validated outcome measures for DLB or prodromal DLB may enhance clinical trial design for the development of specific disease-modifying treatments.

KEYWORDS:

• Zonisamide
• Lewy body dementia
• dementia with Lewy bodies
• parkinson’s disease dementia
• α-synuclein
• p38 inhibitors
• phosphodiesterase inhibitors

Article highlights

• Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia are jointly known as Lewy body dementias, the second most common cause of neurodegenerative dementia over 65 years, although they have different epidemiological, neuropathological, and clinical features.

• At present, there are no drugs approved for DLB in the United States (US) and Europe and no drugs with disease-modifying effects are available.

• DLB treatment is mostly targeted at specific symptoms, trying to counterbalance the underlying neurotransmission disturbances.

• A few compounds are currently in the DLB drug development pipeline, including the promising anticonvulsant agent zonisamide.

• The parkinsonism of DLB is difficult to treat, although low doses of levodopa are usually well tolerated.

• When zonisamide (25 or 50 mg) was used as an adjunct to levodopa in recent Phase II and III RCTs in mild DLB patients, it significantly improved parkinsonism without worsening neuropsychiatric or cognitive symptoms.

• Use of consistent diagnostic criteria for DLB or prodromal DLB, new biomarker strategies, and validated outcome measures may enhance clinical trial designs, assisting in the development of specific disease-modifying treatments.

This box summarizes key points contained in the article.

Declaration of interest

BP Imbimbo is an employee of Chiesi Farmaceutici while M Watling is an employee of TranScrip Partners, Reading, UK. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One referee declares receiving a stipend from the American Academy of Neurology as well as honoraria from MedLink. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript was not funded.