Parkinson’s Disease Treatment: Unmet Needs and Dopamine Receptor Selectivity

Dr Stuart Isaacson discusses unmet needs in Parkinson’s disease treatment and the role of dopamine receptor selectivity.

Hello, and welcome to this discussion on unmet needs in Parkinson’s disease treatment and the role of dopamine receptor selectivity. 

I’m Dr Stuart Isaacson, and I’m the Director of the Parkinson’s Disease & Movement Disorders Center of Boca Raton in Florida. 

Parkinson’s disease, or PD, is a chronic, progressive, and disabling neurodegenerative disorder characterized by motor symptoms, nonmotor symptoms, and functional changes that can affect how patients move, communicate, work, and participate in daily life. As symptoms evolve over time, Parkinson’s disease can create a cumulative burden for patients, making both symptom control and day-to-day function central to treatment discussions.  

A key treatment principle in Parkinson’s disease is to improve symptoms by restoring dopamine activity, a concept that has shaped the modern treatment landscape and remains central to the management of motor symptoms associated with PD.

Current treatment options help address some of these needs, but each comes with important considerations.

Oral levodopa remains a foundational therapy for PD. It can provide meaningful symptomatic benefit. However, as treatment continues and disease progresses, motor complications such as wearing off, increased variability in ON/OFF fluctuations, and dyskinesia may emerge.  

These fluctuations are partly attributed to variability in absorption, progressive loss of striatal terminals, and the short plasma half-life of oral levodopa. They are common, with estimates suggesting that motor and/or nonmotor fluctuations may occur in up to 75% of patients after 4 to 6 years of levodopa treatment and in up to 80% of patients with longer-term levodopa exposure.  

Motor complications can substantially impair functioning and quality of life, adding to patient burden as levodopa needs progressively increase. In a retrospective chart review, approximately half of patients receiving levodopa and peripheral dopa decarboxylase inhibitor monotherapy had a dose escalation within the first year, highlighting the ongoing need to adjust therapy as PD evolves.

Patient-perspective literature has identified fluctuations as among the most bothersome symptoms for many patients with PD, underscoring the need to consider unmet needs across the full spectrum of Parkinson’s disease.  

Dopamine agonists were developed, in part, to provide dopaminergic stimulation while reducing reliance on levodopa exposure, an approach that has been used to help delay or reduce oral levodopa-induced motor complications.  

Dopamine agonists have been used as monotherapy or adjunctive therapy to levodopa to improve motor control in some cases. However, the use of currently available D2/D3 receptor-targeting agents can be limited by an increased risk of adverse events, such as impulse control disorders, somnolence, hallucinations, and edema.

The clinical challenge, then, extends beyond improving motor symptoms at a single point in time. It involves sustaining function, reducing unpredictability, and balancing motor benefit with tolerability as Parkinson’s disease progresses, which can have a significant impact on the patient experience.  

Together, these considerations point to a central question in PD care: how can clinicians improve dopaminergic signaling in a way that supports motor benefit while potentially addressing tolerability concerns?

In that context, the mechanisms of action of PD treatments become clinically relevant.

Within striatal motor pathways, each dopamine receptor subtype family plays distinct but complementary roles. D1/D5 receptors are expressed predominantly in direct pathway neurons, where activation can facilitate movement through nigrostriatal signaling. D2/D3/D4 receptors are expressed predominantly in indirect pathway neurons, where dopaminergic signaling helps reduce inhibitory output through striatopallidal circuitry. Because these pathways influence motor circuit activity differently, selective receptor targeting may influence both intended motor effects and the adverse event profile.

Most currently used dopamine agonists preferentially target D2/D3 dopamine receptors, which may emphasize indirect pathway modulation. By contrast, D1/D5 receptor activation is mechanistically aligned with direct pathway stimulation, a pathway that is closely linked to facilitation of movement. Selective activation of the direct pathway may offer an alternative approach for enhancing motor control in PD.

Receptor selectivity can also be relevant when clinicians consider tolerability. 

D2/D3 receptor activation has been associated with adverse events such as somnolence, hallucinations, and impulse control disorders, which are important to consider in benefit-risk assessment.  

Selectivity can also be considered beyond dopamine receptor subtype targeting. Currently available D2/D3 dopamine agonists can have activity at non-dopaminergic receptors, including adrenergic and serotonergic receptors. A selective D1/D5 agonist with significant binding affinity at D1/D5 receptors may reduce off-target receptor activity.

This mechanistic context brings us to a treatment option for PD with a selective D1/D5 agonist activity.

Tavapadon is an oral, once-daily, selective D1/D5 agonist now approved for the treatment of Parkinson’s disease, which can be taken at any time of day, with or without food.

By selectively targeting D1/D5 receptors, tavapadon introduces a differentiated dopaminergic approach for PD. Its mechanism provides a basis for evaluating how selective D1/D5 agonism may fit into the broader treatment landscape, particularly as clinicians seek options that address motor symptoms while informing benefit-risk discussions.  

The clinical relevance of this mechanism becomes even more important when considering the realities of PD management over time. Patients may begin therapy with good symptom control, but as the disease progresses, treatment often requires ongoing adjustment. Motor fluctuations, dyskinesia, and adverse events can all influence treatment decisions in Parkinson’s disease management. A receptor-selective approach may therefore be relevant not only scientifically, but also practically, as clinicians think through how to individualize therapy.

Together, the unmet needs in Parkinson’s disease, including sustained motor control, preserved function, and balanced efficacy and tolerability, highlight why dopamine receptor selectivity may be clinically relevant when evaluating treatment options for Parkinson’s disease.

First, oral levodopa remains foundational for motor symptom management in PD. However, long-term treatment can be complicated by motor fluctuations and dyskinesia, which may be partly related to levodopa’s short half-life, variability in absorption, and disease progression. As PD progresses, patients and clinicians are often left to continually chase motor control through dose adjustments and add-on strategies, reinforcing the need for approaches that balance motor symptom improvement, durability, and tolerability.

Second, dopamine receptor selectivity may influence both motor benefits and tolerability of PD treatment options, as the D1/D5 and D2/D3/D4 receptor families play distinct roles in motor pathways.  

Third, most current dopamine agonists primarily target D2/D3 receptors, and their benefit-risk profiles can be limited by adverse events such as somnolence, hallucinations, and impulse control disorders.  

Lastly, tavapadon’s selective D1/D5 mechanism provides an important framework for evaluating a newer dopaminergic approach. For healthcare professionals, understanding the mechanistic rationale sets the stage for interpreting the clinical evidence across the PD spectrum.  

Thank you for joining this discussion of unmet needs in Parkinson’s disease treatment and the clinical relevance of dopamine receptor selectivity.

INDICATION

Tavapadon is indicated for the treatment of Parkinson’s disease in adults.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Hypotension/Orthostatic Hypotension: Patients with Parkinson’s disease (PD) may have an impaired capacity to respond to an orthostatic challenge. In clinical studies and clinical experience, dopaminergic medications appear to impair the systemic regulation of blood pressure, resulting in hypotension and/or orthostatic hypotension, especially during dose escalation. Patients with PD being treated with tavapadon should be monitored for signs and symptoms of hypotension/orthostatic hypotension, especially during dose escalation, and should be informed of this risk.

Impulse Control/Compulsive Behaviors: Patients may experience intense urges while on tavapadon. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while on tavapadon. Consider reducing the dose or discontinuing tavapadon if a patient develops such urges.

Hallucinations and Psychotic-like Behavior: Medications for the treatment of PD, including tavapadon, can have effects on thinking and behavior. Age appears to increase the risk of hallucinations in patients taking tavapadon. The risk of hallucination may be increased when tavapadon is co-administered with strong CYP3A inhibitors during the maintenance phase. Consider the risks and benefits prior to initiating treatment with tavapadon in patients with a major psychotic disorder because of the risk of exacerbating psychosis. Consider stopping tavapadon if hallucinations or psychotic-like behaviors occur.

Dyskinesia: Tavapadon may cause or exacerbate pre-existing dyskinesia. Consider decreasing the dosage of tavapadon or other dopaminergic medications if dyskinesia occurs.

Adverse Reactions 

The most common adverse reactions (≥5%) for tavapadon without concomitant levodopa were nausea, headache, dizziness, fatigue, dysgeusia, vomiting, dry mouth, and anxiety.

The most common adverse reactions (≥5%) for tavapadon with concomitant levodopa were nausea, dyskinesia, dizziness, headache, hallucinations, and orthostatic hypotension.

Drug Interactions 

Strong CYP3A inducers: Avoid use with tavapadon. Strong and moderate CYP3A inhibitors: avoid use with tavapadon during titration; tavapadon dosage modification is recommended during maintenance.

Moderate CYP3A inducers: Tavapadon dosage modification is recommended during titration and maintenance. Consult the full Prescribing Information for tavapadon for more information on drug interactions and recommended dosage modifications.

Dosage Forms and Strengths 

Tavapadon is available as 5 mg, 10 mg, and 15 mg tablets, as well as 0.25 mg and 1 mg tablets contained in a Titration Pack.

Please see full Prescribing Information or visit https://www.rxabbvie.com/pdf/juvmo_pi.pdf.

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