Drug-induced parkinsonism (DIP) is a common etiology of Parkinson’s-like motor dysfunction. DIP was discovered in the 1950s and led to the development of the term “neuroleptic” to describe antipsychotic drugs that can lead to movement disorders in some patients. This effect is because some agents block dopamine D2 receptors (D2R) in motor circuitry in the brain causing features of parkinsonism such as tremors, postural instability, and slowed movement.

In a literature review published in Expert Opinion in Drug Safety, authors Hannah Conn and Joseph Jankovic of Parkinson’s Disease Center and Movement Disorders Clinic at Baylor College of Medicine discuss the etiology of DIP causative medications, clinical features and diagnosis, and disease management and treatment.

The epidemiology of DIP is poorly characterized because DIP motor symptoms resembling Parkinson’s may be incorrectly attributed to other neurological conditions. Research suggests that 8-12% of cases of parkinsonism are caused by medication. Patients exposed to neuroleptics are three times more likely than unexposed patients to develop parkinsonism. The elderly population is at considerable risk because of their age and increased exposure to many different therapeutic agents.

First-generation (typical) antipsychotics (i.e., haloperidol, fluphenazine, chlorpromazine, etc.) are the most likely to cause DIP because of their high affinity for D2R. Atypical antipsychotics (e.g., risperidone, quetiapine, aripiprazole, etc.) were not expected to lead to parkinsonism. However, second-generation antipsychotics are now linked to the development of DIP, with the possible exception of clozapine. Other drug classes including monoamine transporter 2 (VMAT2) inhibitors, calcium channel blockers, antiseizure medications, lithium, antiemetics, gastral prokinetics, and antianginal medications are known to cause DIP, but with a lower incidence than neuroleptics.

Symptoms of DIP, which often severely impact quality of life, may emerge within a few days of starting or increasing the dosage of a causative agent, and in most cases, the symptoms resolve within a few days of drug discontinuation, although some cases do not reverse. If symptoms persist three months after discontinuation, Conn and Jankovic note a complicated diagnostic landscape, including tardive syndromes, a group of hyperkinetic and hypokinetic movement disorders with a wide range of clinical presentations that may occur in isolation or in combination.

A suspected diagnosis of DIP can often be clarified clinically by discontinuation of the causative drug followed by observation of symptom resolution. However, in about 15% of cases, symptoms remain, and because DIP and idiopathic Parkinson’s disease present with very similar clinical features, differential diagnosis is necessary.  Ancillary testing such as DaTscan, or single-photon emission computed tomography for dopamine transporter, may help differentiate the two conditions. Patients with Parkinson’s typically have abnormal DaTscan results whereas patients with DIP have normal results. But there have been documented cases of DIP with abnormal DaTscan results, suggesting prodromal Parkinson’s. Because these imaging studies require careful examination, interpreting these results can be a challenge.

Detection of phosphorylated alpha-synuclein may help differentiate DIP from idiopathic Parkinson’s and would imply the patient has Parkinson’s, even in the subclinical stage, rather than DIP.

Differentiating and accurately diagnosing DIP is a critical step in determining management strategies for these patients. The authors note the challenges in treatment selection and management of movement disorders thought to be induced by medications. Underlying conditions may not be amenable to discontinuation of the causative medications, requiring further balancing of medications and ancillary therapies to improve quality of life overall.

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References:

Conn H, Jankovic J. Drug-induced parkinsonism: diagnosis and treatment. Expert Opin Drug Saf. 2024;23(12):1503-1513. doi:10.1080/14740338.2024.2418950

Shin HW, Chung SJ. Drug-induced parkinsonism. J Clin Neurol. 2012;8(1):15-21. doi:10.3988/jcn.2012.8.1.15