New Insights into How Antipsychotic Medications Can Cause Parkinson's-like Side Effects

A recent study conducted by Northwestern Medicine has uncovered the molecular mechanisms responsible for the Parkinson's-like motor side effects often observed in patients taking certain antipsychotic drugs. Published in the journal Molecular Psychiatry, this research focuses on how the drug haloperidol, commonly used to treat conditions like schizophrenia, bipolar disorder, and Tourette syndrome, can lead to involuntary movements and muscle stiffness resembling Parkinson's disease.

Haloperidol functions by blocking dopamine D2 receptors in the brain, particularly within the striatum—a region critical for motor control and decision-making. Although effective, long-term use of haloperidol and similar medications can induce extrapyramidal symptoms, such as tremors and rigidity, which significantly impact patients' quality of life. Until now, the precise biological pathways leading to these adverse effects remained unclear.

The research team investigated whether the protein leucine-rich repeat kinase 2 (LRRK2), known for its link to Parkinson's disease and dopamine signaling pathways, played a role in these side effects. Using mouse models, the scientists administered haloperidol to mimic the motor disturbances seen in humans and then applied small-molecule kinase inhibitors to block LRRK2 activity. Both pharmacological and genetic inhibition of LRRK2 in mice resulted in notable improvements in motor function and decreased movement disorders.

Further analysis suggested that LRRK2 is integral to the signaling processes triggered by dopamine D2 receptors that underpin haloperidol’s motor side effects. These findings point toward potential new treatment strategies that combine antipsychotic drugs with LRRK2 inhibitors, which could reduce adverse motor symptoms. Such approaches are currently in clinical or preclinical development, including small-molecule kinase inhibitors and antisense oligonucleotides aimed at decreasing LRRK2 expression.

Dr. Loukia Parisiadou, senior author of the study, emphasized that integrating these inhibitors with current antipsychotic regimens might improve safety profiles for patients. This research not only advances our understanding of drug-induced Parkinsonism but also opens avenues for safer psychiatric treatments and insights into Parkinson's disease mechanisms.

For more details, the study can be found in Molecular Psychiatry (2025) [DOI: 10.1038/s41380-025-03030-z], and additional information about Northwestern University’s research efforts is available on their website.