Identifying New Therapeutic Strategies for Psychiatric Disorders

A new Northwestern Medicine study has identified the molecular mechanisms that cause a commonly prescribed antipsychotic drug to produce harmful side effects similar to Parkinson’s disease symptoms, according to findings published in Molecular Psychiatry.  

The findings may help inform new therapeutic strategies in which small-molecule kinase inhibitors are paired with the drug to make it safer for patients with psychosis or psychotic disorders, according to Loukia Parisiadou, PhD, assistant professor of Pharmacology and senior author of the study.  

Haloperidol is an antipsychotic drug commonly used to treat a range of neurological disorders, including schizophrenia, Tourette syndrome, bipolar disorder and others. The drug works by blocking dopamine D2 receptors, which are highly expressed in the striatum, a region of the brain that plays a key role in decision-making, motivation and motor control.  

Significant side effects of this medication include extrapyramidal symptoms, or involuntary movements and muscle stiffness, which can lead to motor deficits like those seen in patients with Parkinson’s disease. The underlying mechanisms that contribute to these harmful side effects, however, have remained unknown.  

In the current study, Parisiadou’s team sought to determine whether Parkinson’s disease-associated leucine-rich repeat kinase 2 (LRRK2) — a known link to dopamine D2 receptor signaling — played a role in haloperidol-induced motor side effects. 

 The scientists studied mice given haloperidol to mimic extrapyramidal symptoms seen in human patients. The mice were then given small-molecule kinase inhibitors to pharmacologically inhibit LRRK2. The team also studied genetic mouse models of LRRK2 inhibition.  

Behavioral tests showed that inhibiting LRRK2 both pharmacologically and genetically in the mice reduced the drug’s side effects and improved motor function. Subsequent electrophysiological and anatomical approaches also showed that inhibiting LRRK2 interfered with changes in striatal neurons caused by the drug.  

The findings suggest that LRRK2 plays a key role in dopamine D2 receptor signaling underlying the motor side effects of haloperidol. Furthermore, the findings may inform new treatment strategies for psychiatric diseases as well as improve the understanding of Parkinson’s disease, according to Parisiadou.  

“Those small-molecule kinase inhibitors are now in clinical trials and anti-sense oligonucleotides aimed to decrease the expression levels of the protein are also in clinical development. So, our idea is if we could give either or both of those to patients along with the antipsychotics in an attempt to ameliorate those significant side effects,” Parisiadou said. 

Chuyu Chen, PhD, a postdoctoral fellow in the Parisiadou laboratory, was lead author of the study.  

Co-authors include Daniel Arango, PhD, assistant professor of Pharmacology, and Yevgenia Kozorovitskiy, PhD, associate professor of Neuroscience.  

This work was supported by National Institutes of Health grants R01 NS097901, R01NS107539 and 2021 OneMind Nick LeDeit Rising Star Research Award. This work was also supported in whole or in part by Aligning Science Across Parkinson’s [ASAP-020600] through the Michael J. Fox Foundation for Parkinson’s Research.