Research Uncovers A Connection Between Tardive Dyskinesia and the HSPG2 Gene

Jeffrey A. Lieberman, MD

The root cause and development of tardive dyskinesia (TD), a movement disorder that often occurs after the use of antipsychotic medications, are as of yet largely unclear. However, investigators have uncovered a gene—HSPG2—that is associated with the condition.

“It’s a potentially serious condition, which is caused by treatment… and needs to be taken very seriously in terms of treatments you prescribe that can induce TD, as well as monitoring for it in individuals that are receiving ongoing treatment,” said Jeffrey A. Lieberman, MD, of Columbia University, New York State Psychiatric Institute.

“At the same time, it’s a condition which is diminishing in frequency for the reason that it was particularly common or prevalent with the first-generation antipsychotic medication, which are drugs that have a high affinity for the dopamine 2 receptor and long durations of action,” continued Lieberman.

Despite the reduced frequency of tardive dyskinesia, a recent study brings new insight into the root causes of the condition, proving the significant role that genetic factors play in causing TD.

Researchers have previously hypothesized that the development of tardive dyskinesia may involve super-sensitivity of the nigrostriatal dopaminergic pathway, damage to neurons by free radical overproduction, and dysregulation of the GABAergic system.

However, this study found the HSPG2 gene to be significantly associated with tardive dyskinesia in Japanese patients with schizophrenia. The results were later replicated by an independent research group, according to the study.

Further supporting the evidence for this gene in cases of tardive dyskinesia, researchers conducted a meta-analysis specific to the relationship of HSPG2 rs2445142 with tardive dyskinesia occurrence.

Through a genome-wide association screening of tardive dyskinesia in 100 Japanese patients with schizophrenia—half with treatment-resistant TD and half without TD—researchers identified the association of a single nucleotide polymorphism, rs2445142 in the HSPG2 gene with tardive dyskinesia. This finding was subsequently confirmed in independent samples of 36 treatment-resistant TD and 136 non-TD subjects.

“I think its main significance is that [the study] helps us understand the genetic underpinnings to the susceptibility for this drug-induced side effect,” said Lieberman.

Though the study confirms a significant genetic component of TD, Lieberman postulated that there would be little to no advancement in terms of current treatment methods, due to the reduced frequency of tardive dyskinesia and the reduced risk of developing the condition when using second-generation medications.

“It’s unlikely that there will be new effort placed on developing newer, better, medications because fewer people will be affected by this,” said Lieberman. “On the other hand, there may be things that may be useful in a preventative way… the problem is the population frequency of the gene is not high, so it will only pertain to a small proportion of the patients who are being treated and it may not be cost effective to do screenings.”

While the study may not lead to any new breakthroughs in terms of treatments, the established relationship between TD susceptibility and the HSPG2 gene provides deeper insight into the causes of this severe condition.

The study, “Investigation of the HSPG2 Gene in Tardive Dyskinesia — New Data and Meta-Analysis,” was published in Frontiers in Pharmacology.