Personalized Schizophrenia Treatment Possible with Genomic Testing

Psychiatry Advisor

Michael O'Leary

Personalized Schizophrenia Treatment Possible
with Genomic Testing

Scientists have long known that schizophrenia runs in families. The illness occurs in 1%  of the general population but in 10% of people who have a first-degree relative with the condition, according to the National Institute of Mental Health (NIMH).

People with schizophrenia tend to have higher rates of rare genetic mutations involving hundreds of different genes that may disrupt brain development, researchers have found.

However, known gene variations that contribute to schizophrenia appear to have only a small effect on disease risk. (published site)

It's likely that genes are only one component of the disorder's etiology – interactions between genes and the environment are probably necessary for a patient to develop schizophrenia.1

Identifying Risk Genes

Despite consensus that there is a genetic component to schizophrenia, finding genes directly linked to the disease has eluded researchers for decades. But recently, gene-chip technology and data sets with tens of thousands of subjects have made genomic-wide association studies possible.

Even so, identifying the single gene or handful of genes that play a significant role has been challenging, according to Anil Malhotra, MD, of the Feinstein Institute for Medical Research and director of psychiatry research at Zucker Hillside Hospital in Queens, New York.

“There has been a hypothesis out there that instead of looking for genes for the diagnosis of schizophrenia, it might be better to look for genes for certain characteristics of the illness [because they] might be easier to find,” Malhotra said.

In the first such study to examine the genetic association between schizophrenia-linked genes and genes that regulate general cognitive ability, Malhotra and colleagues  found an overlap among the two gene sets.2

Even though the overlap itself was small, the findings were significant, They suggest the genes that influence general cognitive ability may be good targets for schizophrenia drugs and treatment approaches, according to Malhotra.

Although the study detected a signal, it will take a much larger cohort to refine the signal and identify the specific genes that have the strongest effect, he added.

“I don't see an individualized genetic test for the diagnosis of schizophrenia anytime in the near future,” Malhotra said. “More likely, we'll be able to define a subtype of schizophrenia that is characterized by some different clinical symptomatology that is more genetically driven.”

Pharmacogenetics in Disease Management

Using pharmacogenetic tests to examine clinical response to medications, including both efficacy and adverse effects, can aid in schizophrenia treatment and management and is a more practical application of genomic studies.

William Massey, PhD, of the Department of Psychiatry and Behavioral Sciences at Northwestern University in Evanston, Illinois, said genomic-wide association studies have led to discoveries of clinical utility, resulting in pharmacogenetic tests that are commercially available and provide information on which antipsychotic medication will work most effectively for individual patients.

“These pharmacogenetic tests are currently having a great positive impact in the treatment of these diseases, although they are yet to be widely adopted,” Massey said. “As more awareness of these pharmacogenetic discoveries spreads among the psychiatric community, their adoption will increase among physicians.” 

One such pharmacogenetic test that Massey said is particularly useful identifies variants of the SULT4A1 gene, which codes for sulfotransferase 4A1 enzyme. 

Although little is known about the enzyme's physiological function, data from multiple studies indicated that patients with schizophrenia who tested positive for SULT4A1 were three times more likely to exhibit a clinically significant therapeutic response to olanzapine (Zyprexa) than those who were negative for the marker.3

Another potential marker that may aid in schizophrenia management is a variant of the SV2C gene that encodes the synaptic vesicle 2C protein. Genetic variants of SV2C were associated with a poor response to the antipsychotic drugs olanzapine and quetiapine (Zyprexa), but not to risperidone (Risperdal) and ziprasidone (Geodon).

Conclusion

Although identifying disease-susceptibility genes for schizophrenia may still be years away, genomic-wide association studies have yielded important and clinically useful tests that help guide pharmacological management.

These tests are currently commercially available, but could be more widely employed to improve schizophrenia treatment.

Michael O'Leary is a freelance medical writer based in the greater Seattle Area. This article was medically reviewed by Pat F. Bass III, MD, MS, MPH.

References

1. National Institute of Mental Health. “Schizophrenia” 
2. Malhotra AK et al. “Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).” Molecular Psychiatry. 2014;19:168-174 
3. Massey BW, Li J, Meltzer HY. (2014) “Pharmacogentics in the Treatment of Schizophrenia.” In: Schizophrenia. (pp. 161-173). New York: Springer.