Personalized Psychosis Treatment Poised for Major Strides

Genetic research is rapidly advancing the ability to "personalize" the treatment of schizophrenia. In an address at last month's APA annual meeting in Honolulu, Phillip Harvey, Ph.D., presented emerging data on genetic associations with vital clinical considerations such as treatment resistance, development of metabolic syndrome, and cognitive disabilities.

Within the next decade, Harvey said, these findings will allow clinicians to "personalize," or tailor, therapy to the individual susceptibilities of patients with schizophrenia. Most promising in the short term are genetic associations that may predict treatment response to clozapine and cognitive deficits associated with everyday disability.

Also carrying great potential, but still requiring replication, are findings related to risk for weight gain and metabolic syndrome in response to antipsychotic treatment.

"The idea is that within five years we might be able to pick the patients who should receive cognitive remediation to reduce their disability, pick the patients who will be vulnerable to weight gain and metabolic syndrome, and pick the patients who will be most likely to respond to clozapine and who therefore should be tried on that drug," said Harvey, who is a professor of psychiatry and behavioral sciences at the University of Miami School of Medicine and senior clinical research scientist at the Miami Veterans Affairs Healthcare System (see Potential Areas for Personalized Schizophrenia Treatment).

Until the full potential of genetic data is realized, clinicians can still personalize treatment of their patients using the tried-and-true methods of family history taking, rational treatment choice, side-effect monitoring, and switching patients to other treatments when indicated by side effects or treatment failure. Harvey noted, for instance, that recommendations from APA and the American Diabetes Association to regularly monitor patients receiving antipsychotic medication for weight gain and metabolic syndrome have not produced a measurable change in clinical practice; rates of monitoring have remained virtually unchanged since before the release of those guidelines.

Moreover, he said that the vast majority of patients who fail to respond to first-line antipsychotic medications are never tried on clozapine—which has been shown to be most effective for treatment-refractory patients—largely because of inflated fears of agranulocytosis. "Possibly the most important way to personalize medicine is to use the medicine that works the best, especially if it is the only choice," he said.

Harvey said that genetic variants of serotonin, easily detectable with current technology, can be used to predict clozapine response. Specifically, three measurable subunits of the serotonin HTR3A gene are strongly associated with clozapine response.

Other evidence implicates transporter variants as well. For instance, a polymorphism of the HTTLPR serotonin transporter gene clearly separated responders and nonresponders, with nonresponders to clozapine showing a higher frequency of the S-allele.

"There is very strong evidence showing that you can genotype patients before treating them with clozapine in their initial switch from another antipsychotic medication, and these genetic variants can predict a doubling of the clinical response, so you can identify patients prior to treatment who have a markedly increased likelihood of showing a good clinical outcome," Harvey said. "Conversely, you can identify those patients who have the variation that predicts nonresponse and pass on the treatment with its multiple potential side effects and adverse consequences."

Weight gain and development of metabolic syndrome are among the most vexing clinical problems in the treatment of psychosis, and Harvey described studies indicating candidate genes for obesity- and metabolic-related traits in nonpsychiatric and nonantipsychotic-treated populations. These include the insulin-induced gene (INSIG2), the melanocortin 4 receptor gene (MC4R), and the leptin and leptin receptor genes.

Additionally, multiple studies are examining genetic associations weight gain and metabolic syndrome associated with use of olanzapine and clozapine. Among the candidates are a polymorphism of the cannabinoid (CRN1) gene that affects appetite and the adrenergic alpha-2A receptor (ADRA2A), which promotes lipid storage.

Especially promising, Harvey said, is research looking at the genetics of cognitive deficits and functional disability. He noted that individual aspects of cognitive functioning—episodic memory, vigilance, executive functions, and working memory—appear quite heritable in families of people with schizophrenia and bipolar illness.

And he referenced a study on AJP in Advance titled "Analysis of 94 Candidate Genes and 12 Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia," which shows multiple associations between cognitive abilities that relate to everyday function and genetic variance in a sample of people with schizophrenia.

Two studies are in process to examine heritability of everyday living skills—one is the EPIGEN study funded by the National Institute of Mental Health looking at the heritability of disability in 1,000 Ashkenazi Jews; another is a VA study identifying 18,000 veterans—9,000 with schizophrenia and 9,000 with bipolar disorder—focusing on genetics of performance-based cognitive deficits.