The Role of Genes in Psychiatric Disorders and How Genetic Testing Can Be Used

There is no known gene for any major psychiatric disorder, nor is one ever likely to be found, explained Stephen M. Stahl, MD, PhD, adjunct professor of psychiatry, University of California San Diego, during an overview of the age of personalized medicine and the role of pharmacogenetics at a session of the 2017 Neuroscience Education Institute Congress (NEI).

“The classical theory is that genes cause mental illness, but that theory does not work for psychiatry,” he said.

Genes do not code for psychiatric disorders or psychiatric symptoms, but what they do code for is proteins and epigenetic regulators, many of which regulate the efficiency of information processing in brain circuits, which can be visualized with neuroimaging techniques, explained Stahl, who is also chairman of NEI. Currently, psychiatry research is attempting to link circuits upstream to treatment response and downstream to regulatory genes.

The way an individual inherits a psychiatric disorder or responsiveness to one treatment over another is determined by a genotype having a subtle molecular abnormality, which causes abnormal information processing, which leads to behavior with complex functional interactions and emergent phenomena, said Stahl.

Psychiatric disorders, while descriptive and reliable, are not predictive of treatment response or linked to neurology and therefore are not diseases.

“Each psychiatric disorder is likely to represent many diseases, perhaps hundreds,” said Stahl.

The current diagnostic strategy is to attempt to link symptoms domains that cut across psychiatric disorders to inefficient information processing in specific brain circuits.

There are 4 different genotypes that affect drug metabolism:

• PM: Poor metabolizers of inhibitors of P450 may have increased drug serum levels and adverse events
• IM: Intermediate metabolizers or inhibitors of P450 may have increased drug serum and adverse events
• EM: Extensive metabolizers metabolize substrates normally
• UM: Ultra-rapid metabolizers or inducers of P450 may have reduced drug serum levels and poor efficacy

Stahl finished up the session by discussing how genetic testing fits in modern psychiatric practice.

According to Stahl, pharmacogenomics can add to the modern psychiatric practice because they are:

• Genetically informed
• Neurobiologically empowered
• Data oriented
• Equipoise: weigh all the evidence including genetic test results
• Aware of red herrings in any of the data collected including genomics
• A strategy for when there is no evidence from large randomized controlled trials or all these approaches have failed

For treatment-resistant patients, Stahl recommended providers:

• Exhaust evidence-based solutions.
• Think.
• Take another history, including a new informant. For example, ask the patient’s spouse about the patient’s history.
• Reconsider the diagnosis. The treatment-resistant patient may be bipolar, have dementia, etc.
• Collect new data, including genomics.
• Use this new information to rebalance the evidence and come up with a genetically informed, neurobiologically empowered novel and rational treatment or combination.

“Genetic testing as a clinical tool is still in its infancy,” concluded Stahl. “Genotyping may be especially useful for patients who do not respond to or tolerate a drug as expected. Caution is essential when bringing genetic testing into the selection of treatment in clinical practice.”