The puzzle of matching psychiatric drugs to patients

• Despite decades of research and millions of dollars in investment, there's been limited success treating depression, bipolar disorder, schizophrenia and other disorders — and the burden of these conditions on society has continued to grow.

Driving the news: A study published this week in JAMA Psychiatry looked at patterns in the prevalence of treatment resistant depression (TRD) among the entire population of Taiwan.

• It found those with a family history of TRD were at an increased risk of having it and disorders such as schizophrenia, bipolar disorder and ADHD.
• That suggests "more intensive treatments for depressive symptoms might be considered earlier" than what is prescribed using the standard trial-and-error method, the study authors write.
• The findings underscore something neuroscientists and researchers have been recognizing for some time: Depression and other mental health disorders manifest differently in people, and more effective treatments for some people may hinge on better understanding their biology rather than just their symptoms.

The catch: The tools aren't available today to treat depression — or any other major mental health disorder — as anything other than a monolithic condition.

• That makes even the idea of "treatment resistant" depression somewhat misleading, argues Tara Thiagarajan, founder and chief scientist of Sapien Labs.
• "It just means your treatment isn't hitting the right cause. It's just not relevant," she says.

The big picture: The standard diagnosis and treatment of psychiatric disorders are being reevaluated as massive datasets and powerful machine learning tools begin to reveal biology-based details about how disorders appear in different people.

• Treating these disorders is often a trial-and-error process that can unnecessarily expose people to side effects of a drug, or combination of drugs, that may be irrelevant.
• That's because "the same constellation of symptoms can arise from multiple different causes, and the same set of causes can result in different constellations of symptoms across individuals," researchers recently wrote in Frontiers in Psychiatry.
• "If you are just saying, 'I'm looking at treatments for depression,' it's as vague as saying, 'I'm looking for treatments for general stomach disorder,'" said Thiagarajan, who was one of the paper's authors.

Where it stands: Small biotechs and larger drug companies alike are investing in precision psychiatry, which aims to develop and match drugs to specific patients who will benefit from them.

• But starting from scratch in designing drugs may not be necessary, said Amit Etkin, CEO of Alto Neuroscience, a startup in the field that went public earlier this year.
• Previously developed drugs that haven't made it to market yet — maybe because they were poorly matched to patients in clinical trials — could be retargeted to narrower patient populations, he says.

• "We have the tools waiting for us to figure out how best to use them versus having to make brand-new drugs, brand-new interventions," Etkin said. "I think the drugs are out there in various corners of biotech and pharma. Our approach — our lens — just has to change."

"Advances in imaging, genetics, data science, and biomarkers are enabling us to identify the diseases within the disorders," said Bill Martin, head of neuroscience at Johnson & Johnson Innovative Medicine.

• "In doing so, we now recognize that we can recategorize and stage brain diseases based on biology, which has a profound impact on our ability to discover and develop treatments that can give patients back their lives."

Yes, but: A greater variety of broad-spectrum drugs and treatments are still useful as researchers figure out how to sort and categorize patients, some experts said.

• Until more personalized medication is feasible, "at least give the doctors mechanistic options, because if every drug is an SSRI — the trial-and-error thing is going to be hampered," said James Murrough, director of the Depression and Anxiety Center for Discovery and Treatment.
• New options like esketamine and advances in brain stimulation at least give clinicians more options beyond SSRIs to try with patients, he added.
• The new biology-based thinking also has to account for social and environmental factors.

The bottom line: "We are almost at a tipping point in the field," Etkin said.

• "There's an understanding that something has to change and nothing we're seeing come through the pipeline is going to be a magic bullet."