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Precision Psychiatry

Why we should be cautious about the promise of precision psychiatry.

There’s a new buzzword in the field of mental health: “precision psychiatry.” The idea comes from the broader field of precision medicine, in which patients are matched to treatments based on personal genetic and other relevant characteristics. More recently, those in the field of mental health have been wondering what this concept might look like when applied to treatment with psychotropic drugs.

It is not a mystery why this would be desirable. Psychiatric illness is incredibly complex, not least because the brain is very complicated and in many ways still a mystery. The medications we use to treat psychiatric illness are also incredibly complex. In part because they have pharmacological properties that permit them to cross the blood-brain barrier, they often carry with them a number of somewhat undesirable side effects. To make matters more complicated, an individual’s reaction to a specific psychotropic drug may not follow what is predicted by the drug’s basic pharmacology, and therefore idiosyncratic responses, both beneficial and adverse, frequently occur.

This combination of factors effectively means that treatment with psychotropic drugs, often necessary in the effective management of psychiatric illness, is often a matter of pure trial-and-error. A family member who’s a psychiatrist specializing in psychopharmacology says that she regularly tells new patients to expect it to take up to a year to get the medication regimen right. While this may sound extreme or disheartening, it is simply the state of the field and tends to be an extremely realistic picture in her over 40 years of experience in the profession. We currently have very little scientific basis telling us which medication is going to be right for a given individual.

No small wonder, then, that people are increasingly excited about the promise of precision psychiatry. Who wouldn’t want to skip over the agony of up to 12 months, perhaps more, of trying different medications, all the while continuing to experience symptoms of mental illness and perhaps a broad range of undesirable side effects? Not to mention the fact that most people in this country don’t have access to this kind of specialist treatment. due to the high cost and shortage of psychiatrists and psychopharmacologists in many parts of the country. Wouldn’t it be better if patients could simply take a test that tells the doctor exactly what to prescribe?

The answer to this question is, of course, a resounding “yes.” The problem is, it’s not clear how easy this would be to accomplish, and some media and scientific sources may be offering too much false hope that it is closer to fruition than it actually is. In light of this, it may be beneficial to examine a few questions more closely: How exactly do people think precision psychiatry would work, and how close are we to achieving it?

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In many ways, “precision psychiatry” would not work too differently from the way precision medicine in other fields should work. The idea is to leverage the collection of “big data” to help understand what biomarkers and genetic characteristics align with certain types of responses to different medications. From there, individual patients’ genetic characteristics and biomarkers would be used to better predict what psychiatric medicines might be best for them. For example, it is now possible in some cases of cancer to perform a genetic analysis of the individual patient's tumor, uncover its basic genetic signature, and use that information to select the exact combination of chemotherapeutic medications that are more likely to work for that patient than all the alternative combinations.

So this is clearly not a crazy idea by any means. It is absolutely the case anecdotally that patients who have the benefit of knowing about other family members’ use of certain psychiatric medications can often use this information to narrow the odds of predicting the exact medication that will work. In other words, if you know that your mother responded well to nortriptyline, a tricyclic antidepressant, but didn’t do too well on Prozac, an SSRI, it’s fair to think that you might also respond well to nortriptyline or another tricyclic and not as well to Prozac or another SSRI. It’s not a fool-proof method by any means, but it is input that psychopharmacologists can use and have been able to use with some success. And in a sense, this represents the use of “genetic” information to make a precision psychiatric decision.

The idea of being able to take a test and know what psychiatric drug might work best for you would come as a relief to the vast majority of people struggling with mental health conditions. Expediting symptom relief is, of course, a major goal in any kind of medical treatment, but it is an especially critical goal in the treatment of psychiatric disorders like depression. For reasons that we do not understand, antidepressants generally take two to six weeks before any efficacy occurs. It is hard to figure out why this is the case. We know that all antidepressants work by binding to receptors on the surface of neurons in the brain. We also know that it takes hours to a few days for an antidepressant to fully occupy its target receptors. And yet, there is still that lag before the drugs work. Clearly, there is something else besides simply occupying a receptor that must happen in order for them to work, and this “something else” appears to take weeks to occur.

There are many theories that attempt to explain what the necessary neuronal events are, and we have our own favorite ones based on research we and others have done, but to date, nothing is proven for sure. Figuring out why the drugs take so long to work should give scientists the tools to make new ones that work faster. But, like many, many things about the brain, the solution has remained elusive despite a lot of research. This means that any claim to being able to predict by virtue of a blood test or brain imaging study what specific drug will work for an individual is automatically on shaky ground. If we don’t know exactly how antidepressants and other psychiatric drugs work, it is hard to imagine a test that tells us which drug is best for which person.

Two things make the search for a test to predict medication responsiveness a bit more likely. First, it may not be necessary that the test be linked to an exact molecular mechanism that explains why a drug works. For example, some seemingly random genetic idiosyncrasy could be linked to an increased or decreased chance of a drug working, even if the gene involved doesn’t seem to have anything to do with the brain, psychiatric illness, or the mechanism of action of a medication. It would still be useful. And now that we have immense amounts of data about variability in human genetic sequences, it just might be that such a quirky relationship between a gene and drug outcome exists.

Second, although we don’t know nearly enough about how psychiatric drugs work in the brain, we know a great deal about how the liver metabolizes them. A set of enzymes in a system called cytochrome P450 is responsible for breaking down medications and each of these enzymes is coded for by a specific gene. The base sequence for these P450 genes varies from one person to the next, such that some people have variants that are more efficient at breaking down a specific drug than others. If you have a very efficient enzyme for a drug, it means it gets neutralized quickly and has less of a chance of working. You may need a higher than usual dose of that drug, or to switch to a different drug that uses a different one of the P450 enzymes for its metabolism. If you have an enzyme that is inefficient for a specific drug, then it will hang around at higher levels and longer periods of time, increasing the risk of adverse side effects. In that case, a very low dose might be better. We can now sequence the genes that code for the P450 enzymes and figure out who is going to be a fast or slow metabolizer for many medications. And knowing that can conceivably guide a psychiatrist to picking a drug that is more likely to work.

But while all of this is both possible and promising, there are many challenges to finding a test that really has practical value for psychiatrists and their patients in picking medications. Hence, right now we have to be extraordinarily careful that we are not giving patients false hope about the promises of “precision psychiatry.” Headlines like “precision medicine introduced to psychiatry” and quotes in medical news articles about the “transformational” nature of this approach could mislead people into thinking that this option is already readily available and fully functional. This could result in grave disappointment when they visit their doctors only to discover that this option is not going to be nearly as helpful as advertised, and they will have to endure the old-fashioned trial-and-error approach. For a population that may already suffer from feelings of hopelessness, this is a risky business.

A Forbes article from 2016 even goes so far as to say that: “Precision medicine offers unparalleled hope for patients managing a mental health condition. This benefit cannot be understated or stressed enough, as the challenges experienced by patients with mental health conditions and co-occurring disorders can be crippling and may add to the potential risk of suicide.” We agree that the hope is there, and even predict that hope will be realized fairly soon. But it is not ready for prime time yet. A recent New York Times article pointed out that even in the more scientifically advanced field of precision medicine for cancer treatment, providers and the media need to be more careful about giving patients false hope and sometimes causing them to spend inordinate amounts of money on treatments that may not work.

While the promise of “precision psychiatry” is something we should continue to pursue in the field of mental health, right now we need to be careful about how we communicate about the possibilities and the options currently available to patients. The last thing we want to do is give people, some of whom may be in deep distress about their ability to ever feel better, a false sense of hope. Our task is to be straightforward and realistic with our patients, while also offering them a true sense of hope in the ultimate efficacy of evidence-based psychiatric treatment.

And let’s not forget that while we are waiting for precision psychiatry to get off the ground and while depressed patients are waiting for their antidepressants to work, support and psychotherapy are always there to help people cope.

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