1 Boring Old Man

Personalized Medicine, Pharmacogenomics, and the Practice of Psychiatry:

On the Threshold of Predictive Therapeutics in Psychopharmacology?
^{by Stephen M. Stahl, MD, PhD}
CNS Spectrums 2008 13(2):115-118.
[full text on-line]

^{New Trend in Psychopharmacology: Personalizing medicine by understanding the unique properties of each patient’s genome has the potential of predicting what drug to prescribe for that individual. This approach has already proven useful for several drugs in medicine and promises to become a strategy for selection of therapeutics in psychiatry soon. Understanding some of the key concepts, strategies, and advances in the field of pharmacogenomics can set the stage for adapting emerging findings to the practice of psychopharmacology…}

^{What is Pharmacogenetics, or is it Pharmacogenomics? … Although some experts use the terms “pharmacogenetics” and “pharmacogenomics” interchangeably, many consider pharmacogenetics to be the study of specific SNPs at specific genes with known functions that could plausibly be linked to drug response, whereas pharmacogenomics scans the whole human genome to find SNPs empirically associated with a drug response, without necessarily knowing the function of the SNP (Table 2). Pharmacogenetics tests SNPs identified in advance, such as those linked to various neurotransmitters, receptors, or growth factors, whereas pharmacogenomics scans the entire genome to determine SNPs that are associated with drug response and often identifies genes whose functions are not known or would not have been predicted in advance to be linked to drug response. In either case, SNPs (on the left in Figure 2) alter protein synthesis by making subtle molecular changes in the amino acid sequence of these proteins (middle of Figure 2), hypothetically leading to changes within brain circuits that alter function, including causing symptoms of psychiatric disorders. SNPs may also determine whether these circuits will respond to specific drugs by determining the capability of various molecular targets within specific brain circuits to alter the efficiency of information processing and thereby reduce psychiatric symptoms (on the right in Figure 2…)…}

^{Status of Pharmacogenomics in Medicine Today: Several examples exist where knowing which genetic variant of specific genes that a patient expresses will dictate either the dose of a drug to be given or whether the drug will work or not. What about psychiatry? Can pharmacogenomics lead to individualized treatments for psychiatric disorders (Figure 3)? Some of the key challenges to implementing clinically useful pharmacogenomics in psychiatry today are listed in Table 4 and include the fact that there are generally only preliminary and unconfirmed results for many specific genes with hypothesized links to drug response (Table 5). However, the promising leads shown in Table 5, coupled with proven advances in other fields pave the way for psychiatry. Soon there may be clinically applicable pharmacogenomic markers for psychopharmacologic management. The key question we want answered is: “Does testing for genetic polymorphisms in subjects undergoing psychiatric drug treatment lead to improvement in outcome, or are testing results useful in medical, personal, or public health decision making?” When that answer is “yes,” pharmacogenomics will come of age in psychiatry. Until then, stay tuned and stay informed.}

One would think that I might have had my fill of personalized medicine after sixteen posts about it this last spring. But apparently that wasn’t enough for me:

My problem is that they just can’t stop talking about it either. Personalized Medicine is all over Tom Insel’s NIMH Strategic Plan and in most of his speeches. Dr. Kupfer, directing the DSM-5 revision mentions it. We just heard from Dr. Lieberman about the coming age of genomics. Stephen Stahl is obviously keen on the idea [above]. Genomics is a high-ticket item in everyone’s future plans for psychiatry. But the studies being done point to a more focused research direction than one might think from all of this lofty speechifying.

^{We hope in the near future to be where infectious disease and oncology are in [terms of] individualized treatment… We should be able to see patients, study them in terms of their genomics, characterizing them biologically, then match them to a particular treatment regimen. That’s what we do in oncology, and there is no reason why we can’t do it in psychiatry. Ten or 20 years from now, we will be sending our patients to the laboratory to characterize them in terms of genetic polymorphisms and/or to an imaging laboratory. Then based on those findings, and on the clinical presentation of the patient, we will be able to do what we can’t do right now, which is to answer the question — of all the treatments that are effective for depression, what is the best one for this particular patient?}

^{We have a history of biomarker studies but I think that .?. is very appropriately talking about trying to find some biosignatures for treatment response. And there I think what we have to start focusing on, not so much and I’ve been indirectly saying that throughout in my questions, is that we should not only focus on whether we can predict somebody’s bad outcome or good outcome, because that clinically doesn’t help. If you tell the patient, "bingo you have a bad disease," I don’t think they say, "wonderful doc I’m so glad you told me." So clinically that is a big problem. The second issue is that clinicians have to decide on treatments and therefore the best goal, interim goal at least, we may want to understand the pathophysiology better and I’m not against that, but I think we have to help clinicians decide on one versus the other treatment.}

^{Personalizing medicine by understanding the unique properties of each patient’s genome has the potential of predicting what drug to prescribe for that individual.}

^{These data suggest that today’s most widely used antidepressant drugs are less efficacious than the early drugs. They were marketed not on efficacy but on tolerability and safety. Efficacy for the SSRI drugs always was unimpressive. Ironically, the wide use of such drugs now needs to be considered as a cause of the new epidemic of so-called treatment resistant depression – you know, the cases for whom Abilify and Seroquel are being touted. That is a true iatrogenic train wreck – prescribing antipsychotic drugs for nonpsychotic depressed patients because they did not respond to second rate antidepressants!}

I’m writing about this again for a specific reason. We’ve chased this industry interference in psychiatric treatment long enough to know the ropes. It’s time for some application of preventive medicine on our part. If they genuinely find a robust genetic marker for differential drug response, more power to them. I’m way beyond skeptical that will happen. The worry is that they’ll find a little something and blow it up into the greatest breakthrough since the Facebook and attempt to repeat the absurdities of deceit and pseudoscience we’ve endured for the last twenty-five years.

Martha…   

• Scott T. Aaronson, MD
• Maurizio Fava, MD
• Allan I. Levey, MD, PhD
• Anil Malhotra, MD
• Roy H. Perlis, MD, MSc
• Stephen M. Stahl, MD, PhD