Researchers have tried lots of different kinds of tests from EEGs to blood-based biomarkers. Now genetic tests are a very popular means of trying to understand different psychiatric disorders.
Some psychiatric researchers and clinicians warned recently that blood-based biomarker tests to aid in the diagnosis of schizophrenia and depression are “not ready for prime time” and their early commercialization could “exploit the suffering of patients.”
When asked to comment on the article on biomarker tests for schizophrenia in the August issue of Psychiatric Times,1 Gregory Light, PhD, Associate Professor of Psychiatry at UCSD, and Associate Director of the UCSD Schizophrenia Research Program, noted that “laboratory tests for psychiatric illnesses have come and gone over the decades. Researchers have tried lots of different kinds of tests from EEGs to blood-based biomarkers. Now genetic tests are a very popular means of trying to understand different psychiatric disorders.”
Potential biological markers for mental illness have been of considerable interest through the history of psychiatry-monoamine metabolites in cerebrospinal fluid, the dexamethasone suppression test, and genotyping of receptors-according to Steven Balt, MD, a clinical psychiatrist working with the UCLA/Kern Medical Center. “While enticing, this interest has not translated into significant clinical utility.” Balt describes biomarkers as “a way to make psychiatry more like other branches of medicine.”
“If we are using biomarkers to di-agnose a disease or to predict disease risk, what we are really doing is substituting a biochemical test for what should be a thorough clinical examination,” he said. “At present, there is nothing a biomarker will tell us that a seasoned, experienced clinician wouldn’t be able to determine in a full psychiatric evaluation.”
According to Emily Deans, MD, Clinical Instructor in Psychiatry at Brigham and Women’s Hospital in Boston, biologic markers have always been the holy grail of psychiatry, but there is a basic nosology issue.
“Since the diagnoses are based on a recipe list of symptoms from DSM-IV and not known brain pathology, new biologic markers and tests are re-searched and validated against the formal diagnostic criteria. These criteria are designed to be assessed by mere observation and questioning of the patient. Thus, biomarkers only end up as valid as the original criteria, or less so, depending on the validation of the scale used in research,” she said.
When used to discover pathology and to improve understanding of the biologic process of mental illness, “biomarkers are fascinating,” Deans acknowledged. “But for an experienced clinician, except for cases of feigned disease for secondary gain, or perhaps for a patient who needs to be convinced he or she needs treatment, biomarkers based on DSM-IV will never be as useful as ground up research to link known brain, gene, and MRI findings to the patient’s symptoms.”
Light, who is involved in bio-marker research, said he strongly favors prioritizing the development of biomarkers for understanding and treating our sickest patients. But he believes that this work is far from ready for mass commercial appeal. “Currently, these kinds of tests can’t help us differentiate between the causes and the effects of mental disorders,” he said.
Of particular concern to Light is what he describes as the “commercialization of science.” Patients and their loved ones are suffering after initially receiving the diagnosis, he said, and they are desperate for additional information. “To sell a blood test that has not been validated for use in a clinic and that does not guide treatment decisions may be just exploiting the suffering of these patients for profit,” he added.
He is also troubled by the commercialization of tests before studies have been published and before training in their interpretation and proper use is given to care providers.
“What are you supposed to tell patients and their families? What do you tell someone who has a basic unawareness of their illness about the results of their blood test?” He added that clinicians need to know when to use the tests and what kinds of treatments to provide based on the test results.
“At this point, patients and their physicians are already squeezed for time,” he said. “Who has the time to engage in a speculative discussion about unvalidated blood test results with their schizophrenia patients? Would these tests result in even less available time to discuss and clarify symptoms?”
The August Psychiatric Times article mentioned 3 specific blood tests.1 VeriPsych is a diagnostic test used to confirm the presence of recent-onset schizophrenia on the basis of 51 protein biomarkers. MDDScore is a test that measures 10 biomarkers to help diagnose and manage major depressive disorder (MDD). The Human Metabolome Technologies’ test measures the levels of ethanolamine phosphate in the blood to help in the diagnosis of MDD.
Balt commented, “the ethanolamine phosphate finding is fairly inscrutable, since it still has not been published. Similarly, Ridge Diagnostics’ MDD Score has not been presented in the scientific literature.” Balt noted that the ethanolamine phosphate test failed to identify depression in 18% of the cases and falsely labeled healthy people as “depressed” 5% of time.
“Further,” he said, “what exactly is ethanolamine phosphate, and why would it be low in depressed people? As far as I can tell from a quick literature search, there has been no report-or even a suggestion-of ethanolamine being involved in the pathogenesis of mood disorders.
“Obviously,” he added, “the finding has to be replicated. If it was, in fact, just a lucky result, further research will bear that out.”
In contrast, the VeriPsych test is “more interesting,” Balt told Psychiatric Times. “The data have been published, and it does look like there are some analytes that might correlate specifically with a diagnosis of schizophrenia,” he said. “However, few of their analytes meet all of their selection criteria and many of the proteins are nonspecific and can be altered in other medical conditions.”
Balt contended that it is “absolutely premature for clinicians to order these tests,” because they don’t guide treatment. Rather, he said, “they add to our clinical suspicion about the diagnosis and might distract us from the patient’s actual symptoms and clinical presentation.”
In addition, Balt is concerned about the high cost of the tests.
“The VeriPsych test costs $2500? Why not use that money for therapy, a medication trial, or psychosocial treatment of patients who have actually been diagnosed with schizophrenia?” Balt asked.
Balt is apprehensive about basing the biomarkers on DSM-IV. “The validity of these biomarkers has less to do with their reproducibility and correlation with clinical diagnosis, and more to do with the validity of the diagnoses themselves,” he said.
“The categorical (as opposed to dimensional) diagnoses in DSM-IV give rise to a heterogeneous population of what we call ‘schizophrenia.’ Any good psychiatrist will tell you that there are many types of schizophrenia and depression, so a blood test that can ‘diagnose’ schizophrenia is either a nonspecific measurement of emotional distress (or some such thing) or a stroke of luck. It would be better, in my opinion, to look at subgroups of schizophrenia patients (eg, young versus old, male versus female, paranoid versus grandiose delusions, with or without a history of substance use) and determine markers for those. It would more accurately guide our treatment, and we might learn more about the pathophysiology of specific disease subtypes.”
Biomarkers for treatment?
“Biomarkers as diagnostic tools may take the humanity and subjective experience out of psychiatry. The diagnosis really has to stem from a person’s subjective difficulties, the complications that the disease cre-ates in the patient’s life, and what the doctor recognizes in them that makes them different from what we consider normal.” Balt said.
Biomarkers are best used after the diagnosis has been made, according to Balt, when clinicians are faced with a range of treatment options. “A biomarker to determine response to a particular antipsychotic would be quite useful.”
He cited a recent article in Clinical Pharmacology and Therapeutics2 that he coauthored. That paper described specific gene polymorphisms that seem to be more correlated with antipsychotic-associated weight gain.
Researchers at UCSD are seeking to identify the genes associated with schizophrenia and neurophysiologic and neurocognitive biomarkers. In an ongoing study funded by the NIMH, UCSD has joined the Consortium on the Genetics of Schizophrenia (COGS) to learn more about the genetic basis of specific heritable neurocognitive and neurophysiological deficits (called “endophenotypes”) in schizophrenia patients. David Braff, MD, Professor of Psychiatry at UCSD, serves as the study’s national director.
“Maybe at some point down the road-10 to 20 years-we will have a well-validated screening panel. It might consist of a combination of cognitive, EEG, and other neurophysiologic and genomic biomarkers that will guide treatment decisions predictive of outcomes,” Light said.
The NIMH is looking into bio-markers/biosignatures that will predict response to particular depression treatments, according to Jules Asher, an NIMH spokesperson. The goal of the EMBARC (Establishing Moderators/Mediators for a Biosignature of Antidepressant Response in Clinical Care) multicenter study (just getting under way) is to evaluate the usefulness of clinical and biological markers. Antidepressants will be compared with placebo to develop a depression treatment response index to aid clinicians in matching treatments to patients with MDD. (There are more than 20 different medications that have been approved by the FDA for the treatment of depression.)
“The EMBARC study,” NIMH Director Thomas Insel said recently, “is a great example of our new focus on personalized medicine for mental disorders.”
Kaplan A. Blood tests for diagnosis of schizophrenia and depression?
Psychiatr Times. 2011;28(8):1-5.
2. Balt SL, Galloway GP, Baggott MJ, et al. Mechanisms and genetics of antipsychotic-associated weight gain. Clin Pharmacol Ther. 2011;90:179-183.
3. Akiskal HS, Webb WL, eds. Psychiatric Diagnosis: Exploration of Biological Predictors. New York: Spectrum Publications; 1978.
4. Project on the Decade of the Brain. http://www.loc.gov/loc/brain. Accessed October 6, 2011.