What has been the history of the development of laboratory tests in the field of psychiatry?
During my almost-40-year academic medical career, I have been interested in the development and incorporation of laboratory tests into psychiatry.1 This interest initially focused on therapeutic drug monitoring (TDM) and the genetics of drug responsiveness, with an emphasis on drug metabolism. In addition to TDM—which I have long believed is vastly underutilized in psychiatry—there have been many failed attempts to develop diagnostic tests, including tests to distinguish between what were postulated to be serotonergic and noradrenergic forms of major depression in the 1970s2,3 and the dexamethasone suppression test for melancholia in the 1980s.4 Recently, a 51-analyte immunoassay test was marketed by Rules-Based Medicine, Inc. (RBM), as an aid in the diagnosis of schizophrenia, but the test was found to suffer a high false-positive rate and was withdrawn from the market.5 Given this track record, caution is warranted when examining claims for new tests.
What types of tests are being developed?
Most tests in development are pharmacogenomic (PG)-based or immunoassay (IA)-based.
PG tests examine single nucleotide polymorphisms (SNP) in genes that code for pharmacokinetic mechanisms, primarily cytochrome P450 (CYP) enzymes responsible for drug metabolism and P-glycoprotein, responsible for drug transportation. The next most common type of test examines pharmacodynamic mechanisms, such as SNPs of specific receptor genes, including serotonin (or 5-hydroxytryptophan [5-HT] transporter [SET or 5-HTT]) or the 5-HT2A receptor.
The fact that CYP enzymes lead the list is not surprising: These enzymes and their role in the metabolism of specific drugs have been extensively studied since the late 1980s. Considerable data has been accumulated regarding variants of CYP enzymes, which convey clinically meaningful differences among individuals in terms of their ability to metabolize drug via these pathways. Individuals are commonly divided into 4 phenotypic categories: ultra-rapid, extensive (or normal), intermediate, and poor metabolizers. Based on these phenotypes, clinical consequences can be quantitated in terms of changes in drug concentration, concentration-dependent beneficial or adverse effects, and associated/recommended changes in dosing.
Research into the role of pharmacodynamic variants, however, is still in infancy and more difficult to measure in terms of assessing endpoints, with related limitations in clinical utility.
IA assays generally measure a variety of proteins, particularly those reflecting inflammatory processes (eg, various cytokines, such as interleukin-6).6 As with pharmacodynamic measures, research into the role of inflammatory biomarkers is in early stages. The clinical utility of associated tests is, therefore, less certain; witness the recent study5 I noted that revealed a high false-positive rate for the RBM schizophrenia panel in healthy controls. Nevertheless, considerable research is being conducted in all of these areas so that new developments might lend themselves to greater clinical utility.
(Note that PG biomarkers are trait measures, whereas IA biomarkers are state measures, so that complementary use of both types of tests might prove useful in diagnosis and clinical management. Although such integrative use of these 2 different types of tests generally is not done today.)
What does it take to market these tests?
At a minimum, offering these tests for sale requires that the laboratory be certified by the Centers for Medicare & Medicaid Services, according to the Clinical Laboratory Improvement Amendments (CLIA) standards (www.fda.gov/medicaldevices/deviceregulationandguidance/ivdregulatoryassistance/ucm124105.htm). CLIA-certified laboratories are required to demonstrate the analytical validity of tests that they offer—ie, the accuracy and reliability of the test in measuring a parameter of interest—but not the clinical validity or utility of those tests. The fact that a test in fact measures what it claims to be measuring in and of itself does not mean it has clinical validity or utility (see the discussion below).
Must the FDA approve laboratory tests?
No, but that situation might be changing.
Currently, only tests used in a setting considered high risk—eg, a test intended to detect or diagnose a malignancy or guide its treatment—requires formal FDA approval. The approval of such a test requires submission to the FDA of clinical data supporting its clinical validity and utility, in addition to evidence of analytic validity.
Even in such cases, the degree and quality of the clinical data required are generally not as high as would be required for approval of a drug. That distinction is understandable, given the type and quantity of data necessary for drug approval and the many years and billions of dollars it takes to accumulate such data. For most laboratory tests, providing the same level of data required to have a drug approved would be neither necessary nor feasible given the business model underlying most laboratories providing laboratory tests.