Does Identifying Bipolar I Disorder Come Down To 6 Proteins?

The Mayo Clinic puts on very good conferences in Psychiatry.  Two of the last three that I have attended had a strong biological and genetic emphasis.  I was interested when I saw a reference in my Facebook feed to a study of potential biological markers of Bipolar I Disorder.  It was even better that the article was published in the open access journal Translational Psychiatry.  In the current article the authors looks at the results from the analysis of serum protein levels in controls and adults seeking treatment for depression and bipolar disorder.  The sera of their subjects and controls was analyzed by Myriad RBM in a quantitative immunoassay designed to search for biomarkers through large numbers of proteins.  The actual product and the proteins analyzed are described on the company's web page.  All of the six proteins identified as possibly being discriminating as listed in the above graphic including growth differentiation factor 15 (GDF-15),  hemopexin (HPX), hepsin (HPN), matrix metalloproteinase-7 (MMP-7), retinol-binding protein 4 (RBP-4), and transthyretin (TTR) can be located on this page and additional information is provided about the specific proteins

The authors emphasize in several places that this is a pilot or exploratory study but also point out that sufficient power to detect odds ratios for pairwise comparisons between mood disorders versus controls, bipolar disorder versus controls, and bipolar I versus controls.  They looked at 272 proteins from 288 samples (141 controls, 52 Unipolar depression, 49 Bipolar II, and 46 Bipolar I).  It was a one time cross sectional sample and no longitudinal sampling was done.  Rigorous patient selection was used to reduce the risk of substance abuse disorders and inflammatory conditions. In a table describing patient characteristics, the cases had significantly greater BMI, greater lifetime illicit drug use,  greater BMI, greater percentage of smokers, and fewer years of education.  Existing symptoms were rated with the following scales IDS-C (depression), PHQ-9 (depression), GAD-7 (anxiety), YMRS (mania), and AUDIT (alcohol use).  The cases were also being actively treated with antipsychotics, AED mood stabilizers, lithium, antidepressants, sedative/hypnotics, and thyroxine supplement.

The graphic from the article labelled figure 2 above shows the differences in protein concentrations for the six proteins that were significantly different after Bonferroni correction by diagnosis.  As can be seen from the figure all six proteins were at the highest levels in Bipolar I disorder.  ROC curves and the ROC-AUC was used to determine which proteins were better predictors of Bipolar I Disorder.  The text contains theoretical and speculative discussions of these particular proteins, what they have been associated with so far, and what importance that has for the issue of why their concentrations may vary in bipolar disorder.

There are a number of relevant considerations when looking at this type of proteomic analysis.  The most obvious is the assumption that the underlying dynamics of the biological substrate can be measured in meaningful ways by knowing the protein signature of those systems.  Although most of us are used to looking at cartoon depictions of neuron and synapses but the reality is much more complex.  Recent work in Science shows that there are 62 proteins associated with synaptic bouton (2) and vesicle trafficking and that the copy number of these proteins varies greatly.  The authors of that paper speculate that the production and number of those proteins may vary because some physical locations within the neuron may allow for an enrichment effect.  One of the implicit assumptions in the Frye, et al paper is that psychiatric disorders may have a unique configuration in terms of synaptic architecture and that it will be reflected in the proteins responsible for that architecture.  A further assumption is these CNS protein changes are all going to be reflected in the periphery and detectable in blood samples.  

Although it is premature to draw many conclusions about the data in this study, the implications may be far reaching.  It will be an interesting day in psychiatry if and when proteins will be used as biomarkers.  It will be an interesting day even if variants can be found and reliably detected.  Until then students of neuroscience and psychiatry will be able to appreciate that information flow in these systems is significant and we are just on the cusp of being able to understand it.  We are just at the stage of moving from cartoon versions of neurons - to the real thing.


George Dawson, MD, DFAPA

References:

1: Frye MA, Nassan M, Jenkins GD, Kung S, Veldic M, Palmer BA, Feeder SE, Tye SJ, Choi DS, Biernacka JM. Feasibility of investigating differential proteomic expression in depression: implications for biomarker development in mood disorders. Transl Psychiatry. 2015 Dec 8;5:e689. doi: 10.1038/tp.2015.185. PubMed PMID: 26645624.

2: Wilhelm BG, Mandad S, Truckenbrodt S, Kröhnert K, Schäfer C, Rammner B, Koo SJ, Claßen GA, Krauss M, Haucke V, Urlaub H, Rizzoli SO. Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science. 2014 May 30;344(6187):1023-8. doi: 10.1126/science.1252884. PubMed PMID: 24876496.

Attribution:

The figure at the top of this post is from the above reference 1 and is used per the conditions of a Creative Commons Attribution 4.0 International License.

The Real Role of Biological Tests in Psychiatry

The idea of a "biological test" in psychiatry has appeared on the internet recently, primarily as a way to deny that psychiatric disorders exist.  The contention is that because there is no medical test for a psychiatric disorder - it must not exist.   Time to add a balanced view.

As a backdrop, most people do not understand the concept of "tests" in medicine until they have a problem and realize that the problem is not reflected in the tests ordered by their doctor.  That is a very common experience.  Some studies show that up to 30% of patients presenting to a clinic for investigation of a symptom never find out what the cause of that symptom was.  That is true even after they were given the usual panel of blood tests, imaging studies, and electrophysiological studies.  The assumption that symptoms and disorders in medicine are all diagnosable by a "test" is incorrect.

The second problem occurs at the level of test interpretation.  When a doctor orders a test they have to interpret it correctly and in many cases the idea of an "abnormal" test is blurred by biological variation.  The evaluation of back pain using imaging studies like MRI scans is a good case in point.  As people age there is a greater likelihood that an abnormal MRI scan of the spine is not necessarily the cause of their back pain.  That has very important implications for treatment and the physician interpreting the test may will definitely be influenced by their specialty training, their own personal experience, their knowledge and examination of the patient, and possibly treatment guidelines that they may be mandated to follow.  There is also the question of false positive and false negative testing.  The recent controversy about the utility of prostate specific antigen (PSA) testing for prostate cancer is another good example.  The current guideline says that this test has too many false positive results to use for treatment planning and further invasive procedures.  Even in the case where the diagnosis is made by a specific number there is always the question of whether the test number is accurate or not.  I have frequently repeated thyroid function tests that seemed to show hyperthyroidism only to see them in the normal range on repeat testing.  It is obvious to physicians that the so-called biological tests in medicine have their limitations and  always need to be interpreted in the context of a comprehensive evaluation of the patient.

How are biological tests currently used in psychiatry?  It turns out that there are a lot of applications similar to the rest of medicine.

1.  To detect a medical cause of a psychiatric disorder.  The DSM classification has an entire set of disorders that are caused by underlying neurological illnesses, endocrine disorders, and infectious diseases that need to be recognized and treated.  They often present as psychiatric disorders.  In my experience of treating people with severe problems, up to 15% of the psychiatric presentations had an underlying medical illness that either was a direct cause of the "psychiatric" symptoms or it made a psychiatric disorder worse.  In that case the psychiatrist has to be trained to order the appropriate tests, make the diagnosis and refer the patient for treatment of the underlying disorder.

2.  To screen for medical illnesses that complicate the psychiatric disorder or its treatment.  A good example here is screening blood tests and electrocardiograms based on the clinical assessment of the patient and the likelihood that a disease is present.  At times patients present with significant problems that require urgent treatment that they are unaware of.  A good example would be detecting complete heart block on an ECG because of a patient's responses to the cardiovascular review of systems and the fact that an antidepressant was going to be prescribed.

3.  To monitor the safety of biological treatments.  There is probably no better example than the FDA focus on cardiac conduction and how that can be affected by medications.  The most recent warning occurred with citalopram.  This antidepressant has been used for over a decade by psychiatrists and was widely considered to be a very safe medication. Both the FDA and the Mayo Clinic have guidelines about how this problem needs to be assessed and that is a combination of clinical assessment and electrocardiograms.  In some cases electrocardiograms and referrals to electrophysiologists are required.  In light of this information psychiatrists need to have access to these ECGs and a plan to address any abnormalities.  As specialists, it is common to see patients who are referred taking doses of citalopram that exceed current FDA guidelines and that may involve testing and a plan to modify the dose of antidepressant.

4.  To identify medical emergencies in patients who are being followed for a psychiatric disorder.  Many patients who see psychiatrists either do not have primary care physicians or are very reluctant to see them.  A psychiatrist in this position needs to make every effort possible to encourage the patient to establish primary care, but even then medical emergencies need to be recognized and appropriately triaged.  That can happen more quickly if testing is available to facilitate the referral.  If a patient presents with jaundice, medical consultants are more likely to see him quickly if some basic testing is done that can be discussed with the consultant.

5.  To identify neurobiological correlates of psychiatric disorders.  A common example is an abnormal brain imaging or electrophysiological study that was ordered because of an acute or progressive behavioral change.

6.  For heuristic purposes.  The classic example of a test done for heuristic purposes was the dexamethasone suppression test.  At various times it was suggested as a test for various forms of severe depression and suicide risk.  The test is rarely done today because of the false positive errors but it helped generate a couple of decades of research on the neuroendocrinology associated with psychiatric disorders.

Some of the articles currently out there on the internet deny the existence of psychiatric disorders because there is no biological test for these disorders like depression or schizophrenia.  That really does not differentiate psychiatric disorders from neurological or rheumatic disorders that may have some supporting markers but that in general depend more on pattern recognition and less on a gold standard or pathognomonic test.   From a paper that addresses that subject (1):

"Although the results are often useful, they can be misleading. Few tests yield results that are pathognomonic for particular diseases. For these reasons, test results for autoantibodies alone are insufficient to establish the diagnosis of a systemic rheumatic disease; they must always be interpreted in the clinical context. Positive results for tests such as the ANA test are seen quite commonly in patients with nonrheumatic diseases and even among normal, healthy persons..."

The key sentence here is:  "Few tests yield results that are pathognomonic for particular diseases."  That would mean that in fact there are few so-called gold standard medical tests that confirm or deny the existence of a diagnosis.  Up to 30% of people presenting to a medical clinic for an evaluation of symptoms will never have a diagnosis to explain their symptoms no matter how many tests they have.  People with real illnesses often are frustrated by the fact that the test results they get are often equivocal.  Obvious conditions that have no biomarkers range from migraine headaches to Alzheimer's Disease.  I don't think that any rational person would suggest that neither of these conditions exist.  People who have first hand experience with severe mental disorders know that the profound emotional and cognitive changes that they see in their friend of family member is real - whether there is a biomarker or not.

George Dawson, MD, DFAPA

Reference:

1:  Arthur Kavanaugh, Russell Tomar, John Reveille, Daniel H. Solomon, Henry A. Homburger; Guidelines for Clinical Use of the Antinuclear Antibody Test and Tests for Specific Autoantibodies to Nuclear Antigens. Arch Pathol Lab Med 1 January 2000; 124 (1): 71–81. doi: https://doi.org/10.5858/2000-124-0071-GFCUOT