Biomarkers for Mental Disorders: A Field Whose Time Has Come

The development of laboratory biomarkers for major mental disorders started with Emil Kraepelin, regarded as the father of modern biomedical psychiatry. Kraepelin asked his student, Aloysius “Alois” Alzheimer, to depict the brain pathology of schizophrenia; Alzheimer also discovered the disease that bears his name.

Until recently, the definitive diagnosis for Alzheimer disease or arteriosclerotic dementia required a postmortem pathological examination. Now, I understand, new procedures have evolved that might help diagnose the disease even in its early preclinical stages; that might test current treatments; and that may lead to new treatments to arrest the disease’s progression. It remains to be seen how this research will affect clinical practice, but the procedures may potentially serve as a model for other psychiatric disorders.

Despite the diligent search for biomarkers for the so-called functional mental disorders during the past 100 years, nothing specific has emerged. Some years ago, there was much excitement about biological tests in the field of affective disorders. Enlargement of the adrenal glands was reported as a relatively specific indicator of melancholic depression if Cushing disease was excluded. Along the same lines, the dexamethasone suppression test was considered to have acceptable sensitivity and specificity for melancholia, rather than broadly defined depression. Shortened rapid eye movement latency was reported as a useful marker of more broadly defined depression, including dysthymia.

These developments were sufficiently innovative in their day that their developers, including Athanasios Zis, MD, Charles Nemeroff, MD, PhD, Bernard Carroll, MD, David J. Kupfer, MD, and I, received major national and international prizes in part for our work on these biological markers. Most of these are reviewed in the proceedings of the International Neuroscience Symposium, which took place in 1975 at the University of Tennessee, Memphis.³ To the best of my knowledge, none of the foregoing tests are presently used in routine practice. There simply are insufficient data on specificity and sensitivity of these laboratory markers.

Perhaps a more important reason why biomarkers for mental disorders have not found their place in psychiatry has to do with overcritical rebuttals of the very notion of such an approach in psychiatry. Such criticism is not entirely unjustified in that diagnostic entities in psychiatry are syndromal and almost never refer to disease. With better phenotypic delineation, it will soon be possible to uncover vulnerability genes for major psychiatric illnesses, such as bipolar disorder, on which our group at the University of California at San Diego is working.

I am not personally familiar with Professor Sabine Bahn, MD, PhD, MRCPsych, who is Director and Cofounder of Psynova Neurotech Ltd, maker of VeriPsych. (Dr Bahn’s work is discussed in the August issue of Psychiatric Times.¹) I have great respect for Molecular Psychiatry, in which research conducted by Bahn’s team was published. I cannot comment on the specifics of Dr Bahn’s data. However, I do concur that such work represents an important step in the right direction.

The search for laboratory tests is conceptually rooted in solid ground going as far back as Hippocrates and in more recent history to Wilhelm Griesinger’s 19th century dictum that “mental disorders are brain diseases” and the NIMH’s “Decade of the Brain” from 1990 to 1999, which began during the tenure of Lewis L. Judd, MD.⁴ In particular, it is important to find out how any proposed laboratory tests will perform in clinically ambiguous conditions, such as overlap of schizophrenic and bipolar disorders and in patients in early stages of these disorders as well as patients within the schizophrenia spectrum and those within the bipolar spectrum. Laboratory confirmation for a patient with a classic clinical picture is less pressing than for those patients whose diagnosis is uncertain.

It is also relevant to point out that schizophrenic and bipolar disorders are phenotypically and genetically heterogeneous and that depressive disorders are even more heterogeneous. The development of biological tests for major mental disorders could have a major impact on predicting therapeutic response with stimulation therapies, pharmaceutical agents, and psychotherapies.

Biomarkers for mental disorders is a field whose time has come. Replication, reliability, specificity, and relevance to the stage and subtypes of schizophrenic, bipolar, and depressive disorders represent a broad front, along which extensive further research needs to be undertaken. Optimists will say within a few years, pessimists might say a decade or beyond. Nonetheless, the history of psychiatry teaches us that a major breakthrough can happen any day. Patients with psychiatric illness and their families have waited far too long.

References:

References

1.

Khantzian EJ, Mack JE, Schatzberg AF. Heroin use as an attempt to cope: clinical observations.

Am J Psychiatry

. 1974;131:160-164.

2.

Khantzian EJ. The self-medication hypothesis of addictive disorders: focus on heroin and cocaine dependence.

Am J Psychiatry

. 1985;142:1259-1264.

3.

Duncan DF. Drug abuse as a coping mechanism. Am J Psychiatry.

1974;131

:724.

4.

Frances RJ. The wrath of grapes versus the self-medication hypothesis.

Harv Rev Psychiatry

. 1997;4:287-289.

5.

Berk WA, Bernstein E, Bernstein J, et al. Alcohol and drug abuse: emergency department identification, intervention and referral. In: Tintinalli J, ed.

Emergency Medicine: A Comprehensive Study Guide

. 6th ed. New York: McGraw Hill; 2005.

6.

Abramson R. Psychotherapy of psychosis: some principles for practice in the real world.

J Am Acad Psychoanal Dyn Psychiatry

. 2010;38:483-502.

7.

Gopal A, Pirakitikulr D, Bursztajn HJ. Informed consent in neuropsychosocial pharmacology. 2005.

http://www.forensic-psych.com/articles/artInformedConsentPsychTimes1105.php

. Accessed October 5, 2011.

8.

Gutheil TG, Bursztajn HJ, Brodsky A. Malpractice prevention through the sharing of uncertainty: informed consent and the therapeutic alliance.

N Engl J Med

. 1984;311:49-51.

9.

Bursztajn HJ, Barsky AJ. Facilitating patient acceptance of a psychiatric referral.

Arch Intern Med.

1985;145:73-75.

10. Bursztajn HJ, Feinbloom RI, Hamm RM, Brodsky A. Medical Choices, Medical Chances: How Patients, Families, and Physicians Can Cope With Uncertainty. New York: Delacorte; 1981; New York: Routledge, Chapman & Hall; 1990.