Cautious Optimism About Biomarkers for Psychiatric Illness

So my wife saved one of those popular online medical news items for me to read yesterday. This is another one expressing a lot of enthusiasm for biomarkers related to psychiatric disorders and suicidality. I have just a few cautionary remarks on the article and the open access study the reporter highlighted, both of which I tweeted:

I’m as excited as anyone about new scientific developments in psychiatric assessments and treatments. And I’m always cautious about the overly-optimistic way in which some news items are crafted in order to capture readers.

For example, you don’t get the practical quote from the open access study about biomarkers for suicidality from one of the authors until you’re deep into the news item,

“People could have high levels of biomarkers and no clinical risk factors. We don’t want to hospitalize people based just on biomarkers.”—A. Niculescu, study author [1].

And a lot of the data in the open access study is open to debate on whether the so-called biomarkers are state or trait markers, an important distinction in the search for predictive tools that might help clinicians in the field prevent suicides.

An important question is how quickly could a psychiatrist obtain a result from such a test? If it’s a send-out which takes weeks at an outside lab to complete, I’m not going to use it because I need a result in something more like an hour.

The other important question is what are we to do about the patient who has both clinical and biomarker evidence for what some might want to call an “imminent suicide” attempt? So far we have crude interventions such as clozapine and lithium, both of which are challenging for clinicians to administer safely and effectively and difficult for patients to tolerate. We can hospitalize them, involuntarily if need be, which can damage the therapeutic alliance necessary to deliver treatment, which could include electroconvulsive therapy (ECT), a potentially life-saving procedure which some jurisdictions make difficult to apply owing to restrictive mental health statutes and which stigma makes unacceptable to some families.

Hospitalizing suicidal patients doesn’t always save lives. People can and do kill themselves on secure psychiatric wards.

It’s easy to be dazzled by the biomarker frenzy so it’s important to put it into perspective. We want researchers to continue this work and in the meantime, clinicians on the front lines still need to make do with the tools we have until breakthrough developments are practical, effective, acceptable, and accessible.

Reference:

1. Le-Niculescu, H., et al. (2013). “Discovery and validation of blood biomarkers for suicidality.” Mol Psychiatry 18(12): 1249-1264.
Suicides are a leading cause of death in psychiatric patients, and in society at large. Developing more quantitative and objective ways (biomarkers) for predicting and tracking suicidal states would have immediate practical applications and positive societal implications. We undertook such an endeavor. First, building on our previous blood biomarker work in mood disorders and psychosis, we decided to identify blood gene expression biomarkers for suicidality, looking at differential expression of genes in the blood of subjects with a major mood disorder (bipolar disorder), a high-risk population prone to suicidality. We compared no suicidal ideation (SI) states and high SI states using a powerful intrasubject design, as well as an intersubject case-case design, to generate a list of differentially expressed genes. Second, we used a comprehensive Convergent Functional Genomics (CFG) approach to identify and prioritize from the list of differentially expressed gene biomarkers of relevance to suicidality. CFG integrates multiple independent lines of evidence[mdash]genetic and functional genomic data[mdash]as a Bayesian strategy for identifying and prioritizing findings, reducing the false-positives and false-negatives inherent in each individual approach. Third, we examined whether expression levels of the blood biomarkers identified by us in the live bipolar subject cohort are actually altered in the blood in an age-matched cohort of suicide completers collected from the coroner/’s office, and report that 13 out of the 41 top CFG scoring biomarkers (32%) show step-wise significant change from no SI to high SI states, and then to the suicide completers group. Six out of them (15%) remained significant after strict Bonferroni correction for multiple comparisons. Fourth, we show that the blood levels of SAT1 (spermidine/spermine N1-acetyltransferase 1), the top biomarker identified by us, at the time of testing for this study, differentiated future as well as past hospitalizations with suicidality, in a live cohort of bipolar disorder subjects, and exhibited a similar but weaker pattern in a live cohort of psychosis (schizophrenia/schizoaffective disorder) subjects. Three other (phosphatase and tensin homolog (PTEN), myristoylated alanine-rich protein kinase C substrate (MARCKS), and mitogen-activated protein kinase kinase kinase 3 (MAP3K3)) of the six biomarkers that survived Bonferroni correction showed similar but weaker effects. Taken together, the prospective and retrospective hospitalization data suggests SAT1, PTEN, MARCKS and MAP3K3 might be not only state biomarkers but trait biomarkers as well. Fifth, we show how a multi-dimensional approach using SAT1 blood expression levels and two simple visual-analog scales for anxiety and mood enhances predictions of future hospitalizations for suicidality in the bipolar cohort (receiver-operating characteristic curve with area under the curve of 0.813). Of note, this simple approach does not directly ask about SI, which some individuals may deny or choose not to share with clinicians. Lastly, we conducted bioinformatic analyses to identify biological pathways, mechanisms and medication targets. Overall, suicidality may be underlined, at least in part, by biological mechanisms related to stress, inflammation and apoptosis.

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Comments

  1. I just realized I left out ketamine, an agent for which there’s a good deal of promising evidence in the literature for treatment of suicidality and depression. Please see my most recent post at link https://thepracticalpsychosomaticist.com/2013/07/17/healthy-skepticism-can-be-a-good-thing/

    And the authors (Naughton et al, see below in the section “Biomarkers of ketamine’s antidepressant effects”) of a recent review say, again deep in the paper, “The general consensus in the literature appears to be that ketamine itself may never reach mainstream use as a treatment for TRD or depression in bipolar affective disorder. However many researchers believe that this body of research will be a means to learn more about the pathophysiology of depression that will hopefully offer novel therapeutic agents that act in a similar fashion to ketamine with longer duration of action and less side-effects or that act on the effectors of ketamine known to be involved in its mechanism of action. Translational research is currently exploring the identification of biomarkers that might be involved in prevention, diagnosis, treatment response, severity and prognosis of depression and Zarate et al., (2013b) reviewed the human biomarkers of antidepressant effects and summarise a range of potential biomarkers identified from genetic, functional neuroimaging, sleep and clinical studies implicated in ketamine’s antidepressant action. While, overall, while these biomarker studies have limited practical implications at present they offer huge hope that eventually we will be able to successfully apply these techniques to clinical populations. Moving research in this direction offers opportunities that would ultimately facilitate the development of personalised treatment, increasing the probability of success.”

    Naughton, M., et al. (2014). “A review of ketamine in affective disorders: Current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action.” Journal of Affective Disorders 156(0): 24-35.
    AbstractIntroduction Recent research has seen low-dose ketamine emerge as a novel, rapid-acting antidepressant. Ketamine, an N-methy-d-aspartate (NMDA) receptor antagonist, leads to effects on the glutamatergic system and abnormalities in this neurotransmittor system are present in depression. This article aims to (1) review the clinical literature on low-dose ketamine as a rapid-acting antidepressant in affective disorders, (2) provide a critical overview of the limitations of ketamine and research attempts to overcome these (3) discuss the proposed mechanisms of action of ketamine and (4) point towards future research directions. Method The electronic database Pubmed, Web of Science and sciencedirect were searched using the keywords: ketamine, N-methyl-d-aspartate receptor antagonist, rapid-acting antidepressant, depression, treatment-resistant depression, bipolar depression, suicidal ideation, electroconvulsive therapy, mechanism of action. Result The literature demonstrates evidence supporting a rapid-acting antidepressant effect of low-dose intravenous ketamine in major depressive disorder, in bipolar depression and in depression with suicidal ideation. There are mixed results as to whether ketamine leads to a reduction in time to remission in patients undergoing electroconvulsive therapy (ECT). Efforts to unravel ketamine′s therapeutic mechanism of action have implicated the mammalian target of rapamycin (mTOR)-dependent synapse formation in the rat prefrontal cortex, eukaryotic elongation factor 2 phosphorylation (p-eEF2) and glycogen synthase kinase (GSK-3). Ketamine′s limiting factors are the transient nature of its antidepressant effect and concerns regarding abuse, and research efforts to overcome these are reviewed. Conclusion Current and future research studies are using ketamine as a promising tool to evaluate the glutamatergic neurotransmittor system to learn more about the pathophysiology of depression and develop more specific rapid-acting antidepressant treatments.

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