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Mayo Clinic Researchers Uncover Six Possible Protein Biomarkers for Bipolar Disorder

NEW YORK (GenomeWeb) — Researchers from the Mayo Clinic have uncovered a half-dozen proteins that might serve as biomarkers for bipolar disorder.

Mayo Clinic's Mark Frye and his colleagues examined 272 proteins in a cohort of nearly 300 people with bipolar I depression, bipolar II depression, unipolar depression, and healthy controls. They found six proteins that differed between people with bipolar I depression and controls, suggesting that these proteins might be markers for the condition, as they reported today in Translational Psychiatry.

"The potential of having a biological test to help accurately diagnose bipolar disorder would make a huge difference to medical practice," Frye, Mayo's head of psychiatry and psychology, said in a statement. "It would then help clinicians to choose the most appropriate treatment for hard-to-diagnose individuals."

Using Myriad RBM's Human Multi-Analyte Profiling platform — a multiplex immunoassay technology — the Mayo researchers profiled a set of proteins within 288 blood samples collected from their cohort of 52 people with unipolar depression, 46 people with bipolar I depression, 49 people with bipolar II depression, and 141 controls.

Myriad RBM provided funding for the study, and has long been interested in developing its protein biomarker platform for use in psychiatric disorders.

As Frye and his colleagues noted in their paper, psychiatric disorders are largely diagnosed based on patients' symptoms and behavior — unlike most other medical conditions, there is no biological test to confirm the diagnosis.

Of the 272 proteins examined, 73 pointed to a significant difference between the groups. After correcting for multiple testing and covariates like age and smoking status, six proteins — growth differentiation factor 15 (GDF-15), hemopexin (HPX), hepsin (HPN), matrix metalloproteinase-7 (MMP-7), retinol-binding protein 4 (RBP-4), and transthyretin (TTR) — remained significant.

The levels of these six proteins, the researchers reported, were higher in people with bipolar I depression as compared to those with unipolar depression, bipolar II depression, and controls. GDF-15, RBP-4, and TTR, they noted, were particularly good predictors of bipolar I depression, with an AUC of 0.81.

The researchers also examined whether medications taken by patients like antipsychotics, lithium, or antidepressants, among others, could be behind these differences in proteins levels. Though their comparisons suggested that some medications could augment the difference in protein levels, they did not appear to drive it.

However, they noted, the study's small study size and lack of drug naïve patients made it impossible to formally test this idea.

These six proteins that Frye and his colleagues identified as potential biomarkers are involved in a range of processes, though many have been previously linked to cognition, psychiatric disorders, and brain function.

For instance, GDF-15 is both a growth factor and an immune modulator, and has been associated with cognitive decline. HPX is a type II acute phase reactant glycoprotein that binds heme, and has been shown to be elevated in both bipolar and schizophrenic patients as compared to controls. And MMP-7 is a metalloproteinase that cleaves a protein that is important for neurotransmitter release — a variant in the MMP-7 gene has also been linked to early-onset bipolar disorder, the researchers noted.

While RBP-4 is mostly expressed in the liver, it is a key part of transporting retinol (vitamin A) from the liver to other tissues — and vitamin A is needed in the brain for learning, memory, and cognition, the researchers said. TTR, too, is found in the liver and it helps RBP-4 transport vitamin A.

HPN, however, is a type II membrane serine protease that is thought to possibly have a role in blood coagulation, but it hasn't previously been linked to any mood disorder.

Though the researchers stressed that their findings need to be replicated in a larger sample, they suggested that these proteins might be biomarkers for bipolar I disorder and could help clinicians to better diagnose and treat patients.

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