Antidepressants effectively treat only about ~50% of patients, and current drug treatment is mostly a trial-and-error process, often taking months to find a helpful drug.
Scientists continue to search for biomarkers to help guide therapy and, potentially, improve chances of discovering new drugs.
Clinicians treating depression say that one reason for the lack of predictive biomarkers is that little is known with absolute certainty about how antidepressants improve mood. All currently approved medications for depression act in a similar way, increasing the availability of monoamine neurotransmitters like serotonin in the brain. According to scientists, genetic variation accounts for at least part of why some individuals, but not others, may develop depression.
Genetic variations can, for example, explain why some medications work better than others in an individual. If a genetic mutation affects the target of a particular drug in the cell, it’s unlikely to work.
And as much as clinicians would like a reliable set of relatively easily accessible biological markers for depression, finding them remains challenging. Writing in the May 2012 DANA foundation publication Cerebrum, Madhukar H. Trivedi, M.D., and Marisa Toups, M.D., said, “Despite all the enthusiasm, we have yet to see biomarkers used in doctors’ offices. The single biggest hurdle is that many of the recent discoveries have been in animals, and translating them to humans has been very difficult....There are no direct models of mental illness in animals—what does it mean for a mouse to be depressed?”
Mice though, like humans, show discernable anxiety. In 2008, Chen Xy and colleagues working at the Weill Medical College of Cornell University reported that they had developed a variant brain-derived neurotrophic factor (BDNF) mouse that reproduces the phenotypic characteristics of humans with the variant allele. Either BDNF expression or signaling have been associated with the development of some human neuropsychiatric disorders, including major depression.
Variant BDNF(Met) mice expressed the gene at normal levels, the investigators reported, but its secretion from neurons was defective. In this context, the BDNF(Met/Met) mouse represents a unique model that directly links altered activity-dependent release of BDNF to a defined set of in vivo consequences.
When placed in conflict settings, BDNF(Met/Met) mice display increased anxiety that the antidepressant fluoxetine failed to normalize. A genetic variant BDNF, they concluded, may thus play a key role in genetic predispositions to anxiety and depressive disorders.
Last April, researchers at Dalhousie University Faculty of Medicine, Northwestern University, Ohio State University College of Medicine, and The Jackson Laboratory, Bar Harbor reported that they had identified a group of genetic biomarkers that they say is associated with early-onset major depression, suggesting the possibility of an objective blood test in the future.
The researchers reported that they carried out genome-wide transcriptomic profiles in the blood of two animal models of depression that represented the genetic and the environmental, stress-related etiology of major depressive disorder (MDD). They analyzed this combined set of 26 candidate blood transcriptomic markers in a sample of fourteen 15–19-year-old teenagers with MDD (N=14) and 14 with no disorder (ND).
A panel of 11 blood markers differentiated study participants with early-onset MDD from the ND group. Four transcripts discovered from the chronic stress animal model correlated with maltreatment scores in youths.
This pilot data, the investigators said, suggest that their approach may lead to clinically valid diagnostic panels of blood transcripts for early-onset MDD to reduce diagnostic heterogeneity in this population as well as advance individualized treatment strategies.
A second larger study will involve using hundreds of blood samples from Nova Scotian teenagers, to be conducted at the Dalhousie University in Nova Scotia, Canada.