Tomorrow's Health, Today's Research

Hector J Caruncho

Professor, Neuroscience, Division of Medical Sciences
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Phone: 250-472-5542
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Research Area: the neurobiology of psychiatric illness; the development of biomarkers; the discovery of novel drug targets in mood and psychotic disorders; and animal models of depression
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Research Profile:

Searching for Biomarkers: Can psychiatric illness be diagnosed at the cellular level?

 “Mental illness is an illness, just like any other illness,” says Dr. Hector Caruncho, a professor in UVic’s Division of Medical Sciences, who is studying the neurobiology of psychiatric illness. “There are clear organic changes occurring in the body.”

But when it comes to accurately diagnosing and treating psychiatric disorders, the traditional algorithms used by clinicians often fall short. “In conventional medicine, a neurologist can easily use a series of tasks to definitely diagnose a disease. Psychiatry is completely different,” says Caruncho. “It can be quite difficult to determine an accurate and objective diagnosis.”

The etiology, or cause, of a psychiatric disorder is often complex and variable. Without definitive biomarkers, successful treatment often involves a lengthy process of ‘trial and error’. “We just don’t know much of what is going on in terms of neurological alterations,” says Caruncho. In fact, most of the pharmacological treatments that have been in use since the 1950’s in mental disorders were simply discovered through serendipity.

This is something that Caruncho, who holds a PhD in cell biology, hopes to change. His work with animal models and neuroimaging are already shedding new light on the molecular and cellular changes that underlie psychiatric illness.

Animal models of depression. “It’s not like you’re asking your mouse, ‘Hey, how are you feeling today?’” says Caruncho. “In animal models of depression, you use a series of behavioral tasks that conceptualize depression like behavior.”

Caruncho induces depressed-like behaviors in lab rats with injections of corticosteroids, the precursor to cortisol — the so-called stress hormone. The rats are then monitored for behavioral changes while they undergo a series of tests, both before and after treatment with antidepressants.

Common tests include the forced swim test, which can be used to estimate levels of motivation; and the sucrose preference test, which can indicate the presence of anhedonia (the inability to experience pleasure).

“Depressed-like rats, they just try to float but they don’t make much of an attempt to get out of the water,” says Caruncho. “They don’t consume significantly more amounts of the sugar water than conventional water. “

Drug candidates that can resolve both of these problems — producing sugar-loving, eager-swimming rats — are considered to be effective antidepressants.

But translating animal models to human beings isn’t easy. “Many times, when we analyze human patients, it seems that the only thing they have in common is depression,” jokes Caruncho. Despite this, Caruncho has made some startling discoveries about commonality that could change way clinicians approach psychiatric illness in the future.

Reelin. Caruncho is currently working with a protein called reelin, which appears to play a role in brain development by facilitating the migration and positioning of neurons.

“When we studied the levels of reelin expression in post mortem brain samples, we found that in schizophrenia and bipolar illness, there was about one half the normal levels of reelin.” Caruncho also observed structural deficits in the brains — reductions in layering and size — of schizophrenics, and those with bipolar, and/or depression.

“If there is not enough reelin the migration will not be appropriate and the new neurons will not be properly integrated,” says Caruncho. It has been suggested that this is one of the things that is happening in depression.”

Furthermore, rats, in which the expression levels of reelin was limited, displayed depressive-like behaviors, while the postmortem brain samples of corticosteroid-injected rats showed a deficient maturation of newborn neurons due to reduced levels of reelin. The introduction of imipramine (a first-generation antidepressant) restored both normal levels of reelin and normal animal behavior within the rats.

Caruncho has also observed epigenetic changes — changes in the way a gene is expressed, rather than permanent changes to the genetic code itself — in the promotor region of the reelin gene in schizophrenics that inhibit its transcription, thereby resulting in low levels of reelin protein.

“The data from these experiments brings us towards the possibility that Reelin peptides may have an antidepressant effect.”

SERT clustering. Caruncho is also looking at SERT (serotonin transporter) clustering in blood lymphocytes as a putative biomarker of therapeutic efficacy in major depressive disorder.

Caruncho has discovered an association between reelin levels and the pattern of protein clustering within cell membranes — specifically the size and number of serotonin transporter clusters.

Corticosteroid-treated, depressed-like animals have a significant increase in the average size of serotonin transporter clusters in lymphocytes. Immunolabelling of human lymphocytes shows similar results in depressed humans.

While translating this approach to humans, Caruncho discovered that if he analyzed the clustering distribution of patients in the depressed group on an individual level, he was able to identify two distinct sub-populations in the depressed group, which he called D-I and D-II.

While both subsets had similar levels of depression before treatment, only the D-II group showed significant improvements following a 2-month antidepressant treatment. The D-II group alone also demonstrated a significant increase in lymphocyte SERT clustering.

“Analysis of protein membrane clustering in lymphocytes of unmedicated depressed patients may be a biomarker of therapeutic efficacy in depression,” says Caruncho.

Clinical relevance. In the real world, everyone is operating with limited resources. Biomarkers that facilitate a quick and accurate diagnosis and/or predict the therapeutic efficacy of a given antidepressant would be indispensable in the clinical setting.

“The psychiatrist can make their own decisions,” says Caruncho. “I don’t prescribe for them. But, perhaps we could give them something more scientific, more definitive, to work with.”

Ultimately, Caruncho believes that change and hope stem from lobbying the government, reducing the stigma associated with mental illness through education, and letting the community know that scientists and clinicians are collaborating together to develop new strategies to help them.

“We scientists need to get out of the ivory tower,” says Caruncho. “It’s not just about publishing papers.”