GEN Exclusives

More »

GEN Exclusives

More »
Dec 30, 2009

Part 2—Finding Newer Molecular Targets for Antidepressants

Creating better mouse models is key to developing more effective drugs and understanding how current treatments work.

Part 2—Finding Newer Molecular Targets for Antidepressants

Revealing the pathways that control depression and understanding the mechanism of various drugs is crucial.

  • Basic research focusing on pathways linked to depression is changing how scientists think about viable targets for antidepressant agents. These efforts aim at making drugs more efficacious in a larger number of individuals and with fewer side effects. 

    The first part of GEN’s series on the depression market discussed studies that found that currently available treatments are not as effective as they’re made out to be nor do they work in the majority of patients. This second part details basic research elucidating the complexity of depression and the fact that scientists need to develop better mouse models to improve their knowledge of the various pathways involved in this disorder.

    “The mechanism issue is important because if a patient doesn't respond to one drug, the chances of them responding to another drug that works through the same mechanism are low,” asserted John Wemmie, M.D., Ph.D., associate professor of psychiatry and neurosurgery at the University of Iowa Carver College of Medicine. Eva Redei, Ph.D., the David Lawrence Stein professor of psychiatry at Northwestern University's Feinberg School, and her team aren’t surprised that current antidepressants don’t work very well. They think that currently available antidepressants aim at the wrong targets. “There hasn't been an antidepressant based on a novel concept in 20 years,” Dr. Redei told GEN. She also noted that the causes of depression have been oversimplified.

    Old Drug Development Model Turned on Its Head

    Dr. Redei presented data at the “Neuroscience 2009” conference that contradicted two widely held beliefs about the origins of depression: that stressful life events can cause depression and that brain neurotransmitter imbalances trigger its symptoms. Both beliefs formed the basis for developing the current set of marketed drugs to treat depression. Dr. Redei reported, however, that no overlap exists between expression of stress-related genes and depression-related genes.

    Dr. Redei based her conclusions on a comparison of gene-expression patterns from the hippocampus and amygdala from a depressed rat model and a group of mixed-strain, normal rats that were experimentally subjected to chronic stress. The hippocampus and amygdala are both associated with depression. 

    “If the stress causes depression theory was correct, there should have been a significant overlap between the two sets of genes, but there wasn’t,” Dr. Redei noted. From over 30,000 genes studied, there was an overlap of five genes. “This overlap is insignificant. This finding is clear evidence that at least in an animal model, chronic stress does not cause the same molecular changes as depression does.”

    Additionally, among the differentially expressed genes in the depressed and nondepressed animals, “we didn’t see any that were related to the monoamine deficiency hypothesis,” Dr. Redei pointed out. “That hypothesis is what SSRI and older drug development is based on.” 

    Building a Better Mouse Model

    The use of endogenously depressed animal models, rather than stress-induced depression animal models, will help “open up the doors and really look at mechanisms in an unbiased way,” according to Dr. Redei.

    In the May 28 issue of Neuron, investigators described a mouse depression/anxiety model that permits simultaneous examination of multiple effects and mechanisms of SSRI antidepressants in the same animal. “We developed an anxiety/depression-like model based on elevation of glucocorticoid levels that offered an easy and reliable alternative to existing models,” the authors wrote. Previous research had shown that long-term exposure to glucocorticoids causes anxiety and depression-like states in rodents. Additionally, elevated levels of these steroids have been linked to depression and anxiety in humans.

    Understanding How SSRIs Work

    While the precise mechanisms of how selective serotonin reuptake inhibitor (SSRIs) exert antidepressant effects are not known, new mouse models could help explain their activity and find new drugs. “SSRIs may stimulate changes in a brain region called the hippocampus as well as other brain structures,” suggested Denis J. David from the University of Paris Sud and senior author of the study published in Neuron. “For example, anxiety/depression-like changes in behavior have been linked with a decrease in cell proliferation in the hippocampus, a change that is reversed by antidepressants.”

    Dr. David showed that the antidepressant effects of drugs like Prozac involve at least two different mechanisms that are both neurogenesis-dependent and -independent. His team demonstrated that if they prevented hippocampus neurogenesis, which occurs in mice chronically treated with corticosterone, the efficacy of Prozac was blocked in some but not all of the behavioral paradigms measuring depression and anxiety.

    The researchers also identified genes that were expressed at lower levels in the hypothalamus but were normalized by Prozac. Mice deficient in one of these genes, β-arrestin 2, displayed a reduced response to Prozac in multiple behavioral tasks, indicating that β-arrestin signaling is necessary for Prozac’s antidepressant effects. Investigators are thus testing compounds that may stimulate neurogenesis more directly as well as molecules that directly target the hypothalamus.

    Studies have also suggested that a specific gene variation plays a role in the development of anxiety disorders as well as in resistance to common medications for anxiety and depression. It is thus believed that this variation could eventually help predict whether an SSRI treatment would be effective for an individual patient. Research published in the October 2006 issue of Science found that mice with a variation in the brain-derived neurotrophic factor (BDNF) gene, expressed in both alleles, showed increased anxiety-like behaviors and some resistance to Prozac, an SSRI.

    Finding New Targets

    While the investigators say that no animal models replicate the complexity of human depression, several behavioral tests in rodents, including those that produce stress, are sensitive to antidepressants and may tap underlying biological factors that could point to novel treatment discovery.

    Dr. Wemmie’s studies, published in the April issue of The Journal of Neuroscience, use several animal models to test the idea that the acid-sensing ion channel-1a (ASIC1a) might provide a novel antidepressant drug target. ASIC1a receptors are located in brain structures associated with mood, including the amygdala, which is involved in so-called negative emotions such as anger, anxiety, and fear. The researchers found that disruption/inhibition of the receptor, either genetically or using a drug, had antidepressant-like effects in several stress models like the forced swim test. ASIC1a inhibition effects were independent of and additive to those of several commonly used antidepressants, Dr. Wemmie’s team said.

    When the scientists restored ASIC1a to the amygdalas of mice genetically lacking the ion channel, the forced swim test effects were reversed, suggesting that the amygdala functions in a key site of ASIC1a action in depression-related behavior.

    ASIC1a disruption also reduced BDNF, a protein with a key role in the growth, development, maintenance, and function of several brain neuronal systems in the hippocampus.

    This data is consistent with clinical studies emphasizing the importance of the amygdala in mood regulation and suggests that ASIC1a antagonists have the potential to act as antidepressants through a different biological pathway than currently used antidepressants, Dr. Wemmie pointed out.

    Such studies to find new targets along with efforts to build better models of human depression are steps in the right direction to develop targeted antidepressants that are more effective, in more people, and with fewer side effects.

     


Add a comment

  • You must be signed in to perform this action.
    Click here to Login or Register for free.
    You will be taken back to your selected item after Login/Registration.

Related content

Jobs

GEN Jobs powered by HireLifeScience.com connects you directly to employers in pharma, biotech, and the life sciences. View 40 to 50 fresh job postings daily or search for employment opportunities including those in R&D, clinical research, QA/QC, biomanufacturing, and regulatory affairs.
 Searching...
More »

GEN Poll

More » Poll Results »

Connectomics Advocacy

How might connectomics maintain lasting support?