Novel Antidepressant Candidates for Adolescents

It is no secret that one of most pressing issues for today’s adolescents is mental illness. Unfortunately, most antidepressants come with a warning label that states, “May cause increased thoughts of suicide in children, teens and young adults.” Balancing the risk associated with the use of antidepressants and the real need for medical intervention in severely depressed youths is not an easy task. An article in the Dayton Daily News highlights the tragedy that results from the elevated risk of prescribing antidepressants to adolescents.

Sean Polete shares the story of his son, Jacob Polete, who tragically committed suicide at the age of just 16 years old. His son was prescribed an antidepressant that came with the “black box” warning, but Sean states that he was not informed on the potential risks associated with the medication and teens. He is advocating for parents to look into their children’s prescriptions in an effort to hopefully prevent this from happening to anyone else, or at least to make sure that they are aware of the risks.

Most antidepressants work via similar mechanisms. Whether that be selectively inhibiting the reuptake of serotonin as in SSRIs or inhibiting the reuptake of serotonin and norepinephrine as in SNRIs, most antidepressants work by altering the levels of neurotransmitters or the amount of time they are in the synaptic cleft. Unfortunately, most of these antidepressants carry the “black box” label that has raised so much controversy; however, there is work being done to try to find new antidepressants that work via different means.

In the article “Rho-kinase inhibition has antidepressant-like efficacy and expedites dendritic spine pruning in adolescent mice,” Dr. Lauren Shapiro conducted research in adolescent mice on one such potential antidepressant. The compound she worked with was fasudil, a Rho-kinase (ROCK) inhibitor. When compared to a common antidepressant called fluoxetine (Prozac) as well as a novel antidepressant, subanesthetic ketamine, fasudil showed promise. In a forced swim test (FST), a commonly used screen to predict antidepressant efficacy, reduced time spent immobile is considered an antidepressant-like effect. In an FST fasudil decreased the time spent immobile in female adolescent mice, and fasudil performed just as well as fluoxetine and ketamine.

Like ketamine, fasudil has a novel mechanism of action when compared to conventional antidepressants, but unlike ketamine fasudil functions as a ROCK inhibitor. ROCK, specifically the second isoform ROCK2, is a neuronally-expressed cytoskeleton regulatory factor that can prevent changes in the morphology of the dendritic spine. Fasudil inhibits ROCK2 resulting in the expedition of dendritic spine pruning of neurons in the ventromedial prefrontal cortex (vmPFC). Dendritic synaptic pruning is a normal part of maturation in adolescents, and the inhibition of ROCK through the introduction of fasudil expedites that process. While this could still be an area of concern for adolescent humans, PFC-dependent learning and memory was not affected by the administration of fasudil in adolescent mice.

While much still needs to be investigated when it comes to antidepressant candidates like fasudil, it is exciting to see that new drugs with novel mechanisms of action are being explored in an area of pharmaceuticals that is dominated by just a few kinds of drugs. It may take some time before new drugs that are safer for adolescents come to the market, but research like Dr. Shapiro’s offers some hope of a future solution to such a complex problem. In the meantime, it is important to be informed about the potential risks of conventional antidepressant use in adolescents, and to appropriately weigh those risks with help from a qualified family doctor or psychiatrist. Hopefully in the future, stories like Sean and Jacob Polete will be a thing of the past.

Works Cited

     Shapiro, L. P., Kietzman, H. W., Guo, J., Rainnie, D. G., & Gourley, S. L. (2019). Rho-kinase inhibition has antidepressant-like efficacy and expedites dendritic spine pruning in adolescent mice. Neurobiology of Disease, 124, 520–530. https://doi.org/10.1016/j.nbd.2018.12.015

     Wedell, K. (2019, November 29). Teens and antidepressants: What parents need to know about suicide warnings. Retrieved from https://www.daytondailynews.com/news/local/teens-and-antidepressants-what-parents-need-know-about-suicide-warnings/R0m9XBOp5rXsRG1wUBWUcP/.