Vorhees-Williams-Skelton Lab

  • Models of Depression

    Depression is one of the most common psychiatric illnesses in both children and adults; 12 percent or more of the population takes antidepressants at any given time. Although there are many antidepressant drugs available, most work the same way: they are selective serotonin reuptake inhibitors (SSRIs). In placebo-controlled studies, SSRIs are only consistently effective in severe depression; in milder cases they are only partially or not effective at all.

    There is a need for new antidepressants. Unfortunately, most of the drugs under development are variations of SSRIs. Most of these newer drugs also inhibit serotonin reuptake but in addition inhibit the reuptake of norepinephrine and / or dopamine. These are incremental improvements and all work presynaptically.

    Alternatively, it may be possible to have drugs that work postsynaptically through regulation of second messengers. In cells that signal through second messengers such as cyclic nucleotides, signal timing is under the control of a super family of phosphodiesterases (PDE). These enzymes degrade second messengers after they have interacted with their targets.

    Of the 11 families of PDEs, several are highly expressed in the brain. Two of these are the PDE4 and PDE1 families. PDE4 drugs have been tested as possible antidepressants and found to be effective but have side effects that render them unusable. The lab is currently collaborating with a pharmaceutical company on a drug that activates one of the PDE1 genes (PDE1b). Preliminary data show that PDE1b deficient mice do not respond to the drug when tested for induced-depression, suggesting that this enzyme is a key player in this reaction.