• Models of Depression

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

    There is a need for new antidepressants. Unfortunately, most of the drugs under development are variations of SSRIs. These drugs inhibit serotonin reuptake and the reuptake of other monoamine neurotransmitters, mostly norepinephrine and/or dopamine. All work presynaptically by blocking reuptake transport proteins.

    Alternatively, it may be possible to develop drugs that work postsynaptically. Neurons signal through second messenger cyclic nucleotides. How long second messenger signals last is under the control of a super family of enzymes, phosphodiesterases (PDE), that break down these messengers by hydrolysis.

    Of the 11 families of PDEs, several are highly expressed in the brain. Two of these are the PDE4 and PDE1 families. PDE4 inhibitors have been tested as antidepressants and found to be effective but have unacceptable side effects. We are investigating the role of PDE1, and specifically PDE1b, in depression. Our data show that PDE1b deficient mice are resistant to the induction of depression-like behavior. This suggests that PDE1b may be a target for drug development as a new type of antidepressant or as an enhancer of current antidepressants.