How Drug Metabolism Plays a Role in Drug Therapy Development for Major Depressive Disorder

The development of any new drug requires the knowledge of major drug metabolism pathways such that medicinal chemists can design a drug that targets the desired pathology. Major depressive disorder (MDD) affects so many people worldwide and treatment methods vary. MDD stems from a depletion of the concentration of monoamine neurotransmitters in the synaptic cleft. A common treatment method is prescription antidepressants. Three major classes of antidepressants are monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), and selective serotonin reuptake inhibitors (SSRIs). Each class targets a different portion of the neurotransmitter-release pathway in order to increase concentrations of neurotransmitters and relieve depressive symptoms. However the side effects that accompany each class led to the preference for SSRIs over TCAs and MAOIs. The most commonly prescribed antidepressant is Prozac (fluoxetine). It is a selective serotonin reuptake inhibitor that blocks serotonin reuptake transporters on the presynaptic axon terminal to increase serotonin concentration in the synaptic cleft. Prozac is metabolized, through N-demethylation, by several cytochrome P450 enzymes, including CYP2D6, to produce norfluoxetine, its active metabolite. CYP2D6 has four major residues involved in recognition, binding, and positioning of fluoxetine (Asp301, Glu216, Phe483, and Phe120). There still remains controversy over how exactly these residues contribute to the metabolism of fluoxetine. Overall, while SSRIs are the current go-to class of antidepressants, researchers are continually using our evolving knowledge of drug metabolism and major depressive disorder to develop new antidepressants in hopes to reduce the number and intensity of side effects