<p>Current antidepressant drugs were developed largely based on two serendipitous findings; first, that monoamine depletion with the antihypertensive agent reserpine causes depression in some patients, and second, that the antitubercular agent isoniazid, which inhibits monoamine oxidase, the enzyme responsible for degrading monoamines extracellularly, was noted to improve patients’ mood. Currently available antidepressants act by blocking presynaptic monoamine transporter proteins, inhibiting monoamine oxidase, and/or by differential actions at pre- and post-synaptic monoamine receptors. Despite relatively low remission rates and the lag time between treatment initiation and symptom resolution, new drug development has been slow. Much recent research has been devoted to identifying a common mechanism of action of antdepressant drugs that is more closely associated with the temporal sequence of symptom resolution. Moreover, identifying the basic underlying pathophysiology of major depressive disorder (MDD) may elucidate novel targets leading to development of more efficient and effective treatment. </p> <h4>ABOUT THE AUTHORS</h4> <p>Elizabeth I. Martin; and Charles B. Nemeroff, MD, PhD, are with the Laboratory of Neuropsychopharmacology, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine.</p> <p>Address correspondence to: Elizabeth I. Martin, 101 Woodruff Circle, Suite 4000 WMRB, Atlanta, GA 30322; or fax 404-727-3233.</p> <p>Dr. Martin has disclosed no relevant financial information. Dr. Nemeroff has disclosed the following relevant financial information: American Foundation for Suicide Prevention (AFSP), George West Mental Health Foundation, Mt. Cook Pharma, and Novadel Pharma: Member of Board of Directors; National Institutes of Health (NIH): Research Grant Recipient; AFSP, Astra-Zeneca, Forest Laboratories, Janssen/Ortho-McNeil, Quintiles, NARSAD (National Alliance for Research on Schizophrenia and Depression), and PharmaNeuroboost: Member of Scientific Advisory Board; and CeNeRx, Corcept, Novadel Pharma, PharmaNeuroboost, and Reevax: Equity or Shareholder.</p> <p>This research was supported by NIH MH-77083, MH-69056, MH-58922, MH-39415, MH-42088, and RR-00039.</p> <h4>EDUCATIONAL OBJECTIVES</h4> <ol><li> Describe how antidepressants, as well as other psychiatric drugs, normalize the disturbances in CRF-containing circuits and HPA axis signaling and that these changes are associated with a favorable treatment response.</li> <li>Assess how measures of disrupted CRFergic signaling and downstream changes in HPA axis functioning may be used to predict response to antidepressant treatment and risk of relapse. </li> <li>Determine how individual genetic differences in CRF-related genes may influence predisposition or resiliency to psychiatric disorders as well as likelihood to respond to a given treatment. </li> </ol>