Journal of Psychiatric Practice Vol. 15, No. 2 March 2009 125 This column reviews progress in our understand- ing of the neuroanatomy, pathophysiology, and genetics underlying clinical depression. Such understanding is fundamental to the ability to rationally identify the neural regulatory process- es involved and develop drugs specifically target- ed to those processes. The goal of the column is to help clinicians better conceptualize the nature of depressive illness and its treatment and educate their patients about these issues. (Journal of Psychiatric Practice 2009;15:125–132) KEY WORDS: clinical depression, neuroscience, anti- depressant drug development, brain imaging, hip- pocampus, amygdala, genetics As regular readers of this column know, three vari- ables determine the effect of any drug in any patient as expressed in Equation 1 (p. 126). The pharmacol- ogy of the drug is determined by its ability to bind to and alter the function of one or more sites of action (i.e., regulatory proteins). In doing so, the drug is capable of altering human physiology and thus pro- ducing both its good and adverse effects. As regular readers also know, one can either start with the effects of a drug and search for the mecha- nisms that mediate its effects, or one can start with a site of action and design a drug to produce specific effects. Pharmacology began with the first paradigm: observe an effect and search for the underlying mechanism. That was true for all of the first classes of psychiatric medications: antidepressants, antipsy- chotics, anxiolytics, and mood stabilizers. The reason psychiatric pharmacology began in this way was that not enough was initially known about the physiology underlying psychiatric illness to use the other para- digm. However, that has begun to change over the last decade. This column reviews the progress that has been made in understanding the neuroanatomy and neurophysiology underlying clinical depression. Such understanding is fundamental to the ability to rationally identify new neural regulatory processes for drug development, enabling researchers to use the second paradigm mentioned above. The goal of this column is not to provide an exhaustive explanation of the nuances of this area of research, but rather to provide an adequate frame- work to help clinicians conceptualize the nature of depressive illness and its treatment. With this knowledge, clinicians can in turn educate their patients to help them better understand their illness and improve their active participation in treatment, in much the same manner as clinicians provide such information to patients with diabetes, hypertension, or other general medical conditions. SHELDON H. PRESKORN, MD, is Professor, Department of Psychiatry, University of Kansas School of Medicine-Wichita, and Chief Executive Officer and Medical Director, Clinical Research Institute, Wichita, Kansas. He has more than 30 years of drug development research experience at all levels (i.e., pre- clinical through Phase IV) and has been a principal investigator on over 250 clinical trials including every antidepressant mar- keted in the United States over the last 25 years. Dr. Preskorn maintains a website at <www.preskorn.com> where readers can access previous columns and other publications. WAYNE C. DREVETS, MD, is Senior Investigator, and Chief of the Section on Neuroimaging in Mood and Anxiety Disorders at the National Institutes of Health/National Institute of Health Division of Intramural Research Programs, Bethesda, MD. This column is adapted with permission from Chapter 6 in: Preskorn SH. Outpatient management of depression, 3rd ed. Caddo, OK: Professional Communications; 2009:63–75. Disclosure statement: Dr. Preskorn, as chief executive officer of the Clinical Research Institute, Wichita, KS, and, in many cases, as principal investigator, has received grants from the following entities: AstraZeneca, Biovail, Boehringer-Ingelhaim, Bristol- Myers Squibb, Comentis, Cyberonics, Eisai, EnViVo, GlaxoSmith- Kline, Merck, Memory, Organon, Otsuka, Pfizer, Sepracor, Somerset, Wyeth, and the National Institute of Mental Health. He has served as a consultant, on the advisory board, and/or as a speaker for the following: Biovail, Bristol-Myers Squibb, Comentis, Covedien, Cyberonics, Eli Lilly, EnViVo, Evotec, Fabre- Kramer, Jazz, Memory, Organon, Pfizer, Somerset,Transcept, and Wyeth. Neuroscience Basis of Clinical Depression: Implications for Future Antidepressant Drug Development Psychopharmacology SHELDON H. PRESKORN, MD WAYNE C. DREVETS, MD Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.