Clarifying the Mechanisms of Antidepressants

1 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Commentary on Domschke, et al., Magnetoencephalographic correlates of emotionalprocessing in major depression before and after pharmacological treatment. Understanding the therapeutic effects of psychotropic medication has typically been approached, reasonably enough, with an analysis of the effects on brain chemistry. For example, the effective antidepressant mirtazapine is thought to affect both norepinephrine and serotonin neuromodulators, both of which are important to mood disorders such as major depression. However, understanding the full neuropsychopharmacol-ogy of a therapeutic agent requires an analysis of the multiple levels of neural self-regulation that are involved in the disorder and that are affected by the drug. It has long been apparent that if the mechanism of drug action were simply a correction of a biochemical imbalance, then the therapeutic effect would be rapid, limited only by the pharmacokinetics (Cooper et al., 2002). Instead, antidepressants typically require weeks of continued administration before they achieve a therapeutic effect. Although the complexity of drug action is familiar to most psychopathology researchers, clinicians are typically provided with only a superficial training on the neurophysiological and neuropsychological mechanisms for both psychopathology itself and the therapeutic effects of drugs. The result of this limited training is that a patient with depression, for example, is often told by the physician they have a " biochemical imbalance " that will be corrected by drug therapy. Not only is this explanation scientifically incorrect, it fails to recognize that the chronic changes in clinical depression involve a predictable set of neural mechanisms, including not only impairment of hedonic arousal and reward sensitivity that follow from brainstem neuromodulator changes (Depue and Morrone-Strupinsky, 2005), but blunted right hemisphere processing of affective material and changes in fronto limbic mechanisms of self-regulation (Mayberg, 2007). The chronic alterations of fronto limbic activity are particularly important, because they appear to reflect a disordered pattern of affective self-regulation that may be responsible for both the anhedo-nia and neuromodulator changes (Tucker and Luu, 2007). The fact that improved psychological self-regulation, such as with cognitive therapy, can be as effective as drug therapy (Curry et al., 2006) provides important evidence that depression must be understood to involve multiple levels of neuropsychological function. In a similar way, the therapeutic neuropsychophar-macological effects should …