Neuroplasticity as a target for the pharmacotherapy of psychiatric disorders: new opportunities for synergy with psychotherapy.

Psychiatry has struggled with the role of time in the treatment of psychiatric disorders. Most effective psychiatric treatments unveil efficacy gradually, over a period of weeks or months. The delay in the onset of efficacy is an important limitation, stimulating research on treatments that work more rapidly (1). Other treatment limitations also emerge within a temporal context including the development of tolerance to benzodiazepine agonist anxiolytics and hypnotics, the emergence of the amnestic effects of electroconvulsive therapy (ECT), and the delayed side effects of antipsychotic medications, particularly tardive dyskinesia. Underlying these clinical problems are the time-dependent neural adaptations that appear to be the core processes through which treatments work. A consideration of these mechanisms raises the important question, is it possible to make neuroplasticity, itself, the target for treatment innovations and, to paraphrase many old movies, to harness this power for good rather than ill? This question is highlighted in this issue of Biological Psychiatry by the article by Kushner et al. (pages 835–838) who report that D-cycloserine (DCS) augments the efficacy of exposure therapy in the treatment of obsessivecompulsive disorder (OCD). This article advances an emerging paradigm in the treatment of anxiety disorders, the use of DCS to promote N-methyl-Daspartate (NMDA) glutamate receptor-dependent neuroplasticity to enhance neural adaptations produced by psychotherapy. D-cycloserine has been shown to enhance the rapidity and/or extent of the extinction of heightened responsivity to feared stimuli (2,3), building from preclinical studies suggesting that DCS facilitates the extinction of conditioned fear by promoting NMDA glutamate receptor-dependent neuroplasticity (4,5). The article by Kushner et al. extends this approach to a new disorder, OCD. The combination of a neuroplasticity-promoting treatment with a neuroplasticity-dependent psychotherapy is an important conceptual advance with broad implications for psychiatry, particularly disorders like schizophrenia where deficits in neuroplasticity may be at the heart of their pathophysiology (6). D-cycloserine, if it works, enhances neuroplasticity broadly throughout the brain. The ability of psychotherapy to selectively engage circuits with functional significance from among all circuits with increased neuroplasticity and to activate these circuits in the most natural ways (preserving temporal properties of receptor activation that may be distorted by agonist or antagonist treatments) may underlie a special opportunity for synergy between pharmacotherapy and psychotherapy. The analogy might be drawn to making horseshoes, where one first heats the metal and then pounds it into the shape of a horseshoe. Psychotherapy in the absence of adequate capacity for neuroplasticity could be like pounding cold metal. D-cycloserine in the absence of psychotherapy might be akin to heating the metal without pounding on it. From this perspective, there is benefit to be gained by combining the right sort of neuroplasticity enhancement with the right sort of psychotherapy.