LAUSR

For a depressed patient, a single day without symptom improvement means yet another day of suffering. The currently available antidepressants require weeks or months to achieve appreciable symptom remission and remain ineffective in a large number of patients. Severely depressed patients are at high risk of suicide, making delayed symptom improvement a lifethreatening unresolved problem in psychiatry. Therefore, there is an urgent need to develop new strategies to treat depression more rapidly and more effectively to achieve fast and sustained symptom relief. Research in this area has led to the discovery of the fast-acting antidepressant properties of subanesthetic doses of ketamine, a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist. In addition, the muscarinic receptor antagonist scopolamine has received attention because it exerts rapid antidepressant effects that may not be directly dependent on NMDAR antagonism (1). Rapid antidepressant effects can be achievedwithin 2 hours in the case of ketamine or 3 days in the case of scopolamine. These antidepressant effects last for around 1 week and can be prolonged using repeated administration, even in otherwise treatment-resistant patients. However, fast-acting antidepressants have many side effects, including acute dissociative and psychotomimetic properties, a high potential for abuse, and respiratory and cardiovascular problems (2). Considering these safety concerns, refining our understanding of the cellular and molecular mechanisms underlying rapid antidepressant effects will be important to identify new targets for safer and more effective treatments. In this issue of Biological Psychiatry, Ghosal et al. (3) set out to determine whether common signaling mechanisms can be identified between scopolamine and ketamine that could lead to the discovery of new targets for improved and safer rapidacting antidepressants. A well-established mediator of antidepressant responses to fast-acting and typical monoaminergic antidepressants is brain-derived neurotrophic factor (BDNF). The role of BDNF in fast antidepressant action is supported by studies showing that human carriers of the BDNF Vall66Met polymorphism and BDNF Val/Met knock-in mice (4) are resistant to the rapid antidepressant effects of ketamine (5). In the current study in mice, Ghosal et al. (3) report that three injections of scopolamine over the course of 5 days reduces immobility in the forced swim test and decreases the latency to feed in the novelty suppressed feeding test—measures of depressionand anxiety-like behavior, respectively. Similar to ketamine, the antidepressant effects of scopolamine were absent in BDNF Val/Met mice, which exhibit altered BDNF trafficking and reduced activity-dependent BDNF release. These data demonstrate that the activity-dependent release