LAUSR

Major depressive disorder affects millions of people and leads to debilitating symptoms. Although conventional antidepressants have been available and are often beneficial, they have several limitations, including a slow onset of action and an inadequate response for a substantial fraction of patients. Recently, ketamine—primarily a noncompetitive NMDA receptor antagonist, among other actions—was approved as a novel treatment for treatment-resistant depression and suicidal ideation. This was an exciting development because ketamine can relieve depressive symptoms rapidly and with sustained effect. What is the biological basis for ketamine’s rapid antidepressant action? One framework gaining empirical support is that ketamine promotes neural plasticity. Specifically, ketamine appears to promote synaptogenesis in brain regions such as the medial frontal cortex and hippocampus, countering the dendritic atrophy and synapse loss associated with chronic stress and depression. This framework is supported by several studies showing that a single dose of ketamine increases the number of dendritic spines (1) by elevating their formation rate in the frontal cortex (2,3). Still unclear, though, is when and how the plasticity is boosted. Specifically, when does ketamine enhance the propensity for neural plasticity—so far, studies have looked only at synaptic connections, which is the final link in the chain of events. Moreover, how does ketamine enable neural plasticity? The full complement of molecular and cellular factors remains to be elucidated. Knowledge of both the timing and mechanisms underlying ketamine’s plasticity-promoting potential will be key to harnessing fast-acting antidepressants. In the current issue of Biological Psychiatry, Wu et al. (4) present compelling data to define a time window for ketamine’s plasticity potential and uncover dopamine as a crucial component of the mechanism. Previous studies have provided clues into the time scale of ketamine’s effect on neural plasticity. In one longitudinal twophoton imaging study, a single dose of ketamine increased dendritic spine density in the medial frontal cortex within a day (2). Another recent study indicated that ketamine begins to reverse stress-induced dendritic spine loss within 12 hours of drug administration but not before 6 hours (3). Intriguingly, blocking the plasticity actions of ketamine abolished its effect on motivated escape behavior in a mouse model, suggesting that sustained antidepressant actions require neural plasticity in the medial frontal cortex (3). Together, these previous studies underscored the importance of dendritic structural remodeling for ketamine’s fast-acting antidepressant response. Still, a critical question remained: What is the time window in which ketamine engages neural plasticity to facilitate the behavioral improvements?