Unlike traditional monoamine-based antidepressants that require weeks to exert effects, ketamine alleviates depression within hours, though its clinical use is limited by side effects. While ketamine was initially thought to work primarily through NMDA receptor (NMDAR) inhibition, our research reveals a more complex mechanism. We demonstrate that NMDAR inhibition alone cannot explain ketamine's sustained antidepressant effects, as other NMDAR antagonists like MK-801 lack similar efficacy. Instead, the (2R,6R)-hydroxynorketamine (HNK) metabolite appears critical, exhibiting antidepressant effects without ketamine's side effects. Paradoxically, our findings suggest an inverted U-shaped dose-response relationship where excessive NMDAR inhibition may actually impede antidepressant efficacy, while some level of NMDAR activation is necessary. The antidepressant actions of ketamine and (2R,6R)-HNK require AMPA receptor activation, leading to synaptic potentiation and upregulation of AMPA receptor subunits GluA1 and GluA2. Furthermore, NMDAR subunit GluN2A appears necessary and possibly sufficient for these effects. This research establishes NMDAR-GluN2A activation as a common downstream effector for rapid-acting antidepressants, regardless of their initial targets, offering promising directions for developing next-generation antidepressants with improved efficacy and reduced side effects.

The use of molecular imaging, particularly PET and SPECT, has significantly transformed the treatment of schizophrenia with antipsychotic drugs since the late 1980s. It has offered insights into the links between drug target engagement, clinical effects, and side effects. A therapeutic window for receptor occupancy is established for antipsychotics, yet there is a divergence of opinions regarding the importance of blood levels, with many downplaying their significance. As a result, the role of therapeutic drug monitoring (TDM) as a personalized therapy tool is often underrated. Since molecular imaging of antipsychotics has focused almost entirely on D2-like dopamine receptors and their potential to control positive symptoms, negative symptoms and cognitive deficits are hardly or not at all investigated. Alternative methods have been introduced, i.e. to investigate the correlation between approximated receptor occupancies from blood levels and cognitive measures. Within the domain of antidepressants, and specifically regarding ketamine's efficacy in depression treatment, there is limited comprehension of the association between plasma concentrations and target engagement. The measurement of AMPA receptors in the human brain has added a new level of comprehension regarding ketamine's antidepressant effects. To ensure precise prescription of psychotropic drugs, it is vital to have a nuanced understanding of how molecular and clinical effects interact. Clinician scientists are assigned with the task of integrating these indispensable pharmacological insights into practice, thereby ensuring a rational and effective approach to the treatment of mental health disorders, signaling a new era of personalized drug therapy mechanisms that promote neuronal plasticity not only under pathological conditions, but also in the healthy aging brain.

Emotions and social interactions color our lives and shape our behaviors. Using animal models and engineered manipulations, we aim to understand how social and emotional behaviors are encoded in the brain, focusing on the neural circuits underlying dominance hierarchy and depression. This lecture will highlight our recent discoveries on how downward social mobility leads to depression; how ketamine tames depression by blocking burst firing in the brain’s antireward center; and, how glia-neuron interaction plays a surprising role in this process. I will also present our recent work on the mechanism underlying the sustained antidepressant activity of ketamine and its brain region specificity. With these results, we hope to illuminate on a more unified theory on ketamine’s mode of action and inspire new treatment strategies for depression.

Emotions and social interactions color our lives and shape our behaviors. Using animal models and engineered manipulations, we aim to understand how social and emotional behaviors are encoded in the brain, focusing on the neural circuits underlying dominance hierarchy and depression. This lecture will highlight our recent discoveries on how downward social mobility leads to depression; how ketamine tames depression by blocking burst firing in the brain’s antireward center; and, how glia-neuron interaction plays a surprising role in this process. I will also present our recent work on the mechanism underlying the sustained antidepressant activity of ketamine and its brain region specificity. With these results, we hope to illuminate on a more unified theory on ketamine’s mode of action and inspire new treatment strategies for depression.

Neuronal plasticity has for a long time been considered important for the recovery from depression and for the antidepressant drug action, but how the drug action is translated to plasticity has remained unclear. Brain-derived neurotrophic factor (BDNF) and its receptor TRKB are critical regulators of neuronal plasticity and have been implicated in the antidepressant action. We have recently found that many, if not all, different antidepressants, including serotonin selective SSRIs, tricyclic as well as fast-acting ketamine, directly bind to TRKB, thereby promoting TRKB translocation to synaptic membranes, which increases BDNF signaling. We have previously shown that antidepressant treatment induces a juvenile-like state of activity in the cortex that facilitates beneficial rewiring of abnormal networks. We recently showed that activation of TRKB receptors in parvalbumin-containing interneurons orchestrates cortical activation states and is both necessary and sufficient for the antidepressantinduced cortical plasticity. Our findings open a new framework how the action of antidepressants act: rather than regulating brain monoamine concentrations, antidepressants directly bind to TRKB and allosterically promote BDNF signaling, thereby inducing a state of plasticity that allows re-wiring of abnormal networks for better functionality.