(R,S)-ketamine (ketamine) induces rapid and sustained antidepressant-relevant neuroplastogenic effects in vivo. The metabolite (2R,6R)-hydroxynorketamine (2R6R) forms shortly after the administration of ketamine, and independently elicits rapid plasticity and sustained metaplasticity. Ketamine's therapeutic actions appear to result from distinct, time-sensitive plasticity phases, though the...
Recent antidepressant drug development focuses on a next generation of drugs to rapidly relieve symptoms. Yet, how ketamine, the prototype rapid-acting antidepressant, maintains symptom relief days after drug elimination, and how repeated doses sustain longer-lasting therapeutic effects, remains unclear. Derived from elements of metaplasticity (synaptic priming), this review discusses a...
The pharmacologically active (R,S)-ketamine (ketamine) metabolite (2 R,6 R)-hydroxynorketamine (HNK) maintains ketamine's preclinical antidepressant profile without adverse effects. While hypotheses have been proposed to explain how ketamine and its metabolites initiate their antidepressant-relevant effects, it remains unclear how sustained therapeutic actions arise following drug elimination....
The discovery that subanesthetic doses of (R, S)-ketamine (ketamine) and (S)-ketamine (esketamine) rapidly induce antidepressant effects and promote sustained actions following drug clearance in depressed patients who are treatment-resistant to other therapies has resulted in a paradigm shift in the conceptualization of how rapidly and effectively depression can be treated. Consequently, the...
Ketamine is a well-characterized NMDA receptor (NMDAR) antagonist, although the relevance of this pharmacology to its rapid (within hours of administration) antidepressant actions, which depend on mechanisms convergent with strengthening of excitatory synapses, is unclear. Activation of synaptic NMDARs is necessary for the induction of canonical long-term potentiation (LTP) leading to a...