51 Ketamine

also increases the function of these new synapses shown by an increase in the amplitude and frequency of 5-hydroxytyramine (5-HT)- and hypocretin-induced excitatory postsynaptic currents in layer V pyramidal neurons in the medial PFC. Ketamine increases levels of synaptic proteins after 2 hours, indicating an increase in synapse number, a time that corresponds to the initial therapeutic response in humans.51 Ketamine also produces antidepressant behavioral responses in the forced swim test (decreased immobility or despair) and novelty suppressed feeding (decreased Inhibitors,research,lifescience,medical latency to feed in an open field). Moreover, a single dose of ketamine clinical trial reverses the deficit in the number of synapses caused by exposure to 3 weeks of chronic unpredictable stress (CUS).52 This corresponds with the rapid reversal of the Inhibitors,research,lifescience,medical CUS-precipitated behavioral deficit, anhedonia, which is measured by a decrease in preference for sweetened solution. Together, these findings Inhibitors,research,lifescience,medical demonstrate a novel rapid action of ketamine, the induction of synaptic connections that reverses the effects of CUS and corresponds to an antidepressant behavioral response that requires chronic administration of a typical antidepressant. Assuming that a similar synaptogenic response occurs in humans, a question of intense interest, ketamine would then reverse the atrophy

and synaptic deficits that are a critical pathophysiological component Inhibitors,research,lifescience,medical of depression. Indirect support for this hypothesis is provided by a recent clinical study, using magnetoencephalographic recordings, before and after ketamine infusions, in depressed patients and during somatosensory cortex activation (ie, tactile Inhibitors,research,lifescience,medical stimulation of index fingers).53 The results show that cortical excitability is increased in responders during the period of antidepressant response (≈4 hours after ketamine), but not in those patients who did not respond to ketamine. There was no effect Bay 11-7085 of ketamine on baseline γ-band activity, suggesting that the acute NMDA receptor-blocking effects of ketamine do not account for the antidepressant responses. Rather, the results are consistent with the possibility that increased glutamate activity and enhanced synaptic potentiation underlie the increase in cortical excitability, as well as the antidepressant response to ketamine.53 It is possible that NMDA receptor blockade of glutamate transmission contributes to the therapeutic actions of ketamine, although this would be rapid and transient (ie, when the drug is present in the brain and during the time frame for the psychotomimetic effects, 30 to 60 minutes after dosing) and therefore would not correspond to the delayed time of the therapeutic response (80 to 120 minutes).