Ketamine is a GSK3b inhibitor

After reading the news about a study on ketamine reducing OCD symptoms, I conducted a brief research into the effects of ketamine on intracellular signalling. It turns out that ketamine inhibits GSK3b, and this could be the main reason behind the potent antidepressant effects of low doses of ketamine and its ability to reduce OCD symptoms.

These results demonstrate that ketamine rapidly inhibits GSK3 in mouse brain and that inhibition of GSK3 is necessary, and may be sufficient, for a rapid antidepressant effect in the learned helplessness model of depression-like behavior in mice. These findings add to the substantial evidence already linking active GSK3 to increased susceptibility to mood disorders and inhibition of GSK3 to therapeutic outcomes (R1)

These results demonstrate that ketamine-induced inhibition of GSK3 causes reduced phosphorylation of PSD-95, diminishing the internalization of AMPA GluA1 subunits to allow for augmented signaling through AMPA receptors following ketamine treatment. (R2)

However Ketamine can also increase activation of GSK3b (probably the dual effect depends on the dose):

Ketamine-induced neuroapoptosis is associated with a temporal decrease in GSK-3β phosphorylation, and simultaneous administration of lithium mitigated this response. These findings suggest that GSK-3β is activated during this ketamine-induced neuroapoptosis. (R3)

The results demonstrate that low, subthreshold doses of ketamine combined with lithium or a selective GSK-3 inhibitor are equivalent to higher doses of ketamine, indicating the pivotal role of the GSK-3 pathway in modulating the synaptogenic and antidepressant responses to ketamine. (R4)