The role of mGlu2/3 receptor antagonists in the enhancement of the antidepressant-like effect of ketamine.

Combining a low, subeffective dose of ketamine or its enantiomer (R)-ketamine with an mGlu2/3 receptor antagonist produces antidepressant-like effects in animal models of depression without the undesirable side effects seen with higher doses of ketamine or (S)-ketamine, such as psychostimulatory effects. The antidepressant effect of ketamine appears linked to mGlu2 receptor activity and may be reduced by mGlu2 agonists. This strategy aims to enhance ketamine's therapeutic effect while lowering its dose to reduce side effects, which are particularly concerning in patients with treatment-resistant depression. Further research is needed to confirm effectiveness in humans.

Study at a glance

Abstract

MGlu2/3 receptor antagonists produce antidepressant-like effects in animal models of depression. A number of mechanisms responsible for these actions are convergent to the mechanism of the fast antidepressant-like effect of ketamine. Furthermore, the data indicate that ketamine effect is related to the action of mGlu2 receptors and may be reduced by their agonists. The above facts became the basis for the hypothesis that the antidepressant effect of low doses of ketamine might be enhanced by coadministration of a mGlu2 receptor antagonist. This strategy was aimed not only at enhancing the therapeutic effect of ketamine but also at reducing the risk of undesirable effects by lowering its therapeutic dose. It is known that ketamine, effective in relieving depressive symptoms in patients suffering from treatment-resistant depression (TRD), is burdened with a number of side effects, which may be particularly dangerous in psychiatric patients. Data have confirmed that subeffective doses of ketamine and its enantiomer, (R)-ketamine, coadministered with an mGlu2/3 receptor antagonist, induce antidepressant-like effects in the screening tests and in the chronic-stress-induced model of depression. At the same time, these drug combinations did not cause undesirable effects characteristic of higher doses of ketamine and (S)-ketamine, including those related to psychostimulatory effects. Further research is required to prove whether this strategy will also be effective in depressive patients.