The role of mGlu receptor antagonists in the enhancement of the antidepressant-like effect of ketamine.

MGlu 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 mGlu 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 mGlu 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 mGlu 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.