Betaine enhances antidepressant-like, but blocks psychotomimetic effects of ketamine in mice

Ketamine is emerging as a new hope against depression, but ketamine-associated psychotomimetic effects limit its clinical use. An adjunct therapy along with ketamine to alleviate its adverse effects and even potentiate the antidepressant effects might be an alternative strategy. Betaine, a methyl derivative of glycine and a dietary supplement, has been shown to have antidepressant-like effects and to act like a partial agonist at the glycine site of N-methyl-D-aspartate receptors (NMDARs). Accordingly, betaine might have potential to be an adjunct to ketamine treatment for depression. The antidepressant-like effects of ketamine and betaine were evaluated by forced swimming test and novelty suppressed feeding test in mice. Both betaine and ketamine produced antidepressant-like effects. Furthermore, we determined the effects of betaine on ketamine-induced antidepressant-like and psychotomimetic behaviors, motor incoordination, hyperlocomotor activity, and anesthesia. The antidepressant-like responses to betaine combined with ketamine were stronger than their individual effects. In contrast, ketamine-induced impairments in prepulse inhibition, novel object recognition test, social interaction, and rotarod test were remarkably attenuated, whereas ketamine-induced hyperlocomotion and loss of righting reflex were not affected by betaine. These findings revealed that betaine could enhance the antidepressant-like effects, yet block the psychotomimetic effects of ketamine, suggesting that betaine can be considered as an add-on therapy to ketamine for treatment-resistant depression and suitable for the treatment of depressive symptoms in patients with schizophrenia.