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

Psychopharmacology (Berl). 2016 Sep;233(17):3223-35. doi: 10.1007/s00213-016-4359-x. Epub 2016 Jun 30.


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.

Keywords: Behavior; Depression; NMDA receptor; Prepulse inhibition; Schizophrenia.

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Behavior, Animal / drug effects*
  • Betaine / pharmacology*
  • Depression*
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Hallucinogens / pharmacology*
  • Ketamine / pharmacology*
  • Male
  • Mice
  • Prepulse Inhibition / drug effects*
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Swimming


  • Antidepressive Agents
  • Excitatory Amino Acid Antagonists
  • Hallucinogens
  • Receptors, N-Methyl-D-Aspartate
  • Betaine
  • Ketamine