Lin Jen-Cheng, Lee Mei-Yi, Chan Ming-Huan, Chen Yi-Chyan, Chen Hwei-Hsien
Graduate Institute of Medical Sciences, National Defense Medical Center, 161, Section 6, Minquan East. Road., Neihu District, Taipei, 11453, Taiwan.
Department of Pharmacology and Toxicology, Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien, 97004, Taiwan.
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.
氯胺酮正成为对抗抑郁症的新希望，但氯胺酮相关的拟精神病效应限制了其临床应用。一种与氯胺酮联合使用以减轻其不良反应甚至增强抗抑郁作用的辅助疗法可能是一种替代策略。甜菜碱是甘氨酸的甲基衍生物，也是一种膳食补充剂，已被证明具有类抗抑郁作用，并且在N-甲基-D-天冬氨酸受体（NMDARs）的甘氨酸位点起部分激动剂的作用。因此，甜菜碱有可能成为氯胺酮治疗抑郁症的辅助药物。通过强迫游泳试验和新奇抑制摄食试验评估了氯胺酮和甜菜碱的类抗抑郁作用。甜菜碱和氯胺酮均产生了类抗抑郁作用。此外，我们还确定了甜菜碱对氯胺酮诱导的类抗抑郁和拟精神病行为、运动不协调、运动亢进以及麻醉的影响。甜菜碱与氯胺酮联合使用时的类抗抑郁反应比它们单独使用时更强。相比之下，氯胺酮在预脉冲抑制、新物体识别试验、社交互动和转棒试验中引起的损伤明显减轻，而氯胺酮诱导的运动亢进和翻正反射丧失不受甜菜碱影响。这些发现表明，甜菜碱可以增强氯胺酮的类抗抑郁作用，同时阻断其拟精神病作用，这表明甜菜碱可被视为难治性抑郁症氯胺酮治疗的附加疗法，适用于精神分裂症患者抑郁症状的治疗。
