Efficacy of an Antiglutamatergic Agents in Treatment-Resistant Depression

迫切需要新的靶点来开发治疗难治性重度抑郁症的新疗法。谷氨酸系统是发展改善情绪障碍治疗的一个重要目标。在之前的研究中，我们发现谷氨酸调节剂利鲁唑（谷氨酸释放抑制剂，AMPA运输和谷氨酸再摄取增强剂）对治疗难治性单极和双相抑郁症有效。这些数据表明，谷氨酸能系统可能在抑郁症的病理生理和治疗中起着关键作用，而调节这种神经递质系统的药物可能代表了一类新的抗抑郁药。

Novel targets for developing new treatments for treatment-resistant major depression are urgently needed. The glutamatergic system stands as an important to target to pursue in the developing improved treatments for mood disorders. In previous work, we found that the glutamate modulating agent riluzole (inhibitor of glutamate release, and enhancer of AMPA trafficking and glutamate reuptake) was effective in treatment-resistant unipolar and bipolar depression. These data suggest that the glutamatergic system might have a key role in the pathophysiology and treatment of depression, and that agents which modulate this neurotransmitter system, may represent a novel class of antidepressants. We studied 42 subjects (18-65) with TRD and a MADRS score of 22 received a single intravenous infusion of ketamine (0.5 mg/kg). Four to six hours post-infusion, subjects were randomized to double-blind treatment with either riluzole (100-200 mg/day; n=21) or placebo (n=21) for 4 weeks. Depressive symptoms were rated daily. A significant improvement (P<0.001) in MADRS scores from baseline was found. The effect size of improvement with ketamine was initially large and remained moderate throughout the 28-day trial. Overall, 27% of ketamine responders had not relapsed by 4 weeks following a single ketamine infusion. The average time to relapse was 13.2 days. However, the difference between the riluzole and placebo treatment groups was not significant, suggesting that the combination of riluzole with ketamine treatment did not significantly alter the course of antidepressant response to ketamine alone. We have continued to enroll subjects in the search of biomarkers of treatment response. Preliminary data indicates that subjects with a) family history of alcohol use disorders have a better antidepressant response to ketamine than subjects without a family history of alcohol use disorders, and b) subjects with anxious depression have a better antidepressant response to ketamine than subjects without anxious depression. Studies are examining genetics, ketamine metabolites, and other biomarkers that might be associated with treatment response. Identifying biomarkers of response would ultimately facilitate drug discovery and development and to individualize or personalize treatment interventions.