Major depressive disorder or unipolar depression is a commonly encountered psychiatric disorder, with reported lifetime and one-year prevalence rates of 16.6% and 6.6%, respectively, and is associated with an increased risk of suicide. It is estimated that more than 264 million of the global population have suffered from depression. Major depressive disorder causes significant disabilities, thus adversely affects the quality of life of patients and their caregivers. Despite the clinical significance of depression, its underlying pathophysiology is still not understood comprehensibly, and different potential targets have been explored. One of the most well-researched theories of previous decades has been the monoamine hypothesis; however, it appears that simple monoamine depletion is insufficient to account for the development of the disorder. Drugs acting through enhancing the monoaminergic pathway, i.e., increasing the synaptic concentration of serotonin, noradrenaline, or dopamine, are the most commonly prescribed antidepressant medication in the last five decades. Among them, second-generation antidepressant drugs like selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most effective and most widely used nowadays.

N-Methyl D-Aspartate receptor (NMDAR) modulation is one of the leading novel mechanisms in the pathophysiology of depression that has been postulated for the treatment of depression. The NMDA hypothesis originated from an unexpected observation that D-cycloserine, a partial agonist of the NMDAR, has antidepressant activity. Also, NMDA-enhancing treatment results in a significant reduction in depressive symptoms in patients with schizophrenia. It has also been observed that major depression is associated with decreased expression and release of brain-derived neurotrophic factors (BDNF).

Sarcosine (N-Methyl Glycine), an endogenous amino acid with NMDA receptor function enhancing property, is usually used as a dietary supplement or nutraceutical. Sarcosine increases the availability of glycine for the glycine binding site of the NMDA receptor by inhibiting its reuptake from the synaptic cleft. It also possesses glycine binding site co-agonistic activity. In various animal studies, it has been found that long-term sarcosine treatment significantly ameliorated the induced depression, confirming the potential role of sarcosine as an antidepressant agent. Huang et al. and Chen et al. have demonstrated antidepressant effects of sarcosine in animal behavior models of depression. The only clinical trial of sarcosine done on depressive patients by Huang et al. has shown better and quicker response with superior tolerability as compared to citalopram.

Therapeutic latency, lack of efficacy in a significant proportion of patients, and adverse drug reactions are the primary concerns in current antidepressant therapies. To overcome these treatment challenges, add-on therapy to standard antidepressant drugs may lead to better therapeutic outcomes. Our literature search found that to date, there is no randomized controlled trial on sarcosine as an add-on therapy to first-line antidepressants like SSRIs. The result of the previous study by Huang et al. cannot be generalized because of the inherent limitations in study design. So, the present randomized controlled trial has been planned to evaluate the efficacy and safety of add-on sarcosine to SSRIs in major depressive disorder.