Evaluation of Efficacy and Safety of add-on Sarcosine in Patients With Major Depressive Disorder
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 4

Summary: 
      One-third of the patients with major depressive disorder do not respond to conventional
      antidepressants that act through the mono-aminergic system. The available treatment
      modalities, including SSRIs, are slow to act and have a lag time before showing improvement
      in symptoms of patients. To overcome these treatment hurdles, add-on therapy to standard
      antidepressant drugs may lead to better therapeutic outcomes. Sarcosine, which is a
      nutraceutical, modulates glutamate neurotransmission has an ameliorative effect on the
      disease symptoms of depression and negative symptoms of schizophrenia. The only clinical
      study done on depressive patients by Huang et al. cannot be generalized due to certain
      inherent limitations. To date, there is no randomized controlled trial with add-on sarcosine
      to current antidepressant therapy to the best of our knowledge. So, we considered sarcosine
      can be the candidate drug for add-on therapy due to its multiple mechanisms on the
      glutaminergic system. Adding sarcosine to ongoing antidepressant therapy may either increase
      their response rate or decrease adverse drug reactions by decreasing the dose requirement or
      may show a quicker therapeutic effect. Hence, the present randomized controlled trial has
      been planned to evaluate the efficacy and safety of sarcosine as add-on therapy in major
      depressive disorder.
    

Detailed description: 
      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.
    

Intervention name(s): Sarcosine and SSRI; Placebo and SSRI
Intervention type(s): Drug; Drug
Intervention description(s): Patients in the test group will get Sarcosine 500 mg capsules once daily as an add-on to ongoing SSRI treatment; Patients in the control group will get identical-looking capsules containing placebo in addition to SSRI at an once daily dose
Intervention MeSH terms: Selective Serotonin Reuptake Inhibitors
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment