Evaluation of Efficacy and Safety of add-on Sarcosine in Patients With Major Depressive Disorder

Study Overview
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Brief Summary
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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
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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.

Official Title
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Evaluation of Efficacy and Safety of add-on Sarcosine in Patients With Major Depressive Disorder: A Randomized Controlled Trial

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Sarcosine and SSRI
* Drug: Placebo and SSRI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 18-65 years, of either gender with the clinical diagnosis of major depressive disorder (DSM 5). Patients with MADRS score ≥ 7 and ≤ 34 (Mild to moderate severity). Patients who are on a stable dose of Sertraline 50 mg or any other SSRI (selective serotonin reuptake inhibitor) therapy in equivalent dose. Patients who have given informed written consent. Exclusion Criteria: Major depressive patient treated with Electro Convulsive Therapy recently. History of epilepsy, head trauma, or other major neurological or medical disorders. Patients with a history of bipolar depression. Patients with schizophrenia or other psychotic disorder. Patients with suicidal risk. Patients with cognitive impairment. Initiating or stopping formal psychotherapy within six weeks before enrolment. Patients with comorbidities like any malignancies, hepatic, renal, cardiovascular, neurological or endocrinal, respiratory dysfunction. Substance abuse history of psychoactive agents. Pregnant and lactating mothers.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Test<br>Patients in the test group will get Sarcosine 500 mg capsules once daily as an add-on to ongoing SSRI treatment. | Drug: Sarcosine and SSRI<br>* Patients in the test group will get Sarcosine 500 mg capsules once daily as an add-on to ongoing SSRI treatment<br>|
| Active Comparator: Control<br>Patients in the control group will get identical-looking capsules containing placebo in addition to SSRI at an once daily dose | Drug: Placebo and SSRI<br>* Patients in the control group will get identical-looking capsules containing placebo in addition to SSRI at an once daily dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in severity of depressive symptoms from baseline. | The change in symptoms of depression will be evaluated using Montgomery Asberg Depression Rating Scale score. Each item of the questionnaire yields a score of 0 to 6. The overall score ranges from 0 to 60. A higher score indicates more severe depression. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Response rate is defined by percentage of patients showing 50% decrease in MADRS scores from baseline. | 8 weeks | 
| Remission rate | Remission rate is defined by percentage of patients achieving MADRS scores <7 at 8-week follow-up. | 8 weeks | 
| Severity of symptoms | Severity of symptoms at baseline will be assessed by Clinical Global Impression severity scale. The Clinical Global Impression Severity scale is a 7-point scale that requires the clinician to rate the severity of the patient's illness. A higher score reflects more severe illness. | Baseline | 
| Change in severity of symptoms | Change in severity of symptoms will be assessed by Clinical Global Impression Improvement scale. The Clinical Global Impression Improvement scale is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. A lower value reflects better improvement of symptoms. | 8 weeks | 
| Change in serum Brain Derived Neurotrophic Factor (BDNF) from baseline | Serum BDNF levels will be measured using a commercially available human enzyme-linked immunosorbent assay (ELISA) kit. | 8 weeks | 
| Change in serum Glycine from baseline | Serum Glycine levels will be measured using a commercially available human enzyme-linked immunosorbent assay (ELISA) kit. | 8 weeks | 
| Incidence of adverse drug reactions | During the follow-up visit, occurrence of adverse events will be assessed by the nondirective questioning to the patient. | 8 weeks |