Clinical trial NCT04975100: Evaluation of Efficacy and Safety of add-on Sarcosine in Patients With Major Depressive Disorder
Official title: Evaluation of Efficacy and Safety of add-on Sarcosine in Patients With Major Depressive Disorder: A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Major Depressive Disorder
Lead sponsor: All India Institute of Medical Sciences, Bhubaneswar
Sponsor class: OTHER
First posted: 2021-07-23
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in severity of depressive symptoms from baseline.
timeFrame: 8 weeks
Secondary outcomes:
measure: Response rate
timeFrame: 8 weeks
measure: Remission rate
timeFrame: 8 weeks
measure: Severity of symptoms
timeFrame: Baseline
measure: Change in severity of symptoms
timeFrame: 8 weeks
measure: Change in serum Brain Derived Neurotrophic Factor (BDNF) from baseline
timeFrame: 8 weeks
measure: Change in serum Glycine from baseline
timeFrame: 8 weeks
measure: Incidence of adverse drug reactions
timeFrame: 8 weeks
Other outcomes:
Locations:
city: Bhubaneswar
country: India
facility: AIIMS
state: Odisha
Study officials:
affiliation: AIIMS, Bhubaneswar
name: Rituparna Maiti, MD
role: STUDY_CHAIR
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