This study evaluates the efficacy and safety of ethosuximide in the treatment of refractory depressive disorder in adults. Half of participants will receive ethosuximide and escitalopram in combination, while the other half will receive a placebo and escitalopram.

Ethosuximide is a inhibitor of low-voltage-sensitive T-type calcium channels(T-VSCCs). It has higher selectivity to T-VSCCs and can enter cerebrospinal fluid through the blood-brain barrier, inhibit T-VSCCs on the lateral habenular nucleus neurons, and then inhibit the cluster discharge of neurons, resulting in a rapid antidepressant effect.

Inclusion criteria

1. Inpatient of both sexes are aged from 18 to 65 years;
2. Diagnosis of major depressive disorder(single or recurrent episodes) is made according to DSM-V(the fifth Edition of Diagnostic and Statistical Manual of Mental Disorders) criteria;
3. Subjects with previous or current depressive episodes did not response to two different antidepressants with recommended doses and adequate duration (maximum treatment dose of at least 6 weeks);
4. The subjects who will score more than or equal to 22 points on the MADRS scale at screening and baseline period;
5. The subjects who will score more than or equal to 3 points on the first clause of MADRS scale at screening and baseline period;
6. Subjects who will sign written informed consent and volunteer to participate in the clinical study.

Exclusion criteria

1. Diagnoses of other mental disorders (such as organic mental disorders, schizophrenia, bipolar and related disorders, anxiety disorders, obsessive-compulsive disorders and so on) are made according to DSM-V criteria;
2. Depressive episodes, such as depression caused by hypothyroidism, secondary to a systemic disease or an organic mental disorder caused by a neurological disease;
3. Subjects with a history of attempted suicide, or currently at high suicide risk, or with suicide behavior/attempt, or scoring more than or equal to 3 points on the 10th clause of MADRS scale;
4. Subject whose score of MADRS scale in baseline period will be 25% lower than that in screening period;
5. Subjects with a history of severe or poorly controlled cardiovascular, liver, kidney, blood, endocrine, respiratory diseases, etc;
6. Subjects with a history of epileptic seizures, except for a single febrile convulsion in children;
7. Researchers believe that the results of subjects' physical and laboratory examinations are clinically significant abnormalities in screening or baseline period. The following indicators exceed the following criteria: 1)ALT or AST levels are 1.5 times higher than the upper limit of laboratory normal values. 2)Thyroid Function are 1.1 times higher than the upper or lower limit of normal values. 3) Serum creatinine values are 1.1 times higher than the upper limit of normal values. 4)The levels of blood urea nitrogen are higher than the upper limit of normal values;
8. The result of electrocardiogram (ECG) is abnormal in screening or baseline period, such as male subjects with QTc interval (> 450 ms) and female subjects with QTc interval (> 470 ms) , and the researchers thought it is not suitable for selection;
9. Subjects could not swallow oral medicines or have a history of gastrointestinal surgery or any other diseases that may interfere with drug absorption, distribution, metabolism or excretion;
10. Monoamine oxidase inhibitors (MAOIs) are taken by subjects now or within 2 weeks before screening. Subjects who took antipsychotics, antidepressants or mood stabilizers before randomization and these drugs' cleaning phase had less than five half-lives. Subjects who took fluoxetine within 1 month before screening. Subjects who continue to take Chinese medicines with antidepressant effects specified in the instructions after signing informed consent.
11. Subjects who received modified electroconvulsive therapy (MECT) , transcranial magnetic stimulation (TMS), vagal nerve stimulation (VNS), or systematic psychotherapy within 3 months before screening;
12. Subjects with a history of allergies to two or more foods or drugs;
13. Subjects who addicted to alcohol or substances within 6 months before screening;
14. Prenatal, lactating, or reproductive women who had positive results of HCG tests before participating in the study; Male and female subjects will not take effective contraceptive measures or plan to be pregnant within 3 months after the study;
15. Subjects who participated in clinical research within 30 days before signing the informed consent form for this study;
16. According to the judgement of the researchers, other situations are not suitable for clinical research.

This study is a double-blind and double-simulation design. In the course of clinical study, all subjects, researchers and evaluators are blind to grouping information. The results of the study are audited by blind state data. The placebos are administered in capsules with no difference in appearance, color, weight or odor from the positive drugs. Both subjects and drugs are coded blindly.

In the study, the coding system for research drugs have an emergency blindness detection procedure, so as to quickly identify the drugs in emergency medical condition, without destroying the blind design of clinical research.