Table 1 Inclusion criteria, exclusion criteria, and withdrawal criteria

1. Adult (18~65 years old), outpatients or inpatients, male or female.

2. Patients with a primary diagnosis of major depressive disorder (MDD) based on the criteria of DSM-5, single episode or recurrent episode.

3. The total score of MADRS is ≥ 26 in both screening visit and baseline visit.

4. The first item of MADRS is ≥ 3 in both screening visit and baseline visit.

5. CGI-S is ≥ 4 in both screening visit and baseline visit.

6. The subject understands and consents to takes part in this clinical trial. The subjects should sign an informed consent form.

1. The subject has a current psychiatric diagnosis other than depression according to DSM-5, including schizophrenia spectrum disorders, bipolar and related disorders, anxiety disorders, obsessive-compulsive and related disorders, physical symptoms and related disorders, and other mental disorders.

2. The subject has a suicide attempt within the recent 1 year, has a currently significant risk of suicide, or has a score > 3 on item 10 (suicidal ideation) of MADRS.

3. The subject has a current depressive episode due to somatic general disease or a neurological disease, such as hypothyroidism.

4. When the MADRS total score of baseline visit compares with the screening visit, the decreasing rate is ≥ 25%.

5. Any unstable cardiovascular, hepatic, renal, blood, endocrine, or other medical diseases.

6. Any neurological disease (such as Parkinson’s disease, cerebrovascular accident, and epilepsy) or cerebral injury (traumatic or disease-related). Had a history or a high-risk related disease or medication of seizure disorder, except infantile febrile convulsion.

7. Known hypersensitivity to Piper laetispicum C. DC. or at least to two kinds of drugs.

8. Within 6 months before screening, there were addictions of alcohol and other substances (except nicotine).

9. The subject could not take medication or has a disease affecting drug absorption, distribution, metabolism, and excretion.

10. Clinically significant abnormal laboratory values (e.g., ALT or AST value above 2 times of clinical top limit; Cr value above normal top limit; thyroid gland function index (≥ 2 items in 5 items) above 1.2 times or below 0.8 times of the normal range, or investigator diagnosed with hypothyroidism or hyperthyroidism).

11. Clinically significant electrocardiographic (ECG) abnormalities in screening visit, such as QTc ≥ 450 ms in males or ≥ 470 ms in females.

12. The subject who used at least two different antidepressants with the recommended dose and adequate duration (maximum dosage by at least 4 weeks according to label) treatment still had no response.

13. The subject uses antidepressant drugs normally before 2 weeks of screening and stops using psychotropic drugs before randomization less than 5 half-life period (monoamine oxidase inhibitor: at least 2 weeks; fluoxetine: at least 1 month).

14. The subject received modified ECT, trans-cranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), or systematic psychotherapy within 3 months. The subject received systematic light therapy, laser therapy and acupuncture, other traditional Chinese medicine, or systemic biofeedback therapy within 2 weeks.

15. Women who were pregnant, breastfeeding, or serum-HCG (+) on screening, or planning to become pregnant within 3 months after kick-off of the clinical trial.

16. Education level is below junior high school.

17. The subject has participated in a drug clinical trial within 1 month before screening.

18. The investigator thinks the subject is unsuitable to enroll in this clinical trial.

1. Occurrence of intolerable adverse events or serious adverse events.

2. Obvious protocol violation will impact the efficacy and safety assessment.

3. The subjects had symptoms of self-injury, suicide, manic episode, and with psychopathical feature.

4. The efficacy is not good.

5. The investigator determines to withdraw.

6. The subject will not continue the clinical trial or withdraw his/her informed consent.

7. Loss of follow-up.

8. Other circumstances in which the subject withdraw from the trial (such as changes in residence, which made it impossible to continue medication and follow-up).