This project aims to investigate the effectiveness of existing common antidepressants and to provide new evidence for depressed children and adolescents who are not responding to their first treatment.

This is an open-label Sequential Multiple Assignment Randomized Trial (SMART) of 16 weeks duration with two levels, each stage 8 weeks. In phase 1, adolescents with MDD will be selected into fluoxetine or fluoxetine combination CBT therapy groups and the choice of treatment will be at the discretion of the patient. Subjects who fail to respond will enter phase 2 randomization， where patients will be randomly assigned to oral sertraline, votioxetine, duloxetine or adding one of aripiprazole, lithium carbonate, and olanzapine to fluoxetine. The primary outcome of the treatment phase is the treatment remission rate and response rate. Secondary outcomes included: symptom scale; Quality of life; Sleep therapy; Symptoms of anxiety; Rumination and safety assessment.

Inclusion Criteria:

1. Age 13 - 18
2. As assessed by K-SADS-PL, it meets the DSM-V criteria for MDD with non-psychotic symptoms
3. Score≥40 on the CDRS-R
4. Participants with suicidal ideation are eligible, as long as clinicians consider outpatient treatment to be safe
5. Sufficient audio-visual level to complete this study
6. Written informed consent was obtained from patients and at least one of their parents

Exclusion Criteria:

1. History of bipolar disorder, schizophrenia, autism, eating disorders, primary obsessive compulsive disorder, pervasive developmental disorder, or psychosis not otherwise specified
2. History of serious physical illnesses
3. Substance abuse or dependence
4. Current depressive episode with clear suicidal plans or suicidal behavior
5. Requires inpatient treatment for psychiatric disorders
6. Severe mental disorders requiring
7. 2 or more failed trials of antidepressant drugs: each trial for at least 8 weeks, with the last 4 weeks at full dose (e.g. fluoxetine 40mg/d, citalopram 40mg/d, escitalopram 20mg/d, sertraline 150mg/d )
8. History of clear-cut intolerability of, or lack of effect with, an adequate trial of at least one protocol treatment option
9. Taking any medicine that contraindicates in combination with or interferes with the efficacy of the treatment
10. Taking or administering antidepressants within 5 half-lives
11. Received modified electroconvulsive therapy within 12 months
12. If female, is pregnant

Both the patient and the psychiatrist know which group they are allocated to, while the outcome assessor and data analyst are kept blind to the allocation. The clinicians providing the intervention do not perform the assessment and are unaware of the results.