This study contributes new evidence for the identification of adolescent TRD and sheds light on differing pathophysiologies by delineating distinct plasma metabolic profiles between adolescent TRD and FEDN-MDD.

Inclusion Criteria:

FEDN-MDD：

1. Age 12-18 years
2. Meet the diagnostic criteria for MDD according to the DSM-5
3. First-episode and drug-naive
4. HAMD-17 score > 17

TRD:

1. Age 12-18 years
2. Meet the diagnostic criteria for MDD according to the DSM-5
3. HAMD-17 score > 13
4. Currently or previously taking a standard therapeutic dose of antidepressant for at least 6 weeks, and they had at least one historical failure to an antidepressant (reduction in depressive symptoms <50%)

HC:

1. age 12-18 years
2. HAMD-17 score < 7
3. HCs without a personal history of a mental illness or family history in a first-degree relative

Exclusion Criteria:

FEDN-MDD、TRD：

1. the presence or past history of severe medical, neurological or psychiatric disorders (other than MDD in patients)
2. anxiety comorbidity was not considered an exclusion criterion provided that MDD was the main diagnosis and the primary reason for seeking assistance
3. substance abuse, head trauma, or loss of consciousness
4. Chronic physical diseases that significantly affect peripheral metabolism or neurological function
5. Pregnant and lactating women

HC:

1. the presence or past history of severe medical, neurological or psychiatric disorders
2. substance abuse, head trauma, or loss of consciousness
3. Chronic physical diseases that significantly affect peripheral metabolism or neurological function
4. Pregnant and lactating women

FEDN-MDD: 53 patients with MDD who had a first episode and had not been treated with antidepressants TRD: 53 patients who had been on medication for at least 6 weeks or more and were not responding to antidepressant therapy HC: 56 healthy subjects