This meta-analysis evaluated the relative benefit of antidepressant medication (ADM) versus placebo in patients with varying degrees of depression severity. The study included data from six randomized placebo-controlled trials involving 718 patients. The results showed that the effectiveness of ADM compared to placebo increased with the severity of depression symptoms. For patients with mild or moderate depression, the benefit of ADM over placebo was minimal or nonexistent, while for those with very severe depression, the benefit was substantial. The Hamilton Rating Scale for Depression (HRSD) was used to measure symptom severity, and the analysis found that the magnitude of the ADM/placebo difference crossed the National Institute for Clinical Excellence (NICE) threshold for clinical significance at a baseline HRSD score of 25. For patients with HRSD scores of 25 or higher, the effect size was considered clinically significant, with a Cohen's d-type effect size of 0.53 or higher. The study also found that the severity of depression symptoms influenced the effectiveness of treatment, with more severe symptoms leading to greater differences in treatment outcomes between ADM and placebo. The findings suggest that antidepressants may not be effective for patients with mild or moderate depression, but are more effective for those with severe depression. The study highlights the importance of considering symptom severity when evaluating the effectiveness of antidepressant medications.This meta-analysis evaluated the relative benefit of antidepressant medication (ADM) versus placebo in patients with varying degrees of depression severity. The study included data from six randomized placebo-controlled trials involving 718 patients. The results showed that the effectiveness of ADM compared to placebo increased with the severity of depression symptoms. For patients with mild or moderate depression, the benefit of ADM over placebo was minimal or nonexistent, while for those with very severe depression, the benefit was substantial. The Hamilton Rating Scale for Depression (HRSD) was used to measure symptom severity, and the analysis found that the magnitude of the ADM/placebo difference crossed the National Institute for Clinical Excellence (NICE) threshold for clinical significance at a baseline HRSD score of 25. For patients with HRSD scores of 25 or higher, the effect size was considered clinically significant, with a Cohen's d-type effect size of 0.53 or higher. The study also found that the severity of depression symptoms influenced the effectiveness of treatment, with more severe symptoms leading to greater differences in treatment outcomes between ADM and placebo. The findings suggest that antidepressants may not be effective for patients with mild or moderate depression, but are more effective for those with severe depression. The study highlights the importance of considering symptom severity when evaluating the effectiveness of antidepressant medications.