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Introduction: The early and therapy-specific prediction of treatment success in major depressive disorder is of paramount importance due to high lifetime prevalence, and heterogeneity of response to standard medication and symptom expression. Hence, this study assessed the predictability of long-term antidepressant effects of escitalopram based on the short-term influence of citalopram on functional connectivity.Methods: Twenty nine subjects suffering from major depression were scanned twice with resting-state functional magnetic resonance imaging under the influence of intravenous citalopram and placebo in a randomized, double-blinded cross-over fashion. Symptom factors were identified for the Hamilton depression rating scale (HAM-D) and Beck's depression inventory (BDI) taken before and after a median of seven weeks of escitalopram therapy. Predictors were calculated from whole-brain functional connectivity, fed into robust regression models, and cross-validated.Results: Significant predictive power could be demonstrated for one HAM-D factor describing insomnia and the total score (r = 0.45–0.55). Remission and response could furthermore be predicted with an area under the receiver operating characteristic curve of 0.73 and 0.68, respectively. Functional regions with high influence on the predictor were located especially in the ventral attention, fronto-parietal, and default mode networks.Conclusion: It was shown that medication-specific antidepressant symptom improvements can be predicted using functional connectivity measured during acute pharmacological challenge as an easily assessable imaging marker. The regions with high influence have previously been related to major depression as well as the response to selective serotonin reuptake inhibitors, corroborating the advantages of the current approach of focusing on treatment-specific symptom improvements.