Predicting second-generation antidepressant effectiveness in treating sadness using demographic and clinical information: A machine learning approach
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Updated: Dec 18, 2025

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Amanda Lin1, Adrienne Stolfi2, Tracy Eicher3
1Department of Population and Public Health Sciences, Wright State University, Dayton, OH.
Introduction:
Current guidelines for choosing antidepressant medications involve a trial-and-error process. Most patients try multiple antidepressants before finding an effective antidepressant. This study uses demographic and clinical information to create models predicting effectiveness of different antidepressants in treating sadness in a nationally representative sample of US adults.
Methods:
A secondary analysis of the Collaborative Psychiatric Epidemiology Survey (CPES) was performed. Participants with or without a mental health diagnosis who reported sadness as a symptom, and were taking fluoxetine (n=156), sertraline (n=224), citalopram (n=91), paroxetine (n=156), venlafaxine (n=69), bupropion (n=92), or trazadone (n=26) within the past year were included. Two sets of principal component analyses (PCAs) and logistic regressions were performed: one determined associations between symptom clusters and antidepressant effectiveness for sadness, and the other created models to predict effectiveness. Both PCAs controlled for psychiatric and medical diagnoses, substance use, psychiatric medications, alternative treatments, and demographics.
Results:
Anxiety was associated with ineffectiveness of fluoxetine in treating sadness. Low mood scores were associated with ineffectiveness of paroxetine and venlafaxine, and fatigue was associated with ineffectiveness of sertraline. The models for predicting drug effectiveness had a mean accuracy of 83% and internal validity of 72%.
Limitations:
CPES data were collected from 2001-2003, so newer drugs were not included. Effectiveness was for sadness, so results are not directly comparable to studies using overall depressive symptom reductions as outcomes.
Conclusion:
Since fewer than 50% of patients currently respond to their first antidepressant, this model could provide modest improvement to choosing starting antidepressants in treating sadness.
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