Applying modern educational methods for digital native students seems necessary. Active learning strategies promote students' skills and knowledge. This study was conducted to design and evaluate active learning methods by teaching psychopharmacotherapy to pharmacy students. This was a quasi-experimental study with three randomized study groups (control, game, and multimedia), using a pre-and post-test design, conducted on 155 students of 5-year pharmacy in 2022 at the Faculty of Pharmacy of Tehran University of Medical Sciences, Iran. Overall, 18 clinical cases were designed for the basic structure of interventions. After teaching psychopharmacotherapy contents through lecturing, the pre-test was held. The next steps were playing the educational game, studying the multimedia case-based learning files, and then completing questionnaires, respectively. Then, a post-test was held. 65.33% of participants were female and 34.66% were male. The pre-test and post-test scores comparison showed no difference in control group (P=0.409). However, in the serious game and multimedia groups, the average score of pre-test and post-test had a statistically significant difference (P<0.001, P=0.002 respectively), this difference was higher in the serious game group. Questionnaire evaluation showed substantial differences between game and multimedia groups. The educational interventions were able to improve student's knowledge and skills so they can better help patients and promote public health. In the sections of Confidence, Social Interactions, Fun, Focused attention, Learnability, Relevance, and Perceived Learning, the serious game far outweighed the multimedia case-based learning.
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