BACKGROUND: This study aims to assess the effectiveness of low-dose Escitalopram (10 mg) or low-dose Desvenlafaxine (25 mg) combined with mindfulness-based cognitive therapy (MBCT) in addressing challenges in treating generalized anxiety disorder (GAD), particularly in patients resistant to conventional therapies. METHODS: A prospective cohort study was conducted with individuals diagnosed with treatment-resistant GAD. group A included patients unresponsive to citalopram, imipramine, paroxetine, and sertraline, who were then treated with low-dose Escitalopram (10 mg) combined with MBCT. group B comprised those unresponsive to venlafaxine and duloxetine, who were treated with Desvenlafaxine (25 mg) alongside MBCT. Participants were monitored over 24 weeks for changes in Hamilton Anxiety Rating Scale (HAM-A) and Mindful Attention Awareness Scale (MAAS) scores, with medication adherence measured using the Medication Adherence Rating Scale (MARS). The primary outcomes focused on the improvement in anxiety symptoms and overall mental well-being. RESULTS: Comparative analysis between the groups showed significant improvement in HAM-A and MAAS scores at week 16 in group B compared to group A (P < 0.01). Within-group analysis also demonstrated a significant reduction in scores at week 12 in group B compared to group A at week 16 (P < 0.01). No significant difference was observed in medication adherence between the two groups (P = 0.122). CONCLUSION: Patients treated with low-dose Desvenlafaxine combined with MBCT exhibited greater improvements in managing treatment-resistant GAD compared to those treated with low-dose Escitalopram. This approach highlights the potential for more inclusive and effective mental health strategies, contributing to enhanced quality of life and well-being.