Background: Early improvement (EI) following treatment with antidepressants is a widely reported predictor to the treatment response. This study aimed to identify the resting-state functional connectivity (rs-FC) and its related clinical features that link the treatment response at the time of EI.

Methods: This study included 23 first-episode treatment-naive patients with MDD. After 2 weeks of antidepressant treatment, these patients received 3.0 Tesla resting-state functional magnetic resonance imaging scanning and were subgrouped into an EI group (N = 13) and a non-EI group (N = 10). Using the anterior insula (rAI) as a seed region, this study identified the rs-FC that were associated with both EI and the treatment response at week 12, and further tested the associations of the identified rs-FC with either the clinical features or the early symptom improvement.

Results: Rs-FC between rAI and the left dorsolateral prefrontal cortex (dlPFC) was associated with EI (t₂₁ = -6.091, p = 0.022 after FDR correction for multiple comparisons). This rs-FC was also associated with an interaction between EI and the treatment response at the week 12 (t₂₁ = -5.361, p = 6.37e-5). Moreover, among the clinical features, this rs-FC was associated with the early symptom improvement in the insomnia, somatic symptoms, and anxiety symptoms, and these early symptom improvements were associated with the treatment response.

Conclusion: Rs-FC between the rAI and the left dlPFC played a crucial role in the early antidepressant effect, which linked the treatment response. The early treatment effect relating to rAI may represent an early symptom improvement in self-perceptual anxiety, somatic symptoms and insomnia.