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Resistance and worsening of depression in response to antidepressants (ADs) are major clinical challenges. In a large international sample of patients with major depressive disorder (MDD), we aim to explore the possible associations between different patterns of response to ADs and bipolarity. A total of 2811 individuals with a major depressive episode (MDE) were enrolled in the BRIDGE-II-MIX study. This post-hoc analysis included only 1329 (47%) patients suffering from MDD. Patients with (TRD-MDD, n = 404) and without (NTRD-MDD, n = 925) history of resistance to AD treatment and with (n = 184) and without (n = 1145) previous AD-induced irritability and mood lability (AIM) were compared using Chi-square, t-Student's test and logistic regression models. TRD-MDD patients resulted significantly associated with higher rates of AIM, psychotic features, history of suicide attempts, emotional lability and impulsivity, comorbid borderline personality disorder and polipharmacological treatment, compared to NTRD-MDD group. In comparison to NAIM-MDD patients, subjects in the AIM-MDD group showed significantly higher rates of first-degree family history for BD, previous TRD, atypical features, mixed features, psychiatric comorbidities, lifetime suicide attempts and lower age at first psychiatric symptoms. In addition, patients with AIM presented more often almost all the hypomanic symptoms evaluated in this study. Among these latter symptoms, logistic regressions showed that distractibility, impulsivity and hypersexuality were significantly associated with AIM-MDD. In conclusion, in MDD patients, a lifetime history of resistance and/or irritability/mood lability in response to ADs was associated with the presence of mixed features and a possible underlying bipolar diathesis.