Underlying Bipolar Diathesis May Contribute to Treatment Resistance in MDD

Researchers found data that showed in patients with treatment-resistant major depressive disorder there were higher incidences of antidepressant-induced irritability and mood liability with mixed features and probable underlying bipolar diathesis.

Atypical patterns of response to antidepressants, such as antidepressant-induced irritability and mood liability (AIM) and treatment-resistant depression may be the result of an undiagnosed bipolar diathesis or a form of treatment resistance in patients with major depressive disorder (MDD), according to a recent article published in European Neuropsychopharmacology.

Through a post hoc analysis of an international sample of 1329 patients with MDD out of 2811 from the Bipolar Disorders: Improving Diagnosis, Guidance and Education (BRIDGE)-II-MIX study, researchers sought to clarify the atypical patterns of response to antidepressants between unipolar and bipolar depression through examining these patterns in the context of treatment-resistant depression and AIM. Researchers looked into the rates of hypomanic/manic symptoms, psychiatric comorbidities and clinical features, such as onset and number of suicide attempts, in patients with history of resistance to antidepressant treatment (n=404) and without (n=925), and in patients with previous AIM (n=184) and without (n=1145). The comparisons of these clinical factors were evaluated using Chi-square, t-Student’s test, and logistic regression models.

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The researchers found that, in comparison with patients without treatment-resistant MDD, patients with treatment-resistant MDD were associated with significantly higher rates of AIM (P <.001), psychotic features (P =.021), and history of suicide attempts (P <.001). Of the hypomanic/manic symptoms, the patients with treatment-resistant MDD had increased emotional lability (P =.025) and impulsivity (P =.034). The incidence of these hypomanic symptoms provides a possible link between patients with treatment-resistant depression and bipolarity. Patients with AIM were associated with significantly higher rates of several variables related to bipolarity (first-degree family history for bipolar disorder [P <.001], previous treatment-resistant depression [P <.001], atypical features [P =.003], lifetime suicide attempts [P=.018], bipolar specifier clinical factors [P <.001]) in comparison with the patients without AIM. With these results, the researchers suggest this is “strongly indicating the presence of a bipolar diathesis within this subgroup.” Additionally, patients with AIM showed significant presentation of 13 out of 14 of the hypomanic/manic symptoms (P <.001 to P =.008) excluding grandiosity and 4 out of 8 of the psychiatric comorbidities—of note are panic disorder, attention deficit hyperactivity disorder, and borderline personality disorder (P <.001 to P =.030). An overlap between treatment-resistant depression and AIM affected patients was reported.

Groups with a history of treatment-resistant depression and AIM saw a significant increase in number of suicide attempts in comparison with the groups without history of these. According to the researchers, it should be noted that these groups may be at increased risk for suicidal behaviors and should potentially be monitored as such.

Limitations of this study include the retrospective nature of the information regarding patterns of previous response to antidepressants and the non-random selection of centers that participated in the study.

The researchers suggest that “a lifetime history of resistance and/or irritability/mood lability in response to [antidepressants] was associated with the presence of mixed features and a possible underlying bipolar diathesis,” and “this clinical approach could be useful to differentiate between depression subtypes, empowering the diagnostic process and helping in personalized therapeutic strategies.”

Disclosure: This study was supported by Sanofi-Aventis. Please see the original reference for a full list of authors’ disclosures.


Perugi G, Pacchiarotti I, Mainardi C, et al; for the BRIDGE-II-MIX Study Group. Patterns of response to antidepressants in major depressive disorder: Drug resistance or worsening of depression are associated with a bipolar diathesis [published online June 18, 2019]. Eur Neuropsychopharmacol. doi: 10.1016/j.euroneuro.2019.06.001