APA 2021: Antidepressants in Treatment-Resistant Unipolar and Bipolar Depression

Although the use of antidepressants to treat treatment-resistant bipolar depression (TRD-BD) is common, due to the theoretical continuum between treatment-resistant unipolar depression and TRD-BD, the practice is nevertheless controversial.

The combination of antidepressants (AD) plus antipsychotics (AP) and/or mood stabilizers (MS) generates a greater clinical response in treatment-resistant unipolar depression (TRD-UP) than it does in treatment-resistant bipolar depression (TRD-BD), and no clinical benefit was seen in adding AD to TRD-BD treatment regimens, according to study results presented at the American Psychiatric Association annual meeting, held virtually from May 1 to May 3, 2021.

Although the use of AD to treat TRD-BD is common, due to the theoretical continuum between TRD-UP and TRD-BD, the practice is nevertheless controversial. Study investigators sought to compare response to the combination of AD and MS and/or AP in 76 patients with TRD-UP vs 70 patients with TRD-BD type 1 and 60 TRD-BD type 2, with the secondary objectives of (1) comparing the TRD-BD clinical trajectory, with or without AD treatment and (2) testing for a differential AD response among TRD-BD subtypes.

Scores from the Hamilton Depression Rating Scale (HAMD) at the start of treatment (T0) and after 3 months (T3) were compared; score changes were analyzed, and delta scores for the specific treatment combinations were computed and compared using independent samples t-tests.

Among patients treated with AD, TRD-UP patients showed higher HAMD scores than TRD-BD (F1,139=34.54; P <.001; np2=0.20), and yet TRD-UP patients nonetheless had a greater improvement from T0 to T3 (F1,139=8.88; P =.003; np2=0.06). Greater HAMD reductions were generated with AD+AP in TRD-UP vs TRD-BD (t=2.48; P =.02; d=0.58). In TRD-UP compared with TRD-BD, trends for greater improvement were seen with AD+MS (t=1.81; P =.07; d=0.58) and AD+AP+MS (t=1.9; P =.05; d=0.55). Adding AD to treatment with AP alone or with MS did not modify the TRD-BD clinical trajectory (F1,122=.67; P =.41; np2=0.00), nor did it convey further benefits within BD subtypes .

The study investigators concluded, “The combination AD+AP/MS generates a greater clinical response in TRD-UP than in TRD-BD supporting the existence of a distinct neurobiological profile in TRD-UP vs. TRD-BD. Our results also point out the absence of clinical benefit to add AD in TRD-BD.”


Moderie C, Nuñez N, Comai S, Gobbi G. Distinct effects of antidepressants in treatment-resistant unipolar and bipolar depressions in association with mood stabilizers and antipsychotics. Presented at: APA annual meeting May 1-3, 2021. Abstract/Poster 5271.