To update a comparative effectiveness review (1980-2011) of treatments for adolescents whose depressive episode or disorder (MDE/MDD) did not respond to one or more trials of SSRI antidepressants. MEDLINE, Cochrane Central, PsychINFO, Cochrane Database of Systematic Reviews, EMBASE, CINAHL, and AMED were searched in addition to the grey literature. We spanned May 2011 to September 1, 2017 and included only articles in English. 11 new studies were reviewed based on the criteria of having tested a comparative treatment in adolescents with MDD or MDE who were confirmed to have failed one or more SSRI trials. Data were extracted using standardized forms and a reference guide in DistillerSR; a second reviewer verified the accuracy of the data fields and discrepancies were resolved by consensus. One trial (N = 29) found a small benefit of escalating doses of fluoxetine and the treatment of adolescent depression study (TORDIA, N = 334) found significant benefits of combined SSRI or venlafaxine treatment with CBT for most outcomes. No new studies were identified since the previous review (2012). One trial is currently registered that will be a cross over trial of rTMS; other registered trials are open label. Multiple secondary data analyses of TORDIA have identified important predictors of treatment response and relapse. No new comparative studies were identified since the original review. Trials are desperately needed to identify new treatments for youth with SSRI resistant MDD. These youth should not be deemed as treatment resistant until completing one or two failed trials of SSRI combined with evidence-based psychotherapy.
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