Although more quality research is required to inform clinical practice, serotonin‐noradrenaline reuptake inhibitor ‐ noradrenaline and specific serotonergic antidepressant (SNRI‐NaSSA) combination therapy shows promise for treatment‐resistant depression. Here, Dr Pandarakalam discusses the rationale behind the use of this combination and some of the evidence gained so far for its efficacy. Copyright © 2010 Wiley Interface Ltd