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