Objectives: Treatment resistant depression (TRD), commonly encountered in clinical practice, leads to socioeconomic disability and therapeutic pessimism. This paper reviews evidence for pharmacological approaches used in TRD.

Method: Electronic literature searches were performed using Medline and Psychlit using broad search terms relating to TRD.

Results: Agents that potentiate both serotonin and noradrenaline may allow more patients to achieve full remission. Attention must be paid to dose titration and length of treatment courses in TRD. Augmentation with lithium and switching within antidepressant class or between classes can often improve symptoms but efficacy of other augmentation approaches remains uncertain. Antidepressant combinations and addition of atypical antipsychotics can be useful but combinations of predominantly serotonergic antidepressants should be avoided. Electroconvulsive therapy retains an important role in TRD but pharmacological treatments need to be continued concomitantly.

Conclusions: Good improvement is seen in TRD after vigorous antidepressant treatment but most patients continue to have lower grade symptomatology.