The definition of treatment-resistant depression is variously interpreted. There is no agreement of different authors on its meaning. The present vagueness of criteria for the diagnosis of a refractory depression contrasts with the many studies reporting potentiation of antidepressants by lithium. De Montigny in 1981, after early works by Zall and by Lingjaerde, initiated this approach that still remains poorly understood in terms of biochemical mechanisms. A review of the controlled studies shows that the delay of antidepressant action varies and the term "lithium potentiation" does not seem totally relevant. From a pharmacological point of view, several types of data suggest a synergic potentiation rather than a true potentiation. This effect applies to all classes of antidepressants and improves about 50% of patients who did not respond positively to an adequate treatment received during 4 to 6 weeks. Many questions remain unanswered particularly concerning the lithium levels, factors predicting a positive response and the strategy for the maintenance treatment. Studies are necessary in order to compare the relevance of this potentiation technique with the mere substitution by another antidepressant and to understand the biochemical mechanisms underlying the synergic effect.