Seul un tiers des patients souffrant de dépression répondent de manière satisfaisante aux traitements de première ligne et plus de la moitié des patients n’arriveront pas à une réduction de 50 % de leurs symptômes dépressifs après 3 mois de traitement. Face à l’échec d’un premier traitement antidépresseur bien mené, plusieurs approches pharmacologiques sont alors possibles : adapter la posologie du traitement (optimisation), changer d’antidépresseur (switch), combiner plusieurs classes de traitements antidépresseurs (association) ou encore associer un traitement antidépresseur à une autre classe de psychotrope (potentialisation). Par ailleurs, d’autres stratégies non pharmacologiques peuvent être proposées : différentes formes de psychothérapies, les techniques de neuromodulation (stimulation magnétique transcrânienne, sismothérapie) et, plus récemment, l’utilisation thérapeutique de l’exercice physique. Cet article propose une analyse critique des arguments scientifiques justifiant les indications et cernant la place de chacune de ces alternatives. De surcroît, cet article propose une synthèse actualisée des recommandations Françaises (Afssaps) et de certaines recommandations internationales (EPA [European Psychiatric Association], APA [American Psychiatric Association], WFSBP [World Federation of Societies of Biological Psychiatry]).

Only one third of patients suffering from depression will achieve a satisfactory response with first line treatments and more than half of patients will fail to obtain at least 50 % reduction in their symptoms after 3 months of treatment. This article presents a review of the scientific arguments supporting the various therapeutic strategies when confronted to a first treatment failure after an adequate drug trial. Several pharmacological approaches are possible. A first and classical approach is adjusting the drug dosage (optimization). This strategy is coherent with the pharmacological profile of some antidepressant drugs (tricyclic antidepressants, tetracyclic antidepressants, venlafaxine). There is no scientific basis to a dose-effect relationship with the selective serotonin reuptake inhibitors (SSRIs), as minimal doses of these drugs correspond to a high ratio of serotonin transporter occupation; however increasing doses of SSRIs constitutes a usual practice, endorsed by several experts. A second classic strategy is changing an inefficient antidepressant drug to another antidepressant drug (switch). Theoretically, a different pharmacological class should have more chances to be successful; however, in the case of a failure with an SSRI, an inter-class switch has not consistently proven to be superior to an intra-class switch. In some cases, association of antidepressant drugs can also be an advantageous strategy (combination), particularly in the case of partial response with the first prescribed drug. Due to its particular mechanism of action, mirtazapine is often a drug of choice in the case of such an association. Finally, another approach to recommend in case of partial response is associating an antidepressant drug to another class of drugs, such as lithium, atypical antipsychotics or thyroid hormones (potentiation). Lithium has unfailingly proven its efficacy in case of resistance, but the utilization of atypical antipsychotics, at low-doses, has become increasingly common, certainly, because they are easier to handle. Aside from the pharmacological options, we can consider a number of other strategies, first among them is psychotherapy. Most studies assessing the efficacy of psychotherapy were conducted with this therapy as a first-line treatment. More studies of psychotherapy in depression after unsatisfactory response are distinctly needed. Available data seem to indicate that psychotherapy constitutes an efficient alternative, regardless of the type of psychotherapy (results are more robust in cognitive and behavioural therapies and brief interpersonal psychotherapy, in relation with the greater number of studies using these therapies), with effect sizes comparable to the ones obtained with pharmacological options. Among other strategies, physical exercise has been getting more attention lately, even though evidence in this indication remains deceiving for the moment. Lastly, neuromodulation techniques have an unquestionable place. The rTMS has been largely tested with interesting results. Given the time and staff necessary to conduct this therapy, the question has now switched to how precisely select the patients who will most benefit from rTMs, and how long and at what pace should the sessions take place. ECT is undoubtedly the most efficient treatment, but, apart from life-threatening melancholia and other restricted exceptions, it is usually indicated in multi-resistant depression. Some authors suggest using this therapy earlier, as chronicity of the disease is itself a factor of poor response. Finally, this article reviews also the most recent French and International guidelines in managing patients having showed an unsatisfactory response to a first-line treatment.