Für die Behandlung der therapieresistenten Depression stehen unterschiedliche Strategien zur Verfügung. Wichtig ist der Ausschluss von Pseudoresistenz. Die Lithiumaugmentation sowie die Augmentation mit atypischen Antipsychotika haben die beste Evidenz für die Behandlung der Nonresponse. Die Kombination von Antidepressiva erscheint nur sinnvoll für Wiederaufnahmehemmer und Blocker von präsynaptischen Autorezeptoren (z. B. Mirtazapin). Für einen Antidepressivawechsel ist die Datenlage hingegen nur unzureichend. Tranylcypromin kann eine sinnvolle Option bei Therapieresistenz sein. Eine Dosis-Wirkungs-Beziehung und somit Evidenz für eine Dosiserhöhung bei Nonresponse auf mittlere Dosisbereiche besteht für die Gruppe der TZA und Venlafaxin, nicht jedoch für SSRI. Nichtpharmakologische Strategien beinhalten die Psychotherapie und die EKT, die beide ihre Wirksamkeit bei der therapieresistenten Depression nachgewiesen haben. Eine Kombination von Pharmakotherapie und Psychotherapie kann insbesondere bei schweren depressiven Episoden zu einem besseren Gesamtbehandlungsergebnis führen. Für neuere Stimulationsverfahren wie die rTMS, die VNS oder die Tiefenhirnstimulation wird die weitere Erfahrung den Stellenwert für bestimmte Patientengruppen zeigen. Eine Therapie nach einer algorithmusgestützten Pharmakotherapie kann dazu beitragen, die zur Verfügung stehenden Strategien bestmöglich zu nutzen.
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