Cornelius Schüle, Anna Sobieraj, Helena Rogg
Abstract: Esketamine is an NMDA receptor antagonist and was approved as a nasal spray in March 2019, initially in the USA and then in December 2019 in Europe, as an adjunct to antidepressant pharmacotherapy for the treatment of treatment-resistant major depression or for rapid symptom reduction in psychiatric emergency situations in patients with major depression. In addition, esketamine nasal spray was approved in the United States, but not in Europe, as a monotherapy for the treatment of treatment-resistant depression in January 2025. Particularly at the beginning of a series of acute treatments with esketamine nasal spray (usually 8 treatments over 4 weeks), dissociative effects may occur in the treated patient, although a connection between initial dissociative symptoms and the therapeutic response in the further course cannot be sufficiently proven based on the currently available data. One methodological problem with studies on the antidepressant efficacy of ketamine (racemate) or esketamine (levorotatory enantiomer) is functional unblinding, in which the practitioner and the patient being treated can guess whether they belong to the verum or placebo group due to the characteristic side effects of esketamine. Proponents of ketamine-augmented psychotherapy (KAP) postulate that the rapid improvement in synaptic plasticity induced by ketamine, particularly in pathways to the prefrontal cortex, opens a 'therapeutic window' in which psychotherapeutic intervention is particularly effective. Due to the functional unblinding that cannot be ruled out when ketamine itself is administered, but especially due to the considerable general methodological limitations of psychotherapy studies (no possibility of blinding the practitioner and the patient being treated, problems in finding suitable control conditions, difficulties in empirically verifying complex therapy manuals), it is hardly possible with the currently available research methods to scientifically investigate potential causal relationships between ketamine administration and presumed improved psychotherapeutic efficacy.