Patients with treatment-resistant depression who improved after subcutaneous esketamine treatment reported higher levels of dissociation, particularly feelings that the world seemed unreal or distant, than patients who did not respond, according to a study published in the Journal of Psychiatric Research.
Treatment-resistant depression refers to depression that has not improved after at least two adequate trials of standard antidepressants. Esketamine, a form of ketamine, has emerged as a treatment option for some people with this condition. Ketamine was originally developed as an anesthetic, but researchers later found that it could produce rapid changes in depressive symptoms.
The drug can also cause temporary changes in consciousness. Some patients describe feeling separated from their body or thoughts, while others say that their surroundings seem unreal, distant or dreamlike. These experiences are generally referred to as dissociation. Researchers have debated whether dissociation is simply a side effect of ketamine-based treatment or whether it is connected to the drug’s antidepressant action.
The current study examined data from an open-label clinical trial, meaning both researchers and participants knew what treatment was being administered, at Onofre Lopes University Hospital, affiliated with the Federal University of Rio Grande do Norte in Brazil. Led by Kaike Thiê da C. Gonçalves at the University of São Paulo, the researchers followed adults receiving weekly subcutaneous esketamine.
Of the 30 people originally enrolled, 23 completed all eight treatment sessions and were included in the analysis. The group included 15 females and eight males (average age 34.3 years). Participants initially received 0.5 milligrams of esketamine per kilogram of body weight. The dose could be increased to 0.75 or 1 milligram per kilogram when depressive symptoms had not fallen by at least 50%.
The researchers measured depression before each treatment session and one week after the final session. They assessed dissociation 40 minutes after each dose using a clinician-administered questionnaire. The questionnaire measured overall dissociation as well as three experiences: derealization (feeling that the outside world is unreal); depersonalization (feeling detached from oneself); and amnesia (gaps in memory).
Twelve participants met the study’s definition of a treatment responder, meaning their depression scores fell by at least 50%. Responders had higher overall dissociation scores than the 11 nonresponders across the treatment period. They also reported significantly more derealization. Depersonalization and amnesia were higher among responders as well, but the differences were not statistically significant.
Notably, dissociation levels remained relatively stable across the eight sessions, and the researchers found no significant within-person relationship between dissociation and changes in depression scores. In other words, people who experienced more dissociation than others were more likely to respond, but a person’s dissociation level at a particular session did not reliably predict how much their own symptoms would improve.
The researchers concluded that dissociative experiences, particularly derealization, may represent clinically relevant correlates of antidepressant outcomes. They emphasized that these findings are exploratory and may help guide future research into whether different aspects of altered consciousness are relevant to treatment outcomes.
Several limitations are to be noted. For example, the study did not include a placebo group or blinding. In addition, the analysis also did not fully account for other medications, psychiatric conditions or outside psychotherapy. Importantly, because the researchers increased the dose for patients who were not adequately responding, higher dissociation scores might partly reflect greater cumulative drug exposure rather than a true biological marker of clinical improvement.
The study, “Dissociation and Antidepressant Response to Subcutaneous Esketamine: A Clinical Study,” was authored by Kaike Thiê da C. Gonçalves, Vagner Deuel de O. Tavares, Fernanda Palhano-Fontes, Patrícia Cavalcanti-Ribeiro, Victor Rocha Nóbrega de Almeida, David C. Barbosa, Tatiane Uetti Gomes Fernandes, Eduardo Igor Torquato Cardoso, Nicole Bezerra de Medeiros Lima, Aldielyson Jorge Cavalcante de Brito, Raynara Bolcont, Marcelo Falchi-Carvalho, Emerson Arcoverde, Dráulio Araújo and Nicole Leite Galvão-Coelho.