Holding on or letting go? Patient experiences of control, context, and care in oral esketamine treatment for treatment-resistant depression: A qualitative study

Over the past two decades, intravenous ketamine and its S-enantiomer esketamine have emerged as rapidly acting antidepressant options for patients with major depression, particularly those with treatment-resistant depression (TRD). Alternative routes such as intranasal and oral administration have also shown promise, and intranasal esketamine is now a licensed option for TRD. These agents produce acute psychoactive effects—commonly described as dissociative or psychedelic-like—that include perceptual changes, altered body awareness, and experiences of detachment or unity. While the role of "set and setting" (preparation, expectation, psychological support, and the treatment environment) is well established in classic psychedelic therapies, its relevance to (es)ketamine treatments is poorly understood. Existing psychometric instruments for dissociation may not capture the phenomenology of drug-induced experiences, and there are no clear consensus guidelines on how to address non-pharmacological elements of (es)ketamine care. This study aimed to explore how patients undergoing an "off-label" oral esketamine programme for TRD experienced the treatment, which aspects of care facilitated or hindered those experiences, and how patients made sense of the acute psychoactive effects. Using an interpretative phenomenological approach, the researchers sought to identify unmet needs and practical factors that could improve the quality and safety of (es)ketamine treatment from the patient perspective.

Martinotti and colleagues conducted a qualitative study using Interpretative Phenomenological Analysis (IPA) and individual in-depth interviews to examine patient experiences with oral esketamine for TRD. Participants were purposively sampled from two treatment sites in the Netherlands (University Medical Center Groningen and a specialised depression clinic in The Hague). Inclusion criteria for the treatment programme included a DSM-5 diagnosis of major depressive disorder (assessed with the MINI) and treatment resistance defined as inadequate response to at least three different classes of registered antidepressants. The off-label treatment regimen comprised six weeks of twice-weekly, individually titrated oral esketamine in a liquid formulation, given as an adjunct to standard antidepressant medication. Dosing started at 0.5 or 1 mg/kg and was increased in ~0.5 mg/kg steps up to a maximum of 3 mg/kg according to tolerability and clinical effect; the authors note oral bioavailability estimates of 8–24% and provide an equivalence rationale to common IV doses. Vital signs (blood pressure and heart rate) were measured pre-dose and at 30 and 120 minutes after ingestion. Most sessions occurred in private treatment rooms, though some outpatient sessions involved two or three patients simultaneously. Patients who responded to the initial regimen could be offered continued outpatient at-home treatment after safety assessment and shared decision-making. Seventeen patients (11 women, 6 men; 8 from The Hague, 9 from Groningen) participated in single open in-depth interviews conducted shortly after the six-week clinical period; several interviewees also had months of at-home experience. Fourteen interviews were carried out by the first author and three by the third author; neither interviewer had been involved in participants' clinical care. Interviews followed a semi-structured guide, lasted about one to two hours (mean 1 h 22 min), and were conducted mostly via videoconference due to COVID-19 restrictions. Audio recordings were transcribed verbatim and entered into MAXQDA for analysis. Analytic procedures followed IPA conventions: close, idiographic reading of each transcript, independent coding by multiple authors, iterative discussion to reach consensus, abstraction into exploratory themes, and clustering of themes across cases to identify convergent and divergent patterns. To enhance rigour the study used purposive sampling until data saturation, multidisciplinary triangulation of interpretations, and adherence to SRQR and COREQ reporting standards. The extracted text does not report ethical approval details or specific participant demographic breakdowns beyond sex and site.

Seventeen participants described a range of acute psychoactive effects and broader care-related experiences. The investigators organised findings under six major themes: overwhelming experiences; inadequate preparation; letting go of control; mood states influencing sessions; presence and emotional support; and supportive settings. Overwhelming experiences: Participants recounted diverse, sometimes intense psychoactive phenomena—visual and auditory alterations, depersonalisation, altered sense of time and space, and feelings described as entering "another world", the void, or unity. Reports spanned positively valenced spiritual or peaceful experiences to alienating or frightening ones. A minority reacted strongly even at low doses; most overwhelming episodes occurred at higher dosages. Short participant quotes were used to illustrate the intensity (for example: "I had the feeling I was losing myself" [P14]). Inadequate preparation: Many respondents felt insufficiently informed about the likelihood, content, and intensity of acute subjective effects. Miscommunication was common: when clinicians said patients should not "expect effects" early on, some patients interpreted this to mean no psychoactive effects would occur, and were alarmed when they did experience strong effects during initial sessions. Several participants said advice about how to engage with these experiences (for example, to try to "let go") arrived too late. Side effects or core components?: Staff frequently framed acute experiences as "side effects", and occasionally minimised their relevance to therapeutic benefit. In contrast, participants commonly used the term "trip" to describe sessions and were divided about whether those experiences were therapeutically meaningful. Some believed that having a trip produced immediate and short-term functional improvement, asserting that insights arising during the experience aided subsequent functioning. Letting go of control: A central and recurrent theme was the tension between attempting to maintain control and learning to surrender to the experience. Participants reported that resisting the experience often provoked anxiety and made sessions more distressing, while acceptance tended to produce calmer, more pleasant sessions and better post-session mood. Strategies to maintain control included focusing on external stimuli, trying to think positive thoughts, or communicating during sessions; strategies to facilitate surrender included breathing exercises, changing work or activity commitments, and deliberate permission to disengage from everyday responsibilities. Mood states influencing session experience: Pre-existing restlessness, anxiety, or chaotic life circumstances often amplified negative reactions during sessions. Unpleasant early sessions could linger and adversely affect subsequent dosing days. Conversely, starting sessions in a calm, open-minded mood and relinquishing rigid expectations were described as helpful for better experiences. Presence and emotional support: Physical presence of staff or trusted companions mattered. Many patients wished nurses had remained physically present during at least the first session(s), rather than leaving and returning only to take vital signs or administer questionnaires; being left alone heightened anxiety. Emotional support—empathy, trust and continuity of rapport—was also important, and several patients wished staff had personal experience or greater familiarity with the acute effects to better validate and listen to their accounts. Support with integration: Because acute experiences were often fleeting, participants valued opportunities to share, review or record their experiences soon after sessions to aid memory and meaning-making. Some found peer contact with other patients helpful; others thought professional integration sessions would have been useful. Many said resting and taking the remainder of the day off after dosing helped them process what had occurred. Supportive settings: Environmental factors influenced the capacity to let go. Privacy, silence, and minimising sensory intrusions were repeatedly endorsed; interruptions (including blood-pressure checks at around 30 minutes) and proximity to other patients were disruptive. Clinic environments were often judged too "clinical and sterile", whereas patients preferred warm, comfortable, private spaces where they could lie down. When permitted to continue treatment at home, participants developed personal rituals—timing intake, using earplugs, selecting music, planning no activities—that helped create a "safe bubble". Music, though infrequently suggested by staff, served multiple roles: damping external noise, anchoring time, providing emotional direction, or alternatively keeping some patients too grounded in external reality; calming classical pieces or personally meaningful songs were commonly reported as helpful. The extracted text does not provide quantitative counts for how many participants endorsed each subtheme beyond general statements, nor does it supply detailed adverse-event frequencies or standardised scale scores in the results section.

The researchers interpret their findings as indicating that non-pharmacological factors—preparation, patients' ability to "let go", mood at the time of dosing, interpersonal support, and the physical environment—substantially shape the subjective experience of oral esketamine and, by extension, the perceived quality of care. Letting go emerged as a central process: inability to relinquish control was associated with heightened anxiety, more aversive sessions, and negative carry-over effects on subsequent dosing days, whereas acceptance was often linked to calmer sessions and meaningful experiences. Given that psychological flexibility can be impaired in depression, the authors suggest attention to this process may be clinically relevant. Preparation and education are proposed as modifiable targets. Drawing parallels with classic psychedelic therapies, the authors advocate for preparatory work that normalises challenging experiences and teaches acceptance-based approaches, together with explicit guidance on what to expect. They note that labelling acute phenomena as mere "side effects" may deter patients from recognising potential therapeutic value and from reporting these experiences to staff. The study aligns the observed facilitators and barriers with common factors in psychotherapy: a trusting therapeutic relationship, a safe and healing environment, a coherent explanatory frame for the treatment, and shared rituals that signal care. Practical elements such as minimising noise and interruptions, offering continuity of staff presence, enabling privacy, and supporting post-session integration (including simple techniques like breathing exercises and music) are identified as likely to improve patient comfort and reduce distress. The authors also flag that standard questionnaires (for instance CADSS, SAFTEE, IDS-SR) may be insufficiently sensitive to capture the nuanced, individual subjective effects of esketamine, which partly explains why clinicians remained unaware of some patients' difficult experiences. Limitations acknowledged by the team include potential selection bias because only patients who completed the initial six-week programme were interviewed; the study focused exclusively on oral esketamine so findings may not generalise to other routes or enantiomers; and, as with all IPA work, the aim is contextual and theoretical generalisation rather than statistical inference. The sample comprised highly treatment-resistant patients (failure of at least three antidepressant classes and often other interventions), which the authors note may affect transferability to less treatment-resistant populations. They also defend the sample size (17) as appropriate for phenomenological research and stress methodological reflexivity and multidisciplinary triangulation as strengths. On the basis of their findings, the investigators recommend that future (es)ketamine treatments incorporate structured preparation, attentive presence during early sessions, opportunities for emotional support and integration, carefully designed physical settings, and pragmatic tools (music, breathing/mindfulness exercises, intake rituals) to enhance patient agency and comfort. They call for further research combining quantitative and qualitative methods to more rigorously evaluate how these non-pharmacological elements influence outcomes.

The study concludes that elements of set (preparation, reassurance, anxiety reduction, confidence-building, promotion of agency) and setting (a warm, comfortable, silent, private environment with physical and empathetic professional or informal support) are important determinants of quality of care in oral esketamine treatment, even when the intervention is delivered primarily as a pharmacological therapy. Although conducted in an off-label oral esketamine programme for TRD, the authors suggest the insights may be applicable across other ketamine approaches, study designs, countries, and clinical populations. They propose implementing the practical recommendations derived from patients' reports to improve care and urge future research to pair quantitative outcome measurement with qualitative inquiry into patient experiences.