Patients' recovery and non-recovery narratives after intravenous ketamine for treatment-resistant depression

Many patients with major depressive disorder and bipolar depression do not respond to conventional pharmacotherapy, leaving a substantial subgroup with treatment-resistant depression. Intravenous ketamine has growing empirical support for rapid antidepressant effects, and qualitative work to date has begun to characterise patient experiences such as reductions in suicidal ideation and shifts in thought processes. However, subjective recovery and non-recovery narratives specific to people receiving intravenous ketamine for treatment-resistant depression have not been explored in depth, and questions remain about how patients understand ketamine's effects, the experience of infusions, and how these narratives might inform clinical practice. This exploratory qualitative study, conducted as a single-site sub-study within the multi-site open-label Bio-K clinical trial, aimed to characterise patients' subjective experiences with (1) receiving intravenous ketamine infusions, (2) recovering or not recovering after a standard course of infusions, and (3) beliefs about why ketamine did or did not work. The investigators sought to use patient narratives to inform expectations-setting and support strategies for clinicians treating people with treatment-resistant depression using IV ketamine.

The qualitative sub-study was approved by the University of Michigan Institutional Review Board and recruited participants who had completed the Bio-K trial. Bio-K enrolled adults aged 18–65 with DSM-5 major depressive disorder or bipolar disorder, a baseline PHQ-9 >15, and treatment-resistant depression defined by failure of at least two adequate trials of antidepressant or mood-stabilising treatments (or an adequate course of electroconvulsive therapy). Key exclusions included BMI >40, psychotic disorder, benzodiazepine use, current substance abuse, prior ketamine use, and intellectual disability. The Bio-K protocol delivered three IV ketamine infusions over an 8–11 day period at 0.5 mg/kg up to a 50 mg maximum; infusion durations varied (40 or 100 minutes, or mixed). The clinical trial defined remission as a Montgomery-Åsberg Depression Rating Scale (MÅDRS) score of ≤9 at 24 hours after the final infusion; the qualitative study used the broader term recovery to capture patient-reported outcomes beyond that single time-point rating. (MÅDRS is a 10-item clinician-rated scale commonly used in ketamine research; higher scores indicate more severe depression.) All 75 Bio-K participants were invited; 36 expressed initial interest and 21 completed qualitative interviews (15 women, six men). The qualitative sample was 90% white, mean age 44, and the average interval between the Bio-K infusions and the qualitative interview was about 29 months (range ~11 months to ~50 months). The recruitment goal was to balance approximately 10 remitters and 10 non-remitters, and recruitment stopped after reaching roughly equal numbers. Participants completed a semi-structured, retrospective interview by HIPAA-compliant videoconference; audio only was recorded. Interviews lasted on average about 40 minutes. The interview guide probed first infusion experiences, changes over time after treatment, and beliefs about mechanism, and interviewers received standardised training and supervision. Transcripts were produced from audio, cleaned, and analysed with inductive qualitative methods using Dedoose software. A coding team iteratively developed a codebook: multiple transcripts were double-coded and discussed until consensus, then remaining transcripts were single-coded with periodic audit checks. In sum, 12 transcripts (57%) were coded by more than one team member and nine transcripts (43%) by a single coder. After coding was complete, participants were assigned remission-related attributes based on their MÅDRS scores (≤9 = remitter; >9 = non-remitter), and non-remitters with at least 50% MÅDRS reduction were labelled partial remitters. The assignment of these attributes occurred post hoc to reduce bias in coding.

Twenty-one participants were interviewed. Using the study's MÅDRS-based cut-off, nine participants (43%) were classified as remitters and 12 (57%) as non-remitters; among the full sample three participants (14% overall, 25% of the non-remission subgroup) met the study's threshold for partial remission (≥50% MÅDRS reduction). Most participants (18; 86%) had subsequently obtained further ketamine treatment after Bio-K in community clinics or via a prescribing provider. The qualitative sample was predominantly white and had a wide range in the time elapsed since the original infusions (mean ~29 months). Experiences during infusions were heterogeneous. Twelve participants reported what the authors described as a “psychedelic-like” or dissociative experience (examples given include perceptual distortions, a sense of flying, or euphoria). Reports of pleasant versus unpleasant infusion experiences varied by outcome group: among the combined remitter/partial remitter group some participants described positive or pleasant experiences and a minority described negative experiences, while a larger proportion of non-remitters reported pleasant experiences and none in that subgroup were characterised as having negative infusion experiences in the extracted text. Twelve participants (differentially distributed across outcome groups) described gaining existential insights or shifts in perspective during infusions, such as increased forgiveness, compassion, or acceptance; the presence of a dissociative experience did not perfectly predict whether existential insight occurred. When asked about ketamine's place in their illness trajectory, many participants initially felt optimism and hope, viewing ketamine as a radical option justified by prior treatment failures. Remission narratives frequently included changes in mood, outlook, interpersonal connectedness, energy and cognitive flexibility. By contrast, for some non-remitters the failure of ketamine produced profound disappointment and reinforced a narrative of an untreatable illness—a ‘‘chain’’ of failed treatments that could exacerbate hopelessness. Participants' beliefs about mechanism varied. The majority in both remitter/partial remitter and non-remitter groups described biological or physical explanations (for example, changes to brain chemicals or pathways). A smaller subset—more represented among non-remitters in the extracted text—emphasised experiential explanations (new perspectives or insights). One participant combined both types of beliefs. A notable and unexpected empirical finding was a mismatch between quantitative and qualitative assessments of recovery. The paper reports that five participants who had been classified as non-remitters by MÅDRS nonetheless described substantial subjective improvement or partial/full recovery in the interviews (for example, ceasing anxiety medications and improved functioning leading them to pursue further ketamine). However, the extracted text contains inconsistencies in the reported denominators for non-remitters in different paragraphs, so the exact counts and proportions for this discordance are not reported unambiguously in the provided extract. The authors present illustrative participant quotations to exemplify themes such as dissociation providing relief, biological metaphors for mechanistic action, and increased cognitive flexibility after ketamine.

Lapidos and colleagues interpret their findings as indicating substantial heterogeneity in subjective responses to IV ketamine among people with treatment-resistant depression: psychedelic-like experiences, pleasantness, unpleasantness, and existential insights occurred across both remitters and non-remitters. The investigators highlight a practical implication that clinicians should avoid equating dissociation or ‘‘psychedelic’’ experiences with clinical benefit, because dissociation was neither necessary nor sufficient for improvement; decoupling the phenomenology of the infusion from expected clinical outcomes could help avoid unnecessarily high dosing aimed at producing dissociation. At the same time, the authors argue that clinicians should validate patients who report meaningful insights from infusions and discuss patient preferences about guided conversation or support during treatment, since participants varied in whether they wanted staff interaction. They further recommend explicitly discussing the risk of disappointment when offering novel treatments to people with a long history of treatment resistance, because failure of a new intervention can compound feelings of hopelessness. The discrepancy between questionnaire-based remission (MÅDRS) and patient narratives is emphasised as a reason to supplement standard symptom scales with qualitative inquiry; some participants reported important functional or quality-of-life gains that did not map onto short-term depressive symptom ratings. The authors situate this finding within the idea of two related but distinct continua—mental illness and mental health—and note that changes such as reductions in suicidal ideation can occur independently of mood score improvements. Several limitations are acknowledged. The sample was homogeneous with respect to race and ethnicity and limited to people with treatment-resistant depression, so themes may not generalise to diverse populations or to people with comorbidities such as substance use disorder, chronic pain, or PTSD. The retrospective design introduced heterogeneity in time elapsed since the original infusions (average ~29 months, range ~11–50 months) and in subsequent treatment-seeking (86% obtained further ketamine), which may have influenced recollections. Finally, the authors caution that their qualitative findings do not provide evidence supporting routine provision of psychotherapy during or immediately after IV ketamine, given the lack of manuals and pivotal trials in that area. Overall, the study team conclude that qualitative methods can enrich understanding of IV ketamine's impact by revealing multiple recovery pathways and patient-valued outcomes beyond a single rating-scale endpoint, and they call for comprehensive approaches to assessing recovery in future research.