Clinical outcomes in the biomarkers of ketamine (Bio-K) study of open-label IV ketamine for refractory depression.

OBJECTIVE: We conducted an open-label clinical trial ("Bio-K") using IV ketamine for treatment-resistant depression to identify biomarkers linked to remission. Here, we report the clinical efficacy and side effect outcomes of Bio-K. METHODS: Across 4 US sites, 75 patients ages 18-65 with treatment-refractory unipolar or bipolar depression received 3 IV ketamine infusions over an 11-day period. Key exclusion criteria were psychotic symptoms, significant substance abuse, unstable medical conditions, and any use of cannabis. Pre-existing antidepressant medication was maintained. Primary outcome was remission as measured by Montgomery-Asberg Depression Rating Scale (MADRS), with secondary outcome of 50 % reduction in Beck Suicide Scale score. Safety monitoring and varying durations of infusions were also key parameters. RESULTS: Using remission as MADRS score <10, after 3 infusions 52 % achieved remission, with 67 % achieving response. Of those achieving response after a single infusion, 66 % (22 of 33) reached remission after 3 infusions, while 40 % (16 of 40) non-responders after the first infusion went on to achieve remission after 3 infusions. Only 20 % of non-responders after 2 infusions achieved remission. Most (81 %) participants had significant suicidal ideation at baseline; of these, two-thirds (67 %) experienced at least a 50 % reduction in suicidality. Side effects were minimal. Uniquely, we had three different types of infusion categories, with individuals receiving: (1) slow (100-min) infusions only or (2) regular (40-min) infusions only or (3) a mix of infusion durations. These three infusion groups showed comparable safety and efficacy. Exploration of clinical factors revealed no link between BMI, age, or gender to remission. CONCLUSIONS: The consistency of outcomes across 4 clinical sites and across multiple instruments, suggests high acute efficacy and safety of IV ketamine for serious depressive episodes. Duration of infusion did not alter outcomes. Meaningfully, 40 % of non-responders after a single infusion did reach remission subsequently, while only 20 % of non-responders after 2 infusions achieved remission, suggesting early response is suggestive for eventual remission. Our data on varying ketamine infusion duration adds novel insights into the clinical administration of this new treatment for refractory and severe patients. Our limitations included a lack of a control group, necessitating caution about conclusions of efficacy, balanced by the utility of reporting "real-world" outcomes across multiple clinical sites. We could also not separately analyze results for bipolar disorder due to small numbers. Together, the Bio-K clinical results are promising and provide significant sample sizes for forthcoming biological markers analyses.

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

BACKGROUND: Intravenous (IV) ketamine is an effective therapy for treatment-resistant depression. A large data base is confirmatory and steadily expanding. Qualitative studies can inform best practices and suggest new research directions. As part of a clinical trial designed to identify biomarkers of ketamine response, a qualitative study was conducted to characterize experiences with: receiving infusions; recovering or not recovering from depression; and beliefs about why ketamine worked or did not work. METHODS: Adults with treatment-resistant depression received three IV ketamine infusions in a two-week period and were characterized as remitters or non-remitters via symptom reduction 24 h after the third infusion. Qualitative interviews of a subset of participants were audio recorded, transcribed verbatim, and coded using deductive and inductive methods. Themes were derived and compared across a broader construct of recovery status. RESULTS: Of the 21 participants, nine (43 %) were characterized as having experienced remission and 12 (57 %) non-remission. Of the 12 non-remitters, five were characterized as having experienced partial recovery based on their subjective experiences, reporting substantial benefit from ketamine infusions despite non-remission status based on scale measurements. Attributions for ketamine's effects included biological and experiential mechanisms. Among non-remitters there was risk of disappointment when adding another failed treatment. LIMITATIONS: A more diverse sample may have yielded different themes. Different patients had different amounts of time elapsed between ketamine infusions and qualitative interview. CONCLUSIONS: Qualitative methods may enhance researchers' characterization of IV ketamine's impact on treatment-resistant depression. While requiring confirmation, patients may benefit from a preparatory milieu that prepares them for multiple recovery pathways; decouples the psychedelic experience from clinical outcomes; and addresses potential risks of another failed treatment.