Frontiers in Psychiatry
January 1, 2022
Joost J. Breeksema, Alistair Niemeijer, Bouwe Kuin et al.
41 citations
Patients with treatment-resistant depression undergoing oral esketamine treatment often find the experience overwhelming and struggle with whether to let go or maintain control. Their ability to let go is influenced by preparation, emotional support, and the treatment setting. Better preparation, an optimized environment, and psychological support during sessions may improve patients' experiences and outcomes. The study provides recommendations for improving quality of care, including training for nurses and support staff.
The lancet. Psychiatry
January 1, 2025
Carolina Seybert, Nina Schimmers, Lucio Silva et al.
26 citations
Reporting on the psychological intervention component of psychedelic-assisted psychotherapy is mostly incomplete and inconsistent across studies, limiting replicability and clinical translation. A systematic review of 45 original studies on psilocybin, MDMA, LSD, or ayahuasca for mental disorders found that descriptions of psychotherapy varied widely and completeness of information was generally low, based on an adapted Template for Intervention Description and Replication checklist. Studies involving MDMA showed more homogeneous psychotherapy and more procedural details. Improved reporting on psychological interventions would support replicability, generalisability, and accurate interpretation of research, as well as enhance feasibility and safety of future clinical research and real-world implementation.
Psychopharmacology
July 1, 2023
Joost J. Breeksema, Alistair Niemeijer, Bouwe Kuin et al.
26 citations
The effects of oral esketamine for treatment-resistant depression are highly variable, and psychological distress is common. Patients report perceptual changes, detachment from body and emotions, stillness, mystical-type experiences, and fear. After sessions, many feel hungover and fatigued, while depressive mood is neutralized. Some effects, such as increased openness and detachment, may hold psychotherapeutic potential, but the frequent distress calls for additional patient support throughout treatment.
Molecular Psychiatry
September 1, 2024
Sanne Y Smith-Apeldoorn, Jolien K E Veraart, Jeanine Kamphuis et al.
23 citations
A randomized placebo-controlled trial tested whether a fixed low dose of oral esketamine (30 mg three times daily) could reduce depression severity in patients with treatment-resistant depression. Over six weeks, the drug showed no benefit compared to placebo on the Hamilton Depression Rating Scale. Dizziness and sleep hallucinations were more common with esketamine. In an open-label extension phase where doses were individually titrated up to 3.0 mg/kg twice weekly, depressive symptoms decreased substantially. The findings suggest that fixed low-dose oral esketamine is ineffective, but individually adjusted higher doses may hold promise for treatment-resistant depression.
Psychiatry Research
March 1, 2025
Juliana Lima Constantino, Martijn Godschalk, Jens H van Dalfsen et al.
14 citations
About half of people with treatment-resistant depression do not respond to (es)ketamine, despite its known efficacy. This systematic review of 44 studies examined whether demographic or clinical traits predict who will respond or remit after (es)ketamine treatment. Overall, most demographic and clinical variables showed no consistent predictive value. Preliminary evidence linked better response to anhedonia, sleep disturbances, childhood physical abuse, obesity, openness, better episodic memory and visual learning, poorer neurocognitive performance, slower processing speed, and lower attention, while melancholic depression, benzodiazepine use, and metabolic syndrome were linked to worse response. These associations need replication, but suggest (es)ketamine may benefit patients with characteristics often considered hard to treat.
European Journal of Pharmacology
July 5, 2025
Jolien K E Veraart, Sanne Y Smith-Apeldoorn, Jeanine Kamphuis et al.
2 citations
Oral esketamine shows low and variable bioavailability, complicating its use as an antidepressant. In 17 patients with treatment-resistant depression given oral esketamine twice weekly for six weeks with a titration approach, esketamine and noresketamine serum levels were measured 30 and 60 minutes after administration. No association was found between changes in depressive symptoms and any pharmacokinetic outcomes, including serum levels of esketamine, noresketamine, their sum, or ratios. High inter-individual variability in pharmacokinetics was observed. The small sample and flexible-dose regimen limit conclusions. Clinical response may not correspond to esketamine pharmacokinetics, suggesting individually-based titration according to clinical effects is optimal.
Pharmaceuticals (Basel, Switzerland)
April 25, 2025
Jolien K E Veraart, Cornelis F Vos, Nieko C Punt et al.
2 citations
In patients with treatment-resistant depression receiving oral esketamine for six weeks, plasma concentrations of esketamine and noresketamine on day 39 were 59% and 35% lower than predicted by a pharmacokinetic model. This suggests that auto-induction of drug-metabolizing enzymes CYP3A4 and CYP2B6 occurs, which may explain the diminished therapeutic effects and side effects observed with long-term use. Identifying auto-induction as a mechanism of tolerance could have important clinical implications for maintaining efficacy.
The Journal of ECT
January 21, 2025
Daniël T Coerts, Jolien K E Veraart, Jeanine Kamphuis et al.
1 citation
In eight patients with treatment-resistant depression, repeated oral esketamine was tested as a replacement for maintenance electroconvulsive therapy (M-ECT). Over six weeks, esketamine doses were gradually increased up to 3.0 mg/kg twice weekly. Depression severity remained stable or improved in five patients, while three worsened and resumed M-ECT. Among five patients with available scores, all showed improvement on the Outcome Questionnaire 45. Four patients continue to receive oral esketamine. Oral esketamine may offer a suitable, patient-friendly alternative to M-ECT, though controlled trials are needed to confirm long-term safety and efficacy.
Journal of Psychiatric Research
June 12, 2026
Juliana Lima Constantino, Tobias Stephan Freimann, Jens H van Dalfsen et al.
Oral esketamine can be an effective and well-tolerated treatment for treatment-resistant depression (TRD), but about half of those treated do not respond. This study tested whether sociodemographic and clinical features, including depressive symptoms and treatment resistance, could predict how much depressive symptoms would improve in 131 TRD patients receiving individually adjusted oral esketamine doses (0.5 mg/kg to 3 mg/kg) twice weekly for six weeks. Machine learning models—linear regression, elastic net, and random forest—failed to predict symptom change above chance. The findings suggest that oral esketamine may work similarly across the TRD population, regardless of treatment-resistance levels.
The pharmacogenomics journal
April 24, 2026
Daniël T Coerts, Sanne Y Smith-Apeldoorn, Jérôme C Oude Nijhuis et al.
A genetic variation in the CYP2B6 enzyme, known as 516 G > T, is linked to higher blood levels of oral esketamine four hours after dosing in people with treatment-resistant depression. In a small sample of 18 participants from a placebo-controlled trial, carriers of the variant had median esketamine levels of 5.1 µg/L, compared to 2.1 µg/L in non-carriers. No significant associations were found for two other genetic variants, CYP3A4*22 and CYP3A5*3, but the numbers of carriers were very small. Larger studies are needed to clarify their effects.
February 10, 2026
Jolien K E Veraart
Treatment-resistant depression is a poorly defined label that may harm patients' hope. Survey data show many individuals seeking ketamine treatment have long-standing depressive symptoms and dissatisfaction with standard therapies. Fixed low doses of oral esketamine were not effective in a randomized controlled trial, but higher, individualized dosing led to meaningful improvement in a subgroup. Ketamine was often effective and well tolerated in complex cases, including patients with psychotic symptoms, PTSD, or those on maintenance ECT, especially with supportive monitoring. Combining ketamine with psychotherapy appears promising but needs more research. A key pharmacological finding is that repeated oral use may speed up ketamine's own metabolism (auto-induction), potentially reducing long-term effectiveness.
Pharmacogenomics
December 12, 2025
Jérôme C Oude Nijhuis, Daniël T Coerts, Jens H van Dalfsen et al.
Oral esketamine is a promising treatment for depression that does not respond to other therapies, but how much of the drug reaches the bloodstream varies from person to person. This study tested whether common genetic variations in two drug-transport proteins, ABCB1 and ABCG2, affect esketamine levels in the blood. In 18 participants from a placebo-controlled trial, esketamine concentrations four hours after dosing did not differ significantly among people with different ABCB1 or ABCG2 genotypes. Metabolite levels also showed no association with these genetic variants. The findings suggest that these transporter polymorphisms do not influence oral esketamine pharmacokinetics, though the small sample size means the results are preliminary and need confirmation in larger studies.
Journal of Affective Disorders
July 16, 2026
Sara Massetti, Sanne Y Smith-Apeldoorn, Jolien K E Veraart et al.
Ketamine and its enantiomer esketamine are effective in only 30-35% of patients with treatment-resistant depression. Increased serum brain-derived neurotrophic factor (BDNF) after a single intravenous dose has been proposed as a biomarker of antidepressant response, but effects under different treatment schedules are unclear. In a randomized, placebo-controlled trial of six-week, low-dose, oral esketamine (90 mg/day, three 30 mg intakes), depression severity and serum BDNF were measured in 54 patients at baseline, end of treatment, and after a four-week washout. BDNF levels did not significantly differ between esketamine and placebo groups during treatment or washout. An increase in BDNF occurred regardless of treatment condition.
Psychopharmacology
January 1, 2022
Nina Schimmers, Joost J. Breeksema, Sanne Y Smith-Apeldoorn et al.
Both classical psychedelics (DPT, LSD, psilocybin) and atypical psychedelics (MDMA, ketamine) show promise for reducing anxiety, depression, and existential distress in terminally ill patients, with recent controlled trials indicating positive effects on existential and spiritual well-being, quality of life, and acceptance while causing few adverse and no serious adverse effects. Early studies had serious methodological flaws, but newer trials are of higher quality. Larger high-quality studies are still needed for classical psychedelics and MDMA, and ketamine research should better address existential well-being and psychotherapeutic context.
BMC Psychiatry
November 29, 2019
Sanne Y Smith-Apeldoorn, Jolien K E Veraart, Jeanine Kamphuis et al.
A triple-blind randomized placebo-controlled trial investigates daily oral esketamine versus placebo as an add-on to regular antidepressants in patients with treatment-resistant depression over 6 weeks, followed by a 4-week follow-up. This is the first such trial to examine the efficacy, safety, tolerability, mechanisms of action, and economic impact of repeated oral esketamine administration. If effective and tolerated, oral esketamine offers practical advantages over intravenous administration. The study aims to address the urgent need for additional treatment strategies for treatment-resistant depression.