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.
Journal of psychopharmacology (Oxford, England)
April 25, 2025
Jolien Ke Veraart, Sanne Y Smith-Apeldoorn, Annemarie van der Meij et al.
6 citations
Oral esketamine, taken twice weekly for six weeks at doses from 0.5 to 3 mg/kg, reduced depressive symptom severity in adults with severe treatment-resistant depression who had not benefited from an average of 8.1 prior antidepressant trials and, in 63% of cases, electroconvulsive therapy. Hamilton Depression Rating Scale scores dropped from 21.2 to 15.8. Nearly half of participants achieved a clinically meaningful improvement, 26.8% responded, and 15.6% remitted. Side effects were common but well tolerated, with a 7.6% dropout rate and no significant urinary or cognitive adverse effects. Treatment continued beyond six weeks in 45.9% of participants to maintain gains.
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.
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.