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. 2025;23(10):1301-1312.
doi: 10.2174/011570159X356952241216172603.

The Potential Influence of Associated Antidepressants on the Pharmacokinetic Profile of Esketamine in Patients Affected by Treatment-resistant Depression

Marika Alborghetti  1 , Luana Lionetto  2 , Ginevra Lombardozzi  3 , Luca Montaguti  4 , Giada Trovini  3 , Daniela Donato  3 , Giuseppe Costanzi  2 , Donatella De Bernardini  2 , Federica Catapano  4 , Michele Surano  4 , Ilaria Pagano  4 , Alessia Ceccherelli  4 , Edoardo Bianchini  1   5 , Giorgio Di Lorenzo  6   7 , Maurizio Simmaco  1   2 , Giovanni Martinotti  8   9 , Georgios D Kotzalidis  3 , Ferdinando Nicoletti  4   10 , Sergio De Filippis  3
Affiliations

The Potential Influence of Associated Antidepressants on the Pharmacokinetic Profile of Esketamine in Patients Affected by Treatment-resistant Depression

Marika Alborghetti et al. Curr Neuropharmacol. 2025.

Abstract

Introduction/objective: Esketamine is administered intranasally in combination with at least another antidepressant in patients with treatment-resistant depression. Some of these antidepressants might affect ketamine's pharmacokinetic profile by inhibiting cytochrome-P450 (CYP450) isoforms. Our aim was to establish how different types of combined antidepressants affect serum and salivary levels of esketamine at the time of maximum plasma concentrations and afterward in TRD patients receiving esketamine in a real-world context.

Methods: Serum and salivary samples were collected from 53 patients receiving intranasal esketamine (56 mg) at baseline, after 20 min (roughly corresponding to Tmax), 7 hours (corresponding to the t½ value), 24, and 72 hours. Patients were stratified according to the combined antidepressant medication.

Results: Salivary esketamine levels were several-fold higher than the corresponding serum levels at all time points, and showed high inter-individual variability. Serum 20-min post-esketamine levels and AUC0-72 levels were significantly higher in patients on antidepressants known to inhibit different isoforms of CYP450 (paroxetine, fluoxetine, duloxetine, venlafaxine), with respect to levels detected in patients on sertraline, citalopram, escitalopram, vortioxetine. These changes in the pharmacokinetic profile of esketamine did not affect the clinical outcome of esketamine. However, changes in systolic blood pressure in response to esketamine positively correlated with serum esketamine levels, suggesting a reduction of esketamine dose in patients with cardiovascular comorbidity under treatment with paroxetine, fluoxetine, duloxetine, venlafaxine.

Conclusion: The CY450-related status of co-administered antidepressants may affect esketamine levels. However, the small sample sizes of the co-administered drug subgroups and multiple prescriptions do not allow for drawing strong conclusions.

Keywords: Esketamine; antidepressant drugs; cytochrome P450 isoenzymes.; depression; pharmacokinetics; treatment-resistant.

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Conflict of interest statement

The Dr. Ferdinando Nicoletti is the Editor-in-Chief of the journal Current Neuropharmacology.

Figures

Fig. (1)
Fig. (1)
Serum esketamine levels in subgroups of patients under treatment with different types of antidepressants. Patients were arbitrary subdivided into six groups. Group 1 included patients on SSRIs known to inhibit drug metabolism (fluoxetine and paroxetine); groups 2 and 3 included patients who were on duloxetine or venlafaxine/desvenlafaxine, respectively; patients in group 4 were on SSRIs with low/negligible impact on drug metabolism (citalopram/escitalopram/sertraline); patients in group 5 were on vortioxetine; and patients in group 6 were on mirtazapine, trazodone or clomipramine. Esketamine levels (means ± SEM) at 20 minutes, 7 hours, and 24 hours following intranasal esketamine administration are shown in (A, B and C), respectively, AUC 0.72 values (means ± SEM) are shown in (D). ONE WAY ANOVA + Fisher’s LSD: A, B, C *p< 0.05 vs. groups 4 and 5; (C) #p<0.05 vs. group 4. Statistically significant outliers were identified using Grubbs’ test (alpha=0.05) and excluded from further analysis.
Fig. (2)
Fig. (2)
Salivary esketamine levels in subgroups of patients treated with different types of antidepressants. Patients were arbitrary subdivided into six groups. Group 1 included patients on SSRIs known to inhibit drug metabolism (fluoxetine and paroxetine); groups 2 and 3 included patients who were on duloxetine or venlafaxine/desvenlafaxine, respectively; patients in group 4 were on SSRIs with low/negligible impact on drug metabolism (citalopram/escitalopram/sertraline); patients in group 5 were on vortioxetine; and patients in group 6 were on mirtazapine, trazodone or clomipramine. Esketamine levels (means ± SEM) at 20 minutes, 7 hours, and 24 hours following intranasal esketamine administration are shown in A, B and C, respectively, AUC 0.72 values (means ± SEM) are shown in D. ONE WAY ANOVA + Fisher’s LSD: C *p<0.05 vs. groups 4, 5 and 6. D #p<0.05 vs. groups 2, 4, 5 and 6. Statistically significant outliers were identified using Grubbs’ test (alpha = 0.05) and excluded from further analysis.
Fig. (3)
Fig. (3)
Positive correlation between serum esketamine levels and changes in systolic blood pressure (SBP) at 20 minutes following esketamine administration.
Fig. (4)
Fig. (4)
Positive correlation between serum esketamine levels and changes in agitation/calmness scale (ACES) score at 20 minutes following esketamine administration. Correlation with differential ACES (A) and absolute ACES scores (B) between BL and 20 minutes post intranasal esketamine.
Fig. (5)
Fig. (5)
HAM-A scores. Positive correlation between HAM-A scores and esketamine values at 20 minutes and AUC 0.72 values.
Fig. (6)
Fig. (6)
YMRS scores. Positive correlation between YMRS scores and serum esketamine levels (A) and AUC 0.72 values (B).
Fig. (7)
Fig. (7)
Combination of activity items of BPRS score: 7 (elated mood), 19 (tension), 21 (excitement), 23 (motor hyperactivity), and 24 (mannerism and posturing). Negative correlation between BPRS-activity scores and either esketamine values at 20 minute or AUC 0.72 values are shown in (A and B), respectively.
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