Effect of Esketamine Nasal Spray on Olfactory Function and Nasal Tolerability in Patients with Treatment-Resistant Depression: Results from Four Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Studies.
Administration, Intranasal
/ instrumentation
Antidepressive Agents
/ administration & dosage
Depressive Disorder, Treatment-Resistant
/ drug therapy
Double-Blind Method
Drug Therapy, Combination
/ methods
Female
Humans
Ketamine
/ administration & dosage
Male
Middle Aged
Nasal Sprays
Nose Diseases
/ chemically induced
Olfaction Disorders
/ chemically induced
Olfactometry
/ methods
Time
Treatment Outcome
Journal
CNS drugs
ISSN: 1179-1934
Titre abrégé: CNS Drugs
Pays: New Zealand
ID NLM: 9431220
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
accepted:
04
05
2021
pubmed:
9
7
2021
medline:
1
2
2022
entrez:
8
7
2021
Statut:
ppublish
Résumé
Intranasal drug delivery offers a non-invasive and convenient dosing option for patients and physicians, especially for conditions requiring chronic/repeated-treatment administration. However, in some cases such delivery may be harmful to nasal and olfactory epithelia. The aim of this study was to assess the potential impact of long-term intermittent treatment with esketamine nasal spray, taken in conjunction with an oral antidepressant (AD), on olfactory function and nasal tolerability in patients with treatment-resistant depression (TRD). A total of 1142 patients with TRD participated from four multicenter, randomized, double-blind, phase III studies: three short-term studies (two in patients aged 18-64 years, one in patients ≥65 years), and one long-term maintenance study of esketamine nasal spray + AD versus placebo nasal spray + AD. Across the four studies, assessments were performed at 208 sites in 21 countries. Olfactory function was measured using the 40-item University of Pennsylvania Smell Identification Test (UPSIT Of 1142 participants, 734 were women (64.3%). The mean age of all participants ranged from 45.7 to 70.0 years across the studies. Overall, 855 patients received esketamine nasal spray + AD and 432 received placebo nasal spray + AD. Objective evaluation of nasal function showed no evidence of an adverse impact following esketamine administration. Based on the UPSIT Findings from this analysis indicate that there was no evidence of adverse effect on either olfactory or nasal health measures with repeated intermittent administration of esketamine nasal spray at any dose over the course of short-term (4 weeks) or long-term (16-100 weeks) studies. TRANSFORM-1: NCT02417064, date of registration: 15/04/2015; TRANSFORM-2: NCT02418585, date of registration: 16/04/2015; TRANSFORM-3: NCT02422186, date of registration: 21/04/2015; SUSTAIN-1: NCT02493868, date of registration: 10/07/2015.
Sections du résumé
BACKGROUND
Intranasal drug delivery offers a non-invasive and convenient dosing option for patients and physicians, especially for conditions requiring chronic/repeated-treatment administration. However, in some cases such delivery may be harmful to nasal and olfactory epithelia.
OBJECTIVE
The aim of this study was to assess the potential impact of long-term intermittent treatment with esketamine nasal spray, taken in conjunction with an oral antidepressant (AD), on olfactory function and nasal tolerability in patients with treatment-resistant depression (TRD).
METHODS
A total of 1142 patients with TRD participated from four multicenter, randomized, double-blind, phase III studies: three short-term studies (two in patients aged 18-64 years, one in patients ≥65 years), and one long-term maintenance study of esketamine nasal spray + AD versus placebo nasal spray + AD. Across the four studies, assessments were performed at 208 sites in 21 countries. Olfactory function was measured using the 40-item University of Pennsylvania Smell Identification Test (UPSIT
RESULTS
Of 1142 participants, 734 were women (64.3%). The mean age of all participants ranged from 45.7 to 70.0 years across the studies. Overall, 855 patients received esketamine nasal spray + AD and 432 received placebo nasal spray + AD. Objective evaluation of nasal function showed no evidence of an adverse impact following esketamine administration. Based on the UPSIT
CONCLUSION
Findings from this analysis indicate that there was no evidence of adverse effect on either olfactory or nasal health measures with repeated intermittent administration of esketamine nasal spray at any dose over the course of short-term (4 weeks) or long-term (16-100 weeks) studies.
CLINICAL TRIAL REGISTRATION
TRANSFORM-1: NCT02417064, date of registration: 15/04/2015; TRANSFORM-2: NCT02418585, date of registration: 16/04/2015; TRANSFORM-3: NCT02422186, date of registration: 21/04/2015; SUSTAIN-1: NCT02493868, date of registration: 10/07/2015.
Identifiants
pubmed: 34235612
doi: 10.1007/s40263-021-00826-9
pii: 10.1007/s40263-021-00826-9
pmc: PMC8310483
doi:
Substances chimiques
Antidepressive Agents
0
Nasal Sprays
0
Esketamine
50LFG02TXD
Ketamine
690G0D6V8H
Banques de données
ClinicalTrials.gov
['NCT02418585', 'NCT02417064', 'NCT02422186', 'NCT02493868']
Types de publication
Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
781-794Informations de copyright
© 2021. The Author(s).
Références
Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2012;6:369–88.
doi: 10.2147/PPA.S29716
Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. 1996;19(2):179–200.
doi: 10.1016/S0193-953X(05)70283-5
Berlim MT, Turecki G. Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods. Can J Psychiatry. 2007;52(1):46–54.
doi: 10.1177/070674370705200108
Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiat. 2018;75(2):139–48.
doi: 10.1001/jamapsychiatry.2017.3739
Wei Y, Chang L, Hashimoto K. A historical review of antidepressant effects of ketamine and its enantiomers. Pharmacol Biochem Behav. 2020;190:172870.
Esketamine (Spravato
Andrade C. Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression. J Clin Psychiatry. 2015;76(5):e628–31.
doi: 10.4088/JCP.15f10026
Genter MB, Krishan M, Prediger RD. The olfactory system as a route of delivery for agents to the brain and circulation. In: Doty RL, editor. Handbook of olfaction and gustation. 3rd edn. Wiley-Blackwell; 2015. pp. 453–84.
Fanta S, Kinnunen M, Backman JT, Kalso E. Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing. Eur J Clin Pharmacol. 2015;71(4):441–7.
doi: 10.1007/s00228-015-1826-y
Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Nacran nasal spray medical review comments. 2015. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208411Orig1s000MedR.pdf . Accessed 1 Dec 2020.
Calderón-Garcidueñas L, González-Maciel A, Reynoso-Robles R, Kulesza RJ, Mukherjee PS, Torres-Jardón R, et al. Alzheimer's disease and alpha-synuclein pathology in the olfactory bulbs of infants, children, teens and adults≤ 40 years in Metropolitan Mexico City. APOE4 carriers at higher risk of suicide accelerate their olfactory bulb pathology. Environ Res. 2018;166:348–62.
Kuehn BM. Zicam update. JAMA. 2010;303(16):1587. https://doi.org/10.1001/jama.2010.457 .
doi: 10.1001/jama.2010.457
Doty RL, Shaman P, Dann M. Development of the University of Pennsylvania Smell Identification Test: a standardized microencapsulated test of olfactory function. Physiol Behav. 1984;32:489–502.
doi: 10.1016/0031-9384(84)90269-5
Daly EJ, Trivedi MH, Janik A, Li H, Zhang Y, Li X, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiat. 2019;76(9):893–903.
doi: 10.1001/jamapsychiatry.2019.1189
Fedgchin M, Trivedi M, Daly EJ, Melkote R, Lane R, Lim P, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019;22(10):616–30.
doi: 10.1093/ijnp/pyz039
Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428–38.
doi: 10.1176/appi.ajp.2019.19020172
Ochs-Ross R, Daly EJ, Zhang Y, Lane R, Lim P, Morrison RL, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression-TRANSFORM-3. Am J Geriatr Psychiatry. 2020;28(2):121–41.
doi: 10.1016/j.jagp.2019.10.008
Doty RL, Shaman P, Applebaum SL, Giberson R, Siksorski L, Rosenberg L. Smell identification ability: changes with age. Science. 1984;226(4681):1441–3.
doi: 10.1126/science.6505700
Doty RL, Wylie C, Potter M, Beston R, Cope B, Majam K. Clinical validation of the olfactory detection threshold module of the Snap & Sniff
doi: 10.1002/alr.22377
Doty RL. The Smell Identification Test
Doty RL. The Snap & Sniff
Doty RL, Frye RE, Agrawal U. Internal consistency reliability of the fractionated and whole University of Pennsylvania Smell Identification Test. Percept Psychophys. 1989;45(5):381–4.
doi: 10.3758/BF03210709
Schwartz BS, Doty RL, Monroe C, Frye R, Barker S. Olfactory function in chemical workers exposed to acrylate and methacrylate vapors. Am J Pub Health. 1989;79(5):613–8.
doi: 10.2105/AJPH.79.5.613
Yilmaz Y, Karakas Z, Uzun B, Sen C, Comoglu S, Orhan KS, et al. Olfactory dysfunction and quality of life in patients with transfusion-dependent thalassemia. Eur Arch Otorhinolaryngol. 2017;274(9):3417–21.
doi: 10.1007/s00405-017-4668-7
Hawkes CH, Doty RL. Smell and taste disorders. Cambridge: Cambridge University Press; 2018.
doi: 10.1017/9781139192446
Kamath V, Paksarian D, Cui L, Moberg PJ, Turetsky BI, Merikangas KR. Olfactory processing in bipolar disorder, major depression, and anxiety. Bipolar Disord. 2018;20(6):547–55.
doi: 10.1111/bdi.12625
Amsterdam JD, Settle RG, Doty RL, Abelman E, Winokur A. Taste and smell perception in depression. Biol Psychiatry. 1987;22(12):1481–5.
doi: 10.1016/0006-3223(87)90108-9
Taalman H, Wallace C, Milev R. Olfactory functioning and depression: a systematic review. Front Psychiatry. 2017;8:190.
doi: 10.3389/fpsyt.2017.00190
Croy I, Symmank A, Schellong J, Hummel C, Gerber J, Joraschky P, et al. Olfaction as a marker for depression in humans. J Affect Disord. 2014;160:80–6.
doi: 10.1016/j.jad.2013.12.026
Pause BM, Raack N, Sojka B, Göder R, Aldenhoff JB, Ferstl R. Convergent and divergent effects of odors and emotions in depression. Psychophysiology. 2003;40(2):209–25.
doi: 10.1111/1469-8986.00023
Deems DA, Doty RL. Age-related changes in the phenyl ethyl alcohol odor detection threshold. Trans Pa Acad Ophthalmol Otolaryngol. 1987;39(1):646–50.
pubmed: 2453958
Doty RL, Kamath V. The influences of age on olfaction: a review. Front Psychol. 2014;5:20.
doi: 10.3389/fpsyg.2014.00020