Response to Agomelatine Treatment is Independent of Smoking Status and Dosage: Results From the AGOPSYCH Study

Abstract

Introduction Cigarette smoking influences response to antidepressant treatment. It accelerates the metabolism of several cytochrome P450 (CYP) subtypes, including CYP1A2, and therefore bears the risk of pharmacokinetic interactions with psychotropic drugs using that pathway. Agomelatine is a substrate of CYP1A2; the association between nicotine use and agomelatine dosage, however, has never been studied before.

Methods Smoking habits were correlated with agomelatine doses and treatment outcomes in a sample of 27 patients with lifetime diagnoses within the schizophrenia spectrum who received agomelatine treatment in addition to their stable antipsychotic treatment regimen because of depressive symptoms.

Results No interactions were found between smoking status and agomelatine dosage, and treatment outcomes did not differ between smokers and nonsmokers.

Discussion Agomelatine efficacy appears to be independent of dosage and smoking status, pointing toward mechanisms beyond mere dose-response relationships. Further research will be necessary to validate these findings.

Key words

agomelatine - nicotine - smoking - interaction - pharmacokinetics - CYP1A2 - schizophrenia - depression

• References

• 1 Kalman D, Morissette SB, George TP. Co-morbidity of smoking in patients with psychiatric and substance use disorders. Am J Addict 2005; 14: 106-123
• 2 Oliveira P, Ribeiro J, Donato H. et al. Smoking and antidepressants pharmacokinetics: A systematic review. Ann Gen Psychiatry 2017; 16: 17-24
• 3 Pelkonen O, Turpeinen M, Hakkola J. et al. Inhibition and induction of human cytochrome P450 enzymes: Current status. Arch Toxicol 2008; 82: 667-715
• 4 Zhou SF, Wang B, Yang LP. et al. Structure, function, regulation and polymorphism and the clinical significance of human cytochrome P450 1A2. Drug Metab Rev 2010; 42: 268-354
• 5 Zevin S, Benowitz NL. Drug interactions with tobacco smoking. An update. Clin Pharmacokinet 1999; 36: 425-438
• 6 Hukkanen J, Jacob 3rd P, Peng M. et al. Effect of nicotine on cytochrome P450 1A2 activity. Br J Clin Pharmacol 2011; 72: 836-838
• 7 Lundmark J, Reis M, Bengtsson F. Serum concentrations of fluoxetine in the clinical treatment setting. Ther Drug Monit 2001; 23: 139-147
• 8 Lundmark J, Reis M, Bengtsson F. Therapeutic drug monitoring of sertraline: Variability factors as displayed in a clinical setting. Ther Drug Monit 2000; 22: 446-454
• 9 Unterecker S, Hiemke C, Greiner C. et al. The effect of age, sex, smoking and co-medication on serum levels of venlafaxine and O-desmethylvenlafaxine under naturalistic conditions. Pharmacopsychiatry 2012; 45: 229-235
• 10 Fric M, Pfuhlmann B, Laux G. et al. The influence of smoking on the serum level of duloxetine. Pharmacopsychiatry 2008; 41: 151-155
• 11 Jaquenoud Sirot E, Harenberg S, Vandel P. et al. Multicenter study on the clinical effectiveness, pharmacokinetics, and pharmacogenetics of mirtazapine in depression. J Clin Psychopharmacol 2012; 32: 622-629
• 12 Hsyu PH, Singh A, Giargiari TD. et al. Pharmacokinetics of bupropion and its metabolites in cigarette smokers versus nonsmokers. J Clin Pharmacol 1997; 37: 737-743
• 13 Tsuda Y, Saruwatari J, Yasui-Furukori N. Meta-analysis: The effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine. BMJ Open 2014; 4: e004216
• 14 Racagni G, Riva M, Molteni R. et al. Mode of action of agomelatine: Synergy between melatonergic and 5-HT2C receptors. World J Biol Psychiatry 2011; 12: 574-587
• 15 Owen RT. Agomelatine: A novel pharmacological approach to treating depression. Drugs Today (Barc) 2009; 45: 599-608
• 16 Englisch S, Jung HS, Lewien A. et al. Agomelatine for the treatment of major depressive episodes in schizophrenia-spectrum disorders: An open-prospective proof-of-concept study. J Clin Psychopharmacol 2016; 36: 597-607
• 17 Addington D, Addington J, Schissel B. A depression rating scale for schizophrenics. Schizophr Res 1990; 3: 247-251
• 18 Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56-62
• 19 Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261-276
• 20 Gahr M, Freudenmann RW, Connemann BJ. et al. Agomelatine and hepatotoxicity: Implications of cumulated data derived from spontaneous reports of adverse drug reactions. Pharmacopsychiatry 2013; 46: 214-220
• 21 Gahr M, Kratzer W, Fuchs M. et al. Safety and tolerability of agomelatine: Focus on hepatotoxicity. Curr Drug Metab 2014; 15: 694-702
• 22 Landi MT, Sinha R, Lang NP. et al. Human cytochrome P4501A2. IARC Sci Publ 1999; 148: 173-195
• 23 Kennedy SH, Eisfeld BS. Agomelatine and its therapeutic potential in the depressed patient. Neuropsychiatr Dis Treat 2007; 3: 423-428
• 24 Bogaards J, Hissink EM, Briggs M. et al. Prediction of interindividual variation in drug plasma levels in vivo from individual enzyme kinetic data and physiologically based pharmacokinetic modeling. Eur J Pharm Sci 2000; 12: 117-124
• 25 www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/00915/WC500046227pdf
• 26 Eser D, Baghai TC, Möller HJ. Agomelatine: The evidence for its place in the treatment of depression. Core Evid 2010; 4: 171-179
• 27 Ostad Haji E, Hiemke C, Pfuhlmann B. Therapeutic drug monitoring for antidepressant drug treatment. Curr Pharm Des 2012; 18: 5818-5827
• 28 Lobo ED, Quinlan T, O’Brien L. et al. Population pharmacokinetics of orally administered duloxetine in patients: Implications for dosing recommendation. Clin Pharmacokinet 2009; 48: 189-197
• 29 Buoli M, Mauri MC, Altamura AC. Pharmacokinetic evaluation of agomelatine for the treatment of generalised anxiety disorder. Expert Opin Drug Metab Toxicol 2014; 10: 885-892
• 30 De Berardis D, Fornaro M, Serroni N. et al. Agomelatine beyond borders: Current evidences of its efficacy in disorders other than major depression. Int J Mol Sci 2015; 16: 1111-1130
• 31 Gillette MU, Tischkau SA. Suprachiasmatic nucleus: The brain's circadian clock. Recent Prog Horm Res 1999; 54: 33-58
• 32 Vazquez-Palacios G, Bonilla-Jaime H, Velazquez-Moctezuma J. Antidepressant effects of nicotine and fluoxetine in an animal model of depression induced by neonatal treatment with clomipramine. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 39-46
• 33 Covey LS, Glassman AH, Stetner F. Cigarette smoking and major depression. J Addict Dis 1998; 17: 35-46
• 34 Leucht S, Corves C, Arbter D. et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: A meta-analysis. Lancet 2009; 373: 31-41
• 35 Hasan A, Falkai P, Wobrock T. et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 2: Update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects. World J Biol Psychiatr 2013; 14: 2-44
• 36 Hieronymus F, Nilsson S, Eriksson E. A mega-analysis of fixed-dose trials reveals dose-dependency and a rapid onset of action for the antidepressant effect of three selective serotonin reuptake inhibitors. Transl Psychiatry 2016; 6: e834