Tobacco Consumption Concerns With the Use of CYP1A2 Metabolized Antidepressants
Publication: American Journal of Psychiatry
To the Editor: We report a case of major depressive episode relapse with imipramine in a heavy-smoking depressed patient related to CYP1A2*1F genetic polymorphism (rs762551, 163A>C).
A 47-year-old Caucasian woman was referred to our psychiatric department for a current, untreated severe major depressive episode without psychotic symptoms (score on the 17-item Hamilton Depressive Rating Scale (HAM-D), 28) in a context of major depressive disorder. She had severe tobacco dependence (30 cigarettes/day for 30 years). No other disorder was detected clinically. Results of blood serum screening (including thyroid hormones, glycemia, and calcemia) and cerebral contrast MRI were normal.She was treated with 125 mg/day of imipramine (in addition to oxazepam and zopiclone). Concomitantly, she reduced her smoking spontaneously while in the hospital, a smoke-free facility, to five cigarettes/day. At discharge, she had a full response and remission with 125 mg/day of imipramine (HAM-D score, 6). Imipramine and desipramine (its predominant metabolite) trough plasma concentrations (104 ng/mL and 238 ng/mL, respectively) were within the therapeutic range (180–350 ng/mL for imipramine and desipramine together).Four weeks later, despite good compliance, she relapsed (HAM-D score, 22), requiring an increase in her imipramine dosage to 175 mg/day. But with this dosage, her trough plasma concentrations were lower than expected (imipramine, 50 ng/mL; desipramine, 96 ng/mL).No decrease in compliance and no recent co-medication could explain such low levels except a tremendous increase in the patient’s smoking, which returned to 30 cigarettes/day after discharge.Because tobacco smoking is a CYP1A2 inducer and imipramine is mainly metabolized by CYP1A2, pharmacogenetic tests were performed (CYP1A2*1F, CYP2D6*3,*4,*5,*6,x2N, CYP2C19*17) showing that the patient was a carrier of a genotype heterozygous for the CYP1A2*1F allele (AC) that is associated with increased CYP1A2 activity in smokers.
Induction of CYP1A2 by smoking can result in increased CYP1A2 activity, higher clearance, decreased plasma levels, and decreased efficacy with drugs mainly metabolized by CYP1A2, especially clozapine or the antidepressants imipramine, amitriptyline, clomipramine, duloxetine, fluvoxamine, and mirtazapine (1).
Tobacco smoking and nicotine dependence are common in depressed patients. In the United States, 70% of men and 80% of women with a history of major depressive episode report current or past smoking (2).
The CYP1A2*1F allelic variant, present in 30%−33% of Caucasians, was associated with higher clearance of the CYP1A2 substrate caffeine, as a probe, in smokers but not in nonsmokers (3).
Presence of the CYP1A2*1F allele, even in a heterozygous carrier, and tobacco smoking could cause a lack of efficacy to the CYP1A2 substrate antidepressant and subsequent depression relapse.
Finally, depressed patients treated with CYP1A2 substrates should be closely monitored for cigarette consumption. Psychiatrists should offer smoking-cessation counseling and/or propose a non-CYP1A2 substrate antidepressant, such as citalopram, bupropion, reboxetine, or venlafaxine.
References
1.
Gunes A, Dahl ML: Variation in CYP1A2 activity and its clinical implications: influence of environmental factors and genetic polymorphisms. Pharmacogenomics 2008; 9:625–637
2.
Glassman AH, Helzer JE, Covey LS, et al: Smoking, smoking cessation, and major depression. JAMA 1990; 264:1546–1549
3.
Sachse C, Brockmöller J, Bauer S, et al: Functional significance of a C→A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol 1999; 47:445–449
Information & Authors
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Accepted: June 2015
Published online: 1 September 2015
Published in print: September 01, 2015
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Competing Interests
Dr. Gressier has given talks for Lundbeck and Servier and received a grant from Servier. Dr. Becquemont has received consulting fees from Sanofi-Aventis, Pfizer, and Servier and lecture fees from Genzyme, GlaxoSmithKline, Bristol-Myers Squibb, and Merck Sharp and Dohme; his wife works for Sanofi-Aventis. Dr. Corruble has received consulting fees from Lundbeck, Servier, Sanofi-Aventis, Bristol-Myers Squibb, Eisai, and Otsuka. The other authors report no financial relationships with commercial interests.
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