Suicide, depression, and CYP2D6: How are they linked?

Suicide risk might be increased in depressed patients who are ultra-rapid metabolizers

enetic variations in drug-metabolizing dramatically affect drug pharmacokinetics and can Gresult in clinically relevant differences in drug ef- ficacy or toxicity. P450 (CYP) enzymes such as CYP2D6 are involved in of , including selective reuptake inhibitors (SSRIs), which often are a first-line choice for patients with major depressive disorder (MDD).1,2 CYP2D6 is a highly polymor- phic with 75 allelic variants (CYP2D6*1 to *75) and >30 additional subvariants.3 These variants are associated with where CYP2D6 activity is increased, re- duced, or lost, which can increase the risk of adverse drug reactions, decrease , and possibly influence a pa- © JOHN FEDELE/BLEND IMAGES/CORBIS tient’s suicide risk. Shahid Ali, MD Meharry Medical College In this article, we review the pharmacogenetics of CYP2D6 Nashville, TN and discuss a possible relationship between CYP2D6 Charles D. Mouton, MD and suicidal events during treatment for MDD. Meharry Medical College Nashville, TN Shagufta Jabeen, MD CYP2D6: Many variants Meharry Medical College CYP450 enzymes are a group of 57 , each coded Nashville, TN by a different gene. Five subfamilies in the CYP450 fam- Qiang Zeng, MD, PhD Meharry Medical College ily metabolize most drugs: CYP1A2, CYP3A4, CYP2C19, Nashville, TN CYP2E1, and CYP2D6.4 Gantt Galloway, PharmD Researchers discovered CYP2D6 in studies of nonpsy- and Pharmacology Research Laboratory chotropics (Box).5-9 CYP2D6 is widely expressed in many San Francisco, CA tissues, with dominant expression in the liver. Although John Mendelson, MD CYP2D6 accounts for 2% of the total CYP450 liver Addiction and Pharmacology Research Laboratory San Francisco, CA content, it mediates metabolism in 25% to 30% of drugs in common clinical use and has a major influence on the bio- Current Psychiatry 16 May 2013 transformation of SSRIs (Table, page 18).10 Box Discovering CYP2D6’s link to

the late 1970s, 2 groups of researchers and beta blockers also was defective in these I noted unexpected serious adverse reactions patients. in studies of debrisoquine,5 a sympatholytic Further investigations established that the , and ,6 an enzyme responsible for debrisoquine metabolism antiarrhythmic and oxytocic drug. They was a (CYP) enzyme that is observed that 5% to 10% of patients were now termed CYP2D6.7 In addition to biochemical unable to efficiently metabolize debrisoquine evidence, the colocalization of sparteine and sparteine and went on to define a oxidation deficiency and of the CYP2D6 genetic responsible for these at 22q13.1 confirmed CYP2D6 as metabolic differences. They also observed that the target gene of the debrisoquine/sparteine metabolism of antidepressants, , polymorphism.8,9

Approximately 100 polymorphic CYP2D6 year)—have had impressive declines in (variants) have been identified.3 suicide rates (24% to 57% in the last 2 de- Clinical Point These alleles are active, resulting in nor- cades) with a marked (6- to 8-fold) increase Ultra-rapid mal CYP2D6 enzyme activity, or inactive, in SSRI prescriptions during the same pe- leading to decreased enzyme activity. riod.13-15 On the other hand, a few coun- metabolizers Genotyping for most common CYP2D6 tries, such as Portugal and Spain, have of CYP2D6 may alleles in ethnically defined populations experienced dramatic increases (58% and need higher can predict poor metabolizers (PMs), in- 86%, respectively) in the suicide rate with antidepressant termediate metabolizers (IMs), extensive a similar increase in SSRI prescribing dur- doses to achieve a metabolizers (EMs), and ultra-rapid me- ing the same 20-year period.16 tabolizers (UMs) with high accuracy.11 PMs A review of the distribution of CYP2D6 therapeutic response are compound heterozygous for inactivat- genotype among countries indicates a ing alleles or homozygous for an inactivat- south/north gradient of CYP2D6 gene ing variant. IMs carry one functional duplications, which indicate UM status.16 and one nonfunctional allele but may The proportion of UMs increases by al- demonstrate a range of enzyme activity most 2-fold in southern European coun- levels. EMs have 2 functional gene copies tries (8.4% and 7% to 10% for Portugal and and UMs have >2 functional from Spain, respectively) compared with north- gene duplication, resulting in ultra-rapid ern European countries (1% to 2% and 3.6% metabolism. for Sweden and Germany, respectively); this south/north trend extends to Africa.17 The prevalence of CYP2D6 UMs is lower in Suicide and CYP2D6 status northern countries, where increased anti- The widespread use of antidepressants ap- depressant use appears to have reduced pears to have led to significant decline in suicide rates, and higher in southern coun- suicide rates in many countries.12 Based on tries, where suicide rates increased despite an investigation of suicide mortality in 27 higher antidepressant use. countries from 1980 to 2000, Ludwig and Case reports and observational stud- Marcotte12 found that faster growth in SSRI ies18-21 suggest that compared with other sales per capita was associated with larger CYP2D6 phenotypes, UMs may need to declines in suicide rates. This finding was take higher doses of antidepressants to Discuss this article at not confounded by other suicide risk fac- achieve therapeutic response. In a case re- www.facebook.com/ CurrentPsychiatry tors such as unemployment, sex, age, or port, Bertilsson et al18 described 2 patients divorce rate.12 Countries such as Germany, who were UMs and required high doses of Austria, Estonia, Switzerland, Sweden, and to obtain Denmark, Hungary, and Slovenia—which appropriate plasma drug concentrations. had the highest suicide rate in the world Baumann et al19 described a depressed pa- Current Psychiatry 20 years ago (20 to 46 per 100,000 per tient with CYP2D6 gene duplication who Vol. 12, No. 5 17 Table sociation between CYP2D6 gene duplica- tion and suicide risk suggests CYP2D6’s CYP450 enzymes involved role in suicide risk might not be related in biotransformation of SSRIs solely to antidepressant metabolism. Enzymes involved SSRI in biotransformation CYP2C19, CYP2D6, CYP3A4 Effects on serotonin, CYP2D6 and CYP2C19, CYP2D6, CYP3A4 CYP2D6 is expressed in the brain and local- suicide CYP2D6, CYP2C9, CYP2C19, ized primarily in large principle cells of the CYP3A4 hippocampus and Purkinje cells of the cer- CYP1A2, CYP2D6 ebellum, with no expression in other brain CYP2D6, CYP3A4 regions such as glial cells.25 This heteroge- CYP2C9, CYP2C19, CYP2D6, neous expression among brain regions and CYP3A4 cell types indicates that in addition to its CYP: cytochrome P450; SSRI: selective serotonin reuptake inhibitors role in metabolizing drugs, CYP2D6 might Source: Reference 10 influence levels. In vitro Clinical Point and in vivo animal studies suggest that Depressed patients CYP2D6 plays a role in biotransformation of serotonin and dopamine.26,27 who are ultra-rapid required higher-than-usual doses of clo- CYP2D6 metabolizers mipramine. Rau et al20 found a 3-fold in- Serotonin is likely to play a causal role in may be more likely crease in the frequency of UMs in a group of the pathophysiology of depression, and to commit suicide 16 depressed German patients who did not depressed patients have abnormalities in respond to SSRIs or serotonin–norepineph- serotonin activity.28 Serotonin is gener- due to suboptimal rine reuptake inhibitors, both of which are ated primarily from the transformation of antidepressant levels metabolized by CYP2D6. Kawanishi et al21 tryptophan by tryptophan decarboxylase found a significantly greater prevalence of and tryptamine 5-hydroxylase.29 Yu et al27 UMs among 81 Nordic patients who did found that CYP2D6 may be an additional not respond to SSRIs compared with the pathway to regenerate serotonin through general population. O-demethylation from 5-methoxytrypta- Because suicidality may be caused by mine, but it is unclear what proportion of inadequately treated depressive illness, the physiologic pool of serotonin in synap- MDD patients who are UMs may be more tic nerve terminals is generated through the likely to commit suicide because of sub- CYP2D6 pathway. However, this discovery optimal antidepressant levels. In a 2010 provides a mechanistic basis of CYP2D6 Swedish study, Zackrisson et al22 found involvement in the endogenous serotonin that compared with those who died of balance and by extension, in serotonergic other causes, significantly more individu- physiology and neuropsychiatric disorders als who committed suicide had >2 active such as depression.30 Because SSRIs target CYP2D6 genes. Stingl et al23 found that the serotonergic pathway, baseline levels among 285 depressed German patients, of serotonin and all related components UMs had an elevated risk of having a high of this pathway—including CYP2D6—are suicidality score compared with individu- likely to help determine a patient’s re- als with other , after adjusting sponse to SSRIs. for sex, baseline score on the Hamilton Depression Rating Scale (after exclud- Dopamine also is generated from tyra- ing item 3 for suicidality), and number of mine through CYP2D6,31 and distribution previous depressive episodes. Other re- of CYP2D6 in the brain follows that of searchers found that patients with eating dopamine nerve terminals.32 The seroto- disorders who are UMs have a greater risk nergic system has strong anatomical and of suicidal behavior.24 Although none of functional interaction with the dopaminer- these 3 studies specified if these patients gic system,33 and imbalance between se- Current Psychiatry 18 May 2013 were treated with antidepressants, the as- rotonin and dopamine activity is thought to give rise to behavioral changes,2 which play an important role in the development Related Resources of anxiety and impulsivity. • Peñas-Lledó EM, Blasco-Fontecilla H, Dorado P, et al. CYP2D6 and the severity of suicide attempts. . 2012;13(2):179-184. • Blasco-Fontecilla H, Peñas-Lledó E, Vaquero-Lorenzo C, et CYP2D6 in clinical practice al. CYP2D6 polymorphism and mental and personality dis- orders in suicide attempters [published online February 11, Although research into a possible link 2013]. J Pers Disord. doi: 10.1521/pedi_2013_27_080. between CYP2D6 status and suicide risk Drug Brand Names in depressed patients treated with anti- Citalopram • Celexa Nortriptyline • Aventyl, depressants is ongoing, at present this Clomipramine • Anafranil Pamelor Escitalopram • Lexapro Paroxetine • Paxil connection is speculative. More studies Fluoxetine • Prozac Sertraline • Zoloft are warranted to reveal the exact role of Fluvoxamine • Luvox CYP2D6 in response to SSRI treatment and Disclosure suicide risk. The authors report no financial relationship with any com- Knowledge of this potential association pany whose products are mentioned in this article or with manufacturers of competing products. can help clinicians keep CYP450 genotyping Acknowledgment in mind when prescribing antidepressants to Clinical Point The authors thank Marwah Shahid and Ijlal Yazdani for their as- depressed patients. The FDA has approved sistance with this article. CYP2D6’s role in a pharmacogenetic test to analyze polymor- phisms of CYP2D6 and CYP2C19.34 The suicide risk might results of such testing might guide pharma- not be solely related 6. Eichelbaum M, Spannbrucker N, Steincke B, et al. Defective cotherapy for depressed patients, including N-oxidation of sparteine in man: a new pharmacogenetic to antidepressant defect. Eur J Clin Pharmacol. 1979;16(3):183-187. medication selection and dosing. For exam- 7. Distlerath LM, Reilly PE, Martin MV, et al. Purification and metabolism ple, a patient who is a PM might be started at characterization of the human liver P-450 involved in debrisoquine 4- and a lower antidepressant dosage to avoid po- O-deethylation, two prototypes for genetic polymorphism tential adverse drug effects, whereas it might in oxidative drug metabolism. J Biol Chem. 1985;260(15): 9057-9067. be appropriate to prescribe a higher starting 8. Eichelbaum M, Baur MP, Dengler HJ, et al. Chromosomal dose for a UM patient to achieve an effective assignment of human cytochrome P-450 (debrisoquine/ sparteine type) to . Br J Clin Pharmacol. drug concentration. 1987;23(4):455-458. 9 . Gonzalez FJ, Vilbois F, Hardwick JP, et al. Human References debrisoquine 4-hydroxylase (P450IID1): cDNA and deduced sequence and assignment of the CYP2D locus to 1. Meyer UA, Amrein R, Balant LP, et al. Antidepressants and chromosome 22. Geonomics. 1988;2(2):174-179. drug-metabolizing enzymes—expert group report. Acta Psychiatr Scand. 1996;93(2):71-79. 10. Spina E, Santoro V, D’Arrigo C. Clinically relevant pharmacokinetic drug interactions with second- 2. Kroemer HK, Eichelbaum M. “It’s the genes, stupid”. generation antidepressants: an update. Clin Ther. 2008; Molecular bases and clinical consequences of genetic 30(7):1206-1227. cytochrome P450 2D6 polymorphism. Life Sci. 1995;56(26): 2285-2298. 11. Roses AD. Pharmacogenetics and the practice of medicine. Nature. 2000;405(6788):857-865. 3. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. CYP2D6 allele nomenclature. http://www. 12. Ludwig J, Marcotte DE. Anti-depressants, suicide, and drug cypalleles.ki.se/.htm. Accessed February 25, 2013. regulation. J Policy Anal Manage. 2005;24(2):249-272. 4. Hemeryck A, Belpaire FM. Selective serotonin reuptake 13. Isacsson G. Suicide prevention—a medical breakthrough? inhibitors and cytochrome P-450 mediated drug- Acta Psychiatr Scand. 2000;102(2):113-117. drug interactions: an update. Curr Drug Metab. 2002;3(1): 14 . Rihmer Z. Can better recognition and treatment of 13-37. depression reduce suicide rates? A brief review. Eur 5. Mahgoub A, Idle JR, Dring LG, et al. Polymorphic Psychiatry. 2001;16(7):406-409. hydroxylation of debrisoquine in man. Lancet. 1977; 15. Rihmer Z. Decreasing national suicide rates—fact or fiction? 2(8038):584-586. World J Biol Psychiatry. 2004;5(1):55-56.

Bottom Line Genetic variations in cytochrome P450 (CYP) 2D6 may increase how quickly a patient metabolizes antidepressants. Ultra-rapid CYP2D6 metabolizers may be at risk for adverse consequences of untreated depression, including suicide. CYP2D6 status also may impact a patient’s suicide risk through mechanisms other than Current Psychiatry antidepressant metabolism. Vol. 12, No. 5 19 continued on page 50