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

Case reports and observational studies^18-21 suggest that compared with other CYP2D6 phenotypes, UMs may need to take higher doses of antidepressants to achieve therapeutic response. In a case report, Bertilsson et al¹⁸ described 2 patients who were UMs and required high doses of nortriptyline and clomipramine to obtain appropriate plasma drug concentrations. Baumann et al¹⁹ described a depressed patient with CYP2D6 gene duplication who required higher-than-usual doses of clomipramine. Rau et al²⁰ found a 3-fold increase in the frequency of UMs in a group of 16 depressed German patients who did not respond to SSRIs or serotonin–norepinephrine reuptake inhibitors, both of which are metabolized by CYP2D6. Kawanishi et al²¹ found a significantly greater prevalence of UMs among 81 Nordic patients who did not respond to SSRIs compared with the general population.

Because suicidality may be caused by inadequately treated depressive illness, MDD patients who are UMs may be more likely to commit suicide because of suboptimal antidepressant levels. In a 2010 Swedish study, Zackrisson et al²² found that compared with those who died of other causes, significantly more individuals who committed suicide had >2 active CYP2D6 genes. Stingl et al²³ found that among 285 depressed German patients, UMs had an elevated risk of having a high suicidality score compared with individuals with other genotypes, after adjusting for sex, baseline score on the Hamilton Depression Rating Scale (after excluding item 3 for suicidality), and number of previous depressive episodes. Other researchers found that patients with eating disorders who are UMs have a greater risk of suicidal behavior.²⁴ Although none of these 3 studies specified if these patients were treated with antidepressants, the association between CYP2D6 gene duplication and suicide risk suggests CYP2D6’s role in suicide risk might not be related solely to antidepressant metabolism.

Effects on serotonin, dopamine

CYP2D6 is expressed in the brain and localized primarily in large principle cells of the hippocampus and Purkinje cells of the cerebellum, with no expression in other brain regions such as glial cells.²⁵ This heterogeneous expression among brain regions and cell types indicates that in addition to its role in metabolizing drugs, CYP2D6 might influence neurotransmitter levels. In vitro and in vivo animal studies suggest that CYP2D6 plays a role in biotransformation of serotonin and dopamine.^26,27

Serotonin is likely to play a causal role in the pathophysiology of depression, and depressed patients have abnormalities in serotonin activity.²⁸ Serotonin is generated primarily from the transformation of tryptophan by tryptophan decarboxylase and tryptamine 5-hydroxylase.²⁹ Yu et al²⁷ found that CYP2D6 may be an additional pathway to regenerate serotonin through O-demethylation from 5-methoxytryptamine, but it is unclear what proportion of the physiologic pool of serotonin in synaptic nerve terminals is generated through the CYP2D6 pathway. However, this discovery provides a mechanistic basis of CYP2D6 involvement in the endogenous serotonin balance and by extension, in serotonergic physiology and neuropsychiatric disorders such as depression.³⁰ Because SSRIs target the serotonergic pathway, baseline levels of serotonin and all related components of this pathway—including CYP2D6—are likely to help determine a patient’s response to SSRIs.

Dopamine also is generated from tyramine through CYP2D6,³¹ and distribution of CYP2D6 in the brain follows that of dopamine nerve terminals.³² The serotonergic system has strong anatomical and functional interaction with the dopaminergic system,³³ and imbalance between serotonin and dopamine activity is thought to give rise to behavioral changes,² which play an important role in the development of anxiety and impulsivity.

CYP2D6 in clinical practice

Although research into a possible link between CYP2D6 status and suicide risk in depressed patients treated with antidepressants is ongoing, at present this connection is speculative. More studies are warranted to reveal the exact role of CYP2D6 in response to SSRI treatment and suicide risk.

Knowledge of this potential association can help clinicians keep CYP450 genotyping in mind when prescribing antidepressants to depressed patients. The FDA has approved a pharmacogenetic test to analyze polymorphisms of CYP2D6 and CYP2C19.³⁴ The results of such testing might guide pharmacotherapy for depressed patients, including medication selection and dosing. For example, a patient who is a PM might be started at a lower antidepressant dosage to avoid potential adverse drug effects, whereas it might be appropriate to prescribe a higher starting dose for a UM patient to achieve an effective drug concentration.

Related Resources

• Peñas-Lledó EM, Blasco-Fontecilla H, Dorado P, et al. CYP2D6 and the severity of suicide attempts. Pharmacogenomics. 2012;13(2):179-184.
• Blasco-Fontecilla H, Peñas-Lledó E, Vaquero-Lorenzo C, et al. CYP2D6 polymorphism and mental and personality disorders in suicide attempters [published online February 11, 2013]. J Pers Disord. doi: 10.1521/pedi_2013_27_080.