Genotyping of patients treated with selective serotonin reuptake inhibitors

Discussion

In this study, we found that a patient with an assessed need for genotyping in connection with drug treatment is most likely to have normal metabolism via CYP2D6 or CYP2C19, which are the primary enzymes in the metabolism of serotonin reuptake inhibitors. One-third of patients also have high levels of serotonin transporter in the synapses. Only 12.4 % of patients in our study had the phenotype for normal enzyme activity for both the CYP enzymes as well as high levels of serotonin transporter.

More than two-thirds of patients in our study had a phenotype that suggests intermediate or poor metabolism via CYP2D6 or CYP2C19, as well as high or intermediate levels of serotonin transporter. In this group of patients, genotyping would be able to provide useful information because the majority of these patients had normal activity for the other key SSRI-metabolising CYP enzyme (CYP2D6/CYP2C19). Therefore, it is possible that a patient with adverse effects or therapeutic failure with, for instance, escitalopram (CYP2C19) and functional serotonin transporter may benefit from switching to an SSRI primarily metabolised by the CYP2D6 enzyme. Therefore, genotyping may be a useful supplement to serum concentration measurements in order to personalise treatment and reduce the risk of adverse effects and therapeutic failure.

Use of the Hamilton depression scale has shown an increased response rate to treatment with escitalopram when there are high serotonin transporter levels compared to intermediate and very low levels (11). Therefore, it could be assumed at the start of treatment with an SSRI that the L/L genotype of SLC6A4 in combination with normal metabolism of the relevant drug by CYP2C19/CYP2D6 is most favourable. However, as our study shows, most patients have intermediate serotonin transporter levels, and this is still considered to lead to an adequate clinical effect from SSRIs. Therefore, the clinical benefit of genotyping SLC6A4 is not entirely clear since the S/S genotype does not cause a complete lack of serotonin transporter either. Consequently, an analysis result revealing the S/S genotype does not rule out efficacy for all SSRIs (12) and must never override clinical assessment of treatment response, despite several meta-analyses and review articles demonstrating that patients with SLC6A4 genotype S/S have less favourable treatment outcomes (8–10).

Rationally, other types of antidepressants should nonetheless be considered in preference to SSRIs if it is known that the patient has the S/S genotype of SLC6A4. The small group of patients who have the phenotype for poor CYP2D6 and/or CYP2C19 metabolism in addition to low serotonin transporter levels (S/S) are likely to be particularly susceptible to adverse effects. In total, only 8.2 % (n = 56) of patients with the S/S genotype of SLC6A4 in our study were in this category. Contrary to the case for use of SSRIs such as escitalopram (7, 9), no association was found in one study between decreased serotonin transporter levels and efficacy of treatment with the SNRI (serotonin and noradrenaline reuptake inhibitor) duloxetine (13). Depending on the indication and clinical presentation, other antidepressants that do not exclusively work via the serotonin transporter, e.g. vortioxetine, venlafaxine, bupropion, mirtazapine and mianserin, may also be appropriate alternatives.

Due to QT prolongation and the risk of serious arrhythmias (5, 14–16), the maximum recommended daily dose of escitalopram is 20 mg. It is natural to assume that patients in the group with poor metabolism have a much higher risk of these adverse effects, since at any given dose they will have serum escitalopram concentrations almost three times higher than concentrations in patients in the group with normal metabolism. Some studies suggest that the difference between the groups with poor and normal metabolism is even greater (17). Given the risk of ventricular arrhythmias and sudden cardiac death (15), it is important to prevent serum concentrations reaching toxic levels, even with the use of normal doses. Therefore, it is advisable to adjust escitalopram dosage based on CYP2C19 phenotype (Table 2) and to monitor with serum concentration measurements. In this way, the risk of serious adverse effects can be reduced. Patients with a phenotype that suggests ultra-rapid or normal metabolism often require higher doses than patients with intermediate or poor metabolism (17).

Another serious and very common adverse effect of SSRIs is sexual dysfunction. There may be an effect on arousal, libido, orgasm and ejaculation, with an overall prevalence of between 25 % and 73 % of patients. These adverse effects can lead to decreased adherence to treatment, and many patients are reluctant to talk to their doctor about sexual adverse effects (18). Since these adverse effects can be dose-related (19), patients with intermediate or poor CYP2D6 and/or CYP2C19 metabolism will probably be at increased risk if they are being treated with an SSRI metabolised by the relevant enzyme. These patients would benefit from adjustment of their SSRI treatment to the CYP phenotype.

As well as there being a clear difference in serum concentrations of escitalopram between the phenotypes with normal, intermediate and poor CYP2C19 metabolism, there is wide variation within the groups. In our study, this is particularly apparent in the group with increased enzyme activity, in which two patients had unexpectedly high serum concentrations of over 150 nmol/L. On one hand, this shows that the phenotypes include a heterogeneous range of genotypes, and that hitherto unknown variants may exist which cause different enzyme activity than is currently known about and which are reflected in serum concentrations. On the other hand, it shows that genotyping alone cannot predict serum concentrations (and thus efficacy of treatment) or the risk of adverse effects in patients, which is demonstrated, for instance, by the fact that the number of SSRI serum concentration measurements above the upper limit of the reference range are two-fold higher in patients aged 60 years or older compared with patients younger than 60 years (20).

It is possible that our patient material consists of patients who have an abnormal effect from escitalopram, and therefore it has a different distribution of genotypes than the average population. However, frequency studies with European patients demonstrate figures consistent with the data in our study (21, 22). Nevertheless, this may change over time because migration may change the prevalence of various CYP genotypes (23). Our material from genotyped patients originates from a group with far wider indications for genetic testing than treatment with SSRIs because these tests may be appropriate during treatment or before initiating treatment with a wide variety of drugs. Therefore, the selection is as relevant as it is possible to get in a retrospective study from normal clinical practice. Nevertheless, genotyping alone cannot be used to predict efficacy of treatment of SSRIs, and in our material this particularly applies to patients with ultra-rapid metabolism. To be able to give accurate recommendations about dosage of SSRIs, we require more information about other factors that can affect the bioavailability and elimination of drugs from the body. In addition to metabolising enzymes and age, serum concentrations are also affected by weight, sex, renal function, hepatic function, bowel disease, interactions with other drugs and a number of other factors. Several SSRIs can also inhibit the metabolism of other drugs. Therefore, systematised clinical information may improve patient treatment and lead to a decrease in the number of drug-related hospital admissions. This is important because this patient group accounts for up to 20 % of all admissions to Norwegian emergency departments (24).