Table 1.

Actionable drug–gene interactions for CYP2C19 and CYP2D6, for drugs commonly used by the HD population, including suggested dosing recommendations.

CYP2C19	PM	IM	UM
Citalopram	Do not exceed the following daily doses (50% of the standard maximum dose): adults <65 years: 20 mg as tablets or 16 mg as drops, adults 65 years or older: 10 mg as tablets or 8 mg as drops.	Do not exceed the following daily doses: adults <65 years: 30 mg as tablets or 22 mg as drops, adults 65 years or older: 15 mg as tablets or 10 mg as drops.	No action is needed for this gene–drug interaction. The gene variation increases the conversion of citalopram to a weakly active metabolite. However, there is no significant effect on the plasma concentration of citalopram, the tolerance, or the response.
Clopidogrel a	Determine the level of inhibition of platelet aggregation by clopidogrel. Consider an alternative for poor responders. Prasugrel and ticagrelor are not metabolized by CYP2C19 (or to a lesser extent).	No action is required.	The genetic variation results in increased conversion of clopidogrel to the active metabolite. However, this can result in both positive effects (reduction in the risk of serious cardiovascular and cerebrovascular events) and negative effects (increase in the risk of bleeding).
Escitalopram	Do not exceed the following doses (50% of the standard maximum dose): adults <65 years: 10 mg/day, adults 65 years or older: 5 mg/day.	Do not exceed the following doses (75% of the standard maximum dose): adults <65 years: 15 mg/day, adults 65 years or older: 7.5 mg/day.	Avoid escitalopram. Antidepressants that are not metabolized or that are metabolized to a lesser extent by CYP2C19 are, for example, paroxetine or fluvoxamine.
Imipramine b	Use 70% of the standard dose and monitor the effect and side effects of the imipramine and active metabolite desipramine plasma concentrations to determine the maintenance dose or avoid imipramine. Antidepressants that are not or to a lesser extent metabolized by CYP2C19 include, for example, nortriptyline, fluvoxamine, and mirtazapine.	No action is required.	No action is required.
Sertraline	Do not give doses exceeding 75 mg/day. Guide the dose by the response and side effects and/or sertraline plasma concentration.	No action is required. The gene variation has a minor effect on the sertraline plasma concentration. No effect on side effects was found.	No action is required. The gene variation has a negligible effect on the plasma concentration of sertraline. Moreover, no significant effect on response and side effects has been found.
CYP2D6	PM	IM	UM
Amitriptyline	Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of amitriptyline and nortriptyline to adjust the maintenance dose.	Use 75% of the standard dose and monitor the efficacy and side effects or the plasma concentrations of amitriptyline and nortriptyline to adjust the maintenance dose.	Increase the dose to 1.4 times the standard dose, monitor the effect and side effects of the plasma concentrations, and be alert to increased plasma concentrations of the cardiotoxic Z-10-hydroxy metabolites. If a dose increase is not desirable due to the cardiotoxic hydroxy metabolite, avoid amitriptyline. Consider anti-depressants that are not metabolized by CYP2D6, or to a lesser extent, such as citalopram and sertraline.
Aripiprazole	Administer no more than 10 mg/day or 300 mg/month (68–75% of the standard maximum dose of aripiprazole).	No action is needed for this gene–drug interaction. The genetic variation increases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is insufficient evidence that this increases the risk of side effects.	No action is needed for this gene-drug interaction. The genetic variation decreases the plasma concentration of the sum of aripiprazole and the active metabolite dehydroaripiprazole to a limited degree. There is no evidence that this increases the risk of reduced effectiveness.
CYP2D6	PM	IM	UM
Clomipramine	For depression, use 50% of the standard dose. For anxiety disorders and obsessive-compulsive disorder, use 50% of the standard dose if side effects occur. Monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine to set a maintenance dose. If dose reduction does not have the desired effect, avoid clomipramine.	Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of clomipramine and desmethylclomipramine.	Use 1.5 times the standard dose and monitor the effect and side effects of the plasma concentrations of clomipramine and desmethylclomipramine to set the maintenance dose. If a dose increase is not wanted due to potential cardiotoxic hydroxy metabolites, avoid clomipramine.
Codeine	For cough, no action is required. For pain, choose an alternative. Do not select tramadol, as this is also metabolized by CYP2D6. Morphine is not metabolized by CYP2D6. Oxycodone is metabolized by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.	For cough, no action is required. For pain, try a dose increase in the case of inadequate effectiveness. Choose an alternative if this does not work. Do not select tramadol, as this is also metabolized by CYP2D6. Morphine is not metabolized by CYP2D6. Oxycodone is metabolized by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.	Doses >20 mg every 6 h for adults and 10 mg every 6 h for children aged 12 years or older and/or additional risk factors, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function: Codeine is contra-indicated, if possible select an alternative: For cough, noscapine is not metabolized by CYP2D6. For pain, see alternatives under IM.
Doxepin	Use 40% of the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin to set the maintenance dose.	Use 80% of the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin to set the maintenance dose.	Double the standard dose and monitor the effect and side effects or the plasma concentrations of doxepin and nordoxepin to set the maintenance dose. If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites, avoid doxepin.
Haloperidol	Use 60% of the standard. This gene variation increases the plasma concentration 1.7 times, indicating an increased risk for side effects.	No action is required.	Use 1.5 times the standard dose or choose an alternative. Antipsychotics that are not metabolized by CYP2D6 – or to a much lesser extent – include, for example, flupentixol, penfluridol, quetiapine, olanzapine, or clozapine.
Imipramine b	Use 30% of the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine to set the maintenance dose.	Use 70% of the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine to set the maintenance dose.	Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentrations of imipramine and desipramine to set the maintenance dose. If a dose increase is not wanted due to the potentially cardiotoxic hydroxy metabolites, avoid imipramine.
Metoprolol	If a gradual reduction in heart rate is desired, or in the event of symptomatic bradycardia, use smaller steps in dose titration and/or prescribe no more than 25% of the standard dose.	If a gradual reduction in heart rate is desired, or in the event of symptomatic bradycardia, use smaller steps in dose titration and/or prescribe no more than 50% of the standard dose.	Use the maximum dose for the relevant indication as a target dose. Increase the dose based on effectiveness and side effects to 2.5 times the standard dose or select an alternative.
Nortriptyline	Use 40% of the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline to set the maintenance dose.	Use 60% of the standard dose and monitor the effect and side effects or the plasma concentration of nortriptyline to set the maintenance dose.	Use 1.7 times the standard dose and monitor the effect and side effects or the plasma concentration. Be alert to an increase in the cardiotoxic metabolite Z-10-hydroxynortriptyline. Alternatively, avoid nortriptyline.
CYP2D6	PM	IM	UM
Paroxetine	No action is required.	No action is required.	It is not possible to offer substantiated advice for dose adjustment based on the literature. Efficacy is likely to be absent. Avoid paroxetine.
Pimozide	Use no more than 10 mg/day in adults (50% of the standard maximum dose).	Use no more than 16 mg/day in adults (80% of the standard maximum dose).	No action is required.
Risperidone	Use 67% of the standard dose. If problematic side effects originating in the central nervous system occur despite this reduced dose, then reduce the dose further to 50% of the standard dose.	No action is required.	Choose an alternative or titrate the dose according to the maximum dose for the active metabolite paliperidone.
Tramadol	It is not possible to provide a recommendation for dose adjustment, because the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes. Try a dose increase or choose an alternative (see codeine) in the case of inadequate effectiveness.	Try a dose increase or choose an alternative (see codeine) in the case of inadequate effectiveness.	As the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes, the effect of a dose reduction cannot be predicted with certainty. Select an alternative (see codeine). If an alternative is not possible, use 40% of the standard dose.
Venlafaxine	Avoid venlafaxine or reduce the dose. Monitor the effect and side effects or check the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. Antidepressants that are not metabolized by CYP2D6 – or to a lesser extent – include, for example, duloxetine, mirtazapine, citalopram, and sertraline.	Avoid venlafaxine or reduce the dose. Monitor the effect and side effects or check the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. Antidepressants that are not metabolized by CYP2D6 – or to a lesser extent – include, for example, duloxetine, mirtazapine, citalopram, and sertraline.	No action is required.
Zuclopenthixol	Use 50% of the standard dose.	Use 75% of the standard dose.	Try a dose increase if the effectiveness is insufficient. Do not exceed 1.5 times the standard dose.

^aOther recommendations apply in case of percutaneous coronary intervention, stroke, and transient ischemic attack.

^bConsult a pharmacist when both CYP2C19 and CYP2D6 polymorphic variants are present.Normal metabolizers are not included since they are considered the reference category that does not require specific clinical recommendations. Guidelines and content are subject to updates and modifications, and users should confirm they are accessing the most current content.

IM, intermediate metabolizer; PM, poor metabolizer; UM, ultra-rapid metabolizer.