Escitalopram pharmacogenetics: CYP2C19 relationships with dosing and clinical outcomes in autism spectrum disorder

Abstract

Background and aim: Selective serotonin reuptake inhibitors such as escitalopram are commonly used to treat patients with autism spectrum disorder (ASD), but there are individual differences in treatment response and tolerability. CYP2C19 encodes the primary enzyme responsible for escitalopram metabolism and we investigated whether polymorphisms in CYP2C19 were related to symptoms and dosing in a pharmacogenetic study of ASD.

Participants and methods: Participants completed the Aberrant Behavior Checklist--Community Version (ABC-CV) weekly for 6 weeks. Escitalopram was initiated at a dose of 2.5 mg per day, with weekly increases to 20 mg unless intolerable side-effects occurred. Three CYP2C19 metabolizer groups, including ultrarapid, extensive, and reduced metabolizers, were examined in relation to symptom improvement and tolerated dose.

Results: ABC-CV scores improved over the course of treatment (P<0.0001). No differences were identified in the rate of improvement across metabolizer groups for the ABC-CV irritability subscale, which was the primary outcome for clinical symptoms. There was a trend for a metabolizer group by time interaction with respect to dose (P=0.10). This interaction was driven by the linear rate of change from week 1 to study endpoint between the reduced metabolizers and ultrarapid metabolizer groups (P=0.05). Post-hoc analyses identified significant differences in the rate of dose escalation between ultrarapid metabolizers and extensive metabolizers and for ultrarapid metabolizers compared with reduced metabolizers (P's<0.04), whereby ultrarapid metabolizers showed a slower rate of change in dose over time.

Conclusion: CYP2C19 ultrarapid metabolizers were associated with reduced tolerance to a fixed titration schedule of open-label escitalopram in this ASD study sample. Possible explanations may involve the altered kinetics of faster metabolizers or previously unknown activities of escitalopram metabolites.

Figure 1. ABC-CV Irritability

Aberrant Behavior Checklist – Community Version (ABC-CV) assessments were completed weekly over the course of the study. Results shown are stratified by CYP2C19 metabolizer groups.

Figure 2. Escitalopram dose titration

Participants were initiated on a dose of 2.5 mg escitalopram at the beginning of week 1 of the study followed by weekly increases to 5, 10, 15, and finally 20 mg po qd. If participants experienced adverse effects, the titration escalation was altered to maintain a tolerated dose. Results shown are stratified by CYP2C19 metabolizer groups. Significance values represent differences in the linear rate of dosing change from week 1 to time of follow-up assessments. Follow-up analyses indicated differences in the slope of dosing change starting from week 4 and continuing through week 6 in the ultrarapid metabolizers compared to extensive metabolizers (week 4 vs week 1 p=0.04; week 5 vs week 1 p=0.016; week 6 vs week 1 p=0.02). The difference in the slope of dosing change was evident at week 6 when comparing the ultrarapid metabolizers to reduced metabolizers (p=0.0025).