Genetic diversity of cytochrome P450 in patients receiving psychiatric care in Greece: a step towards clinical implementation

Abstract

Aim: We herein inferred the genetic diversity of CYP450 isoenzymes to predict the percentage of patients who need dose adjustment in drugs used in psychiatry. Materials & methods: Data of 784 Greek patients receiving psychiatric care who were genotyped for CYP2D6, CYP2C19, CYP1A2, CYP3A5 and CYP2C9 isoenzymes were inferred to gene–drug pairs according to the US FDA, Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group annotations and published literature. Results: Atypical metabolism was found for 36.8% of patients in CYP2D6, 49.2% in CYP2C19, 45% in CYP1A2, 16.7% in CYP3A5 and 41.8% in CYP2C9. Dosage adjustment need was estimated for 10.2% of venlafaxine, 10.0% of paroxetine, 6.4% of sertraline, 30.8% of citalopram, 52.1% of escitalopram, 18.2% of fluvoxamine, 54.1% of tricyclic antidepressants, 16.7% of zuclopenthixol, 10.6% of haloperidol and 13.3% of risperidone treated patients. Conclusion: Clinical psychiatric pharmacogenomic implementation holds promise to improve drug effectiveness and safety.

Plain language summary

What is this summary about?

Pharmacogenomic dosing guidelines exist for several antidepressant and antipsychotic drugs. However, psychiatric pharmacogenomics is not yet broadly applied in clinical practice. We herein examined the genetics of enzymes involved in the metabolism of psychiatric drugs to predict the percentage of patients who need dose adjustment. Gene–drug pairs were examined according to the US FDA, Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group annotations for CYP2D6 and CYP2C19, and according to existing literature for the other CYP450 isoenzymes.

What were the results?

In the total population consisting of 784 patients receiving psychiatric care, 36.8% of patients had atypical metabolism in CYP2D6, 49.2% in CYP2C19, 45% in CYP1A2, 16.7% in CYP3A5 and 41.8% in CYP2C9. Within cases that experienced adverse events, 35% had reduced metabolism in CYP2D6, 16.7% in CYP2C19, and 25% in CYP2C9. In cases showing lack of response, 5.8% were CYP2D6 ultra rapid metabolizers (UMs), 39.3% CYP2C19 UMs, 44.1% CYP1A2 fast metabolizers and 14.2% CYP3A5 expressors. Dosage adjustment need was estimated for 10.2% of venlafaxine, 10.0% of paroxetine, 6.4% of sertraline, 30.8% of citalopram, 52.1% of escitalopram, 18.2% of fluvoxamine, 54.1% of tricyclic antidepressants, 16.7% of zuclopenthixol, 10.6% of haloperidol and 13.3% of risperidone treated patients.

What do the results mean?

CYP450 genotyping can predict interindividual differences in drug response in the field of psychiatry. Clinical psychiatric pharmacogenomic implementation holds promise to improve drug effectiveness and safety.

GRAPHICAL ABSTRACT

Summary points

Background

• For psychiatric disorders, the advantage of pharmacogenomic testing before drug treatment, has been well reported for several single gene–drug combinations.

• Preemptive pharmacogenomic (PGx) testing accompanied with guided dose and drug selection, appears to lead to an overall reduction of drug adverse reactions.

• Psychiatric PGx markers mostly involve CYP450 isoenzymes aiming to adjust scheme doses and therapeutic regimens toward prevention of adverse drug reactions (ADRs) and improvement of therapeutic response.

Patients & methods

• Study cohort consists of a total of 784 patients receiving psychiatric care who were referred for PGx analysis.

• Patients were genotyped for CYP2D6, CYP2C19, CYP1A2, CYP3A5 and/or CYP2C9 isoenzymes.

• Gene–drug pairs were inferred according to US FDA, CPIC and DPWG annotations for CYP2D6 and CYP2C19, and according to existing literature for the other CYP450 isoenzymes.

Results

• In the total population, 36.8% of patients had atypical metabolism in CYP2D6, 49.2% in CYP2C19, 45% in CYP1A2, 16.7% in CYP3A5 and 41.8% in CYP2C9.

• Within patients who experienced adverse events, 35% had reduced metabolism in CYP2D6, 16.7% in CYP2C19 and 25% in CYP2C9.

• In patients showing lack of response, 5.8% were CYP2D6 ultra rapid metabolizers (UMs), 39.3% CYP2C19 UMs, 44.1% CYP1A2 fast metabolizers and 14.2% CYP3A5 expressors.

• Dosage adjustment need was estimated for 10.2% of venlafaxine, 10.0% of paroxetine, 6.4% of sertraline, 30.8% of citalopram, 52.1% of escitalopram, 18.2% of fluvoxamine, 54.1% of tricyclic antidepressants, 16.7% of zuclopenthixol, 10.5% of haloperidol and 13.3% of risperidone treated patients.

Discussion

• CYP450 genotyping can predict interindividual differences in drug response in the field of psychiatry.

• Clinical psychiatric pharmacogenomic implementation holds promise to improve drug effectiveness and safety.

Keywords: :

• antidepressants
• antipsychotics
• CYP2C19
• CYP2D6
• CYP450
• pharmacogenomics
• precision medicine
• psychiatry

Author contributions

Conceptualization, G.R. and V.G.M.; data acquisition, G.R. and Y.M.; experimental procedures, G.R..; formal analysis, G.R. and M.P.; writing-original draft preparation, G.R., M.P. and T.V.; writing-review and editing, G.R. and V.G.M.; final manuscript editing, V.G.M.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

G.R. and Y.M. were employed by DNALEX. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Data sharing statement

Data can be made available upon reasonable request.

Ethical conduct of research

The authors state that they have followed the principles outlined in the Declaration of Helsinki for their investigation. In addition, informed written consent has been obtained from the participants involved.