2 Neuroscience2.12 Neurobiology of specific treatments

2.12.2 Pharmacogenetics

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Written by Resident Doctor Committee · Published

New in the 2027 syllabus

The College added this topic for exams from January 2027.

From genotype to drug exposure

Pharmacogenetics is the study of how inherited variation changes a person's response to a drug. It can affect metabolism, transport, the drug's target and the risk of adverse reactions.

The metaboliser phenotype is the enzyme activity predicted from a person's combination of relevant alleles. Each gene has its own categories and scoring rules.

What low enzyme activity does depends on the drug. Reduced metabolism of an active drug can raise exposure. Reduced activation of a prodrug (an inactive drug the body converts to its active form) can lower its effect.

These are conditional examples for a relevant metabolic pathway, not dosing rules. The consequence depends on whether the enzyme clears an active drug or forms its active metabolite; inhibition, organ function and other pathways also affect exposure. Original illustration drawn in Python for MRCPsychiatrist; see images/ATTRIBUTION.md

Genes relevant to psychiatry

Gene or group

Psychiatric relevance

Limitation

CYP2D6

Changes exposure to some antidepressants and antipsychotics

Duplications and interacting drugs make prediction harder

CYP2C19

Changes exposure to some antidepressants

Recommendations differ between medicines

CYP2B6

Helps metabolise sertraline

Interpret using a drug-specific guideline

HLA variants

Can signal risk of severe skin reactions to particular anticonvulsants

Relevance depends on the allele, drug and population

SLC6A4 and HTR2A

Studied as predictors of antidepressant response

Evidence does not support prescribing on these results alone

CYP means the cytochrome P450 enzymes. Human leucocyte antigen (HLA) variation concerns immune recognition, not drug metabolism.

Applying a result

  • Phenoconversion is when an inhibitor or another factor makes actual enzyme activity differ from what the genotype predicts.

  • Smoking, organ function, age and adherence change exposure regardless of inherited variants. Keep them in the assessment.

  • For a defined gene-drug pair, clinical guidelines may advise a different dose, slower titration or another medicine.

  • A result does not identify the best treatment for every patient or guarantee a response. Therapeutic drug monitoring answers a different question: how much drug is actually present.

  • Commercial panels vary in evidence and interpretation. Separate validated gene-drug guidance from unvalidated response predictions.

  • When taking consent and documenting the result, cover its lasting relevance and how future prescribers will be able to see it.

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.