When Genes, Enzymes, and Timing Collide: Pharmacogenetics, drug interactions, and why psychiatry is complex medical care

Psychiatry is often misunderstood as “just prescribing medications.”

In reality, it is one of the few specialties where brain, biology, behavior, and biochemistry collide—sometimes with consequences that are subtle, and sometimes with consequences that are dangerous.

Over the past two decades, my research and clinical work have focused on one recurring theme: medications do not act in isolation, and neither do patients.

Two of my early publications—one on lamotrigine rash following carbamazepine discontinuation (2005) (1), and another on CYP2D6 pharmacogenetics and aripiprazole-related extrapyramidal symptoms (2008) (2) —highlight different sides of the same reality: psychiatric prescribing is deeply medical, and errors in understanding metabolism and interactions can cause harm.

The invisible machinery: metabolism matters

Most psychiatric medications are processed by the liver’s cytochrome P450 enzyme system, including:

• CYP2D6

• CYP2C19

• CYP1A2

• CYP3A4

More than 70–80% of psychotropic medications rely on these enzymes for clearance.

Variability comes from:

• Genetics (pharmacogenetics)

• Drug–drug interactions

• Enzyme induction and de-induction

• Smoking, diet, hormones

• Timing of medication changes

Ignoring any one of these can be clinically consequential.

Case example #1 (2005):

Surja A, Broetzge K, El-Mallakh R: Serious rash with Lamotrigine after carbamazepine discontinuation; Journal of Clinical Psychiatry 2005, 66 (#): 401-402

We described a patient who developed a serious rash with lamotrigine after carbamazepine was discontinued. Lamotrigine is one of the medication that carry high risk of consequences if not done properly which can lead to serious rash such as SJS--Steven Johnson Syndrome or even Toxic Erythema Necrolisis (TEN) with high rate of mortality.

This was not a coincidence.

What happened can be explained biologically

• Carbamazepine is a potent enzyme inducer

• It accelerates metabolism of lamotrigine via UGT enzymes

• While carbamazepine is present, lamotrigine levels stay lower

• When carbamazepine is stopped:

  • Enzyme induction fades over 1–3 weeks

  • Lamotrigine clearance drops

  • Serum lamotrigine levels can double or triple

  • Rash risk increases dramatically

Importantly:

• The lamotrigine dose had not changed

• The patient did nothing “wrong”

• The danger came from timing and metabolic shift

This still matters today

• Serious lamotrigine rash occurs in ~0.3–0.8% of adults

• Risk increases with:

  • Rapid titration

  • Valproate coadministration

  • Changes in enzyme induction status

This case illustrated an enduring lesson:

Stopping a medication can be just as dangerous as starting one—if metabolism is not understood.

Case example #2 (2008):

Surja A, Reynolds K, Linder M, El-Mallakh R: Pharmacogenetic testing of CYP2D6 in patient with Aripiprazole-related Extrapyramidal symptoms: a case -control study; Personalized Medicine 2008, 5 (4): 361-365

We published one of the early clinical studies examining CYP2D6 pharmacogenetics in children who developed extrapyramidal symptoms (EPS) on aripiprazole—then widely viewed as a low-risk antipsychotic due to unique Dopamine D2 partial agonist activity.

What we observed then

• All patients with EPS had reduced CYP2D6 function

• 50% were poor metabolizers

• 50% were intermediate metabolizers

• Symptoms occurred at standard or low doses

At the time, this was among the earliest signals that:

• “Atypical” does not mean metabolically neutral

• Genetic variability can affect tolerability, not just blood levels

Later, larger studies showed mixed results—confirming higher drug exposure in poor metabolizers but weaker, inconsistent correlations with clinical EPS. That evolution of evidence is expected and healthy science.

Early studies generate hypotheses; They don’t provide final answers—but they shape the questions we continue to ask.

Genetics vs reality: why pharmacogenetics is helpful—but incomplete

• 5–10% of individuals of European ancestry are CYP2D6 poor metabolizers and even more in certain population such as Asian, Middle Eastern and Native population

• 30–40% are intermediate metabolizers

• Up to 80% higher plasma drug concentrations have been documented in poor metabolizers for certain drugs

But here’s the catch:

Genetics can be overridden

• Bupropion can reduce CYP2D6 activity by ~90%

• Fluoxetine and paroxetine functionally convert normal metabolizers into poor metabolizers

• Smoking induces CYP1A2 and can lower clozapine levels by up to 50%

• Enzyme induction or de-induction can occur within days to weeks

This phenomenon—phenoconversion—is invisible to DNA tests.

This matters for patient safety

Pharmacogenetic testing can be helpful, but it cannot replace:

• Fundamental understanding enzyme induction and inhibition

• Knowing half-lives and washout periods

• Anticipating delayed metabolic effects

• Monitoring during transitions—not just steady states

The lamotrigine–carbamazepine case is a reminder that danger often lies in transitions, not maintenance. It perfectly sums up "You don't know what you don't know"

Psychiatry is medical care—full stop

These cases illustrate why psychiatry is not simply about choosing a medication from a list.

It requires:

• Deep knowledge of pharmacology

• Understanding of physiology and metabolism

• Ability to anticipate delayed adverse effects

• Medical training in managing risk, not just symptoms

Medication interactions, enzyme shifts, and genetic variability are not abstract concepts—they affect real patients, sometimes with irreversible consequences.

This is why experience matters.

Choosing a psychiatrist: why training and credentials matter

Psychiatric medications:

• Affect multiple organ systems

• Interact with hormones, smoking, diet, and other drugs

• Can cause severe adverse effects when mismanaged

A psychiatrist with medical training (MD/DO) brings:

• Full understanding of systemic physiology

• Training in medication safety and adverse event recognition

• Experience integrating genetics, interactions, and clinical context

Psychiatry is not “just prescribing.” It is medical decision-making under uncertainty, informed by science and experience.

Final reflection

Over 20 years, the science has advanced—but the core lesson remains unchanged:

Genes matter. Enzymes matter. Timing matters. But, clinical judgment matters most.

Pharmacogenetics is a valuable tool when used thoughtfully. Drug–drug interactions are predictable when understood. Harm occurs when complexity is underestimated.

Good psychiatric care respects that complexity—because patients deserve nothing less.