What enzymes break down psychiatric medications and what are their inhibitors?

Key Cytochrome P450 Enzymes in Psychiatric Medication Metabolism

The four critical CYP enzymes you must know are CYP2D6, CYP2C19, CYP1A2, and CYP3A4, with CYP2D6 and CYP2C19 being the most clinically important for psychiatric medications. 1

Primary Metabolic Enzymes and Their Substrates

CYP2D6 (Most Critical)

• Metabolizes the majority of antidepressants including fluoxetine, paroxetine, venlafaxine, and most tricyclic antidepressants 2, 1
• Also metabolizes antipsychotics including risperidone, aripiprazole, and many typical antipsychotics 2, 3
• Approximately 5-8% of Caucasians are poor metabolizers (PM), leading to 2-5 fold higher drug levels and increased side effects 2, 1, 4
• About 1-7% are ultrarapid metabolizers (UM), who break down medications too quickly, risking treatment failure 2, 1

CYP2C19 (Second Most Important)

• Works alongside CYP2D6 to metabolize SSRIs, particularly important for citalopram and certain tricyclics 2, 1
• Involved in N-demethylation of tertiary amines like amitriptyline 2
• About 2-5% of Caucasians are poor metabolizers for this enzyme 1

CYP1A2 (Supporting Role)

• Primary enzyme for clozapine and olanzapine metabolism 3
• Highly inducible by tobacco smoke, which can dramatically lower drug levels in smokers 2

CYP3A4 (Supporting Role)

• Metabolizes quetiapine, ziprasidone, and contributes to metabolism of many other antipsychotics 3
• Shows wide interindividual variability but lacks clinically significant genetic polymorphisms for most psychiatric medications 2, 4

Major CYP Inhibitors to Avoid or Monitor

Potent CYP2D6 Inhibitors

• Fluoxetine and paroxetine are the most potent SSRI inhibitors of CYP2D6 4, 5, 6
• Paroxetine can increase desipramine levels 5-fold and risperidone levels 4-fold 4
• Bupropion and terbinafine also significantly inhibit CYP2D6 7
• Quinidine is a potent non-psychiatric CYP2D6 inhibitor 4

Potent CYP2C19 Inhibitors

• Fluvoxamine is the most potent SSRI inhibitor of CYP2C19 5, 6

Potent CYP1A2 Inhibitors

• Fluvoxamine is the most potent inhibitor, causing significant interactions with clozapine and olanzapine 5, 6
• Ciprofloxacin and other fluoroquinolones can significantly inhibit CYP1A2 2

Potent CYP3A4 Inhibitors

• Ketoconazole, itraconazole, and fluconazole (azole antifungals) 7
• Clarithromycin and erythromycin (macrolide antibiotics) 7
• Fluoxetine's metabolite norfluoxetine has moderate CYP3A4 inhibitory effects 5, 6
• Nefazodone is a potent inhibitor 7

Critical Clinical Considerations

Fluoxetine Deserves Special Attention

• Inhibitory effects persist for several weeks after discontinuation due to the long half-life of fluoxetine (4-6 days) and its active metabolite norfluoxetine (4-16 days) 5
• This creates a prolonged risk period for drug interactions even after stopping the medication 5

Sertraline and Citalopram Are Safer Options

• Sertraline is only a moderate CYP2D6 inhibitor at therapeutic doses 8, 5
• Citalopram has minimal effects on major CYP isoforms, making it the safest choice when drug interactions are a concern 5

Smoking Status Matters Critically

• Tobacco smoke induces CYP1A2, requiring higher doses of clozapine and olanzapine in smokers 2
• Smoking cessation can cause toxic drug levels if doses are not reduced appropriately 2

Common High-Risk Drug Combinations

Frequently Co-Prescribed Problematic Pairs

• Paroxetine with codeine (116 documented events in one study) - codeine requires CYP2D6 for conversion to morphine, rendering it ineffective 7
• Paroxetine or fluoxetine with metoprolol - can cause excessive beta-blockade 7
• CYP3A4 inhibitors with simvastatin or other statins - increases myopathy risk 7

Contraindicated Combinations

• Paroxetine with thioridazine - risk of serious ventricular arrhythmias and sudden death 4
• Paroxetine with pimozide - narrow therapeutic index makes this combination dangerous 8

Practical Management Approach

When prescribing psychiatric medications, follow this algorithm:

1. Identify all CYP substrates the patient is taking - focus on drugs with narrow therapeutic indices
2. Check for potent CYP inhibitors - particularly fluoxetine, paroxetine, and fluvoxamine among antidepressants
3. Consider genetic testing for CYP2D6 in specific situations: treatment-resistant depression, multiple medication failures, or severe adverse effects at standard doses 2
4. Monitor for tobacco use - critical for clozapine and olanzapine dosing 2
5. Adjust doses preemptively when combining known inhibitors with substrates, rather than waiting for problems 4

Important Caveat About Genetic Testing

Despite the theoretical appeal, routine CYP450 genetic testing for patients starting SSRIs is NOT recommended because evidence does not show it improves clinical outcomes 2. Testing may be useful in specific cases of treatment failure or severe adverse effects, but should not be routine practice 2.