Depression Symptoms Treatment

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Question. Can you please give me your opinion on the P450 inhibitory effects of SSRIs, namely, fluoxetine, paroxetine, citalopram, sertraline and fluvoxamine? Which appears to have the least clinically significant effects on this and other liver enzymes? How do these effects demonstrate themselves to patients? How clinically significant are the effects?

Answer. I’ll give you the bottom line first, then fill in some of the details: if you are only worried about inhibitory effects of SSRIs on the cytochromes, it’s best to avoid using fluoxetine [Prozac], fluvoxamine [Luvox], and paroxetine [Paxil]. Instead, go to either sertraline [Zoloft] or citalopram [Celexa]. Neither of these latter two SSRIs have substantial inhibitory effects on the cytochromes, though that doesn’t mean they are fail-safe medications.

Furthermore, for many patients, Prozac, Luvox, or Paxil may simply work better for depression. To cite some data from Dr. Sheldon Preskorn [see Harvey & Preskorn, Journal of Clinical Psychopharmacology, 1996; 16:273-85], “both fluoxetine and paroxetine have substantial inhibitory effects on the cytochrome P450 2D6 (CYP 2D6) system. Fluoxetine also has substantial inhibitory effects on CYP 2C9 and moderate inhibitory effects on CYP 2C19. Fluvoxamine has substantial inhibitory effects on CYP 1A2 and 2C19, and moderate effects on CYP 3A3/4.”

In and of themselves, these inhibitory effects rarely are felt by patients, unless they are taking some other medication whose blood levels rise in the presence of one of these strongly-inhibiting SSRIs. For example, someone taking the antipsychotic clozapine [Clozaril] may experience marked side effects (sedation, dizziness) if fluvoxamine [Luvox] is added. This is because clozapine is metabolized (in part) through CYP 1A2, which fluvoxamine strongly inhibits. In other cases, the psychiatrist may actually take advantage of these inhibiting effects, by using the SSRI as a kind of magnifying glass, that is, using it to boost blood levels of some other therapeutic agent, which is prescribed in a very small dose.

In other cases, the rise in blood levels effected by one of these SSRIs is clinically insignificant, from the patient’s standpoint. It is always a matter of the particular drugs involved, and the particular patient. For example, some patients may lack the CYP enzymes required to break down a particular drug, or have an unusually active form of the enzyme. You might want to get hold of some of Dr. Preskorn’s recent articles on this subject for further details.