Risk of serotonin toxicity with procarbazine

A question recently came up regarding the risk of serotonin toxicity from a drug interaction between procarbazine and a number of different serotonergic agents.  When checking for an interaction between procarbazine and medications like sertraline, duloxetine, nortriptyline, and tramadol on resources such as Lexicomp and Micromedex, the interactions are listed inconsistently, from no interaction to contraindicated, with varying degrees of evidence, from theoretical to established.

A literature search for this interaction revealed a single retrospective chart review.  The authors reviewed charts for patients who received either procarbazine (n=39) or procarbazine plus an antidepressant (n=26) for signs and symptoms of serotonin toxicity.  Here are some of their findings:

• No patient in either group experienced serotonin toxicity according to the highly sensitive (84%) Hunter Serotonin Toxicity Criteria
• Patients mostly received SSRIs, followed by SNRIs, and one patient received a TCA
• The authors recommend close monitoring for signs of serotonin toxicity - see the table below for monitoring parameters
• The authors conclude that even though there are many limitations of their study, clinicians should not be dissuaded from managing depressive symptoms in patients receiving procarbazine because of its MAO inhibitory activity

Mechanism of the interaction

Procarbazine was first synthesized in the early 1960s during a search for monoamine oxidase (MAO) inhibitors and was found to have anticancer activity.  While the parent drug is inactive as an antineoplastic agent and a MAO inhibitor, the drug's cytochrome P450 metabolites have both properties.  Procarbazine easily crosses the blood brain barrier and has weak MAO inhibition so exposure to catecholamines, sympathomimetics, and dietary tyramine may cause a number of adverse effects including serotonin toxicity.

Take home points:

• There are no reports of serotonin toxicity from drug interactions involving procarbazine
• If continuation of the serotonergic agent is necessary, monitor for signs of toxicity
• Abrupt discontinuation of antidepressants can result in a withdrawal syndrome also, which can affect your monitoring (previously described in a post about the interaction between linezolid and SSRIs).

References:
1.  Kraft SL, Baker NM, Carpenter J et al.  Procarbazine and antidepressants: a retrospective review of the risk of serotonin toxicity.  Psychooncology  2014;23(1):108-13.
2.  Chabner BA, Bertino J, Cleary J, et al.  Chapter 61: Cytotoxic Agents. In: Brunton LL, Chabner BA, Knollman BC. eds.  Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e.  New York, NY: McGraw-Hill; 2011.

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