What are the clinical determinants for a risk of serotonergic syndrome when combining a tricyclic

Fråga: "What are the clinical determinants for a risk of serotonergic syndrome when combining a tricyclic antidepressant (TCA) and an irreversible monoamine oxidase inhibitor (MAOI)?

The question concerns a young woman treated for obsessive-compulsive disorder with phenelzine 90 mg/d and clomipramine 100mg/d since more than a month. She is now described as "jittery". She does not have pyrexia."

Sammanfattning: The exact risk-benefit situation in combining TCA and MAOI treatment is unknown, but given the fact that lethal side effects have occurred, the expected clinical benefit must be large in order to mandate the combination. Amitryptiline may be a more appropriate therapeutic choice than clomipramine.

Svar: The serotonergic syndrome is most often the result of the interaction between serotonergic acting agents and monamine oxidase inhibitors. It is clinically slightly nebulous, but resembles the neuroleptic malignant syndrome, with changes in mental status, restlessness, myoclonus, hyperreflexia, shivering and tremor. It may be complicated by circulatory shock, rhabdomyolysis, seizures and renal failure (1).

The published literature does not seem to allow an exact estimate of the frequency of this serious reaction in combination therapy, and several series have been published were patients have been treated successfully with combinations of TCA and MAOI (2).

Cases have been published were phenelzine in combination with desipramine and clomipramine have caused the serotonergic syndrome. The published literature indicates that amitryptiline may be safer than the aforementioned TCAs (2). Theoretical support of this assumption might be represented by the fact that clomipramine is relatively more of an inhibitor of serotonin reuptake than is amitryptiline.

Concerning the timing of onset of the serotonergic syndrome, it seems that most of the cases described have been during the first weeks of combined therapy, or after a recent dose alteration (2,3). Though the evidence base is scanty, it has been suggested that the dose of phenelzine should be limited to 45 mg/d when combined with a TCA (4).

Most serotonergic syndromes seem to have occurred at the initiation of therapy, but the symtomatology of the patient may represent enhanced serotonergic activity. Discontinuing combination therapy should be seriously considered is the present case. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148(6):705-13. Stockley IH. Drug interactions. 6th ed. London: The Pharmaceutical Press; 2002. s. 682-3. Francois B, Marquet P, Desachy A, Roustan J, Lachatre G, Gastinne H. Serotonin syndrome due to an overdose of moclobemide and clomipramine. A potentially life-threatening association. Intensive Care Med 1997;23:122-4. Phenelzine. Drugdex(R) System; Micromedex, Inc., Englewood, Colorado (Edition expires)