Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity

Aims To investigate the spectrum of toxicity of moclobemide overdose, the occurrence of serotonin toxicity, and to estimate toxicokinetic parameters. Methods All moclobemide overdoses presenting over a 10-year period to the Hunter Area Toxicology Service were reviewed. Clinical features, complications, length of stay (LOS) and intensive care (ICU) admission rate were extracted from a standardized, prospectively collected database. Comparisons were made between moclobemide alone and moclobemide with a serotonergic coingestant poisoning. Serotonin toxicity was defined by a combination of Sternbach's criteria and a clinical toxicologist's diagnosis. In five patients serial moclobemide concentrations were measured. Time to maximal plasma concentration (T-max), peak plasma concentration (C-max) and terminal elimination half-lives were estimated. Results Of 106 included patients, 33 ingested moclobemide alone, 21 ingested moclobemide with another serotonergic agent ( in some cases in therapeutic doses) and 52 ingested moclobemide with a nonserotonergic agent. Eleven (55%) of 21 patients coingesting a serotonergic drug developed serotonin toxicity, which was significantly more than one (3%) of 33 moclobemide-alone overdoses ( odds ratio 35, 95% confidence inteval 4, 307; P < 0.0001). In six of these 21 cases severe serotonin toxicity developed with temperature > 38.5 degreesC and muscle rigidity requiring intubation and paralysis. The 21 patients had a significantly increased LOS ( 34 h) compared with moclobemide alone overdoses ( 12 h) ( P < 0.0001) and a significantly increased ICU admission rate of 57% vs. 3% ( P < 0.0001). Time to peak plasma concentration was delayed in two patients where prepeak samples were obtained. C-max increased slightly with dose, but all three patients ingesting greater than or equal to 6 g vomited or had charcoal. The mean elimination half-life of moclobemide in the five patients in whom serial moclobemide concentrations were measured was 6.3 h and elimination was first order in all cases. There was no evidence of a dose-dependent increase in half-life. Conclusions The effects of moclobemide alone in overdose are minor, even with massive ingestions. However, moclobemide overdose in combination with a serotonergic agent ( even in normal therapeutic doses) can cause severe serotonin toxicity. The elimination half-life is prolonged by two to four times in overdose, compared with that found in healthy volunteers given therapeutic doses. This may be a result of wide interindividual variation in overall elimination, also seen with therapeutic doses, but appears not to be due to saturation of normal elimination pathways.