A number of case reports describe serotonin syndrome in patients given SSRIs with MAOIs: some have been fatal. Concurrent use is contraindicated. Some studies suggest that moclobemide may not interact with SSRIs, but there have alsobeen case reports of serotonin syndrome and concurrent useis contraindicated. A suitable washout interval is needed when switching between MAOIs or RIMAs and SSRIs.
Clinical evidence,mechanism, importance and management
A very high incidence (25 to 50%) of adverse effects occurred in 12 patients taking fluoxetine 10 to 100mg daily with either phenelzine 30 to 60mg daily or tranylcypromine 10 to 140mg daily,and in 6 other patients started on either of these MAOIs 10 days or more after stopping fluoxetine. There were mental changes such as hypomania,racing thoughts, agitation, restlessness and confusion. The physical symptoms included myoclonus,hypertension, tremor, teeth chattering and diarrhoea (See reference number 1).
A detailed review of cases reported to manufacturers described 8 acute cases, 7 of them fatal, in patients given fluoxetine with either tranylcypromine or phenelzine (See reference number 2). Uncontrollable shivering,teeth chattering, double vision, nausea, confusion, and anxiety developed in a woman giventranylcypromine after stopping fluoxetine. The problem resolved within a day of stopping tranylcypromine, and did not recur when fluoxetine was tried again 6 weeks later (See reference number 3).
A number of other reports describe similar reactions in patients given fluoxetine and tranylcypromine,(See reference number 3-8) some occurring up to 6 weeks after SSRI was stopped,(See reference number 6) and several resulting in fatalities (See reference number 3,7)
A man taking tranylcypromine and clonazepam was additionally given sertraline 25 to 50mg daily. Within 4 days he began to experience chills,increasing confusion, sedation, exhaustion, unsteadiness and incoordination. Other symptoms included impotence,urinary hesitancy and constipation. These problems rapidly resolved when sertraline was stopped and tranylcypromine dosage reduced from 30 to 20mg daily (See reference number 9).
A woman with a major depressive disorder taking lithium,thioridazine, doxepin and phenelzine was also given sertraline 100mg daily for worsening depression. Within 3 hrs she became semi-comatose,with a temperature of 41°C, a heart rate of 154 bpm and symptoms of rigidity and shivering. She was treated with diazepam,midazolam, ice-packs and dantrolene (See reference number 10). Two other similar cases, involving use of sertraline withisocarboxazid(See reference number 11) and phenelzine(See reference number 12) have been reported. The latter case was fatal (See reference number 12). Another case of mild serotonin syndrome (managed with cyproheptadine) occurred in a woman who took a single dose of sertraline 11 days after stopping isocarboxazid (See reference number 13).
A 34-year-old man who had been taking moclobemide 100mg every 8 hrs for several months was switched to citalopram 20mg daily without a break. An hour later he started getting agitated and had involuntary movements of legs, which progressed to generalised rigidity. Apart from a heart rate of 100 bpm all other vital signs were normal. He was treated with benzodiazepines and recovered uneventfully (See reference number 14). Three patients developed serotonin syndrome (tremor, convulsions, hyperthermia, unconsciousness) and died 3 to 16 hrs after taking overdoses of moclobemide and citalopram (See reference number 15). Other cases of serotonin syndrome after overdose of moclobemide and citalopram have been reported:(See reference number 16,17) one also included sertraline and sumatriptan (See reference number 16).
A placebo-controlled trial in 18 healthy subjects found that use of fluoxetine 20mg with moclobemide 100 to 600mg daily for 9 days gave no evidence of an adverse interaction (See reference number 18). Other studies in healthy subjects and patients similarly found no evidence of serotonin syndrome (See reference number 19,20)
However, 3 patients have developed serotonin syndrome(See reference number 22-24) and one developed agitation and confusion(See reference number 25) following use of moclobemide and fluoxetine. A fatal case of serotonin syndrome occurred in a patient who took an overdose of moclobemide, fluoxetine, and clomipramine,(See reference number 26) and another patient taking moclobemide developed serotonin syndrome after taking an overdose of fluoxetine (See reference number 27). A study suggests that combination may cause a high rate of adverse effects (insomnia, dizziness, nausea and headache) (See reference number 22).
A double-blind study in 41 healthy subjects found that when they were given fluoxetine 40mg daily for 7 days,then 20mg for 9 days, immediately followed by befloxatone (2.5,5, 10 or 20mg daily) for 5 days, no unusual adverse reactions occurred and no changes in body temperature, haemodynamics or ECGs were seen (See reference number 28).
When 13 of 22 healthy subjects given fluvoxamine 100mg daily for 9 days were also given moclobemide in increasing doses of 50 to 400mg daily for 4 days from day 7,no serious adverse reactions occurred. Any adverse events were mild to moderate (some increase in headaches, fatigue, dizziness, all of which may occur with both drugs alone) and there was no evidence of serious serotonin syndrome (See reference number 18,29). An open study in 6 depressed patients given moclobemide 225 to 800mg daily and fluvoxamine 50 to 200mg daily found a marked improvement in depression. Insomnia was commonest adverse effect (treated with trazodone) but none of patients showed any evidence of serotonin syndrome (See reference number 30). Similar results were found in other studies (See reference number 20,31). However, a fatal case of serotonin syndrome occurred in a woman who took an overdose of moclobemide and fluvoxamine, and another fatal overdose was attributed to same combination (See reference number 32).
An open 6-week study in 19 patients with major depression taking paroxetine (or fluoxetine) 20mg daily to which moclobemide up to 600mg daily was added,indicated that these combinations were possibly effective (See reference number 33). An extension of this study with 50 patients is reported elsewhere (See reference number 22). However, a range of adverse effects occurred in some patients, clearest one being insomnia, and serotonin syndrome was seen in one patient (See reference number 22,33). Conversely, serotonin syndrome was not seen in another study, where low initial doses and gradual up-titration of both paroxetine and moclobemide was used (See reference number 20). Two possible cases of mild serotonin syndrome occurred in women on moclobemide within 2 to 24 hrs of starting additional paroxetine (See reference number 34). Similarly,cases of severe serotonin syndrome have been reported with overdoses of moclobemide and paroxetine (See reference number 35,36).
In one study,31 severely ill patients were given moclobemide 35 to 800mg daily with SSRIs including sertraline 25 to 100mg daily, initially using lower than usual starting doses of both drugs and then gradually titrating them slowly upwards. The other SSRIs used were fluoxetine,fluvoxamine and paroxetine. There was no evidence of serotonin syndrome (See reference number 20). An open study in 5 depressed patients given moclobemide 150 to 600mg daily and sertraline 25 to 200mg daily found improvements ranging from minimal to complete remission. Insomnia was commonest adverse effect (treated with trazodone) but none of patients showed any evidence of serotonin syndrome (See reference number 30). However,one case of possible serotonin syndrome occurred in a woman who took an overdose of moclobemide and sertraline,(See reference number 34) and another after an overdose of moclobemide, citalopram, sertraline and sumatriptan (See reference number 16). Similarly, a fatality has been reported with an overdose of moclobemide, sertraline and pimozide, with blood levels suggesting that none of drugs individually would have been fatal (See reference number 37).
Serotonin toxicity (the serotonin syndrome) occurred in 5 patients who took an overdose of moclobemide with an SSRI [specific drugs not mentioned]. In this analysis of moclobemide overdoses, risk of developing serotonin toxicity was increased 35 times in patients who also took another serotonergic drug. Of 11 cases mentioned 5 patients were taking SSRIs (See reference number 38).
MAO-A is involved in metabolism of serotonin, so combined use of MAOIs or RIMAs with SSRIs may lead to excessive serotonin levels, which can result in serotonin syndrome. For more information see the serotonin syndrome,.
Direct information about interaction between MAOIs and SSRIs is limited. However,it is clear that severe, sometimes fatal interactions (the serotonin syndrome or similar) have occurred with MAOIs and fluoxetine or sertraline, so these reports should certainly be taken seriously. The incidence appears to be low, possibly as combined use of any MAOI and any SSRI is contraindicated. In addition, at least 2 weeks should elapse between stopping any MAOI and starting any SSRI to allow for effects of MAOI to diminish. Moreover, manufacturers of each SSRI give guidance on appropriate intervals that should be left between stopping SSRI and starting an MAOI, that is, 14 days for sertraline,(See reference number 39,40) seven
days for citalopram,(See reference number 41)escitalopram, fluvoxamine(See reference number 43) or paroxetine(See reference number 44)(14 days in US),(See reference number 45-47) and at least 5 weeks for fluoxetine, with an even longer interval if long-term or high-dose fluoxetine has been used (See reference number 48,49).
The RIMAs (e.g. moclobemide) also have serotonergic effects, and so they are unlikely to be any safer than non-selective MAOIs in regard to interactions with SSRIs. The few cases of serotonin syndrome cited with therapeutic doses of this combination confirm that it is not necessarily safe. The combination may be particularly problematic in overdose, and negates generally benign course of moclobemide overdose alone. It should be noted that manufacturer of moclobemide contraindicates its use with SSRIs (See reference number 50). Because effects of moclobemide are readily reversible, only one day need elapse between stopping moclobemide and starting an SSRI. However, if stopping an SSRI and starting moclobemide, same intervals are required as for irreversible MAOIs.
For management of serotonin syndrome, see Importance and management under MAOIs or RIMAs + Tricyclic and related antidepressants interaction.
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