MAOIs or RIMAs + Venlafaxine - Drug Interactions

Serious and potentially life-threatening reactions (the serotoninsyndrome) can develop if venlafaxine and non-selective MAOIs(isocarboxazid,phenelzine, tranylcypromine) are given concurrently, or even sequentially if insufficient time is left in between.The situation with moclobemide,in therapeutic doses, is uncertain.

Isocarboxazid. A man with recurrent depression taking isocarboxazid 30mg daily was additionally given venlafaxine 75 mg. After second dose he developed agitation, hypomania, diaphoresis, shivering and dilated pupils. These symptoms subsided when venlafaxine was stopped. He subsequently developed myoclonic jerks and diaphoresis when given both drugs (See reference number 1).

Phenelzine. A woman who had stopped taking phenelzine 45mg daily 7 days previously,developed sweating, lightheadedness and dizziness within 45 minutes of taking a single 37.5mg dose of venlafaxine. In emergency department she was found to be lethargic, agitated and extremely diaphoretic. The agitation was treated with lorazepam. A week later, after she had recovered, she was again started on same regimen of venlafaxine without problems (See reference number 2). A man similarly developed serotonin syndrome when he started venlafaxine day after he stopped taking phenelzine (See reference number 3). A woman developed serotonin syndrome within less than an hour of taking phenelzine and venlafaxine together,(See reference number 4) and 4 other patients similarly developed reaction when phenelzine was replaced by venlafaxine (See reference number 5). Twelve days after an overdose of phenelzine (53 tablets of 15 mg),benztropine, haloperidol and lorazepam, a 31-year-old man was given venla

faxine 75mg every 12 hrs in addition to existing treatment with olanzapine and diazepam. About an hour after first dose, he developed leg shakiness and stiffness, diaphoresis, blurred vision, difficulty breathing, chills, nausea and palpitations. Venlafaxine and olanzapine were discontinued and man recovered within 24 hours, after treatment with intravenous fluids, propranolol and paracetamol (See reference number 6).

3. Tranylcypromine. A woman who had been taking tranylcypromine for 3 weeks developed a serious case of serotonin syndrome within 4 hrs of inadvertently taking a single tablet of venlafaxine. She recovered within 24 hours,when treated with ice packs, a cooling blanket, diazepam and dantrolene (See reference number 7). The serotonin syndrome developed in a man taking tranylcypromine within 2 hrs of taking half a venlafaxine tablet (See reference number 8). Another case of serotonin syndrome has been described in a man taking tranylcypromine 60mg daily who accidentally took venlafaxine 300mg (See reference number 9).

A 32-year-old man taking moclobemide 20mg twice daily and diazepam developed serotonin syndrome 40 minutes after taking a single 150mg dose of venlafaxine (See reference number 10). Serotonin toxicity (the serotonin syndrome) occurred in 4 patients who took an overdose of moclobemide with venlafaxine (just 150mg in one case and 750mg in another). In this analysis of moclobemide overdoses, risk of developing serotonin toxicity was increased 35 times in patients who also took another serotonergic drug. Venlafaxine was taken in 4 of 11 cases mentioned (See reference number 11). Another man very rapidly developed serotonin syndrome after taking considerable overdoses of moclobemide (3 g) and venlafaxine (2.625 g) (See reference number 12).

The serotonin syndrome is thought to occur because venlafaxine can inhibit serotonin re-uptake (its antidepressant effect is related to this activity), and MAOIs and RIMAs inhibit metabolism of serotonin. The result is an increase in concentrations of serotonin apparently causing overstimulation of 5-HT1A receptors in brain and spinal cord. See also the serotonin syndrome,.

An established,serious and potentially life-threatening interaction. The manufacturers of venlafaxine say that adverse reactions,some serious, have been seen in patients who had recently stopped taking an MAOI and started venlafaxine, or who had stopped venlafaxine and then started an MAOI. Some have been fatal (See reference number 13,14). They recommend that venlafaxine should not be used in combination with an MAOI or within 14 days of stopping treatment with MAOI (See reference number 13,14). Based on half-life of venlafaxine they say that at least 7 days should elapse between stopping venlafaxine and starting an MAOI. The manufacturers do not distinguish in this recommendation between irreversible older non-selective MAOIs and RIMAs such as moclobemide. In one of studies it was suggested that a wash-out period of several weeks is required between stopping MAOIs such as phenelzine and initiating a second serotonergic drug such as venlafaxine (See reference number 6).

Klysner R,Larsen JK, Sørensen P, Hyllested M, Pedersen BD. Toxic interaction of venlafaxine and isocarboxazide. Lancet (1995) 346, 1298–9.

Phillips SD,Ringo P. Phenelzine and venlafaxine interaction. Am J Psychiatry (1995) 152, 1400–1401.

Heisler MA,Guidry JR, Arnecke B. Serotonin syndrome induced by administration of venlafaxine and phenelzine. Ann Pharmacother (1996) 30, 84.

Weiner LA,Smythe M, Cisek J. Serotonin syndrome secondary to phenelzine-venlafaxine interaction. Pharmacotherapy (1998) 18, 399–403.

Diamond S,Pepper BJ, Diamond ML, Freitag FG, Urban GJ, Erdemoglu AK. Serotonin syndrome induced by transitioning from phenelzine to venlafaxine: four patient reports. Neurology (1998) 51, 274–6.

Mason PJ,Morris VA, Balcezak TJ. Serotonin syndrome. Presentation of 2 cases and reviewof the literature. Medicine (2000) 79, 201–9.

Hodgman M,Martin T, Dean B, Krenzelok E. Severe serotonin syndrome secondary to venlafaxine and maintenance tranylcypromine therapy. J Toxicol Clin Toxicol (1995) 33, 554.

Brubacher JR,Hoffman RS, Lurin MJ. Serotonin syndrome from venlafaxine-tranylcypromine interaction. Vet Hum Toxicol (1996) 38, 358–61.

Claassen JAHR,Gelissen HPMM. The serotonin syndrome. N Engl J Med (2005) 352, 2455.

Chan BSH,Graudins A, Whyte IM, Dawson AH, Braitberg G, Duggin GG. Serotonin syndrome resulting from drug interactions. Med J Aust (1998) 169, 523–5.

Isbister GK,Hackett LP, Dawson AH, Whyte IM, Smith AJ. Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity. Br J Clin Pharmacol (2003) 56, 441–50.

Roxanas MG,Machado JFD. Serotonin syndrome in combined moclobemide and venlafaxine ingestion. Med J Aust (1998) 168, 523–4.

Efexor (Venlafaxine hydrochloride). Wyeth Pharmaceuticals. UK Summary of product characteristics,May 2006.

Effexor XR (Venlafaxine hydrochloride). Wyeth Pharmaceuticals Inc. US Prescribing information,June 2007.

MAOIs + MAOIs or RIMAs - Drug Interactions

Strokes, fatal reactions (possibly including serotonin syndrome), hypertensive reactions and CNS disturbances have beenseen, either when one MAOI was abruptly replaced by another,when two MAOIs were given together, or when there was aninsufficient MAOI-free interval. A case of serotonin syndrome occurred in a patient who overdosed on moclobemide and tranylcypromine.

Clinical evidence,mechanism, importance and management

A patient who had been taking isocarboxazid for 3.5 weeks (starting at 10mg daily and gradually increased to 30mg daily) was switched to tranylcypromine 10 mg, starting same day, followed by 10mg three times daily on following day. Later that night she complained of feeling funny,had difficulty in talking, developed a headache, was restless, flushed, sweating, had an elevated temperature of 39.5°C,and a pulse rate of 130 bpm. She died following day (See reference number 1). Another patient, switched without a drug-free period, from phenelzine 75mg daily (by tapering dose by 15mg daily until discontinued) to tranylcypromine (starting at 10mg daily, increasing by 10mg daily, until a dose of 20mg twice daily was reached), suffered a subcortical cerebral haemorrhage on fourth day following morning 20mg dose of tranylcypromine, which resulted in total right-sided hemiplegia (See reference number 2,3). The patient remained significantly disabled from sequelae of her stroke (See reference number 4). A third patient experienced a mild cerebral haemorrhage, without residual problems, when she took phenelzine 45mg and tranylcypromine 20mg at bedtime; MAOIs were being switched by reducing dose of phenelzine and gradually increasing dose of tranylcypromine. Consumption of soy sauce,, may have contributed to this reaction (See reference number 5). In a fourth case, phenelzine 45mg daily was stopped, and then after a two-day drug-free period tranylcypromine 20mg was given, with a further 30mg dose next day. The patient experienced a rise in blood pressure to 240/130 mmHg,but recovered uneventfully, and a year later was successfully switched from phenelzine to tranylcypromine with a 2-week drug-free interval (See reference number 2). In another case,hypertension with severe headache, inability to walk and slurred speech, but without permanent sequelae, resulted from starting tranylcypromine 30mg seven days after discontinuing phenelzine. Tranylcypromine 10 mg daily was restarted 3 days later (10 days after discontinuing thephenelzine) with no adverse effects, but when dose was increased to 20mg daily (14 days after discontinuing phenelzine) patient experienced a milder version of same symptoms (See reference number 6).

Acute CNS toxicity,hypertension, tachycardia, tremor and urinary retention occurred in a woman 48 hrs after phenelzine was abruptly stopped and isocarboxazid started. In this patient,phenelzine was poorly tolerated causing hypertension and headache (See reference number 7).

Switching from iproniazid to tranylcypromine/trifluoperazine may have been cause of a fatal reaction (fever, shivering, sweating, cyanosis) in a patient also given ephedrine(See reference number 8,9) (see also MAOIs or RIMAs + Sympathomimetics; Indirectly-acting interaction).

In contrast, one woman was switched directly from phenelzine 60mg daily to tranylcypromine 20mg daily without any obvious problems (blood pressure was on high side, but within usual range for this patient). She was abruptly switched directly back to phenelzine,again without any adverse effect (See reference number 10,11). Similarly, a review of 8 cases of patients who were switched rapidly from tranylcypromine to phenelzine (3 cases) or vice versa (5 cases) found that 7 patients tolerated switch well with minimal or no adverse effects. However eighth patient experienced anxiety, nausea, hyperventilation, flushing, sense of doom, and increased insomnia, which may have been a mild form of serotonin syndrome (See reference number 12).

The reasons for these reactions are not understood, but one idea is that amphetamine-like properties of tranylcypromine may have had some part to play. Certainly there are cases of spontaneous rises in blood pressure and intracranial bleeding in patients given tranylcypromine (See reference number 13). Not all patients experience adverse reactions when switched from one MAOI to another,(See reference number 10,12) but because of sometimes severe reactions, it would seem prudent to have a drug-free wash-out interval when doing so, and to start dosing in a conservative and step-wise manner.

The serotonin syndrome occurred in a patient who took an overdose of moclobemide and tranylcypromine. In this analysis of moclobemide overdoses, risk of developing serotonin toxicity was increased 35-fold in patients who also took another serotonergic drug, of which this case with tranylcypromine was one of 11 mentioned (See reference number 14).

Bazire SR. Sudden death associated with switching monoamine oxidase inhibitors. Drug In-tell Clin Pharm (1986) 20,954–6.

Gelenberg AJ. Switching MAOI. Biol Ther Psychiatry (1984) 7,33 and 36.

Gelenberg AJ. Switching MAOI. The sequel. Biol Ther Psychiatry (1985) 8,41.

Mattes JA. Stroke resulting from a rapid switch from phenelzine to tranylcypromine. J Clin Psychiatry (1998) 59,382.

Anon. Switching MAOIs: part three. Biol Ther Psychiatry (1987) 10,7.

Chandler JD. Switching MAOIs. J Clin Psychopharmacol (1987) 7,438.

Safferman AZ,Masiar SJ. Central nervous system toxicity after abrupt monoamine oxidaseinhibitor switch: a case report. Ann Pharmacother (1992) 26, 337–8.

Low-Beer GA,Tidmarsh D. Collapse after "Parstelin". BMJ (1963) 2, 683–4.

Schrire I. Collapse after “Parstelin”. BMJ (1963) 2,748.

True BL,Alexander B, Carter B. Switching monoamine oxidase inhibitors. Drug Intell Clin Pharm (1985) 19, 825–7.

True BL,Alexander B, Carter BL. Comment: switching MAO inhibitors. Drug Intell Clin Pharm (1986) 20, 384–5.

Szuba MP,Hornig-Rohan M, Amsterdam JD. Rapid converson from one monoamine oxidaseinhibitor to another. J Clin Psychiatry (1997) 58, 307–10.

Cooper AJ,Magnus RV, Rose MJ. A hypertensive syndrome with tranylcypromine medication. Lancet (1964) 1, 527–9.

Isbister GK,Hackett LP, Dawson AH, Whyte IM, Smith AJ. Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity. Br J Clin Pharmacol (2003) 56, 441–50.

MAOIs + Monosodium glutamate - Drug Interactions

Hypertension in patients taking MAOIs who had eaten certainfoods (soy sauce,chicken nuggets) has been attributed, in anecdotal reports, to an interaction with monosodium glutamate. However, a small controlled study found no evidence to support thisidea, and reaction was probably related to tyramine,.

Five healthy subjects were given monosodium glutamate 400 to 1600mg or a placebo with or without tranylcypromine for at least 2 weeks. Episodes of hypertension were seen in 2 subjects taking tranylcypromine with both placebo and monosodium glutamate,but no changes in blood pressure or heart rate occurred that could be attributed to an interaction while taking monosodium glutamate. The largest dose of monosodium glutamate used was about twice amount usually found in meals containing large amounts of monosodium glutamate (See reference number 1).

There have been anecdotal reports of hypertensive reactions in patients taking MAOIs that were attributed to interactions with monosodium

Monosodium glutamate alone can cause a small rise in blood pressure,and MAOIs alone very occasionally cause hypertensive episodes. However, reactions reported with soy sauce and chicken nuggets were probably due to a high tyramine content, as a high tyramine content has subsequently been detected in some soy sauces,(See reference number 4) (see also MAOIs or RIMAs + Tyramine-rich foods interaction).

No interaction between monosodium glutamate per se and MAOIs has been established, although it should be pointed out that number of subjects studied was very small. It is quite possible that anecdotal reports were due to tyramine content of foods, and not to monosodium glutamate. In Hong Kong,patients on MAOIs are not advised to avoid monosodium glutamate, but are instructed to avoid excessive soy sauce because of its possible high tyramine content (See reference number 4).

Balon R,Pohl R, Yeragani VK, Berchou R, Gershon S. Monosodium glutamate and tranylcypromine administration in healthy subjects. J Clin Psychiatry (1990) 51, 303–6.

McCabe B,Tsuang MT. Dietary consideration in MAO inhibitor regimens. J Clin Psychiatry (1982) 43, 178–81.

Pohl R,Balon R, Berchou R. Reaction to chicken nuggets in a patient taking an MAOI. Am J Psychiatry (1988) 145, 651.

Lee S,Wing YK. MAOI and monosodium glutamate interaction. J Clin Psychiatry (1991) 52,

43.

MAOIs or RIMAs + SSRIs - Drug Interactions

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.

Feighner JP,Boyer WF, Tyler DL, Neborsky RJ. Adverse consequences of fluoxetine-MAOIcombination therapy. J Clin Psychiatry (1990) 51, 222–5.

Beasley CM,Masica DN, Heiligenstein JH, Wheadon DE, Zerbe RL. Possible monoamineoxidase inhibitor — serotonin uptake inhibitor interaction: fluoxetine clinical data and pre-clinical findings. J Clin Psychopharmacol (1993) 13, 312–20.

Sternbach H. Danger of MAOI therapy after fluoxetine withdrawal. Lancet (1988) ii,850–1.

Ooi,TK. The serotonin syndrome. Anaesthesia (1991) 46, 507–8.

Spiller HA,Morse S, Muir C. Fluoxetine ingestion: A one year retrospective study. Vet Hum Toxicol (1990) 32, 153–5.

Coplan JD,Gorman JM. Detectable levels of fluoxetine metabolites after discontinuation: anunexpected serotonin syndrome. Am J Psychiatry (1993) 150, 837.

Kline SS,Mauro LS, Scala-Barnett DM, Zick D. Serotonin syndrome versus neuroleptic malignant syndrome as a cause of death. Clin Pharm (1989) 8, 510–14.

Miller F,Friedman R, Tanenbaum J, Griffin A. Disseminated intravascular coagulation andacute myoglobinuric renal failure: a consequence of the serotonergic syndrome. J Clin Psychopharmacol (1991) 11, 277–9.

Bhatara VS,Bandettini FC. Possible interaction between sertraline and tranylcypromine. Clin Pharm (1993) 12, 222–5.

Graber MA,Hoehns TB, Perry PJ. Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann Pharmacother (1994) 28, 732–5.

Brannan SK,Talley BJ, Bowden CL. Sertraline and isocarboxazid cause a serotonin syndrome. J Clin Psychopharmacol (1994) 14, 144–5.

Keltner N. Serotonin syndrome: a case of fatal SSRI/MAOI interaction. Perspect Psychiatr Care (1994) 30,26–31.

Lappin RI,Auchincloss EL. Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med (1994) 331, 1021–2.

Gumà M,Clemente F, Segura A, Costa J. Síndrome serotoninérgico: moclobemida y citalopram. Med Clin (Barc) (1999) 113, 677–8.

Neuvonen PJ,Pohjola-Sintonen S, Tacke U, Vuori E. Five fatal cases of serotonin syndromeafter moclobemide-citalopram or moclobemide-clomipramine overdoses. Lancet (1993) 342, 1419.

Höjer J,Personne M, Skagius A-S, Hansson O. Serotoninergt syndrom: flera allvarliga fallmed denna ofta förbisedda diagnos. Lakartidningen (2002) 99, 2054–5, 2058–60.

Dams R,Benijts THP, Lambert WE, Van Bocxlaer JF, Van Varenbergh D, Van Peteghem C,De Leenheer AP. A fatal case of serotonin syndrome after combined moclobemide–citalopram intoxication. J Anal Toxicol (2001) 25, 147–51.

Dingemanse J. An update of recent moclobemide interaction data. Int Clin Psychopharmacol (1993) 7,167–80.

Dingemanse J,Wallnöfer A, Gieschke R, Guentert T, Amrein R. Pharmacokinetic and pharmacodynamic interactions between fluoxetine and moclobemide in the investigation of development of the "serotonin syndrome". Clin Pharmacol Ther (1998) 63, 403–13.

Bakish D,Hooper CL, West DL, Miller C, Blanchard A, Bashir F. Moclobemide and specificserotonin re-uptake inhibitor combination treatment of resistant anxiety and depressive disorders. Hum Psychopharmacol (1995) 10, 105–9.

Dingemanse J,Guentert TW, Moritz E, Eckernas S-A. Pharmacodynamic and pharmacokinetic interactions between fluoxetine and moclobemide. Clin Pharmacol Ther (1993) 53,

178.

Hawley CJ,Quick SJ, Ratnam S, Pattinson HA, McPhee S. Safety and tolerability of combined treatment with moclobemide and SSRIs: a systematic study of 50 patients. Int Clin Psychopharmacol (1996) 11, 187–91.

Benazzi F. Serotonin syndrome with moclobemide-fluoxetine combination. Pharmacopsychiatry (1996) 29,162.

Liebenberg R,Berk M, Winkler G. Serotonergic syndrome after concomitant use of moclobemide and fluoxetine. Hum Psychopharmacol (1996) 11, 146–7.

Chan BSH,Graudins A, Whyte IM, Dawson AH, Braitberg G, Duggin GG. Serotonin syndrome resulting from drug interactions. Med J Aust (1998) 169, 523–5.

Power BM,Pinder M, Hackett LP, Ilett KF. Fatal serotonin syndrome following a combinedoverdose of moclobemide, clomipramine and fluoxetine. Anaesth Intensive Care (1995) 23, 499–502.

Chambost M,Liron L, Peillon D, Combe C. Syndrome serotoninergique lors d’une intoxication par la fluoxetine chez une patiente prenant du moclobemide. Can J Anesth (2000) 47, 246–50.

Pinquier JL,Caplain H, Durrieu G, Zieleniuk I, Rosenzweig P. Safety and pharmacodynamicstudy of befloxatone after fluoxetine withdrawal. Clin Pharmacol Ther (1998) 63, 187.

Wallnöfer A,Guentert TW, Eckernäs SA, Dingemanse J. Moclobemide and fluvoxamine coadministration: a prospective study in healthy volunteers to investigate the potential development of the serotonin syndrome. Hum Psychopharmacol (1995) 10, 25–31.

Joffe RT,Bakish D. Combined SSRI-moclobemide treatment of psychiatric illness. J Clin Psychiatry (1994) 55, 24–5.

Ebert D,Albert R, May A, Stosiek I, Kaschka W. Combined SSRI-RIMA treatment in refractory depression. Safety data and efficacy. Psychopharmacology (Berl) (1995) 119, 342–4.

Rogde S,Hilberg T, Teige B. Fatal combined intoxication with new antidepressants. Humancases and an experimental study of postmortem moclobemide redistribution. Forensic Sci Int (1999) 100, 109–16.

Hawley CJ,Ratnam S, Pattinson HA, Quick SJ, Echlin D. Safety and tolerability of combinedtreatment with moclobemide and SSRIs: a preliminary study of 19 patients. J Psychopharmacol (1996) 10, 241–5.

Graudins A,Stearman A, Chan B. Treatment of the serotonin syndrome with cyproheptadine.J Emerg Med (1998) 16, 615–19.

Robert P,Senard JM, Fabre M, Cabot C, Cathala B. Syndrome sérotoninergique lors d’uneintoxication aiguë aux antidépresseurs. Ann Fr Anesth Reanim (1996) 15, 663–5.

FitzSimmons CR,Metha S. Serotonin syndrome caused by overdose with paroxetine and moclobemide. J Accid Emerg Med (1999) 16, 293–5.

McIntyre IM,King CV, Staikos V, Gall J, Drummer OH. A fatality involving moclobemide,sertraline, and pimozide. J Forensic Sci (1997) 42, 951–3.

Isbister GK,Hackett LP, Dawson AH, Whyte IM, Smith AJ. Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity. Br J Clin Pharmacol (2003) 56, 441–50.

Lustral (Sertraline hydrochloride). Pfizer Ltd. UK Summary of product characteristics,October 2005.

Zoloft (Sertraline). Pfizer Inc. US Product information,December 2005.

Cipramil (Citalopram hydrobromide). Lundbeck Ltd. UK Summary of product characteristics,January 2007.

Cipralex (Escitalopram oxalate). Lundbeck Ltd. UK Summary of product characteristics,December 2005.

Faverin (Fluvoxamine). Solvay Healthcare Ltd. UK Summary of product characteristics,June 2006.

Seroxat (Paroxetine hydrochloride hemihydrate). GlaxoSmithKline UK. UK Summary ofproduct characteristics,April 2007.

Celexa (Citalopram hydrobromide). Forest Pharmaceuticals,Inc. US Prescribing information, May 2007.

Lexapro (Escitalopram oxalate). Forest Pharmaceuticals Inc. US Prescribing information,May 2007.

Paxil (Paroxetine hydrochloride). GlaxoSmithKline. US Prescribing information,July 2006.

Prozac (Fluoxetine hydrochloride). Eli Lilly and Company Ltd. UK Summary of productcharacteristics,March 2007.

Prozac (Fluoxetine hydrochloride). Eli Lilly and Company. US Prescribing information,May2007.

Manerix (Moclobemide). Roche Products Ltd. UK Summary of product characteristics,September 2005.

MAOIs or RIMAs + Lithium - Drug Interactions

A rapid, serious and potentially life-threatening hypertensive re-Two cases of tardive dyskinesia have been described following action can occur in patients taking MAOIs if they are also given long-term use of tranylcypromine and lithium, which did not relevodopa. An interaction with levodopa given with carbidopa or solve when MAOI was stopped. Limited evidence suggests benserazide is unlikely. No serious hypertensive reaction has been that no problems occur when moclobemide is given with lithium.

Clinical evidence,mechanism, importance and management

These symptoms did not resolve when tranylcypromine was stopped

There appear to be no other reports suggesting that combination of MAOIs and lithium is unsafe. However,there are a few reports of patients taking MAOIs and lithium who developed hyperpyrexia when given tryptophan, . The role (if any) of lithium in these cases is unknown. Note that lithium has been used to augment antidepressants although most of data relate to tricyclics or SSRIs (See reference number 2). Bear these cases in mind in event of any unexpected response to treatment with MAOIs and lithium.

There was no evidence of any adverse interaction when moclobemide 150 to 675mg daily was given for 3 to 52 weeks to 50 patients taking lithium (See reference number 3). Similarly,lithium augmentation was used in a small uncontrolled study in patients on high-dose moclobemide without any evidence of important adverse effects (See reference number 4).

1. Stancer HC. Tardive dyskinesia not associated with neuroleptics. Am J Psychiatry (1979) 136,

727.

Nelson JC. Augmentation strategies in depression 2000. J Clin Psychiatry (2000) 61 (Suppl 2),13–19.

Amrein R,Güntert TW, Dingemanse J, Lorscheid T, Stabl M, Schmid-Burgk W. Interactionsof moclobemide with concomitantly administered medication: evidence from pharmacologicaland clinical studies. Psychopharmacology (Berl) (1992) 106, S24–S31.

Magder DM,Aleksic I, Kennedy SH. Tolerability and efficacy of high-dose moclobemidealone and in combination with lithium and trazodone. J Clin Psychopharmacol (2000) 20, 394–

5.

MAOIs or RIMAs + Levodopa - Drug Interactions

A patient who had been taking phenelzine daily for 10 days was given 50mg of oral levodopa. In just over an hour his blood pressure had risen from 135/90 mmHg to about 190/130 mmHg, and despite a 5mg intravenous injection of phentolamine it continued to rise over next 10 minutes to 200/135 mmHg, before falling after a further 4mg injection of phentolamine. The following day experiment was repeated with levodopa 25 mg, but no blood pressure changes were seen. Three weeks after withdrawal of phenelzine even 500mg of levodopa had no hypertensive effect (See reference number 1).

Similar cases of severe, acute hypertension, accompanied in most instances by flushing, throbbing and pounding in head, neck and chest, and light-headedness have been described in other case reports and studies

involving concurrent use of levodopa with pargyline,(See reference number 2)nialamide,

A study in 12 healthy subjects given a single dose of levodopa/benserazide with moclobemide 200mg twice daily found that nausea,vomiting and dizziness were increased, but no significant hypertensive reaction was seen (See reference number 7).

Not fully understood. Levodopa is enzymatically converted in body, firstly to dopamine and then to noradrenaline, both of which are normally broken down by monoamine oxidase. But in presence of an MAOI this breakdown is suppressed, which means that total levels of dopamine and noradrenaline are increased. Precisely how this then leads to a sharp rise in blood pressure is not clear, but either dopamine or noradrenaline, or both, directly or indirectly stimulate alpha-receptors of cardiovascular system.

The interaction between non-selective MAOIs (listed in table 1 below,) and levodopa on its own is well documented, serious and potentially life-threatening. Patients should not be given levodopa on its own during treatment with any of these MAOIs,nor for a period of 2 to 3 weeks after their withdrawal. Note that this interaction is inhibited by presence of dopa-decarboxylase inhibitors(See reference number 4)such as carbidopa and benserazide (as in Sinemet and Madopar) so that a serious interaction is unlikely to occur with these preparations. Even so, manufacturers continue to list MAOIs among their contraindications.

No important acute adverse interaction appears to occur between levodopa/benserazide and moclobemide,but some adverse effects can apparently occur.

Hunter KR,Boakes AJ, Laurence DR, Stern GM. Monoamine oxidase inhibitors and L-dopa. BMJ (1970) 3, 388.

Hodge JV. Use of monoamine-oxidase inhibitors. Lancet (1965) i,764–5.

Friend DG,Bell WR, Kline NS. The action of L-dihydroxyphenylalanine in patients receiving nialamide. Clin Pharmacol Ther (1965) 6, 362–6.

Teychenne PF,Calne DB, Lewis PJ, Findley LJ. Interactions of levodopa with inhibitors of monoamine oxidase and L-aromatic amino acid decarboxylase. Clin Pharmacol Ther (1975) 18, 273–7.

Sharpe J,Marquez-Julio A, Ashby P. Idiopathic orthostatic hypotension treated with levodopa and MAO inhibitor: a preliminary report. Can Med Assoc J (1972) 107, 296–300.

Kassirer JP,Kopelman RI. A modern medical Descartes. Hosp Pract (1987) 22, 17–25.

Dingemanse J. An update of recent moclobemide interaction data. Int Clin Psychopharmacol (1993) 7,167–80.

Table 1 Monoamine oxidase inhibitors (MAOIs)
Irreversible non-selective MAO-inhibitors (MAO-A and MAO-B) Reversible Inhibitors of MAO-A (RIMAs) Irreversible inhibitors of MAO-B*
Iproniazid Brofaromine Rasagiline
Isocarboxazid Moclobemide Selegiline
Mebanazine Toloxatone
Nialamide
Phenelzine
Tranylcypromine
Tranylcypromine with trifluoperazine

MAOIs + Ginseng - Drug Interactions

Clinical evidence,mechanism, importance and management

A 64-year-old woman taking phenelzine developed headache,insomnia, and tremulousness on two occasions after taking ginseng (See reference number 1). Three years later, she experienced same symptoms and an increase in depression 72 hrs after starting to take ginseng capsules (See reference number 2). Another depressed woman taking ginseng and bee pollen experienced a relief of her depression and became active and extremely optimistic when she was started on phenelzine 45mg daily,but this was accompanied by insomnia, irritability, headaches and vague visual hallucinations. When phenelzine was stopped and then re-started in absence of ginseng and bee pollen, her depression was not relieved (See reference number 3). It seems unlikely that bee pollen had any part to play in these reactions and suspicion therefore falls on ginseng. It would seem that psychoactive effects of ginsenosides from ginseng and MAOI were somehow additive. Ginseng has stimulant effects,but its adverse effects include insomnia, nervousness, hypertension and euphoria. These two cases once again illustrate that herbal medicines are not necessarily problem-free if combined with orthodox drugs.

Shader RI,Greenblatt DJ. Phenelzine and the dream machine—ramblings and reflections. J Clin Psychopharmacol (1985) 5, 65.

Shader RI,Greenblatt DJ. Bees, ginseng and MAOIs revisited. J Clin Psychopharmacol (1988) 8, 235.

Jones BD,Runikis AM. Interaction of ginseng with phenelzine. J Clin Psychopharmacol (1987) 7, 201–2.

Lithium + Herbal medicines - Drug Interactions

Clinical evidence,mechanism, importance and management

A 26-year-old woman who had been taking lithium 900mg twice daily for 5 months,with hydroxyzine, lorazepam, propranolol, risperidone and sertraline, came to an emergency clinic complaining of nausea, diarrhoea, unsteady gait, tremor, nystagmus and drowsiness, (all symptoms of lithium toxicity). Her lithium level,which had previously been stable at

1.1 mmol/L was found to be 4.5 mmol/L. For past 2 to 3 weeks she had been taking a non-prescription herbal diuretic containing corn silk, Equisetum hyemale, juniper, ovate buchu, parsley and uva ursi, all of which are believed to have diuretic actions. The other ingredients were bromelain,paprika, potassium and vitamin B6 (See reference number 1).

The most likely explanation for what happened is that herbal diuretic caused lithium toxicity. It is impossible to know which herb or combination of herbs actually caused toxicity, or how, but this case once again emphasises that herbal remedies are not risk-free just because they are natural. It also underscores need for patients to avoid self-medication without first seeking informed advice and supervision if they are taking potentially hazardous drugs like lithium.

Pyevich D,Bogenschutz MP. Herbal diuretics and lithium toxicity. Am J Psychiatry (2001) 158, 1329.

Natural health products and adverse reactions. Can Adverse React News (2004) 14 ,2–3. Available at: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/carn-bcei_v14n1_e.pdf(accessed 23/08/07).

Lithium + Antiepileptics; Phenytoin - Drug Interactions

Symptoms of lithium toxicity (sometimes with unchanged lithiumlevels) have been seen in a few patients concurrently treated withphenytoin, although interaction has not been clearly demonstrated.

Clinical evidence,mechanism, importance and management

A patient with a history of depression and convulsions was treated with increasing doses of lithium carbonate and phenytoin over a period of about 4 years. Although serum levels of both drugs remained within therapeutic range, he eventually began to develop symptoms of lithium toxicity (thirst, polyuria, polydipsia and tremor) that disappeared when lithium was stopped. Later, when lithium was restarted, symptoms returned, this time abating when phenytoin was replaced by carbamazepine. The patient then claimed that he felt normal for first time in years (See reference number 1). Another report describes symptoms of lithium toxicity in a patient with lithium levels within normal range. This patient was also taking phenytoin (See reference number 2).

In a further case(See reference number 3) a man taking phenytoin became ataxic within 3 days of starting to take lithium. He had no other toxic symptoms and his serum-lithium level was 2 mmol/L. However, as he only ever took lithium in presence of phenytoin, it is not possible to say whether effects were as a result of an interaction, or whether toxic levels would have occurred with lithium alone. Another similar case has also been reported (See reference number 4).

Information seems to be limited to these reports and none of them presents a clear picture of role of phenytoin in reactions described (See reference number 1-4). Patients taking lithium should be aware of symptoms of lithium toxicity and told to report them immediately should they occur. Increased serum lithium monitoring does not appear to be of value in this situation as interaction occurred in patients with lithium levels within normally accepted range

MacCallum WAG. Interaction of lithium and phenytoin. BMJ (1980) 280,610–11.

Speirs J,Hirsch SR. Severe lithium toxicity with “normal” serum concentrations. BMJ (1978)1, 815–16.

Salem RB,Director K, Muniz CE. Ataxia as the primary symptom of lithium toxicity. Drug Intell Clin Pharm (1980) 14, 622–3.

Raskin DE. Lithium and phenytoin interaction. J Clin Psychopharmacol (1984) 4,120.

Lithium + Antiepileptics; Valproate - Drug Interactions

Clinical evidence,mechanism, importance and management

In a crossover study,16 healthy subjects were given valproate (as valproate semisodium) or a placebo twice daily for 12 days, to which lithium carbonate 300mg three times daily was added on days 6 to 10. The valproate-serum levels and AUC rose slightly, while serum-lithium levels were unaltered. Adverse events did not change significantly. It was concluded that concurrent use of these drugs is safe (See reference number 1). A review on efficacy of lithium/anticonvulsant combinations in bipolar disorder lists several studies in which combination of valproate (as valproate semi-sodium) and lithium was used. On whole combination was considered safe and well tolerated, although a few patients discontinued treatment due to adverse effects, which included gastrointestinal symptoms and raised liver transaminases. It was, however, difficult to know if these adverse effects were due to individual drugs or result of an interaction. Other adverse effects that have been reported with combined treatment include tremor, cognitive impairment and alopecia (See reference number 2).

Granneman GR,Schneck DW, Cavanaugh JH, Witt GF. Pharmacokinetic interactions and sideeffects resulting from concomitant administration of lithium and divalproex sodium. J Clin Psychiatry (1996) 57, 204–6.

Pies R. Combining lithium and anticonvulsants in bipolar disorder: a review. Ann Clin Psychiatry (2002) 14,223–32.