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Re: A little message to Scott

Posted by ed_uk on November 11, 2004, at 9:03:59

In reply to Re:A Combination which has caused much controversy » ed_uk, posted by SLS on November 9, 2004, at 10:27:23

Hello Scott,

RE: amitriptyline+MAOI versus nortriptyline+MAOI

I think it's very difficult to compare the risk of SS with these two combinations. Amitriptyline is more potent that nortriptyline as a serotonin reuptake inhibitor, at a glance it might be expected that the risk of SS would be higher with amitriptyline. On the other hand, amitriptyline appears to be more potent as an antagonist at 5-HT2a receptors. It seems likely that this might provide some protection from the SS.

This rather dubious little table claims that amitriptyline is more potent at the 5-HT2a receptor than nortriptyline. I took it from Dr. Gillman's psychopharmacology website, it doesn't say where the information came from! .......

5-HT2A receptors
Low numbers means high potency, ie bigger effect.

SSRIs nil sig except
fluoxetine 280

Trimipramine 15
Amitriptyline *18*
Clomipramine 23
Doxepin 27
Trazodone 25
Nefazodone 26
mirtazapine ~30
Nortriptyline *41*

Imipramine 150
desipramine 350
lofepramine 200


This study (in rats) claims that the SS can be attenuated by 5-HT2a antagonists.........

Brain Res. 2001 Jan 26;890(1):23-31. Related Articles, Links

Potent serotonin (5-HT)(2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome.

Nisijima K, Yoshino T, Yui K, Katoh S.

Department of Psychiatry, Jichi Medical School, Minamikawachi-Machi, Kawachi-Gun, Tochigi-Ken, 329-0498, Japan.

The serotonin (5-HT) syndrome is the most serious side effect of antidepressants, and it often necessitates pharmacotherapy. In the present study, the efficacy of several drugs was evaluated in an animal model of the 5-HT syndrome. When 2 mg/kg of clorgyline, a type-A monoamine oxidase inhibiting antidepressant, and 100 mg/kg of 5-hydroxy-L-tryptophan, a precursor of 5-HT, were administered intraperitoneally to rats to induce the 5-HT syndrome, the rectal temperature of the rats increased to more than 40 degrees C, and all of the animals died by 90 min after the drug administration. The noradrenaline (NA) levels in the anterior hypothalamus, measured by microdialysis, increased to 15.9 times the preadministration level. Pretreatment with propranolol (10 mg/kg), a 5-HT(1A) receptor antagonist as well as a beta-blocker, and dantrolene (20 mg/kg), a peripheral muscle relaxant, did not prevent the death of the animals, even though these two drugs suppressed the increase in rectal temperature to some extent. Chlorpromazine and cyproheptadine prevented the lethality associated with the 5-HT syndrome only at high doses. By contrast, pretreatment with ritanserin (3 mg/kg) and pipamperone (20 mg/kg), both potent 5-HT(2A) receptor antagonists, completely prevented the increase in rectal temperature and death of the animals, and the hypothalamic NA levels in these two groups increased less than that in the other groups. These results suggest that potent 5-HT(2A) receptor antagonists are the most effective drugs for treatment of the 5-HT syndrome, and that NA hyperactivity occurs in the 5-HT syndrome.

As you mention in your psychiatric drug chart, ritanserin is not selective for the 5-HT2a receptor. Here is another study which examined the importance of the different 5-HT(2)R subtypes in the SS. It looks like 5-HT2a antagonists can reduce some of the signs of SS in rats. Other receptors such as the 5-HT(2c)R may also be important, however................

Behav Pharmacol. 2002 Jul;13(4):313-8. Related Articles, Links

Role of 5-HT(2) receptors in the tryptamine-induced 5-HT syndrome in rats.

Van Oekelen D, Megens A, Meert T, Luyten WH, Leysen JE.

Discovery Research, Janssen Research Foundation, Beerse, Belgium.

We distinguished the functions of the different 5-hydroxytryptamine-2 (5-HT(2)) receptor (5-HT(2)R) subtypes in the tryptamine-induced 5-HT syndrome in rats using (1) the 5-HT(2A)R antagonist R93274 (N-[(3-p-fluorophenyl-1-propyl)-4-methyl-4-piperidinyl]-4-amino-5-iodo-2-methoxybenzamide), the 5-HT(2A/C)R antagonist R99647 (2-(dimethylaminomethyl)2,3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepine), the 5-HT(2B/C)R antagonist SB-242084 (6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline), and several 5-HT(2)R antagonists (ketanserin, risperidone, pipamperone and mianserin); and (2) chronic 5-HT(2)R activation by 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM). In contrast to SB-242084, the selective 5-HT(2A)R antagonist R93274 as well as the non-selective 5-HT(2A)R antagonists (R99647, ketanserin, risperidone, pipamperone and mianserin) significantly inhibited tryptamine-induced forepaw treading and tremors, and reversed peripherally mediated cyanosis into hyperaemia; only the 5-HT(2A/C)R antagonists R99647 and mianserin inhibited the tryptamine-induced hunched back. Intermittent DOM administration (intravenously every 48 h for 12 days) did not change the centrally mediated tryptamine-induced forepaw treading, tremors and hunched back at 1, 4 or 7 days after the last DOM pretreatment. The DOM-induced head twitch response, measured immediately after every DOM injection, was not affected. In contrast, peripherally mediated cyanosis was reversed into hyperaemia in 75, 11 and 20% of all pretreated rats at 1, 4 and 7 days, respectively, after the last DOM administration. Taken together, these finding suggest that central 5-HT(2A)Rs mediate tryptamine-induced forepaw treading and tremors, that peripheral 5-HT Rs mediate tryptamine-induced cyanosis, and that 5-HT(2A)Rs mediate tryptamine-induced hunched back. Peripheral 5-HT(2C)Rs are more sensitive to desensitization after intermittent treatment with an agonist than central 5-HT(2A)Rs.


After all that, it's still difficult to compare the risks associated with combining amitriptyline or nortriptyline with an MAOI.

Did you say you experienced SS with nort but not with ami? Have you ever taken a high dose of an MAOI with ami? Were you on a high dose of an MAOI when you were taking nort and experienced symptoms of the SS?

Have a look at this article from Stockley's if you're interested...........

Monoamine oxidase inhibitors (MAOIs) + Tricyclic antidepressants
Because of the very toxic and sometimes fatal reactions (similar to or the same as the serotonin syndrome) which have very occasionally taken place in patients taking both MAOIs and tricyclic antidepressants, concurrent use came to be regarded as totally contraindicated, but informed opinion now considers that with extremely careful control it is permissible and advantageous to use both these drugs together for some refractory patients.

Clinical evidence
(a) Toxic reactions or other interactions
The toxic reactions have included (with variations) sweating, flushing, hyperpyrexia, restlessness, excitement, tremor, muscle twitching and rigidity, convulsions and coma. An illustrative example:

A woman who had been taking 20 mg tranylcypromine daily for about 3 weeks, stopped taking it 3 days before taking a single tablet of imipramine. Within a few hours she complained of an excruciating headache, and soon afterwards lost consciousness and started to convulse. The toxic reactions manifested were a temperature of 40°C, pulse rate of 120, severe extensor rigidity, carpal spasm, opisthotonos and cyanosis. She was treated with amobarbital and phenytoin, and her temperature was reduced with alcohol-ice-soaked towels. The treatment was effective and she recovered. 1

Similar reactions have been recorded on a number of other occasions with normal therapeutic doses of iproniazid, 2 isocarboxazid, 2,3 pargyline, 4 or phenelzine 5-11 with imipramine; phenelzine with desipramine 12 or clomipramine; 13-15 tranylcypromine 16-19 with clomipramine; and moclobemide with imipramine. 20. Moclobemide is reported not to interact with amitriptyline or desipramine 17,21-23 but a reaction similar to the serotonin syndrome occurred in 2 patients when clomipramine (50 mg daily) was replaced by moclobemide, 24,25 and 4 patients developed the serotonin syndrome (3 of them died) after taking moderate overdoses of moclobemide and clomipramine. 26-29 However another study found that doses of up to 300 mg moclobemide could be given 24 h after the last dose of treatment with either amitriptyline or clomipramine without any major risks. 23 Another study found a 39% rise in serum trimipramine levels in 15 patients and a 25% rise in serum maprotiline levels of 6 other patients when concurrently treated with moclobemide. No serious toxic reactions were reported. 30 Only a minor and clinically unimportant change in the pharmacokinetics of amitriptyline occurs in patients given toloxatone. 31

Some other reports are confused by overdosage with one or both drugs, or by the presence of other drugs and diseases. There have been fatalities. 12,16,32 In some instances the drugs were not taken together but were swapped without a washout period in between. There are far too many reports of these interactions to list all of them here, but they are extensively reviewed elsewhere. 33-35 Three patients with bipolar disorder developed mania when treated with isocarboxazid and amitriptyline. 36

(b) Advantageous or uneventful concurrent use
Dr GA Gander of St Thomas’s Hospital, London, has stated 37 that 98 out of 149 patients on combined therapy (phenelzine, isocarboxazid or iproniazid with imipramine or amitriptyline) over periods of 1–24 months improved significantly and that the side-effects were . . . identical in nature and similar in frequency to those seen with a single antidepressant. . .. Side effects were easily controlled by adjusting the dosage. None of the serious side-effects previously reported, such as muscle twitching or loss of consciousness was seen. He also states that more than 1400 patients having combined antidepressants over a period of 4 years . . . tend to confirm these findings described. Dr William Sargant from the same department has also written 38 that . . . we have used combined antidepressant drugs for nearly 10 years now on some thousands of patients. We still wait to see any of the rare dangerous complications reported.

There are a number of other reports and reviews describing the beneficial use of MAOI/tricyclic antidepressant combinations. 34,35,39-42

Not understood. One idea is that both drugs cause grossly elevated monoamine levels (5-HT, norepinephrine (noradrenaline)) in the brain which ‘spill-over’ into areas not concerned with mood elevation. It may be related to, or the same as the serotonin-syndrome seen with selective serotonin re-uptake inhibitors. 14,20 Some of the tricyclics (e.g. clomipramine, imipramine) are potent inhibitors of serotonin uptake. Less likely suggestions are that the MAOIs inhibit the metabolism of the tricyclic antidepressants, or that active and unusual metabolites of the tricyclic antidepressants are produced. 34

Importance and management
An established, serious and life-threatening but apparently uncommon interaction. There is no precise information about its incidence but it is probably much lower than was originally thought. No detailed clinical work has been done to find out precisely what sets the scene for it to occur, but some general empirical guidelines have been suggested so that it can, as far as possible, be avoided when concurrent treatment is thought appropriate: 11,33-35,43

• Treatment with both types of drug should only be undertaken by those well aware of the problems and who can undertake adequate supervision.

• Only patients refractory to all other types of treatment should be considered.

• Tranylcypromine, phenelzine, clomipramine and imipramine appear to be high on the list of drugs which have interacted adversely. Amitriptyline, trimipramine and isocarboxazid are possibly safer.

• Drugs should be given orally, not parenterally.

• It seems safer to give the tricyclic antidepressants first, or together with the MAOI, than to give the MAOI first. If the patient is already taking an MAOI, it may not be safe to start the tricyclic antidepressant until recovery from MAO-inhibition is complete.

• Small doses should be given initially, increasing the levels of each drug, one at a time, over a period of 2—3 weeks to levels generally below those used for each one individually.

• Do not exchange either the MAOI or the tricyclic antidepressant for other members of these drug groups without taking full precautions. A good washout period between the drugs is advisable. In the case of moclobemide, not less than 24 h, but with other MAOIs the usual advice is that washout should be up to 3 weeks. However one study reported switching 178 patients from tricyclics to MAOIs within 4 days or less. 63 of these patients were given the MAOI while still being tapered from the tricyclic, all without any apparent problems. 42

Doses of 50 and 100 mg chlorpromazine given intramuscularly have been used successfully in the treatment of this adverse interaction 17,19 and one report suggests that patients should carry 300 mg chlorpromazine and take it if a sudden, throbbing, radiating occipital headache occurs, and seek medical help at once. 44 It has been suggested that dantrolene can probably be used to reduce the muscle rigidity and hyperpyrexia, and possibly methysergide which is a 5-HT receptor antagonist. 26

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3. Kane FJ, Freeman D. Non-fatal reaction to imipramine-MAO inhibitor combination. Am J Psychiatry (1963), 120, 79–80.
4. McCurdy RL, Kane FJ. Transient brain syndrome as a non-fatal reaction to combined pargyline imipramine treatment. Am J Psychiatry (1964), 121, 397–8.
5. Loeb RH. Quoted in ref 10 below as written communication (1969).
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11. Graham PM, Potter JM, Paterson JW. Combination monoamine oxidase inhibitor/tricyclic antidepressant interaction. Lancet (1982) ii, 440.
12. Bowen LW. Fatal hyperpyrexia with antidepressant drugs. BMJ (1964) 2, 1465.
13. Beeley L, Daly M (eds). Bulletin of the W. Midlands Centre for Adverse Drug Reaction Reporting. (1986) 23, 16. (1986) 23, 16.
14. Nierenberg DW, Semprebon M. The central nervous system serotonin syndrome. Clin Pharmacol Ther (1993) 53, 84–8.
15. Stern TA, Schwartz JH, Shuster JL. Catastrophic illness associated with the combination of clomipramine, phenelzine, and chlorpromazine. Ann Clin Psychiatry (1992) 4, 81–5.
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