Overview: MAOI and TCA interactions
Overview: MAOI and TCA interactions
This is a brief outline of the safety of combinations of MAOIs and TCAs to assist those who are not already familiar with these issues to grasp the overall picture. Contrary to most of the (mis)information in standard texts there is an enormous amount of published evidence demonstrating such combinations are perfectly safe. How the contrary view got into the literature is an object lesson in misinformation, overreliance on poor quality case reports, biasing influences, and poor scholarship, which I have discussed elsewhere.
The list of references below is almost certainly the most comprehensive such list that has ever been compiled. If anyone is aware of significant other references that I had missed please inform me, and I will add them — I daresay there is mention of such things in various older textbooks to which I do not have access; although some of that information is of limited value, it is worth documenting it for the record.
We must remember that what is published in the scientific literature is but the tip of the iceberg in terms of the totality of clinical practice experience. What is ‘published’ can quite often give a seriously misleading impression of clinical reality.
Also, the categorisation used in relation to these drugs is changing. I have repeatedly discussed the move towards neuroscience-based classification of drugs elsewhere. The group of drugs referred to as tricyclics antidepressants (TCAs) which were brought into use in the early 1960s were grouped together on the basis that they all had a three-ring central structure. However more recent pharmacological advances in research have made it clear that their pharmacological properties and actions differ substantially from one another (1). Pharmacologically, they are a heterogenous group. Statements about these drugs that start ‘the TCAs’ are almost certain to be wrong.
They are structurally related to the first-generation antihistamine drugs, which are all ‘tricyclics’, and also to the first generation of neuroleptic drugs, represented by chlorpromazine. Indeed, all of those drugs share many properties, especially, for instance, their potency as sedative antihistamines (H1 antagonists).
Some of the drugs that were marketed as antihistamines in the 1960s would now be classified as antidepressants, and several of the ‘antidepressants’ would now be classified as specific and potent antihistamines (for example trimipramine and doxepin — indeed doxepin has recently been re-marketed as a sleeping tablet, as suggested in my TCA review paper some years ago (1)). Both trimipramine and doxepin are still used, in my opinion misguidedly, as antidepressants (in some countries). A full appreciation of this new knowledge has still not percolated widely into everyday clinical practice, nor into the product information approved by the FDA.
The relevance of this is that the past reports of dangerous interactions between MAOIs and ‘TCAs’ were not informed by an understanding of their neuropharmacology and they confused different adverse effects and toxicities (2).
Indeed, almost all the past reports were poor quality case reports of single cases, usually with incomplete data and poorly informed discussion — I have discussed at length the frequently misleading nature of case reports previously (3-5). Such reports produce a great deal of misinformation and wasted clinical time and effort, especially for less experienced practitioners.
We now understand that the only serious interaction between MAOIs and TCAs is caused by excessive elevations of serotonin. Such elevations of serotonin (5-HT) can only be produced if MAOIs are combined with therapeutic doses of potent serotonin reuptake inhibitors (SRIs). There are various other drugs that possess SRI properties to the extent that they are occasionally able to reach high enough levels to increase serotonin, and therefore become risky (e.g. meperidine).
Of the TCAs the only ones that possess significant SRI potency are clomipramine and imipramine: however, imipramine is weak and only occasionally causes a severe interaction. Indeed, interactions with imipramine are sufficiently uncommon and mild that some practitioners (incorrectly) consider the combination to be safe.
All the other tricyclics are so much weaker for this SRI effect that there are no reports of serotonin toxicity when these have been combined with MAOIs (and this agrees with experiments in animals, and other data).
The references about MAOI & TCA combinations provided below refer to a considerable number of publications describing thousands of patients treated safely with such combinations. In addition to that, many experienced psycho-pharmacologists all over the world use such combinations and would state that they are safe. Certainly, my own first-hand experience of such treatments encompasses several hundred cases.
The property of these old TCAs that is beneficial, potentially to an extent which will reduce, or even obviate, the need to follow a tyramine restricted diet, is their ability to block noradrenaline reuptake (NRI).
Ironically, not only is the risk of a tyramine pressor response reduced, but also there is a definite suggestion that some combinations of an MAOI and a TCA can have less ‘day-to-day’ side effects overall than either drug given separately. That is not as strange as it might at first seem, because sometimes one drug can mitigate the side-effects of another — that is what may be occurring with this combination.
The contraindications given in the product information approved by the FDA (often long ago) relate to the earlier period of knowledge referred to above, when the actual pharmacological properties of these drugs were not precisely known. Why the PIs have not caught up with modern knowledge is not something I can give an explanation for. However, it is clear that drug-regulatory agencies, e.g. the FDA, deal with drugs on an individual basis and do not necessarily review the overall developments in clinical toxicology. I suspect the explanation is quite simple, which is that dealing with drugs on an individual basis, and not reviewing the ‘big picture’, means that they ‘cannot see the forest for the trees’. That, and the over-reliance on unreliable case reports, may also explain why the warnings they have been giving about ST with the antiemetic drugs (like ondansetron), and the anti-migraine drugs like sumatriptan, have also been criticised. Indeed, I think they are generally ignored.
As a world expert in ST I am well-placed to state that our theoretical knowledge about ST, derived from pharmacology and animal experimentation, is now both thorough and well-established. It allows accurate predictions of which drugs are potentially a risk from this interaction. This knowledge coincides well with an informed interpretation of all of the clinical data from clinical trials, and case reports. It is therefore possible to be extremely confident that TCAs (other than clomipramine and imipramine) have no significant effect on elevating serotonin, and no risk of precipitating serotonin toxicity.
There are no other serious or dangerous interactions between (therapeutic doses) of MAOIs and TCAs.
The question of whether these combinations result in an improved antidepressant effect is a different question, which is not addressed in this commentary.
All these publications attest to the safety of MAOI/TCA combinations and describe a total of thousands of patients thus treated (1, 6-54).
- Gillman, PK, Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol, 2007. 151(6): p. 737-48.
- Gillman, PK, Serotonin Syndrome: History and Risk. Fundam. Clin. Pharmacol., 1998. 12(5): p. 482-491.
- Gillman, PK, Extracting value from case reports: lessons from serotonin toxicity. Anaesthesia, 2006. 61: p. 419-422.
- Gillman, PK, Lessons continue: serotonin toxicity. Consult Pharm, 2009. 24: p. 398-399.
- Gillman, PK, Combining antidepressants: Understanding Drug Interactions is the Sine Qua Non. Adv Psychiatr Treat, 2010. 16: p. 76-78.
- Beresford Davies, E, MAOI TCA. Lancet, 1963. 2: p. 781.
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- Gander, DR, Treatment of depressive illness with combined antidepressants. Lancet, 1965. 1: p. 107-109.
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- Sargant, W, Safety of Combined Antidepressant Drugs. Br. Med. J., 1971. 1(6 March): p. 555-556.
- Schuckit, M, Robins, E, and Feighner, J, Tricyclic antidepressants and monoamine oxidase inhibitors. Arch. Gen. Psychiatry, 1971. 24: p. 509-514.
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- Sethna, ER, A study of refractory cases of depressive illness and their response to combined antidepressant treatment. Br J Psychiatry, 1974. 124: p. 265-272.
- Ayd, FJ, Psychotropic drug combinations: good and bad. Drugs in combination with other therapies
Greenblatt (Ed) pp 165-188 Grune & Stratton, New York, 1975.
- Sargant, W, Antidepressant drugs. Br. Med. J., 1975(october): p. 101.
- Shopsin, B, Tricyclics and MAO inhibitors: rational poly-pharmacy in treatment-resistant depression. Paper presented at the 10th Collegium Internationale Neuro-Psychopharmacologicum Congress,
Quebec, Canada, 1976: p. July 6.
- Spiker, DG and Pugh, DD, Combining tricyclic and monoamine oxidase inhibitor antidepressants. Arch. Gen. Psychiatry, 1976. 33(7): p. 828-30.
- Ananth, J and Luchins, A, A review of combined tricyclic and MAOI therapy. Compr. Psychiatry, 1977. 18: p. 221-230.
- Davidson, J, McLeod, M, Law-Yone, B, and Linnoila, M, A comparison of electroconvulsive therapy and combined phenelzine-amitriptyline in refractory depression. Arch. Gen. Psychiatry, 1978. 35(5): p. 639-42.
- Goldberg, RS and Thornton, WE, Combined tricyclic-MAOI therapy for refractory depression: a review, with guidelines for appropriate usage. J Clin Pharmacol, 1978. 18(2-3): p. 143-7.
- Young, J, Lader, M, and Hughes, W, Controlled trial of trimipramine, monoamine oxidase inhibitors, and combined treatment in depressed outpatients. Br. Med. J., 1979. 2(6201): p. 1315-1317.
- White, K, Pistole, T, and Boyd, JL, Combined monoamine oxidase inhibitor-tricyclic antidepressant treatment: a pilot study. Am J Psychiatry, 1980. 137(11): p. 1422-5.
- White, K and Simpson, G, Combined MAOI-tricyclic antidepressant treatment: a reevaluation. J Clin Pharmacol, 1981. 1: p. 264-281.
- White, K, Razani, J, Simpson, G, Rebal, R, et al., Combined MAOI-tricylic antidepressant treatment: a controlled trial. Psychopharmacol. Bull., 1982. 18(4): p. 180-1.
- Razani, J, White, KL, White, J, Simpson, G, et al., The safety and efficacy of combined amitriptyline and tranylcypromine antidepressant treatment. A controlled trial. Arch. Gen. Psychiatry, 1983. 40: p. 657-661.
- Tollefson, GD, Monoamine oxidase inhibitors: a review. J Clin Psychiatry, 1983. 44(8): p. 280-8.
- Feighner, JP, Herbstein, J, and Damlouji, N, Combined MAOI, TCA, and direct stimulant therapy of treatment-resistant depression. J Clin Psychiatry, 1985. 46(6): p. 206-9.
- Kupfer, DJ and Detre, TP, Tricyclic and monoamine-oxidase-inhibitor antidepressants: Clinical use, in Handbook of psychopharmacology. 1987, Springer. p. 199-232.
- Schmauss, M, Kapfhammer, HP, Meyr, P, and Hoff, P, Combined MAO-inhibitor and tri- (tetra) cyclic antidepressant treatment in therapy resistant depression. Prog. Neuropsychopharmacol. Biol. Psychiatry, 1988. 12(4): p. 523-32.
- Pande, AC, Calarco, MM, and Grunhaus, L, Combined MAOI-TCA treatment in refractory depression. . In: Amsterdam J, ed. Refractory Depression. New York, NY: Raven Press, 1991: p. 115-121.
- O’Brien, S, McKeon, P, O’Regan, M, O’Flaherty, A, et al., Blood pressure effects of tranylcypromine when prescribed singly and in combination with amitriptyline. J Clin Psychopharmacol, 1992. 12(2): p. 104-9.
- O’Brien, S, McKeon, P, and O’Regan, M, The efficacy and tolerability of combined antidepressant treatment in different depressive subgroups. Br J Psychiatry, 1993. 162: p. 363-8.
- Berlanga, C and Ortega-Soto, HA, A 3-year follow-up of a group of treatment-resistant depressed patients with a MAOI/tricyclic combination. J Affect Disord, 1995. 34(3): p. 187-92.
- Thase, ME, Trivedi, MH, and Rush, AJ, MAOIs in the contemporary treatment of depression. Neuropsychopharmacology, 1995. 12(3): p. 185-219.
- Amsterdam, JD, Garcia-Espana, F, and Rosenzweig, M, Clomipramine augmentation in treatment-resistant depression. Depress. Anxiety, 1997. 5(2): p. 84-90.
- Schmauß, M and Messer, T, Kombinationstherapie tri-(tetra-) zyklischer Antidepressiva mit MAO-Hemmern. Interaktionen und Wirkmechanismen ausgewählter Psychopharmaka, 2003. 2: p. 125-135.
- Amsterdam, JD, Monoamine Oxidase Inhibitor Therapy in Severe and Resistant Depression. Psych Annals, 2006. 36(9): p. 607-613.
- Gillman, PK, A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action. Biol Psychiatry, 2006. 59(11): p. 1046-51.
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- Gillman, PK, CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. J Psychopharmacol (Oxf), 2011. 25(3): p. 429-3.
- Ferreira-Garcia, R, da Rocha Freire, RC, Appolinario, JC, Levitan, MN, et al., Tranylcypromine Plus Amitriptyline for Electroconvulsive Therapy-Resistant Depression: A Long-Term Study. J Clin Psychopharmacol, 2018. 38(5): p. 502-504.
- Stewart, JW, Deliyannides, DA, and McGrath, PJ, How treatable is refractory depression? J Affect Disord, 2014. 167: p. 148-52.