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.
Below is a footnote about the lengthy report submitted to the American College of Neuropsychopharmacology by White and Simpson in 1980. Although this is now only of historical interest, it is a useful source of references. Its timing was unlucky, because it was just after 1980 that much of the data that forms the substance of my papers, explaining the interaction as a manifestation of serotonin toxicity, became known.
The list of references below is almost certainly the most comprehensive such list yet to be 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. I have been unable to source a copy of the 1964 UK ‘Witts Committee’ report.
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 give a misleading impression of clinical reality. RCTs especially can be unrepresentative and misleading: we are unlikely to advance the treatment of depression by fiddling with statistics. Many eminent writers, including Ronald Kuhn, Sargant, and Bradford Hill, have made such observations.
Also, the categorisation used in relation to these drugs is changing. I have repeatedly discussed elsewhere the move towards neuroscience-based classification of drugs. The group of drugs referred to as tricyclic 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 . Pharmacologically, they are a heterogenous group. Statements about these drugs that start ‘the TCAs’ are almost certain to be wrong. Insufficient knowledge of their pharmacology was the root of the earlier misunderstanding, as exemplified in the report of White and Simpson below.
TCAs 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 ). 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 standard texts, nor 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 .
Indeed, almost all the past reports were poor quality case reports of single cases, usually with incomplete data and poorly informed discussion — I have previously discussed at length the frequently misleading nature of case reports [3-5]. Such reports produce a great deal of misinformation and wasted clinical time and effort, especially for less experienced practitioners. Better quality data has emerged from prospective monitoring of toxicity in toxicology databases, foremost among such sources is the seminal data collected by Professor Whyte and colleagues, from Newcastle [6-13]. Unfortunately, such data are not well-known or recognised in the psychiatric literature.
We now understand that the only serious interaction between MAOIs and TCAs is caused by excessive elevations of serotonin. Such great elevations of serotonin (5-HT) can only be produced if MAOIs are combined with therapeutic doses of potent serotonin reuptake inhibitors (SRIs). There are a few other drugs that possess SRI properties to the extent that they are occasionally able to reach high enough levels to increase serotonin substantially , and therefore become risky (e.g. meperidine, tramadol, chlorphenamine).
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 ST interaction. Indeed, interactions with imipramine are sufficiently uncommon and mild that some practitioners (incorrectly) consider the combination to be safe (see White and Simpson and Gillman  for more information).
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, even in overdoses (and this agrees with experiments in animals, and much 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 without significant adverse effects.
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 some TCA/MAOI combinations.
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 pharmacological properties of these drugs were not precisely known. Why general texts and the PIs have not caught up with modern knowledge is not something I will expound on here. However, it is clear that drug-regulatory agencies, e.g. the FDA and the EMA, deal with drugs on an individual basis and do not necessarily review the overall developments in pharmacology and clinical toxicology. I suspect the explanation is quite simple, it 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 (e.g. see ). This knowledge coincides well with an informed interpretation of all the clinical data from 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.
For those not familiar with my numerous papers on serotonin toxicity it should be noted that these contain exhaustive details explaining the pharmacology of this interaction as it pertains to all relevant drugs and gives clear guidance on what is and is not safe.
Notes on ‘Combined MAOI-tricyclic antidepressant treatment: A reevaluation’ [A report to the American College of Neuropsychopharmacology] :
This report (adopted as the ACNP position statement) is now only of historical interest, because its timing was unfortunate, as it was just after 1980 that important explanatory data about serotonin toxicity became known: particularly; the better defined clinical features of ST and its differentiation from other reactions, and the more precisely assayed potency of these drugs for different receptors, particularly the serotonin transporter. Those data provided essential explanatory power to understand this interaction which was not available to White and Simpson at that time.
Nevertheless, certain comments they made are interesting and revealing and some remain true today, as the following quotations reveal:
- However, a number of factors have combined to reduce their apparent risk [MAOI+TCA] or at least make it seem more acceptable: appreciation of the rarity of such crises leading to severe complications; better understanding of the mechanism of these crises resulting in prevention and dietary and drug precautions: increased awareness of the toxicity of alternate antidepressant treatments and the risks involved with inadequately treated depression: and evidence that MAOIs may have a unique role in therapy many depressed patients poorly responsive to alternative treatments.
- provides little support for the idea that TCP is more problematic when used in combinations with TCAs than our other MAOIs.
- informal discussions with many physicians it is obvious that thousands of patients have been thus treated with MAOI TCA combinations.
- predicting responders from clinical attributes is unreliable.
- the riskiness of the combination is largely superstition.
- in 1977 Ayd commented that the prohibition was “one of several myths and unscientific generalisations that plague contemporary psychopharmacology”
- [They agree] the hazards of been exaggerated, but that the risks are greater if the TCA is added with within a week or two after starting the MAOI
- there is little evidence of an increased rate of mild side-effects with the combination
- they mention possible advantages in improving sleep and possibly reducing the tyramine pressor response (citing Ghose ).
7: we can now be confident that statement is incorrect: there is no significant evidence that the order in which the drugs are given is relevant; but the mantra ‘start low, go slow’ should always be observed as part of the practice of good clinical pharmacology. Also concerning 9, I concur with this view.
Addendum: for those not familiar with Google searches: Google has, for several years, been placing what their algorithm designates is the ‘best answer’ available to a question in a special box at the top of the search result
As Google states: ‘Introduced in 2015, Google’s Answer Box is the holy grail for internet users. You ask, and Google answers. Appearing above the organic search results on position zero, this box features a snippet of content borrowed from a site Google thinks provides the best answer – not necessarily the #1 ranking result.’
It is relevant to understand that a great proportion of my commentaries appear on page 1 of Google, often at or near the top, and a few of them have been granted ‘holy grail’ status. That may help some people to understand why I think it is largely a waste of time for me to publish still more scientific papers, at least to achieve the objectives that I have.
Here is what you see if you search for ‘the safety of combinations of TCAs and MAOIs’.
Complete list of references
The following list is as complete as I can make it and contains all known publications that attest to the safety of MAOI/TCA combinations and describes, or alludes to, a total of many thousands of patients thus treated.
[1, 14-16, 18-70].
1. Gillman, P.K., Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. British Journal of Pharmacology 2007. 151(6): p. 737-48.
2. Gillman, P.K., Serotonin Syndrome: History and Risk. Fundamental and Clinical Pharmacology, 1998. 12(5): p. 482-491.
3. Gillman, P.K., Extracting value from case reports: lessons from serotonin toxicity. Anaesthesia, 2006. 61: p. 419-422.
4. Gillman, P.K., Lessons continue: serotonin toxicity. Consulting Pharmacy, 2009. 24: p. 398-399.
5. Gillman, P.K., Combining antidepressants: Understanding Drug Interactions is the Sine Qua Non. Advances in Psychiatric Treatment, 2010. 16: p. 76-78.
6. Buckley, N.A., et al., Greater toxicity in overdose of dothiepin than of other tricyclic antidepressants. Lancet, 1994. 343: p. 159-162.
7. Reith, D.M., et al., Clinical features of self-poisoning with monoamine oxidase inhibitors and / or serotonin reuptake inhibitors. Proceedings of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1996. 3( (Abstract)): p. 29.
8. Whyte, I.M. and A.H. Dawson, Relative toxicity of venlafaxine and serotonin specific reuptake inhibitors in overdose. Journal of Toxicology. Clinical Toxicology, 2001. 39: p. 255.
9. Dawson, A.H. and I.M. Whyte, Evidence in clinical toxicology: the role of therapeutic drug monitoring. Ther Drug Monit, 2002. 24(1): p. 159-62.
10. Whyte, I.M. and A.H. Dawson, Redefining the serotonin syndrome. Journal of Toxicology Clinical Toxicology, 2002. 40: p. 668-669.
11. Dunkley, E.J.C., et al., Hunter Serotonin Toxicity Criteria: a simple and accurate diagnostic decision rule for serotonin toxicity. Quarterly Journal of Medicine, 2003. 96: p. 635-642.
12. Isbister, G.K., et al., Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity. British Journal of Clinical Pharmacology, 2003. 56: p. 441-450.
13. Isbister, G.K., et al., Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. Journal of Toxicology. Clinical Toxicology, 2004. 42(3): p. 277-85.
14. Gillman, P.K., A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action. Biological Psychiatry, 2006. 59(11): p. 1046-51.
15. Gillman, P.K., CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of Psychopharmacology, 2011. 25(3): p. 429-3.
16. White, K. and G.M. Simpson, Combined MAOI-tricyclic antidepressant treatment: A reevaluation. A report to the American College of Neuropsychopharmacology, 1980. Oct: p. 1-54.
17. Ghose, K., A. Coppen, and P. Turner, Autonomic actions and interactions of mianserin hydrochloride (Org. GB 94) and amitriptyline in patients with depressive illness. Psychopharmacology (Berl), 1976. 49(2): p. 201-4.
18. Beresford Davies, E., MAOI TCA. Lancet, 1963. 2: p. 781.
19. Davies, E.B., Combining the antidepressants. Lancet, 1963. 2: p. 781-782.
20. Watts, C.A., Antidepressant Drugs. Br Med J, 1964. 1(5390): p. 1114.
21. Gander, D.R., Combining the antidepressant drugs. British Medical Journal, 1965. 1: p. 521.
22. Gander, D.R., Treatment of depressive illness with combined antidepressants. Lancet, 1965. 1: p. 107-109.
23. Hall, G.F., Combining Antidepressant Drugs. Br Med J, 1965. 1(5431): p. 383-4.
24. Hynes, B., Combining the Antidepressant Drugs. Br Med J, 1965. 1(5434): p. 589-90.
25. Marks, J., Interactions involving drugs used in psychiatry, in The Scientific Basis of Drug Therapy in Psychiatry. 1965, Elsevier. p. 191-201.
26. Pare, C.M., Treatment of Depression. Lancet, 1965. 1(7392): p. 923-5.
27. Randall, J., Combining the antidepressant drugs. British Medical Journal, 1965. 1: p. 521.
28. Sargant, W., Combining the antidepressant drugs. British Medical Journal, 1965. 1: p. 1251.
29. Sargant, W., C. Walter, and N. Wright, New treatment of some chronic tension states. British medical journal, 1966. 1(5483): p. 322.
30. Gander, D.R., The clinical value of monoamine oxidase inhibitors and tricyclic antidepressants in combination. In Garrantinis & Dukes. Antidepressant drugs, 1967: p. 336-343.
31. Sargant, W., The treatment of depressive states. Int J Neurol, 1967. 6: p. 53.
32. Kelly, D., et al., Treatment of phobic states with antidepressants. A retrospective study of 246 patients. Br J Psychiatry, 1970. 116(533): p. 387-98.
33. Sargant, W., Safety of Combined Antidepressant Drugs. British Medical Journal, 1971. 1(6 March): p. 555-556.
34. Schuckit, M., E. Robins, and J. Feighner, Tricyclic antidepressants and monoamine oxidase inhibitors. Archives of General Psychiatry, 1971. 24: p. 509-514.
35. Winston, F., Combined antidepressant therapy. Br J Psychiatry, 1971. 118(544): p. 301-4.
36. Ray, I., Combinations of antidepressant drugs in the treatment of depressive illness. Can Psychiatr Assoc J, 1973. 18(5): p. 399-402.
37. Shaw, D.M. and R. Hewland, Correspondence: The management of resistant depression. Br J Psychiatry, 1973. 123(575): p. 489-90.
38. Davidson, J., The management of resistant depression. British Journal of Psychiatry, 1974. 124(579): p. 219-20.
39. Sethna, E.R., A study of refractory cases of depressive illness and their response to combined antidepressant treatment. British Journal of Psychiatry, 1974. 124: p. 265-272.
40. Abdala, E.N., [Combination of tricyclic antidepressants and MAOI in the depressions]. Acta Psiquiatr Psicol Am Lat, 1975. 21(1): p. 52-5.
41. Ashcroft, G.W., Psychological medicine. Management of depression. British Medical Journal, 1975. 2(5967): p. 372-6.
42. Ayd, F.J., Psychotropic drug combinations: good and bad. Drugs in combination with other therapies
Greenblatt (Ed) pp 165-188 Grune & Stratton, New York, 1975.
43. Sargant, W., Antidepressant drugs. British Medical Journal, 1975(october): p. 101.
44. 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.
45. Spiker, D.G. and D.D. Pugh, Combining tricyclic and monoamine oxidase inhibitor antidepressants. Arch Gen Psychiatry, 1976. 33(7): p. 828-30.
46. Ananth, J. and A. Luchins, A review of combined tricyclic and MAOI therapy. Comprehensive Psychiatry, 1977. 18: p. 221-230.
47. Ponto, L.B., et al., Drug therapy reviews. Tricyclic antidepressant and monoamine oxidase inhibitor combination therapy. American Journal of Hospital Pharmacy, 1977. 34: p. 954-961.
48. Davidson, J., et al., A comparison of electroconvulsive therapy and combined phenelzine-amitriptyline in refractory depression. Arch Gen Psychiatry, 1978. 35(5): p. 639-42.
49. Goldberg, R.S. and W.E. Thornton, Combined tricyclic-MAOI therapy for refractory depression: a review, with guidelines for appropriate usage. J Clin Pharmacol, 1978. 18(2-3): p. 143-7.
50. Young, J., M. Lader, and W. Hughes, Controlled trial of trimipramine, monoamine oxidase inhibitors, and combined treatment in depressed outpatients. Br Med J, 1979. 2(6201): p. 1315-1317.
51. Laska, E., C. Siegel, and G. Simpson, Automated review system for orders of psychotropic drugs. Arch Gen Psychiatry, 1980. 37(7): p. 824-7.
52. White, K., T. Pistole, and J.L. Boyd, Combined monoamine oxidase inhibitor-tricyclic antidepressant treatment: a pilot study. Am J Psychiatry, 1980. 137(11): p. 1422-5.
53. White, K. and G. Simpson, Combined MAOI-tricyclic antidepressant treatment: a reevaluation. Journal of Clinical Pharmacology, 1981. 1: p. 264-281.
54. White, K., et al., Combined MAOI-tricylic antidepressant treatment: a controlled trial. Psychopharmacology Bulletin, 1982. 18(4): p. 180-1.
55. Razani, J., et al., The safety and efficacy of combined amitriptyline and tranylcypromine antidepressant treatment. A controlled trial. Archives of General Psychiatry, 1983. 40: p. 657-661.
56. Tollefson, G.D., Monoamine oxidase inhibitors: a review. J Clin Psychiatry, 1983. 44(8): p. 280-8.
57. Feighner, J.P., J. Herbstein, and N. Damlouji, Combined MAOI, TCA, and direct stimulant therapy of treatment-resistant depression. Journal of Clinical Psychiatry, 1985. 46(6): p. 206-9.
58. Kupfer, D.J. and T.P. Detre, Tricyclic and monoamine-oxidase-inhibitor antidepressants: Clinical use, in Handbook of psychopharmacology. 1987, Springer. p. 199-232.
59. Schmauss, M., et al., Combined MAO-inhibitor and tri- (tetra) cyclic antidepressant treatment in therapy resistant depression. Prog Neuropsychopharmacol Biol Psychiatry, 1988. 12(4): p. 523-32.
60. Pande, A.C., M.M. Calarco, and L. Grunhaus, Combined MAOI-TCA treatment in refractory depression. . In: Amsterdam J, ed. Refractory Depression. New York, NY: Raven Press, 1991: p. 115-121.
61. O’Brien, S., et al., Blood pressure effects of tranylcypromine when prescribed singly and in combination with amitriptyline. Journal of Clinical Psychopharmacology, 1992. 12(2): p. 104-9.
62. O’Brien, S., P. McKeon, and M. O’Regan, The efficacy and tolerability of combined antidepressant treatment in different depressive subgroups. Br J Psychiatry, 1993. 162: p. 363-8.
63. Berlanga, C. and H.A. Ortega-Soto, A 3-year follow-up of a group of treatment-resistant depressed patients with a MAOI/tricyclic combination. Journal of Affective Disorders, 1995. 34(3): p. 187-92.
64. Thase, M.E., M.H. Trivedi, and A.J. Rush, MAOIs in the contemporary treatment of depression. Neuropsychopharmacology, 1995. 12(3): p. 185-219.
65. Amsterdam, J.D., F. Garcia-Espana, and M. Rosenzweig, Clomipramine augmentation in treatment-resistant depression. Depression and Anxiety, 1997. 5(2): p. 84-90.
66. Schmauß, M. and T. Messer, Kombinationstherapie tri-(tetra-) zyklischer Antidepressiva mit MAO-Hemmern. Interaktionen und Wirkmechanismen ausgewählter Psychopharmaka, 2003. 2: p. 125-135.
67. Amsterdam, J.D., Monoamine Oxidase Inhibitor Therapy in Severe and Resistant Depression. Psych Annals, 2006. 36(9): p. 607-613.
68. Schmauß, M. and T. Messer, [Combining Antidepressants: a Useful Strategy for Therapy Resistant Depression?] Kombination von Antidepressiva – eine sinnvolle Behandlungsstrategie bei therapieresistenten Depressionen? Fortschr Neurol Psychiat, 2009. 77(316-325): p. 125-135.
69. Ferreira-Garcia, R., et al., Tranylcypromine Plus Amitriptyline for Electroconvulsive Therapy-Resistant Depression: A Long-Term Study. J Clin Psychopharmacol, 2018. 38(5): p. 502-504.
70. Amsterdam, J.D. and T.T. Kim, Relative Effectiveness of Monoamine Oxidase Inhibitor and Tricyclic Antidepressant Combination Therapy for Treatment-Resistant Depression. J Clin Psychopharmacol, 2019. 39(6): p. 649-652.