In 'Listening to Prozac' (Pg. 305) Kramer notes that once monoamine oxidase inhibitors (MAOIs) poop-out, depressed patients are often unresponsive to subsequent pharmacological interventions (and in some cases ECT (1)), and can suffer particularly severe tardive dysphoria. His statement is supported by this paper.

What is the Antidepressant response post MAOI tachyphylaxis? Does the treatment resistance and exacerbation of underlying depression apply to all MAOIs regardless of reversibility (e.g.: the older MAOIs that covalently bond to the MAO such tranylcypromine and phenelzine vs. moclobemide) and selectivity (e.g.: the MAO-B selective selegiline vs. the MOA-A selective moclobemide)?


  1. Identification and Treatment of Antidepressant Tachyphylaxis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008298/
  • 4
    This is a great question!
    – Dave Liu
    Commented Feb 16, 2018 at 21:33

1 Answer 1


All Anti-Depressants poop out equally for TR patients. Having just now signed up on this site, it seems a prerequisite to post is that you ought to have at least minimally researched the question, since the site compels ME not to ask for clarification. Either your or Kramer's interpretation (or both) of the phenomenon of tachyphylaxis, especially related to MAOIs is misfounded. Here is the quotation from your source [emphasis mine]:

ADT tachyphylaxis (“poop-out”) was initially recognized in patients receiving monoamine oxidase inhibitors (MAOIs) before the advent of selective serotonin reuptake inhibitors (SSRIs) in the early 1980s.(1,4,5,7) Patients who lost their initial response to a MAOI responded poorly to subsequent treatment and revealed greater depressive severity after relapse than before the new treatment was initiated.(7,8) SSRIs were introduced in the United States in 1988 and ADT tachyphylaxis was subsequently identified with these drugs as well.(3,9,10) Fava et al found that 26 of 77 depressed patients (33.7%) who had achieved full remission of symptoms on fluoxetine 20mg daily experienced a recurrence of symptoms (ADT tachyphylaxis) between 14 and 54 weeks despite maintenance treatment.(10) In another small study, 15 patients who had lost their response to antidepressants failed multiple treatment strategies including augmentation with mood stabilizers and, in some cases, electroconvulsive therapy.(11)

In other words, ALL Anti-Depressants, as any above-his/her-weight-punching psychiatrist will tell you, will poop out, and often not just for 2-3 AD trials, but even 15 or more. This is called by any definition "Treatment Resistant".

The difference between (I assume you mean) MAOIs that covalently bond versus those that do not (Non-selective versus RIMAs) is an important one, and points out why RIMAs like Moclobemide are no better than SSRIs, and why irreversible, non-selective MAOIs raise Serotonin levels > ~2000% over baseline, while SSRIs like Vortioxetine only raise it a few hundred percent.

I hope a poster or referee will call me out on this, as I've got magazines of ammo on this. As the OP's thesis bears no relation to any of his references, I feel free for now, not to give any of my own.


  1. Cohen B, Baldessarini R. Tolerance to therapeutic effects of antidepressants. Am J Psychiatry. 1985;142:489–490. [PubMed]
  2. Frank E, Kupfer DJ, Perel JM, et al. Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry. 1990;47:1093–1099. [PubMed]
  3. Byrne SE, Rothschild AJ. Loss of antidepressant efficacy during maintenance therapy: possible mechanisms and treatments. J Clin Psychiatry. 1998;59:279–288. [PubMed]
  4. Lieb J, Balter A. Antidepressant tachyphylaxis. Med Hypotheses. 1984;15:279–291. [PubMed]
  5. Lieb J. Antidepressant tachyphylaxis. J Clin Psychiatry. 1990;51:36. [PubMed]
  6. Nierenberg AA, Alpert JE. Depressive breakthrough. Psychiatr Clin North Am. 2000;23(4):731–742. [PubMed]
  7. Mann JJ. Loss of antidepressant effect with long-term monoamine oxidase inhibitor treatment without loss of monoamine oxidase inhibition. J Clin Psychopharmacol. 1983;3:363–366. [PubMed]
  8. Donaldson S. Tolerance to phenelzine and subsequent refractory depression: three cases. J Clin Psychiatry. 1989;50:33–35. [PubMed]
  9. Solomon D, Leon AC, Mueller TI, et al. Tachyphylaxis in unipolar major depressive disorder. J Clin Psychiatry. 2005;66:283–290. [PubMed]
  10. Fava M, Rappe SM, Pava JA, et al. Relapse in patients on long-term fluoxetine treatment respond to increased fluoxetine dose. J. Clin Psychiatry. 1995;56:52–55. [PubMed]
  11. Sharma V. Loss of response to antidepressants and subsequent refractoriness: diagnostic issues in a retrospective case series. J Affect Disord. 2001;64:99–106. [PubMed]
  • 1
    This site most certainly does not compel you to not ask for clarification. That's exactly what comments are for.
    – Carey Gregory
    Commented May 18, 2019 at 14:59

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