Shortly after the introduction of MAOIs into clinical practice in the early 1960s, the very serious adverse effect of hypertensive crisis was observed. The hypertensive crisis was initially described as a “cheese effect.”6 It is now known that this effect is caused by and proportional to the amount of tyramine ingested. Tyramine is a potent releaser of NE. When MAO activity is normal, the NE released by oral tyramine can be metabolized,including metabolism by MAO-A in the gut wall. However, when MAO is inhibited, the amount of NE released can elevate blood pressure. The average person can ingest about 400 mg of tyramine before excessive stimulation of adrenergic receptors occurs and blood pressure rises.7
Because MAOIs inhibit MAO-A and MAO-B, if an MAOI such as tranylcypromine or phenelzine(Drug information on phenelzine) is administered before tyramine ingestion, tyramine sensitivity is dramatically increased. Ingesting foods high in tyramine can cause a pressor response in a patient with MAO-A and MAO-B inhibition, which is an increase in systolic blood pressure of 30 mm Hg or more. Tyramine that escapes into the systemic circulation is delivered to noradrenergic sympathetic neurons, where it causes the release of NE. Since MAO-A is inhibited, NE release results in a rise in blood pressure. In patients who have received either tranylcypromine or phenelzine, the amount of tyramine that can safely be ingested is likely less than 8 mg.7
The tyramine-cheese reaction, hypertensive crises, and MAOI diets
The amino acid tyrosine (from the Greek word for cheese, tyros) was isolated from cheese as early as 1846. By 1911, it was known that tyramine (derived from tyrosine) had the potential to increase blood pressure. However, it was a series of case reports in the 1960s that described hypertensive crises associated with MAOIs that brought the MAOI-cheese relationship to the forefront and contributed to the rapid decline in MAOI use at a time of increasing medicolegal sensitivity.6,8
This also led to the development of detailed dietary restrictions that were not always evidence-based. An international survey conducted in the early 1980s found that as many as 70 restricted food items had appeared on various MAOI diets.9 Shulman and colleagues10 went on to conduct a series of systematic and carefully conducted tyramine analyses that in conjunction with a literature review of case reports led to a dramatically simpler MAOI diet (Table). This diet attempts to find a balance between patient safety and compliance—only a few food items are restricted, such as aged cheeses and meats, draft beer, concentrated yeast extract (marmite), sauerkraut, and soy sauces.
The use of MAOIs has declined since the 1960s. Health care data from 1997 through 2007 were used in a population-based observational cohort study to determine prescribing trends and safety profiles of MAOIs in older adults.11 Only 348 new continuous users of irreversible MAOIs were identified over the 10-year period. The yearly incidence rate of MAOI prescriptions (new users for whom no MAOIs had been prescribed in the previous year) decreased from 3.1 per 100,000 in 1997 to 1.4 per 100,000 in 2006, while prevalence (among individuals in Ontario for whom MAOIs were prescribed) decreased from 400 in 1997 to 216 in 2006. During 2002, antidepressants as a whole were being prescribed at an increasing rate (10,900 per 100,000 of older adults). In stark contrast, during the same year, prescriptions for MAOIs were down to 21.3 per 100,000. In other words, only 1 of 500 prescriptions for antidepressants for older adults was for an MAOI. As expected, MAOIs were being used primarily for those older adults who had a high rate of prior use of other antidepressants and ECT.
While the use of MAOIs as first-line treatment has declined dramatically, these agents have remained in the clinical armamentarium for refractory depression and atypical depression. Winbiscus and colleagues12 reviewed the evidence for the use of MAOIs in atypical depression. This subtype of depression is defined by mood reactivity and 2 of the following symptoms: weight gain or hyperphagia, increased sleep, subjective feeling of leaden paralysis, and a personality trait of rejection hypersensitivity. It has been estimated that 30% of patients with unipolar depression may meet criteria for atypical depression.13
The largest study of atypical depression was undertaken by Quitkin and colleagues.14 Phenelzine was shown to be superior to the TCA amitriptyline(Drug information on amitriptyline) for atypical depression in more than 400 patients. Using a meta-analysis, Henkel and associates 15 found a mean effect size of 0.45 in favor of MAOIs over placebo and a more modest effect size of 0.27 in favor of MAOIs over TCAs, similar to the results of Quitkin and colleagues.14
The widely cited STAR*D (Sequenced Treatment Alternatives to Relieve Depression) naturalistic study conducted in the US provided for a sequence of therapeutic options depending on response. The primary outcome measure in this study was remission, defined as a score of less than 7 on the Hamilton Depression Rating Scale. The secondary outcome was response defined by a 50% reduction on the Quick Inventory of Depressive Symptomatology (QUIDS).