PS03/20

Use of monoamine
oxidase inhibitors
(MAOIs) in psychiatric
practice

July 2020

POSITION STATEMENT
Working group

Royal College of Psychiatrists’ Psychopharmacology Committee

Samuel R. Chamberlain
Antonio Metastasio
Paul R. A. Stokes
David S. Baldwin

With additional input from

Hamish McAllister-Williams
Royal College of Psychiatrists’ Psychopharmacology Committee

Julia Sinclair
Chair, Royal College of Psychiatrists’ Addictions Faculty

Michael Browning
British Association for Psychopharmacology

Allan Young
British Association for Psychopharmacology

PS03/20: Use of monoamine inhibitors in psychiatric practice 2

Scope
This Position Statement provides clinicians with practical advice relating to the use of
monoamine oxidase inhibitors (MAOIs) in treating adult patients with moderate-to-severe
depression or anxiety disorders.

Background
MAOIs were one of the first classes of antidepressant medication to be discovered, but
have fallen out of mainstream clinical use. Data collected from European tertiary treat-
ment centres indicated that MAOIs were used as the primary treatment in just 0.3% of
the patients with unipolar depression (Dold et al., 2016). The reasons for low prescribing
rates of MAOIs include safety concerns, the relative complexity of prescribing them, a
lack of sufficient clinician training (Shulman, Herrmann and Walker, 2013), and potential
problems in the continuity of drug supplies.

MAOIs are not a first-line pharmacological treatment for depression or anxiety, for sev-
eral reasons: if compared to selective serotonin reuptake inhibitors (SSRIs), they are
less safe in overdose, their prescribing is not straightforward, and there are important
safety issues that need to be carefully addressed for each patient (including drug–drug
interactions, and dietary restrictions).

A consideration regarding the use of MAOIs, and particularly irreversible MAOIs, is to

minimise the risk of adverse reactions, which have sometimes been fatal; these can occur
if an MAOI is taken in combination with food or drink that has a high tyramine content.

Approximately two thirds of patients with depression do not experience adequate

symptom relief from first-line pharmacological treatments, such as SSRIs, and MAOIs
can be effective in some patients with treatment-resistant depression, especially in
people with ‘atypical’ symptoms.

Atypical depression is characterised by some or all of the following features: over-eat-

ing, over-sleeping, mood reactivity, and rejection sensitivity (Angst et al., 2002; Henkel
et al., 2006).

PS03/20: Use of monoamine inhibitors in psychiatric practice 3

Mechanism
Monoamine oxidase (MAO) is an important enzyme in the degradation pathway of the
monoamines (serotonin [5-hydroxytryptamine], dopamine, and noradrenaline), and
exists in two forms (isomers): MAO-A and MAO-B. Both isomers degrade dopamine
and tyramine, whereas MAO-A has additional effects serving to deactivate serotonin,
noradrenaline, and melatonin (Shulman, Herrmann and Walker, 2013). Different MAOIs
are available: some irreversibly deactivate the enzyme (e.g. phenelzine), whereas others
are reversible (e.g. moclobemide); some are non-selective (e.g. phenelzine), whereas
others selectively inhibit either MAO-A (e.g. moclobemide) or MAO-B (e.g. selegiline,
when given in standard dosages). MAO-A inhibition is thought to be important for anti-
depressant properties (Figure 1), and MAOIs differ in their propensity to act on each
isoform.

Figure 1. Enzyme MAO-A metabolises serotonin. By blocking this enzyme, MAOIs act to
increase serotonin levels (and noradrenaline). MAO-B’s role in breaking down serotonin (and
noradrenaline) is much less prominent, because it only does so at high concentrations. From
(Stahl S.M., 2008), with permission.

PS03/20: Use of monoamine inhibitors in psychiatric practice 4

When should MAOIs be considered?
The 2015 British Association for Psychopharmacology guidelines for depression
recommend that MAOI treatment is generally reserved for patients where first-line
antidepressant therapy has not been effective, and should be initiated only by prac-
titioners with expertise in treating mood disorders (Cleare et al., 2015). MAOIs may
provide advantages for the treatment of depression with atypical features (Ricken et al.,
2017). A 2006 meta-analysis indicated that MAOIs had greater efficacy than placebo in
the treatment of atypical depression, with medium-to-large effect sizes (Henkel et al.,
2006). MAOI efficacy effect sizes were higher than for tricyclic medication and were
similar to those with SSRIs (Henkel et al., 2006). However, the number of data trials
was relatively small.

In people with treatment resistant depression, a paper from the Sequenced Treatment
Alternatives to Relieve Depression (STAR*D) group found that, in those patients who had
not achieved remission from three previous antidepressant trials, 6.9% remitted after
being treated with the MAOI tranylcypromine, compared to 13.7% who remitted on the
combination of extended release venlafaxine plus mirtazapine (McGrath et al., 2006).
This difference in remission between the two groups was not statistically significant. A
study of people with treatment resistant depression found that use of MAOIs while an
in-patient was independently associated with both remission at the point of discharge
after controlling for other treatments, particularly for unipolar treatment-resistant depres-
sion, and with being in full remission at the time of final follow-up (Fekadu et al., 2012).

A number of randomised controlled trials have indicated that MAOIs can also be effective
in the treatment of patients with panic disorder, social anxiety disorder (social phobia), or
post-traumatic stress disorder (Menkes, Bosanac and Castle, 2016; Cipriani et al., 2018).
The 2014 British Association for Psychopharmacology guidelines for anxiety disorders
recommend that MAOIs are considered as potential treatments after non-response
to more conventional pharmacological (e.g. SSRI) and psychological (e.g. cognitive
behaviour therapy) approaches (Baldwin et al., 2014).

PS03/20: Use of monoamine inhibitors in psychiatric practice 5

Tolerability and side effects
In a network meta-analysis, MAOIs did not differ significantly from SSRIs or seroto-
nin-noradrenaline reuptake inhibitors (SNRIs) in how likely patients are to discontinue
treatment due to adverse events (Meister et al., 2016). Nonetheless, the differing classes
of antidepressants vary in their characteristic side effect profiles. The most common
adverse effects of MAOIs occurring early in treatment are orthostatic hypotension,
daytime sleepiness, insomnia, and nausea; later common effects include weight gain,
muscle pain, myoclonus, paraesthesia, and sexual dysfunction (Fiedorowicz and Swartz,
2007). More serious adverse reactions include hypertensive crisis (see below), persis-
tent hypotension and overstimulation (activation and nervousness). Other important
safety considerations include potential drug–drug interactions, and the need for dietary
restrictions. These are considered below.

For safety reasons, MAOIs should not generally be prescribed in people with a his-
tory of substance use disorders, over-use of prescribed medications, or overdoses.
Other contraindications to MAOIs include: cerebrovascular disease, history of recur-
rent or frequent headaches, hepatic disease/dysfunction, blood dyscrasias, and
phaeochromocytoma.

MAOIs are not generally recommended for use in pregnant or breast-feeding patients,
due to the lack of adequate safety data; more safety data are available for other classes
of antidepressant. Nonetheless, there may be some patients for whom the benefits of
continuing a MAOI in pregnancy and/or lactation, with close monitoring (including of
blood pressure) might outweigh the risks of continued treatment. Specialist advice is
particularly needed in this situation.

Drug–drug interactions
MAOIs must not be prescribed alongside SSRIs, or other substances with serotonin
reuptake inhibition effects (including SNRIs, trazodone, and clomipramine), due to the
risk of inducing serotonin syndrome. Serotonin syndrome is characterised by a com-
bination of autonomic hyperactivity, neuromuscular hyperactivity, and/or mental state
changes (for more detail see Volpi-Abadie, Kaye and Kaye, 2013). Other medications
that have serotonergic effects should also not be concomitantly prescribed, including
certain analgesics, opioids (e.g. tramadol), and some triptan migraine medications
(Culpepper, 2013). Some non-prescribed substances taken by patients have SSRI-like
properties, including St John’s Wort, and so also must be avoided.

When switching a patient from an SSRI to a MAOI, clinicians must ensure there is a
suitable washout period of at least five half-lives of the particular SSRI (Grady and Stahl,
2012). This would typically be approximately seven days for most SSRIs, but around
six weeks for fluoxetine due to its much longer half-life.

A washout period of 2–3 weeks is always advised after stopping a MAOI, before com-
mencing an alternative antidepressant. This includes when switching from one MAOI
to another MAOI based on conventional practice.

PS03/20: Use of monoamine inhibitors in psychiatric practice 6

As there are occasional reports of the emergence of features of serotonin syndrome
even 10 weeks after an MAOI is stopped, introduction of medicines with serotonin-re-
uptake inhibitor properties should be conducted cautiously with careful monitoring.
MAOIs can be combined with some tricyclic medications (not clomipramine) (Pilowsky
and Kerwin, 1997) but this should only be considered in psychiatric inpatient units, or
specialist outpatient clinics for patients with treatment-resistant affective disorders, due
to the need for cautious dose titration and close monitoring.

Medications with potent noradrenergic effects should also be avoided whenever pos-
sible in people taking MAOI, due to the potential risk of synergistic effects on blood
pressure (Grady and Stahl, 2012). Examples of such medications include stimulant and
stimulant-like medications (e.g. methylphenidate, amphetamine, modafinil), noradrenaline
reuptake inhibitors (including atomoxetine and reboxetine), and certain anaesthetic
agents. For surgical procedures needing local anaesthetic, a non-noradrenergic anaes-
thetic agent should be used. For surgical procedures needing general anaesthetic,
input from an anaesthetist should be sought well in advance, as it is likely the MAOI
will need to be discontinued at least 10 days prior to surgery. MAOIs can have serious
(including life-threatening) interactions with anaesthetic medications such as certain
opioid analgesics.

Patients should be advised to check carefully and discuss with a doctor or pharmacist
before using over-the-counter cold remedies and/or anti-congestants (including nasal
sprays). This is because some of these can interact with MAOI effects, and increase
levels of noradrenaline and/or serotonin. In turn, this can increase the risk of high blood
pressure or serotonin syndrome.

As with other antidepressant medicines, abrupt withdrawal of MAOIs can be associated

with distressing psychological and physical symptoms. Particular caution needs to be
exercised when considering potential further pharmacological management of patients
with these symptoms, due to the risk of potential severe drug–drug interactions.

Dietary restrictions
Consuming high levels of dietary tyramine while also taking MAOI medication can lead
to raised blood pressure, including in some cases serious life-threatening hypertensive
crises. Tyramine is normally metabolised by MAO in the liver and intestinal cells. With
MAO inhibition, tyramine is not metabolised in the gut and passes directly into the cir-
culation, where it may release norepinephrine, so causing hypertension.

Even though reversible MAOIs theoretically have a lower risk of this reaction, current
best practice is that all patients taking MAOI should be advised to follow the dietary
restrictions. Table 1 provides a useful general guideline for common foods and drinks
to avoid, and those that are allowed, in people taking MAOIs. Patients’ individual dietary
practices should also be considered on a case-by-case basis, in case their usual diet
includes tyramine-containing food or drink not considered in the table.

PS03/20: Use of monoamine inhibitors in psychiatric practice 7

Table 1. Foods and drinks to avoid, and those that are allowed, in people taking MAOI.
Table reprinted with permission of the authors from the Sunnybrook Health Sciences Centre
(Shulman, Herrmann and Walker, 2013).

Foods and drinks to avoid Foods and drinks allowed

Cheese
All matured or aged cheese Fresh cottage cheese, cream cheese,
ricotta cheese, and processed cheese
slices; all fresh milk products that have
been stored properly (e.g. sour cream,
yoghurt, ice cream)
All casseroles made with these mature/
aged cheeses e.g. lasagne
Please note: all cheeses are considered
matured or aged except for those listed
opposite
Meat, fish, and poultry
Fermented/dry sausage: e.g. salami All fresh packaged or processed meat,
fish, or poultry; store in refrigerator and
eat as soon as possible
Improperly stored meat, fish, or poultry
Improperly stored pickled herring
Fruit and vegetables
Fava or broad bean pods Banana pulp
Banana peel All others
Drinks
All on-tap beer Other alcohol (NB: no more than two
bottled or canned beers or two standard
glasses of wine per day; this applies
also for low alcohol / alcohol-free beer).
Miscellaneous
Marmite concentrated yeast extract Other yeast extract (e.g. brewer’s yeast)
Sauerkraut Pizza without aged cheeses
Soy sauce and other soy bean condiments Soy milk, tofu
Tyramine-containing nutritional
supplements

When MAOIs are stopped, patients should be advised to continue their restricted diet
(with avoidance of tyramine-containing foods and beverages) and their avoidance of
some proprietary cough medicines for 2–3 weeks after treatment is withdrawn.

Studies in healthy volunteers have found that reversible MAOIs interact less with tyramine
than an irreversible MAOI (Finberg, 2014 ). It follows that reversible MAOIs are less likely
to cause a hypertensive reaction when combined with high levels of dietary tyramine.
However, confirmatory prospective clinical data are not currently available.
PS03/20: Use of monoamine inhibitors in psychiatric practice 8
Choice of MAOI
Efficacy studies demonstrate that reversible MAOIs (principally moclobemide) are as
effective as tricyclic antidepressants, but maybe less effective than irreversible MAOIs
(Shulman et al., 2013). However, there have been no recent systematic reviews or
meta-analyses comparing the efficacy and safety of reversible MAOIs and irreversible
MAOIs. As such, an irreversible MAOI may be preferred in patients with severe treat-
ment-resistant depression, providing they are likely to comply with the necessarily strict
dietary regime. An initial approach would be to trial phenelzine as it appears better
tolerated; and then to switch to tranylcypromine (following washout) if there is not ade-
quate symptom remission.

While head-to-head comparisons are lacking, phenelzine may be associated with weight
gain, with some other MAOIs (such as tranylcypromine and moclobemide) being weight
neutral (Ricken et al., 2017).

Intermittent supply issues occur with MAOIs, in part due to low prescribing rates. If
other MAOIs are not available, the use of oral selegiline (an irreversible MAO-B inhib-
itor thought to have MAO-A inhibition effects at higher doses) can be considered for
depression ‘off-label’, since supplies of this may be more readily available .

The selegiline transdermal system (administered via a skin patch that is replaced every
24h) shows efficacy in the treatment of depression and is licensed for depression in
the USA (Bied, Kim, and Schwartz, 2015). The selegiline transdermal system is not
currently available for licensed use in the UK for this indication. Prescribers are advised
to consult the Royal College of Psychiatrist’s College Report Use of licensed medicines
for unlicensed applications in psychiatric practice (2nd Edition, CR210, December
2017), for advice about provisions relating to prescribing outside the terms of marketing
authorisation (product licence).

Price and supply considerations

At present, phenelzine is more than ten times cheaper to prescribe on the NHS than
either tranylcypromine or isocarboxazid. Prescribers are advised to consult the latest
edition of the British National Formulary (BNF) for current pricing (www.medicinescom-
plete.com).

The acquisition cost of MAOI antidepressants is often high (and higher than with alter-
native antidepressants), and supplies of MAOIs to pharmacies can appear limited;
patients who are benefiting from MAOI treatment should be encouraged to ensure that
prescriptions are regularly filled, so that potentially upsetting treatment interruptions
can be avoided.

PS03/20: Use of monoamine inhibitors in psychiatric practice 9

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