Monoamine Oxidase Inhibitors (MAOI) – Mechanism of Action | Psychopharmacology | Clinical Application
Monoamine oxidase inhibitors (MAOIs) were the first antidepressant drugs along with imipramine to be developed for treating depression. Following WW2, large amounts of rocket fuel hydrazine were given to the pharmaceutical industry. In 1952 isoniazid derived from hydrazine was found to have anti-tubercular properties. Isoniazid was serendipitously found to have mood-elevating properties, and subsequently, numerous hydrazine and non-hydrazine structures were synthesized.
However, toxicity issues coupled with its complex and numerous interactions with other drugs and dietary amines have triggered a decline in clinical use as well as causing the discontinuation of many other MAOI derivatives. [Yáñez et al. 2012]
Due to their side effect profile, MAOIs are not considered as first or second-line therapies for depression, although they still have a place in treatment-resistant depression and other disorders such as panic disorder, social phobia, and depression with atypical features. [Thase 2012]
MECHANISM OF ACTION OF MAOIs
The monoamine oxidase (MAO) enzyme catalyses the oxidative deamination of various amine substrates, including serotonin, dopamine, and noradrenaline. [Gaweska and Fitzpatrick 2011]
Inhibition of the MAO enzyme increases the synaptic availability of these neurotransmitters, the accumulation of which is suggested to be responsible for MAOIs’ antidepressant effect.
There are two types of monoamine oxidase, MAO-A and MAO-B, both of which are bound to the mitochondrial membrane’s outer surface, where they preferentially bind amines. However, these two isoforms differ in their expression levels in different tissues. [Saura Marti et al. 1990]:
- MAO-A isoenzyme metabolises serotonin, noradrenaline and dopamine, and is distributed throughout the placenta, gut, and liver.
- MAO-B preferentially metabolises benzylamine, dopamine, and phenylethylamine and is primarily found in the brain, liver, and platelets. In the brain, MAO-B is expressed mainly in glial cells and serotonergic neurons in the raphe nucleus. MAO-B breaks down serotonin only at high concentrations.
Within the CNS, Norepinephrine and dopamine neurons contain MAO-A and MAO-B with greater MAO-A content.
Outside the CNS, MAO-A predominates with only platelets and lymphocytes having MAO-B.
CLASSIFICATION OF MAOIs
MAOIs are primarily classified on whether they are selective or non-selective and reversible or non-reversible. [Meyer, 2017]
Non-selective MAOIs inhibit MAO-A and MAO-B isoforms, whereas selegiline and rasagiline are selective inhibitors of MAO-B, and moclobemide is a reversible selective inhibitor of MAO-A (RIMA). [Van den Eynde et al, 2022]
Irreversible and nonselective:
- Hydrazine derivatives – Isocarboxazid (Marplan) and Phenelzine (Nardil)
- Cyclopropylamine inhibitor – Tranylcypromine (Parnate)
- The irreversible inhibitors will irreversibly inactivate the MAO enzyme. Their action can only be reversed by the generation of new enzyme molecules, a process that can take days or weeks.
- When given daily over several days, cumulative inhibition up to 90% or more of the target enzyme in the brain occurs in clinical use.
- Continued drug administration ensures that newly-formed enzyme molecules are also inhibited and that the enzyme activity is maintained at a constant low level.
- The clinical importance of irreversible MAOI prescribing is that a constant high degree of enzyme inhibition can be maintained over time. However, on stopping treatment, enzyme activity will remain low even after the drug itself has been cleared from the body. [Finberg and Rabey, 2016]
- Tranylcypromine, also has activity as a noradrenaline reuptake inhibitor (NARI) at a dose of 40 to 60 mg and potential dopamine-releasing activity at 100 mg
- Phenelzine is metabolised to several metabolites, including β-phenethylamine (releases DA and NA) and β-phenylethylidinehydrazine (increases brain GABA levels).
Non-reversible and selective
- Selegiline (Emsam) is a selective (MAO-B) and non-reversible propargylamine MAOI. Selegiline in oral form generates low plasma levels and hence acts as a selective MAO-B inhibitor. The transdermal form generates higher plasma levels and acts as a non-selective irreversible MAOI.
- Rasagiline (Azilect) is also selective (MAO-B) and non-reversible but is approved as monotherapy or adjunct therapy to levodopa in Parkinson’s disease.
- They also exert a neuroprotective activity not related to MAO inhibition. The molecular mechanism of this neuroprotective activity involves regulation of B-cell lymphoma/leukaemia 2 (BCL2) family proteins and protein kinase-dependent signalling pathways and interactions with glyceraldehyde-3-phosphate dehydrogenase and induction of some antioxidant enzymes. [Youdim, 2006]
Reversible and selective
- Reversible Selective inhibitor of MAO-A (RIMA)
- Moclobemide is a benzamide compound approved for treating depression in Australia, Europe, and Canada but not in the US.
PHARMACOLOGICAL PROFILE - PHARMACOKINETICS AND DRUG INTERACTIONS
In general, MAOIs have high bioavailability and reach peak plasma concentrations within two to three hours. Except for moclobemide (RIMA), MAOIs bind irreversibly and cumulatively inhibits up to 90% of target receptors; however, antidepressant effects are typically not observed until after 4 to 8 weeks of therapy.
MAOIs should be started at a low dose and gradually titrated up to the recommended daily dosage. If well tolerated after the first dose, increases can be made every 3-5 days. If postural hypotension occurs, consider slower increases.
- Isocarboxazid – Starting dose of 10-20 mg/day and titration up to 30-60 mg/day
- Tranylcypromine– Starting dose of 10 mg/day and titration up to 30-60 mg/day
- Phenelzine – Starting dose of 15 mg/day and titration up to 45-90 mg/day
- Selegiline – Starting dose of 6 mg/day and titration up to 6-12 mg/day
- Moclobemide – Starting dose of 150 mg/day and titration up to 300-600 mg/day
Maximum dose of 80 to 100 mg tranylcypromine have been used.
Phenelzine may take 8-12 weeks for response as phenelzine is both a substrate and inhibitor of MAO.
Case studies of successful treatment with very high MAOI doses; 120 to 170 mg tranylcypromine or 120 mg phenelzine are present in literature.
- Tranylcypromine is an inhibitor of CYP2A6, CYP2C19, CYP2C9, CYP2D6, CYP3A4, and CYP2B6.
Phenelzine is an inhibitor of CYP3A4, CYP2C19, CYP1A2, CYP2C9, CYP2D6, and CYP2B6.
While starting and titrating recommendations are to measure BP 3 times a week, twice a day (sitting and lying), followed by 2 successive measurements while standing for ≥1 minute to assess the degree of orthostatic hypotension.
Moclobemide is subject to substantial first-pass metabolism in the liver (short half-life); this contrasts with transdermal selegiline, which bypasses the first-pass metabolism.
Transdermal selegiline was developed to bypass impairments in the gastrointestinal tract as well as hepatic first-pass metabolism. [Robinson D 2002]
Side Effects [Fiedorowicz & Swartz, 2004]
Common adverse effects of MAOIs
- MAOIs are well known to have a potent hypotensive effect, which causes dizziness in approximately 50% of patients.
- MAOIs are also known to potentiate insomnia through their downstream effects on GABA and melatonin receptors.
- Other common side effects include constipation, dry mouth, sexual dysfunction, and weight gain.
Early in treatment
- Orthostatic hypotension
- Daytime sleepiness
Later in treatment:
- Weight gain
- Muscle pain
- Paraesthesia (pyridoxine deficiency may be causal)
- Sexual dysfunction
Serious Adverse Effects :
- Hypertensive crisis or pressor response (see below)
- Persistent hypotension
- Overstimulation (activation and nervousness).
- Phenelzine and isocarboxazid can be associated with hypoglycemia due to their hydrazine group.
- Hypoglycemia is less likely at therapeutic doses of tranylcypromine.
- Consider pyridoxine supplementation with phenelzine treatment (25-50mg).
- Orthostatic hypotension is a common side effect with MAOI especially phenelzine. This side effect improves over time. It is most prominent during dose changes and peaks 10-14 days later.
Strategies to address orthostatic hypotension:
- Spread the MAOI daily dose
- Increase water intake
- Increase dietary salt intake (or using salt tablets)
- Use compression stockings
- Temporarily add fludrocortisone
Strategies for transient BP increase (can occur with tranylcypromine) :
- Spread out the daily dose of tranylcypromine (lowers peak plasma concentrations)
- Temporarily reduce the dose, and/or administering propranolol. Short term benzodiazepine. Long-term treatment with a benzodiazepine is inadvisable.
- If no significant improvement, consider swapping (after washout of 14 days) to phenelzine.
Note: Selegiline has L-methamphetamine metabolites and can be stimulating at higher doses. Selegiline has the potential for false-positive drug screens.
- History of substance use disorders
- Overuse of prescribed medications
- Cerebrovascular disease
- History of recurrent or frequent headaches
- Hepatic disease/dysfunction
- Blood dyscrasias
MAOIs are not generally recommended for pregnant or breastfeeding patients due to the lack of adequate safety data. Specialist involvement is recommended.
Drug interactions involving MAO inhibitors are frequently reported, although evidence is inconsistent and of poor quality.
Two major interactions with MAOIs are:
- Stimulant like medications (amphetamine, methylphenidate, modafinil etc.)
- NARIs (atomoxetine, reboxetine)
- Anaesthetic agents
- Catecholamine-like drugs with sympathomimetic activity (i.e. mimic stimulation of sympathetic nerves, thus activating adrenergic receptors) such as ephedrine and its stereoisomer, pseudoephedrine.
Serotonergic [Gillman 2006]
- Non-selective MAOIs have also been implicated in producing serotonin syndrome (SS) when co-prescribed with SSRIs, tricyclic antidepressants, opioids (pethidine, methadone, tramadol) or amphetamines.
- Triptan migraine medications
- Tramadol, pethidine, methadone
Note that Mirtazapine and Bupropion are not present as agents that increase the risk of SS. Mirtazapine is a serotonin antagonist (5HT2A and 5HT2C antagonist) with alpha-2 antagonist effects at higher doses. Bupropion is an NDRI.
There are case reports of the emergence of serotonin syndrome even 10 weeks after MAOI is stopped.
See switching principles later.
Other reported drug interactions include:
- Other sympathomimetic drugs that are specifically contraindicated with MAOIs include apraclonidine (a selective α-2-adrenergic agonist).
- Meperidine (an opioid analgesic) is also specifically highlighted as having the potential to trigger serious drug interactions resulting in unpredictable adverse events, including death.
- MAOIs can also interact with anti-seizure medications such as carbamazepine and zonisamide, although the mechanism of interaction is not clear.
- Although not contraindicated, beta-blockers can theoretically also interact with MAOIs resulting in hypotension and bradycardia due to exaggerated vasoconstriction (i.e. a pressor response). As such, careful coadministration is recommended when these medications are used concomitantly.
TYRAMINE PRESSOR RESPONSE
Patients who are prescribed MAOIs are advised to avoid foods rich in tyramine (e.g. aged cheeses and red wine). MAOIs inhibit the breakdown of tyramine, which can quickly develop into a hypertensive crisis characterised by severe headache, anxiety, confusion, and palpitations. [Anderson et al. 1993]
- Tyramine is an amine absent in animal protein sources of diet but is enriched after decay or fermentation.
- Tyramine oxidase is found in the intestinal mucosa and breaks down the amino acid tyrosine to tyramine, which is metabolised by MAO.
- Tyramine is mainly metabolised by MAO-A with doses up to 400 mg, causing no known side effects (during a meal, people rarely ingest > 25 mg)
- Tyramine is also a substrate for (i.e. broken down) DAT, NAT, VMAT 2 and TAAR1.
- Tyramine is taken up into the cell by Noradrenaline transporter (NAT), where it interacts with TAAR1; agonistic properties at TAAR1 results in the potent release of noradrenaline. TAAR1 has a predominantly intracellular location, in which both pre-and postsynaptic effects are possible.
- Since Tyramine is metabolised by MAO, with MAO inhibition, tyramine is not metabolised in the gut and passes into the systemic circulation and cross the blood-brain barrier, displacing noradrenaline and resulting in peripheral and CNS effects.
- Complications from this crisis include haemorrhaging, cardiac failure, pulmonary oedema, and death.
- Oral agents that produce gut MAO-A inhibition tyramine doses as low as 8-10 mg may increase systolic pressure by 30 mm/hg.
- When ingested as food, tyramine doses of <50 mg are unlikely to cause a pressor response to warrant clinical attention, although some may be sensitive to 10-25 mg. (e.g. 100 mg of tyramine would require consumption of 100gm (3.5 oz) of the highest tyramine laden cheeses. [Meyer, 2017]
- For patients prescribed non-selective MAOIs, current evidence indicates that only foodstuffs having greater than 6 mg tyramine per serving pose a significant risk; these include soy sauce, air-dried sausages, sauerkraut, aged chicken liver and some cheeses. [Menkes et al., 2016]
It is important to note that the tyramine content is low due to the changes in production and hygiene regulations in modern diets.
Very few foods now contain problematically high tyramine levels, that is a result of great changes in international food production methods and hygiene regulations. Cheese is the only food that, in the past, has been associated with documented fatalities resulting from hypertension. Nowadays most cheeses are quite safe, and even ‘matured’ cheeses are usually safe in healthy-sized portions. The variability of sensitivity to tyramine between individuals, and the sometimes unpredictable amount of tyramine content in foods, means a little knowledge and care are still required. [Gillman, 2016]
Of note, the transdermal delivery of selegiline allows for more targeted inhibition of MAO in the brain with minimal effect on MAO-A enzymes in the gut and hepatic systems, thus reducing its interaction with food-derived tyramine.
RANZCP clinical practice guidelines suggest that irreversible MAOIs have a third-line role in the acute treatment of depressive disorders, with particular utility for
- Melancholic depression
- Atypical depression
- Treatment-resistant depression
If psychomotor retardation is a prominent symptom, or in the case of a predominantly endogenous (melancholic) depression, tranylcypromine may be preferred over phenelzine.
The response rates of tranylcypromine in treatment-resistant depression have ranged from 29% to 75% in two open-label and four double-blind studies, with a median rate of 50%. [Menkes et al., 2016]
In a chart review of such patients, there was evidence that non-selective MAOIs were effective in 56% of patients who had not responded to at least three prior trials of antidepressants and in 12% who had not responded to four. [Amsterdam, 2005]
In the STAR*D study, tranylcypromine was compared with mirtazapine combined with venlafaxine in patients who had not responded to citalopram over 12–14 weeks and two further antidepressant trials. Whilst remission rates did not significantly differ [6.9% for tranylcypromine vs 13.7% for mirtazapine plus venlafaxine]. [McGrath et al., 2006]
The average dose of tranylcypromine (37 mg/day) in the STAR*D was likely to have been suboptimal; despite this, those receiving the MAOI had almost twice the discontinuation rate (41%) due to adverse effects. [Menkes et al., 2016]
Problems with tolerability rather than efficacy would thus tend to relegate tranylcypromine to a third-line choice in treatment-resistant depression.
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 depression, and with being in full remission at the time of final follow-up. [Fekadu et al., 2015]
A network meta-analysis investigating the efficacy and acceptability of MAOIs in depressive disorders showed: [Suchting et al., 2021]
- Phenelzine demonstrated the strongest evidence for efficacy
- Clomipramine demonstrated superior evidence for acceptability
MAOIs may be used in Bipolar depression, but the evidence base is weak. MAOIs may be of particular advantage, as they appear to produce a lower manic ‘switch’ rate than TCAs and SSRIs. [Menkes et al., 2016]
The MAOI phenelzine has been studied the most, and the literature supports its ability to reduce intrusive symptoms associated with PTSD. [Kosten et al 1991]; [Stein et al 2006]
However, not all MAOIs have shown efficacy, and these agents are not considered first-line. Also, it is unknown whether this effect is independent of its efficacy in reducing the symptoms of depression.
In addition, selective MAO-B inhibitors have shown efficacy in the symptomatic treatment of mild Parkinson disease during the early stages. [Ives et al. 2004]
This includes reductions in motor symptoms and a reduced requirement for levodopa without any safety concerns observed.
MAOIs may be effective for treatment-resistant anxiety and panic disorders. [Van den Eynde et al, 2022]
Phenelzine is preferred over tranylcypromine in premorbid anxiety disorder, or in the case of comorbid panic disorder, due to its GABA potentiating activity.
SSRI TO MAOI –
- Ensure a suitable washout period of 5 half-lives of the SSRI
A washout period of 2-3 weeks is always advised after stopping an MAOI before commencing an alternative AD. (includes switching from one MAOI to another).
Fluoxetine requires a longer washout period as its half life is longer due to its metabolite norfluoxetine (half life 7-15 days). higher doses may need > 6 weeks.
Switching from Vortioxetine also requires a longer washout period as Vortioxetine has a median elimination half-life of approximately 66 hours equating to a minimum washout duration of 14 days.
AUGMENTATION OPTIONS FOR PATIENTS TAKING MAOIs
The following augmentation options have been described in literature however clinicians should exercise caution and carry out an individualised risk benefit analysis. [Van den Eynde et al, 2022]
- Lithium augmentation
- Second generation APs (SGAs) except Ziprasidone
- Thyroid hormone augmentation
- Successful treatment of MDD and comorbid ADHD using transdermal selegiline and lisdexamfetamine. [Israel, 2015]
- High dose Selegiline (60 mg /day) [Fiedorowicz & Swartz, 2004]
- RIMA and SSRI [Fiedorowicz & Swartz, 2004]
- Irreversible MAOIs with TCAs (safety data is limited) [Fiedorowicz & Swartz, 2004]
- TCAs (other than clomipramine and imipramine) have been mentioned.
- Successful combinations of MAOI in partial responders described are with full- dose trazodone (200-400 mg), or mirtazapine (45-60 mg)
- Amitriptyline (80-150 mg) with tranylcypromine has been used in ECT treatment resistant depression. [Ferreira-Garcia et al, 2018]
The MAOIs were the first antidepressants to be developed; however, continued reports on their substantial side effects resulted in these drugs being quickly replaced by safer and more effective options.
Data collected from European tertiary treatment 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
- Lack of sufficient clinician training [Shulman, Herrmann and Walker, 2013]
- Potential problems in the continuity of drug supplies.
Today there is a renewed interest in the pharmacology of MAOIs, particularly in patients who show a lack of response to more modern antidepressants.
Clinicians should familiarise themselves with the psychopharmacology of MAOIs and re-consider them as a valid option in treating psychiatric disorders.
Dold M, Kautzky A, Bartova L, Rabl U, Souery D, Mendlewicz J, Porcelli S, Serretti A, Zohar J, Montgomery S, Kasper S (2016). Pharmacological treatment strategies in unipolar depression in European tertiary psychiatric treatment centers – A pharmacoepidemiological cross-sectional multicenter study. Eur Neuropsychopharmacol., 26(12): 1960–71.