Posted on:April 7, 2021 Show Last Updated: December 27, 2021 Time to read: 11–13 minutesMonoamine 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 MAOIsThe 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]:
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 MAOIsMAOIs 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). Irreversible and nonselective:
Non-reversible and selective
Reversible and selective
PHARMACOLOGICAL PROFILE - PHARMACOKINETICS AND DRUG INTERACTIONSPharmacokinetics: 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.
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
Early in treatment
Later in treatment:
Serious Adverse Effects :
Note: Selegiline has L-methamphetamine metabolites and can be stimulating at higher doses. Selegiline has the potential for false-positive drug screens. Contraindications and Caution:
MAOIs are not generally recommended for pregnant or breastfeeding patients due to the lack of adequate safety data. Specialist involvement is recommended. Drug interactions Drug interactions involving MAO inhibitors are frequently reported, although evidence is inconsistent and of poor quality. Two major interactions with MAOIs are: Noradrenergic
Serotonergic [Gillman 2006]
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:
TYRAMINE PRESSOR RESPONSEPressor 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]
It is important to note that the tyramine content is low due to the changes in production and hygiene regulations in modern diets.
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. CLINICAL EVIDENCEDepression RANZCP clinical practice guidelines suggest that irreversible MAOIs have a third-line role in the acute treatment of depressive disorders, with particular utility for
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]
Bipolar Depression: 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] PTSD 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. Parkinson’s Disease 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. SWITCHING PRINCIPLESSSRI TO MAOI –
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) AUGMENTATION OPTIONS FOR PATIENTS TAKING MAOIs
SUMMARYThe 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:
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. Why are monoamine oxidase inhibitors not used?MAOIs have fallen out of favor for treatment of depression due to side effects from adverse drug and food interactions. However, their use in treatment of Parkinson's disease is increasing. Drugs that selectively inhibit MAO-B disproportionately increase dopamine concentrations in the striatum.
Why are MAOIs a last resort antidepressant?Tricyclics and other mixed or dual action inhibitors are third line, and MAOI's (monoamine oxidase inhibitors) are usually medications of last resort for patients who have not responded to other medications, due to their low tolerability, dietary restrictions, and drug-drug interactions.
Why do MAOIs have more side effects?Although SSRIs are the current frontline treatment for depression, monoamine oxidase inhibitors (MAOIs) were the first antidepressants developed. They are typically more potent than SSRIs because they affect more neurotransmitters, and they can cause more side effects.
Why are MAOIs used less frequently that SSRIs to treat depression?Monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs) are types of antidepressants used to treat depression. MAOIs are an older class of antidepressants that are not used as much because of drug and food interactions.
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