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What is a MAOI?
Monoamine oxidase (MAO) inhibitors or MAOIs are a unique class of prescription antidepressants with anxiolytic and antihypertensive effects. MAOIs play an important role in treating a wide variety of psychiatric and mental health conditions.
MAO inhibitors were among the first antidepressants to be discovered in the 1950s. [1] Because they were noted to increase neurotransmitter or chemical messenger levels in the brain via inhibition of the MAO enzyme, their discovery led to an idea which ultimately grew into the monoamine hypothesis of depression, a belief among the medical and psychiatric academic communities that depression was caused or worsened by a depletion of one or more neurotransmitters in the brain. [2]
Despite remaining as a highly effective treatment for atypical and major depression, bipolar disorder, and a variety of anxiety disorders including generalized anxiety, social anxiety, phobias, obsessive compulsive disorder (OCD), and post traumatic stress disorder (PTSD), their use has dwindled over time largely of exaggerated concerns of dietary restrictions and reactivity with other serotonergic medications. With introduction of newer antidepressants such as selective serotonin reuptake inhibitors (SSRIs), MAO inhibitors gradually fell out of favor as despite the very limited dietary restrictions compared to the 1950s and 1960s, when tyramine content in foods was immensely higher than it is today, and despite the fact that numerous studies have shown that many “serotonergic” drugs can safely be combined with MAO inhibitors to augment treatment. [3, 4]
In the United States, there are four MAO inhibitors that are FDA-approved for treatment of major depressive disorder:
Why Are MAO Inhibitors So Effective? How Do MAOIs Work?
MAO inhibitors are highly effective compared to many first-line and second-line treatments such as selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) for major depression, atypical depression, and treatment-resistant depression [5-9], narcolepsy [9, 10], and a variety of anxiety disorders including generalized anxiety disorder, social phobia, and panic disorder. [11-15] They are also efficacious in treating more severe cases of bipolar disorder [16, 17] and post-traumatic stress disorder (PTSD). [18]
MAO inhibitors bind to and inhibit the activity of monoamine oxidase, an enzyme responsible for destroying several neurotransmitters or chemical messengers in the brain, including serotonin, norepinephrine, dopamine, epinephrine, and tyramine.
There are two subtypes of the MAO enzyme: MAO-A and MAO-B. MAO-A is responsible for degrading serotonin, norepinephrine, and tyramine, while MAO-B is responsible for degrading amine-based chemical messengers. Both MAO subtypes degrade dopamine. [19]
Parnate (Tranylcypromine), Nardil (Phenelzine), and Marplan (Isocarboxazid) are non-selective MAO inhibitors. In other words, they do not show a preference for one MAO isotype inhibiting one subtype over the other). Selegiline, by contrast, is a selective MAO inhibitor that preferentially binds to and destroys MAO-B at lower doses. At higher doses, however, Selegiline is non-selective and destroys both MAO subtypes equally. [20] Through inhibition of MAO, MAO inhibitors increase concentrations of neurotransmitters or chemical messengers in the brain.
At therapeutic doses, MAO inhibitors typically inhibit >50% of the total body’s MAO. [21-22] When MAO inhibitors are stopped, MAO regenerates in the body at a rate of approximately 3% per a day. [23] Thus waiting 2 weeks after discontinuing a MAO inhibitor is recommended to allow for sufficient regeneration of MAO before starting a serotonergic drug such as a selective serotonin reuptake inhibitor (SSRI) or tertiary amine tricyclic antidepressant (TCA). [24]
Secondary or Alternative MAOI Mechanisms of Action
In addition to irreversible inhibition of the MAO enzyme, some MAO inhibitors possess secondary mechanisms of action. possess additional activities in the body. At higher doses, Parnate and, to a lesser extent, Nardil may act as a direct norepinephrine reuptake inhibitor (NRI) [25]. High-dose Parnate may also act as a dopamine releasing agent (DRA) to a mild extent. [26] Additionally, Nardil is associated with significantly greater levels of GABA, a neurotransmitter or chemical messenger responsible for inhibiting activity in the brain. [27] Parnate and Selegiline also have amphetamine metabolites. [28, 29]
How Long Do MAO Inhibitors Last?
The half-life or time until half of the drug has been metabolized (broken down) or excreted (removed from the body) of each of the MAO inhibitors is relatively short:
But unlike the effects of many other drugs, the effects of MAO inhibitors do not strictly correlate with the drugs’ serum level because their primary mechanism of action involves the irreversible inhibition of MAO which regenerates at approximately 3% of the total body’s baseline level of MAO per day. [23] As a result, although Selegiline, for example, is virtually entirely eliminated from the body 24 hours later, its effects linger for a much longer period. In fact, a study with Selegiline dosing found that it can be effectively used with larger doses given only twice per week. [34]
However, some of the secondary mechanism of actions of various MAO inhibitors discussed above correlate with drug serum level. Thus, the stimulating effects of Parnate, for example, which are believed to be due to its dopamine releasing effects, norepinephrine reuptake inhibition, and amphetamine metabolites, typical only last a few hours after consumption. [35]
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