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Monoamine Oxidase Inhibitors (MAOIS) are older-style antidepressants that are occasionally prescribed for the treatment of treatment-resistant anxiety. They carry risks and side effects which typically make then a last resort in treatment.

Monoamine Oxidase Inhibitors (MAOIS) were one of the early antidepressants, alongside tricyclic antidepressants. They were initially prescribed for the treatment of tuberculosis and an unusual side effect was noted. Those patients in the hospital who were taking a MAOI called Iproniazid suddenly had increased vitality, appeared more sociable and asked to return home despite knowing they had reached the end of their life. Based on the observations of the doctors in-situ, this drug was therefore given a new lease of life in the treatment of mental disorders. 

It was concluded that Iproniazid works by slowing down a monoamine oxidase enzyme that breaks down and removes serotonin, norepinephrine, and dopamine, so increasing the amount of them circulating in the brain. So, as MAOIs inhibit this enzyme's action and in turn maintain the presence of these chemicals, communication among brain cells is boosted and mood improved.

Having made this discovery, it was then hypothesized that a catecholamine (that is, norepinephrine and dopamine and serotonin) deficiency, may be the cause of depression; and this was the basis of the monoamine hypothesis of mood disorders that persist to this day. These findings about monoamines caused much excitement and has led to this hypothesis which forms the basis of modern prescribing.

However, extensive investigation has failed to find supportive evidence for a primary dysfunction of a specific monoamine system in patients with major depressive disorders. For example, when investigating selective serotonin reuptake inhibitors (SSRIs), contemporary research has been unable to confirm any serotonergic deficit in any mental disorder, and has actually provided significant evidence to the contrary – that there is no scientifically established ideal “chemical balance” of serotonin, let alone an identifiable imbalance in the condition.

Despite this discovery, MAOIs were never widely used as they had dangerous side effects such as high blood pressure, and adverse or even life-threatening reactions sometimes resulted from reactions to certain foods. Cheese was considered the primary culprit and was associated with “hypertensive crises” or sudden high blood pressure which manifested itself by extreme headaches, palpitations, excessive sweating, a stiff neck, and nausea. On occasion, this was known to lead to fatal health events such as a stroke.

These reactions were eventually linked to a specific interaction with tyramine, which is an amino acid that regulates blood pressure. It is naturally present in the human body and also in particular foods. Monoamine oxidase breaks down excess tyramine in the body and so when it is blocked through the use of a MAOI, there is a risk of an excess build-up of tyramine in the body and this causes a spike in blood pressure.

Many of the foods once believed to be dangerous for patients on MAOIs are now considered to be safe. Over the years the tyramine content of foods has been subject to considerable scrutiny and understanding of the mechanics behind food interactions have meant that fewer and fewer foods are formerly restricted. Food production techniques have changed over the years, which means that few foods are thought to contain tyramine levels sufficiently high to be problematic to someone on MAOIs. The risk of serotonin syndrome due to drug interactions (even with over the counter medications) remains a serious problem, even if dietary restrictions are less of a concern than previously thought.

So, while the use of these early anti-depressants as first-line treatment has reduced considerably (good practice guidelines recommend that their use is limited to those who have failed to respond to other treatment), they remain part of the battery of treatment approaches for some mood disorders including anxiety. Some research has found that MAOIs are possibly more effective than tricyclic antidepressants in treating anxiety disorders, especially when phobic anxiety is a feature or where there are other unusual depression or anxiety features; such as heaviness in the arms and legs, being highly sensitive to rejection, and mood reactivity. 

MAOIs used in anxiety

Phenelzine (Nardil)

This has been purported to be useful in treating a range of anxiety disorders, including obsessive compulsive disorder, social anxiety, generalized anxiety disorder and PTSD. One study found that phenelzine reduced panic attack symptoms in as many as three quarters of the patients trialed, and other research promotes its use in social anxiety and phobia.

Side effects include significant weight gain and blood pressure dropping when standing (postural hypotension) as well as edema (swelling around the ankles), headaches, dyskinesic features such as tremors/shaking, fatigue/sleepiness or insomnia, constipation, dryness in the mouth, appetite loss, heart beat irregularities and reduced libido and sexual dysfunction.

Tranylcypromine (Parnate)

This medication has been argued to be useful in treating a range of anxiety disorders, including obsessive compulsive disorder, social anxiety, generalized anxiety disorder and PTSD. It is reported to cause less sedation (which is a common problem with older-style antidepressants) and considerably less issues around weight gain.

Side effects include insomnia, low blood pressure on standing, ankle swelling/edema and sexual dysfunction.

In summary, they are an unusual choice of medication and are usually reserved for those deemed treatment-resistant to the other first-line medication approaches. There are anecdotal reports of their success and research suggests they may be of benefit, although a recent meta-analysis indicated that the small number of trials supporting their efficacy provided “low quality evidence” in research terms. Given this and their tolerability and sometimes serious side effects, it is understandable they are typically avoided. However, for those who endure the stress of anxiety, where nothing else provides relief, they are clearly a last resort.

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