Monoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of drug that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A and monoamine oxidase B. MAOIs are effective antidepressants due to their specialized function of the inhibition of the enzyme that is responsible for neurotransmitter degradation in the synaptic cleft. This is especially true for treatment-resistant depression, which is a type of depression that is resistant to common treatments of typical depression, such as selective-serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors.
MAOIs are also utilized to treat panic disorder, social anxiety disorder, Parkinson's disease, and several other disorders.
Reversible inhibitors of monoamine oxidase A are a subclass of MAOIs that selectively and reversibly inhibit the MAO-A enzyme. RIMAs are used clinically in the treatment of depression and dysthymia. Due to their reversibility, they are safer in single-drug overdose than the older, irreversible MAOIs, and weaker in increasing the monoamines important in depressive disorder. RIMAs have not gained widespread market share in the United States.
Medical uses
MAOIs have been found to be effective in the treatment of panic disorder with agoraphobia, social phobia, atypical depression or mixed anxiety disorder and depression, bulimia, and post-traumatic stress disorder, as well as borderline personality disorder, and obsessive–compulsive disorder. MAOIs appear to be particularly effective in the management of bipolar depression according to a retrospective-analysis from 2009. There are reports of MAOI efficacy in OCD, trichotillomania, body dysmorphic disorder, and avoidant personality disorder, but these reports are from uncontrolled case reports.MAOIs can also be used in the treatment of Parkinson's disease by targeting MAO-B in particular, as well as providing an alternative for migraine prophylaxis. Inhibition of both MAO-A and MAO-B is used in the treatment of clinical depression and anxiety.
MAOIs appear to be particularly indicated for outpatients with dysthymia complicated by panic disorder or hysteroid dysphoria.
Newer MAOIs such as selegiline and the reversible MAOI moclobemide provide a safer alternative and are now sometimes used as first-line therapy.
Pargyline is a non-selective MAOI that was previously used as an antihypertensive agent to treat hypertension.
Side effects
Hypertensive crisis
People taking MAOIs generally need to change their diets to limit or avoid foods and beverages containing tyramine. If large amounts of tyramine are consumed, they may develop a hypertensive crisis, which can be fatal. Examples of foods and beverages with potentially high levels of tyramine include cheese, Chianti wine, and pickled fish. Excessive concentrations of tyramine in blood plasma can lead to hypertensive crisis by increasing the release of norepinephrine, which causes blood vessels to constrict by activating alpha-1 adrenergic receptors. Ordinarily, MAO-A would destroy the excess NE; when MAO-A is inhibited, however, NE levels get too high, leading to dangerous increases in blood pressure.RIMAs are displaced from MAO-A in the presence of tyramine, rather than inhibiting its breakdown in the liver as general MAOIs do. Additionally, MAO-B remains free and continues to metabolize tyramine in the stomach, although this is less significant than the liver action. Thus, RIMAs are unlikely to elicit tyramine-mediated hypertensive crisis; moreover, dietary modifications are not usually necessary when taking a reversible inhibitor of MAO-A or low doses of selective MAO-B inhibitors.
Drug interactions
The most significant risk associated with the use of MAOIs is the potential for drug interactions with over-the-counter, prescription, or illegally obtained medications, and some dietary supplements. It is vital that a doctor supervise such combinations to avoid adverse reactions. For this reason, many users carry an MAOI-card, which lets emergency medical personnel know what drugs to avoid.Tryptophan supplements can be consumed with MAOIs, but can result in transient serotonin syndrome.
MAOIs should not be combined with other psychoactive substances except under expert care. Certain combinations can cause lethal reactions; common examples include SSRIs, tricyclics, MDMA, meperidine, tramadol, and dextromethorphan, whereas combinations with certain psychedelics like LSD or psilocybin appear to be relatively safe. On the other hand, MAOIs can strongly potentiate psychedelics metabolized by MAO like dimethyltryptamine, 5-MeO-DMT, and 2C-B, potentially resulting in serious toxicity or death. Findings for mescaline are less clear. Drugs that affect the release or reuptake of epinephrine, norepinephrine, serotonin or dopamine typically need to be administered at lower doses due to the resulting potentiated and prolonged effect. MAOIs also interact with tobacco-containing products and may potentiate the effects of certain compounds in tobacco. This may be reflected in the difficulty of smoking cessation, as tobacco contains naturally occurring MAOI compounds in addition to the nicotine.
While safer than general MAOIs, still possess significant and potentially serious drug interactions with many common drugs; in particular, they can cause serotonin syndrome or hypertensive crisis when combined with almost any antidepressant or stimulant, common migraine medications, certain herbs, or most cold medicines.
Ocular alpha-2 agonists such as brimonidine and apraclonidine are glaucoma medications which reduce intraocular pressure by decreasing aqueous production. These alpha-2 agonists should not be given with oral MAOIs due to the risk of hypertensive crisis.
Withdrawal
including MAOIs have some dependence-producing effects, the most notable one being a discontinuation syndrome, which may be severe especially if MAOIs are discontinued abruptly or too rapidly. The dependence-producing potential of MAOIs or antidepressants in general is not as significant as benzodiazepines. Discontinuation symptoms can be managed by tapering, a gradual reduction in dosage over a period of days, weeks or sometimes months to minimize or prevent withdrawal symptoms.MAOIs, as with most antidepressant medication, may not alter the course of the disorder in a significant, permanent way, so it is possible that discontinuation can return the patient to the pre-treatment state. This consideration complicates prescribing between an MAOI and an SSRI, because it is necessary to clear the system completely of one drug before starting another. One physician organization recommends the dose to be tapered down over a minimum of four weeks, followed by a two-week washout period. The result is that a depressed patient will have to bear the depression without chemical help during the drug-free interval. This may be preferable to risking the effects of an interaction between the two drugs.
Mechanism of action
MAOIs act by inhibiting the activity of monoamine oxidase. Monoamine oxidase is an enzyme that is responsible for the degradation of monoamine neurotransmitters, such as dopamine, serotonin, and norepinephrine, and prevents these neurotransmitters from remaining in the synaptic cleft for extended periods of time. Monoamine Oxidase Inhibitors are responsible for inhibiting monoamine oxidase, ultimately leading to prevention of the degradation of neurotransmitters in the synaptic cleft, leading to higher concentrations of neurotransmitters remaining in the synaptic cleft for longer periods of time.There are two isoforms of monoamine oxidase, MAO-A and MAO-B. MAO-A preferentially deaminates serotonin, melatonin, epinephrine, and norepinephrine. MAO-B preferentially deaminates phenethylamine and certain other trace amines; in contrast, MAO-A preferentially deaminates other trace amines, like tyramine, whereas dopamine is equally deaminated by both types.
Reversibility
The early MAOIs covalently bound to the monoamine oxidase enzymes, thus inhibiting them irreversibly; the bound enzyme could not function and thus enzyme activity was blocked until the cell made new enzymes. The enzymes turn over approximately every two weeks. A few newer MAOIs, a notable one being moclobemide, are reversible, meaning that they are able to detach from the enzyme to facilitate usual catabolism of the substrate. The level of inhibition in this way is governed by the concentrations of the substrate and the MAOI.Harmaline found in Peganum harmala, Banisteriopsis caapi, and Passiflora incarnata is a reversible inhibitor of monoamine oxidase A.
Selectivity
In addition to reversibility, MAOIs differ by their selectivity of the MAO enzyme subtype. Some MAOIs inhibit both MAO-A and MAO-B equally, other MAOIs have been developed to target one over the other.MAO-A inhibition reduces the breakdown of primarily serotonin, norepinephrine, and dopamine; selective inhibition of MAO-A allows for tyramine to be metabolised via MAO-B. Agents that act on serotonin, if taken with another serotonin-enhancing agent, may result in a potentially fatal interaction called serotonin syndrome; if taken with irreversible and unselective inhibitors a hypertensive crisis may result due to tyramine food interactions. Tyramine is broken down by MAO-A and MAO-B, therefore inhibiting this action may result in its excessive build-up, so diet must be monitored for tyramine intake.
MAO-B inhibition reduces the breakdown mainly of dopamine and phenethylamine, so there are no associated dietary restrictions. MAO-B would also metabolize tyramine, as the only differences between dopamine, phenethylamine, and tyramine are two phenylhydroxyl groups on carbons 3 and 4. The 4-OH would not be a steric hindrance to MAO-B on tyramine. Selegiline is selective for MAO-B at low doses, but non-selective at higher doses.