Monoamine oxidase inhibitor

Monoamine oxidase

Monoamine oxidase inhibitors (MAOIs) are chemicals that inhibit the activity of the monoamine oxidase enzyme family. They have a long history of use as medications prescribed for the treatment of depression. They are particularly effective in treating atypical depression.^[1] They are also used in the treatment of Parkinson's disease and several other disorders.

Because of potentially lethal dietary and drug interactions, monoamine oxidase inhibitors have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs (for example selective serotonin reuptake inhibitors and tricyclic antidepressants) have failed.^[2] New research into MAOIs indicates that much of the concern over their dangerous dietary side effects stems from misconceptions and misinformation, and that despite the proven effectiveness of this class of drugs, it is underutilized and misunderstood in the medical profession.^[3] New research also questions the validity of the perceived severity of dietary reactions, which has historically been based on outdated research.^[4] However, this research also notes that many practitioners have a poor understanding of drug interactions, and "drug interactions can be serious, and concomitant medication use must be stringently overseen" as they "can cause a dangerous or fatal serotonin syndrome/toxicity".^[3]

Indications

Newer MAOIs such as selegiline (typically used in the treatment of Parkinson's disease) and the reversible MAOI moclobemide provide a safer alternative^[5] and are now sometimes used as first-line therapy.

MAOIs have been found to be effective in the treatment of panic disorder with agoraphobia,^[6] social phobia,^[7][8][9] atypical depression^[10][11] or mixed anxiety disorder and depression, bulimia,^{[12][13][14][15]} and post-traumatic stress disorder,^[16] as well as borderline personality disorder.^[17] MAOIs appear to be particularly effective in the management of bipolar depression according to a recent retrospective-analysis.^[18] There are reports of MAOI efficacy in obsessive-compulsive disorder (OCD), trichotillomania, dysmorphophobia, and avoidant personality disorder, but these reports are from uncontrolled case reports.^[5]

MAOIs can also be used in the treatment of Parkinson's disease by targeting MAO-B in particular (therefore affecting dopaminergic neurons), 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, which involves repeated episodes of depressed mood in response to feeling rejected.^[19]

Mechanism of action

MAOIs act by inhibiting the activity of monoamine oxidase, thus preventing the breakdown of monoamine neurotransmitters and thereby increasing their availability. 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.^[20]

Harmaline found in Peganum harmala, Banisteriopsis caapi, and Passiflora incarnata is a reversible inhibitor of monoamine oxidase A (RIMA).^[21]

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.^[22] Agents that act on serotonin if taken with another serotonin-enhancing agent may result in a potentially fatal interaction called serotonin syndrome or with irreversible and unselective inhibitors (such as older MAOIs), of MAO a hypertensive crisis as a result of tyramine food interactions is particularly problematic with older MAOIs. 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 dietary restrictions associated with this. 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.^[23] Two MAO-Bi drugs, selegiline and rasagiline have been approved by the FDA without dietary restrictions, except in high-dosage treatment, wherein they lose their selectivity.^[24][25]

Dangers

Hypertensive crisis & tyramine

Patients 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 suffer hypertensive crisis, which can be fatal.^[3] Examples of foods and beverages with potentially high levels of tyramine include liver and fermented substances, such as alcoholic beverages and aged cheeses.^[26] (See a List of foods containing tyramine).

Tyramine leads to hypertensive crisis by increasing the release of norepinephrine (NE), which causes blood vessels to constrict (through binding to alpha-1 adrenergic receptors).^[27] Ordinarily, MAO-A would destroy the excess NE. When MAO-A is inhibited, though, NE levels get too high, leading to dangerous increases in blood pressure.

Of note, no dietary modifications are needed when taking a reversible inhibitor of MAO-A (i.e., moclobemide) or low doses of selective MAO-B inhibitors (e.g., selegiline 6 mg/24 hours transdermal patch).^[27][28][29]

Drug interactions

The most significant risk associated with the use of MAOIs is the potential for interactions with over-the-counter and prescription medicines, illicit drugs or medications, and some dietary supplements (e.g., St. John's wort, tryptophan). 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. (E.g., adrenaline dosage should be reduced by 75%, and duration is extended.)^[26]

Tryptophan supplements should not be consumed with MAOIs as the potentially fatal serotonin syndrome may result.^[30]

MAOIs should not be combined with other psychoactive substances (antidepressants, painkillers, stimulants, both legal and illegal etc.) except under expert care. Certain combinations can cause lethal reactions, common examples including SSRIs, tricyclics, MDMA, meperidine,^[31] tramadol, and dextromethorphan.^[32] Agents with actions on epinephrine, norepinephrine, or dopamine must be administered at much lower doses due to potentiation and prolonged effect.

Nicotine, the substance most implicated in tobacco addiction, has been shown to have "relatively weak" addictive properties when administered alone.^[33] The addictive potential increases dramatically after co-administration of an MAOI, which specifically causes sensitization of the locomotor response in rats, a measure of addictive potential.^[34][35] This may be reflected in the difficulty of smoking cessation, as tobacco contains naturally occurring MAOI compounds in addition to the nicotine.^[36][37][38]

Withdrawal

Antidepressants including MAOIs have some dependence-producing effects, the most notable one being a withdrawal syndrome, which may be severe especially if MAOIs are discontinued abruptly or overly rapidly. However, the dependence-producing potential of MAOIs or antidepressants in general is not as significant as benzodiazepines. Withdrawal symptoms can be managed by a gradual reduction in dosage over a period of weeks, months or years to minimize or prevent withdrawal symptoms.^[39]

MAOIs, as with any antidepressant medications, do not alter the course of the disorder, so it is possible that discontinuation can return the patient to the pre-treatment state.^[40]

This consideration greatly complicates switching a patient between a MAOI and a SSRI, because it is necessary to clear the system completely of one drug before starting another. If one also tapers dosage gradually, the result is that for weeks 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, but it is often not easy for the patient.

Listing of interactions

The MAOIs are infamous for their numerous drug interactions, including the following kinds of substances:

• Substances that are metabolized by monoamine oxidase, as they can be boosted by up to several-fold.
• Substances that increase serotonin, norepinephrine, or dopamine activity, as too much of any of these neurochemicals can result in severe acute consequences, including serotonin syndrome, hypertensive crisis, and psychosis, respectively.

Such substances that can react with MAOIs include:

• Phenethylamines: 2C-B, mescaline, phenethylamine (PEA), etc.
  • Amphetamines: amphetamine,^[41] MDMA, dextroamphetamine, methamphetamine, DOM, etc.
• Tryptamines: DMT, psilocin/psilocybin ("Magic Mushrooms"), etc.
  • Lysergamides: ergolines/LSA, LSD ("Acid"), etc.
• Norepinephrine, and/or dopamine reuptake inhibitors:
  • Serotonin-norepinephrine reuptake inhibitors (SNRIs): desvenlafaxine, duloxetine, milnacipran, venlafaxine.
  • Norepinephrine-dopamine reuptake inhibitors (NDRIs): amineptine, bupropion, methylphenidate, nomifensine.
  • Norepinephrine reuptake inhibitors (NRIs): atomoxetine, mazindol, reboxetine.
  • Tricyclic antidepressants (TCAs): amitriptyline, butriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine, lofepramine, nortriptyline, protriptyline, trimipramine.
  • Tetracyclic antidepressants (TeCAs): amoxapine, maprotiline.
  • Phenylpiperidine derivative opioids: meperidine/pethidine, tramadol, methadone, fentanyl, dextropropoxyphene, propoxyphene.
  • Others: brompheniramine, chlorpheniramine, cocaine, cyclobenzaprine, dextromethorphan (DXM), ketamine, MDPV, nefazodone, phencyclidine (PCP), pheniramine, sibutramine, trazodone
• Serotonin, norepinephrine, and/or dopamine releasers: 4-methylaminorex (4-MAR), amphetamine, benzphetamine, cathine, cathinone, diethylcathinone, ephedrine, levmetamfetamine, lisdexamfetamine, MDMA ("Ecstasy"), methamphetamine, pemoline, phendimetrazine, phenethylamine (PEA), phentermine, propylhexedrine, pseudoephedrine, phenylephrine, tyramine.
• Local and general anesthetic in surgery and dentistry, in particular those containing epinephrine. There is no universally taught or accepted practice regarding dentistry and use of MAOIs such as phenelzine, and therefore it is vital to inform all clinicians, especially dentists, of the potential effect of MAOIs and local anesthesia. In preparation for dental work, withdrawal from phenelzine is specifically advised, however since this takes two weeks it is not always a desirable or practical option. Dentists using local anesthesia are advised to use a non-epinephrine anesthetic such as mepivacaine at a level of 3%. Specific attention should be paid to blood pressure during the procedure, and the level of the anesthetic should be regularly and appropriately topped-up, for non-epinephrine anesthetics take longer to come into effect and wear off faster. Patients taking phenelzine are advised to notify their psychiatrist prior to any dental treatment.
• Certain other supplements: Hypericum perforatum ("St John's wort"), inositol, Rhodiola rosea, S-adenosyl-L-methionine (SAMe), L-theanine.
• Antibiotics such as Linezolid^[42]
• Other monoamine oxidase inhibitors.

History

MAOIs started off due to the serendipitous discovery that iproniazid was a potent MAO inhibitor (MAOI).^[43] Originally intended for the treatment of tuberculosis, in 1952, iproniazid's antidepressant properties were discovered when researchers noted that the depressed patients given iproniazid experienced a relief of their depression. Subsequent in vitro work led to the discovery that it inhibited MAO and eventually to the monoamine theory of depression. MAOIs became widely used as antidepressants in the early 1950s. The discovery of the 2 isoenzymes of MAO has led to the development of selective MAOIs that may have a more favorable side-effect profile.^[44]

The older MAOIs' heyday was mostly between the years 1957 and 1970.^[22] The initial popularity of the 'classic' non-selective irreversible MAO inhibitors began to wane due to their serious interactions with sympathomimetic drugs and tyramine-containing foods that could lead to dangerous hypertensive emergencies. As a result, the use by medical practitioners of these older MAOIs declined. When scientists discovered that there are two different MAO enzymes (MAO-A and MAO-B), they developed selective compounds for MAO-B, (for example, selegiline, which is used for Parkinson's disease), to reduce the side-effects and serious interactions. Further improvement occurred with the development of compounds (moclobemide and toloxatone) that not only are selective but cause reversible MAO-A inhibition and a reduction in dietary and drug interactions.^[45][46] Moclobemide, was the first reversible inhibitor of MAO-A to enter widespread clinical practice.^[47]

A transdermal patch form of the MAOI selegiline, called Emsam, was approved for use in depression by the Food and Drug Administration in the United States on February 28, 2006.^[24]

List of MAO inhibiting drugs

Marketed drugs

• Nonselective MAO-A/MAO-B inhibitors
  • Hydrazines
    • Isocarboxazid (Marplan)
    • Nialamide (Niamid)
    • Phenelzine (Nardil, Nardelzine)
    • Hydracarbazine
  • Non-hydrazines
    • Tranylcypromine (Parnate, Jatrosom)
• Selective MAO-A inhibitors
  • Bifemelane (Alnert, Celeport) (available in Japan)
  • Moclobemide (Aurorix, Manerix)
  • Pirlindole (Pirazidol) (available in Russia)
  • Toloxatone (Humoryl) (available in France)
• Selective MAO-B inhibitors
  • Rasagiline (Azilect)
  • Selegiline (Deprenyl, Eldepryl, Emsam, Zelapar)

Linezolid is an antibiotic drug with weak MAO-inhibiting activity.^[48]

Methylene blue, the antidote indicated for drug-induced methemoglobinemia, among a plethora of other off-label uses, is a highly potent, reversible MAO inhibitor.^[49]

Drugs withdrawn from the market

• Nonselective MAO-A/MAO-B inhibitors
  • Hydrazines
    • Benmoxin (Nerusil, Neuralex)
    • Iproclozide (Sursum)
    • Iproniazid (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida) (discontinued worldwide except for France)
    • Mebanazine (Actomol)
    • Octamoxin (Ximaol, Nimaol)
    • Pheniprazine (Catron)
    • Phenoxypropazine (Drazine)
    • Pivalylbenzhydrazine (Tersavid)
    • Safrazine (Safra) (discontinued worldwide except for Japan)
  • Non-hydrazines
    • Caroxazone (Surodil, Timostenil)
• Selective MAO-A inhibitors
  • Minaprine (Cantor)

See also

• Reversible inhibitor of MAO-A (RIMA)
• Hydrazine (antidepressant)
• MAO, MAO-A, MAO-B

References