Monoamine oxidase inhibitors

Monoamine oxidase inhibitors (MAOIs) or inhibitors (MAOIs) are psychotropic drugs that are used against depression ( antidepressants ). They develop their effect by blocking the monoamine oxidases (MAO) . The task of these enzymes is to break down monoamines such as serotonin , noradrenaline and dopamine and thus reduce their availability for signal transmission in the brain. The MAOIs inhibit these breakdown enzymes, which increases the concentration of monoamines.

The MAO inhibitor iproniazid was the first antidepressant to be marketed . However, the first available MAOIs required a low-tyramine diet and had adverse drug effects . As a result, the use of MAO inhibitors fell sharply overall, although moclobemide, a well-tolerated MAO inhibitor with few side effects, came onto the market since the mid-1990s .

Classification of MAO inhibitors

The monoamine oxidase occurs naturally in two different variants, type A (MAO-A) and type B (MAO-B). MAOIs are accordingly divided into two aspects: selectivity for one type of enzyme (selective or nonselective) and reversibility (reversible or irreversible).

Reversibility means that the drug binds only weakly to one or both MAOs and releases them again intact at the latest when the drug breaks down. Irreversible MAO inhibitors, on the other hand, permanently bind the monoamine oxodase enzymes. In order to neutralize the effect, the affected enzyme must first be regenerated by the body, which can take a few weeks.

Selective inhibitors of MAO-A (e.g. moclobemide , reversible) only inhibit type A of monoamine oxidase. They show an antidepressant effect and are generally well tolerated. Selectively MAO-B-inhibiting agents (e.g. selegiline , rasagiline , both irreversible) are primarily used in Parkinson's treatment.

Non-selective MAOIs (e.g. tranylcypromine , irreversible) inhibit MAO-A and MAO-B equally and are highly effective in the treatment of depression and anxiety disorders.

drug

Medicines that block MAO-A and MAO-B inhibit the breakdown of serotonin, norepinephrine and dopamine to the same extent. These non-selective MAOIs include:

• Tranylcypromine (irreversible)
• Iproniazid (irreversible, product has since been withdrawn from the German market)
• Isocarboxazid (irreversible, product has since been withdrawn from the German market)
• Phenelzine (irreversible, product has since been withdrawn from the German market)
• Nialamid (irreversible, product has since been withdrawn from the German market)

Drugs that block almost only the MAO-A selectively inhibit the breakdown of serotonin, noradrenaline and, to a lesser extent, dopamine (according to the strength of their effect). They do not require any diet measures.

• Moclobemide (reversible)
• Toloxaton (irreversible, not yet launched on the German market and not available)

Drugs that selectively block the MAO-B especially inhibit the breakdown of dopamine. They are therefore used in Parkinson's therapy , usually in combination with L-Dopa . In combination with an MAO-A inhibitor, they increase its noradrenergic effect. Representatives of this type are:

• Selegiline (irreversible, no strict diet normally required up to medium dose)
• Rasagiline (irreversible, no diet required)
• Lazabemid (reversible, not yet launched on the market)
• Safinamide (reversible, no diet required, but not approved for monotherapy)

Natural substances

A reversible, unselective MAO inhibitor of natural origin is harmalin (see below ).

Mode of action

The monoamine oxidase enzymes break down hormones (such as adrenaline ) and neurotransmitters (such as noradrenaline , dopamine, and serotonin ). By inhibiting one or both MAO enzyme types, these monoamines accumulate in the body, which is pharmacologically important, particularly at the synapses . This means that more neurotransmitters are available for signal transmission, which usually has an antidepressant effect.

However, the MAO also break down other substances in the human body, so that the use of irreversible and at the same time non-selective MAO inhibitors requires special precautionary measures (see below ).

application areas

Psychiatry and neurology

MAOIs (especially MAO-A inhibitors) are mainly used for severe and atypical depression, especially when other antidepressants fail. The newer reversible, selective MAO-A inhibitor moclobemide, for example, does not require a low-tyramine diet and has only minor side effects. In studies, moclobemide was similarly effective as selective serotonin reuptake inhibitors ( SSRIs ). It is therefore also suitable as an antidepressant of first choice because of its often immediate antidepressant effect. Reversible selective MAO-A inhibitors such as moclobemide seem to be considered far too rarely as a therapy, apparently due to the misjudgment that their side effects and risk potential correspond to those of irreversible, non-selective MAOIs.

It is known from clinical practice that MAOIs can also be used successfully to treat anxiety disorders (especially social phobia, panic disorders ) and obsessive-compulsive disorder . Larger studies on this are still pending.

For the treatment of post-traumatic stress disorders are MAO inhibitors for a meta-analysis of van Etten & Taylor (1998, cit. N. Ehlers, 1999, pp 74-77) no more effective than placebos or waiting for therapy ( Cohen d = 0, 61). Some meta-analyzed studies may underestimate the effect because the study period was too short. However, selective serotonin reuptake inhibitors ( SSRIs ) are preferred for treatment (d = 1.38).

However, in many cases SSRIs work worse than MAOIs. Ehler's psychotherapeutic treatment approach even surpasses this (d = 2.6 to 2.8). In the case of obsessive-compulsive disorder or anxiety disorders , MAO inhibitors can be very effective and represent a potent treatment alternative. Phenelzine seems particularly suitable for comorbid anxieties and panic attacks .

Selective MAO-B inhibitors (active ingredient: selegiline or rasagiline) are approved for the treatment of Parkinson's disease . They prevent the breakdown of endogenous or exogenously supplied dopamine.

Targeted non-medical use

Reversible MAOIs are also used to increase or modify the effect of psychoactive drugs or to enable an oral effect in the first place. A MAO inhibitor of natural origin that is used for this purpose is harmaline , which is found in the steppe rue ( Peganum harmala ) or the liana Banisteriopsis caapi . The combination with psychedelic tryptamines is known. The combination with dimethyltryptamine (DMT) as South American ayahuasca (yagé) is traditionally taken in the Amazon regions by indigenous peoples for religious and shamanic healing purposes. In addition, western drug tourism has developed with regard to Yagé. Native (European) plants that contain DMT are, for example, the reed (Phragmites australis) and the pile reed (Arundo donax).

Orally some tryptamines like DMT without additional intake of reversible MAO inhibitors are not effective. The effects of medical or reversible MAO inhibitors (MAOIs) with other drugs are unpredictable and can potentially be dangerous.

The harmaline has only a psychotropic effect, but it is not one of the "classical" hallucinogens (such as LSD). In higher doses, its effect is accompanied by certain unpleasant side effects (e.g. vomiting).

unwanted effects

MAOIs increase the risk of hypertensive crises , hypotension and malignant hyperthermia .

Interactions

Combinations of MAO inhibitors with certain drugs such as dextromethorphan (DXM) or drugs such as ethanol , ecstasy , opiates or opioids , mescaline or amphetamine derivatives as well as combinations with antidepressants of other types can cause life-threatening disorders of body functions. It can u. a. lead to an excess of serotonin , which can lead to life-threatening serotonin syndrome .

For this reason, when switching between an irreversible, non-selective MAOI and other types of antidepressant, there is usually at least a two-week safety interval during which the previously administered medication is broken down by the body. Nevertheless, in rare cases, MAO inhibitors are combined with other antidepressants or stimulants in a controlled manner in psychiatric treatment for augmentation .

During treatment with MAOI there is an absolute contraindication for the administration or ingestion of pethidine , tramadol and indirect sympathomimetics.

Diet guidelines

Effect of a TAAR1- ( English trace amine-associated receptor 1 ) agonists to a Neuron

Since MAO -A and -B also use other monoamines such as B. break down tyramine , nonselective MAO inhibitors can trigger dangerous high blood pressure after ingestion of foods with more than 8-10 mg tyramine ( English "cheese effect" ). Tyramine acts as a noradrenaline releaser through a potent TAAR1 receptor agonism ; Norepinephrine, in turn, can raise blood pressure to a critical level. Even foods with very high amounts of tyrosine carry this risk, as tyrosine is metabolized into tyramine in the body.

For this reason, dietary guidelines must be adhered to when using irreversible, unselective MAO inhibitors such as tranylcypromine , since tyramine-rich foods contain up to 40 mg of tyramine. Stahl and Felker in "Monoamine Oxidase Inhibitors: A Modern Guide to an Unrequited Class of Antidepressants" offer an overview of the effects of MAO inhibitors, new products such as transdermal selegiline patches and their connection to diet guidelines. A modern, less restrictive MAOI diet is described in Gardner, Shulman, Walker and Tailor “The making of a user friendly MAOI diet”.

Food (selection) which shows questionable interactions in combination with MAO-inhibitors. If a rule allows exceptions, they are listed on the same line:

• Aged cheese (tyramine), but not cream cheese . Parmesan and pecorino only in very small quantities.
• Yeast extracts (tyramine), but not baker's yeast
• Products matured through (air) drying, aging, smoking or fermentation such as fish or meat (tyramine), but not freshly prepared meat or fish.
• Field beans ( levodopa , synergistic effect with MAOIs), kefruit pods , but not lentils or peas in general.
• Many types of wine (tyramine), especially robust red wines like Chianti .
• Unpasteurized beers
• Sauerkraut (tyramine).
• Tofu , soybeans or products made from them, but not soy or teriyaki sauce up to a quarter of a glass a day.
• Chocolate or other products containing cocoa must be limited to smaller quantities.
• Tea and coffee ( caffeine , synergistic effect with MAO inhibitors) must be limited to smaller quantities.
• Highly concentrated extracts, oils or similar must not be consumed without prior information, as the concentration process can enrich otherwise harmless foods to critical amounts of tyramine, tyrosine, phenylethylamine or levodopa.

literature

• Anke Ehlers: Post-Traumatic Stress Disorder , Hogrefe, Göttingen 1999, ISBN 3-8017-0797-0 (Advances in Psychotherapy; Vol. 8)
• Michael Freissmuth, Stefan Offermanns: Pharmacology and Toxicology: From the Molecular Basics to Pharmacotherapy , Springer, 2012. ISBN 978-3-642-12353-5 .
• Klaus Aktories , Ulrich Förstermann, Franz Bernhard Hofmann, Klaus Starke: General and special pharmacology and toxicology: Founded by W. Forth, D. Henschler, W. Rummel . Elsevier, Urban & Fischer, 2013. ISBN 978-3-437-16888-8 .
• Bert Marco Schuldes: Psychoactive plants: more than 65 plants with stimulating, euphoric, calming, sexually arousing or hallucinogenic effects , Nachtschatten-Verlag, Solothurn 1994 ISBN 3-925817-64-6 (including detailed description of the MAO inhibitors including risks and Hazards)

Web links

Commons : Monoamine Oxidase Inhibitors  - Collection of Pictures, Videos and Audio Files

Individual evidence

1. ↑ M. Wimbiscus, O. Kostenko, D. Malone: MAO inhibitors: risks, benefits, and lore. In: Cleveland Clinic journal of medicine. Volume 77, Number 12, December 2010, pp. 859-882, doi: 10.3949 / ccjm.77a.09103 . PMID 21147941 .
2. ↑ N. Kaludercic, A. Carpi, R. Menabò, F. Di Lisa, N. Paolocci: Monoamine oxidases (MAO) in the pathogenesis of heart failure and ischemia / reperfusion injury. In: Biochimica et Biophysica Acta . Volume 1813, Number 7, July 2011, pp. 1323-1332, doi: 10.1016 / j.bbamcr.2010.09.010 . PMID 20869994 . PMC 3030628 (free full text).
3. ↑ Y Kitaichi, T Inoue, S Nakagawa, S Boku, T Izumi, T Koyama: Combined treatment with MAO-A inhibitor and MAO-B inhibitor increases extracellular noradrenaline levels more than MAO-A inhibitor alone through increases in beta-phenylethylamine . In: Eur J Pharmacol . 2010 Jul 10, 637 (1-3), pp. 77-82. doi: 10.1016 / j.ejphar.2010.04.014 . Epub 2010 Apr 18. PMID 20406628
4. ↑ AM Cesura, A Pletscher: The new generation of monoamine oxidase inhibitors . In: Prog Drug Res . 38, 1992, pp. 171-297. PMID 1609114 .
5. ^ PB Mitchell, MS Mitchell: The management of depression. Part 2. The place of the new antidepressants . In: Aust Fam Physician . 23, No. 9, September 1994, pp. 1771-1773, 1776-1781. PMID 7980178 .
6. ^ M Roth, JD Guelfi: The efficacy of reversible monoamine oxidase inhibitors in depressive illness . In: Can J Psychiatry . 37 Suppl 1, September 1992, pp. 18-24. PMID 1394027 .
7. ↑ Torsten Kratz, Albert Diefenbacher: Psychopharmacotherapy in old age. Avoidance of drug interactions and polypharmacy. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f. (July 22) 2019, pp. 508-517, p. 515 (cited).
8. ↑ M. Bischoff, BM Graf, A. Redel: Perioperative handling of concomitant medication. In: Anaesthesiology & Intensive Care Medicine. Volume 60, December 2019, pp. 560-571, here: pp. 566 f.
9. ↑ ^{a b} Stephen M. Stahl, Angela Felker: Monoamine oxidase inhibitors: a modern guide to an unrequited class of antidepressants . In: CNS spectrums . 13, No. 10, October 2008, pp. 855-870. PMID 18955941 .
10. ↑ DM Gardner, KI Shulman, SE Walker, SA Tailor: The making of a user friendly MAOI diet . In: The Journal of clinical psychiatry . 57, No. 3, March 1996, pp. 99-104. PMID 8617704 .
11. ↑ Low Tyramine Diet. Patient education. Northwestern Memorial Hospital, archived from the original on February 28, 2013 ; Retrieved February 18, 2014 . 
12. ↑ Drug interactions with food and beverages , Austrian Chamber of Pharmacists , accessed on June 10, 2015.

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