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Ronald A. Remick, MD, FRCPC Colleen Froese, MD Inhibitors: Clinical Review SUMMARY RESUME Monoamine oxidase inhibitors (MAGIs) are Les inhibiteurs de la monoamine-oxydase sont efficaces comme antidepresseurs. On les utilise de effective agents. They are plus en plus efficacement dans un certain nombre increasingly and effectively used in a d'autres syndromes medicaux tant psychiatriques number of other psychiatric and que non psychiatriques. Leur potentiel toxique (i.e. non-psychiatric medical syndromes. Their reaction hypertensive) semble moindre que ne le potential for serious toxicity (i.e., laissaient supposer les rapports originaux, et de nouveaux substrats specifiques aux IMAO semblent hypertensive reaction) is far less than presenter encore moins de toxicit. L'auteur revise la original reports suggest, and newer pharmacologie, le mecanisme d'action, les indications reversible substrate-specific MAOIs may offer cliniques et les strategies permettant des posologies even less toxicity. The author reviews the appropriees aux IMAO. On en decrit les effets pharmacology, mechanism of action, clinical secondaires les plus frequents (hypotension, gain strategies of ponderal, dysfonction sexuelle, insomnie, sedation indications, and dosing MAOIs. diurne, myoclonie et episodes hypertensifs) et on en The common MAOI side-effects propose le traitement approprie. On y decrit (hypotension, weight gain, sexual egalement les developpements cliniques recents dysfunction, insomnia, daytime sedation, entourant les IMAO. myoclonus, and hypertensive episodes) are described and management techniques suggested. Recent clinical developments involving MAOIs are outlined. (Can Fam Physician 1990; 36:1151-1155.) Key words: , family medicine, monoamine oxidase inhibitors, mood disorders, pharmacologic agents, psychiatry

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Dr. Remick is an Associate clinical interest in MAOIs because of a Efficacy Professor and Assistant Head, number of factors. Early studies, which suggested that Department of Psychiatry, 1. More critical reviews of earlier stu- MAOIs are less effective than University of British Columbia, and dies, coupled with recent research on antidepressants,' were not methodolog- is Director, Mood Disorders Service, MAOI efficacy, suggest that they are ef- Department of Psychiatry, fective antidepressants. ically sound and have been critiqued.' University Hospital, University of 2. Monoamine oxidase inhibitors could Recent trials with and iso- British Columbia Site, Vancouver. have a broader range ofactivity thanjust (Parnate), (Nardil), Dr. Froese is a Resident in depressive syndromes, which could carboxazid (Marplan) provide evidence Psychiatry, Department of then extend their use in the medical that these drugs are superior to placebo Psychiatry, University of British and equivalent or superior to Columbia, Vancouver. Requests for community. 3. There is a growing awareness that in depressed patients.-6 All recent stu- reprints to: Dr. R.A. Remick, dies indicate that MAOIs are effective in Assistant Head, Department of these drugs are less toxic than previous reports suggest. a variety of depressive states, although Psychiatry, University Hospital, depression with associated features of UBC Site, 2255 Wesbrook Mall, 4. Newer, more specific and perhaps Vancouver, B.C. V6T 2A1 less toxic MAOIS may further increase anxiety, somatization, and hypochon- their safety and spectrum of activity. driasis (the so-called atypical depres- -9 ONOAMINE OXIDASE inhibi- With these factors in mind, this clinical- sions) seem particularly responsive.37 IlVXtors have been marketed as anti- ly oriented review is intended to evalu- In addition to their use in major de- depressants for 30 years,' yet are used ate new developments and to reacquaint pression, MAOIs have been used suc- infrequently. There is now a renewed physicians with MAOIS. cessfully in a variety of other disorders,

CAN. FAM. PHYSICIAN Vol. 36: JUNE 1990 1151 including panic attacks, panic disorders whether this directly results in their an- cult to manage on MAOIS. Patients with and agoraphobia,8'0 obsessive-compul- tidepressant effect as originally hypoth- substance or alcohol abuse or who can- sive disorder," social phobia,'2 esized. not responsibly comply with dietary re- post-traumatic stress syndrome, buli- The antidepressant effects are known strictions should not receive MAOIS. Re- mia,' attention deficit disorders,'4 to be less likely to occur when peripher- cent work suggests that patients receiv- chronic pain syndrome,'5 narcolepsy, al monoamine oxidase inhibition is less ing should discontinue this Parkinson's disease, and migraine than 75%.2° Comments concerning how drug for five weeks before initiating headaches. 16 MAOIS work in depression (or other psy- MAOI treatment.23 chiatric syndromes) must be considered Pharmacology speculative. Recent theories postulate Dosing Brain monoamine oxidase is located that the accumulation of monoamine After deciding to use an MAOI, the pa- presynaptically and oxidatively deami- due to monoamine tient should be instructed to observe the nates a wide variety of monoamines, in- oxidase inhibition leads to either pre- or food, drink, and drug restrictions for at cluding the putative monoamine neuro- post-synaptic receptor changes that re- least 24 hours before starting the first transmitters (noradrenaline, , sult in their psychoactive effects.2' 22 dose and for two weeks after stopping ) and a variety of monoamines the last dose (Chart 1). Doses less than found in foodstuffs (, phenele- Clinical Use thylamine). 16 Before starting a patient on MAOI Chart 1 In the 1 950s, , a drug tested therapy, the following questions should Instructions for Patients Taking for its antituberculous activity, was be answered. Monoamine Oxidase Inhibitors found to have mood-elevating proper- 1. Does the patient have a disorder that Foods to avoid ties.'7 Later, it was discovered this ef- will respond to MAOI treatment? Evi- * Cheese (cottage cheese, ricotta, fect was from the MAOI properties ofthe dence suggests that patients with a ma- and cream cheese are permitted). Be- drug, and research into less toxic MAOIS jor depressive disorder, and especially ware of pizza, fondues, many Italian began. Currently available MAOIS in the depressive states associated with anxi- dishes, and salad dressings United States ety, panic attacks, or agoraphobia, will . Red wine and sherry and Canada are phenel- * Smoked or pickled fish (especially zine, tranylcypromine, and isocarboxa- respond to an MAOI. If the patient war- herring, lox, anchovies, and caviar) zid. Phenelzine and isocarboxazid are rants antidepressant therapy, consider * Dry sausage (pepperoni, salami, compounds; tranylcypro- MAOIS. They may be the treatment of bologna, summer sausage) mine is not. choice for patients who do not respond * Aged meats (chicken or beef pate, Two forms of brain monoamine oxi- to tricyclic agents or for patients who corned beef dase are now recognized, and they are are intolerant of tricyclic antidepres- * Fava or broad bean pods classified as type A or type B, according sants. Symptoms of atypical depres- * Yeast vitamin supplements (brew- to substrate specificity. Monoamine A sion, including anxiety, somatization, er's yeast) acts upon the following substrates: ser- hypersomnia, hyperphagia, and lethar- * Meat extracts (Bovril, marmite, soup otonin, epinephrine, , gy, may respond preferentially to cubes, and soups with meat extracts) In general, avoid all foods that may , octopamine, tyra- MAOIs. be slightly off, fermented, aged, mine, and dopamine. Monoamine B se- 2. Will the patient comply with diet and or leftovers. lects benzylamines, phenelethylamine, drug restrictions? The willingness of Do not use cold decongestants, N-methylhistamine, tyramine, and do- the patient to follow strict dietary con- hayfever, or sinus remedies (i.e., pamine. All currently marketed MAOIS trol (Chart 1) should be determined. Of- Dristan, Sudafed, Sinutab, Con- are non-selective with to A or B ten meal on other tac C, Coricidin "D," Neo-syneph- respect preparation depends rine nose drops, Novahistine) substrates, but newer MAOIS currently family members; any MAOI dietary dis- containing pseudoephedrine, under investigation are A- or B-specific. cussions must include the preparer of phenylephedrine, and phenylpro- Selective inhibi- family meals. Involvement by family panolamine. Be sure to tell your tors are superior antidepressants com- members will also improve the patient's physician, surgeon, and dentist pared with selective monoamine oxi- and you are taking this medication. drug dietary compliance. Other medications to avoid are dase B inhibitors.'8 3. Are there any potential advantages to antihypertensive agents (methyl- All clinically available MAOIs are ir- selecting an MAOI for some patients? dopa, guanethidine, reserpine), reversible in their binding to mono- Patients with cardiac problems, espe- narcotics (meperidine), sympa- amine oxidase. Enzyme resynthesis, cially conduction defects, which require thomimetics (dopamine, metara- which has been estimated to occur with caution with could be minol), anesthetic drugs, and in- tricyclic agents, sulin. Do not use diet pills (am- a half-life of 10 to 12 days in the brain, treated with MAOIS. Patients with hy- phetamines) or stimulants (me- accounts for the long duration of action pertension may benefit from the blood thylphenidate, cocaine, methyle- after discontinuation of the drug. Some pressure-lowering side-effect of the nedioxyamphetamine [MDA]). newer MAOIS do not form covalent MAOIS. Monoamine oxidase inhibitors Go to the nearest emergency medi- bonds (i.e., competitive inhibitors) with have fewer anticholinergic side-effects, cal facility if you experience a sudden throbbing headache as- the enzyme and may be reversible.'6"'9 such as urinary retention, making these sociated with high blood pres- drugs a consideration in geriatric de- sure, nausea, or vomiting. You Mechanism of Action pression. may wish to carry a wallet card While MAOIS exert their pharmaco- 4. Are there patients in whom MAOIS listing the necessary medical be avoided? Patients with precautions and wear a med- logic effect by inhibiting the deamina- should ic-alert bracelet. tion of biogenic amines, it is unknown pre-existing hypotension may be diffi- 1152 CAN. FAM. PHYSICIAN Vol. 36: JUNE 1990 45 mg ofphenelzine or 30 mg of tranyl- mechanism of this reaction is that tyra- Orthostatic Hypotension cypromine or isocarboxazid are rarely mine, a pressor amine found in certain Mechanism. Orthostatic hypotension effective. Physicians should avoid pre- foods, is not metabolized due to mono- is the most common MAOI side-effect. scribing inadequate doses because they amine oxidase inhibition. It then circu- The hypotension associated with MAOIS expose the patient to drug side-effects lates peripherally, where it can displace usually occurs three to four weeks after without providing any benefit. Mono- the increased stores of norepinephrine, treatment initiation and is thought to be amine oxidase inhibitors usually take a resulting in precipitous increases in related to the inhibition of the normal minimum of three weeks and often as blood pressure. Tyramine, which is breakdown oftyramine. This excess ty- long as six weeks to obtain significant found in fermented, decaying, and to side-effects be- ramine undergoes ,B-hydroxylation therapeutic benefit, but over-ripe foods, is particularly at form a "false ," which gin much earlier. fault. Other offending agents are starting regimen is phenel- is stored in nerve terminals. This trans- A suitable over-the-counter decongestants. When mitter has little adrenergic activity, re- zine, 15 mg (or tranylcypromine or iso- careful dietary and drug restrictions are the first morn- sulting in decreased sympathetic out- carboxazid, 10 mg), on followed, MAOIs are unlikely to cause flow.28 ing. This dose can be increased by one this type of reaction (Chart 1).26 tablet every 24 to 72 hours until the The hypertensive crisis is character- Management. It is essential to inform minimum therapeutic dose is reached. ized by the sudden onset of a severe the patient and to be aware of the possi- Divided morning and noon dose times throbbing headache. It is often asso- bility ofhypotension, as it is easy to for- are best tolerated by most patients. ciated with flushing, sweating, blurred get about a potential problem occurring Tranylcypromine, the non-hydra- vision, nausea, palpitations, chest pain, so late in treatment. Dizziness, weak- zine, is associated with more hyperten- and shortness ofbreath. Symptoms typ- ness, faintness, or light-headedness sive reactions, but less sexual dysfunc- ically occur within minutes of ingestion upon standing are typical symptoms. tion or urinary retention. The hydra- of the suspected foodstuff. Reassurance with instructions to rise zines, phenelzine and isocarboxazid, slowly from a lying or sitting position to produce fewer hypertensive crises, but Management. Treatment in the past has a standing position may be all that is re- slightly more postural hypotension, focused on ax-adrenergic blockade with quired. Mild symptoms frequently re- weight gain, sexual dysfunction, and such drugs as phentolamine and chlor- solve over time. urinary retention.24 promazine. These widely quoted rec- If the problem continues, contribut- Therapeutic dose ranges typically ommendations are not in keeping with ing factors, such as dieting, a low-salt are: the agents now used in managing hyper- diet, dehydration, diuretics, antihyper- tensive emergencies. Calcium channel * phenelzine, 45 to 90 mg/day; tensive drugs, and hypothyroidism, blockers, such as nifedipine, may be the should be corrected. The next proce- * tranylcypromine, 30 to 60 mg/day; treatment of choice in the management dure might be to alter the schedule of and of hypertensive patients treated with medications by prescribing a divided * isocarboxazid, 30 to 60 mg/day. MAOIS.27 Nifedipine has an onset of ac- dose or all medication at bedtime, or if The average course of treatment tion in less than five minutes, peaks in possible, lowering the dose slightly. would be approximately six months. 20 minutes, and lasts three to five hours. Elastic support stockings are effec- When the drug is discontinued, one After oral administration, the onset of tive, but limited in use because ofthe ex- should reduce the dose by a 10- or action is approximately 20 minutes, pense, inconvenience of having them 15-mg tablet every one to three weeks with peak effect in 45 minutes. The dos- fitted, and refusal by most male patients until it has been discontinued. Some pa- age is 10 to 20 mg, and the drug is readi- to wear them. Others suggest that drink- tients with frequent recurrent depres- ly available in most emergency rooms. ing tea or coffee throughout the day may sions have used the medication for long Side-effects, including hypotensive be helpful. When all of these measures periods with minimal side-effects. overshoot and reflex tachycardia, are are insufficient, volume expanders, unusual. such as salt tablets or fludrocortisone Side-Effects (Florinef), have proven helpful.29 The Chart 2 dose of salt tablets is 600 to 1800 mg One reason MAOIs have been un- Side-Effects of Monoamine Oxidase twice a day, or fludrocortisone in dos- derprescribed is because of physician Inhibitors ages less than 0.5 mg/day. The use of concern about drug side-effects. Seri- salt or mineralocorticoids is, of course, ous side-effects with MAOIs are ex- Most frequent side-effects contra-indicated in several concomitant tremely rare (Chart 2), and the com- Orthostatic hypotension with dizziness medical disorders. In an otherwise mon, non-life-threatening, "nuisance" Weight gain, edema healthy young depressive, this may re- side-effects can be either effectively Sexual dysfunction lieve the problem.28 managed or tolerated by patients with- Other side-effects out drug discontinuation. Insomnia Sexual Dysfunction Daytime sedation Mechanism. Sexual dysfunction, quite Hypertensive Reactions Myoclonus separate from the decreased libido asso- with can occur with Mechanism. Hypertensive reactions Uncommon but serious toxicities ciated depression, (the so-called cheese reaction) are the MAGIS. Orgasmic and ejaculatory ca- Hypertensive crises more often affected than most frequently mentioned side-effects Drug interactions with the MAOI-CNS pacity are due to the seriousness of the problem, syndrome arousal.30 Possible mechanisms by although they are uncommon.25 The which antidepressants affect sexual 1153 CAN. FAM.. PHYSICIAN Vol. 36: JUNE 1990 function include anticholinergic activ- much higher for bipolar patients (up to may alleviate the problem. For some ity, changes in adrenergic tone, or 60%).3' The onset ofhypomania occurs patients this side-effect fades over time. changes in CNS serotonin levels. anywhere from two to 28 weeks after Additional Side-Effects Management. The most important initiation of treatment. point in the management of sexual dys- Management. The initial treatment of Uncommonly reported adverse reac- function is to inquire about it. Patients hypomania is dose reduction. If this tions from MAOIS include skin rashes, may discontinue treatment due to sexual treatment is unsuccessful, the drug photosensitivity, leukopenia, lupus-like difficulties (perhaps without telling could be discontinued or added. syndrome, mouth sores, inappropriate their physician). Some patients will be antidiuretic syndrome, altered prolactin reassured if they understand what prob- Insomnia secretion, and hepatotoxicity. lems can be expected and that these Mechanism. Insomnia is commonly re- side-effects may fade over time. It is ported with MAOIS, especially ifmost of New Developments important to reassure patients that these the dose is given in the evening. Mono- MAOIs and Tricyclic Antidepressants changes are reversible. Some suggest amine oxidase inhibitors interfere with Recent studies and reviews indicate that tranylcypromine produces less and suppress rapid eye movement sleep. that combined treatments are safe and anorgasmia and impotence than phenel- Rapid eye movement rebound asso- effective in patients unresponsive to ei- zine.24.31 ciated with vivid dreams is observed ther class of drug alone and may be use- Other methods of treatment include about 10 days after withdrawal of ful for refractory depressions.38 Both bethanechol (Duvoid, Urecholine), a MAOIs. cholinergic drug, and cyproheptadine, a drugs should be started together or the serotonin antagonist. Starting with Management. Attempts should be MAOI gradually added to the tricyclic in doses of bethanechol, 10 mg t.i.d., and made to modify the dose schedule so low doses. Tricyclic antidepressants increasing by 30 mg every day to 100 that most ofthe drug is given in the early should not be added without a mg/day, may resolve the problem in a part of the day. Dose reductions, if fea- seven-day washout period if a patient is short time.32 Cyproheptadine in dos- sible, may alleviate the problem. Recent already receiving an MAOI. Interactions ages of4, 8, or 12 mg b.i.d. can produce reports suggest that the more sedative have caused hyperthermia, agitation, normal sexual responsiveness. Some antidepressant , prescribed in delerium, convulsions, and coma. It is patients have found that, instead of reg- low bedtime doses, can alleviate recommended that not be ulardoses, they need only to take the cy- MAOI-induced insomnia.35 the tricyclic used in this combination. proheptadine one to two hours before Further, this combination should be un- intercourse.33 Myoclonus, Paresthesias dertaken only with the supervision ordi- Mechanism. Monoamine oxidase rection of a skilled psychopharmacolo- Weight Gain and Peripheral Edema drugs produce neuromuscular effects gist. Mechanism. Weight gain is a common that range from muscle tension and MAOIs and Lithium and Other Drugs side-effect of many antidepressant twitches to myoclonicjerks. They more treatments, and it is unclear which commonly occur during rest, sleep on- Monoamine oxidase inhibitors have mechanisms are involved. It may be due set, and sleep. These effects occur after been safely combined with lithium, neu- to an increase in appetite, fluid reten- at least two weeks of treatment and ap- roleptics, and benzodiazepines. Me- tion, blockade, changes in pear to be dose related. Proposed mech- thylphenidate and amphetamine should glucose , or hypothalamic be avoided because they increase the anisms include an increased serotonerg- research in- dysfunction.34 ic tone and central disinhibition.36 One risk of hypertension. Some that dicates that the addition oflithium in pa- Management. Dietary considerations study suggests numbness, paresthe- who do not to MAOIS sias, and "electric shock" sensations are tients respond may to reduce carbohydrates and fat intake convert these patients to drug respond- with regular exercise should be encour- caused by pyridoxine deficiency.37 This ers.39 aged. Edema can be treated with diuret- condition usually develops over six to ics and careful monitoring of electro- eight weeks of treatment. Selective MAOIs lytes. In some cases, switching from Management. Myoclonicjerks may re- The selective irreversible MAOI-A phenelzine to tranylcypromine can help spond to a simple decrease in the dosage clorgyline (not available in Canada) is reduce weight gain, but often there is no ofMAOIS. Pyridoxine, in doses of 150 to an effective antidepressant,40although it suitable treatment. 300 mg/day, is inexpensive, is benign, offers no particular advantages over Hypomania and may be helpful for paresthesias and non-selective agents. The selective irre- "electric shock" sensations. versible MAOI-B deprenyl appears to Mechanism. Hypomania is often de- have benefit in conditions with dopa- scribed as a side-effect of tricyclic anti- Daytime Sedation mine deficits, such as Parkinson's dis- depressants and MAOIS, although it is ease.4' clear that the incidence of this reac- Mechanism. Fatigue and daytime MAOI-A not Al- The selective reversible tion is greater than what one would ex- drowsiness occur in some patients. compounds (meclobemide, brofaro- is un- pect from the natural history of the ill- though the exact mechanism mine) have antidepressant activity42 and ness. The overall incidence of hypo- known, speculation includes a hypogly- are in phase II and III trials in Canada mania in unipolar patients is approxi- cemic type of reaction. today. Their reversibility results in little mately 10% for patients treated with tri- Management. Modification of the dos- tyramine potentiation43 and little re- cyclic antidepressants and MAOIS, but is age schedule or reduction in the dose ported risk of hypertensive episodes. 1154 CAN. FAM. PHYSICIAN Vol. 36: JUNE 1990 This, in theory, could make them safer anorexia nervosa and bulimia: a prelimi- 29. Munjack DJ. The treatment of phenel- and easier to use. nary trial of isocarboxazid. J Clin Psycho- zine-induced hypotension with salt tablets: pharmacol 1985; 5:279-85. case report. J Clin Psychiatry 1984; 45(2):89-90. Conclusion 14. Zametkin A, Rapoport JL, Murphy DL, evidence that et al. Treatment of hyperactive children 30. Harrison WM, Rabkin JG, Ehrhardt There is substantial with monoamine oxidase inhibitors. Arch AA, et al. Effects of antidepressant medica- MAOIs are effective antidepressant Gen Psychiatry 1985; 42:962-77. tion on sexual function: a controlled study.J drugs. When proper dietary precautions Clin Psychopharmacol 1986; 6:144-9. are followed, the risk of hypertensive 15. Davidson J, Raft D. Monoamine oxi- drugs safer dase inhibitors in patients with chronic pain. 31. Rabkin J, Quitkin F, McGrath P, Harri- crises is low, making these Arch Gen Psychiatry 1985; 42:635-6. son W, Tricamo E. Adverse effects to mono- than previously thought. One is often amine oxidase inhibitors: part II: treatment able to manage other side-effects with a 16. McDaniel KD. Clinical pharmacology correlates and clinical management. J Clin variety of interventions. Monoamine ofmonoamine oxidase inhibitors. Clin Neu- Psychopharmacol 1985; 5:2-9. ropharmacol 1986; 9:207-34. oxidase inhibitors may be particularly 32. 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JClin Psychiatry MAOI hypertensive crisis with sublingual ni- fective Disord 1985; 8:29-35. 1983; 44:131-2. fedipine. J Clin Psychiatry 1987; 12. Liebowitz MR, FyerAJ, Gorman JM, et 48:249-50. 43. Kom A, Eichler HG, Fishbach R, et al. al. Phenelzine in social phobia. J Glin Psy- , a new reversible MAO inhibi- chopharmacol 1986; 6:93-8. 28. Cockhill L, Remick RA. Blood pres- tor-interaction with tyramine and tricyclic sure effects of monoamine oxidase inhibi- antidepressants in healthy volunteers and 13. Kennedy SH, Piran N, Gaffinkel PE. tors-the highs and lows. Can J Psychiatry depressive patients. Psychopharmacology Monoamine oxidase inhibitor therapy for 1987; 32:803-8. (Berlin) 1986; 88:153-7. CAN. FAM. PHYSICIAN Vol. 36: JUNE 1990 1155