CNS Spectr. 2008;13(10):855-870
Faculty Affiliations and Disclosures
Dr. Stahl is adjunct professor of psychiatry in the Department of Psychiatry at the University of California–San Diego in La Jolla. Ms. Felker is an associate medical writer at the Neuroscience Education Institute in Carlsbad.
Faculty Disclosures: Dr. Stahl receives grant/research support from AstraZeneca, Biovail, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Neurocrine Biosciences, Organon, Pfizer, Sepracor, Shire, Somaxon, and Wyeth; is a consultant to Acadia, Amylin, Asahi, AstraZeneca, Biolaunch, Biovail, Boehringer-Ingelheim, Bristol-Myers Squibb, Cephalon, CSC Pharma, Cyberonics, Cypress Bioscience, Eli Lilly, Epix, Fabre Kramer, Forest, GlaxoSmithKline, Jazz, Neurocrine Biosciences, NeuroMolecular, Neuronetics, Nova Del Pharma, Novartis, Organon, Otsuka, PamLab, Pfizer, Pierre Fabre, Sanofi-Synthelabo, Schering-Plough, Sepracor, Shire, Solvay, Somaxon, Takeda, Tetragenex, and Wyeth; and is on the speaker’s bureau of Pfizer. Ms. Felker does not have an affiliation with or financial interest in any organization that might pose a conflict of interest.
Disclaimer: As this is widely excerpted with all figures and tables from Stahl’s Essential Psychopharmacology textbook, and much of the text is adapted from chapter 12 of the textbook, the copyright for the work as a whole, the tables, figures and text, will continue to be held by Cambridge University Press, with permission to publish in CNS Spectrums without charge. Every effort has been made in preparing this material to provide accurate and up-to-date information that is in accord with accepted standards and practice at the time of publication. Nevertheless, the authors, editors and publisher can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors and publisher therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this article. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs that they plan to use.
If you would like to comment on this column or submit a suggestion to Dr. Stahl for future columns, please e-mail email@example.com.
New Trend in Psychopharmacology
Monoamine oxidase inhibitors (MAOIs) currently have a “bad rap” and are thus infrequently used in psychopharmacology, even by experienced clinicians. Misinformation about the dietary and drug interactions of MAOIs is widespread, whereas pragmatic tips for utilizing MAOIs to minimize risks and to maximize therapeutic actions are largely lacking in the contemporary literature. While clearly not first-line treatments, MAOIs, in the hands of experienced and well-informed clinicians, can be a powerful therapeutic intervention for patients with depression, panic disorder, and other anxiety disorders who have failed first-line treatments.
This article focuses on the pharmacologic mechanisms of MAOIs, since an understanding of these mechanisms may provide a rationale to empower experts to expand their use of these agents. Discussed here are not only the mechanisms of therapeutic action of MAOIs, but also the mechanisms explaining their side effects, including hypertensive interactions with dietary tyramine (so-called “cheese reactions”) and drug interactions that can lead to hypertensive reactions with some drugs and serotonin toxicities with others.
This article also provides practical tips on how to use MAOIs, including debunking certain myths and giving specific guidance about which foods and drugs to avoid. Those with no previous interest in MAOIs may discover in this article a new “secret weapon” to add to their therapeutic armamentarium for patients who fail to respond to the better-known agents.
The antidepressant effects of monoamine oxidase inhibitors (MAOIs) were discovered serendipitously when an antituberculosis drug, iproniazid, was observed to help depression that coexisted in some of the patients who had tuberculosis.1-3 This antituberculosis drug was eventually found to work in depression by inhibiting the enzyme MAO. However, inhibition of MAO was unrelated to its antituberculosis actions.2,4
MAOIs, while best known for their powerful antidepressant effects, can also be efficacious in treating certain anxiety disorders, including panic disorder and social phobia.3,5-7 Additionally, some selective MAO-B inhibitors may also be efficacious in treating Parkinson’s disease, though at lower doses than necessary to achieve antidepressant effects.8 MAOIs, however, are rarely utilized anymore in psychopharmacology practice. Only a few thousand prescriptions for antidepressant use of MAOIs are written in the United States annually, almost all by a few hundred psychiatrists, whereas several million serotonin selective reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors prescriptions are written in the US annually by many thousands of practitioners, mostly primary care physicians.9
There are many reasons for the low use of MAOIs, including the fact that numerous other options exist for treatment, preventing many modern-day clinicians from gaining experience with MAOIs. Since these are old drugs with essentially no marketing support, there is also a good deal of misinformation and mythology about their present-day dietary and drug-interaction dangers. It may simply be that clinicians are unaware of the potential benefits of treating a current patient with an MAOI; how to manage patients taking these drugs, including diet and concomitant drugs; and how to determine the risk-benefit ratio for an individual patient.2,7
This review will attempt to heighten awareness of MAOIs as second- or third-line therapeutics for patients who fail to respond to first-line treatments. Mechanisms of action for therapeutic and adverse effects will be discussed, including the mechanism of dietary interactions with tyramine, and the reasons behind the drug interactions to avoid. With renewed understanding of the mechanisms of action behind the potentially important and effective therapeutic effects as well as the manageable adverse effects, the MAOIs may return to a more prominent place on the sophisticated clinician’s pharmaceutical shelf. (This article is excerpted and adapted [with permission] from the antidepressant chapter of the recently published textbook, Stahl’s Essential Psychopharmacology.2 The reader is also encouraged to consult standard reference sources for prescribing information on the MAOIs, including the companion prescriber’s guide to this textbook.10)
Overview of the Mechanism of Therapeutic Action
Three of the original MAOIs are still clinically available: phenelzine, tranylcypromine, and isocarboxazid (Table 1).11 Each of these is an irreversible enzyme inhibitor that binds to MAO covalently, destroying its function forever.4,11 Activity returns only after new enzyme is synthesized.
Perhaps surprising to many clinicians is the fact that amphetamine is actually a reversible MAOI in addition to its better known and more potent actions inhibiting the dopamine (DA) transporter and the norepinephrine (NE) transporter (Table 1).2,13 Interestingly, some MAOIs, such as tranylcypromine, have chemical structures modeled on amphetamine and thus, in addition to their well-known MAO inhibitor properties, also have amphetamine-like DA- and NE-releasing properties due to additional inhibitory actions on DA transporter and NE transporter (Table 1).2 Selegiline itself does not have amphetamine-like properties but is metabolized to both l-amphetamine and l-methamphetamine (Table 1).14-16 Thus, some MAOIs have amphetamine-like properties, and amphetamines themselves are, in fact, reversible MAOIs (Table 1). Since some MAOIs have a mechanism of action that combines MAO inhibition with amphetamine-like actions of DA and NE release, it is not surprising that one of the augmenting agents utilized to boost MAOIs in especially treatment-resistant depression (TRD) patients, is amphetamine, administered by experts with great caution while monitoring blood pressure.10,17-19 The actions of stimulants and MAOIs may thus be additive or synergistic, both for antidepressant efficacy and for raising blood pressure in some patients. This combination is not for amateurs to administer but can be a heroic and life-saving combination for selected patients.
Role of MAO Subtypes in the Mechanism of Antidepressant Action of MAOIs
MAO exists in two subtypes, A and B. The original MAOIs are nonselective, inhibiting both forms.20-22 The A form of MAO preferentially metabolizes serotonin (5-HT) and NE, the monoamines most closely linked to depression (Table 2 and Figure 1).2 The B form preferentially metabolizes trace amines, including phenethylamine (Table 2 and Figure 1).2 MAO-A and MAO-B metabolize DA and tyramine (Table 2).
Both forms of MAO are present in the brain.23,24 Specifically, noradrenergic and dopaminergic neurons are thought to contain MAO-A and MAO-B, with perhaps MAO-A activity predominant, whereas serotonergic neurons are thought to contain only MAO-B.2 MAO-A can thus be found in the locus ceruleus, the reticular formation, and the presynaptic terminals of dopaminergic neurons, whereas MAO-B is located in the dorsal raphe nucleus and basal ganglia.25 MAO-A is the major form of this enzyme outside of the brain, with the exception of platelets and lymphocytes, which have only MAO-B (Table 2). The ratio of MAO-A to MAO-B in the human brain is 25%:75%, whereas in the liver, the ratio is 50%:50%. The ratio is 80%:20% in the intestine, and in the peripheral adrenergic neurons, the ratio is 90%:10%.25
Brain MAO-A must be inhibited for antidepressant efficacy to occur (Figure 1).2,22,26-27 This is not surprising, since this is the form of MAO that metabolizes 5-HT and NE, two of the three components of the trimonoaminergic neurotransmitter system linked to depression and to antidepressant actions; both 5-HT and NE demonstrate increased brain levels after MAO-A inhibition (Figure 1). MAO-A, along with MAO-B, also metabolizes DA, but inhibition of MAO-A alone does not appear to lead to robust increases in brain DA levels since MAO-B can still metabolize DA (Figure 1).
Inhibition of MAO-B is not effective as an antidepressant,26-28 as there is no direct effect on either 5-HT or NE metabolism, and little or no DA accumulates due to the continued action of MAO-A (Figure 2). What, therefore, is the therapeutic value of MAO-B inhibition? When this enzyme is selectively inhibited, it can boost the action of concomitantly administered levodopa in Parkinson’s disease.8,29 Evidently, in the presence of a large amount of DA derived from administration of a large dose of its precursor levodopa, selective MAO-B inhibition is sufficient to boost DA action in the brain.8,14,30 MAO-B is also thought to convert some environmentally derived amine substrates, called “protoxins,” into toxins that may cause damage to neurons and possibly contribute to the cause or decline of function in Parkinson’s disease.2,8 Inhibiting MAO-B may thus halt this process, and there is speculation that this may slow the degenerative course of various neurodegenerative disorders, including Parkinson’s disease. Thus, two MAOIs in Table 1, selegiline and rasagiline, when administered orally in doses selective for inhibition of MAO-B, are approved for use in patients with Parkinson’s disease, but they are not effective at these selective MAO-B doses as antidepressants.
Perhaps the most important role of MAO-B in psychopharmacology is when it is inhibited simultaneously with MAO-A (Figure 3). In that case, there is a robust triple monoaminergic boost of DA as well as 5-HT and NE (Figure 3).22 This would theoretically provide the most powerful antidepressant efficacy across the range of depressive symptoms. Indeed, MAO-A plus B inhibition is one of the few therapeutic strategies available to increase DA in depression and, therefore, to treat refractory symptoms of diminished positive affect theoretically linked to DA deficiency.31 Symptoms associated with reduced positive affect include not only depressed mood but also loss of happiness and joy, loss of interest and pleasure, loss of energy and enthusiasm, decreased alertness, and decreased self-confidence.2,31 This action on DA theoretically treating such symptoms of reduced positive affect is an incentive for specialists in psychopharmacology to become adept at administering MAOIs; it will give them an additional strategy within their armamentarium for cases with treatment-resistant symptoms of diminished positive affect, a common problem in a referral practice.1,2,17-19
Mechanism of "Tyramine Reactions" and Rationale for Modern Dietary Restrictions
Utilizing MAOIs has often been considered risky due to the potential of developing a hypertensive crisis (Table 3) after ingesting high amounts of tyramine from the diet.16 Tyramine is a potent releaser of NE and can thus elevate blood pressure.32 Normally, NE cannot accumulate to dangerous levels, due to the efficient destruction of NE by MAO-A (Figure 4).2 When foods high in tyramine content are ingested, MAO-A in the intestinal wall and liver safely destroys massive amounts of tyramine before it is absorbed.32,33 If any tyramine escapes into the systemic circulation and is delivered to the noradrenergic sympathetic neuron, the MAO-A there destroys any synaptic NE that tyramine releases (Figure 5). Thus, there is a large capacity to protect the sympathetic nervous system from ingested tyramine. The average person can handle ~400 mg of ingested tyramine before excessive stimulation of postsynaptic adrenergic receptors occurs, and thus results in elevated blood pressure (Figure 5).2 Since a “high tyramine meal” generally contains only about 40 mg of tyramine, a tyramine reaction usually does not occur in a normal unmedicated person eating a normal diet.32
When MAO-A is inhibited, the capacity to handle dietary tyramine is significantly reduced. A high-tyramine meal is sufficient to increase blood pressure when a substantial amount of MAO-A is irreversibly inhibited (Figure 6). It may take only 8–10 mg of dietary tyramine to increase blood pressure when MAO-A is “knocked out” by high doses of an MAOI, which is discussed later in Figure 11.34 Such blood pressure elevations can potentially be sudden and dramatic, creating a hypertensive crisis, which can (rarely) cause intracerebral hemorrhage or even death (Table 3).2 This risk is generally alleviated by restricting the diet so foods high in tyramine are eliminated (Table 4). Until recently, dietary restrictions and the risk of a hypertensive crisis were the price most patients had to pay in order to receive the therapeutic benefits of the MAOIs in the treatment of depression (Tables 3 and 4).32,33,35-38
Due to this potential danger of a hypertensive crisis from a tyramine reaction in patients taking an irreversible MAOI (Table 3),2 various myths have arisen surrounding the amount of tyramine in certain foods and which dietary restrictions are necessary. The “cheese reaction” has led to the myth that all cheese must be restricted.7,32-39 This is not the case, as only aged cheeses (eg, English Stilton) are high in tyramine, whereas most processed cheeses (Figure 7, top panel) or those utilized on commercial chain pizzas (Figure 7, middle panel) do not contain high levels of tyramine.36-38
Another myth is that patients on an MAOI must avoid all wine and beer. Canned and bottled beer are low in tyramine, and many wines, including Chianti, contain low levels of tyramine (Figure 7, bottom panel).36-38 Generally, only draft and unpasteurized beers should be avoided.2,36-38 Thus, unless someone taking an irreversible inhibitor of MAO-A is going to eat 25–100 pieces of standard pizza or drink 25–100 glasses of most wines or 25–100 cans or bottles of most beers at a party, it is likely that they can still have a moderate amount of fun. Of course, every prescriber should counsel patients taking MAOIs about diet and advise patients to keep up-to-date with the tyramine content of foods they wish to eat.
Exploiting the Mechanism of Tyramine Reactions to Increase Safety: New Developments with MAOIs
Two recent developments appear to mitigate the risk of tyramine reactions with MAOIs. First, inhibitors have been developed that are not only selective for MAO-A, but are also reversible.23-34 Second, an MAOI can now be delivered through a skin patch, resulting in inhibition of both MAO-A and MAO-B in the brain, but with much less MAO-A simultaneously inhibited in the gut.40,41 While neither of these innovations enhances MAOI efficacy, both reduce the risk of a hypertensive crisis with ingestion of tyramine.
Reversible Inhibitors of Monamine
Reversible inhibitors of monoamine (RIMAs) are an ingenious development because they have the potential of providing MAO-A inhibition with decreased risk of a tyramine reaction (Figure 8).6,23,24,30,42-45 For example, if someone taking a RIMA eats aged cheese high in tyramine, as the tyramine is absorbed it will release NE; however, this released NE will chase the reversible inhibitor off the MAO-A enzyme, reactivating MAO-A in the intestine, liver, and sympathomimetic neurons and allowing destruction of the dangerous amines (Figure 9).2,23,34 Recent trials4,30 have shown that RIMAs can be effective in treating patients with endogenous depression and geriatric depression.
Moclobemide is the best known RIMA and has demonstrated efficacy similar to amitriptyline, clomipramine, fluvoxamine, and imipramine.4
Numerous studies have indicated that moclobemide can maintain its antidepressant effects for 6–12 months.4 There is still a warning posted regarding tyramine reactions with moclobemide, as some degree of dietary caution is still recommended. Nevertheless, when adequately dosed, there is much less likelihood of a dangerous reaction when tyramine is ingested in conjunction with a reversible MAOI. Although the risk for a hypertensive reaction from dietary tyramine may be reduced by RIMAs, the risk for serotonin syndrome with drugs that block 5-HT reuptake may not be similarly reduced, as the mechanism of 5-HT toxicity is different, as discussed in the section below.
Transdermal Delivery of a Selective MAO-B Inhibitor
While RIMAs may be as efficacious as irreversible MAOIs and may theoretically require less dietary tyramine restriction, transdermal delivery of an MAOI can allow the patient to have a diet without any dietary tyramine restrictions. Selective MAO-B inhibitors given orally at low doses do not inhibit a significant amount of MAO-A (Figure 2), and thus there is little risk of hypertension from dietary amines.45-48 However, at low oral doses, MAO-B inhibitors are also not effective antidepressants due to the lack of significant elevations in brain 5-HT or NE (Figure 2).26-28 An antidepressant effect, however, can be achieved when the MAO-B inhibitor selegiline is given orally in doses that cause it to lose its selectivity and inhibit MAO-A as well (Figure 10, left).49,50 However, this type of dose would also cause a tyramine reaction (Figure 10, left).27
In order to prevent this problem, selegiline is administered transdermally, thus delivering the drug directly into the systemic circulation, hitting the brain in high doses and avoiding a first pass through the liver (Figure 10, right).2,40-41,51 Once the drug recirculates to the intestine and liver, the levels have decreased and mostly MAO-B is inhibited (Figure 10, right). This action is sufficiently robust and selective that for low doses of transdermal selegiline, no dietary tyramine restrictions are necessary. At high doses of transdermal selegiline, there is likely some MAO-A inhibition in the gut, and thus some dietary tyramine restrictions may be prudent.7 In some studies of depressed patients receiving transdermal selegiline,46 dietary restrictions were not followed, yet tyramine reactions were not reported. Therefore, at high doses of transdermal selegiline, some dietary caution may be warranted, but it appears that at low doses, dietary restrictions may not be necessary (Figure 11).52
Although the risk for a hypertensive reaction from dietary tyramine may be reduced by transdermal delivery of selegiline, the risk for serotonin syndrome with administration of drugs that block 5-HT reuptake is not similarly reduced. The mechanism of 5-HT toxicity is different, as discussed in the section below.
Mechanism of Dangerous Drug Interactions with MAOIs: Decongestants and Drugs that Boost Sympathomimetic Amines
While MAOIs are famous for their tyramine reactions, drug-drug interactions are potentially more important clinically. Drug-drug interactions may not only be more common, but also some interactions can be incredibly dangerous and potentially lethal.53,54 Also, drug interactions with MAOIs are poorly understood by many practitioners. Most candidates for MAOI treatment will require treatment with many concomitant drugs over time, including treatment for coughs and colds, so not knowing which drugs are safe to give and which ones to avoid can unnecessarily prevent a practitioner from using an MAOI at all for someone who requires any concomitant medications.
There are two general types of potentially dangerous drug interactions with MAOIs for a practitioner to understand: those that can raise blood pressure by sympathomimetic actions (discussed in this section; Tables 5 and 6) and those that can cause a potentially fatal serotonin syndrome by 5-HT reuptake inhibitory actions (discussed in the section below; Table 7).
When drugs that boost adrenergic stimulation by a mechanism other than MAO inhibition are added to an MAOI, potentially dangerous hypertensive reactions can occur. For example, many decongestants can adversely interact with MAOIs to elevate blood pressure (Table 5 and Figure 12).2 Decongestants to be avoided with an MAOI include those that add to the pro-noradrenergic actions of MAO inhibition to stimulate alpha 1 postsynaptic vascular receptors excessively.55 Currently, this applies mostly to over-the-counter phenylephrine and oxymetazoline, both relatively selective alpha 1 agonists, since ephedrine, phenylpropanolamine, and pseudoephedrine have either been withdrawn from the US and other markets or are available only by signing for them at a pharmacy (eg, pseudoephedrine) (Table 5).2 An additional ingredient found in cold medicines is the cough suppressant and opiate derivative dextromethorphan, which should be avoided not because it is a sympathomimetic agent but because it is a weak 5-HT reuptake inhibitor (discussed below; Table 7).
Decongestants work by constricting nasal blood vessels.2 If topically applied (eg, nasal oxymetazoline) or taken in low doses, they generally do not have sufficient systemic actions to elevate blood pressure by themselves (Figure 12). However, in potentially vulnerable patients (such as those with hypertension, especially those whose hypertension is not controlled), decongestants, particularly when systemically administered orally, can elevate blood pressure by themselves.
MAOIs alone can potentiate NE, but this alone is generally insufficient to cause hypertension (Figure 12). In fact, in the past, MAOIs have been marketed as antihypertensives and, by themselves, are probably more likely to cause hypotension, especially orthostatic hypotension.56 However, a hypertensive drug interaction can occur when the mechanisms of decongestants and MAOIs are combined, especially in vulnerable patients. In these patients, the pro-noradrenergic actions of MAO inhibition in concert with the direct stimulation of alpha 1 receptors by an agent like phenylephrine can result in elevated blood pressure or a hypertensive crisis (Figure 12).57
It is a myth that a patient on an MAOI cannot take any cough or cold medication. Generally, a patient on an MAOI should avoid oral phenylephrine in order to minimize the risk of a hypertensive reaction (Figure 12). For different reasons, namely to avoid the serotonin syndrome, patients on an MAOI should also avoid ingredients in cough and cold preparations that inhibit 5-HT reuptake, as discussed in the next section. (This includes dextromethorphan and some antihistamines, especially chlorpheniramine and brompheniramine; Table 7.) Other antihistamines and cough suppressants, including codeine, are generally acceptable to be administered with MAOIs.
MAOIs are sometimes combined with tricyclic antidepressants (TCAs) in heroic cases,2,10,18,58 though MAOIs are formally contraindicated in the prescribing information for patients taking antidepressants that are NE reuptake inhibitors, such as most TCAs (Table 5). This is because the sudden addition of NE reuptake blockade in someone on an MAOI may result in a hypertensive reaction. On the other hand, MAOIs can be combined with some TCAs (never clomipramine; Table 7) that inhibit NE reuptake if both agents are started simultaneously, at low doses, and if the titration of both agents is done carefully, with blood pressure monitoring, by someone experienced in this rather heroic combination.2,10,18,58 Combining TCAs (though never clomipramine) with an MAOI has fallen out of favor due to the potential danger of this combination; the legal risks, since it is mentioned as contraindicated in prescribing information; and the paucity of clinicians who understand the risks and the benefits of this controversial approach to heroic management of TRD.
Stimulants such as methylphenidate, which potentiate NE at adrenergic synapses by blocking NE reuptake, and amphetamines, which do this and also release NE, can elevate blood pressure on their own and are formally contraindicated in prescribing information even as monotherapies for patients with structural cardiac abnormalities or uncontrolled hypertension.
It is therefore not surprising that combining stimulants with MAOIs is also formally contraindicated in prescribing information because, together, MAOIs and stimulants increase the chances of a hypertensive reaction (Tables 5 and 6).2,10,17-19 Thus, use of this combination should generally be reserved for the most treatment-resistant cases. On the other hand, as mentioned earlier in this article, some MAOIs are themselves stimulants or are metabolized to stimulants (Table 6), so it is also not surprising that stimulants can sometimes be combined with MAOIs to attain antidepressant efficacy in heroic cases, with extreme caution, with careful blood pressure and cardiovascular monitoring and with appropriate risk-benefit assessment for that individual.2,10,17-18,58
In the 1960s, fatalities were reported when amphetamine was used to increase the potential of MAOIs for refractory depression.17 However, perhaps surprisingly, one current study has indicated that up to 40 mg of intravenous cocaine added to an existing transdermal selegiline regimen 20 mg/day was well tolerated in a group of cocaine-dependent subjects.59 Also, selective case reports document the usefulness of combining an MAOI with a stimulant.17 A general rule of thumb if attempting to utilize this combination is to prescribe a slow titration and start with a low dose (ie, amphetamine 2.5 mg/day and methylphenidate 5 mg/day) added to ongoing MAOI therapy.17
Any drugs that block NE reuptake, including not only the stimulants but also antidepressants, attention-deficity/hyperactivity drugs (such as atomoxetine), appetite suppressants (such as sibutramine and other sympathomimetics), and the analgesic tramadol should generally be avoided in combination with an MAOI or used only by experts if deemed necessary, with adequate monitoring (Table 5).60,61
Mechanism of Dangerous Drug Interactions with MAOIs: Combining MAOIs with Serotonin Reuptake Blockade
A potentially much more dangerous combination than that of adrenergic stimulants and MAOIs can occur when combining agents that inhibit 5-HT reuptake with those that inhibit MAO (Table 7). One particular combination that has gained substantial attention in psychopharmacology lore is when a patient taking an MAOI is given an injection of meperidine (an opioid analgesic and inhibitor of 5-HT reuptake) for pain relief in the emergency room and perishes as a result of this preventable interaction and resulting 5-HT toxicity.62
Inhibition of the serotonin transporter (SERT) leads to increased synaptic availability of 5-HT (Figure 13).61 Similarly, inhibition of MAO leads to increased synaptic 5-HT levels. When these mechanisms are combined, excessive stimulation of postsynaptic 5-HT receptors occurs, which can lead to the collective symptoms known as “serotonin syndrome” (Figure 13).63 Theoretically, excessive stimulation of postsynaptic 5-HT receptors causes a disruption in thermoregulation, resulting in dangerous hyperthermia.2 Since the 5-HT neuron has MAO-B (or the “wrong” form of MAO for its substrate 5-HT that is actually preferentially metabolized by MAO-A; Figure 1, top panel), the 5-HT neuron may normally prevent excessive concentrations of 5-HT from accumulating by being vitally dependent on the integrity of functioning of the 5-HT reuptake pump.64 Thus, blocking 5-HT transporter alone robustly elevates 5-HT at 5-HT neurons.2 When extrasynaptic removal of 5-HT by MAO-A is also inhibited, a potentially dangerous accumulation of 5-HT can occur.
Consequences from this situation are grouped into a triad of features including neuromuscular hyperactivity, autonomic hyperactivity, and altered mental status. Presenting symptoms range from migraines, myoclonus, diarrhea, agitation, and psychosis at the lower end of the severity spectrum, to hyperthermia, seizures, coma, cardiovascular collapse, permanent hyperthermic brain damage, and death at the higher end.65,66 The Hunter Area Toxicology Service in Australia66 has documented >2,000 cases of serotonergic drug overdose. This particular research group has labeled 5-HT toxicity as a spectrum concept of serotonin syndrome, with weak 5-HT reuptake inhibitors (eg, pethidine, also known as meperidine, an opioid analgesic) sometimes precipitating 5-HT toxicity, but only in susceptible individuals or when taken in large doses, and other drugs with more robust 5-HT reuptake inhibition often instigate 5-HT toxicity.66
It is suggested that agents with potent 5-HT reuptake inhibition should never be combined with agents that cause substantial MAO inhibition.66 This would include any SSRI or serotonin-norepinephrine reuptake inhibitors, and clomipramine, a TCA. Occasionally, tricyclics with weak 5-HT reuptake inhibition can be combined with MAOIs, but, as mentioned earlier, this is rarely done.45,58,63,67 Opioids that block 5-HT reuptake, including meperidine, methadone, propoxyphene, dextromethorphan, and tramadol, especially at high doses, must be avoided in the presence of an MAOI (Table 7). Injection of meperidine given concomitantly with an MAOI may be the most frequent drug combination causing serious complications and even death.68 However, any agent with 5-HT reuptake blockade has the potential to cause serotonin syndrome. Analgesics, including opiates, that are safe to administer with an MAOI are those lacking 5-HT reuptake inhibiting properties, such as aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs, codeine, oxycodone, fentanyl, buprenorphine, and morphine.
Usually, the serotonin syndrome caused by an MAOI together with a 5-HT reuptake inhibitor results from the prescriber not recognizing that a patient on an MAOI is also on a drug with 5-HT reuptake inhibiting properties, such as certain analgesics, appetite suppressants, antihistamines, etc. (Table 7). More recently, the serotonin syndrome is being caused by the prescriber not recognizing that a patient on a 5-HT reuptake inhibitor is also on an antibiotic that is also an MAOI, namely, linezolid (Zyvox). Linezolid exhibits MAO-A and MAO-B inhibitory effects.55 Linezolid was approved by the Food and Drug Administration in 2000 and is the first oxazolidinone antimicrobial approved for use in the US.55 It is used in the treatment of vancomycin-resistant Enterococcus and methicillin-resistant Staphylococcus aureus.57 Oxazolidinones are similar in chemical structure to toloxatone, which is an inhibitor of MAO. Linezolid appears to have weak reversible MAO-A and MAO-B inhibitory effects,55 and there are now appeared numerous case reports57 of serotonin syndrome when linezolid was combined with SSRIs.
Treatment of serotonin syndrome includes discontinuation of all serotonergic agents and subsequent supportive care. Moderate cases may benefit from administration of 5-HT2A antagonists. Severe cases with hyperthermia may also require intubation and sedation. Benzodiazepines may be useful in alleviation of agitation, while diazepam may improve hyperadrenergic symptoms. Some evidence61 has also supported the use of β-blockers, which may also block 5-HT1A receptors.
MAOIs should not be discounted in the fight against TRD, as well as various treatment-resistant anxiety disorders. While patients on MAOI pharmacotherapy should maintain a watchful eye over their dietary intake, they may not need to be fully restricted from certain foods once erroneously thought to be high in tyramine content and, therefore, potentially dangerous, especially with certain MAOIs. Educating clinicians and patients on recent findings regarding tyramine reactions and MAOIs may aid in dispelling this particular stigma surrounding MAOIs. Furthermore, clinicians who are fully aware of drugs with the ability to inhibit the SERT should be able to avoid them when they prescribe MAOIs. Clinicians should also be able to determine when a combination or augmentation pharmacotherapy, risky or otherwise, is needed. Expert clinicians may carefully administer and monitor specific drugs that may require close supervision in conjunction with MAOIs, such as stimulants, as this tactic may help certain refractory cases of depression. In addition, recent advancements in technology may alleviate some of the issues surrounding administration and resulting blockade of MAO-A by administering MAO inhibitors transdermally, such as the transdermal selegiline patch. The RIMA moclobemide, may create less concern over potential side effects and interactions from dietary tyramine. With knowledge of MAOI therapeutic mechanisms as well as the mechanisms underlying dietary tyramine reactions and various potentially dangerous drug interactions, the MAOIs may enjoy renewed interest and may be revived as a therapeutic tool in the modern psychopharmacologist’s toolkit for the treatment of difficult cases of depression and other psychiatric disorders.
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