Introduction
Oral irreversible inhibitors of the intracellular enzyme, monoamine oxidase, have been in clinical use for over 60 years. As a group, they constitute the oldest class of antidepressants. The monoamine oxidase inhibitors (MAOIs) were developed decades ago out of the search for novel antituberculous drugs. One such drug, iproniazid, was serendipitously discovered to have mood-elevating properties in patients with tuberculosis ( ). These observations, first described in the 1950s, were confirmed in subsequent trials ( ). From there, a series of pivotal studies showed that iproniazid was a potent inhibitor of monoamine oxidase; that inhibition of monoamine oxidase increased the levels of serotonin, norepinephrine, and dopamine in the brain; and that iproniazid was capable of reversing depressive states induced by reserpine, a drug that depletes catecholamines and serotonin from central and peripheral nerve terminals ( ; ).
Following the discovery of iproniazid’s antidepressive effects, other irreversible MAOIs were developed, including the hydrazine compounds, phenelzine and isocarboxazid, and the nonhydrazine drug, tranylcypromine. Iproniazid soon fell out of favor as a pharmaceutic due to reports of hepatotoxicity and nephrotoxicity ( ). The remaining MAOIs became the predominant form of treatment for a variety of depressive states until they, too, were temporarily withdrawn from the market due to hepatotoxicity (in the case of the hydrazine compounds) and deaths due to hypertensive crises and intracranial hemorrhages (all MAOIs) when combined with sympathomimetic drugs or after the consumption of foods containing high concentrations of tyramine ( ; ). As knowledge accumulated regarding the mechanisms of hypertensive reactions to selected drugs and tyramine-containing foodstuff in people taking MAOIs, they were subsequently reintroduced and have since remained important therapeutic options for patients suffering from a wide variety of mood and anxiety disorders.
Unlike other antidepressants that function primarily as inhibitors of monoamine transporters (mainly inhibition of the norepinephrine transporter, the serotonin transporter, or both), MAOIs are inhibitors of the enzyme that degrades the monoamine neurotransmitters—a distinctive and important mechanism that allows MAOIs to increase synaptic availability of all three neurotransmitters (serotonin, norepinephrine, and dopamine) implicated in the pathophysiology of depressive states and the hypothesized mechanisms of action of antidepressants ( ). The MAOI class of antidepressants is diverse ( Table 9.1 ) and includes three orally administered irreversible inhibitors of monoamine oxidase (phenelzine, isocarboxazid, and tranylcypromine), a transdermally administered irreversible MAOI (transdermal selegiline, an older drug that is marketed in pill form to treat Parkinson’s disease), and an orally administered reversible inhibitor of monoamine oxidase (moclobemide, which is not available for clinical use in the United States).
| Drug name | Brand names (United States) | Reversibility a | MAO isoenzyme selectivity b | |
|---|---|---|---|---|
| MAO-A | MAO-B | |||
| Phenelzine | Nardil | Irreversible | Yes | Yes |
| Tranylcypromine | Parnate | Irreversible | Yes | Yes |
| Isocarboxazid | Marplan | Irreversible | Yes | Yes |
| Selegiline, transdermal | EMSAM c | Irreversible d | Yes, but only at higher doses | Yes |
| Moclobemide | … e | Reversible | Yes | No |
| Brofaromine | … f | Reversible | Yes | No |
| Clorgyline | … f | Reversible | Yes | No |
a Irreversible inhibition of MAO indicates that the drug binds to the enzyme permanently, rendering it inactive for its entire lifespan. Reversible inhibition of MAO indicates that the drug can be displaced from its binding site by tyramine.
b “Yes” in both columns indicates that the drug is a nonselective inhibitor of monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B). “Yes” in only one box indicates that the drug is a selective inhibitor of that MAO isoenzyme.
c Selegiline is available in both oral and transdermal forms. EMSAM is the transdermal form of selegiline that has regulatory approval as an antidepressant drug.
d Selegiline selectively inhibits MAO-B at low doses (30–60 mg/day of oral selegiline, or ≤ 6 mg/day of transdermal selegiline [EMSAM]). At higher doses, selegiline inhibits both MAO-A and MAO-B.
e Not marketed in the United States.
Despite being highly effective, the clinical use of MAOIs has been limited by waning clinical experience and a poor understanding of dietary restrictions and drug interactions—to the point that they are now rarely prescribed by most psychiatrists ( ; ; ). Because of infrequent use, drug manufacturers have reduced production and thus have limited the availability of some MAOIs, phenelzine in particular, throughout the world ( ). MAOIs have been relegated to third-line or lower status in nearly all practice guidelines for the pharmacological treatment of major depression ( ; ; ; ; ; ). Nevertheless, there has been renewed interest in the clinical use of MAOIs given the high rates of treatment resistance in people with major depression, the clinical effectiveness of selected irreversible MAOIs for treatment-resistant depressive states (reviewed below), and changes in food preparation techniques and hygiene regulations that have greatly increased the safety of MAOIs in people who consume modern diets ( ). This chapter reviews the clinical pharmacology and efficacy of MAOIs for treatment-resistant depression and provides practical advice on the safe and effective use of this often-misunderstood, yet highly effective class of antidepressant medications.
Pharmacological properties
Mechanism of action
MAOIs inhibit the enzyme, monoamine oxidase, leading to a rapid increase in the synaptic transmission of serotonin, norepinephrine, and dopamine ( ). This pharmacological effect occurs acutely ( ), and does not correlate in time with the 3–6-week delay in the onset of antidepressive effects after starting MAOI treatment. The chronic administration of MAOIs, on the other hand, may lead to secondary downregulation of monoamine receptors, an effect that appears to parallel the delayed onset of antidepressive effects with MAOIs ( ; ). Whether these chronic effects of MAOI administration better explain the therapeutic action of these drugs for depression is unclear at this time.
Specificity and irreversibility of monoamine oxidase inhibition
The more clinically relevant aspects of MAOI pharmacology involve specificity for various monoamine oxidase isoenzymes and irreversibility of enzyme inhibition. There are two monoamine oxidase isoenzymes: Monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B). MAO-A is found in the brain, gut, liver, pancreas, heart, placenta, and skin; MAO-B is found in the brain, platelets, and lymphocytes ( ; ). Levels of serotonin, dopamine, and norepinephrine are increased by inhibition of MAOI-A, whereas inhibition of MAO-B increases levels of dopamine and phenylethylamine ( ; ; ), as summarized in Table 9.2 .
| MAO-A | MAO-B | |
|---|---|---|
| Serotonin | Yes | No |
| Norepinephrine | Yes | No |
| Dopamine | Yes | Yes |
| Tyramine | Yes | No |
| Melatonin | Yes | Yes |
| Phenylethylamine | No | Yes |
Inhibition of MAO-A is necessary for the antidepressive effect of MAOIs due to its specificity for serotonin and norepinephrine ( ). Even though both MAO-A and MAO-B metabolize tyramine, the irreversible inhibition of MAO-A in the small intestine is believed to be the key mechanism by which potentially severe hypertensive reactions due to tyramine overaccumulation occur ( ). Ingested tyramine is “detoxified” while passing through the gut wall from its metabolism by MAO-A and never reaches the bloodstream. When MAO-A is inhibited, tyramine does reach the bloodstream, where it is thought to push out NE from peripheral neurons that regulate blood vessel constriction, thereby elevating blood pressure.
The MAOIs can be subgrouped based on their selectivity for specific monoamine oxidase isoenzymes and whether they display irreversible or reversible binding to monoamine oxidase. Phenelzine, isocarboxazid, and tranylcypromine irreversibly inhibit MAO-A and MAO-B, meaning that these drugs render MAO-A and MAO-B permanently inactive ( ). Following irreversible inhibition, normal monoamine oxidase activity can be restored only after new enzyme is synthesized, a process that requires approximately 14–28 days ( ). The relative selectivity of selegiline for monoamine oxidase isoenzymes is dose-dependent. At low doses, selegiline is highly selective for MAO-B, where it acts as an irreversible inhibitor ( ). At higher doses (i.e., > 6 mg/24 h of transdermal selegiline), selectivity for MAO-B is lost and both MAO-A and MAO-B are irreversibly inhibited ( ). Moclobemide is a selective reversible inhibitor of MAO-A (RIMA). The “reversibility” of MAO inhibition with moclobemide refers to the fact that it can be displaced by high concentrations of dietary tyramine ( ). Therefore, MAO-A activity is recovered more quickly and the pressor effect of concomitantly ingested tyramine appears to be less pronounced with the use of moclobemide than with the use of irreversible MAOIs ( ). Combining moclobemide with serotonergic agents can, however, lead to severe serotonin toxicity ( ).
Other nonselective irreversible MAOIs (nialamide), reversible (brofaromine, toloxatone, comoxatone, befloxatone) and irreversible (clorgyline) MAO-A selective drugs, and irreversible MAO-B selective drugs (pargyline) have been developed. However, these drugs are unavailable, untested, or not routinely available for clinical use in depressed patients and will not be discussed further.
Additional pharmacodynamic properties
The irreversible nonselective MAOIs, phenelzine and tranylcypromine, have additional properties that may be clinically relevant. In addition to inhibiting monoamine oxidase, phenelzine is thought to potentiate gamma-aminobutyric acid (GABA)-ergic neurotransmission by inhibiting GABA transaminases ( ), the principle group of enzymes responsible for the degradation of GABA. This mechanism is believed to contribute to phenelzine’s sedating and anxiolytic effects ( ). Tranylcypromine, on the other hand, has a chemical structure that is similar to amphetamine and has been shown to produce a stimulant-like effect ( ). There is debate in the literature as to whether tranylcypromine is in fact metabolized into amphetamine, with the consensus being that it is not ( ).
Pharmacokinetics
Phenelzine, isocarboxazid, and tranylcypromine
There is surprisingly little information about the pharmacokinetic properties of most orally administered irreversible MAOIs. All are readily absorbed from the gastrointestinal tract and generally reach peak concentrations within a few hours of administration ( ; ; ). In general, oral MAOIs are extensively metabolized and have relatively short elimination half-lives—generally in the range of 1.5–4 h. Phenelzine and isocarboxazid are acetylated into largely inactive metabolites ( ; ; ). However, drug metabolizing characteristics have no impact on the duration of the antidepressive effects of MAOIs. Instead, the duration of antidepressive effects of MAOIs is primarily dependent upon the inhibition of monoamine oxidase and the rate of monoamine oxidase synthesis. There are no known sex-specific effects on drug absorption, distribution, metabolism, or elimination.
Transdermal selegiline
The form of selegiline that is approved for use in people with depression is delivered transdermally. About 25%–30% of the selegiline content of the patch is delivered systemically over 24 h, reaching steady-state concentrations within 5 days ( ). The release of less than one-third of the active drug contained in a patch over 24 h raises the possibility that a single patch could be kept on for up to 3 days—a clinical hypothesis that, to our knowledge, has not been empirically investigated. Because additional selegiline may be delivered beyond 24 h when using the transdermal form, it is important to warn patients to avoid wearing more than one patch at any given time. Once absorbed transdermally, selegiline is distributed extensively without accumulating in the skin ( ). Selegiline undergoes hepatic metabolism by several cytochrome CYP450 isoenzymes, including CYP2B6, CYP2C9, CYP2A4/5, and others ( ). The mean elimination half-life of transdermal selegiline ranges from 15 to 25 h ( ). As is the case for oral MAOIs, the degradation characteristics of transdermal selegiline do not influence the duration of its antidepressive effects, and sex does not appear to influence its pharmacokinetic properties.
Moclobemide
Moclobemide is rapidly absorbed following oral dosing and reaches peak plasma concentrations within 1 h ( ). Moclobemide is extensively metabolized in the liver by CYP2C19 and appears to inhibit CYP2C19, CYP2D6, and CYP1A2 isoenzymes ( ). The mean elimination half-life of moclobemide is 1.8 h for CYP2C19 extensive (normal) metabolizers and is 4 h for CYP2C19 poor metabolizers ( ). The pharmacokinetic properties of moclobemide do not appear to vary according to sex.
Indications
MAOIs are effective for a wide range of psychiatric disorders ( ). They are most commonly used for treating major depressive disorder (MDD), particularly MDD with atypical features and treatment-resistant cases that fail to respond to first-line and tricyclic antidepressants. They are also effective treatments for persistent depressive disorder (formerly referred to as dysthymic disorder) and mixed anxiety and depressive states ( ; ), as well as social anxiety disorder ( ), panic disorder ( ; ; ), posttraumatic stress disorder ( ), and selected symptoms of bulimia nervosa ( ). Below, we discuss the clinical evidence supporting the use of MAOIs for treating MDD and other unipolar depressive syndromes, with an emphasis on treatment-resistant cases. The use of MAOIs for treatment-resistant bipolar depression is discussed in a separate chapter.
Depressive disorders, broadly defined
Numerous studies support the effectiveness of MAOIs for a variety of unipolar depressive syndromes, including MDD. Rather than reviewing each of the individual studies separately, we summarize below the main results of four key metaanalyses of MAOIs for depressive disorders, defined broadly.
Phenelzine, isocarboxazid, and tranylcypromine were all shown to be about equally effective in a metaanalysis of heterogeneous randomized trials that enrolled patients with a range of depressive disorders ( ). Response rates were 57.9% with phenelzine (14 outpatient studies and 7 inpatient studies, totaling 981 treated subjects), 60.1% with isocarboxazid (five outpatient studies and four inpatient studies, totaling 434 treated subjects), and 52.6% for tranylcypromine (five outpatient studies and four inpatient studies, totaling 293 treated subjects). All of the MAOIs were more effective than placebo in outpatient trials. In subgroup analyses, the MAOIs as a whole were found to be superior to tricyclic antidepressants for atypical depression, and were found to be effective for patients who were poorly responsive to tricyclic antidepressants. An updated metaanalysis focused on the clinical effectiveness of tranylcypromine for broadly defined depressive states ( ). Treatment response was defined as achieving > 50% improvement in total scores on depression rating scales or a predetermined cut-off score on measures of clinical global state. Tranylcypromine was superior to placebo for achieving a positive treatment response (pooled logOR 0.51, 95% CI 0.03 to 0.99, four studies) and was equal in efficacy to other antidepressants—mainly, tricyclic antidepressants (pooled logOR 0.21, 95% CI − 0.13 to 0.54, 10 studies).
The efficacy of transdermal selegiline for MDD is supported by a metaanalysis of five short-term randomized trials, totaling 1289 subjects ( ). Four studies used a fixed dose of 6 mg/24 h, and one trial used flexible dosing in the 6 mg/24 h to 12 mg/24 h range. After adjusting for baseline depression severity, transdermal selegiline was found to be superior to placebo for improving core depressive symptoms (depressed mood, guilt, impairment in work and activities, psychomotor retardation, psychic anxiety, and general somatic symptoms), as well as reverse vegetative symptoms (hypersomnia and overeating). In two pivotal randomized trials, response rates (defined as ≥ 50% reduction in depression scale scores) were significantly higher with transdermal selegiline than placebo at 6 weeks (37.5% vs 22.7%) and at 8 weeks (33.1% vs 20.8%) ( ; ).
Finally, in a metaanalysis of over 700 depressed patients, moclobemide was found to be superior to placebo and comparable in efficacy to tricyclic antidepressants ( ). The results of pooled analyses suggested that moclobemide may be more efficacious for stress-induced depression than for depression without an apparent external cause (referred to as “endogenous” depression). Additional evidence suggests that moclobemide may be as effective as selective serotonin reuptake inhibitor (SSRI) antidepressants for depressed outpatients ( ). However, moclobemide was found to be less-effective than clomipramine, a tricyclic antidepressant with very high affinity for the human serotonin transporter ( ), in two large multicenter trials ( ; ).
Depression with atypical features
An estimated 15%–30% of people with MDD have atypical features ( ; ; ). This subtype of depression is characterized by preserved reactivity of mood—that is, the ability for mood to improve in response to positive life events—and at least two of the following symptoms: weight gain or appetite stimulation, hypersomnia, severe fatigue causing the sensation of intense heaviness in the upper and lower extremities, and rejection sensitivity ( ; ). Rejection sensitivity in this case is not confined to the depressive episode. Instead, it is a stable and enduring character trait marked by feelings of unease around others and proneness to feelings of inadequacy or being negatively judged ( ).
Substantial evidence supports the effectiveness of irreversible oral MAOIs for depression with atypical features, as compared with tricyclic antidepressants, suggesting a preferential response profile ( ; ; ). Subgroup analyses from two of the metaanalyses reviewed earlier showed superior antidepressive responses to irreversible oral MAOIs compared with tricyclic antidepressants for participants with atypical depression ( ; ). In a separate metaanalysis of eight randomized trials (six phenelzine studies, two moclobemide studies) that focused specifically on the clinical effects of MAOIs for depression with atypical features, MAOIs were found to be superior to both placebo (ES 0.45, 95% CI 0.35–0.60) and tricyclic antidepressants (ES 0.27, 95% CI 0.16–0.42) ( ). These findings were similar to those of an additional pooled analysis of data from clinical trials showing superiority of MAOIs over tricyclic antidepressants, but not SSRIs, for depression with atypical features ( ).
At present, the neurobiological basis for the apparent efficacy advantage of MAOIs over tricyclic antidepressants in people with atypical depression is unknown. An interesting positron emission tomography (PET) study of 42 people with MDD showed that so-called reversed neurovegetative symptoms (which are features of atypical depression) were associated with elevated MAO-A V T , a proxy measure for MAO-A density ( ). Such findings may provide some insights into a putative mechanism underlying the preferential response to MAOIs over tricyclic antidepressants in people with MDD with atypical features, although it does not explain the apparent equivalence in efficacy between MAOIs and SSRIs.
Randomized trials of transdermal selegiline for depression with atypical features are sparse. In a post hoc analysis of data from five acute-phase trials of transdermal selegiline for MDD ( ), the presence of atypical features was defined on the basis of specific individual item scores on the 28-item version of the Hamilton Depression Rating Scale ( ). A total of 352 subjects satisfied the criteria for atypical depression. Transdermal selegiline was nearly equally efficacious for subjects with atypical and nonatypical depression. Randomized trials assessing the efficacy of transdermal selegiline for people with clinically defined atypical depression are still needed.
Individual studies of moclobemide for depression with atypical features have not yet pointed to a clear efficacy advantage compared with other antidepressant classes. For example, in a 12-week randomized trial comparing the antidepressive effects of moclobemide (300–450 mg/day) and sertraline (50–100 mg/day) in 197 outpatients with atypical depression, both groups improved from baseline but no significant differences in response rates (67.5% with moclobemide vs 77.5% with sertraline) were observed ( ). In a 6-week randomized trial of 167 depressed outpatients (17 of whom had atypical features), moclobemide was no more effective than clomipramine ( ). There were no significant between-group differences in the distribution of people with atypical depression.
Persistent depressive disorder and chronic depression
There is evidence supporting the use of oral irreversible MAOIs for the treatment of persistent depressive disorder and other forms of chronic depression. For instance, a metaanalysis of 15 placebo-controlled trials showed similar efficacy for MAOIs, tricyclic antidepressants, SSRIs, and other antidepressants for people with persistent depressive disorder ( ). The number needed to treat (NNT) for positive treatment response (vs placebo) was 2.9 for MAOIs, as compared with 4.3 for tricyclic antidepressants and 4.7 for SSRIs, suggesting a large clinical effect size for MAOIs and a possible small efficacy advantage when compared with the remaining classes of antidepressants.
Individual studies of phenelzine for persistent depressive disorder showed greater effectiveness than imipramine and placebo ( ; ; ); however, imipramine was superior to phenelzine in subgroup analyses focused on patients with melancholic rather than atypical depressive features ( ). In a pooled analysis of data from clinical studies of patients with chronic depression or comorbid MDD and dysthymic disorder, phenelzine was found to be significantly more effective than imipramine and placebo ( ). For the small number of subjects with persistent depressive disorder, there were no significant differences in efficacy between phenelzine and imipramine, although only imipramine was superior to placebo.
Regarding the long-term treatment of chronic depressive states, the efficacy of phenelzine is supported by the results of a randomized maintenance trial of 60 people with chronic atypical depression ( ). Enrollees had previously responded to either phenelzine or imipramine, and were randomly assigned to continued treatment with the same medication or switch to placebo ( ). During the maintenance phase of the trial, recurrence rates were lower with phenelzine than imipramine (23% vs 41%), and only phenelzine resulted in significantly greater efficacy than placebo for preventing depressive recurrences.
There are fewer randomized trials of isocarboxazid for chronic depression or persistent depressive disorder. In a pooled analysis of data from a three-site randomized trial, the enrolled participants with “minor” depression (a term that encompassed chronic forms of depression including persistent depressive disorder) as well as MDD, treatment with isocarboxazid resulted in a numerically higher response rate than placebo (58% vs 44%) ( ). Drug-placebo differences favoring isocarboxazid were larger and statistically significant, however, for the subgroup of 95 patients with MDD.
We were not able to locate randomized trials of tranylcypromine or transdermal selegiline for persistent depressive disorder. However, there is evidence supporting the clinical effectiveness of moclobemide. In a large network metaanalysis of 45 randomized trials (> 5300 patients) that examined the clinical effectiveness of 28 drugs for persistent depressive disorder, moclobemide was found to be superior to placebo (clinical response, OR 6.98, 95% CI 3.68–13.74), with no between-group differences in premature discontinuation for any cause as a proxy for treatment acceptability ( ). One randomized trial focused specifically on patients with comorbid MDD and dysthymic disorder and showed a higher response rate with moclobemide than fluoxetine (71% vs 38%) after 6 weeks of treatment, although both drugs were comparable on other depression treatment outcomes ( ).
Clinical studies in people with treatment-resistant depression
There is evidence that some MAOIs are effective treatments for depressed patients that have failed to respond to prior therapeutic trials of other antidepressants, although empirical data from randomized trials of subjects with well-defined treatment-resistant depression are relatively sparse ( ). The available evidence supporting the use of MAOIs for treatment-resistant unipolar depression is summarized in Table 9.3 .
| Study | Sample | Design | Comparator groups | TRD definition | Key findings |
|---|---|---|---|---|---|
| 30 Elderly adults (ages 60–84 years) with TRD | Open, uncontrolled trial (7 weeks) | Phenelzine 30–75 mg/day (mean 49.5 mg/day) | Failed to respond to TCA (37% also resistant to ECT) | 65% responded to phenelzine (HAM-D ≤ 10 at study termination) | |
| 29 Elderly hospitalized adults with TRD | Open randomized trial (6 weeks) | Phenelzine 30–60 mg/day (mean 46.0 mg/day) vs venlafaxine or TCA plus lithium | Failed to respond to TCA or venlafaxine monotherapy | Response rates (≥ 50% decrease in 17-item HAM-D) higher with phenelzine (46.7%) than comparator (7.1%) | |
| 66 Adults with TRD (nonmelancholic, mood-reactive, DSM-III) | RCT (6 weeks) with secondary cross-over | Phenelzine (up to 90 g/day) vs imipramine (up to 300 mg/day) | Failed to respond to initial trial of phenelzine, imipramine, or placebo a | Higher response rates (much improved or very much improved according to CGI-I) with phenelzine (51.2%) than imipramine (32.0%) | |
| 26 Adults with TRD | Randomized cross-over trial (6 weeks) | Phenelzine 60–90 mg/day (mean 72.0 mg/day) vs imipramine 200–300 mg/day (mean 275.0 mg/day) | Failed to respond to phenelzine, imipramine, or placebo prior to cross-over | Higher response rate (much improved or very much improved according to CGI-I) with phenelzine (65.4%) than imipramine (28.6%) | |
| 67 Hospitalized adults with TRD | RCT (5 weeks) | Phenelzine 20–100 mg/day vs tranylcypromine 20–100 mg/day | Failure to respond to TCA or fluvoxamine | Comparable response rates (≥ 50% decrease in 17-item HAM-D) between phenelzine (47.4%) and tranylcypromine (43.6%) | |
| 109 Adults with TRD | RCT (12 weeks) | Tranylcypromine 10–60 mg/day (mean 36.9 mg/day) vs mirtazapine (mean 35.7 mg/day)/venlafaxine (mean 275.0 mg/day) combination therapy | Failure to remit (or tolerate) three prospective antidepressant treatment trials | Low response rates (≥ 50% decrease in QIDS-SR) for both tranylcypromine (12.1%) and combination (23.5%) | |
| 39 Hospitalized adults with TRD (59% with melancholic depression) | RCT (4 weeks) | Tranylcypromine 20–100 mg/day (mean 81.2 mg/day) vs brofaromine 50–250 mg/day (mean 215.9 mg/day) | Failure to respond to nortriptyline or maprotiline | Lower response rate (≥ 50% decrease in 17-item HAM-D) with tranylcypromine (29.4%) than brofaromine (45.5%), but similar HDSS response rates (52.9% vs 45.5%) and proportion rated as “very much improved” on CGI-I (58.9% vs 59.1%) | |
| 47 Hospitalized patients with TRD | RCT (4 weeks) with secondary cross-over | Tranylcypromine 40–100 mg/day (mean 78.0 mg/day) vs L-5HTP up to 200 mg/day (mean 191.7 mg/day) in phase 1; nomifensine 50–250 mg/day (235.0 mg/day) in phase 2 | Failure to respond to fluoxetine or oxaprotiline (phase 1); nonresponders in phase 1 crossed over into phase 2 b | Higher response rate (≥ 50% decrease in 17-item HAM-D) with tranylcypromine (57.1%) than L-5HTP (0.0%) in phase 1; higher response rate with tranylcypromine (62.5%) than nomifensine (0.0%) in phase 2 | |
| 26 Hospitalized patients with TRD | Randomized cross-over trial (4 weeks) | Tranylcypromine 20–100 mg/day (mean 82.0 mg/day) vs L-5HTP 20–100 mg/day (mean 182.0 mg/day) | Failure to respond to at least one antidepressant trial of adequate design, followed by failure to respond to fluvoxamine or oxaprotiline and sleep deprivation | Higher response rate (≥ 50% decrease in 17-item HAM-D) with tranylcypromine (57.7%) than L-5HTP (0.0%) | |
| 40 Patients with TRD (67.5% with atypical features) | Open, uncontrolled trial (6 weeks) with two historical control groups | Tranylcypromine 20–60 mg/day (mean 38.5 mg/day) vs phenelzine 30–60 mg/day (mean 60.0 mg/day) | Failure to respond to 16 weeks of imipramine + interpersonal psychotherapy | Comparable response rates (≥ 50% decrease in 17-item HAM-D) with tranylcypromine (55.0%) and phenelzine (57.5%) | |
| 90 Hospitalized patients with TRD (mixture of unipolar [82.2% with MDD] and bipolar patients [4.4%]), 10.0% with atypical features | RCT (6 weeks) | Tranylcypromine 20–30 mg/day (mean 26.2 mg/day) vs brofaromine 100–150 mg/day (mean 133.0 mg/day) | Failure to respond to two or more classes of non-MAOI antidepressants | Comparable response rates (≥ 50% decrease in 21-item HAM-D) between tranylcypromine (72.3%) and brofaromine (73.0%) |
a A total of 66 patients crossed over to the opposite active treatment following initial failure to respond to phenelzine or imipramine.
b A total of 18 nonresponders during phase 1 were eligible for phase 2 treatment. Eight of the ten patients who were eligible for tranylcypromine received treatment and five of the remaining patients who were eligible for nomifensine received treatment during phase 2.
Metaanalyses of MAOIs for treatment-resistant depression
Two reviews document the effectiveness of phenelzine and tranylcypromine for patients with depression and a history of poor response to tricyclic antidepressants. In the report by presented earlier, the authors conducted a review of controlled and uncontrolled studies of MAOIs for tricyclic-resistant depression, and concluded that an estimated 50% of such patients respond favorably to MAOIs. When only tricyclic-resistant patients with atypical depression were considered, the estimated positive response rate with MAOIs increased to 70%. These estimated response rates may be inflated, however, by the inclusion of uncontrolled studies and by uncertainty about the number of therapeutic trials of antidepressants prior to tricyclic antidepressant failure—information that would be important for determining whether included subjects were also resistant to other types of antidepressants.
The more recent metaanalysis by , also reviewed earlier, confirmed the efficacy of tranylcypromine in patients who failed to respond to tricyclic antidepressants and SSRIs. Within that subgroup of depressed patients, tranylcypromine was associated with significantly greater likelihood of positive treatment response than placebo (logOR 2.83, 95% CI 1.49–4.16, one study) and nonestablished antidepressants (pooled logOR 1.98, 95% CI 0.91–3.05, four studies). Tranylcypromine was as effective as treatment with other MAOIs or combination therapy with venlafaxine and mirtazapine (pooled logOR 0.37, 95% CI − 0.87 to 0.14, four studies).
Individual studies of MAOIs for treatment-resistant depression
Phenelzine, isocarboxazid, and tranylcypromine
In individual studies of MAOIs for treatment-resistant depression ( Table 9.3 ), rates of positive treatment response ranged from approximately 13% to 67%. Such wide variation in response rates is the likely result of high degrees of heterogeneity between trials, making it difficult to provide a broad interpretation of these results. For instance, while MAOIs have been tested in patients who have responded poorly to prior antidepressant trials, particularly tricyclic antidepressants, the definition of treatment-resistance varies substantially across the individual studies. For most studies, treatment resistance was defined as either failing to respond to tricyclic antidepressants ( ; ; ), at least one prior therapeutic trial involving tricyclic or nontricyclic antidepressants ( ; ; ; ), or two or more classes of antidepressants ( ; ). Two cross-over studies involved depressed patients who failed to respond to an MAOI or tricyclic antidepressant ( ). All studies were controlled using either cross-over or traditional parallel-group designs, with the exceptions of one open uncontrolled study ( ) and one study that used two historical control groups ( ). A very wide range of doses (10–100 mg/day) was investigated in flexible-dose studies of phenelzine and tranylcypromine. Definitions of treatment response also varied from study to study. Importantly, none of the studies in Table 9.3 focused on the effects of isocarboxazid, transdermal selegiline, or moclobemide in patients with treatment-resistant depression.
Methodological variations aside, a number of the existing studies of MAOIs for treatment-resistant depression included patients with a relatively small number of prior treatment failures. This fact may limit the translational impact of study results on modern practice where patients who are being considered for MAOI treatment will have failed to respond to multiple classes of antidepressants; and, very likely, multiple agents within each class. Therefore, rather than conducting an exhaustive review of each of the trials summarized in Table 9.3 , the remaining discussion will focus on the few clinical studies of MAOIs for patients with well-characterized treatment-resistant depression who are in the latter stages of treatment resistance and may better-resemble depressed patients for whom treatment with MAOIs would warrant serious consideration in current clinical practice.
In the fourth phase of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, 109 patients with MDD were randomized to next-step treatment with either tranylcypromine or combination therapy with venlafaxine and mirtazapine ( ). Study participants previously failed to respond to three carefully conducted prospective antidepressant trials beginning with citalopram (phase 1); augmentation of citalopram or cognitive behavioral therapy (phase 2); and switching to bupropion, sertraline, venlafaxine, or CBT without citalopram (phase 3). The response rates for tranylcypromine and combination therapy with venlafaxine and mirtazapine were low (12.1% vs 23.5%). Remission rates were even lower (6.9% vs 13.7%). After restricting the analyses to the 21 patients with atypical depression, there were no significant between-group differences in rates of positive treatment response. These findings have been criticized due to the low doses of tranylcypromine used in this trial (mean dose 36.9 mg/day) ( ), which may have at least partially accounted for the low response and remission rates with tranylcypromine in contrast with what appeared to be more aggressively dosed combination therapy with venlafaxine and mirtazapine. Despite the low mean tranylcypromine dose, dropout rates due to adverse effects were proportionally higher with tranylcypromine than combination therapy (41.4% vs 21.6%). Additionally, a higher proportion of tranylcypromine-treated patients entered into the study due to previous medication intolerance (rather than treatment failure) than those randomized to combination therapy (41% vs 22%) ( ). This may have introduced some bias toward higher risk of premature discontinuation from the study due to adverse effects and poorer rates of treatment response in the tranylcypromine group. The number of prior trials (a proxy for the stage of treatment resistance) was not statistically correlated with the likelihood of a positive treatment outcome with tranylcypromine. It should be noted, however, that several patients who did achieve remission with tranylcypromine had a history of previous failure to respond to bitemporal electroconvulsive therapy (ECT).
In an interesting retrospective chart review study, information was abstracted from 400 records to test the hypothesis that MAOI therapy would be similarly effective for patients with treatment-resistant depression who had failed to respond to at least four prior therapeutic trials of antidepressants, as compared to those who had failed to respond to three or fewer trials ( ). Over half (59%) of the 59 unique patients in the chart review sample had MDD, while the rest had treatment-resistant bipolar I (2%), bipolar II (34%), or unspecified bipolar depression (5%). These 59 patients had a total of 75 MAOI treatment trials with tranylcypromine ( n = 47, mean peak dose 57 mg/day), phenelzine ( n = 12, mean peak dose 58 mg/day), isocarboxazid ( n = 13 mean peak dose 47 mg/day), and oral selegiline ( n = 3, mean peak dose 53 mg/day). After an average of 39 weeks of follow-up, MAOI treatment yielded a favorable response, defined as a CGI-change score of 1 (very much improved) or 2 (much improved), in 56% of patients who responded poorly to fewer than four prior antidepressant trials and 12% of those who failed to respond to four or more previous trials. This study was limited by its retrospective design, small sample size, lack of a non-MAOI comparator group, and inability to verify the adequacy of prior antidepressant trials.
In a longitudinal study, 118 people with confirmed treatment-resistant depression (77 with unipolar depressive disorders) who were initially managed in a psychiatric hospital setting were started on various antidepressive treatments and were followed for an average of 39 months ( ). Most of the study participants eventually achieved remission (60.2%), 48.3% of whom had a sustained recovery defined as continued remission for at least 6 months. After controlling for other treatments, there was a positive association between treatment with a MAOI and remission—both at hospital discharge and at the end of long-term follow-up. The relationship between MAOIs and remission was especially strong for people with MDD at discharge (OR 6.49, 95% CI 1.62–25.91) and at the end of follow-up (OR 4.78, 95% CI 1.15–19.85). The mean daily doses of phenelzine, tranylcypromine, isocarboxazid, and moclobemide were 70.0, 32.5, 40.0, and 650.0 mg, respectively.
We were unable to locate studies that focused exclusively on the clinical effects of MAOIs in people with treatment-resistant MDD who failed to respond to ECT, still broadly considered a gold standard therapeutic for drug-resistant depression ( ). Limited information is available about MAOI effectiveness in ECT-resistant depression from a handful of the trials that included depressed patients who had previously failed to respond to ECT during the current episode. For example, in a 7-week uncontrolled trial of elderly patients with treatment-resistant MDD who had failed to respond to treatment with a tricyclic antidepressant, over one-third of enrollees had also failed to respond to ECT ( ). The overall rate of positive response (defined as a HAMD total score ≤ 10 at termination) was 66.7%. However, response rates in the ECT-refractory subgroup were not reported.
Transdermal selegiline
Randomized trials of transdermal selegiline for patients with well-defined treatment-resistant depression are needed. One small randomized trial of oral selegiline (60 mg/day) enrolled 16 elderly subjects who had failed to respond after at least two therapeutic antidepressant trials ( ). Study participants had failed to respond to an average of 4.2 antidepressants prior to treatment with selegiline. A total of 10 participants had failed to respond to oral MAOIs and six participants had failed to respond to ECT. During the 3-week randomized treatment phase, there were significant improvements in depressive symptoms, as well as global measures of depression and anxiety, with oral selegiline relative to placebo. No serious adverse effects were reported. The response rate with oral selegiline was 50%, based on a 17-item HAM-D total score of 11 or lower, which is reasonably high given the 3-week duration of the study. However, the durability of treatment response beyond 3 weeks was not reported, and the generalizability of findings from this study to nongeriatric adults with treatment-resistant depression or to the use of transdermal selegiline for treatment-resistant depression is unclear.
Moclobemide
To our knowledge, there are no randomized trials of moclobemide for well-defined treatment-resistant depression. Moclobemide may be expected to have tolerability advantages over irreversible MAOIs ( ); however, moclobemide and other RIMAs may be less-effective antidepressants than orally administered irreversible MAOIs such as phenelzine and tranylcypromine ( ). Randomized trials are needed to determine whether or not moclobemide is worth considering as a treatment option for even early stage treatment-resistant depression.
Adverse effects and toxicology
Common adverse effects
Phenelzine, isocarboxazid, and tranylcypromine
Common adverse effects for most oral irreversible MAOIs occur at the early stages of treatment and include insomnia, sedation, orthostatic hypotension, dizziness, headache, dry mouth, loose stools, blurry vision, appetite changes, and nausea ( ; ). In our experience, many patients will adapt to these adverse effects over time, although several weeks may be required. Orthostatic hypotension is the most common dose-limiting adverse effect, especially in elderly persons. Tranylcypromine can sometimes cause a transient increase in blood pressure that typically resolves after a few hours. Longer-term adverse effects can include muscular pain, sexual dysfunction, edema, and weight ( ). The risk of weight gain is generally lower with tranylcypromine than with phenelzine ( ). Oral MAOIs do not directly block muscarinic acetylcholine receptors and, therefore, do not cause anticholinergic side-effects, per se. In this regard, there are no known adverse effects on cognitive functioning with the long-term use of oral irreversible MAOIs.
Transdermal selegiline
Common adverse effects of transdermal selegiline include headache, insomnia, and local skin irritation (itching, redness, and swelling) at the patch application site ( ). Transdermal selegiline is associated with a very low risk of sexual dysfunction and weight gain, even with longer-term treatment ( ).
Uncommon or rare adverse effects
Some MAOIs have been associated with rare but potentially severe adverse effects. Up to 3% of patients treated with MAOIs (including moclobemide) experience asymptomatic mild elevations in liver function enzymes ( ). However, oral irreversible MAOIs are associated with a higher risk of hepatotoxicity than newer antidepressants, such as SSRIs ( ; ). The risk of MAOI-associated hepatotoxicity is small overall, but appears to be higher with the hydrazine class than with tranylcypromine ( ). Although acute liver injury due to MAOIs is usually self-limited, cases of progressive, severe, and fatal acute liver injury have been reported, particularly for phenelzine. Selegiline has been reported to cause hepatic enzyme elevations in up to 40% of patients who receive long-term treatment, but these were usually mild and self-limited, without leading to clinically apparent acute liver injury. Therefore, selegiline is currently classified as an unlikely cause of clinically apparent liver injury ( ).
There are rare reports of drug-induced lupus erythematosus associated with phenelzine ( ). Symptoms of phenelzine-associated lupus are similar to those observed in cases of systemic lupus erythematosus. These include flu-like symptoms, myalgias, arthralgias, skin rash, and fever. Antinuclear antibody and antihistamine antibody testing may also be positive. The symptoms of MAOI-associated lupus typically resolve within 2 weeks following medication discontinuation, either spontaneously or with the use of nonsteroidal antiinflammatory medications or oral corticosteroids. Transdermal selegiline has been associated with reports of flu-like symptoms although, to our knowledge, there are no published reports of well-defined cases of drug-induced lupus.
Other rare or uncommon adverse effects associated with mainly oral irreversible MAOIs include severe daytime somnolence, mental status changes, weakness, involuntary muscle jerks, urinary hesitancy, and nystagmus. Hydrazine MAOIs (phenelzine and isocarboxazid) may cause inactivation of vitamin B6 that can lead to paresthesias. Oral irreversible MAOIs may cause generally asymptomatic electrocardiographic changes including bradycardia and shortening of the PR and corrected QT intervals ( ).
Discontinuation syndrome
Discontinuation syndromes occur rarely with immediate or rapid discontinuation of MAOIs, especially when they are used at usual effective doses for depression. However, the risk may be increased on immediate or rapid discontinuation of MAOIs in people who have taken higher doses and those who have been on long-term maintenance treatment. Common symptoms include nausea, vomiting, anxiety, diaphoresis, chills, and nightmares. More severe symptoms described in case reports include hallucinosis, agitation, paranoia, movement disorders, convulsions, and delirium ( ). Therefore, whenever feasible, tapering over 4 weeks or more is recommended when discontinuing treatment with MAOIs. Longer tapering periods may be needed if discontinuation syndrome symptoms occur while reducing the dose. In cases of strongly suspected hypertensive crisis or serotonin toxicity, immediate discontinuation of MAOIs (and interacting drugs) is needed regardless of the risk of precipitating a discontinuation syndrome.
Overdose
Phenelzine, isocarboxazid, and tranylcypromine
Overdoses on oral irreversible MAOIs are potentially fatal, and thus require emergency assessment and management. Common symptoms observed with MAOI overdose include altered mental status, hyperthermia, increases in blood pressure and heart rate, and increased respiratory rate. Hyperglycemia and leukocytosis may also occur. Severe toxicity associated with large overdoses may be characterized by hyperpyrexia, seizures, respiratory depression, cardiovascular collapse, and death. Although deaths due to MAOI overdoses are rare, ingestions of 2–3 mg/kg or more are generally considered life-threatening ( ).
Transdermal selegiline
There is a paucity of overdose toxicity data for transdermal selegiline. A review of postmarketing data from 29,141 unique patients who were treated with transdermal selegiline yielded a total of four cases of completed suicide and four additional cases of attempted suicide ( ). All completed suicides involved the ingestion of multiple drugs including contraindicated substances like crystal methamphetamine. It is unclear whether transdermal selegiline is safer in overdose than orally administered selegiline or other orally administered MAOIs. The loss of pharmacological selectivity for MAOI-B at high doses of selegiline make it likely that the signs, symptoms and risks associated with overdoses of transdermal selegiline may be similar to overdoses of oral nonselective MAOIs. Therefore, transdermal selegiline overdose is as much a medical emergency as is an overdose on oral nonselective MAOIs.
Moclobemide
Signs and symptoms of moclobemide toxicity include mental status changes, dizziness, headaches, muscle rigidity and seizures ( ). The effects of moclobemide overdose as a sole ingestion are thought to be relatively minor; however, severe serotonin toxicity can occur in the setting of moclobemide overdose with the coingestion of serotonin-potentiating drugs such as SSRIs ( ), as reviewed further below.
Interactions
Pharmacokinetic interactions
There are few clinically relevant pharmacokinetic drug-drug or drug-nutrient interactions for most MAOIs. Phenelzine displays weak but irreversible inhibition of CYP2C9 and 3A4 in vitro; however, there are no clinically relevant drug reactions related to such activity ( ). Tranylcypromine is a competitive inhibitor of CYP2C19 although, at therapeutically relevant doses, the significance of this effect is also unknown ( ). At antidepressive doses, tranylcypromine is a more potent inhibitor of CYP2A6, which can result in increased plasma nicotine levels and possibly affect the metabolism of a few commonly used medications such as tamoxifen and propofol ( ).
Pharmacodynamic interactions
The inhibition of MAO-A, a pharmacological activity shared by nearly all MAOIs used to treat depression, in combination with certain medications or tyramine-containing foodstuffs, can lead to pharmacodynamic interactions that are highly significant and, in some cases, potentially life-threatening. These include serotonin toxicity when MAOIs are combined with certain serotonergic medications, hypertensive crises when they are combined with some sympathomimetic agents, and hypertensive responses following the ingestion of a sufficient amount of dietary tyramine. Frequent assessment for potential drug interactions and adherence to dietary guidelines is needed to avoid these outcomes. Fortunately, such interactions are predictable and relatively easy to avoid.
Serotonin toxicity
Serotonin toxicity (sometimes referred to as serotonin syndrome) is a potentially life-threatening toxicity syndrome that is precipitated by the concomitant use of MAOIs and selected serotonin-potentiating drugs, leading to excessive central and peripheral serotonergic activity ( ). Clinical signs and symptoms of serotonin toxicity are grouped into three categories: altered mental status (confusion, agitation, excitement); autonomic hyperactivity (fever, diaphoresis, mydriasis, tachypnea, tachycardia); and neuromuscular hyperactivity (tremor, clonus, myoclonus, hyperreflexia, hypertonicity) ( ). The successful management of serotonin toxicity depends on the rapid recognition of the signs of serotonin toxicity, immediate cessation of all serotonergic agents, and the availability of supportive care—the latter of which includes intravenous hydration, cooling blankets or ice packs for hyperthermia, benzodiazepines for myoclonus, and airway protection or respiratory support (including mechanical ventilation) when required ( ). Stabilization in an intensive care unit may be needed for severe cases.
Serotonin toxicity is precipitated, for purposes of our discussion, by any combination of MAOIs and drugs that display serotonin reuptake inhibition ( ). As shown in Table 9.4 , this includes not only SSRI or serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants, but also selected tricyclic antidepressants (TCAs, e.g., clomipramine and imipramine), newer antidepressants (e.g., vortioxetine and vilazodone), and selected nonpsychotropics ( ; ; ; ; ; ). These drugs should be avoided in people who are being treated with any MAOIs ( ; ). In our experience, most atypical antipsychotic drugs that are used to augment minimal or partial therapeutic responses to antidepressants can be safely combined with irreversible MAOIs. Ziprasidone is probably best avoided, however, because it blocks serotonin reuptake pumps ( ; ). Case literature describes the safe coadministration of irreversible MAOIs and other commonly used adjuncts, such as trazodone ( ). Lithium is thought to have serotonergic properties, but there are several reports of the safe use of lithium for improving the antidepressive effects of irreversible MAOIs without precipitating serotonin toxicity ( ; ; ). It is often recommended that people taking MAOIs avoid augmentation with buspirone, a serotonin 5-HT1A partial agonist, although the association between buspirone and the risk of serotonin toxicity in people taking MAOIs is not clear ( ). A more detailed discussion of augmentation of irreversible MAOIs is provided below.
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Combining antidepressants to address treatment-resistant depression
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