Monoamine oxidase inhibitors: Seriously underused in the treatment of major depression

IF 5.3 2区 医学 Q1 PSYCHIATRY Acta Psychiatrica Scandinavica Pub Date : 2024-09-03 DOI:10.1111/acps.13753
Tom K. Birkenhager, Willemijn T. Heijnen
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In addition, tranylcypromine is similar in chemical structure to amphetamine and shares its dopamine-releasing and stimulant-like effects. Tranylcypromine and phenelzine are the most frequently used non-selective MAOIs, which bind the MAO enzyme irreversibly, and deactivate it permanently. Moclobemide is a selective MAO-A inhibitor, and enters into a reversible binding to the enzyme. Tranylcypromine and Phenelzine were widely prescribed until the late 1960s. The use of MAOIs has declined dramatically, as stated in their network meta-analysis by Gimenez-Palomo et al.<span><sup>2</sup></span> The historical perspective is important in understanding this decline.</p><p>In the 1960s it was not well understood that MAOIs inhibit the breakdown of tyramine, and that excessive tyramine intake when using an MAOI, can lead to a hypertensive crisis. A series of initially unexplained hypertensive crises actually occurred, some even resulting in stroke. The cause of this “cheese reaction” was uncovered in the late 1960s, but the fear for the hypertensive reaction remained. Furthermore, in one of the first large randomized clinical trials in psychiatry,<span><sup>3</sup></span> which included 260 depressed patients, both ECT and imipramine appeared to be effective, whereas phenelzine and placebo were not. In hindsight, one may well argue, that both the duration of treatment with phenelzine (4 weeks) and its dose (maximum 60 mg daily) were insufficient, therefore, phenelzine fell short of its full efficacy potential. Subsequently, MAOIs were regarded as not very effective and dangerous antidepressant drugs. This perception influenced physicians to strongly favor tricyclic antidepressants (TCAs) over MAOIs. Usage of MAOIs further declined, following the development of newer antidepressants, especially the selective serotonin reuptake inhibitors (SSRIs). Concerns about the safety profile of MAOIs, including potentially dangerous drug–drug interactions, which could result in serotonin syndrome, and the risk of a hypertensive crisis restricted their use. Furthermore, the use of MAOIs was not promoted by any pharmaceutical company.</p><p>In several countries the number of prescriptions of MAOIs is extremely low: about 500 patients treated in a population of 16 million.<span><sup>4</sup></span></p><p>A consequence of this low prescription rate is that psychiatrists in training are rarely educated about MAOIs. Residents in psychiatry may graduate from excellent training programs with hardly any knowledge about MAOIs, not knowing specific indications for treatment with MAOIs, and how to avoid safety issues with these drugs.</p><p>Education within psychiatric training usually focuses on recent literature and systematic reviews.<span><sup>5</sup></span> Since the large majority of studies on MAOIs are dated, they tend to be strongly underrepresented in recent literature.</p><p>Therefore, the comprehensive systematic review by Gimenez-Palomo et al.<span><sup>2</sup></span> is a valuable contribution emphasizing the role of MAOIs in the treatment of major depression.</p><p>The authors concluded that the antidepressant efficacy of MAOIs and other antidepressants was similar. However, as pointed out by Lee and Wei<span><sup>6</sup></span> in a letter to the editor in response to the systematic review, MAOIs have shown to be superior to other antidepressants in several subtypes of major depression. At Columbia University New York, a series of six studies were performed in patients with atypical depression. In patients with atypical depression, defined as major depression with preserved mood reactivity and two secondary atypical symptoms, phenelzine consequently proved to be more effective than both imipramine and placebo.<span><sup>7</sup></span> These six studies comprised 409 patients with an overall response rate of 26% for placebo versus 44% for imipramine versus 72% for phenelzine.</p><p>The second subtype of major depression, in which MAOIs probably are superior in efficacy is bipolar depression. In a systematic review, Heijnen et al.<span><sup>8</sup></span> found an overall response rate of 74% for tranylcypromine (40–60 mg) compared with 28% in control conditions in bipolar depression. Their results emphasize the statement by Thase and Sachs<span><sup>9</sup></span> in a previous review: “All other things equal, the MAOI tranylcypromine could be considered a treatment of first choice for bipolar depression. The track record of this drug spanning open-label, placebo-controlled, and imipramine-comparator clinical trials.”</p><p>In an open study in patients with bipolar depression,<span><sup>10</sup></span> who already received a mood stabilizer, the antidepressant effect of tranylcypromine appeared to be superior to that of paroxetine, as demonstrated by a recovery rate of 53% on tranylcypromine versus 27% on paroxetine.</p><p>Furthermore, current evidence suggests tranylcypromine and other MAOIs may have a low risk of inducing a switch into mania.<span><sup>8</sup></span></p><p>Therapeutic experience and non-controlled open studies suggest a clear therapeutic benefit from tranylcypromine in patients resistant to adequate antidepressant treatment. Unfortunately, there are only relatively few randomized controlled trials with MAOIs in patients with treatment-resistant depression (TRD), even though this is a major indication for their use.</p><p>However, a previous meta-analysis comprising a number of controlled studies, reported an overall response rate of 58% to tranylcypromine in patients with TRD.<span><sup>11</sup></span> Some authors consider tranylcypromine as a first choice in stage-3 TRD according to the Thase and Rush classification.<span><sup>12, 13</sup></span></p><p>In summary regarding the efficacy of non-selective MAOIs (especially tranylcypromine): they appear to be effective in two forms of major depression, which are notoriously difficult to treat: bipolar depression and treatment-resistant depression. MAOIs, specifically phenelzine, are also very effective in atypical depression, which may be less of a clinical challenge.</p><p>Moclobemide, a selective MAO-A inhibitor, has less side-effects than the non-selective MAOIs. Selective MAOI-A inhibitors, such as moclobemide, were developed as alternatives lacking the “cheese effect” and vigorously promoted in the late 1980s and early 1990s, with industry sponsored research, leading to substantial prescription of this drug. However, many clinicians believe that moclobemide is not as effective as nonselective MAOIs such as tranylcypromine or phenelzine. Consistent with these clinical impressions, is the result of a meta-analysis showing a clinically significant advantage for the older MAOIs compared with moclobemide.<span><sup>14</sup></span></p><p>When using a non-selective, irreversible MAOI (tranylcypromine, phenelzine) it is necessary to follow a tyramine-restricted diet. Many of the traditional MAOI diets, which remain standard at numerous hospitals, are unnecessarily restrictive. Reports of food interactions with MAOIs published in the early 1960s led to the development of stringent dietary restrictions. Consumption of numerous foods, principally cheese, by patients on MAOIs was associated with potentially fatal hypertensive crises.</p><p>However, many of the foods once thought to be dangerous for patients on MAOIs are now considered to be safe. Although the clinician's initial response may be to choose the more conservative diet, an excessively stringent diet may actually be unfavorable, since psychiatrists and patients may refrain from considering a potentially effective treatment with an MAOI. Furthermore, patients may become lax with their diet after accidentally discovering that certain diet items are actually not harmful.</p><p>Numerous studies have attempted to quantify the tyramine content of food. A tyramine content of less than 6 mg per portion is generally considered safe. Concurrent administration of an MAOI with drugs increasing the availability of serotonin might lead to the serotonin syndrome. Excessive stimulation of the 5-HT1a and 5-HT2 receptors may result in symptoms of serotonin syndrome. Most cases of serotonin syndrome have been reported when an MAOI was combined with meperidine, L-tryptophan, dextromethorphan, an SSRI, or a TCA that inhibits the reuptake of serotonin (clomipramine, imipramine).<span><sup>15</sup></span></p><p>Irreversible MAOIs (tranylcypromine, phenelzine) are very effective drugs in the treatment of both resistant and bipolar major depression. They can induce full remission when other antidepressants, combinations, and augmentation strategies, and even electroconvulsive therapy (ECT), have failed. Despite this, they are infrequently prescribed, in part because of substantial overestimation of their risk profile. 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引用次数: 0

Abstract

Monoamine oxidase inhibitors (MAOIs) were the first licensed antidepressants, they were discovered serendipitously, during a trial of iproniazid in patients with tuberculosis in the 1950s. Iproniazid appeared to have a “psychic energizing effect,” which resulted in the improvement of depressive symptoms in some tuberculosis patients,1 around that time, iproniazid was shown to inhibit the MAO enzyme. Iproniazid was approved as an antidepressant, and this led to the development of several other MAOIs. Brain neurotransmitter levels are inactivated by MAO-A (serotonin, norepinephrine, dopamine) and MAO-B (dopamine) isoenzymes. Inhibition of the MAO enzyme leads to an increasing synaptic availability of these monoamines. In addition, tranylcypromine is similar in chemical structure to amphetamine and shares its dopamine-releasing and stimulant-like effects. Tranylcypromine and phenelzine are the most frequently used non-selective MAOIs, which bind the MAO enzyme irreversibly, and deactivate it permanently. Moclobemide is a selective MAO-A inhibitor, and enters into a reversible binding to the enzyme. Tranylcypromine and Phenelzine were widely prescribed until the late 1960s. The use of MAOIs has declined dramatically, as stated in their network meta-analysis by Gimenez-Palomo et al.2 The historical perspective is important in understanding this decline.

In the 1960s it was not well understood that MAOIs inhibit the breakdown of tyramine, and that excessive tyramine intake when using an MAOI, can lead to a hypertensive crisis. A series of initially unexplained hypertensive crises actually occurred, some even resulting in stroke. The cause of this “cheese reaction” was uncovered in the late 1960s, but the fear for the hypertensive reaction remained. Furthermore, in one of the first large randomized clinical trials in psychiatry,3 which included 260 depressed patients, both ECT and imipramine appeared to be effective, whereas phenelzine and placebo were not. In hindsight, one may well argue, that both the duration of treatment with phenelzine (4 weeks) and its dose (maximum 60 mg daily) were insufficient, therefore, phenelzine fell short of its full efficacy potential. Subsequently, MAOIs were regarded as not very effective and dangerous antidepressant drugs. This perception influenced physicians to strongly favor tricyclic antidepressants (TCAs) over MAOIs. Usage of MAOIs further declined, following the development of newer antidepressants, especially the selective serotonin reuptake inhibitors (SSRIs). Concerns about the safety profile of MAOIs, including potentially dangerous drug–drug interactions, which could result in serotonin syndrome, and the risk of a hypertensive crisis restricted their use. Furthermore, the use of MAOIs was not promoted by any pharmaceutical company.

In several countries the number of prescriptions of MAOIs is extremely low: about 500 patients treated in a population of 16 million.4

A consequence of this low prescription rate is that psychiatrists in training are rarely educated about MAOIs. Residents in psychiatry may graduate from excellent training programs with hardly any knowledge about MAOIs, not knowing specific indications for treatment with MAOIs, and how to avoid safety issues with these drugs.

Education within psychiatric training usually focuses on recent literature and systematic reviews.5 Since the large majority of studies on MAOIs are dated, they tend to be strongly underrepresented in recent literature.

Therefore, the comprehensive systematic review by Gimenez-Palomo et al.2 is a valuable contribution emphasizing the role of MAOIs in the treatment of major depression.

The authors concluded that the antidepressant efficacy of MAOIs and other antidepressants was similar. However, as pointed out by Lee and Wei6 in a letter to the editor in response to the systematic review, MAOIs have shown to be superior to other antidepressants in several subtypes of major depression. At Columbia University New York, a series of six studies were performed in patients with atypical depression. In patients with atypical depression, defined as major depression with preserved mood reactivity and two secondary atypical symptoms, phenelzine consequently proved to be more effective than both imipramine and placebo.7 These six studies comprised 409 patients with an overall response rate of 26% for placebo versus 44% for imipramine versus 72% for phenelzine.

The second subtype of major depression, in which MAOIs probably are superior in efficacy is bipolar depression. In a systematic review, Heijnen et al.8 found an overall response rate of 74% for tranylcypromine (40–60 mg) compared with 28% in control conditions in bipolar depression. Their results emphasize the statement by Thase and Sachs9 in a previous review: “All other things equal, the MAOI tranylcypromine could be considered a treatment of first choice for bipolar depression. The track record of this drug spanning open-label, placebo-controlled, and imipramine-comparator clinical trials.”

In an open study in patients with bipolar depression,10 who already received a mood stabilizer, the antidepressant effect of tranylcypromine appeared to be superior to that of paroxetine, as demonstrated by a recovery rate of 53% on tranylcypromine versus 27% on paroxetine.

Furthermore, current evidence suggests tranylcypromine and other MAOIs may have a low risk of inducing a switch into mania.8

Therapeutic experience and non-controlled open studies suggest a clear therapeutic benefit from tranylcypromine in patients resistant to adequate antidepressant treatment. Unfortunately, there are only relatively few randomized controlled trials with MAOIs in patients with treatment-resistant depression (TRD), even though this is a major indication for their use.

However, a previous meta-analysis comprising a number of controlled studies, reported an overall response rate of 58% to tranylcypromine in patients with TRD.11 Some authors consider tranylcypromine as a first choice in stage-3 TRD according to the Thase and Rush classification.12, 13

In summary regarding the efficacy of non-selective MAOIs (especially tranylcypromine): they appear to be effective in two forms of major depression, which are notoriously difficult to treat: bipolar depression and treatment-resistant depression. MAOIs, specifically phenelzine, are also very effective in atypical depression, which may be less of a clinical challenge.

Moclobemide, a selective MAO-A inhibitor, has less side-effects than the non-selective MAOIs. Selective MAOI-A inhibitors, such as moclobemide, were developed as alternatives lacking the “cheese effect” and vigorously promoted in the late 1980s and early 1990s, with industry sponsored research, leading to substantial prescription of this drug. However, many clinicians believe that moclobemide is not as effective as nonselective MAOIs such as tranylcypromine or phenelzine. Consistent with these clinical impressions, is the result of a meta-analysis showing a clinically significant advantage for the older MAOIs compared with moclobemide.14

When using a non-selective, irreversible MAOI (tranylcypromine, phenelzine) it is necessary to follow a tyramine-restricted diet. Many of the traditional MAOI diets, which remain standard at numerous hospitals, are unnecessarily restrictive. Reports of food interactions with MAOIs published in the early 1960s led to the development of stringent dietary restrictions. Consumption of numerous foods, principally cheese, by patients on MAOIs was associated with potentially fatal hypertensive crises.

However, many of the foods once thought to be dangerous for patients on MAOIs are now considered to be safe. Although the clinician's initial response may be to choose the more conservative diet, an excessively stringent diet may actually be unfavorable, since psychiatrists and patients may refrain from considering a potentially effective treatment with an MAOI. Furthermore, patients may become lax with their diet after accidentally discovering that certain diet items are actually not harmful.

Numerous studies have attempted to quantify the tyramine content of food. A tyramine content of less than 6 mg per portion is generally considered safe. Concurrent administration of an MAOI with drugs increasing the availability of serotonin might lead to the serotonin syndrome. Excessive stimulation of the 5-HT1a and 5-HT2 receptors may result in symptoms of serotonin syndrome. Most cases of serotonin syndrome have been reported when an MAOI was combined with meperidine, L-tryptophan, dextromethorphan, an SSRI, or a TCA that inhibits the reuptake of serotonin (clomipramine, imipramine).15

Irreversible MAOIs (tranylcypromine, phenelzine) are very effective drugs in the treatment of both resistant and bipolar major depression. They can induce full remission when other antidepressants, combinations, and augmentation strategies, and even electroconvulsive therapy (ECT), have failed. Despite this, they are infrequently prescribed, in part because of substantial overestimation of their risk profile. Thus, it is essential to have MAOIs available in the psychiatrist's therapeutic arsenal and to have clinicians who are knowledgeable about their usage.

The authors declare no conflicts of interest.

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单胺氧化酶抑制剂:治疗重度抑郁症的药物严重不足。
单胺氧化酶抑制剂(MAOIs)是第一种获得许可的抗抑郁药物,是在 20 世纪 50 年代对结核病患者进行异丙嗪试验时偶然发现的。异丙嗪似乎具有 "精神振奋作用",从而改善了一些肺结核患者的抑郁症状1。异丙嗪被批准为抗抑郁药,并由此带动了其他几种 MAOIs 的开发。大脑神经递质水平会被 MAO-A(血清素、去甲肾上腺素、多巴胺)和 MAO-B(多巴胺)同工酶灭活。抑制 MAO 酶会增加这些单胺类物质在突触中的供应量。此外,氨甲环酸的化学结构与苯丙胺相似,也具有释放多巴胺和类似兴奋剂的作用。曲酰丙咪嗪和苯乙肼是最常用的非选择性 MAOIs,它们与 MAO 酶的结合是不可逆的,并使其永久失活。吗氯贝胺是一种选择性 MAO-A 抑制剂,与 MAO 酶的结合是可逆的。曲安奈德和苯乙肼在 20 世纪 60 年代末之前一直被广泛使用。正如 Gimenez-Palomo 等人在其网络荟萃分析中所述,MAOIs 的使用已急剧下降。2 历史的视角对于理解这种下降非常重要。在 20 世纪 60 年代,人们还不太了解 MAOIs 可抑制酪胺的分解,以及在使用 MAOI 时摄入过量的酪胺会导致高血压危象。一系列最初无法解释的高血压危象确实发生了,有些甚至导致了中风。这种 "奶酪反应 "的原因在 20 世纪 60 年代末被揭开,但人们对高血压反应的恐惧依然存在。此外,在精神病学最早的一项大型随机临床试验3 中,有 260 名抑郁症患者接受了治疗,其中电痉挛疗法和丙咪嗪似乎都有效,而苯乙肼和安慰剂则无效。事后看来,人们很可能会认为,苯乙肼的治疗时间(4 周)和剂量(每天最多 60 毫克)都不够,因此,苯乙肼没有充分发挥其疗效潜力。随后,MAOIs 被认为是不太有效且危险的抗抑郁药物。受这种观念的影响,医生们更加青睐三环类抗抑郁药(TCA)而非 MAOIs。随着新型抗抑郁药,尤其是选择性血清素再摄取抑制剂(SSRIs)的开发,MAOIs 的使用率进一步下降。人们担心 MAOIs 的安全性,包括可能导致血清素综合征的潜在危险的药物间相互作用,以及高血压危象的风险,这些都限制了 MAOIs 的使用。此外,任何制药公司都没有推广使用 MAOIs。在一些国家,MAOIs 的处方数量极低:在 1,600 万人口中约有 500 名患者接受了治疗。精神科住院医师从优秀的培训项目毕业时可能几乎不了解 MAOIs,不知道 MAOIs 治疗的具体适应症,也不知道如何避免这些药物的安全性问题。因此,Gimenez-Palomo 等人的全面系统综述2 强调了 MAOIs 在重度抑郁症治疗中的作用,是一项宝贵的贡献。作者认为 MAOIs 和其他抗抑郁药的抗抑郁疗效相似。然而,正如 Lee 和 Wei6 在给编辑的信中针对该系统综述所指出的,在几种亚型重度抑郁症中,MAOIs 的疗效优于其他抗抑郁药。纽约哥伦比亚大学对非典型抑郁症患者进行了六项系列研究。在非典型抑郁症患者中,苯乙肼的疗效被证明优于丙咪嗪和安慰剂。7 这六项研究包括 409 名患者,安慰剂的总体反应率为 26%,丙咪嗪为 44%,而苯乙肼为 72%。Heijnen 等人8 在一项系统综述中发现,在双相抑郁症患者中,氨甲环丙胺(40-60 毫克)的总体应答率为 74%,而对照组的应答率为 28%。他们的研究结果强调了 Thase 和 Sachs9 在上一篇综述中的观点:"在其他条件相同的情况下,MAOI 类药物氨酰环丙胺可被视为双相抑郁症的首选治疗药物。
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来源期刊
Acta Psychiatrica Scandinavica
Acta Psychiatrica Scandinavica 医学-精神病学
CiteScore
11.20
自引率
3.00%
发文量
135
审稿时长
6-12 weeks
期刊介绍: Acta Psychiatrica Scandinavica acts as an international forum for the dissemination of information advancing the science and practice of psychiatry. In particular we focus on communicating frontline research to clinical psychiatrists and psychiatric researchers. Acta Psychiatrica Scandinavica has traditionally been and remains a journal focusing predominantly on clinical psychiatry, but translational psychiatry is a topic of growing importance to our readers. Therefore, the journal welcomes submission of manuscripts based on both clinical- and more translational (e.g. preclinical and epidemiological) research. When preparing manuscripts based on translational studies for submission to Acta Psychiatrica Scandinavica, the authors should place emphasis on the clinical significance of the research question and the findings. Manuscripts based solely on preclinical research (e.g. animal models) are normally not considered for publication in the Journal.
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