In the second part of our discussion on the art and science of treating various mood disorders, we feature a panel of clinicians who openly discuss monoamine oxidase inhibitors (MAOIs) and whether they can be effective treatment modalities.
Because of the probable heterogeneity of mood disorder, we must employ all options available within the limitations of current science. The reader of the MAOI clinical colloquy Feature article can sense the frustration expressed by the discussants about patients suffering when there may be an effective treatment through the inhibition of monoamine oxidase (MAO). Alarmingly, psychiatric clinicians do not prescribe medicines unless well marketed; this standard eliminates treatment with classes of medicine that are very effective.
During the discussion, Jeffrey P. Staab, MD, made a comment that I believe represents a prominent view, “Curiously, many clinicians are afraid to prescribe MAOIs that have a 50-year track record with well-known drug and food interactions. Yet, they may prescribe a patient multiple psychotropic medicines (four, five, sometimes more) that have never been tested together in any medication trial. From an informed consent standpoint, that’s problematic. Patients often are being prescribed combinations of medicines that have never been studied.”
In the first of this special two-part issue, Mirowska-Guzel and Bałkowiec-Iskra,1 both distinguished clinicians, offer a scholarly study of the MAO isoenzymes. “MAOs can potentially modulate all the processes involving bioactive amines, including regulation of mood, emotional behavior, and other brain function.” MAO enzymes have a critical role in many neuropsychiatric and neurodegenerative diseases. The authors explain the implications of genetic variation of MAO, the location of the isoenzymes, and the changes of concentration of the isoenzymes from birth to the elderly. This article provides the reader with an invaluable fundamental understanding of the MAO enzyme; without this contribution, the reader would lack the full appreciation of why the inhibition of MAO has such a profound effect on the cascade of enzymes that enable metabolic balance.
Rybakowski,2 a prominent Polish clinician, and the 2012 recipient of the Lifetime Achievement Award of the European Bipolar Forum for research on bipolar disorder, introduces the reversible inhibitors of monoamine oxidase-A (RIMAs). His vast experience in treating patients with moclobemide provides the reader clinical guidance, the pharmacodynamics, and effectiveness of RIMAs. This review is a critical contribution especially for physicians in the United States, who have not had training about the theory and practice of therapy with the RIMAs. There is a prolific international literature about RIMAs. His article motivates the reader to not only explore other research that reference RIMAs, but also to be prepared for the hopeful introduction of RIMAs in the US. While writing this editorial, I spoke with Rybakowski about moclobemide. The marketing of selective serotonin reuptake inhibitors in Poland has been so effective that moclobemide is no longer a favored prescription, even though moclobemide is a more effective drug.
The backgrounds of Pumariega and Pradhan,3 who boldly undertook MAOI therapies for children (purportedly contraindicated), enhance the cultural range of highly experienced scholars and clinicians about MAOI therapy. In a balanced, critical paper, the authors provide strong evidence supporting reevaluating the contrast between the “limited psychopharmacological armamentarium” in child and adolescent psychiatry versus adult psychiatry. “This limitation is due to well-documented disincentives for pharmacological research and development for children and youth, and adversely affects both pediatrics and psychiatry.” Most mood and anxiety disorder patients have manifestations of illness during their youth. The authors endorse “the goal of treatment is to enable the child’s growth and development.” This article requires study because of the subtleties of analyzed case reports of treatment by Pradhan of three children who each failed two prior treatments but responded to moclobemide—a RIMA. The authors explain that with the development of the transdermal selegiline system, there is greater safety because of its selectivity of inhibition of MAO-B when prescribed at low doses. The authors also favor the introduction of RIMA to treat youth in the US.
Zajecka and Zajecka4 contribute an article that provides the clinician with direct excellent guidance about when and how to employ MAOI therapy. The authors provide a succinct overview of the development of antidepressants, their pharmacodynamics, and efficacy. The practical but essential information enables the clinician to successfully prescribe MAOIs. Please refer to detailed tables in the article of drug interactions and dietary guidelines. The authors emphasize that MAOI therapy should be an early consideration of MAOI therapy in a routine sequence. “Failure to treat depression to full remission is associated with significant morbidity, mortality, disability, and high risk of death from suicide.” The authors suggest considering MAOI therapy earlier in the choice of treatment in atypical depression.
To conclude Part 1, my contribution,5 attempts to encourage the clinician to consider the biological “multiplicity of depression” characterized by pathological deviations of delicately balanced complex enzymatic functions of distinct tissues creating a cascade of metabolic events that compromise neuroplasticity or lead to cellular apoptosis. The fact that MAO is found in all tissues of the body and is mostly attached to the outer membrane of mitochondria emphasizes the significance of the microenvironment surrounding this enzyme.
To begin Part 2 in this issue of Psychiatric Annals, Jonathan W. Stewart, MD, provides a scholarly, critical dissection of the validity of identifying atypical depression. The presentation successfully introduces the reader to the preferential response of atypical depressed patients to MAOI therapy. The accurate identification of atypical depression and major depressive disorder with atypical features provides the clinician effective direction to treat atypical depressed patients. “Atypical depression as defined by significant mood reactivity plus 1 of 4 symptoms (hyperphagia, hypersomnia, leaden paralysis, or pathologic rejection sensitivity) having onset prior to age 20 years and a very chronic course of illness appears to be a valid clinical entity worthy of further research into its pathophysiology and treatment.”
Donald F. Klein, MD, DSc, and Peter C. Arden, BA, provide a scholarly history of the MAOIs, including the initial warm reception and later ill regard. Because Klein was intimately associated with the evolution of psychotropics, he offers an invaluable perspective—a history that is not reproducible, such as the “lost” history of moclobemide in the US. Klein has a prudent stance in the treatment of depression: “no depressed or anxious patient should be considered treatment refractory until given an adequate trial of an MAOI.” He has supported prescribing reversible inhibitors of MAO. In certain cases, he favors MAOI therapy as a first-line treatment, and favors a thoughtful augmentation toward achieving remission. Recently, he wrote to me and stated, “There are patients happy with a 70% response who despite extensive educational attempts refuse medication alteration. My goal is to educate and negotiate since we only give advice.”
Arden, Penchaya Atiwannapat, MD, and Stewart present evidence for and against MAOI treatment in various psychiatric disorders. The authors evaluate MAOI therapy in treatment resistant depression, bipolar depression, endogenous depression, eating disorders, obsessive compulsive disorder, borderline personality disorder (BPD), attention-deficit/hyperactive disorder, social phobia, and panic disorder. The authors cogently condensed a vast amount of data and concluded, “MAOIs should be considered in the treatment of unipolar depression, panic disorder, social phobia, and bulimia, especially if the patient failed to remit after at least two standard alternative treatments.” These recommendations resulted from a critical review of the literature in search of definitive evidence to favor MAOI therapy for specific disorders. While preparing this editorial, I asked Stewart why the most complex questions involve BPD. He said, “This is likely because BPD is a complex group of disorders having no single effective treatment. As with many of the other problems for which MAOIs may be appropriately considered, there are likely multiple underlying pathophysiologies that lead to patients being diagnosed with BPD and the other disorders. It is important for clinicians to realize that just because a medication, such as an MAOI, is indicated for BPD or any other psychiatric condition does not mean the next patient with that disorder will do well with an indicated treatment. Instead, ‘indicated’ means there are people with that condition for whom efficacy has been adequately demonstrated.”
In parallel with Schildkraut’s6 views, Stewart added, “Until we sort out the underlying pathophysiologies, we shall continue to have to treat our patients by trial and error. Research into the pathophysiologies of these disorders will allow physicians to transcend ‘indicated,’ instead shifting to assigning the treatments known to alleviate the underlying disturbance of that particular patient.”
- Mirowska-Guzel D, Bałkowiec-Iskra E. The role of monoamine oxidase in humans and its metabolism. Psych Ann. 2014;44(11):495–501. doi:10.3928/00485713-20141106-04 [CrossRef]
- Rybakowski JK. Moclobemide—a reversible inhibitor of monoamine oxidase-A. Psych Ann. 2014;44(11):502–506. doi:10.3928/00485713-20141106-05 [CrossRef]
- Pumariega AJ, Pradhan BK. Revisiting the role of monoamine oxidase inhibitors in pediatric psychopharmacology. Psych Ann. 2014;44(11):507–512. doi:10.3928/00485713-20141106-06 [CrossRef]
- Zajecka JM, Zajecka AM. A clinical overview of monoamine oxidase inhibitors: pharmacological profile, efficacy, safety/tolerability, and strategies for successful outcomes in the management of major depressive disorders. Psych Ann. 2014;44(11):513–523. doi:10.3928/00485713-20141106-07 [CrossRef]
- Tobe EH. Monoamine oxidase inhibitor therapy and the catecholamine hypothesis of depression revisited. Psych Ann. 2014;44(11):524–529. doi:10.3928/00485713-20141106-08 [CrossRef]
- Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry. 1965;122(5):509–522. doi:10.1176/ajp.122.5.509 [CrossRef]