Use of monoamine oxidase inhibitors in chronic neurodegeneration

ABSTRACT

Introduction: Neurotransmission by biogenic monoamines is important for brain function. Biogenic amine turnover employs the enzymes catechol-O-methyltransferase and monoamine oxidase in neuronal and glial cells. Inhibition of these enzymes elevates biogenic amine levels in the synaptic cleft. Subtype selectivity of inhibition is lost during long-term use of ‘selective’ monoamine oxidase inhibitors.

Areas covered: This narrative review discusses use of monoamine oxidase inhibitors in the context with chronic neurodegeneration.

Expert opinion: Antidepressant drugs increase synaptic concentrations of biogenic amines. In the aging brain, then one of the two enzymes involved in degrading synaptic amines, catechol-O-methyl transferase, increasingly catalyzes methylation processes. Therefore, metabolism by monoamine oxidase plays an incremental, predominant role in biogenic amine turnover, leading to greater oxidative stress. In patients with chronic neurodegenerative disorders, symptoms, such as depression and apathy, are often treated with drugs that elevate biogenic amine levels. This therapeutic strategy increases biogenic amine turnover, thereby generating neurotoxic aldehydes and enhanced oxidative stress, each of which influence and accelerate the course of neurodegeneration. We propose that antidepressant therapy should be initiated first with monoamine oxidase inhibitors only. If adequate clinical response is not achieved, only then they should be supplemented with a further antidepressant.

KEYWORDS:

• Monoamine oxidase
• selegiline
• rasagiline
• depression
• moclobemide
• DOPAL
• oxidative stress
• antidepressants

Article highlights

• Metabolism of biogenic amines by monoamine oxidase (MAO) B exacerbates chronic neurodegenerative processes particularly via apoptosis.

• The specificity of MAO subtype inhibition is lost at higher doses, when a total blockade of the monoamine oxidase enzyme takes place.

• In the course of long term therapy, ‘selective’ MAO-B inhibitors also reduce MAO-A activity.

• Oxidative stress is continuously generated through elevated biogenic amine turnover by MAOs.

• Long term effects of classic antidepressant drugs with respect to initiating or accelerating chronic neurodegenerative processes in the brain are not currently considered during drug development or by therapeutic guidelines.

• Early treatment of depression — for example, during the prodromal phase of Parkinson’s disease or dementia disorders — should primarily use a non-selective MAO inhibitor.

• The long term combination of antidepressants with MAO inhibitors may reduce the likelihood of acute or chronic neurodegenerative events associated with elevated biogenic amine turnover.

This box summarizes key points contained in the article.

Acknowledgments

This review is dedicated to Prof. Dr. Gerhard Bringmann at the occasion of his 65th anniversary. The authors would like to thank Paul Foley for editing this manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.