Medical Pharmacology: Pharmacology of Antidepressant Medications

Antidepressant medications II

Monoamine Oxidase^{167, 168}

There are two principal forms or isoenzymes of monoamine oxidase (MAO).

These forms are designated MAO-A and MAO-B.

Both isoforms are present in the periphery and inactivate intestinal monoamines.

However, MAO-B is the principal form found in the stratum; furthermore, this form is the form responsible for oxidative catabolism of brain dopamine.

**Percentage of total MAO-A and MAO-B enzymatic activity in some human tissues^{176,177,178,179}**
Tissue	MAO-A Percent Activity	MAO-B Percent Activity
Brain	<20%	>80%
GI Tract	>80%	<20%
Kidney	25%	75%
Lung	55%	45%
Platelets	<5%	>95%

The rationale for use of MAO-B inhibitors is that they may increase steady-state dopamine levels and thus mitigate reduced striatal dopamine effects.
MAO-B inhibitors at appropriate doses are relatively selective and are classified as irreversible inhibitors of monoamine oxidase.
- If these agents are used alone, as monotherapy, some symptomatic motor benefit is likely to occur.
- Also, MAO-B inhibitors in combination with carbidopa/L-DOPA enhance the carbidopa/L-DOPA effect.
As noted earlier, the two isoforms of monoamine oxidase exhibit differing substrate specificity as well as differences in distribution and inhibitor specificity.¹⁸³
- Substrates for MAO-A include serotonin; whereas, an example substrate for MAO-B is phenylethylamine.
- Examples of neuroactive molecules which are substrates for both MAO isoforms include epinephrine, norepinephrine, dopamine, and tyramine.

Tissue distribution of MAO has been analyzed in rodent, cat, primate and human brain using a number of techniques including immunohistochemistry.¹⁸³

MAO-A and MAO-B distributions appear relatively insensitive to species variation.
The MAO-A form is mainly localized in catecholaminergic neurons; however, MAO-B appears most prominently in serotonergic, histaminergic, and glial cells.

The highest concentration of MAO-A is associated with the locus coeruleus; the highest concentration of MAO-B is associated with the raphe nuclei.

**MAO-A and MAO-B levels in rodent brain using immunohistochemical, enzyme autoradiographic and in situ hybridization methods¹⁸³**
Neuron and Region		MAO-A			MAO-B
	Neuron Staining¹⁸⁹	Protein¹⁹⁰	mRNA¹⁹¹	Neuron Staining¹⁸⁹	Protein¹⁹⁰	mRNA¹⁹¹
Serotonergic raphe nucleus	-	-

Locus coerulus catecholaminergic neurons				-	-	-

-, undetectable; , high concentration MAO-A, , moderate concentration MAO-A, , high concentration MAO-B

With respect to developmental biology, MAO-A appears earlier than MAO-B. MAO-A is present at nearly adult levels from birth; however, MAO-B enzyme activity increases with age.
- A possible explanation of the increase in MAO-B activity with age may be that, since MAO-B is mainly glial cell-localized, glial cell proliferation over time is responsible.

The identification of two MAO forms¹⁸⁴ was reported in 1968and raised a question whether MAO-A and MAO-B were different proteins or the same protein associated with different carbohydrate or lipid post-translational modifications.¹⁸³
- In 1988, two cDNAs coding for human liver MAO-A and MAO-B were cloned and found to exhibit 70% amino acid sequence identity.¹⁸⁵
- Transfecting MAO-A and MAO-B cDNA into mammalian cells resulted in cells' exhibiting substrate and inhibitor specificities similar to endogenous MAO-A and MAO-B, appropriate to which gene was transfected.

Genes for MAO-B are localized on the ex-chromosome in a number of mammalian species, including human.

Both in human and mouse, MAO-A and MAO-B genes appear localized at adjacent sites at Xp11.23 and were noted to be deleted in individuals with Norrie disease.
Norrie disease is a neurological disorder, X-linked recessive, associated with blindness, mental retardation and hearing loss.¹⁸²

**X-linked recessive inheritance^186,187**

(A) Carrier mother (B) Affected father Modified images from the U.S. National Library of Medicine¹⁸⁷ "Norrie disease (ND) is a familial disorder caused by mutations in the Norrie Disease Pseudoglioma (NDP) gene. It is inherited in an X-linked recessive mode and usually affects only males. Women carrying the mutated gene are typically healthy, but statistically have a 50% risk to pass the disease to their children (Figure 1A). Sons of a carrier mother are at 50% risk of being affected and 50% of daughters will be carriers like their mothers. Norrie males will only have healthy sons, but all of their daughters will be mutation carriers (Figure 1B)."¹⁸⁶

**Retinal cross sections in Norrie disease (right image)¹⁸⁶**

"Sections through retinas of a healthy (left) and a Norrie mouse (right) showing the differences in the blood vessel system (labeled in red)."

This disorder is one of several oculoencephalic (cranio-occular) defects.
- Broadly speaking, oculoencephalic disorders are due to simultaneous failure or imperfect eye and brain development.
- In Norrie disease some sight may be present at birth; however, later eyes may become shrunken and recessed (phithisis bulbi).
  - Norrie Disease: Tractional Retinal Detachment¹⁸⁸
  - Some patients exhibit decreased digit length, anger outbursts, hallucinations and possibly psychomotor function regression. H gene, norrin, associated with the X chromosome may be responsible

Classically, administration of MAO inhibitors or even MAO-A inhibitors is associated with the warning that ingestion of foods containing tyramine may precipitate hypertensive reactions.
- These reactions occur because tyramine, a vasopressor, is normally inactivated in the G.I. tract by MAO which, when inhibited, allows tyramine access to the blood.
  - Such dietary tyramine limitations do not apparently apply to MAO-B inhibitors, at least at the recommended doses.
Drug Overview and a few examples: As a reminder, specificity in drug action is intimately tied to drug concentration.
- In this case, MAO-B inhibitors target the MAO-B isoenzyme; however, at higher MAO-B inhibitor concentrations of the MAO-A isoenzyme is also subject to inhibition.
  - Some examples of nonspecific MAO inhibitors include tranylcypromine, phenelzine, and isocarboxazid.
- Selegiline (deprenyl) is an example of a selective MAO-B inhibitor.
- Rasagiline (Azilect)
- Selegiline administration tends to reduce mild ""on-off"" or ""wearing-off"" effects associated with L-DOPA treatment.
  - In addition, selegiline prolongs the L-DOPA antiparkinsonism effect.
    - The dosage range which supports selective MAO-B inhibition is less than or equal to 10 mg/day.
  - With respect to side effects, although selegiline appears well-tolerated in mild Parkinson's disease.
    - Unfortunately, in those patients with more advanced disease or who exhibit underlying cognitive impairment, selegiline make worsen adverse motor and cognitive effects associated with L-DOPA treatment.
    - Also, selegiline metabolites include amphetamine and methamphetamine. These metabolites may induce anxiety, insomnia as well as other unwanted side effects.
- A more potent MAO-B inhibitor has been introduced and allows for once-daily dosing.
  - This agent Rasagiline (Azilect) is approved for both initial monotherapy and adjunctive treatment (FDA approval in 2009) .
    - Its metabolite does not exhibit amphetamine-like properties of selegiline.
    - As monotherapy Rasagiline increases daily ""on"" time by about two hours.
    - It is more selective for MAO-B compared to MAO-A by a factor of about 14.¹⁸⁰
- Selegiline and Rasagiline: Cytochrome P450-mediated Metabolism¹⁸¹
Neither selegiline nor Rasagiline should be administered to individuals receiving meperidine.
- As a further caution, these agents should not be used to treat patients receiving either trycyclic antidepressant or serotonin reuptake inhibitors since, at least in theory, such combination might promote ""serotonin syndrome."
- Finally, combination of L-DOPA administration and administration of a nonselective MAO inhibitor should be avoided because the combination might cause hypertensive crisis possibly as a result of peripheral norepinephrine accumulation.
Zydis selegiline is a special selegiline formulation, an orally disintegrating, freeze-dried tablet which dissolves on contact with saliva and is directly absorbed by the oral mucosal.
- This route of administration avoids the hepatic ""first-pass"" metabolism effect. As a consequence, both increased selegiline blood levels and reduced plasma levels of amphetamine-like metabolites are noted.

Human monoamine oxidase A (hMAO-A) is localized in the outer mitochondrial membrane.^{167, 168}

MAO-A is present on mitochondrial outer membranes in the whole extent of both noradrenergic and dopaminergic neurons, including localization in axonal terminals.¹⁷⁰
- The situation with respect to type B is more complex.
- Double-immunofluorescence labeling and electron microscopic immunohistochemistry have been used to address this issue.¹⁷⁰
  - Focusing on the dorsal raphe nucleus, serotonin-positive neuronal cell bodies were clustered and contained monoamine oxidase type B.
    - On the other hand, serotonin-negative neuronal cell bodies generally did not exhibit MAO.
    - For neuronal cell bodies and dendrites associated with MAO type B, some but not all mitochondria exhibited the enzyme.
- The authors conclude that, at least with respect to serotonergic neuronal cell bodies and dendrites, there are two kinds of mitochondria-one containing monoamine oxidase type B on the outer membranes and the other deficient in this enzyme.¹⁷⁰

The enzyme is categorized as a membrane-bound flavoprotein and catalyzes deamination (oxidative) reactions of both biogenic and xenobiotic amines.

**Oxidative deamination of monoamines catalyzed by monoamine oxidase (MAO)¹⁷¹**

Note that the amine group is removed and a corresponding aldehyde and ammonia are formed.¹⁷¹

"FAD can be reduced to FADH₂, whereby it accepts two hydrogen atoms (a net gain of two electrons)"¹⁷³

**Flavin adenine dinucleotide structure¹⁷⁴**

Chemical structure of flavine adenine dinucleotide (ChemDraw)¹⁷⁴

These amines include neurotransmitter/neuromodulator substances such as serotonin (5-HT), dopamine, norepinephrine. MAO contains a flavin adenine dinucleotide (FAD) which is covalently linked to the cysteine residue by an 8α-(S-cysteinyl)-riboflavin linkage.

**"Ribbon diagram of a monomer of human monoamine oxidase A, with FAD and clorgyline bound, oriented as if attched to the outer membrane of a mitochondrion"¹⁷²**

Reduced expression of hMAO A (deficiency) in this enzyme may be associated in a phenotype exhibiting aggressive behavior.¹⁶⁹
MAO appears to play an important role in certain psychiatric as well as neurological disorders, such as Parkinson's disease and depression.
Since inhibition of MAO increases neurotransmitter levels in the CNS, discovery and identification of effective inhibitors represent one method of treatment.
- In the case of MAO, two subtypes, MAO-A and MAO-B have been identified.
- Although amino acid sequence homology is about 70%, these enzyme subtypes exhibit distinct substrate and inhibitor specificities.
- For example, MAO-A oxidizes serotonin; however, MAO-B does not.
  - Also, MAO-A is inhibited selectively by the drug clorgyline; by contrast, MAO-B is inhibited by selegiline (L-deprenyl and others)

Monoamine Oxidase Inhibitors (MAOIs)¹⁰⁷

Monoamine oxidase inhibitors (MAOIs) are identified as the first group of drugs exhibiting somewhat specific antidepressant activity.^107,166

The prototypical agent was iproniazid (IUPAC name: N'-propan-2-ylpyridine-4-carohydrazide), developed initially for management of tuberculosis and found to be "mood-elevating" in this patient group.

iproniazid	↔	isoniazid	↔	phenelzine
	↔		↔

Iproniazid (Iprazid and others)

Other MAOIs were then developed and include tranylcypromine (IUPAC name: (1R,2R)-2-phenylcyclopropan-1-amine) , isocarboxazid, and phenelzine.¹⁰⁷
- Tranylcypromine (Parnate)
- MAOIs inhibit catabolism of endogenous monoamines such as norepinephrine, dopamine, and serotonin (5-HT); inactivation of the exogenous amine tyramine is also inhibited.
- The mechanism of inhibition is classified as "irreversible" or long-term of both MAO-A and MAO-B enzyme subtypes.¹⁰⁷
  - Other MAO inhibitors exhibit greater selectivity (e.g. selegiline) and are classified as reversible inhibitors.
One concern in the clinical use of MAOIs is the potential for these agents to induce a life-threatening hypertensive response.¹⁷⁵
- The mechanism for this effect, associated with non-selective, irreversible MAO-A and MAO-B inhibition, is reduced catabolism (degradation) of tyramine from dietary sources.
  - As a result, tyramine, which exhibits a weak vasoconstrictor sympathomimetic effect, increases blood pressure.
  - Adverse drug effects may also be observed if monoamine oxidase is a primary detoxification mechanism of another drug.
    - This circumstance constitutes a "drug-drug" interaction. Administration of newer MAOIs exhibiting selectivity for MAO-A and reversibility result in reduced drug and food interactions compared to first generation MAOIs.

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