Major Depression and MAO-A
According to the National Institute of Mental Health, in the year 2022 about 18 million Americans were afflicted with major depression annually and 280 million people worldwide. It has been estimated to be the second leading cause of disability, surpassed only by heart disease. The World Health Organization predicted depression would become the leading cause of disability by the year 2020. Currently, the antidepressant market is $17.41 billion in global sales in 2023. The US antidepressant market accounted for 71% of the global market in 2004.
Common symptoms of depression include, persistent feelings of hopelessness or pessimism, feelings of guilt, worthlessness, decreased energy, memory deficits, difficulty concentrating, insomnia, early morning wakening or oversleeping, appetite loss and/or weight loss or overeating and weight gain, suicide ideations, thoughts of death, physical ailments such as headaches, chronic pain or digestive problems. Note that many of these symptoms are also associated with aging and neurodegenerative diseases such as Multiple Sclerosis.
The causes of depression have not been conclusively identified, but it has generally been believed that depression is a result of inadequate levels of the neurotransmitters, serotonin and norepinephrine with most emphasis on the former. Thus, efforts at treatment of depression have concentrated on increasing the levels of serotonin and/or norepinephrine. Past and current antidepressant treatments consisted of monoamine oxidase inhibitors, tricyclic antidepressants, and selective serotonin reuptake inhibitors. All of these treatments are believed to be of benefit in treating depression by increasing the amount of serotonin in the nerve synapses. Despite these efforts to increase the level of serotonin, there continue to be unmet clinical needs that need to be addressed. These include improvements in efficacy, speed of onset, safety/tolerability of treatments, and a reduction in relapse rates.
All of these unmet clinical needs are addressed with an exogenous MAO-A agonist as described in the following treatment for depression, for which MedDEV Inc has a patent. MAO-A is required for the metabolism of serotonin, histamine, and norepinephrine. Contrary to the current belief of the medical community, these amines are not active, but must be metabolized into their active metabolites. This is evidenced by the effectiveness in alleviating the symptoms of depression by administering reserpine, which stimulates the activity of MAO-A.
The first antidepressant therapies were monoamine oxidase inhibitors (MAO inhibitors) such as iproniazid. Monoamine oxidase has two subtypes, A and B. Monoamine oxidase A (MAO-A) metabolizes both norepinephrine and serotonin. Thus, it is believed that the antidepressant effect of MAO inhibitors is the result of the increased levels of neurotransmitters – serotonin and norepinephrine due to the MAO inhibitors, blocking the breakdown of these neurotransmitters. Despite the efficacy of the MAO inhibitors as antidepressants, their use today has become very limited due to the serious side effects associated with MAO inhibitors. One of the side effects is hepatotoxicity. MAO is a very important amine-oxidizing enzyme in the liver and the brain and the inactivation of MAO interferes in the breakdown of tyramine. Tyramine is a common amine in food and some beverages. MAO inhibitors can cause excessive amounts of tyramine to accumulate in the brain, which can result in a hypertensive crisis and death. Most of the older MAO inhibitors were irreversible non-selective inhibitors meaning that they inhibited both MAO-A and MAO-B and predominantly inhibited the MAO-B. Today there are several reversible selectively specific MAO-A inhibitors being studied or in use outside of the USA. Because of their reversibility they have a short duration of action and thus they are less apt to result in the inactivation of liver metabolism and the accumulation of tyramine.
Another class of antidepressants is tricyclic antidepressants such as imipramine. Tricyclic antidepressants inhibit the reuptake of norepinephrine and serotonin by blocking the reuptake transporters resulting in increased levels of these neurotransmitters in the nerve synapses (synaptic clefts). Because of the increased levels of the norepinephrine in the nerve synapses, excessive cardiac stimulation can result. These cardiac arrhythmias can be difficult to treat and be potentially life threatening. These side effects prompted the development of selective serotonin reuptake inhibitors (SSRIs), which are the most commonly used antidepressants today. Although the SSRIs do not result in increased concentrations of norepinephrine, so they don’t cause cardiac arrhythmias, the elevation in the serotonin in the nerve synapses can cause agitation, restlessness, gastrointestinal distress and sexual side effects, all of which are common symptoms of depression.
The clinical efficacy of the SSRIs in treating depression has supported the hypothesis that
a serotonin deficiency is the etiology of depression. However it is not clear as to how the SSRIs, tricyclic antidepressants, or MAO inhibitors relieve depression since there is a lag of several weeks before any mood-elevating effects are noticed, after these treatments are started, despite the rapid increase in the levels of serotonin in the nerve synapses. Furthermore, the elevated concentrations of the serotonin in the nerve synapses have been shown to cause symptoms common in depression. The effect of the administration of serotonin or its precursors was markedly less, or not effective at all, when compared to the MAO inhibitors, tricyclic antidepressants, or the SSRIs in depressed persons. So the question arises, if depression is due to the deficiency of serotonin, then why isn’t the administration of serotonin or its precursors L-tryptophan or 5-Hydroxytryptophan more or as equally effective as these antidepressant treatments? And if depression is due to the deficiency of serotonin, then why does it take several weeks before any benefit may be seen from these antidepressant therapies that increase the concentration of serotonin in the nerve synapses immediately upon administration?
MedDEV Hypothesis: Depression is due to deficient MAO-A activity resulting in
deficient production of the active metabolite of serotonin,
5-Hydroxyindole acetaldehyde (5-HIAL).
The MAO-A agonist used in MedDEV’s treatment for depression is Reserpine. This agent has been stabilized in a proprietary solution that is delivered transdermally, 0.01 mg daily. Reserpine activates mitochondrial MAO-A and to a greater extent microsomal MAO-A, and inhibits aldehyde dehydrogenase. Medical literature states that reserpine is contraindicated in depression and this is due to the higher doses that are administered for its approved indication, hypertension. The usual oral and parenteral dosage range for hypertension is 0.1 to 0.25 mg daily. Administration of higher doses of reserpine can result in depletion of MAO-A and/or 5-HT* by stimulating the activity of MAO-A beyond the rate of synthesis of MAO-A and/or 5-HT. MAO-A is destroyed during its oxidized deamination of its monoamine substrates so, if the activity of MAO-A is stimulated beyond the rate of MAO-A synthesis, MAO-A levels can become depleted. Likewise, if MAO-A activity is stimulated beyond the rate of 5-HT synthesis, 5-HT levels can become depleted. Depleted levels of 5-HT and/or MAO-A result in deficient production of the active metabolite 5-HIAL (5-Hydroxyindole acetaldehyde) and symptoms of depression occur.
Results of a 40-patient double blind crossover placebo controlled study using the proprietary transdermal solution of reserpine showed very significant effect in alleviating the symptoms of depression in patients with major depression, and also in those with bipolar depressive disorder. The effect is profoundly more immediate and significant than the current antidepressant therapies of MAO inhibitors, tricyclic antidepressants, and serotonin reuptake inhibitors. The increased metabolism of serotonin is contrary to the belief as to how the current antidepressants are working, yet there is proven benefit from the use of MAO inhibitors, tricyclic antidepressants, and serotonin reuptake inhibitors in the treatment of depression. So how can this be?
Research has shown that the MAO inhibitors, the tricyclic antidepressants (imipramine, clomipramine, amitriptyline, zimeldine, viloxazine, nortriptyline, maprotiline, nomifensine, and doxepine), and some of the serotonin reuptake inhibitors (fluoxetine, fluvoxamine, citalopram) showed inhibitory activity towards MAO-A and MAO-B with clear, more potent, selectivity for MAO-B. Long-term administration (4weeks or more) of these antidepressants resulted in a significant increase in the inhibition of MAO-B during treatment. Furthermore, these antidepressants were competitive inhibitors of MAO-A and noncompetitive inhibitors of MAO-B. Competitive inhibitors can have more of a reversible effect in that saturating concentrations of the substrate (such as increased levels of the substrate serotonin or norepinephrine) can remove the inhibition, thus negating the MAO inhibitory effect. Noncompetitive inhibitors are irreversible and do not compete with the natural substrate, thus an increased concentration of the substrate does not negate the inhibitory effects of the MAO inhibitor. Thus, the antidepressants have a short acting MAO-A inhibitory effect because, after a couple weeks of treatment, the concentration of the substrates, serotonin or norepinephrine, increase to the level capable of negating the MAO-A inhibitory effect, but the MAO-B inhibitory effect of the antidepressants persists. This results in an increased ratio of MAO-A:MAO-B activity, which may account for the antidepressant effect of these treatments. This may also explain why there is a lag of several weeks before any benefit is seen with these antidepressant treatments.
Based on the current prevalent theory and antidepressant treatments, it would be contraindicated to administer any agent that would enhance the metabolism of serotonin. All of the current antidepressant medications are aimed at increasing the levels of serotonin, i.e. the MAO inhibitors are aimed at preventing the metabolism of serotonin, and the tricyclic antidepressants and SSRIs are aimed at maintaining higher levels of serotonin in the nerve synapses. The use of a MAO-A agonist such as reserpine as described in MedDEV Inc’s patent is directly contrary to the prior and current use of MAO inhibitors and even more so to the recent focus exploring the use of specific reversible MAO-A inhibitors as a treatment for depression. In fact, reserpine-treated rats is an animal model of depression. Therefore, MedDEV’s use of MAO-A agonists for depression and depressive disorders is a very unique and novel treatment for these conditions. What is this MAO-A agonist? Respen-A™!
Based on results, we have seen extraordinary success with using Respen-A™ for Anxiety, Depression, Bipolar Disorder, ADD/ADHD, Autism and more. To quote one mother and wife, "It's like the monster in my brain is gone". To quote another, "My family members tell me I've really changed and that, whereas they used to dread visiting me, they actually enjoy spending time with me now".
Please don't keep this a secret from any friends or family that might be suffering from one of these diagnoses...they will be VERY HAPPY to get their lives back, and will thank you when they do.
*The hypothalamus has serotonin accumulating neurons, capacity to uptake 5-Hydroxytryptophan (5-HTP, a precursor of serotonin) with the ability to decarboxylate 5-HTP into serotonin (5-HT) and marked activity of MAO-A to metabolize serotonin into its metabolites 5-HIAL (5-Hydroxyindole acetaldehyde) and 5-HIAA (5-Hydroxyindoleacetic acid). The hypothalamus is involved in: cognitive functions; thyroid function; adrenal cortex function that regulates blood pressure, water balance, cortisol production, steroid hormone production; essential in maintaining the waking state; appetite regulation; sense of well being; body temperature regulation. Many of the symptoms associated with depression can perhaps be correlated to a hypothalamic dysregulation.
(Written by Elaine DeLack)
