Overview


“Depression is a disorder of mood, so mysteriously painful and elusive in the way it becomes known to the self -- to the mediating intellect-- as to verge close to being beyond description. It thus remains nearly incomprehensible to those who have not experienced it in its extreme mode.”
― William Styron, Darkness Visible

Depression is a universal experience that everyone in their lifetime experiences in varying degrees. These experiences are maybe mild and can help with restructuring the person. It is often psychologically beneficial and best treated without medical and pharmaceutical intervention.

However, if depressive episodes become more pronounced, recur often and etc., then usually it’s diagnosed as depressive illness and disorder and need to be treated differently with medical help. Depressive disorder unfortunately isn’t a single entity but a group of disorders that comes in many forms such as dysthymia, atypical depression and major depression. Each mood disorder has multiple forms of causes and symptoms and is quite hard for healthcare practitioners to effectively treat patients with major depressive disorder.

The regulation of the essential amines is controlled by monoamine oxidase (MAO), specifically A type enzyme. Researchers have found that MAO-A concentration is increased in overall regions. With the overactive enzyme, there is a decrease in available monoamines. (Meyer, et al., 2006)










1. Amine Hypothesis




The amine hypothesis, created in the 1950’s, states abnormalities in the physiology and metabolism of biogenic amines, particularly catecholamines (norepinephrine and dopamine) and an indoleamine (serotonin), are involved in the causes and courses of mood disorders. Therefore, a deficiency of amines in important brain areas is associated with depression and an excess of certain amines is associated with mania. (Meyer, et al., 2006)

2. Neurotransmitters involved




Of all the neurotransmitters involved in regulation the brain in alertness, learning and memory and mood, Norepinephrine, serotonin and dopamine are involved with setting mood levels throughout the day.

Dopamine is a catecholamine derived from tyrosine that plays an important role in a wide array of physiological function in the animal body. Dopamine in the brain is mainly produced in the substantia nigra and ventral tegmental area and acts of five dopamine receptors. Dopamine is then projected throughout the brain such as prefrontal cortex, amygdala and hippocampus, neostriatum and the thalamus. In humans, dopamine has large effect on human behaviour such as reward-driven learning, motor control, cognition, sleep, mood and attention.



Dopamineseratonin.png

Norepinephrine, which is further made from dopamine, is another catecholamine that works and affects states in the brain. Primarily focusing in the brain, norepinephrine is released from the locus coeruleus diffuses nearly everywhere in the brain. Norepinephrine in the CNS is mostly responsible for decision making and mood elevation.












external image sero1.GIF

Serotonin (5-HT) is seen in many ways opposite to tyrosine derived monoamines. Made from tryptophan, it is a neurotransmitter found in bilateral animals. Serotonin neurons are found in the raphe nuclei and projects its axons nearly every part of the CNS and spinal cord. It has 7 receptors, each having their own effect, either mixture of inhibitory or excitatory, when serotonin is bound. It’s main function within the CNS is appear to involve control of appetite, sleep, memory and learning, temperature regulation, mood, behavior (including sexual and hallucinogenic behavior), endocrine regulation, and depression. (4)

3. Affected brain region



Many of these hormones have areas they share when diffusing throughout the brain and also have associations in depression:
Cingulate gyrus
Cingulum
Hippocampus
Striatum
Amygdala
Hypothalamus
Neocortex
Spinal cord
Thalamus

4. Monoamine Oxidase A




Monoamine Oxidase A
Monoamine Oxidase A

The monoamine oxidase is a family of enzymes that catalyze/breakdown available monoamines within the CNS. Found in the early 20th century called tyramine oxidase (5), this enzyme was found in the liver, GI tract, placenta, platelets, neurons and astroglia. In particular, the monoamine oxidase A enzyme aka MAOA is important in regulating mood levels in the CNS. It does this by regulating monoamines and the A subtype has a substrate specificity for serotonin, norepinephrine and dopamine (both A and B can degrade this). Research into the enzyme has shown although the CNS enzyme can’t be picked up for content analysis, the platelet and liver form of the enzymes may be good indicators of whether the enzyme is properly working.

i.Mechanisms

The MAOA enzyme is responsible for the degradation of monoamines present in the CNS. It catalyzes serotonin,
dopamine and norepinephrine through oxidative deamination. Oxygen, when present, is used to remove the amine group seen in every monoamine and causes the formation of ammonia and aldehyde. Further reactions are done to ensure that a safe by-product remains and it is later excreted in the urine.


Figure 3. (More Information by clicking the picture.)  Modernization of monoamine theory of depression. (A) Description of monoamine release in a synapse in a healthy person. (B) During a major depressive episode, monoamine oxidase A (MAO-A) density is elevated, resulting in greater metabolism of monoamines, such as serotonin, norepinephrine, and dopamine, in the brain. (C) and (D), Range of outcomes.
Figure 3. (More Information by clicking the picture.) Modernization of monoamine theory of depression. (A) Description of monoamine release in a synapse in a healthy person. (B) During a major depressive episode, monoamine oxidase A (MAO-A) density is elevated, resulting in greater metabolism of monoamines, such as serotonin, norepinephrine, and dopamine, in the brain. (C) and (D), Range of outcomes.







5. Association to Major Depression Disorder





Some originally believed that hormones had an influence in how the brain and mood was exhibited and such. Studies done in the sixties (1) had shown that neurotransmitters in brain had an association to varying degrees of depression. Thus one aspect that is in the field of studies of depression is the level of hormone concentrations and enzyme activity.


Criteria for Major Depressive Episode from DSM-IV
Criteria for Major Depressive Episode from DSM-IV



One of the reason why there is varying levels of neurotransmitter is the deregulation of MAOA enzyme. Research done on monoamines and depression found that low levels of serotonin and noerpinephrine caused patients to experience down feeling for a certain period or to hasten depression those susceptible to it. Further inspection had shown that a mutation in the MAOA gene had caused the enzyme to either had more quantity or rapidly degraded the monoamines rapidly before an effect occurred.



Figure 2. Comparison of monoamine oxidase A (MAO-A) DVS(an index of MAO-A density) between depressed and healthy study participants. On average, MAO-A DVSwas elevated by 34% or 2 SDs in depressed individuals. The hippocampal region also samples the parahippocampus. Differences between groups were highly statistically significant in each region. *P<1x10–5; P<1x10–4; P = .001.
Figure 2. Comparison of monoamine oxidase A (MAO-A) DVS(an index of MAO-A density) between depressed and healthy study participants. On average, MAO-A DVSwas elevated by 34% or 2 SDs in depressed individuals. The hippocampal region also samples the parahippocampus. Differences between groups were highly statistically significant in each region. *P<1x10–5; P<1x10–4; P = .001.




















In the synapse, when any of the neurotransmitters are released from the pre-synaptic terminal,
Illustration of the Synapse
Illustration of the Synapse
such as norepinephrine and serotonin, through the synaptic cleft and mainly goes to the post-synaptic neuron to initiate a reaction (i.e. action potential). In a normal MAOA, the left over monoamines are either degraded or taken back into the pre-synaptic neuron in a process called re-uptake. In depressed individual either or both mechanisms are hyperactive, which means that majority of the neurotransmitter is degraded immediately from the synaptic cleft




In depression, the neurobiological starting-point begins in the malfunction of the noradrenergic or innervations from the locus coeruleus (or dopaminergic), which in turn leads to dysregulation of serotonergic and dopaminergic neurotransmission. With the hyperactive MAOA enzyme in depressed individuals, the rapid degradation of norepinephrine and serotonin has a relationship, where as one neurotransmitter is rapidly degraded, it causes the other to follow the same pathway. This is why pharmaceutical companies are making drugs that interact with norepinephrine and serotonin staying much longer.

Symptoms seen with the lack of these monoamines are also seen in symptoms of depression such as lack of motivation and emotional control, slowed motor control/movement, sensitivity to pain and etc. Thus showing that enzyme activity are somewhat responsible for the varying degrees of depression.

6. Specific treatments



i.MAO-A Inhibitors


With the insight gained from testing fluctuating levels of monoamines can induce changes in mood and connection between MAO enzyme, scientist were busy making inhibitors of the enzyme in order to reverse the mechanisms behind depression. Believing that by inhibiting the MAO enzyme would reduce its catalyzing activity, neurotransmitters can linger much longer in the synaptic cleft. Thus early MAO inhibitors were irreversible which only affected MAO and permanently deactivated it until replaced by the body two weeks later. Such drugs included Nerusil, Neuralex, Apresoline and Marplan.



Marplan
Marplan









However, scientist discovered that there were different isotopes of the MAO enzymes with different substrate specificity and phenotypes. Later finding out the MAOA was responsible for depression, newer drugs were made that were selective for MAOA such as Consonar, Cantor and Manerix.
Moclobemide
Moclobemide


Although these drugs were made in the 50’s, the irreversible MAO drugs were quite a health risk since it also reacted with dietary amine and thus were falling out of favour due to safer and effective antidepressants such as tri-cyclic antidepressants and SSRIs/SNRIs. However new selective and reversible MAOI are being made and used as a last resort if the newer drug aren’t working.

7. Future



It must be kept in mind that although depression may be caused by the level of hormone concentrations and enzyme activity, full efforts should not be placed into only treating the enzyme when, in fact, Major Depressive Disorder is a multi-causal disorder and should be treated with psycho-pharmaceuticals and with cognitive based therapy.



See Also


Alcohol Addiction
Disorders and Deprivation
Monoamine Oxidase Inhibitors (MAOIs) for Depression






References


(1) Coper H. Et al, “Depression and Monoamine Oxidase” Prog. Neuro-Psychpharmacology, vol.3, pp. 441-463

(2) Meyer J.H, “Neuroimaging Markers of Cellular Function in Major Depressive Disorder: Implications for Therapeutics, Personalized Medicine, and Prevention” Clinical Pharmacology & Therapeutics 91, 201-214 (February 2012).

(3) Meyer J.H , “An Explanation for the Monoamine Imbalance of Major Depression” Arch Gen Psychiatry. 2006;63:1209-1216

(4) Borne R. “Serotonin: The Neurotransmitter for the '90s”

(5) Hare ML (1928). "Tyramine oxidase: A new enzyme system in liver". Biochem. J. 22 (4): 968–79.

(6) Harro J & Oreland L (1996) Depression as a spreading neuronal adjustment disorder. Eur Neuropsychopharmacol 6: 207–223.

(7) Green CA & Pope CR (2000) Depressive symptoms, health promotion, and health risk behaviors. Am J Health Promot 15: 29–34.

(8) Lin S. Et al, “Association analysis between mood disorder and monoamine oxidase gene”, American Journal of Medical Genetics, 2000,96(1), 12-14

(9) Brandon S., Monoamine Oxidase Inhibitors in Depression, British Medical Journal (Clinical Research Edition), 1982,285(6355),1594-1595

(10) Duman RS, Heninger GR & Nestler EJ (1997) A molecular and cellular theory of depression. Arch Gen Psychiatry 54: 597–606.

(11) American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders, 4th edn., text revision. American Psychiatric Association, Washington, DC.

(12) Syvälahti EKG (1994) Biological aspects of depression. Acta Psychiatr Scand 89 (Suppl 377): 11–15.