Major Depressive Disorder

Major Depressive disorder (MDD) is a disease that affects many adolescents and adults globally; according to the NIMH (National Institute of Mental Health) 6.7 percent of adults as well as 3.3 percent of adolescents 13 to 18 years old in the United States will experience MDD.  Characterized by feelings of hopelessness, guilt, fatigue and often thoughts of suicide, this disease can be harder to classify than other (Johnson et al. 2011) more physical diseases.  The resurgence rate of MDD is 50 percent, so a “cure” could still only be temporary.  Research in the field of MDD has majorly focused on specific proteins to find to actual cause of MDD.

It had been discovered around 1960 that a certain protein was associated with MDD, an enzyme called monoamine oxidase A and B (MAO-A and MAO-B).  These enzymes are responsible for helping reactions in the brain that break down neurotransmitters.  Of the neurotransmitters that are broken down, serotonin, norepinephrine, GABA and dopamine are shown to be broken down by MAO-A; both of these neurotransmitters are shown to be important in regulating mood (Duncan et al. 2012).

Figure 1: In this figure, we see that in patients with MDD, there is less R1 protein.  Less R1 protein means that there will be more production of MAO-A, which is seen in part b of the figure.  More MAO-A leads to more degradation of neurotransmitters. (From:!po=37.5000)
Figure 1: In this figure, we see that in patients with MDD, there is less R1 protein. Less R1 protein means that there will be more production of MAO-A, which is seen in part b of the figure. More MAO-A leads to more degradation of neurotransmitters. (From:!po=37.5000)

Recent work in the field has tried to figure out how MAO-A works and what other proteins affect MAO-A.  Studies such as Figure 1 (Johnson et al. 2011) show us that there is an increase in MAO-A in patients with MDD.  They were also able to show that there was less of a repressor protein called R1 in patients with MDD.  Having less R1 means having more MAO-A; having more MAO-A means having less serotonin, norepinephrine, GABA and dopamine to regulate mood.  This is the predominant theory of mechanism  for MDD in research today.

Figure 2: Neurotransmitters bind to a receptor to initiate a reaction response.  Neurotransmitter is also taken back into the neuron through reuptake. (From:
Figure 2: Neurotransmitters bind to a receptor to initiate a reaction response. Neurotransmitter is also taken back into the neuron through reuptake. (From:

Other theories of mechanism for the disease center around the neuro- transmitters themselves and how their receptors are the cause of MDD (Hvenegaard et al. 2012Peng et al. 2012).  As shown in Figure 2 (McCord 2003), neurotransmitters such as serotonin or dopamine bind to a receptor to initiate a response in an adjacent neuron to stimulate activity in that neuron; when the receptor is either damaged or not working this response doesn’t work and can cause MDD symptoms. 

New drugs are being developed to target the above mentioned proteins specifically.  Researchers are also creating drugs to help these receptors interact with the neurotransmitters or to stimulate the receptor itself.  Drugs are also being developed to stop the reuptake of these neurotransmitters, so they can react longer.  Only by studying all mechanisms of MDD and investigating all treatment options can we be closer to treating this disease.

10 Replies to “Major Depressive Disorder”

  1. Great job! A couple just pure editorial points: could you incorporate the photos more in the text of your title page, that way the reader doesn’t have to keep scrolling up to see what you are talking about? Additionally, try to break up the second paragraph into mechanisms and then treatment options so it doesn’t appear to be such a long paragraph. I was wondering what the role of MAO B is, and whether MAO B has any role in degrading serotonin and dopamine. Besides for MAO, what other enzymes are hypothesized to be responsible for MDD? Thanks!

    1. Thanks for the feedback Ramzy! I am going to split the last paragraph into a more mechanism then treatment one two paragraph punch. I wouldn’t have thought about that until I read this comment so thank you!

      The role of MAO-B is involved in the breakdown of different substrates. Whereas MAO-A is associated with the breakdown of serotonin, norepinephrine, dopamine (and more recently GABA), MAO-B has been shown to be responsible for the deamination of phenylethylamine and benzylamine (which I read in one paper to be more related to parkinson’s). So while both of the MAOs are able to deaminate dopamine, MDD is mostly based off of MAO-A overexpression because serotonin, norepinephrine and GABA are what is responsible for the progression of MDD.

  2. The title is informative and immediately tells me what the page is about, without bogging me down in too much jargon from the get go. There is a minor typo in the first paragraph, the closed parentheses after “physical” should not be there. I like the way that I am given a brief overview of the history of researching MDD, which relays the scope of the research and gives context for the more recent work done on the disease. The charts at the beginning are a little jarring, since I do not know what they refer to at first, so perhaps placing them throughout the piece would be better aesthetically. Overall it is informative and accessible to someone like me who lacks a science background.

    1. Thanks for your comments A.J! I am sorry that figures were a little out of place (I had no idea how to put them into the body of the paragraph) and now that I have the opportunity to move them I believe they will be more understandable when placed in the correct spot. I have also spotted the type and will fix it asap. I am glad that you found the information accessible and I encourage you to read through the rest of the material (its not that bad).

  3. This was well put together. As you might know, I’m working on Bipolar Disorder and I have found that melatonin, which is synthesized from serotonin, shows up a lot in the literature I’ve found. Since people with Bipolar Disorder exhibit the same symptoms as those with Major Depressive Disorder while they are in the middle of a Depressive episode, I was wondering: have you had come across similar findings linking changes in melatonin levels or changes in its synthesis to Major Depressive Disorder?

    1. Hey Evan thanks for the feedback! I had not run across anything pertaining to melatonin in my research. I believe that it could definitely be a contributing factor to MDD as a forwarded synthesis of melatonin could lower serotonin levels and cause depressive moods. Since the majority of MDD research is focused on MAO-A, I believe that most of the serotonin is being deaminated by this and is not going to melatonin synthesis abnormally. It would be interesting to see if someone who has MDD actually has less melatonin in their system than normal, maybe resulting in the sometimes depressive symptom of insomnia. I was not able to find anything linking MDD specifically to melatonin but I will keep my eyes open! The research of the field is so focused in on MAO-A that it isn’t really doing much more besides that, it might be a good future experiment to look into this relationship.

  4. I thought this page was really informative and fairly easy to follow but at the very beginning where you say that “We see here that in someone with MDD there is both an increase in MAO A and a decrease in R1 ” I didn’t have any idea how I was supposed to have gotten to that result, nor knew what MAO A or R1 was at that point. It may be helpful to include that later in the page after you have explained the role the enzyme and the receptor play in the disease.

    1. Thank you for your feedback Morgan! I revised that paragraph and I think that reading the new edited version will be a little more logically sound. I would not have caught that without a head up so thanks! Also, I am glad that the rest of the material was easy to follow and understand, so I will model my description of R1 after the rest of the intro to make it easier to understand. I hope that you are able to check out the rest of the site.

  5. Awesome job! A few things may be useful to link to the Biochemistry Primer to make sure anyone can get a general understanding of the terms such as depressor, serotonin, and dopamine. Two other points of interest, I’m currently doing cocaine (for my project) and was interested in the fact that cocaine stops the reuptake of dopamine and seratonine to give its high. Are one of the proposed treatment methods the inhibition of dopamine reuptake proteins? Also I would be interested to see whether you have an increase in cocaine use by individuals with MDD as it may give a sense of normalcy, though the general behavioral changes associated with MDD may be more the culprit. Finally do you know how MDD is diagnosed and if it is necessary rooted in something as simple as a protein isoform? I would be interested in whether our attempt to characterize any separation from a ‘normal’ mental wellness is biased by a western reductionist movement and whether our attempts to simplify the formation of MDD by using simplified models deters a more holistic understanding of depression.

    1. As I would expect great feedback thanks! I will be linking those terms to the primer as soon as this comment is finished and I edit the homepage. I think, too, that linking them is definitely beneficial and having too many links never hurt anyone. To answer your questions:

      1) We do actually see that there is the use of serotonin and norepinephrine reuptake inhibitors for the treatment of MDD, not so much dopamine (I am not sure why not dopamine but it might be that inhibiting the reuptake of serotonin and norepinephrine is more related to MAO-A which is the major research point in the field right now). This treatment makes sense to give someone with less serotonin and norepinephrine a sense of normalcy because inhibiting this reuptake is a way of fighting back against the depletion of serotonin and norepinephrine in the first place. I am personally interested to see if they take the GABA discovery (covered in my molecular basis page) and try to make a reuptake inhibitor of that as well. This drug will probably be used most of all because it has the least negative side effects.

      2) I did not read anything on MDD and cocaine relation, but I feel that since cocaine works in the same was as prescription SSRI (selective serotonin reuptake inhibitor) and SNRI (serotonin and norepinephrine reuptake inhibitor) it is possible that someone might do cocaine as a way coping. If crack cocaine uses the same mechanism as cocaine, then a person could buy crack cocaine pretty cheap to deal with this problem because of the racial stigmas around crack making it less expensive and way more illegal.

      3) There has been a new experimental method of diagnosis for MDD using an enzyme called salivary alpha-amylase (sAA) that could potentially be used to detect elevated levels of MAO-A. This research, however, is still very young (it was done this year) so most diagnosis is still done through behavioral changes. I definitely agree that the method of detecting depression can be culturally biased (it is written in the english DSM) and this kind of assay could be helpful to eliminate such bias of depression being “all in one’s head” and now being an actual disease.

Comments are closed.