MDD is a disorder that is affecting many adults and adolescents in the United States and throughout the rest of the world. To combat this disease, the scientific community have taken a firm stance on MAOs (specifically MAO-A) as the target of MDD research. Results have been promising so far with discoveries of transcription factors and regulators of MAO-A within the last 4 years (Johnson et al. 2011 and Grunewald et al. 2012) and MAO-A has also been given a new target of deamination that was never shown before with the introduction of GABA as a MAO-A metabolite (Goldberg et al. 2014) (see Figure 10).
However, there are still areas within this field of research that need to be addressed before more progress can be continued. Firstly, obtaining a crystal structure of MAO-A with its substrate could illuminate the mechanistic activity of MAO-A that is lacking in the research today. Although Ma et al. (2004) were able to crystalize the protein, work today could produce a better resolution than 3.2 angstroms and could also show a crystal structure of MAO-A bound to serotonin, norepinephrine, dopamine, or GABA. Without this mechanistic information of how MAO-A actually works, the field could be missing out on an opportunity to inhibit it. Knowing its mechanism of action could allow the field to develop new treatments that were not already established. Future work to crystalize MAO-A bound to serotonin, norepinephrine, GABA and dopamine will be essential to
Secondly, the field needs to consider the new information that GABA is broken down by MAO-A (see Figure 11). This new study in 2014 could be the reason that SSRIs and SNRIs are not as effective as we would like. This information could be used to study GABA reuptake and regulation; new drugs could be designed that are able to block the reuptake of all three monoamines (serotonin, dopamine and norepinephrine). If that kind of drug is impossible to make, it may be wise for patients to take SSRIs or SNRIs while being supplemented with GABA. The community has not been able to address the issue of GABA deamination, and now is the time to move forward and try to stop MAO-A from destroying yet another neurotransmitter.
Lastly, there has not been a lot of crosstalk with what is going on with the postsynaptic side of the synaptic cleft. Research has not clearly identified if an increase in MAOs has any negative effects on the serotonin receptors themselves. This kind of information could explain why SSRIs and SNRIs don’t work perfectly; it wouldn’t matter how much serotonin and norepinephrine is left in the synaptic cleft if the receptors on the postsynaptic cell are not able to detect them. Studies that address this issue of damage to the receptor from excessive ROS generation might be useful information in considering treatment. If the receptors are damaged, it may be more beneficial to attack the MAOs instead of trying to keep neurotransmitters out of the presynaptic neuron longer. Another area of study that could also be looked at is damage to the 5-HT transporter, where damage could actually let more serotonin back into the presynaptic cell. Both of these damage based questions have not been answered in the literature so far and are worth considering.
It is also wise to consider another possibility of mechanism for MDD besides the MAO theory. Much like Alzheimer’s having the amyloid beta dominance in the literature, there is a possibility that another factor besides MAOs are responsible for this disease. Shyn et al. (2010) wrote a review explaining how there should be more focus on the genetics of this disease as well as looking at epigenetic modifications of this disease. Their paper was published before the findings of Johnson et al. (2011) and Grunewald et al. (2012) when there was not as much relevant literature on MAOs, but their point in looking at genetics and epigenetics of the disease is still valid. Other research with other neurotransmitters or even the production of the neurotransmitters themselves might be another good area of study. The important thing for the field of MDD study is to not get too focused in on MAO. Understanding MAO-A mechanism and creating a more effective inhibitor might be the forefront of research now, but more discoveries could possibly be made studying other aspects that could be affected by the disease.