History and Metabolic Context

Major Depressive Disorder (MDD) is most often what an individual is referencing when they are talking about depression in general.  This disorder has been defined by the MAYO clinic to be, “…a mood disorder that causes a persistent feeling of sadness and loss of interest” (MAYO Clinic 2014).  This definition is a solid first step to explaining MDD, but it is often difficult to explain MDD in bodily terms when this is a neurological/mood disorder.  To expand on the definition of MDD, the National Institute of Mental Health (NIMH) has also defined MDD as, “severe symptoms that interfere with your ability to work, sleep, study, eat, and enjoy life. An episode can occur only once in a person’s lifetime, but more often, a person has several episodes” (NIMH).

Figure 3: It is shown in this study by the NIMH that 6.7% of adults will experience MDD.  It also shows the percentage of people who classify this disorder as severe.
Figure 3: It is shown in this study by the NIMH that 6.7% of adults will experience MDD. It also shows the percentage of people who classify this disorder as severe. (From: http://www.nimh.nih.gov/statistics/1MDD_ADULT.shtml)

Symptoms of MDD often include hopelessness, guild, irritability, difficulty concentrating, suicidal thoughts or actions, and other symptoms when can be viewed in the following link (NIMH).  MDD has been shown to affect 6.7 percent of adults living in the United States as well as 3.3 percent of adolescents 13 to 18 years old (Figure 3).  MDD not only affects this many adults and adolescents in the United States, but the resurgence rate of this disorder is 50 percent; MDD will resurface after being cured 50 percent of the time (NIMH).  With such a high resurgence rate, the importance of finding the mechanism of this disease has been the center of research in this field.

MDD has been classified throughout historical writing (both works of fiction and nonfiction) as far back as ancient Greek culture.  In Letters of Hippocrates symptoms of MDD are seen described by the word melancholia (we still see the word melancholy used today to describe symptoms of MDD) (Zimmerman 1995).  This definition of MDD persisted throughout history until a landmark publication in the psychiatric field; the American Psychiatric Association published The Diagnostic and Statistical Manual of Mental Disorders (DSM) in 1952, which was later revised by Robert Spitzer to include a new set of criteria for the diagnosis of MDD (Yukozimo 2014).  The DSM has been the major mode of diagnosing MDD since its publication, and is still used today by psychologists and psychiatrists.  In the fourth edition of the DSM, a list of diagnostic criteria was established to differentiate MDD from other types of depression such as bipolar disorder and other mood disorders (DSM-IV-TR 2000).

Most diagnosis of MDD is carried out using the DSM; there is no metabolic test established for the diagnosis of MDD.  This was the case until a recent study by Cubala et al. (2014) showed baseline work to establish an assay to diagnose MDD.  The researchers were looking at an enzyme called Salivary α-amylase (sAA); MDD has been shown to have effects on the autonomic nervous system (ANS), and sAA has been used as a marker for ANS activity.  The researchers were able to show that low baseline levels of sAA were correlated to MDD, but the researchers themselves correctly state that this data is limited.  Small sample size and other saliva sampling problems have limited their results; with more work in this kind of assay, there could be a diagnostic test for MDD.

Most of the work today in the field of MDD research, however, is focused more on the metabolism of MDD than a metabolic assay for MDD.  In a study by Freis (1954), it was shown that patients taking large doses of a drug called Reserpine had begun showing symptoms of MDD.  Reserpine is a drug that has been shown to destroy monoamine neurotransmitters (norepinephrine, serotonin and dopamine), leading researchers to believe that a depletion of these monoamine neurotransmitters is a likely cause of depression (Goldberg et al. 2014).  A study by Schildkraut et al. (1967) was able to show that there was a correlation between monoamine neurotransmitters and depression, allowing for another study by Takahashi (1977) to establish that there is an increase in monoamine oxidases (MAOs) found in the blood platelets of those with MDD.  This landmark study has led the scientific community to find the mechanism of MAOs in MDD.

Figure 4: Here we see the normal function of MAOs.  MAOs in healthy individuals regulate the amount of monoamine neurotransmitters through degradation.  However, in an unhealthy individual we see that this is not the case, as there are more MAOs to destroy more monoamine neurotransmitters (From: http://www.cnsspectrums.com/aspx/articledetail.aspx?articleid=1085)
Figure 4: Here we see the normal function of MAOs. MAOs in healthy individuals regulate the amount of monoamine neurotransmitters through degradation. However, in an unhealthy individual we see that this is not the case, as there are more MAOs to destroy more monoamine neurotransmitters (From: http://www.cnsspectrums.com/aspx/articledetail.aspx?articleid=1085)

Normally, MAOs are supposed to breakdown monoamine neurotransmitters to prevent them from accumulating in the brain (Duncan et al. 2012); see also Figure 4.  However, an overproduction of MAOs can lead to too little monoamine neurotransmitters and can result in less signaling from these molecules.  Research today is mostly trying to understand why there is this accumulation of MAOs and what direct metabolic side effects this accumulation has on MDD.