The Biochemical Theory of Depression


How many times in a casual conversation about depression have you heard someone use the term chemical imbalance? Have you ever asked yourself where that idea comes from?  

This is the way many people think about depression, as a “chemical imbalance.” It all seems so intuitive. If there is a chemical missing from the body, you should theoretically be able to replace that chemical and solve the problem. However, the question remains, how did we come up with this idea in first place? This post will attempt to explain how the biological basis of depression was formed. If you can understand these concepts, it lays the groundwork for understanding how many medications for depression work.

Biogenic Amine Hypothesis

The current prevailing biochemical theory of depression is called the biogenic amine hypothesis. The name is a little complex so we can use serotonin as our example. It’s the neurotransmitter most commonly associated with depression and it happens to be a biogenic amine. This was the first attempt to explain the biological basis for depression and evolved from observations that certain medication had either a positive or negative effect on mood. 

Mood & Neurotransmitters 

One early observation of medication effecting mood was with the drug iproniazid which was designed to treat tuberculosis. The researchers observed that it wasn’t very effective for tuberculosis, but it did enhance the mood of some patients. The researchers hypothesized that it was the medications ability to inhibit metabolism of norepinephrine, serotonin and dopamine thus increasing these levels in the brain that provided the antidepressant effect. Iproniazid is what you would call a monoamine oxidase inhibitor (MAOI) which is an older class of medication for depression. It’s rarely used today due to the side effect profile, but hopeful this illustrates the concept. 

Further support for the theory comes from animal studies with the antidepressant medications in the tricyclic antidepressant (TCA) family. These medications block the reuptake of serotonin and norepinephrine thus increasing the levels in the brain. This illustrates the same concept as the (MAOI) discussed above, increase serotonin and norepinephrine in the brain and mood improves. 

Problems with the Theory

One issue with the theory was these medications begin blocking reuptake within minutes, but the antidepressant effects take several weeks to occur. More recent research has shown that these medications down regulate certain receptors, but even with this it’s unlikely to fully explain the antidepressant effects of the medication. While this remains the prevailing theory, it’s clear that there is more to learn about the way these neurotransmitters interact with receptors. Some of the newer medications for depression do not function in the manner as those listed above, but still provide antidepressant effects.

Final Points

  • The biogenic amine hypothesis, is just that it’s a hypothesis about how these medications work on depression 
  • Most of the early evidence was observational, and with medications initially designed to address other disorders. 
  • While the biogenic amine hypothesis is incomplete and does not fully explain depression, It provides a useful framework for future study and drug design 

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