The Chemistry of Depression

What is the Biochemical Basis of Depression?

neurotransmitters and the synaptic cleft showing vesciles and receptors
Illustration showing how neurotransmitters are released into the synaptic cleft and either bind with a receptor or are reabsorbed (reuptake) into the the neuron. Photo©ttsz

You may have heard that depression is caused by abnormal chemistry in the brain, and that antidepressants work by altering the levels of these substances (neurotransmitters), but what does this mean? What is the chemistry behind depression?

Neurotransmitters - Chemical Messengers of the Brain

You've probably heard the term "neurotransmitter" before, but what are these molecules and ow do they work? Neurotransmitters are chemical messengers in the brain that are the means by which nerve cells communicate with each other.

Illustration of Neurotransmitters in Action

The old adage that a picture is worth a thousand words was never more true than when talking about how nerve cells in our brain communicate with each other.

The illustration above depicts the junction between two nerve cells. Packets of neurotransmitter molecules are released from the end of the presynaptic cell (the axon) into the space between the two nerve cells (the synapse). These molecules may then be taken up by receptors (such as serotonin receptors) of the postsynaptic nerve cell (the dendrite) and thus pass along their chemical message. Excess molecules are taken back up by the presynaptic cell and reprocessed.

Neurotransmitters and Mood Regulation

There are three neurotransmitters, known chemically as monoamines, which are thought to play a role in mood regulation:

These are just a few of the neurotransmitters that function as messengers in the brain. Others include glutamate, GABA, and acetylcholine.

History of The Chemistry of Depression - Norepinephrine

In the 1960s Joseph J. Schildkraut of Harvard University cast his vote with norepinephrine as the causative factor for depression in the now classic "catecholamine" hypothesis of mood disorders.

He proposed that depression stems from a deficiency of norepinephrine in certain brain circuits and that mania arises from an overabundance of this substance. There is indeed a large body of evidence that supports this hypothesis, however, changes in norepinephrine levels do not affect mood in everyone. It was known that some medications which specifically target norepinephrine worked to alleviate depression in some people, but not in others.

History of the Chemistry of Depression - Add in Serotonin

Obviously there must be some other factor that interacts with norepinephrine to cause depression. Serotonin has been found to be another factor. This molecule has taken center stage in the past two decades thanks to Prozac (fluoxetine) and other selective serotonin reuptake inhibitors (SSRI's), which selectively act on this molecule. Serious investigations into serotonin's role in mood disorders, however, have been going on for almost 30 years, ever since Arthur J. Prange, Jr., of the University of North Carolina at Chapel Hill, Alec Coppen of the Medical Research Council in England and their co-workers put forward the so-called "permissive hypothesis." This view held that synaptic depletion of serotonin was another cause of depression, one that worked by promoting, or "permitting," a fall in norepinephrine levels.

So, although, norepinephrine still played a major role in depression, serotonin levels could be manipulated to indirectly raise norepinephrine.

Newer antidepressants called serotonin-norepinephrine reuptake inhibitors (SNRI's) like Effexor (venlafaxine) are actually targeted at both serotonin and norepinephrine. Tricyclic antidepressants (TCAs) also affect both norepinephrine and serotonin, however, they have the added effect of influencing histamine and acetylcholine, which produces the side-effects that TCAs are known for, such as dry mouth or eyes, peculiar taste in mouth, sensitivity to light of the eyes, blurry vision, constipation, uninary hesitancy, and others. SSRIs do not affect histamine and acetylcholine and thus do not have the same side-effects as the older medications.

The Chemistry of Depression - Add in Dopamine

A third substance that may play a role in mood is dopamine. Dopamine is associated with the reward, or reinforcement, that we get which causes us to continue participating in an activity. It has been implicated in such conditions as Parkinson's Disease and schizophrenia. There is also some evidence that, at least for a subset of patients, dopamine plays a role in depression. Medications which act like dopamine or stimulate the release of dopamine in the brain have worked for some people with depression when other measures have failed.Some studies have investigated dopaminergic agents as a rapid method of relieving depression (in contrast to medications which may take up to six weeks to exhibit their full effect).

Although agents that work selectively on dopamine have the benefit of fast action, they have also exhibited some properties which have kept them from being as widely used as other antidepressants. Dopamine is a neurotransmitter that is associated with addiction and it's production is stimulated by drugs such as cocaine, opiates and alcohol (which may explain why depressed persons choose to self-medicate with drugs and alcohol. Drugs specifically targeted at dopamine, for example Survector (amineptine (Survector)), present the potential for abuse.

Processes That Might Lower Brain Neurotransmitter Levels

Now that is appears decreased levels of the neurotransmitters norepinephrine, serotonin, and dopamine contribute to depression, what causes these reduced levels in the first place? In other words, what causes the low levels of serotonin, norepinephrine, or dopamine, which in turn may sometimes cause the symptoms of depression? Several things might potentially go wrong with this process and lead to a neurotransmitter deficit. Some of the possibilities include:

  • Not enough of the neurotransmitter (for example, serotonin) is produced
  • Not enough receptor sites to receive the neurotransmitter
  • The neurotransmitter is being taken back up too quickly (into the presynaptic) before it can reach receptor sites
  • Chemical precursors (molecules from which neurotransmitters are built) may be in short supply
  • Molecules that facilitate the production of neurotransmitters, such as specific enzymes, may be in short supply

As you can see, if there is a breakdown anywhere along the path, neurotransmitter supplies may not be adequate for your needs. Inadequate supplies may then lead to the symptoms that we know as depression.

Treating Depression from a Biochemical Standpoint

Understanding the chemistry of depression may help people better understand the treatments available for depression. If a biochemical imbalance is the cause of depression symptoms it becomes clear why all the psychotherapy in the world could not correct the problem, just as psychotherapy alone cannot raise insulin levels in a person with diabetes.

What is missed often, however, in our take-a-drug-and-get-better society, is that psychotherapy has been found to be very helpful for some people with depression. What is not spoken of often enough is that we do not understand very well how specific neurotransmitter levels in the brain become low in the first place. It could very well be that some of the processes above are brought about by situations in our lives which can be helped with therapy. For example, therapy to reduce stress and improved stress management may have an effect on the chemical precursors available in the brain from which neurotransmitters are produced. In this sense, drugs may alleviate the symptoms of depression caused by a reduction in, say, serotonin, but do nothing to prevent the neurotransmitter deficiency from recurring in the future.

It could also be that we don't have the complete picture when it comes to neurotransmitters in the brain. Researchers are studying other molecular pathways in the brain as well, for example, the glutaminergic, cholinergic, and opioid systems to see what role they may play in depression. In addition, rather than a simple deficiency in any of these brain chemicals, some depression symptoms may instead be related to the relative levels of different neurotransmitters in different regions of the brain.

Depression - More Than a Simple Change in the Brain Chemistry

Rather than being a simple equation of some unknown factor causing low levels of one or more neurotransmitters, and these low levels creating the symptoms of depression, the actual basis of depression is much more complex than this. If you have been living with depression, we don't really need to tell you this. You realize that healing depression, unlike giving an insulin shot to someone with diabetes, is much more complex and intricate.

In addition to the role of neurotransmitters, we know thereĀ are multiple factors involved in causing depression ranging from genetic factors, to childhood experiences, to our day to day relationships with other people.

Bottom Line on the Chemistry of Depression

It's clear that neurotransmitters play some role in depression, but much less is known about how these changes come about. It's also clear that biochemical changes alone cannot explain all we see about depression, and that other factors are at work as well.

Until we know more, understanding the little we truly know about the chemistry of depression can be helpful for those using medications for depression. It may help you understand why one medication may work and another doesn't, and why it sometimes requires a trial of several drugs until the right drug is found. It may also help those who are offered hurtful advice, such as the insensitive remark to "just snap out of it." It is no easier for someone to forget they are depressed than for someone with diabetes to restore their insulin levels by just not thinking about it.

Knowing what we know and the limitations of our knowledge may also help people understand why there is not a single treatment that works for everyone with depression, and why the most successful approaches to treating depression involve a combination of therapies.


Kasper, Dennis L., Anthony S. Fauci, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, and Joseph Loscalzo. Harrison's Principles of Internal Medicine. New York: McGraw Hill Education, 2015. Print.

Papakostas, G., and D. Ionescu. Towards New Mechanisms: An Update on Therapeutics for Treatment-Resistant Major Depressive Disorder. Molecular Psychiatry. 2015. 20(10):1142-50.

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