The Chemistry of Depression

What Is the Biochemical Basis of Depression?

Illustration showing how neurotransmitters are released into the synaptic cleft and either bind with a receptor or are reabsorbed (reuptake) into the the neuron
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In This Article

There are several theories about what causes depression. The condition most likely results from a complex interplay of individual factors, but one of the most widely accepted explanations cites abnormal brain chemistry.

Sometimes, people with depression relate the condition back to a specific factor, such as a traumatic event in their life. However, it's not uncommon for people who are depressed to be confused as to why—they may even feel as though they don't have "a reason" to be depressed. In these cases, learning about the theories of what causes depression can be helpful.

Researchers have suggested that for some people, having too little of certain substances in the brain (called neurotransmitters) could contribute to depression. Restoring the balance of brain chemicals could help alleviate symtpoms—which is where the different classes of antidepressant medications may come in.

It seems simple, but even with the help of medications that work to increase or balance specific neurotransmitters in the brain, depression is a highly complex condition to treat. What proves to be an effective treatment for one person with depression may not work at all for someone else. Even something that has worked well for someone in the past may become less effective over time, or even stop working, for reasons we're still trying to understand.

Researchers continue to try to better understand the mechanisms of depression, including brain chemicals, in hopes of finding explanations for these complexities and developing more effective ways to treat them.

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Depression is also a multi-faceted condition, but having an awareness of the brain chemistry component can be useful for medical and mental health professionals, researchers, and many people who have depression.

Here's an overview of what is known (and not-yet-known) about how chemical imbalances in the brain may influence depression.

Neurotransmitters

Put simply, neurotransmitters are chemical messengers in the brain. The nerve cells of the brain use three neurotransmitters (known chemically as monoamines) to communicate with each other. The messages they send are believed to play a role in mood regulation.

The three neurotransmitters implicated in depression are:

There are other neurotransmitters that can send messages in the brain, including glutamate, GABA, and acetylcholine. Researchers are still learning about the role these brain chemicals play in depression and other conditions, such as Alzheimer's and fibromyalgia.

Communicating With Neurotransmitters

The space between two nerve cells is called the synapse. When cells want to communicate, neurotransmitters can be packaged up and released from the end (axon) of a presynaptic cell.

As a packet of neurotransmitters crosses the space, it can be taken up by receptors for a specific chemical on postsynaptic cells (dendrite). For example, serotonin receptors pick up serotonin molecules.

If there are any excess molecules in the space, the presynaptic cell will gather them back up and reprocess them to use in another communication.

Each type of neurotransmitter can carry a different message and plays a unique role in creating an individual's brain chemistry. Imbalances in these chemicals may contribute to mental health conditions such as depression.

Norepinephrine

Norepinephrine is a neurotransmitter and a hormone. It plays a role in the "fight or flight response" along with adrenaline. It helps send messages from one nerve cell to the next.

In the 1960s, Joseph J. Schildkraut suggested norepinephrine was the brain chemical of interest for depression when he presented the "catecholamine" hypothesis of mood disorders.

He proposed depression occurred when there is too little norepinephrine in certain brain circuits. Alternatively, mania results when there is too much of the neurotransmitter in the brain.

There is evidence that supports the hypothesis, however, it has not gone unchallenged by researchers. For one, changes in norepinephrine levels do not affect mood in every person. Further, medications specifically targeting norepinephrine may alleviate depression in some people, but not in others.

Therefore, researchers now understand that having too-little norepinephrine isn't the only chemical cause of depression.

Serotonin

Another neurotransmitter is serotonin or the "feel good" chemical. In addition to helping regulate your mood, serotonin has a number of different jobs throughout the body; from your gut to blood clotting to sexual function.

In relation to its role in depression, serotonin has taken center stage in the past two decades thanks to the advent of antidepressant medications like Prozac (fluoxetine) and other selective serotonin reuptake inhibitors (SSRI's). As their name implies, these medications specifically act on serotonin molecules.

Researchers have been looking into serotonin's role in mood disorders for almost 30 years. Arthur J. Prange, Jr. and Alec Coppen's "permissive hypothesis" originally suggested low serotonin levels allowed levels of norepinephrine to fall as well, but that serotonin levels could be manipulated to indirectly raise norepinephrine.

Newer antidepressants called serotonin-norepinephrine reuptake inhibitors (SNRI's) like Effexor (venlafaxine) target both serotonin and norepinephrine.

Tricyclic antidepressants (TCAs) also affect both norepinephrine and serotonin, however, they have the added effect of influencing histamine and acetylcholine. These substances produce the side effects TCAs are known for, such as dry mouth or eyes, a peculiar taste in the mouth, sensitivity to light, blurry vision, constipation, urinary hesitancy, and a quite a few others.

SSRIs, on the other hand, do not affect histamine and acetylcholine and don't have the same side effects. Therefore, doctors, psychiatrists, and people with depression tend to prefer them to older classes of antidepressants.

Dopamine

A third substance that might play a role in mood is dopamine. Dopamine creates positive feelings associated with reward or reinforcement that motivates us to continue with a task or activity. Dopamine is believed to play an important role in a variety of conditions affecting the brain, including Parkinson's and schizophrenia.

There is also evidence that reduced dopamine levels can contribute to depression in some people. When other treatments have failed, medications that behave like dopamine or stimulate the release of the neurotransmitter in the brain have worked for some people with depression.

Most of the available medications used to treat depression can take six weeks or longer to be effective. Researchers are interested in finding out if dopaminergic agents could provide a more rapid method for treating depression.

However, there are some potentially serious downsides. Dopamine production is stimulated by drugs like cocaine, opiates, and alcohol. It's not uncommon for people who are depressed to self-medicate with these or other substances.

When the dopamine reward cycle is activated by substance use, addiction can develop. It's possible that drugs developed to be targeted at dopamine receptors could carry an especially high risk for abuse.

Low Neurotransmitter Levels

If low levels of neurotransmitters can contribute to depression, an important question is what causes the low levels of serotonin, norepinephrine, or dopamine in the first place?

Research has indicated several potential causes of chemical imbalances in the brain, including:

  • Too little of a specific neurotransmitter (for example, serotonin) is being produced
  • There aren't enough receptor sites to receive the neurotransmitter
  • Presynaptic cells are taking the neurotransmitter back up before it has a chance to reach the receptor cell
  • Too few of the molecules that build neurotransmitters (chemical precursors)
  • Molecules that help make neurotransmitters (specific enzymes) are in short supply

When there is a breakdown anywhere in the process, low levels of neurotransmitters can result.

Several emerging theories are concerned with the factors that promote lowered levels, such as cellular (specifically mitochondrial) stress.

One of the main challenges for researchers and doctors hoping to connect depression to low levels of specific brain chemicals is that they don't have a way to consistently and accurately measure.

It's also important to note that neurotransmitters are made in other parts of the body, not just the brain. Whether making a diagnosis of depression or trying to determine the most effective treatment, these amounts would also need to be measured and considered.

Treating Depression

Understanding the chemistry of depression may help people better understand the treatments available. While psychotherapy is helpful for some people with depression, if there is a chemical imbalance in the brain it may not be enough to address a person's symptoms.

If a person does not find therapy alone is helping them manage their depression, they may want to try medication. For some people, antidepressants combined with psychotherapy proves especially effective for addressing their symptoms.

To complicate treatment further, medication does not always work for people with depression. One study evaluating the effectiveness of currently available antidepressants found that these medications only work in about 60% of people with depression.

Even if your depression is primarily linked to an imbalance of chemicals in the brain, depression affects both your internal and external life. Therefore, medication without therapy may not be sufficient to address all the ways in which depression can affect you.

There is also research that suggests neurotransmitter levels can be affected by factors other than medication and that psychotherapy can help a person learn about them.

For example, stress may contribute to low levels of certain neurotransmitters. While taking an antidepressant medication might help with the symptoms, it doesn't necessarily address the cause of the low levels.

In this situation, therapy to improve stress management and reduce stress could help regulate the chemical precursors available in the brain from which neurotransmitters are produced.

Combating Stigma

Acknowledging the limitations of our current knowledge of depression and its treatment is important. In recent years, some researchers have expressed concerns that pharmaceutical companies marketing antidepressant medications may have misled consumers by oversimplifying or misrepresenting the research into the brain chemistry of depression.

Additionally, sociological research has found that the stigma attached to depression (and taking medication to treat it) is not necessarily lessened by the theory of chemical imbalance. Several studies have found that when told depression is caused by a chemical imbalance, people tend to feel less confident in their ability to manage the condition.

Other studies have found that when depression is framed as a disease of the brain, people are more likely to feel the need to avoid a person with depression (usually out of the fear that they are dangerous).

Not all the research has been negative, though. Several studies included in a 2012 meta-analysis indicated that one of the most effective ways to address and challenge social stigma around mental illness is to educate and discuss conditions and treatment—which includes being upfront and honest about what is still unknown or not well understood.

More Than Changing Brain Chemistry

Researchers are studying other molecular pathways in the brain (the glutaminergic, cholinergic, and opioid systems) to see what role they may play in depression. It may be that rather than a simple deficiency in a one specific brain chemical being the causative factor, some depression symptoms could be related to the relative levels of each type of neurotransmitter in different regions of the brain.

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. While this complexity is often evident to people living with depression, medical professionals and researchers are still trying to understand the intricate nature of diagnosing and treating the condition.

For example, in addition to the role of neurotransmitters, we know there are multiple sources involved in causing depression ranging from genetic factors and childhood experiences to our present day-to-day lives and relationships. Even inflammation is being explored as a potential contributing factor.

A Word From Verywell

Neurotransmitters likely play a role in depression, but it's also clear that biochemical changes alone cannot explain the complete reality of depression; other factors must be at play as well.

Accepting how little we truly know about the chemistry of depression can help us maintain perspective and expectations for the medications used to treat depression. For people who are trying to find the right treatment, understanding the complex chemistry can be reassuring when a particular drug doesn't work for them or if they need to try more than one antidepressant.

Understanding the complexity of depression can also be helpful for those who have been offered hurtful advice, such as being told to "just snap out of it." It is no easier for someone to forget they are depressed than it would be for someone with diabetes to lower their blood sugar by simply not thinking about it.

Being realistic about the limitations of our knowledge can help us remember that for the time being, there is no one treatment that will work for everyone with depression. More often than not an interdisciplinary approach is needed. At the very least, every person dealing with depression needs and deserves a support team.

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