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The Chemistry of Depression

What Is the Biochemical Basis of Depression?

By Nancy Schimelpfening

Updated on July 21, 2024

Medically reviewed by Steven Gans, MDPrint

Table of Contents

Watch Now: 7 Most Common Types of Depression

Brain Chemicals and Depression

Previously, it was suggested that, for some people, having too little of certain substances in the brain (called neurotransmitters) could contribute to the onset or worsening of depression. According to this idea, restoring the balance of brain chemicals could help alleviate symptoms.

This is where the different classes of antidepressant medications may come in. Many antidepressants alter levels of certain neurotransmitters in the brain.

The most commonly prescribed class of antidepressants, known as SSRIs, or selective serotonin reuptake inhibitors, block the reabsorption of serotonin, a neurotransmitter that can affect mood. The “serotonin hypothesis” suggested that low levels of this neurotransmitter were linked to depression. The idea was that increasing serotonin levels could help improve mood and relieve symptoms of depression.

Recent Evidence

The belief that depression is caused by chemical imbalances has been declining in the scientific and medical community for some time. A study published in a 2023 issue of the journal Molecular Psychiatry found further reason to doubt this explanation. The research indicated there is little evidence to suggest that depression is caused by chemical imbalances in the brain.³

The belief that chemical balances cause depression is still widely held by the general public.⁴ This indicates a need to communicate the more current understanding that depression is a heterogeneous condition that may have many underlying causes.

Understanding the Biopsychosocial Model of Health and Wellness

While such findings challenge the idea that a serotonin deficiency is responsible for causing depression, it doesn’t mean that mental health treatments are ineffective. More research is needed to fully understand what causes depression, how antidepressants affect the condition, and what other treatments may also be effective for managing symptoms of depression.

Warning!

These findings represent a significant shift in our understanding of depression, but this does not mean people taking antidepressants should stop their medication!

The 2023 study also found a strong connection between traumatic life events and the onset of depression.³ This suggests that depression is caused by complex factors, including environmental variables, and cannot be reduced to simply a chemical imbalance in the brain.

The Evidence Is In: Depression Might Not Be Linked to Low Serotonin After All

Depression Is Complex

Even with the help of medications that affect 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 for someone else. Even something that has worked well for someone in the past may become less effective or even stop working for reasons researchers are still trying to understand.

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

Depression is a multi-faceted condition. While researchers do not fully understand what causes it, having an awareness of brain chemistry can be useful for medical and mental health professionals, researchers, and many people with depression.

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What Are Neurotransmitters?

Put simply, neurotransmitters are chemical messengers in the brain. The nerve cells of the brain use neurotransmitters to communicate with each other, and the messages they send are believed to play a role in mood regulation.

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 (reuptake) 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.

The chemical theory of depression suggested that imbalances in brain chemistry were a primary cause of depression. However, recent findings found no evidence to support this idea.

It is important to remember that we do not fully understand how imbalances in these chemicals affect mental health conditions such as depression. While research indicates that serotonin levels may not cause depression, other neurotransmitters and interactions may play a part.

How Neurotransmitters Work

The Role of Key Neurotransmitters

The three neurotransmitters that are often implicated in depression are:

Other neurotransmitters, including glutamate, GABA, and acetylcholine, can send messages within the brain. Researchers are still learning about the role these brain chemicals play in depression and other conditions, such as Alzheimer’s, fibromyalgia, and sleep disorders.

Dopamine

Dopamine creates positive feelings associated with reward or reinforcement that motivate us to continue with a task or activity. Dopamine is believed to play an essential 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.⁵ When other treatments have failed, medications that affect the dopamine system are often added and can be helpful for some people with depression.

Norepinephrine

Norepinephrine is both 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.

Schildkraut proposed depression occurs when there is too little norepinephrine in specific brain circuits. Alternatively, mania results when too much of this neurotransmitter is 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 others.

Catecholamines and the Stress Response

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.⁶

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

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

Newer antidepressants called serotonin-norepinephrine reuptake inhibitors (SNRIs) like Effexor (venlafaxine) target both serotonin and norepinephrine. Tricyclic antidepressants (TCAs) also affect norepinephrine and serotonin, but they have the added effect of influencing histamine and acetylcholine. These substances produce side effects, such as dry mouth, blurry vision, constipation, and urinary hesitancy.

SSRIs, on the other hand, do not affect histamine and acetylcholine, don’t have the same side effects, and are safer from a cardiovascular standpoint. Therefore, doctors, psychiatrists, and people with depression tend to prefer them to older classes of antidepressants like TCAs.

How to Increase Serotonin

Causes of Low Neurotransmitter Levels

While recent findings found no evidence to support the idea that chemical imbalances are responsible for causing depression, many people do find relief from taking antidepressants that impact neurotransmitter levels. An important question is what might cause the low levels of serotonin, norepinephrine, or dopamine in the first place?

Low levels of neurotransmitters can result when there is a breakdown anywhere in the process. Research has indicated several potential causes of chemical imbalances in the brain, including:

Molecules that help make neurotransmitters (specific enzymes) are in short supply
Not 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)
Too little of a specific neurotransmitter (for example, serotonin) is being produced

Several emerging theories are concerned with the factors that promote lowered levels, such as cellular (specifically mitochondrial) stress.⁷ However, 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 them.

Current and Future Depression Treatments

Understanding the chemistry of depression may help people better understand the treatments available. Psychotherapy is helpful for some people with depression, but others also find greater relief when these treatments are used alongside medications.

If a person finds that therapy alone is not helping them manage their depression, they may want to try medication. For some people, antidepressants combined with psychotherapy prove 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.⁸

Whatever might be causing your symptoms, depression affects your internal and external life. Therefore, medication alone may not be sufficient to address all the ways in which depression can affect you.

Research suggests that 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 other underlying causes of depression. In this situation, therapy to improve stress management, heal from emotional wounds, learn to regulate emotions, and improve thinking patterns could potentially be helpful.

If you or a loved one are struggling with depression, contact the Substance Abuse and Mental Health Services Administration (SAMHSA) National Helpline at 1-800-662-4357 for information on support and treatment facilities in your area.

For more mental health resources, see our National Helpline Database.

Depression Treatments on the Horizon

Researchers are studying other molecular pathways in the brain (including the glutaminergic, cholinergic, and opioid systems) to see their role in depression. It may be that rather than a simple deficiency in 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 brain regions.

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 factors 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.⁹

Combatting the Chemical Imbalance 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.¹⁰

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.¹¹ 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 fear that they are dangerous).¹²

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.¹³

Recap

Improving people’s understanding of the many factors that can contribute to an increased risk for depression might help people feel more motivated and empowered as they manage their condition.

Depression Statistics Everyone Should Know

Final Thoughts

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.¹⁴

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.

The Best Online Resources for Depression

14 Sources

By Nancy Schimelpfening
Nancy Schimelpfening, MS is the administrator for the non-profit depression support group Depression Sanctuary. Nancy has a lifetime of experience with depression, experiencing firsthand how devastating this illness can be.

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