Biology of Depression – Neurotransmitters

Erin L. George, MFT
Erin L. George, MFT
Medical editor

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Depression, formally known as major depressive disorder, is a mental health condition characterized by a persistent depressed mood or a loss of pleasure or interest in activities you once enjoyed. It can significantly affect your functioning at home, work, or school, and can cause many medical and emotional issues.[1],[2] Depression is a complex psychiatric disorder without one cause—rather, its development is influenced by many interacting and compounding factors like genetics, individual biochemistry, environment, and personality.[1]


A literal ton of research has been done on the causes of depression. Below is a brief discussion of the multiple biological, psychological, and social factors that have been identified as being related to the development of depression, with a particular focus on neurotransmitters as key messengers in the brain affecting mood and behavior.

In the context of the Diathesis-Stress hypothesis, the biological factors typically function as diatheses, the psychological factors may serve as diatheses or stressors, and sociological and lifestyle factors may tend to function as stressors or triggers.

What is the Diathesis-Stress Model?

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This model, also referred to as the vulnerability-stress model, is a theory asserting that medical and mental health conditions are caused by a person’s genetic predisposition and how they experience stress. Diathesis refers to the predisposition like genes or other biological factors and stress refers to environmental stressors like trauma that contributed to an onset of depression or other mental health condition. Both genes and environmental triggers can influence neurotransmitter production and levels in different people, which can then lead to depression. [3]

Biology of Depression

You may have heard that depression is the result of a simple chemical imbalance of brain chemicals. Although brain chemicals are certainly part of the cause, this explanation is too simplistic. Even just considering the biological dimension of depression, the brain has multiple layers of complexity. If you think you are suffering from symptoms of depression, get a clear picture of your depression with an online depression quiz.

Is Depression Biological?

Yes, partially. Depression is a complex condition that involves biological, psychological, and environmental factors. There is evidence that suggests that depression has a biological basis. Research has shown that depression is associated with changes in the structure and function of the brain.[4]

These changes can affect the production, function, and levels of neurotransmitters in the brain. The relationship between depression and neurotransmitters lies in the intricate interplay of chemicals in the brain that regulate mood, emotions, and well-being. Neurotransmitters like serotonin, dopamine, and norepinephrine act as messengers, transmitting signals between nerve cells. With depression, there may be low levels of neurotransmitters like serotonin, which can result in symptoms like low mood, lack of pleasure, and disturbed sleep.

However, this “imbalance” is complex and multifaceted and is likely influenced by many biological, environmental, and genetic factors.[4]

Additionally, genes can also play a role in the development of depression, and there is a higher risk of depression in individuals with a family history of the condition. Therefore, while depression has psychological and environmental factors, it is also a biological condition that can have a significant impact on a person's life.

Chemical Imbalances and Depression

The concept of chemical imbalances in depression refers to disruptions in the normal levels of neurotransmitters, such as serotonin, dopamine, and norepinephrine.

While the theory of a simple, one-size-fits-all chemical imbalance causing depression has been challenged, research suggests that neurotransmitter dysregulation plays a nuanced role. [4] Factors like genetics, environmental stressors, and individual variations in brain function contribute to this complex interplay, highlighting the need for a personalized understanding of the neurobiological underpinnings of depression.

Neurotransmitters and Depression

The brain uses several chemicals as messengers to communicate with other parts of itself and with the nervous system. These chemical messengers, called neurotransmitters, are released and received by the brain's many nerve cells, which are also called neurons. Neurons are constantly communicating with each other by way of exchanging neurotransmitters. This communication system is essential to all of the brain's functions.

A tiny space called a synapse connects neurons to one another. In a simple scenario, one neuron (the sender) sends a neurotransmitter message across the synapse and the next neuron (the receiver) receives that message by way of a receptor embedded on its surface. Receptors are tiny molecules in nerve cells that function like a lock on a door. Receptors have chemical channels with particular shapes, which perfectly match the shape of neurotransmitter molecules that are sent across the synapse.

When a "matching" neurotransmitter and receptor come into contact with each other, the neurotransmitter fits itself into the receptor molecule's channel. As a result, the receptor becomes activated or opened, just like when a key enters a lock and turns to open it. When there are no neurotransmitter molecules around to unlock the receptors, the receptors remain in a closed or inactive state.

In music, it's not just the notes that make up a melody; it is also the spaces or rests between the notes that make each note stand out and be distinct. It's exactly the same with regard to neurotransmitters and synapses. There needs to be some quiet time between neurotransmitter messages for those messages to have any meaning. It is important that receptors be allowed to reset and deactivate between messages so that they can become ready to receive the next burst of neurotransmitters. In order to achieve this "resetting", the receptors relax and release their captured neurotransmitters back into the synapse where about 90% of them get taken up again (in a process called reuptake) by the original sending neuron.

The neurotransmitters are then repackaged and reused the next time a message needs to be sent across the synapse. Even though this seems like a complicated set of steps, this entire information transmission cycle occurs in the brain within a matter of seconds. Any problem that interrupts the smooth functioning of this chain of chemical events can negatively impact both the human brain and nervous system.

How Does Depression Affect Neurotransmitters?

Depression affects neurotransmitters in the brain, such as serotonin and norepinephrine, which can lead to changes in a person's mood, energy, and overall mental state

Studies have shown that in people with depression, there may be a decrease in the amount of these neurotransmitters available, which can cause symptoms like loss of interest or pleasure in activities, changes in appetite or sleep, and feelings of anxiety.

Antidepressants work by increasing the availability of these neurotransmitters, which can help alleviate symptoms and improve mood. Understanding the role of neurotransmitters in depression is important for developing effective treatments for severe depression and helping patients lead a better quality of life.

a man thinking about the biology of depression

What Neurotransmitter Causes Depression?

Serotonin, norepineprhine, and dopamine are the main neurotransmitters involved in depression.[5]

Depression is a mood disorder that affects many people. Research has shown that the levels of certain neurotransmitters, which are chemicals that send signals in the brain, can be linked to depression. One such neurotransmitter is serotonin, which plays a role in regulating mood, sleep, and appetite

Another neurotransmitter, norepinephrine, is also believed to be involved in depression. Studies have found changes in the levels of these and other neurotransmitters in people with depression. Antidepressant medications are often used to treat depression by increasing the levels of these neurotransmitters in the brain. Understanding the role of neurotransmitters in brain development and depression is important for finding effective treatments.

Depression has been linked to problems or imbalances in the brain with regard to the neurotransmitters serotonin, norepinephrine, and dopamine. The evidence is somewhat indirect on these points because it is very difficult to actually measure the level of neurotransmitters in various brain regions of a person's brain.

What we do know is that antidepressant medications (used to treat the symptoms of depression) are known to act upon these particular neurotransmitters and their receptors. We'll talk more about antidepressant medications in the treatment section of this article.

Norepinephrine and Depression

Norepinephrine, a neurotransmitter, plays a crucial role in modulating the stress response, influencing energy levels, and enhancing focus. Research suggests that norepinephrine contributes to increased alertness and arousal during stress, as well as promoting attention and concentration.[6]

Another line of research has investigated linkages between the stress response, hormones, depression, and norepinephrine.

Norepinephrine helps our bodies to recognize and respond to stressful situations. Researchers suggest that people who are vulnerable to depression may have a norepinephrinergic system that doesn't handle the effects of stress very efficiently.

Dopamine and Depression

The neurotransmitter dopamine is also linked to depression. Dopamine plays an important role in regulating our drive to seek out rewards, as well as our ability to obtain a sense of pleasure. Low dopamine levels may in part explain why many depressed patients or people don't derive the same sense of pleasure out of activities or people that they did before becoming depressed.[6]

Serotonin and Depression

The neurotransmitter serotonin is involved in regulating many important physiological (body-oriented) functions, including sleep, aggression, eating, sexual behavior, and mood. Serotonin is produced by serotonergic neurons. Current research suggests that a decrease in the production of serotonin by these neurons can cause depression in some people, other mood disorders, and more specifically, a mood state that can cause some people to feel suicidal.

In the 1960s, the "catecholamine hypothesis" was a popular explanation for why people developed depression. This hypothesis suggested that a deficiency of the neurotransmitter norepinephrine (also known as noradrenaline) in certain areas of the brain was responsible for creating depressed mood. More recent research suggests that there is indeed a subset of depressed people who have low levels of norepinephrine.

For example, autopsy studies show that people who have experienced multiple depressive episodes have fewer norepinephrinergic neurons than people who have no depressive symptoms or history of depressive behavior.

However, research results also tell us that not all people experience mood changes in response to decreased norepinephrine levels. Some people who are depressed actually show hyperactivity within the neurons that produce norepinephrine. More current studies suggest that in some people, low levels of serotonin trigger a drop in norepinephrine levels, which then leads to depression.

Other Neurotransmitters and Depression

Other neurotransmitters may be involved in the development of and susceptibility to depression. These include:[7],[8]

  • Glutamate: This neurotransmitter plays a role in how easily neurons can strengthen their connections. Glutamate dysregulation has been linked to depressive symptoms.
  • GABA: GABA is crucial for maintaining neural balance and has been identified in many mood disorders, including depression.
  • Acetylcholine: This neurotransmitter is involved in cognitive functions and has been associated with mood regulations. Dysruptions in acetylcholine signaling has been found in people with depression.


  1. American Psychiatric Association. (2020). What is Depression?
  2. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.).
  3. Broerman R. Diathesis-stress model. In: Zeigler-Hill V, Shackelford TK, eds. Encyclopedia of Personality and Individual Differences. Springer International Publishing; 2018:1-3. doi:10.1007/978-3-319-28099-8_891-1
  4. Harvard Health Publishing. (2022). What causes depression?
  5. Hasler G. (2010). Pathophysiology of depression: do we have any solid evidence of interest to clinicians?. World psychiatry : official journal of the World Psychiatric Association (WPA), 9(3), 155–161.
  6. España, R. A., Schmeichel, B. E., & Berridge, C. W. (2016). Norepinephrine at the nexus of arousal, motivation and relapse. Brain research, 1641(Pt B), 207–216.
  7. Duman, R. S., Sanacora, G., & Krystal, J. H. (2019). Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficits and Reversal by Novel Treatments. Neuron, 102(1), 75–90.
  8. Dulawa, S. C., & Janowsky, D. S. (2019). Cholinergic regulation of mood: from basic and clinical studies to emerging therapeutics. Molecular psychiatry, 24(5), 694–709.

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