DEPRESSION CAUSES

The Chemistry of Depression

What Is the Biochemical Basis of Depression?
By Nancy Schimelpfening Updated on December 09, 2022

Medically reviewed by Steven Gans, MD

Verywell / Ellen Lindner

Table of Contents
Brain Chemicals and Depression
:
 What Are Neurotransmitters?

Key Neurotransmitters

Chemical Imbalance Causes

Depression Treatments

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There are several theories about what causes depression. The condition
most likely results from a complex interplay of individual factors, but one
long-prevalent explanation suggested that abnormal brain chemistry
played a primary role. [1]

More recent Rndings indicate that depression is likely not the result of
chemical imbalances in the brain. However, the belief that chemical
imbalances are responsible for causing depression is widely held by the
American public. One survey found that nearly 85% of respondents
believed that such imbalances were the likely cause of depression. [2]

Sometimes, people with depression relate the condition to a speciRc

:
 factor, such as a traumatic event in their life. However, it's not uncommon
for people who are depressed to be confused about the cause. They may
even feel they don't have "a reason" to be depressed.

In these cases, learning about the theories of what causes depression can
be helpful. Here's an overview of what is known (and not-yet-known)
about how the brain's chemistry may in^uence depression.

4:33

Watch Now: 7 Most Common Types of Depression

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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 di`erent 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,

block the reabsorption of serotonin, a neurotransmitter that can a`ect
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 scientiRc and medical community for some time. And a
study published in a 2022 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 of 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.

While such Rndings challenge the idea that a serotonin deRciency is

responsible for causing depression, it doesn't mean that mental health
treatments are ine`ective.

Such Rndings represent a signiRcant shift in our understanding of

depression, but this does not mean people taking antidepressants should
stop their medication. More research is needed to fully understand what
causes depression, how antidepressants a`ect the condition, and what
other treatments may also be e`ective for managing symptoms of
depression.

The 2022 study also found a strong connection between traumatic life
events and the onset of depression. [3] This further suggests that
depression is caused by complex factors, including environmental
variables, and cannot be reduced to simply a chemical imbalance in the
brain.
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Related: The Evidence Is In: Depression Might Not Be Linked to Low

Serotonin After All

Depression Is Complex
Even with the help of medications that a`ect speciRc neurotransmitters in
the brain, depression is a highly complex condition to treat. What proves
to be an e`ective 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 e`ective over time, 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 Rnding explanations for these
complexities and developing more e`ective 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. 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 speciRc 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 di`erent
message and plays a unique role in creating an individual's brain
chemistry.
:
 The chemical theory of depression suggested that imbalances in this brain
chemistry were a primary cause of depression. However, recent Rndings
found no evidence to support this idea.

It is important to remember that we do not fully understand how

imbalances in these chemicals a`ect mental health conditions such as
depression. While research indicates that serotonin levels may not
cause depression, other neurotransmitters and interactions may play
a part.

Related: How Neurotransmitters Work

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The Role of Key Neurotransmitters

The three neurotransmitters that are often implicated in depression are:

Dopamine
:
 Norepinephrine
Serotonin

Other neurotransmitters can send messages in the brain, including

glutamate, GABA, and acetylcholine. Researchers are still learning about
Ad
the role these brain chemicals play in depression and other conditions,
such as Alzheimer's and Rbromyalgia.

Dopamine
Another substance that might play a role in mood is 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 important role in a variety of conditions a`ecting the brain,
including Parkinson's and schizophrenia.

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There is also evidence that reduced dopamine levels can contribute to

depression in some people. [5] When other treatments have failed,
medications that a`ect the dopamine system are often added and can be
helpful for some people with depression.
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 Norepinephrine
Norepinephrine is both a neurotransmitter and a hormone. It plays a role
in the "Rght or ^ight 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 occurred when there is too little

norepinephrine in certain brain circuits. Alternatively, mania results when
too much neurotransmitter is in the brain.

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There is evidence that supports the hypothesis, however, it has not gone
unchallenged by researchers. For one, changes in norepinephrine levels do
not a`ect mood in every person. Further, medications speciRcally
targeting norepinephrine may alleviate depression in some people but not
others.
:
 Related: 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
di`erent 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 few decades thanks to the advent of antidepressant medications
like Prozac (^uoxetine) and other selective serotonin reuptake inhibitors
(SSRIs). As their name implies, these medications speciRcally 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 E`exor (venlafaxine) target both serotonin and
norepinephrine. Tricyclic antidepressants (TCAs) also a`ect
norepinephrine and serotonin, but they have the added e`ect of
in^uencing histamine and acetylcholine. These substances produce side
e`ects, such as dry mouth, blurry vision, constipation, and urinary
hesitancy.

SSRIs, on the other hand, do not a`ect histamine and acetylcholine and
don't have the same side e`ects, 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.

Related: How to Increase Serotonin

Causes of Low Neurotransmitter Levels

:
 While recent Rndings found no evidence to support the idea that chemical
imbalances are responsible for causing depression, many people do Rnd
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 Rrst 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 (speciRc 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 speciRc neurotransmitter (for example, serotonin) is being
produced
:
 Several emerging theories are concerned with the factors that promote
lowered levels, such as cellular (speciRcally mitochondrial) stress. [6] But
one of the main challenges for researchers and doctors hoping to connect
depression to low levels of speciRc 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 Rnd greater relief when these
treatments are used alongside medications.

If a person Rnds that therapy alone is not helping them manage their
depression, they may want to try medication. For some people,
antidepressants combined with psychotherapy proves especially
e`ective for addressing their symptoms.
:
 To complicate treatment further, medication does not always work for
people with depression. One study evaluating the e`ectiveness of
currently available antidepressants found that these medications only
work in about 60% of people with depression. [7]

Whatever might be causing your symptoms, depression a`ects your

internal and external life. Therefore, medication alone may not be
sulcient to address all the ways in which depression can a`ect you.

Research suggests that neurotransmitter levels can be a`ected 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 and
reduce stress 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 deRciency in one speciRc
brain chemical being the causative factor, some depression symptoms
:
 could be related to the relative levels of each type of neurotransmitter in
di`erent 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 in^ammation is being explored as a potential
contributing factor. [8]

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. [9]

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 conRdent in their ability to
manage the condition. [10] 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). [11]

Not all the research has been negative, though. Several studies included in
a 2012 meta-analysis indicated that one of the most e`ective 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. [12]

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.

Related: Depression Statistics Everyone Should Know

A Word From Verywell

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 Rnd 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. [13]​

Understanding the complexity of depression can also be helpful for those

who have been o`ered 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.

Read Next: The Best Online Resources for Depression

13 Sources

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

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