The Chemistry of Depression

Table of ContentsView AllTable of ContentsBrain Chemicals and DepressionWhat Are Neurotransmitters?Key NeurotransmittersChemical Imbalance CausesDepression TreatmentsCombatting Stigma

Table of ContentsView All

View All

Table of Contents

Brain Chemicals and Depression

What Are Neurotransmitters?

Key Neurotransmitters

Chemical Imbalance Causes

Depression Treatments

Combatting Stigma

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

Sometimes, people with depression relate the condition to a specific factor, such as atraumatic eventin their life. However, it’s not uncommon for people who are depressed to be confused about the cause. They may even feel theydon’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 influence depression.

4:33Watch Now: 7 Most Common Types of Depression

4:33

Watch Now: 7 Most Common Types of 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 differentclasses of antidepressant medicationsmay come in. Many antidepressants alter levels of certain neurotransmitters in the brain.

The most commonly prescribed class of antidepressants, known as SSRIs, orselective 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

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!

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

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, andacetylcholine, 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, includingParkinson’sandschizophrenia.

There is also evidence that reduced dopamine levels can contribute to depression in some people.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,maniaresults when too much of this neurotransmitter is in the brain.

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 fromyour gutto 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 (fluoxetine) and otherselective 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 calledserotonin-norepinephrine reuptake inhibitors(SNRIs) likeEffexor(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 produceside 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 Stimulate 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:

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

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.

While taking an antidepressant medication might help with the symptoms, it doesn’t necessarily address the otherunderlying causesof depression. In this situation, therapy to improvestress management, heal fromemotional wounds, learn toregulate emotions, andimprove thinking patternscould potentially be helpful.

If you or a loved one are struggling with depression, contact theSubstance Abuse and Mental Health Services Administration (SAMHSA) National Helplineat1-800-662-4357for information on support and treatment facilities in your area.For more mental health resources, see ourNational Helpline Database.

For more mental health resources, see ourNational 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.

Combatting the Chemical Imbalance Stigma

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.

RecapImproving 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.

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.

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 SourcesVerywell Mind uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read oureditorial processto learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.Albert PR, Benkelfat C, Descarries L.The neurobiology of depression—revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms.Philosophical Transactions of the Royal Society B: Biological Sciences. 2012;367(1601):2378-2381. doi:10.1098/rstb.2012.0190France CM, Lysaker PH, Robinson RP.The “chemical imbalance” explanation for depression: Origins, lay endorsement, and clinical implications.Professional Psychology: Research and Practice. 2007;38(4):411-420. doi:10.1037/0735-7028.38.4.411Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA.The serotonin theory of depression: A systematic umbrella review of the evidence.Mol Psychiatry. 2023;28(8):3243-3256. doi:10.1038/s41380-022-01661-0Pilkington PD, Reavley NJ, Jorm AF.The Australian public’s beliefs about the causes of depression: Associated factors and changes over 16 years.J Affect Disord. 2013;150(2):356-362. doi:10.1016/j.jad.2013.04.019Garcia-Arocena D.Happy or SAD: The chemistry behind depression. The Jackson Laboratory.Israelyan N, Del Colle A, Li Z, et al.Effects of serotonin and slow-release 5-hydroxytryptophan on gastrointestinal motility in a mouse model of depression.Gastroenterology. 2019;157(2):507-521.e4. doi:10.1053/j.gastro.2019.04.022Allen J, Romay-Tallon R, Brymer KJ, Caruncho HJ, Kalynchuk LE.Mitochondria and mood: Mitochondrial dysfunction as a key player in the manifestation of depression.Frontiers in Neuroscience. 2018;12. doi:10.3389/fnins.2018.00386Gartlehner G, Hansen RA, Thieda P, et al.Comparative effectiveness of second-generation antidepressants in the pharmacologic treatment of adult depression. Agency for Healthcare Research and Quality (US); 2007.Zunszain PA, Hepgul N, Pariante CM.Inflammation and depression.Behavioral Neurobiology of Depression and Its Treatment. 2012:135-151. doi:10.1007/7854_2012_211Lacasse J, Leo J.Antidepressants and the chemical imbalance theory of depression: A reflection and update on the discourse.the Behavior Therapist. 2015;38(7):206–213.Lebowitz MS, Ahn WK, Nolen-Hoeksema S.Fixable or fate? Perceptions of the biology of depression.Journal of Consulting and Clinical Psychology. 2013;81(3):518-527. doi:10.1037/a0031730Kvaale EP, Gottdiener WH, Haslam N.Biogenetic explanations and stigma: A meta-analytic review of associations among laypeople.Social Science & Medicine. 2013;96:95-103. doi:10.1016/j.socscimed.2013.07.017Corrigan PW, Morris SB, Michaels PJ, Rafacz JD, Rüsch N.Challenging the public stigma of mental illness: A meta-analysis of outcome studies.Psychiatr Serv.2012;63(10):963-973. doi:10.1176/appi.ps.201100529Delgado PL.Depression: The case for a monoamine deficiency.The Journal of Clinical Psychiatry. 2019;61(suppl 6):7-11. doi:10.4088/JCP.v61n0103Additional ReadingMajor Depressive Disorder Working Group of the Psychiatric GWAS Consortium.A mega-analysis of genome-wide association studies for major depressive disorder.Molecular Psychiatry. 2012;18(4):497-511. doi:10.1038/mp.2012.21Papakostas G, Ionescu D.Towards new mechanisms: An update on therapeutics for treatment-resistant major depressive disorder.Molecular Psychiatry. 2015;20(10):1142-1150. doi:10.1038/mp.2015.92

14 Sources

Verywell Mind uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read oureditorial processto learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.Albert PR, Benkelfat C, Descarries L.The neurobiology of depression—revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms.Philosophical Transactions of the Royal Society B: Biological Sciences. 2012;367(1601):2378-2381. doi:10.1098/rstb.2012.0190France CM, Lysaker PH, Robinson RP.The “chemical imbalance” explanation for depression: Origins, lay endorsement, and clinical implications.Professional Psychology: Research and Practice. 2007;38(4):411-420. doi:10.1037/0735-7028.38.4.411Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA.The serotonin theory of depression: A systematic umbrella review of the evidence.Mol Psychiatry. 2023;28(8):3243-3256. doi:10.1038/s41380-022-01661-0Pilkington PD, Reavley NJ, Jorm AF.The Australian public’s beliefs about the causes of depression: Associated factors and changes over 16 years.J Affect Disord. 2013;150(2):356-362. doi:10.1016/j.jad.2013.04.019Garcia-Arocena D.Happy or SAD: The chemistry behind depression. The Jackson Laboratory.Israelyan N, Del Colle A, Li Z, et al.Effects of serotonin and slow-release 5-hydroxytryptophan on gastrointestinal motility in a mouse model of depression.Gastroenterology. 2019;157(2):507-521.e4. doi:10.1053/j.gastro.2019.04.022Allen J, Romay-Tallon R, Brymer KJ, Caruncho HJ, Kalynchuk LE.Mitochondria and mood: Mitochondrial dysfunction as a key player in the manifestation of depression.Frontiers in Neuroscience. 2018;12. doi:10.3389/fnins.2018.00386Gartlehner G, Hansen RA, Thieda P, et al.Comparative effectiveness of second-generation antidepressants in the pharmacologic treatment of adult depression. Agency for Healthcare Research and Quality (US); 2007.Zunszain PA, Hepgul N, Pariante CM.Inflammation and depression.Behavioral Neurobiology of Depression and Its Treatment. 2012:135-151. doi:10.1007/7854_2012_211Lacasse J, Leo J.Antidepressants and the chemical imbalance theory of depression: A reflection and update on the discourse.the Behavior Therapist. 2015;38(7):206–213.Lebowitz MS, Ahn WK, Nolen-Hoeksema S.Fixable or fate? Perceptions of the biology of depression.Journal of Consulting and Clinical Psychology. 2013;81(3):518-527. doi:10.1037/a0031730Kvaale EP, Gottdiener WH, Haslam N.Biogenetic explanations and stigma: A meta-analytic review of associations among laypeople.Social Science & Medicine. 2013;96:95-103. doi:10.1016/j.socscimed.2013.07.017Corrigan PW, Morris SB, Michaels PJ, Rafacz JD, Rüsch N.Challenging the public stigma of mental illness: A meta-analysis of outcome studies.Psychiatr Serv.2012;63(10):963-973. doi:10.1176/appi.ps.201100529Delgado PL.Depression: The case for a monoamine deficiency.The Journal of Clinical Psychiatry. 2019;61(suppl 6):7-11. doi:10.4088/JCP.v61n0103Additional ReadingMajor Depressive Disorder Working Group of the Psychiatric GWAS Consortium.A mega-analysis of genome-wide association studies for major depressive disorder.Molecular Psychiatry. 2012;18(4):497-511. doi:10.1038/mp.2012.21Papakostas G, Ionescu D.Towards new mechanisms: An update on therapeutics for treatment-resistant major depressive disorder.Molecular Psychiatry. 2015;20(10):1142-1150. doi:10.1038/mp.2015.92

Albert PR, Benkelfat C, Descarries L.The neurobiology of depression—revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms.Philosophical Transactions of the Royal Society B: Biological Sciences. 2012;367(1601):2378-2381. doi:10.1098/rstb.2012.0190France CM, Lysaker PH, Robinson RP.The “chemical imbalance” explanation for depression: Origins, lay endorsement, and clinical implications.Professional Psychology: Research and Practice. 2007;38(4):411-420. doi:10.1037/0735-7028.38.4.411Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA.The serotonin theory of depression: A systematic umbrella review of the evidence.Mol Psychiatry. 2023;28(8):3243-3256. doi:10.1038/s41380-022-01661-0Pilkington PD, Reavley NJ, Jorm AF.The Australian public’s beliefs about the causes of depression: Associated factors and changes over 16 years.J Affect Disord. 2013;150(2):356-362. doi:10.1016/j.jad.2013.04.019Garcia-Arocena D.Happy or SAD: The chemistry behind depression. The Jackson Laboratory.Israelyan N, Del Colle A, Li Z, et al.Effects of serotonin and slow-release 5-hydroxytryptophan on gastrointestinal motility in a mouse model of depression.Gastroenterology. 2019;157(2):507-521.e4. doi:10.1053/j.gastro.2019.04.022Allen J, Romay-Tallon R, Brymer KJ, Caruncho HJ, Kalynchuk LE.Mitochondria and mood: Mitochondrial dysfunction as a key player in the manifestation of depression.Frontiers in Neuroscience. 2018;12. doi:10.3389/fnins.2018.00386Gartlehner G, Hansen RA, Thieda P, et al.Comparative effectiveness of second-generation antidepressants in the pharmacologic treatment of adult depression. Agency for Healthcare Research and Quality (US); 2007.Zunszain PA, Hepgul N, Pariante CM.Inflammation and depression.Behavioral Neurobiology of Depression and Its Treatment. 2012:135-151. doi:10.1007/7854_2012_211Lacasse J, Leo J.Antidepressants and the chemical imbalance theory of depression: A reflection and update on the discourse.the Behavior Therapist. 2015;38(7):206–213.Lebowitz MS, Ahn WK, Nolen-Hoeksema S.Fixable or fate? Perceptions of the biology of depression.Journal of Consulting and Clinical Psychology. 2013;81(3):518-527. doi:10.1037/a0031730Kvaale EP, Gottdiener WH, Haslam N.Biogenetic explanations and stigma: A meta-analytic review of associations among laypeople.Social Science & Medicine. 2013;96:95-103. doi:10.1016/j.socscimed.2013.07.017Corrigan PW, Morris SB, Michaels PJ, Rafacz JD, Rüsch N.Challenging the public stigma of mental illness: A meta-analysis of outcome studies.Psychiatr Serv.2012;63(10):963-973. doi:10.1176/appi.ps.201100529Delgado PL.Depression: The case for a monoamine deficiency.The Journal of Clinical Psychiatry. 2019;61(suppl 6):7-11. doi:10.4088/JCP.v61n0103

France CM, Lysaker PH, Robinson RP.The “chemical imbalance” explanation for depression: Origins, lay endorsement, and clinical implications.Professional Psychology: Research and Practice. 2007;38(4):411-420. doi:10.1037/0735-7028.38.4.411

Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA.The serotonin theory of depression: A systematic umbrella review of the evidence.Mol Psychiatry. 2023;28(8):3243-3256. doi:10.1038/s41380-022-01661-0

Pilkington PD, Reavley NJ, Jorm AF.The Australian public’s beliefs about the causes of depression: Associated factors and changes over 16 years.J Affect Disord. 2013;150(2):356-362. doi:10.1016/j.jad.2013.04.019

Garcia-Arocena D.Happy or SAD: The chemistry behind depression. The Jackson Laboratory.

Israelyan N, Del Colle A, Li Z, et al.Effects of serotonin and slow-release 5-hydroxytryptophan on gastrointestinal motility in a mouse model of depression.Gastroenterology. 2019;157(2):507-521.e4. doi:10.1053/j.gastro.2019.04.022

Allen J, Romay-Tallon R, Brymer KJ, Caruncho HJ, Kalynchuk LE.Mitochondria and mood: Mitochondrial dysfunction as a key player in the manifestation of depression.Frontiers in Neuroscience. 2018;12. doi:10.3389/fnins.2018.00386

Gartlehner G, Hansen RA, Thieda P, et al.Comparative effectiveness of second-generation antidepressants in the pharmacologic treatment of adult depression. Agency for Healthcare Research and Quality (US); 2007.

Zunszain PA, Hepgul N, Pariante CM.Inflammation and depression.Behavioral Neurobiology of Depression and Its Treatment. 2012:135-151. doi:10.1007/7854_2012_211

Lacasse J, Leo J.Antidepressants and the chemical imbalance theory of depression: A reflection and update on the discourse.the Behavior Therapist. 2015;38(7):206–213.

Lebowitz MS, Ahn WK, Nolen-Hoeksema S.Fixable or fate? Perceptions of the biology of depression.Journal of Consulting and Clinical Psychology. 2013;81(3):518-527. doi:10.1037/a0031730

Kvaale EP, Gottdiener WH, Haslam N.Biogenetic explanations and stigma: A meta-analytic review of associations among laypeople.Social Science & Medicine. 2013;96:95-103. doi:10.1016/j.socscimed.2013.07.017

Corrigan PW, Morris SB, Michaels PJ, Rafacz JD, Rüsch N.Challenging the public stigma of mental illness: A meta-analysis of outcome studies.Psychiatr Serv.2012;63(10):963-973. doi:10.1176/appi.ps.201100529

Delgado PL.Depression: The case for a monoamine deficiency.The Journal of Clinical Psychiatry. 2019;61(suppl 6):7-11. doi:10.4088/JCP.v61n0103

Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium.A mega-analysis of genome-wide association studies for major depressive disorder.Molecular Psychiatry. 2012;18(4):497-511. doi:10.1038/mp.2012.21Papakostas G, Ionescu D.Towards new mechanisms: An update on therapeutics for treatment-resistant major depressive disorder.Molecular Psychiatry. 2015;20(10):1142-1150. doi:10.1038/mp.2015.92

Papakostas G, Ionescu D.Towards new mechanisms: An update on therapeutics for treatment-resistant major depressive disorder.Molecular Psychiatry. 2015;20(10):1142-1150. doi:10.1038/mp.2015.92

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Watch Now: 7 Most Common Types of Depression#

Recent Evidence#

Warning!#

Depression Is Complex#

The Role of Key Neurotransmitters#

Dopamine#

Norepinephrine#

Serotonin#

Causes of Low Neurotransmitter Levels#

Current and Future Depression Treatments#

Depression Treatments on the Horizon#

Combatting the Chemical Imbalance Stigma#

Recap#

Final Thoughts#