DepressionCauses The Chemistry of Depression What Is the Biochemical Basis of Depression?ByNancy SchimelpfeningNancy SchimelpfeningNancy 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.Learn about our editorial processUpdated on January 05, 2021Medically reviewed Verywell Mind articles are reviewed by board-certified physicians and mental healthcare professionals. Medical Reviewers confirm the content is thorough and accurate, reflecting the latest evidence-based research. Content is reviewed before publication and upon substantial updates. Learn more. by Steven Gans, MDMedically reviewed bySteven Gans, MDSteven Gans, MD is board-certified in psychiatry and is an active supervisor, teacher, and mentor at Massachusetts General Hospital.Learn about our Medical Review BoardVerywell / Ellen Lindner Table of Contents View All Table of ContentsBrain Chemicals and DepressionWhat Are Neurotransmitters?Key NeurotransmittersChemical Imbalance CausesDepression TreatmentsCombatting Stigma 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 about the cause. 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. Here's an overview of what is known (and not-yet-known) about how chemical imbalances in the brain may influence depression. 4:33 Watch Now: 7 Most Common Types of Depression Brain Chemicals and Depression 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 symptoms—which is where the different classes of antidepressant medications may come in. Even with the help of medications that 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 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 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, but having an awareness of brain chemistry can be useful for medical and mental health professionals, researchers, and many people who have depression. Depression Discussion Guide Get our printable guide to help you ask the right questions at your next doctor's appointment.Download PDF 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 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. How Neurotransmitters Work The Role of Key Neurotransmitters The three neurotransmitters implicated in depression are: DopamineNorepinephrineSerotonin 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. 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 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 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 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. 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. 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 and 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 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? When there is a breakdown anywhere in the process, low levels of neurotransmitters can result. Research has indicated several potential causes of chemical imbalances in the brain, including: Molecules that help make neurotransmitters (specific enzymes) are in short supplyNot enough receptor sites to receive the neurotransmitterPresynaptic cells are taking the neurotransmitter back up before it has a chance to reach the receptor cellToo 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. But 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. 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 their symptoms. 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 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 alone 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 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 what role they may play 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 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 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 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.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.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 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. The Best Online Resources for Depression 10 Sources Verywell Mind uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to 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.2012.0190Dolores Garcia-Arocena, Ph.D. Happy or SAD: The chemistry behind depression. The Jackson Laboratory.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.2018.00386Gartlehner G, Hansen RA, Thieda P, et al. Comparative Effectiveness of Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression. Rockville (MD): 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. the Behavior Therapist, 38(7), 206–213. Antidepressants and the Chemical Imbalance Theory of Depression: A Reflection and Update on the Discourse.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):963-73. 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 Additional 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):1142-50. doi:10.1038/mp.2015.92By 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. See Our Editorial ProcessMeet Our Review Board Share FeedbackWas this page helpful?Thanks for your feedback!What is your feedback? Other Helpful Report an Error Speak to a Therapist for Depression Advertiser Disclosure × The offers that appear in this table are from partnerships from which Verywell Mind receives compensation.