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For decades, experts have been researching the role of neurotransmitters in mental health. The majority of these studies so far closely associated serotonin and depression through a relationship termed “the serotonin deficiency hypothesis of depression.” This association attracted a great deal of interest in the mechanism of development of depression while centering its focus on the use of serotonin-boosting antidepressant medications. While this theory received worldwide acceptance initially, it has also garnered a lot of criticism, with some experts even claiming that serotonin and depression are not related at all. With all the criticism this theory has been receiving, many have been left speculating, “Is depression caused by a chemical imbalance?” and the role of serotonin in its development and progression.
The Serotonin Theory of Depression: A Brief Overview
Originating during the 1960s, the serotonin theory of depression focused on the activation levels of serotonin in the brain.  At the core, it suggested that depressive symptoms were due to low levels of active serotonin in the central nervous system. The theory further explained that the low serotonin levels were possibly due to a lack of its receptors, called 5-HT serotonin receptors, ultimately leading to depression. Due to the mechanism it proposed, the theory was also referred to as the 5-HT hypothesis of depression.
While many people may not know it, the serotonin theory of depression was based on another hypothesis proposed during the 1950s. Known as “the monoamine theory of depression,” it claimed that depression happened due to the increased activity of monoamine oxidase.  This enzyme, in turn, breaks down various neurotransmitters, including norepinephrine, dopamine, and serotonin. The serotonin theory overtook this theory very soon in terms of more widespread acceptance.
The monoamine theory proposed earlier had led experts to formulate certain medications, now known as first-generation antidepressants. This class of medications works by blocking the activity of the monoamine oxidase to improve the overall levels of various mood-regulating neurotransmitters in the brain. Despite the high efficacy rates of first-generation antidepressant medications, many people began avoiding them due to their multiple side effects, such as high blood pressure. These medications are still in use but are only limited to people with treatment-resistant depression who have tried all alternative treatment options.
With the introduction of the serotonin theory of depression, experts began working on a newer class of antidepressant medications. Known as selective serotonin reuptake inhibitors or SSRIs, these medications were made available to the public during the 1980s. Also known as second-generation antidepressants, these drugs specifically targeted serotonin and aimed to keep it active for longer to prolong its effects on the brain. While the medications were found to be successful in successfully alleviating the symptoms of depression, they were also much more easily tolerated by users. Due to this reason, the FDA eventually made SSRIs the first line of treatment for depression. The high success rate of this antidepressant category further strengthened the association between serotonin and depression.
Serotonin Levels and Depression: What the Naysayers Believe
So far, multiple studies have confirmed the inverse relationship between serotonin and depression. However, many critics have raised their concerns against the validity and legitimacy of the serotonin theory for depression. Their criticism is mainly focused on the following three points:
No information on how serotonin truly affects depression
Even the supporters of the serotonin theory for depression admit that the mechanism of serotonin remains unclear. Researchers are still trying to investigate how this neurotransmitter affects a person’s mood when it comes to depression.
Other proven risk factors of depression
While the serotonin theory only uses a biological and chemical approach to depression, it fails to acknowledge the other risk factors that may play a role in the development and progression of this illness. These risk factors may include personality, genetics, disposition, and exposure to destabilizing triggers during early childhood. So far, studies investigating these risk factors have shown that serotonin levels alone do not bring on depression; in reality, it is the combined effect of all factors.
No clear proof of the serotonin theory of depression
In 2022, a group of researchers performed a comprehensive meta-analysis of all serotonin-related research work published during the past five decades.  The study concluded that no consistent evidence links serotonin and depression. Moreover, the meta-analysis failed to find clear evidence proving this theory.
The conclusions proposed by the meta-analysis shocked the entire mental health community, with many feeling that they have been deceived for decades regarding depression management.
If Not Serotonin, Then What? Exploring the Causes of Depression
Following the negation of the famous serotonin theory, scientists have been investigating the mechanism of depression development with more care and concern. So far, their knowledge about mental health conditions has considerably improved since the 1960s, especially in a way that it is no longer considered a single disease with one definitive cause.
Today, experts largely accept depression as a heterogeneous disorder with multiple underlying causes. Some of these causes include the following:
- Abuse: Different types of abuse, such as emotional, sexual, and physical abuse, can make a person more vulnerable to developing depression in later stages of life.
- Certain medications: Using certain drugs, such as isotretinoin for acne, steroids, and antiviral drugs, may make a person more vulnerable to developing depression.
- Age: The elderly community is at a higher risk of developing depression. This risk may be further heightened by other factors, such as a lack of social support or living alone.
- Conflict: People with biological vulnerability to depression may experience this mental health disorder due to personal disputes or conflicts with friends and family members.
- Loss or Death: Grief and sadness following the loss of a loved one are completely natural; however, some people may struggle to cope with these difficult times and develop depression.
- Gender: Females are two times more likely to become depressed than men. Scientists have yet to find an explanation for this gender-based difference; however, most believe it happens because women go through a different time and life.
- Substance Abuse: Up to 30 percent of people with substance abuse issues also report having clinical depression. Even if alcohol or drugs make them feel better temporarily, they end up aggravating the condition.
- Serious Illnesses: Sometimes, a person coping with a severe or end-stage condition, such as cancer, may develop depression.
- Major Life Events: Sometimes, even positive events, such as graduating, starting a new job, or getting married, may trigger depression. Similarly, losing a job, retiring, or getting divorced may also make them vulnerable to depression.
- Genes: Having a family history of depression can also increase the risk of developing it at some point in life. Experts consider depression as a complex trait, which means more than one gene is responsible for triggering it. The genetics of depression and other psychiatric disorders are not as simple as other purely genetic diseases.
- Other Personal Issues: Personal problems, such as social isolation or being cast out of a social group, can contribute to the development of clinical depression.
What is serotonin?
Serotonin is a natural neurotransmitter, a chemical secreted in the brain that helps the organ relay signals from one area to another. Although it is primarily manufactured in the brain, up to 90 percent of its supply is present in other parts of the body.
Can too much serotonin cause depression?
So far, studies have not proven any relationship between serotonin and depression development. Hence, the mental health community believes that any dips or rises in serotonin do not affect the chance of developing depression.
Can you develop depression without having low serotonin?
While depression has been linked with a chemical or neurotransmitter imbalance for decades, the association has been negated more recently. Hence, it is possible for a person to have depression without having low serotonin levels, as plenty of other risk factors can contribute to it. Some other ways through which a person may develop depression are through genetic vulnerability, faulty mood regulation by the central nervous system, and stressful life events.
1 Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA. The serotonin theory of depression: a systematic umbrella review of the evidence. Molecular psychiatry. 2022 Jul 20:1-4.
2 Delgado PL. Depression: the case for a monoamine deficiency. Journal of clinical Psychiatry. 2000 Jan 1;61(6):7-11.
3 Möller HJ, Falkai P. Is the serotonin hypothesis/theory of depression still relevant? Methodological reflections motivated by a recently published umbrella review. European Archives of Psychiatry and Clinical Neuroscience. 2023 Feb;273(1):1-3.