Serotonin and Depression: What is the Connection?

Depression is a serious yet common mood disorder, affecting millions of people — in 2020, possibly as many as 21 million adults in the U.S. went through a depressive episode. While common, the exact cause of this mood disorder is still relatively unknown. Several theories have been developed, including the “chemical imbalance” theory of depression that centers around depression and serotonin — an essential chemical involved in regulating certain aspects of your moods and basic daily functions.

This particular theory supports that the connection between serotonin and depression is one possible explanation for this mood disorder.

While the chemical imbalance theory doesn’t accurately or fully define how complex this illness is, serotonin is one of several neurotransmitters thought to play a role in depression, as well as in the effective treatment of it.

We’ll explore what is known about depression and serotonin levels and ways to get help if you struggle with depression.

Depression isn’t just feeling sad or being in an occasional low mood. It’s actually a severe mood disorder that can negatively affect your daily activities and quality of life.

This mood disorder can affect a person of any age or background, but is more common in young women.

Signs of depression in women can include a sad or “empty” mood that happens for no reason, low energy, trouble sleeping and more.

Someone can even experience different types of depression that have different causes — such as perinatal depression caused by pregnancy or childbirth.

You can learn more about the different types of depression and their particular symptoms in our guide to depression.

In short? We don’t yet understand what, exactly, causes depression.

Chemicals like serotonin and norepinephrine are involved in developing symptoms of depression. But how a depressive disorder originates isn’t as simple as one chemical being too low or another being too high.

Major depression is a complex disorder with several different possible factors playing a role in how a depressive disorder develops. Depression is considered a heterogeneous disorder, or a disorder that can have several root causes.

The causes of depression can include environmental, social and biological factors.

These risk factors can include:

• Major life changes. Going through traumatic or stressful life events or even just an overall big change in life can potentially lead to developing depression.

• Medical illness. Depression can also occur at the same time as serious medical conditions like cancer, heart disease or Parkinson’s disease.

• Medications. If you take a medication for the above physical conditions, the side effects can lead to depression in some cases.

• Genetic factors. Research suggests that you may be more at risk of becoming depressed if you’ve previously dealt with depression or have a family history of depression.

• Environment. Some forms of depression develop when certain environmental factors occur. Seasonal affective disorders, for example, are when people experience depression symptoms in certain seasons, typically during the fall and winter months due to less sunlight.
  

Certain naturally occurring chemicals like serotonin and norepinephrine may play a role in the development of depression. Also, one of the most effective treatments for depression involves the use of antidepressant medications that modulate these neurotransmitters — particularly serotonin.

So, what connection is there exactly between serotonin and depression?

Serotonin is a neurotransmitter in our bodies made from an essential amino acid known as tryptophan. 

This particular neurotransmitter works by transporting “messages” between the central nervous system and your body to help your body work and perform certain functions.

For example, serotonin regulates our mood and is often called the “feel good” chemical. When your serotonin levels are normal, you may feel happier, calmer and more focused.

There are certain ways to increase the activity of serotonin levels through exercise, sunlight and eating certain foods that increase levels of tryptophans.Antidepressant medications are also thought to increase serotonin abnormalities (or low serotonin levels) in people with depression.

Although the exact way these medications work is unclear, different types of antidepressants are thought to prevent the brain from reabsorbing serotonin, which allows serotonin levels to increase.

The medications that work this way are:

• Selective serotonin reuptake inhibitors (SSRIs). SSRIs are believed to work primarily on serotonin. Common SSRIs include fluoxetine (Prozac®), sertraline (Zoloft®), escitalopram (Lexapro®) and citalopram (Celexa®).

• Serotonin-norepinephrine reuptake inhibitors (SNRIs). SNRIs are thought to work by increasing both serotonin as well as the neurotransmitter norepinephrine. Common SNRIs include duloxetine (Cymbalta®) and venlafaxine (Effexor®).

• Tricyclic antidepressants (TCAs). Tricyclic antidepressants are an older class of antidepressants that also work to increase serotonin and norepinephrine. Examples of TCAs include amitriptyline (Elavil®), amoxapine (Asendin®) and doxepin (Sinequan®).

Despite how these medications work being unclear, there is decades of evidence that antidepressant treatments are effective for most people with depression, which we’ll explain further below.

Because of how selective serotonin reuptake inhibitors and the other above antidepressants are thought to work by increasing serotonin levels, the “serotonin theory” developed on the idea that serotonin levels and depression were related and that a serotonin deficiency is the most likely cause of depression.

The serotonin theory — also referred to as the serotonin hypothesis — was discovered accidentally from the actions of antidepressants such as monoamine oxidase inhibitors and tricyclic antidepressants on serotonin.

As more scientific evidence about depression emerges, the serotonin hypothesis has been found to not have enough convincing evidence to explain why depression occurs.

Researchers have found though that the role of serotonin in depression could be from a lack of tryptophan (the amino acid that creates serotonin), discovered from tryptophan depletion studies.

An early small study found that women with a history of depression were vulnerable to experiencing depressive symptoms again due to the effects of tryptophan depletion.

Similarly, a more recent small study on people with depression who were not on medication also found that the effects of tryptophan depletion were more likely to cause a relapse of depressive symptoms.

A review of multiple tryptophan depletion studies also found that the effects of tryptophan depletion result in a lowered mood amongst those with a family history of depression or those with depression not using medications.

As more experimental studies on depression and antidepressants come about, the connection between depression and serotonin levels has increasingly weak evidence.

However, even as scientific evidence accumulates, depression is still a complex disorder to explain.

Modulating levels of serotonin through the use of antidepressants, however, has been found to improve depression and anxiety symptoms. This is why antidepressants, particularly ones that are thought to modify serotonin, are a commonly prescribed treatment for depression.

If you struggle with a depressive disorder, there are treatment options to help you manage the symptoms of depression. Some of the most common treatments for people with depression are antidepressants, therapy, lifestyle changes or a combination of these treatments.

While the exact relationship between serotonin levels and depression isn’t entirely clear, it’s also important to uznderstand that antidepressants are effective at treating the symptoms of depression.

While not a “cure” for depression, these medications can reduce the severity of depression symptoms and help you move toward recovery. Multiple studies and decades of research have proven how effective antidepressant drugs can be to offer relief and a way toward recovery.

Studies found that SSRIs and SNRIs were more effective than taking a placebo (treatment that has no real effect), improving depressive symptoms in an extra 20 out of 100 people.

A 2018 large-scale review concluded that 21 common antidepressants were more effective than placebos at treating major depression.

This meta-analysis also found that the commonly-prescribed modern SSRIs citalopram, escitalopram, fluoxetine and sertraline were better tolerated than other antidepressants.

So although the effectiveness of antidepressants varied, they were all still more helpful — especially certain drugs that affect serotonin levels — in treating depression than taking nothing.

Other treatments for depression include psychotherapy (also known as “talk therapy”) or making changes to your habits. These can help you work through unhealthy thought and behavior patterns and whatever might trigger your symptoms as well as lift your low mood.

Our full guide to dealing with depression goes into more detail about your options, from therapy and medication to regular exercise and other easy changes you can make to your daily life.

While discovering the specific connection between serotonin and depression — or even the exact cause of depression — would be groundbreaking, the reality is that a lot of research is more about learning small-yet-significant details that lead to steady progress.

As new research emerges, we can learn more about what types of treatments work for depression and other forms of mental illness, whether it’s the effectiveness of antidepressants or other forms of treatment.

If you’re struggling with major depression, talk to your healthcare provider about treatment. Mental health treatment is the result of a healthcare provider’s professional opinion of the best course of treatment for you. 

An easy way to start is by completing a consultation with a licensed psychiatry provider online.

Taking the next step, however big or small, is the best thing you can do for your mental health.