The Serotonin Theory of Depression

For decades, one of the most widely discussed ideas in psychiatry has been the serotonin theory of depression. The theory suggests that depression results from an imbalance in serotonin, a neurotransmitter that influences mood, sleep and appetite.

While this explanation helped shape modern antidepressant treatments, research in recent years shows that depression is far more complex than a single chemical imbalance. Understanding serotonin and depression can help patients make informed decisions about treatment options and what truly supports recovery.

What Is the Serotonin Theory of Depression?

The serotonin theory of depression emerged in the 1960s and became mainstream in the 1980s with the introduction of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and sertraline. The theory proposed that low levels of serotonin in the brain caused depressive symptoms, and increasing serotonin through medication would relieve them.

For many years, this explanation dominated both clinical practice and public understanding. However, while serotonin does play a role in regulating mood, newer research shows that depression involves multiple biological, psychological and environmental factors, not just neurotransmitter imbalance.

How Does Serotonin Affect Depression?

Serotonin is a neurotransmitter that helps transmit signals between nerve cells in the brain. It contributes to emotional regulation, sleep cycles, appetite and cognitive functions such as memory and focus. Changes in serotonin levels can influence mood and behaviour. Low serotonin activity has been associated with symptoms such as sadness, irritability, fatigue and poor concentration.

However, studies have shown that serotonin levels alone do not determine who develops depression. Some people with low serotonin do not experience depressive symptoms, while others with normal levels do. This suggests that serotonin may be one part of a much larger system involving genetics, stress hormones, inflammation and brain circuitry.

What Recent Research Tells Us

A major review published in Molecular Psychiatry (2022) examined several decades of studies on serotonin and depression. The review concluded that there is no clear evidence that depression is caused by low serotonin or reduced serotonin activity. Instead, the results pointed to more complex biological processes, including how the brain responds to stress and how inflammation and genetics interact with neurotransmitters.

The review’s findings do not mean that antidepressants are ineffective. Many people still benefit from SSRIs and related medications. However, these drugs may work through broader mechanisms that involve neural plasticity and emotional regulation rather than simply “fixing” serotonin levels.

Understanding Treatment-Resistant Depression

While many people experience improvement from antidepressants and therapy, some continue to struggle with persistent symptoms despite multiple treatment attempts. This condition, known as treatment-resistant depression (TRD), affects roughly one in three people with major depressive disorder. It shows that depression involves far more than a simple imbalance of serotonin or any single brain chemical.

TRD is typically diagnosed when at least two different antidepressants, taken at adequate doses and durations, fail to produce significant improvement. The reasons vary and may include genetic factors, chronic stress, medical conditions, or overlapping disorders such as anxiety or bipolar depression. Because depression affects several neural pathways, a more targeted approach is often required.

One of the most effective options for TRD is Transcranial Magnetic Stimulation (TMS). This non-invasive therapy uses magnetic pulses to stimulate areas of the brain that regulate mood and emotional function.

There are several types of TMS used in clinical practice. Repetitive TMS (rTMS) delivers focused magnetic pulses to specific brain regions, while Deep TMS reaches broader and deeper neural networks linked to mood regulation. Both forms help restore normal brain activity patterns and improve communication between mood-related regions.

TMS treatments for depression are generally well tolerated, with few side effects and are performed in outpatient settings. Many patients begin noticing gradual improvement over several weeks as neural activity becomes more balanced. For those with treatment-resistant depression, TMS offers an evidence-based, medication-free pathway to recovery and long-term symptom relief.

Can Too Much Serotonin Cause Depression?

It may seem counterintuitive, but excessive serotonin activity can also have negative effects. Very high serotonin levels can cause agitation, restlessness, confusion and sleep problems. In severe cases, a condition called serotonin syndrome can occur, which is a medical emergency.

Although too much serotonin is not typically a direct cause of depression, research suggests that imbalances in serotonin signalling (whether too low or too high) can disrupt normal brain function. This reinforces the idea that depression cannot be explained by one simple chemical theory. The balance of multiple neurotransmitters, hormones and neural pathways likely determines how mood disorders develop and respond to treatment.

Beyond Serotonin: Other Factors in Depression

Modern science recognises that depression arises from an interaction of biological, psychological and environmental influences. These include:

• Genetics: A family history of mood disorders can increase susceptibility.
• Stress and trauma: Long-term stress changes how the brain regulates emotion.
• Inflammation: Elevated inflammatory markers are linked to depressive symptoms.
• Brain structure and connectivity: Changes in areas such as the hippocampus and prefrontal cortex can affect mood and motivation.
• Lifestyle factors: Poor sleep, diet and physical inactivity can worsen symptoms.

This broader understanding allows for more individualised and effective treatment approaches.

Understanding Treatment-Resistant Depression

While many people experience improvement from antidepressants and therapy, some continue to struggle with persistent symptoms despite multiple treatment attempts. This condition, known as treatment-resistant depression (TRD), affects roughly one in three people with major depressive disorder. It shows that depression involves far more than a simple imbalance of serotonin or any single brain chemical.

TRD is typically diagnosed when at least two different antidepressants, taken at adequate doses and durations, fail to produce significant improvement. The reasons vary and may include genetic factors, chronic stress, medical conditions, or overlapping disorders such as anxiety or bipolar depression. Because depression affects several neural pathways, a more targeted approach is often required.

One of the most effective options for TRD is Transcranial Magnetic Stimulation (TMS). This non-invasive therapy uses magnetic pulses to stimulate areas of the brain that regulate mood and emotional function. There are several types of TMS used in clinical practice.

Repetitive TMS (rTMS) delivers focused magnetic pulses to specific brain regions, while Deep TMS reaches broader and deeper neural networks linked to mood regulation. Both forms help restore normal brain activity patterns and improve communication between mood-related regions.

TMS treatments are generally well tolerated, with few side effects and are performed in outpatient settings. Many patients begin noticing gradual improvement over several weeks as neural activity becomes more balanced. For those with treatment-resistant depression, TMS offers an evidence-based, medication-free pathway to recovery and long-term symptom relief.

Why the Serotonin Theory Still Matters

Although the serotonin theory of depression may be incomplete, it opened the door to decades of valuable research and led to treatments that have improved millions of lives. The theory also helped reduce stigma by framing depression as a medical condition rather than a personal weakness.

Today, the conversation has shifted from focusing on one neurotransmitter to understanding depression as a complex brain and body condition. This perspective promotes personalised treatment and ongoing exploration of new therapies that address the multiple pathways contributing to mood disorders.

Moving Toward Personalised Mental Health Care

Understanding serotonin and depression encourages a more nuanced approach to mental health care. Instead of searching for a single cause or cure, clinicians now assess each person’s symptoms, medical history and lifestyle to develop individualised plans.

Monarch Mental Health Group continues to lead in this area, offering comprehensive psychiatric evaluation, psychological support and advanced neuromodulation therapies to help patients achieve better long-term outcomes.

Recovery is possible with the right combination of care, science and support. Contact us today for more information on how we approach treatment for depression.

FAQs

Are antidepressants based on the serotonin theory of depression?

Yes, many antidepressants, particularly SSRIs, were developed to increase serotonin levels in the brain. However, research shows that for some people, they are much less effective and may also influence other neural pathways, minimising effectiveness. Monarch Mental Health Group offers medication management and alternative treatments like TMS for patients who do not respond to antidepressants. Contact our clinics in Sydney or Melbourne for personalised treatment advice.

What if antidepressants don’t work for me?

Some patients do not respond to antidepressants, and that’s not uncommon. Monarch Mental Health Group provides alternative options for treating depression, such as rTMS, Deep TMS and psychological therapy to support recovery. Our psychiatrists and psychologists create tailored plans that address the root causes of depression. Book a consultation at our Sydney or Melbourne clinic today.

Is serotonin the only chemical linked to depression?

No. Depression involves several neurotransmitters, including dopamine, norepinephrine and glutamate, along with hormonal and inflammatory changes. Monarch Mental Health Group uses a holistic approach to depression treatment that addresses these complex interactions through evidence-based psychiatry and therapy. Our clinics in Sydney and Melbourne are equipped to support patients with all types of depression.

What is rTMS and how does it help treat depression?

Repetitive Transcranial Magnetic Stimulation (rTMS) is a safe and effective non-invasive treatment that uses magnetic fields to stimulate brain areas involved in mood regulation. It is effective for people who have not improved with medication. Monarch Mental Health Group provides rTMS and Deep TMS at our Sydney and Melbourne clinics, led by experienced psychiatrists and clinicians.

Can depression occur without low serotonin levels?

Yes. Some people experience depression even when serotonin levels are normal. Other biological and psychological factors often contribute. Monarch Mental Health Group specialises in comprehensive diagnosis and personalised treatment for all forms of depression. Our psychiatrist-led clinics in Sydney and Melbourne can help identify the best approach for each patient.