Inside out: the chemistry of depression

This is Article 2 in a series on psychiatric disorders and the brain. Next article coming soon. Previous article: What does depression do to your brain?

Ever wondered what’s going on inside your brain when you’re feeling down? Imagine the scene from Inside Out, where Sadness takes over the control room, overshadowing the other emotions. That’s actually not too far from what happens during depression, but the changes in your brain are much more than just a battle of emotions.

Depression is the most common mental illness globally. It is typically marked by a persistently low mood and energy, and a loss of interest or pleasure in everyday activities. Risk factors include chronic stress, traumatic life events, genetic vulnerability, ageing, and female sex. While these influences are widely recognised, have you ever thought about what is actually happening inside your brain when you're depressed? You've probably heard phrases like “I need a serotonin boost,” but what does that really mean? What is serotonin, and how does it influence our emotions and mental health?

What are neurotransmitters?

Think of neurotransmitters as messenger pigeons between neurons. They are involved in communication between different neurons. Communication between neurons is called synaptic transmission. In synaptic transmission, neurotransmitters are released from vesicles in one neuron into the synaptic cleft (the gap between two neurons) and then bind to receptors on the receiving neuron. This is how information travels through the brain, allowing us to think, feel, and act. Serotonin is an example of a neurotransmitter. Others include dopamine, noradrenaline, acetylcholine.

The monoamine theory of depression

One of the most widely supported explanations for the neurobiology of depression is the monoamine theory. This theory suggests that depression results from an imbalance or deficiency of monoamines in the brain. Monoamines are a group of neurotransmitters, including serotonin, dopamine, and noradrenaline, that are synthesised from the amino acids L-tryptophan and L-tyrosine.

Different neurotransmitter systems are involved in depression and even everyday emotion processing and regulation. The dopamine (DA) system plays a key role in experiencing reward and pleasure, often linked to feelings of joy. In contrast, the serotonin (5-HT) system is more associated with responses to punishment and aversive experiences, such as sadness or disgust. Noradrenaline (NE), on the other hand, is closely tied to fear, anger, and the activation of the "fight or flight" response during stressful situations. These neurotransmitters are thought to underlie three fundamental emotional states, which can combine in different ways to form a wide range of complex emotions. In the brain, these monoamines regulate mood, motivation, pleasure, and emotional stability. When levels are low, people may experience sadness, fatigue, apathy, and changes in appetite or sleep.

This is why many antidepressant medications, such as selective serotonin reuptake inhibitors (SSRIs), aim to increase the availability of these monoamines in the synapse, improving communication between neurons and, over time, alleviating symptoms. SSRI treatment, in particular, is based on the serotonin hypothesis, a subset of the broader monoamine theory of depression, which suggests that reduced serotonin levels contribute to depressive symptoms.

Conclusion: why depression is more than a mood

Depression isn’t just “feeling sad”; it is a real condition that involves real chemical changes in the brain. The monoamine theory helps explain this by focusing on key neurotransmitters like serotonin, dopamine, and noradrenaline, which help control mood, motivation, and emotional balance. When these chemicals are out of sync, too low or not working properly, it can lead to the emotional numbness, low energy, and hopelessness that many people with depression experience. These neurotransmitters do not work in isolation; they influence how we respond to rewards, stress, and even daily activities. By understanding the biological changes behind depression, we take an important step toward not only understanding the condition but also reducing the stigma around it. 

Written by Chloe Kam

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REFERENCES

Barchas, J.D. and Altemus, M. (1999) ‘Monoamine Hypotheses of Mood Disorders’, in Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Lippincott-Raven. Available at: https://www.ncbi.nlm.nih.gov/books/NBK28257/ (Accessed: 3 May 2025).

Jiang, Y. et al. (2022) ‘Monoamine Neurotransmitters Control Basic Emotions and Affect Major Depressive Disorders’, Pharmaceuticals, 15(10), p. 1203. Available at: https://doi.org/10.3390/ph15101203.