The Neurobiology of Depression

By Marina Artemiou

Unhappiness and sadness are emotions that we all have felt. In fact most people often go through periods of feeling down, but depression is more than simply feeling unhappy or fed up for a few days. When someone is depressed, they persistently feel sad for weeks or months on end, rather than just a few days. This can negatively impact their ability and willingness to perform everyday tasks and, hence, their quality of life. Often times, people perceive depression as trivial and not a genuine mental condition, but these people are awfully wrong. Depression is a genuine illness with real symptoms and dangerous effects. It is not a sign of weakness or something that the sufferer can “snap out of” by “pulling themselves together”. Sufferers are commonly treated using anti-depressant pharmacotherapy, which acts in a way to restore the chemical alterations in the affected areas of the brain, thereby alleviating the symptoms they experience (MentalHelp, n.d.). 

You may have heard of depression as being simply an imbalance of chemicals in the brain, and although this may be partially true, major depressive disorder (MDD) is an illness with significant neurobiological consequences produced as a result of structural, functional, and molecular alterations in several areas of the brain. Despite the complexity of this mental disorder, anti-depressant pharmacotherapy, which is the current golden standard for the treatment and management of depression, only acts in a way to reverse and restore the chemical imbalances experienced in certain areas of the brain, hence alleviating some of the symptoms experienced (MentalHelp, n.d.). 

Two main neurotransmitters have been found to be implicated in depression (Cowen et al, 2015, Priory, n.d). These are serotonin and norepinephrine. Although the evidence supporting the involvement of these neurotransmitters in the development of depression is somewhat indirect, becauset is very difficult to actually measure the level of neurotransmitter in a person’s brain and present in a particular synapse at any one time, the successful use of anti-depressant drugs which selectively act upon these particular neurotransmitters and their respective receptors has provided an indication concerning their involved in this condition (MentalHelp, Priory, n.d.). 

The neurotransmitter serotonin is involved in regulating numerous physiological functions including sleep, aggression, eating and mood. Due to its prominent role in regulating mood and temper, serotonin has been given the title “Feel Good” chemical of the brain. This idea paved the way for the “serotonin hypothesis” of clinical depression which is now almost 50 years old. Simply framing it, this hypothesis proposes that diminished activity of serotonin pathways plays a causal role in the pathophysiology of depression. This notion was further reinforced by the ‘comedown’ experienced by alcoholics and drug users (specifically ecstasy/MDMA users), where the majority reported feeling depressed the days following drug usage, later found to be attributed to a significant drop in serotonin. Due to the strong evidence supporting the serotonin hypothesis, it has become the most common neurotransmitter targeted by anti-depressant drugs (Cowen et al, 2015).

In the 1960s, the “catecholamine hypothesis” was also introduced and quickly became a popular explanation for why people developed depression (Moret et al, 2011). This hypothesis suggested that a deficiency of norepinephrine (noradrenaline) in specific brain regions was responsible for the development of depression. It has since been supported by post-mortem studies which demonstrated that people who have experienced multiple depressive episodes have fewer norepinephrinergic neurones than people with no depressive history, suggesting that a loss of norepinephrinergic neurones may be the cause. Despite this, the cause of neuronal loss remains unknown (Moret et al, 2011).

Although several theories have emerged supporting the hypotheses mentioned above, the main challenge still remains; “how can we confirm these hypotheses if the amount of neurotransmitter cannot be directly, consistently and accurately measured?”. Additionally, an increasing number of neurotransmitters are thought to play a role in the development of depression in addition to serotonin and norepinephrine, which makes identifying the exact underlying cause or causes of depression increasingly harder to pinpoint. 

The World Health Organization (WHO), estimates that 264 million people worldwide are currently suffering from depression, with close to 800,000 sufferers dying as a result of suicide each year, making suicide the second leading cause of death for 15-29-year-olds. The burden of depression and other mental health conditions is on the rise globally and so it is important, now more than ever, for adequate research to be conducted such that the underlying cause can be determined, early diagnostic testing developed and effective treatment, whether that is pharmacological, psychological or a combination of both, can be provided to everyone who requires it (WHO, n.d.).


  1. MentalHelp (n.d.) Biology of Depression – Neurotransmitters. [Online]. Available from: [Accessed: 31 May 2021].
  2. Priory (n.d.) What is the link between serotonin and depression? [Online]. Priory Group. Available from: [Accessed: 31 May 2021].
  3. Cowen, P.J. & Browning, M. (2015) What has serotonin to do with depression? World Psychiatry. [Online] 14 (2), 158–160. Available from: doi:10.1002/wps.20229.
  4. Moret, C. & Briley, M. (2011) The importance of norepinephrine in depression. Neuropsychiatric Disease and Treatment. [Online] 7 (Suppl 1), 9–13. Available from: doi:10.2147/NDT.S19619.
  5. WHO (n.d.) Depression. [Online]. Available from: [Accessed: 1 June 2021].

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