Dr Nick StaffordFor years, a ‘chemical imbalance’ in the brain has been thought to be behind depression, but now other biological processes are believed to be the primary causes, says Dr Nick Stafford.

For decades we have thought that the biological cause of depression was primarily and perhaps singularly a ‘chemical imbalance’ of molecules such as serotonin. This narrow view has perhaps been partly driven by the overwhelming success of modern anti-depressants in the treatment of depression, and their action on effecting changes in these chemical balances. 

While the science of depression has progressed markedly in recent years, in the public eye a ‘chemical imbalance’ remains the main and only description most of my patients will talk about when they explain their understanding of depression and other psychiatric conditions. However, it is more likely that the primary causes of depression include other biological processes, and any ‘chemical imbalances’ or effects on neurotransmitters – the chemicals that communicate between brain cells – are a side effect of these processes.

These other biological causes are varied. Firstly, genetic changes can cause alterations in the chemical communication processes of brain cells. These genetic changes are likely ‘switched on’ in childhood due to the experience of some kind of adversity. The downstream chemical imbalances of these genetic changes can be measured, even when under relatively minor stresses and can also give a prediction of suicidal risk. 

Secondly, there are small biological batteries in most cells in the body, called mitochondria, whose function is impaired in depression. Inefficiencies in the energy producing processes of the mitochondria of brain cells cause a build-up of toxic chemicals, which mean charged ‘free-radicals’ also build up and that in turn damages brain cells and circuits. In addition, the function of these mitochondria become increasingly inefficient when the person is experiencing stress. 

Thirdly, dysfunction in brain-body systems connecting the pituitary gland of the brain and the adrenal glands sitting on top of the kidneys lead to abnormal levels of stress hormones, such as cortisol being produced in the body that in turn impacts negatively on the brain and the physical health of the body generally.

A new area of research into the causes of depression has concentrated on inflammation (or neuroinflammation). While it has been known for some time that neuroinflammation may play a key role in depression – in particular difficult to treat depression – only more recently has attention been switched to the role our own immune system plays in the process of neuroinflammation. Inflammation itself is an immune mechanism. Most general psychiatrists will not be surprised about this finding, as many will report patients who have co-existing inflammatory processes, such as arthritis, have an increased chance of experiencing depression.

A recently reported finding by a consultant rheumatologist at the Glasgow Royal Infirmary, Dr Iain McInnes and colleagues (2015), recognised that in his clinical practice he saw a disproportionate improvement in the mood and wellbeing of patients who had received anti-inflammatory treatment for their arthritic conditions. Furthermore, when these patients’ brains were scanned, ‘quite remarkable’ changes were seen in the neuro-chemical circuitry.

While at this stage no cause-effect link has been proven, it adds to the increasing body of evidence linking the effects of inflammation and depression. Earlier research shows that inflammatory markers in the blood are increased in depression and bipolar disorder, and that infections of any kind can cause a biological stress that leads to a relapse in these conditions.

In terms of treatment there is the possibility that by measuring these inflammatory chemicals in people with depression we might be able to predict more complex or difficult to treat cases at an early stage (Catteneo et al, 2015). Moreover, other areas of research are focusing on developing current and new anti-inflammatory drugs that have the potential to treat a depressive relapse or prevent one in the first instance. 

There is now research in Australia and the USA, called ASPREE, into yet another treatment for the humble aspirin – which already plays a clinical role in the treatment of pain, myocardial infarction, stroke, dementia and some cancers – the prevention of depression. The research, based in general practice and through family practitioners, focuses on the prevention of a range of conditions in older people, of which depression is one sub study. About 19,000 subjects have been recruited over the age of 70 years. If this research proves positive the cost of preventative treatment for depression would be around £1.10 a month per person. The estimated cost to UK society in of depression alone in the UK is £7.5 billion (Department of Health, 2011).

Another interesting hypothesis is that the role of inflammation in depression may be an evolutionary product that has, in the past, helped us enhance our immunity and fight off infection. Infections have in the past been the major cause of death, more so in days prior to antibiotics. Given the many tens of thousands of years homosapiens have existed without the medicine of antibiotics, depression may have been a protective process that allowed people to survive infections. “Depression [as a byproduct] and the genes that promote it may have been very adaptive for helping people survive infections in the ancestral environment… even though depressive behaviors are maladaptive for social relationships.” (Hsu, 2012).


ASPREE (ASPirin in Reducing Events in the Elderly), Lead investigator Professor Michael Berk, Deakin University, Australia. http://www.aspree.org/aus/sub-studies/aspree-depression/

Catteneo A et al (2015) Absolute measurements of macrophage migration inhibitory factor and interleukin-1-beta mRNA levels accurately predict treatment response in depressed patients. The International Journal of Neuropsychopharmacology.

Department of Health (2011) No Health without Mental Health: A Cross-Government mental health outcomes strategy for people of all ages. London: DH.

Hsu, C. Depression may have evolved to enhance immune response & fight mortality’. Mar ch1, 2012. Medical Daily.

McInnes IB et al (2015) Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study. Annals of the Rheumatic Diseases 74(4) 694-702.

About the author

Dr Nick Stafford is a consultant psychiatrist in Lichfield, Staffordshire.

This article also appeared on www.careknowledge.com