Children with high everyday levels of a protein released into the blood in response to infection are at greater risk of developing depression and psychosis in adulthood, according to new research which suggests a role for the immune system in mental illness.
The study, published today in JAMA Psychiatry, indicates that mental illness and chronic physical illness such as coronary heart disease and type 2 diabetes may share common biological mechanisms.
When we are exposed to an infection, for example influenza or a stomach bug, our immune system fights back to control and remove the infection. During this process, immune cells flood the blood stream with proteins such as interleukin-6 (IL-6), a tell-tale marker of infection. However, even when we are healthy, our bodies carry trace levels of these proteins – known as 'inflammatory markers' – which rise exponentially in response to infection.
Now, researchers have carried out the first ever longitudinal study – a study that follows the same cohort of people over a long period of time – to examine the link between these markers in childhood and subsequent mental illness.
A team of scientists led by the University of Cambridge studied a sample of 4,500 individuals from the Avon Longitudinal Study of Parents and Children – also known as Children of the 90s – taking blood samples at age 9 and following up at age 18 to see if they had experienced episodes of depression or psychosis. The team divided the individuals into three groups, depending on whether their everyday levels of IL-6 were low, medium or high. They found that those children in the 'high' group were nearly two times more likely to have experienced depression or psychosis than those in the 'low' group.
Dr Golam Khandaker from the Department of Psychiatry at the University of Cambridge, who led the study, says: "Our immune system acts like a thermostat, turned down low most of the time, but cranked up when we have an infection. In some people, the thermostat is always set slightly higher, behaving as if they have a persistent low level infection – these people appear to be at a higher risk of developing depression and psychosis. It's too early to say whether this association is causal, and we are carrying out additional studies to examine this association further."
The research indicates that chronic physical illness such as coronary heart disease and type 2 diabetes may share a common mechanism with mental illness. People with depression and schizophrenia are known to have a much higher risk of developing heart disease and diabetes, and elevated levels of IL-6 have previously been shown to increase the risk of heart disease and type 2 diabetes.
Professor Peter Jones, Head of the Department of Psychiatry and senior author of the study, says: "Inflammation may be a common mechanism that influences both our physical and mental health. It is possible that early life adversity and stress lead to persistent increase in levels of IL-6 and other inflammatory markers in our body, which, in turn, increase the risk of a number of chronic physical and mental illness."
Indeed, low birth weight, a marker of impaired foetal development, is associated with increased everyday levels of inflammatory markers as well as greater risks of heart disease, diabetes, depression and schizophrenia in adults.
This potential common mechanism could help explain why physical exercise and diet, classic ways of reducing risk of heart disease, for example, are also thought to improve mood and help depression. The group is now planning additional studies to confirm whether inflammation is a common link between chronic physical and mental illness.
The research also hints at interesting ways of potentially treating illnesses such as depression: anti-inflammatory drugs. Treatment with anti-inflammatory agents leads to levels of inflammatory markers falling to normal. Previous research has suggested that anti-inflammatory drugs such as aspirin used in conjunction with antipsychotic treatments may be more effective than just the antipsychotics themselves. A multicentre trial is currently underway, into whether the antibiotic minocycline, used for the treatment of acne, can be used to treat lack of enjoyment, social withdrawal, apathy and other so called negative symptoms in schizophrenia. Minocycline is able to penetrate the 'blood-brain barrier', a highly selective permeability barrier which protects the central nervous system from potentially harmful substances circulating in our blood.
The 'blood-brain barrier' is also at the centre of a potential puzzle raised by research such as today's research: how can the immune system have an effect in the brain when many inflammatory markers and antibodies cannot penetrate this barrier? Studies in mice suggest that the answer may lie in the vagus nerve, which connects the brain to the abdomen. When activated by inflammatory markers in the gut, it sends a signal to the brain, where immune cells produce proteins such as IL-6, leading to increased metabolism (and hence decreased levels) of the 'happiness hormone' serotonin in the brain. Similarly, the signals trigger an increase in toxic chemicals such as nitric oxide, quinolonic acid, and kynurenic acid, which are bad for the functioning of nerve cells.
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More information: Khandaker, G. et al. Serum Interleukin-6 and C-Reactive Protein in Childhood as Predictors of Depression and Psychosis in Young Adult Life: A Population-Based Longitudinal Study. JAMA Psychiatry. DOI: 10.1001/jamapsychiatry.2014.1332. Published online August 13, 2014
Elevated levels of IL-6 have previously been shown to increase the risk of heart disease and type 2 diabetes: Danesh J, Kaptoge S, Mann AG, et al. Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Medicine 2008; 5(4): e78.
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA: 2001; 286(3): 327-34.
Indeed, low birth weight, a marker of impaired foetal development, is associated with increased everyday levels of inflammatory markers as well as greater risks of heart disease, diabetes, depression and schizophrenia in adults: Barker DJP. Fetal and Infant Origins of Adult Disease. London: British Medical Journal; 1993.
Abel KM, Wicks S, Susser ES, et al. Birth weight, schizophrenia, and adult mental disorder: is risk confined to the smallest babies? Archives of general psychiatry 2010; 67(9): 923-30
Previous research has suggested that anti-inflammatory drugs such as aspirin used in conjunction with antipsychotic treatments may be more effective than just the antipsychotics themselves: Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H. Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. The Journal of clinical psychiatry 2010; 71(5): 520-7.
Studies in mice suggest that the answer may lie in the vagus nerve, which connects the brain to the abdomen:
Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Reviews Neuroscience 2008; 9(1): 46-56.