High IL-6 Levels in Kids Predict Future Psychiatric Illness

Pam Harrison

August 18, 2014

The risk for depression and psychotic experiences in adolescence is almost 2-fold higher in individuals with the highest vs the lowest levels of interleukin-6 (IL-6) in childhood, a major longitudinal study shows.

Investigators at the University of Cambridge in the United Kingdom found that children who were in the top tertile of IL-6 levels at the age of 9 years were 55% more likely to be diagnosed with depression at the age of 18 than those with the lowest childhood levels of IL-6.

Children in the highest tertile of IL-6 levels at the age of 9 were also 81% more likely to report psychotic experiences at the age of 18.

"We were able to take into account the effect of a number of other factors that are relevant for IL-6 and depression, including body mass index, ethnicity, maternal depression, and past psychological and behavioral problems in the subjects themselves, and we still found that the association between IL-6 and depression as well as psychotic experiences persist," Dr. Khandaker told Medscape Medical News.

"And keeping the public health implications of these findings in mind, exercise and diet are 2 very effective ways of controlling inflammation and could lead to health benefits at a population level by reducing the risk of chronic physical and psychiatric illness."

The study was published online August 13 in JAMA Psychiatry.

No Link to CRP Levels

To test the hypothesis that higher serum IL-6 as well as C-reactive protein (CRP) levels in childhood would predict future risk for depression and psychosis, investigators extracted data from the Avon Longitudinal Study of Parents and Children (ALSAC), a general population birth cohort.

Approximately 5000 children provided enough blood to measure IL-6 and CRP levels at the age of 9. Roughly 500 of them were excluded because the child had an infection at the time of blood collection. Acute infection sharply increases both IL-6 and CRP levels, as investigators point out.

Out of this risk set, approximately 2500 adolescents attended assessment for depression at the age of 18, and approximately the same number were assessed for psychotic experiences, again at the age of 18. Depression was measured using a computerized version of the Clinical Interview Schedule–Revised as well as the short version of the Mood and Feelings Questionnaire. Psychotic experiences were identified through a face-to-face semistructured psychosislike symptoms interview.

Investigators found no association between childhood CRP levels and the risk for psychiatric illness at the age of 18.

In contrast, the association between childhood IL-6 levels and psychiatric illness at 18 was significant.

At the age of 18, 20.5% of adolescents in the top third of IL-6 levels in childhood had been diagnosed with depression compared with 18% for those in the middle third and 13.6% for those in the bottom third.

Table. Serum IL-6 Values at Age 9 Years and Depression/Psychotic Experience at Age 18 Years

  Depression at 18 Years No Depression at 18 Years Psychotic Experience at 18 Years No Psychotic Experience at 18 Years
Serum IL-6, mean (pg/ml) 1.35 1.16 1.56 1.16
Serum IL-6, median (pg/ml) 0.87 0.74 0.98 0.75


"To our knowledge, this is the first longitudinal study of any inflammatory marker in childhood and subsequent psychotic disorder," investigators write.

"A clearer understanding of the role of inflammation in the pathogenesis of depression and psychosis may lead to new treatments."

In the future, the investigators would like to examine the effect of early-childhood adversity on levels of inflammation and whether those inflammatory markers in turn are associated with psychiatric outcomes such as depression and psychosis in adult life.

Particularly Important Study

Asked to comment on the study, Carmine Pariante, MD, PhD, professor of biological psychiatry, Institute of Psychiatry, King's College London, United Kingdom, told Medscape Medical News that there have been other longitudinal studies showing that inflammation in early adulthood predicts depression at a later stage in life.

"However, this is the first time that this has been shown in children, so I think this is particularly important," he said.

The fact that elevated IL-6 levels at the age of 9 predicts not only depression but also psychotic experience was also very interesting, he added, because it shows that inflammation is relevant not only to depressive symptoms but also to a broader spectrum of psychopathology.

"The point Dr. Khandaker makes about preventing inflammation through a healthy diet and physical exercise is correct," said Dr. Pariante.

"I think the bottom line is that this study shows that depression, even if it becomes clinically evident only at the age of 18, is actually already there biologically early and presents as a signature of something that is happening in the infants' development.

"So if a high level of inflammation can be used as a marker for young people at particular risk for depression and psychotic experiences, perhaps these are the children who can benefit from increased psychosocial support to help prevent the onset of psychopathology."

Andrea Danese, MD, PhD, senior lecturer, who is also affiliated with the Institute of Psychiatry, King's College London, told Medscape Medical News that there are a few remarkable features of the current research.

"On the one hand, baseline inflammation levels were measured in childhood instead of adult life, as in most previous research, and this suggests that the origins of the association between inflammation and depression can be traced back to childhood and should probably be addressed early on to avoid long-term liability to depression and psychosis."

On the other hand, Dr. Danese cautioned that the influence of inflammation on later depression and psychosis is not simply explained by previous childhood psychopathology.

"Despite the limitations of using a general psychopathology measure for the baseline assessment, this suggests the association of inflammation with depression and psychosis is not simply explained by known continuities in developmental psychopathology," she said.

"The residual variance highlights the likely contribution of other factors which increase inflammation and also predict later depression and psychosis," Dr. Danese added.

Research by Dr. Danese and colleagues, for example, suggested that childhood trauma, including maltreatment, may also trigger inflammation that in turn could drive depression risk in some individuals.

The study was funded mainly by the Wellcome Trust, with further support from the National Institute for Health Research and the Medical Research Council. The authors and commentators have disclosed no relevant financial relationships.

JAMA Psychiatry. Published online August 13, 2014. Abstract


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