The British Journal of Psychiatry (2004) 185: 353-354. “Insulin-like growth factors, insulin resistance and schizophrenia”

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The British Journal of Psychiatry (2004) 185: 353-354


Insulin-like growth factors, insulin resistance and schizophrenia

D. Gunnell

Department of Social Medicine, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK. E-mail:

J. M. P. Holly

Division of Surgery, University of Bristol, Bristol Royal Infirmary, Bristol, UK

Abel (Abel, 2004) speculates that imprinting of the gene for insulin-like growth factor-II (IGF-II) as well as other genes may be one pathway through which environmental exposures influence the risk of schizophrenia. We too have hypothesised that factors influencing the growth-hormone–IGF axis may contribute to the well-recognised associations of pre-adult exposures with schizophrenia (Gunnell & Holly, 2004).

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We feel that evidence for a direct role of IGF-I is more compelling than that for IGF-II (whose biological functions are poorly understood). Possible pathways for an association with IGF-I lie not only in its role in neurodevelopment but also through its role in neuroprotection following brain damage (e.g. following birth asphyxia, head injury or meningitis) (Gluckman et al, 1998). Insulin-like growth factors exert powerful anti-apoptotic actions and low levels may reduce the survival probability of damaged cells. The influence of IGF-I may extend beyond foetal life as low IGF-I is associated with low birth weight, reduced childhood growth and low body mass index, which are, in turn, associated with the development of psychosis (Wahlbeck et al, 2001; Gunnell et al, 2003). It is therefore possible that low IGF-I levels not only impair neurodevelopment but also render individuals more susceptible to neurodevelopmental insults such as traumatic brain injury and hypoxic brain damage (Gunnell & Holly, 2004).

Several lines of direct and indirect evidence support a possible role of IGF-I in the aetiology of schizophrenia (Gunnell & Holly, 2004). Intriguing indirect evidence for the role of IGF-I, as Abel points out, comes from the observation that low levels protect against a range of different cancers (Renehan et al, 2004) and individuals with psychosis, and their families, appear to be at reduced risk of some malignancies. This may well reflect shared genetic influences on IGF levels influencing susceptibility to both schizophrenia and cancer. Evidence for aetiological associations of IGF-II with cancer risk are less consistent than those for IGF-I. A further indirect line of evidence comes from current concern that insulin resistance may both be more common in people with schizophrenia and be precipitated by antipsychotic medication. Prospective studies indicate that low IGF-I levels are associated with the development of insulin resistance (Sandhu et al, 2002). We speculate that the co-occurrence of insulin resistance and psychosis may in part arise through the shared susceptibility of both these disorders associated with low IGF-I levels.

Evaluation of the possible role of the IGF-system in schizophrenia might not only further our understanding of the aetiology of this disorder but also give insights into its prevention and the reduction of comorbidities such as insulin resistance.


1. Abel, K. M. (2004) Foetal origins of schizophrenia: testable hypotheses of genetic and environmental influences. British Journal of Psychiatry, 184, 383 -385.[Free Full Text]
2. Gluckman, P. D., Guan, J., Williams, C., et al (1998) Asphyxial brain injury – the role of the IGF system. Molecular and Cellular Endocrinology, 140, 95-99.[CrossRef][Medline]
3. Gunnell, D. & Holly, J. M. P. (2004) Do insulin-like growth factors underlie associations of birth complications, fetal and pre-adult growth with schizophrenia? Schizophrenia Research, 67, 309 -311.[CrossRef][Medline]
4. Gunnell, D., Fouskakis, D., Rasmussen, F., et al (2003) Patterns of fetal and childhood growth and the development of schizophrenia and psychosis in young males: a cohort study. American Journal of Epidemiology, 158, 291 -300.[Abstract/Free Full Text]
5. Renehan, A. G., Zwahlen, M., Minder, C., et al (2004) Insulin-like growth factor (IGF)-1, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet, 363, 1346 -1353.[CrossRef][Medline]
6. Sandhu, M. S., Heald, A. H., Gibson, J. M., et al (2002) Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study. Lancet, 359, 1740 -1745.[CrossRef][Medline]
7. Wahlbeck, K., Forsen, T., Osmond, C., et al (2001) Association of schizophrenia with low maternal body mass index, small size at birth, and thinness during childhood. Archives of General Psychiatry, 58, 48-52.[Abstract/Free Full Text]

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