Genetics of early-onset depression

D. Smith, W. Muir and D. Blackwood

Department of Psychiatry, School of Molecular and Clinical Medicine, The University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Morningside Park, Edinburgh EH10 5HF, UK

We were very interested to read the recent, thought-provoking editorial by Andrews et al (2002) on the prevention of depression in young people. However, we are concerned that they have understated the important role of genetics in early-onset depression. Contrary to their assertion that the children of parents with depression are likely to be at heightened risk for psychological rather than genetic reasons, available evidence suggests that childhood-onset depression represents a strongly genetic subtype of affective disorder (Neuman et al, 1997; Sullivan et al, 2000). Up to 50% of pre-pubertal children with depression eventually develop bipolar disorder (Geller et al, 2001) and recurrent, early-onset depression (defined as two or more episodes before age 25) is recognised as a malignant form of affective disorder characterised by high genetic loading, frequent recurrence and poor long-term outcome (Zubenko et al, 2001). Furthermore, one recent study suggests that the inheritance of depression in these families is compatible with a single major locus (Maher et al, 2002).

Preliminary findings from our own study of early-onset depression in a university population support the view that early age at onset defines a subgroup at very high genetic risk. Using the Family Interview for Genetics Studies (FIGS; National Institute of Mental Health, 1999), 76% of the subjects seen so far (36 out of 47) report at least one first-degree relative with affective disorder, with 87% (41 out of 47) reporting either a first- or second-degree relative affected. The mean age at onset in this group is 15.6 years (s.d.=2.6).

Population-based interventions are unlikely to reduce the prevalence of depression in young people as long as we have an incomplete understanding of how genetic and non-genetic risk factors interact to bring about the depressive phenotype. Interventions such as the cognitive therapy programme described by Clarke and colleagues (Clarke et al, 2001) might be cost-effective strategies if they can be targeted to high-risk groups. Unfortunately, we are not yet in a position to reliably identify those individuals at high risk.

EDITED BY KHALIDA ISMAIL

REFERENCES

Andrews, G., Szabo, M. & Burns, J. (2002) Preventing major depression in young people. British Journal of Psychiatry, 181, 460-462.[Free Full Text]

Clarke, G. N., Hornbrook, M., Lynch, F., et al (2001) A randomised trial of group cognitive intervention for preventing depression in adolescent offspring of depressed parents. Archives of General Psychiatry, 58, 1127-1134.[Abstract/Free Full Text]

Geller, B., Zimmerman, B., Williams, M., et al (2001) Bipolar disorder at prospective follow-up of adults who had prepubertal major depressive disorder. American Journal of Psychiatry, 158, 125-127.[Abstract/Free Full Text]

Maher, B., Marazita, M. L., Zubenko, W. N., et al (2002) Genetic segregation analysis of recurrent, early-onset depression: evidence for single major locus transmission. American Journal of Medical Genetics, 114, 214-221.[CrossRef][Medline]

National Institute of Mental Health (1999) FIGS face sheet. http://zork.wustl.edu/nimh/figs/FIGS.pdf

Neuman, R. J., Geller, B., Rice, J. P., et al (1997) Increased prevalence and earlier onset of mood disorders among relatives of prepubertal versus adult probands. Journal of the American Academy of Child and Adolescent Psychiatry, 36, 466-473.[Medline]

Sullivan, P., Neale, M. C. & Kendler, K. S. (2000) Genetic epidemiology of major depression: review and meta-analysis. American Journal of Psychiatry, 157, 1552-1562.[Abstract/Free Full Text]

Zubenko, G., Zubenko, W. N., Spiker, D. G., et al (2001) Malignancy of recurrent, early-onset depression: a family study. American Journal of Medical Genetics, 105, 690-699.[CrossRef][Medline]


 

Authors' reply

G. Andrews, M. Szabo and J. Burns

School of Psychiatry, The University of New South Wales, Sydney 2052, Australia

EDITED BY KHALIDA ISMAIL

Smith et al worry that we have underestimated the role of genetics in early-onset depression. They draw our attention to the published evidence for the importance of genetic factors in prepubertal depression, which itself is a marker for adult bipolar disorder, although not necessarily a marker for major depression (the topic of our editorial). From their own data, they report that three-quarters of 47 subjects who had a depressive episode by a mean age of 15 had a first-degree relative with an affective disorder. Strong evidence indeed of familiarity, but not necessarily of a genetic cause. Despite their certainty, many of us have problems with the precise nature of the evidence supporting genetic factors in major depression, in part because of the dimensional nature of depression, and in part because of the extensive comorbidity.

We opined that the heightened risk of depression in young people whose parents had depression was likely to be ‘more psychological than genetic’ and referred the reader to the review by Beardslee et al (1998). We provided evidence that intervention programmes for adolescents can reduce by half the probability of depression in the future. Smith et al argue that universal interventions are unlikely to be effective until we have complete understanding of how genetic and non-genetic factors interact to bring about the depressive phenotype, and that interventions targeted to high-risk groups should be deferred until we can reliably identify those individuals at high risk.

We strongly oppose this thinking. Most interventions in medicine are introduced before there is a complete understanding of the aetiology of the disorder, and usually before there is precise information as to which individuals will respond. Simply to know that an intervention can produce a reliable and significant benefit is sufficient to warrant implementation. We believe that this is the situation in regard to the prevention of major depression in young people.

REFERENCES

Beardslee, W. R., Versage, E. M. & Gladstone, T. R. G. (1998) Children of affectively ill parents: a review of the past 10 years. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 1134-1141.[Medline]





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