Malignancy of recurrent, early-onset major depression: A family study

Coordinated efforts to identify susceptibility genes for unipolar major dep ressive disorder (MDD) and related disorders are now underway. These studie s have focused on recurrent, early-onset MDD (RE-MDD), the most heritable f orm of this disorder. The goal of this study was to characterize the burden of MDD and other mood disorders, comorbid mental disorders, and excess mor tality in RE-MDD families. A total of 81 families were identified through p robands over the age of 18, who met criteria for recurrent (greater than or equal to2 episodes), early-onset (less than or equal to 25 years), nonpsyc hotic, unipolar MDD (RE-MDD), and included 407 first-degree relatives and 8 35 extended relatives. Psychiatric diagnoses for probands and their family members who provided blood samples were formulated from structured personal interviews, structured family history assessments, and available medical r ecords. The remaining family members who participated and those who were de ceased were evaluated through the family history method augmented by availa ble medical records. Best estimate diagnoses were made during a consensus c onference according to established diagnostic criteria. Approximately half of the first-degree relatives and a quarter of extended relatives of RE-MDD probands suffered from at least one mood disorder, typically MDD. As commo nly observed for other oligogenic, multifactorial disorders, the severity o f MMD reflected by age at onset and number of episodes attenuated with incr easing familial/genetic distance from the proband. A substantial fraction o f RE-MDD probands and their first-degree relatives met diagnostic criteria for additional psychiatric disorders that include prominent disturbances of mood. The deceased relatives of RE-MDD probands died at a median age that was 8 years earlier than for the local population; over 40% died before rea ching age 65. These differences in mortality statistics resulted from a shi ft toward younger ages at death across the lifespan, including a fivefold i ncrease in the proportion of individuals who died in the first year of life . Several-fold increases in the proportion of deaths by suicide, homicide, and liver disease were observed among the relatives of RE-MDD probands. How ever, the rank order of the three most common causes of death-heart disease , cancer, and stroke-remained unchanged and differences in the proportions of deaths from the remaining causes were small. RE-MDD is a strongly famili al condition with a high rate of psychiatric comorbidity, whose malignant e ffects have a significant negative impact on the health and longevity of pa tients and their family members. (C) 2001 Wiley-Liss, Inc.