The Children at High and Low Risk Study is approaching its 30th consecutive year of NIMH funding and is planning on continuing to collect additional clinical, genetic, EEG, and MRI data. The sample now includes 4 generations grandparents (G1), parents (G2), grandchildren (G3), and great-grandchildren(G4) and consists of families at high or low risk for depression based on the depression status of the original sample (G1).

In the 1st and 2nd Waves [Data Collection 1982-1986], clinical assessments were conducted on G1 and G2. We found an increased overall prevalence of major depression and substance abuse, psychiatric treatment, poor social functioning, and school problems in the children of high as compared to low risk families. In addition, the age of onset of MDD was significantly earlier in the children of high risk families and the children of parents who also had an onset of major depression younger than at age 20. These subjects overall had the highest risk of major depression. These higher rates were nearly all accounted for by prepubertal onsets of major depression in their children. Through additional research it was determined that family risk factors (e.g., low family cohesion, affectionless control) were associated with G2 major depression and any diagnosis in low risk families and with G2 conduct disorder in high and low risk families. In high risk families parental depression was more important than any of the family risk factors in models predicting major depression, anxiety disorders, and any diagnosis.

In the 3rd Wave [Data Collection 1992-1994], grandchildren (G3) were assessed for the first time. G1 and G2 were clinically assessed again. Grandparent (G1) and parent (G2) MDD were associated with grandchild (G3) anxiety. Grandchildren with both a depressed parent and grandparent had the highest risk for anxiety. Parental (G2) MDD was associated with an increased risk for grandchild disruptive disorder. For G2, there was a greater than 4-fold increased risk of prepubertal-onset conduct disorder in boys and a greater than 5-fold increased risk of adolescent-onset drug dependence in girls whose mothers smoked 10 or more cigarettes almost daily during pregnancy. In addition, G2 with childhood/adolescent onset MDD were at significantly greater risk for recurrence in adulthood (after age 25) as compared with offspring without an onset of childhood/adolescent MDD, when they came from high risk families.

In the 4th wave [Data Collection 1999-2002], we added electroencephalographic (EEG) and startle response measures to the assessments. EEG measures showed significant alpha asymmetry over the parietal cortex (relatively less right than left parietal activity) in G2 and G3 from high as compared to low risk families, independent of a lifetime history of MDD or anxiety. Startle response was elevated in high as compared to low risk families in G2 males and G2 females as well as G3 females. In G2, The risks for anxiety disorders, major depression, and substance dependence were approximately three times as high in the offspring of depressed as compared to nondepressed parents. Social impairment was also greater. Higher rates of medical problems and mortality in the offspring of depressed parents were beginning to emerge as the offspring entered middle age. In G3, There were high rates of psychiatric disorders, particularly anxiety disorders, with 2 generations of major depression, with 59.2% of these G3 (mean age, 12 years) already having a psychiatric disorder. The effect of parental depression on grandchildren's outcomes differed significantly with grandparental depression status. Among families with a depressed grandparent, increased risk of anxiety and increased risk of any disorder were observed in grandchildren with a depressed parent as compared with those with nondepressed parents. The severity of parental depression, as measured by impairment, significantly increased the rate of a mood disorder. In contrast, among grandchildren with nonfamilial depression, ie, depressed parents with no depressed grandparents, there was no significant effect of parental MDD on grandchildren diagnoses. However, parental MDD, regardless of whether families had a depressed grandparent, had a significant impact on the grandchildrens overall functioning.

In the 5th wave of assessments [Data Collection 2002-2007], we added Magnetic Resonance Imaging (MRI) measures. We found a robust association of familial risk for MDD with asymmetries in cortical thickness in this region, with a 30% reduction in thickness observed in the lateral parietal, temporal, and frontal cortices of the right hemisphere of the high risk families. Taken together, the EEG and MRI findings strongly suggest that the predisposition to familial depression derives from anatomical and functional disturbances of cortical gray matter in the right cerebral hemisphere. Both the MRI and EEG findings were present in high-risk individuals who never had MDD in their lifetimes, suggesting that these abnormalities were not simply a consequence of previously having been depressed or having been treated for depression. Thinning of the cortical mantle and reduced electrophysiological activity in the right hemisphere therefore may constitute related endophenotypes for familial vulnerability to developing MDD.

In the 6th wave of assessments [Data Collection 2010-2015], we are collecting additional MRI and EEG measures, as well as clinical and cognitive neuroscience data, that will inform us about the neural bases of the right hemisphere thinning and their consequences for brain function and emotional processing. We will also determine whether additional cortical thinning in the left cerebral hemisphere predicts new or recurrent MDD in those people who were imaged in Wave 5.