Families at high and low risk for depression: a 3-generation study

BACKGROUND: The familial nature of early-onset major depressive disorder (MDD) has been documented in numerous family studies of adults and is supported by studies of offspring of parents with MDD, for whom the risk is more than 3-fold. None of the published high-risk studies have gone beyond 2 generations, and few have a longitudinal design. We report results of an approximately 20-year follow-up of families at high and low risk for depression. The first 2 generations were interviewed 4 times during this period. The offspring from the second generation are now adults and have children of their own, the third generation of the original cohort. OBJECTIVE: To examine the familial aggregation of psychiatric disorders and functioning in grandchildren by their parents' and grandparents' depression status. DESIGN: Longitudinal, retrospective cohort, family study. PARTICIPANTS: One hundred sixty-one grandchildren and their parents and grandparents. MAIN OUTCOME MEASURES: Lifetime rate of psychiatric disorder and functioning in grandchildren, stratified by parental and by grandparental depression status, collected by clinicians blind to diagnoses of previous generations and to previous interviews. RESULTS: There were high rates of psychiatric disorders, particularly anxiety disorders, in the grandchildren with 2 generations of major depression, with 59.2% of these grandchildren (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 (relative risk, 5.17; 95% confidence interval, 1.4-18.7; P = .01) and increased risk of any disorder (relative risk, 5.52; 95% confidence interval, 2.0-15.4; P = .002) 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 these grandchildren (relative risk, 2.44; 95% confidence interval, 1.1-5.5; P = .03). 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 grandchildren's overall functioning. Potential confounding variables did not affect the strength of the association with parental and grandparental depression. CONCLUSIONS: The association between parental MDD and child diagnosis is moderated by grandparental MDD status. The rates of psychopathology are highest in grandchildren of parents and grandparents with a moderately to severely impairing depression. Anxiety disorders are the early sign of psychopathology in the young grandchildren. Early interventions in the offspring of 2 generations affected with moderately to severely impairing MDD seem warranted. This familial group may be the target for neuroimaging, genetic, and other biological studies.     

Offspring of depressed parents: 20 years later

OBJECTIVE: This study was a 20-year follow-up of offspring of depressed and nondepressed parents to determine the magnitude and continuity of the risk of parental depression to the offspring. METHOD: The authors followed 151 offspring of moderately to severely depressed parents or nonpsychiatrically ill comparison subjects for about 20 years, to a mean age of 35 years. Four interviews and diagnostic assessments from childhood or adolescence to adulthood were conducted by assessors blind to the parents' clinical status or the offspring's previous history. Final best-estimate diagnoses were also made by blinded psychologists or psychiatrists. RESULTS: The risks for anxiety disorders, major depression, and substance dependence were approximately three times as high in the offspring of depressed parents as in the offspring of nondepressed parents. Social impairment was also greater. The period of highest incidence for major depressive disorder remained between ages 15 and 20 years, largely in females. The early onset of disorder seen in the high-risk group was not offset by a later onset in the low-risk group as they matured. Higher rates of medical problems and mortality in the offspring of depressed parents were beginning to emerge as the offspring entered middle age. CONCLUSIONS: The offspring of depressed parents constitute a high-risk group for psychiatric and medical problems, which begin early and continue through adulthood. Early detection seems warranted.     

Anxiety and depressive disorders in offspring at high risk for anxiety: A meta-analysis

This paper presents a meta-analysis of studies examining prevalence of psychopathology among offspring of anxiety-disordered parents, with the purpose of determining overall risk among these offspring for developing anxiety and depressive disorders. Pooled odds ratios for these disorders among high-risk offspring, compared to offspring of psychiatric and non-psychiatric controls, were calculated. Sixteen papers (including three follow-up studies) were identified, encompassing 1892 offspring (ages 4–25 years). Results revealed that: (1) offspring of parents with anxiety disorders have greater risk for anxiety and depressive disorders than offspring of non-psychiatric controls (ORs = 3.91 and 2.67, respectively) and greater risk for anxiety disorders than offspring of psychiatric controls (OR = 1.84); (2) offspring of anxious parents have significantly greater odds of having each type of anxiety disorder and MDD compared to offspring of non-psychiatric controls (ORs range from 1.96 to 8.69); and (3) offspring of parents with anxiety only, anxiety plus MDD, and MDD only have similar odds of having anxiety and depressive disorders but significantly higher odds than offspring of parents without disorder. Results suggest that parental anxiety disorders confer significant risk for anxiety and depression in offspring. Additional studies are needed to examine whether there are differences among specific parental anxiety disorders.     

Family discord, parental depression, and psychopathology in offspring: ten-year follow-up

OBJECTIVE: To determine the independent effects of parental depression and family discord on psychopathology in offspring at high and low risk for major depression. METHOD: One hundred eighty-two offspring of depressed or nondepressed parents were followed over 10 years. In direct interviews, parents' and offspring's psychopathology was evaluated by raters blind to parents' clinical status. Five dimensions of family discord-poor marital adjustment, parent-child discord, low family cohesion, affectionless control, and parental divorce-were assessed. RESULTS: Offspring exposed to either parental depression or family discord had higher rates of psychopathology than their counterparts. High-risk offspring had few family discord measures associated with their psychopathology; in low-risk offspring, family discord was associated with all offspring diagnoses. Between the two risk factors, parental depression proved a more important predictor for offspring major depressive disorder (MDD) and anxiety disorder, whereas family discord was a more important predictor for substance use disorder. CONCLUSIONS: Parental depression is a strong and consistent risk factor for offspring MDD and anxiety disorder. Without parental depression, offspring have less exposure to family discord and lower rates of psychopathology. In the presence of family discord, rates of MDD, anxiety disorder and substance use disorder increased. When offspring matured into young adulthood, effects of parental depression and family discord persisted.     

Grandparents, parents, and grandchildren at high risk for depression: a three-generation study

OBJECTIVE: High-risk studies of psychiatric disorders in parents and offspring that include 3 generations are uncommon. Multigenerational studies can be clinically useful as they can provide information for risk prediction from one generation to another for the development of empirically based interventions. Using a high-risk design, this study examines the association of grandparent major depressive disorder (MDD) and parent MDD with psychopathology in grandchildren. METHOD: Using Cox proportional hazards in a sample of 90 grandchildren at high and low risk for depression by virtue of their grandparents' and parents' depression status, the authors examined the risk for offspring depression and anxiety. RESULTS: Grandparent and parent MDD were associated with grandchild anxiety (relative risk [RR] = 5.51 and R = 3.09, respectively). Grandchildren with both a depressed parent and grandparent had the highest risk for anxiety. Parental MDD is associated with an increased risk for grandchild disruptive disorder (RR = 10.77). Forty-nine percent of the grandchildren in families in which both the parent and grandparent were depressed had some form of psychopathology. The grandchildren from those families were the most impaired. CONCLUSIONS: Prepubertal-onset anxiety disorder is a risk factor for the later development of clinically significant recurrent MDD across several generations of families at high risk for depression. Parental impaired functioning increases the risk for disruptive disorders. Children in families with multiple generations of depression are at particularly high risk for some form of psychopathology.     

Family discord, parental depression, and psychopathology in offspring: 20-year follow-up

OBJECTIVE: To determine the independent effects of parental depression and family discord on offspring psychopathology among children at high and low risk of depression. METHOD: Family discord factors were assessed when subjects were approximately 17 years old, and offspring diagnoses were assessed about 20 years later. Parental and offspring psychopathology was assessed by interviewers blind to parents' clinical status. The following dimensions of family discord were assessed: poor marital adjustment, parent child discord, low family cohesion, affectionless control, and parental divorce. RESULTS: Most family discord factors were associated with parental depression. Among children of depressed parents, none of the measures of family discord had a statistically significant association with offspring major depressive disorder or anxiety disorders. Among children of nondepressed parents, parental affectionless control was associated with an almost fivefold increased risk of major depressive disorder (odds ratio [OR] = 4.8; p < or = .05) and with more than a 14-fold increased risk of substance use disorders (OR = 14.3; p < or = .01). CONCLUSIONS: Parental depression is associated with family discord and is a consistent risk factor for offspring major depressive disorder and anxiety disorders, as shown over a 20-year follow-up of offspring of depressed and nondepressed parents. Family discord factors may be a risk factor for major depressive disorder and substance use disorders in offspring of nondepressed parents.     

Physical health problems in depressed and nondepressed children and adolescents of parents with opiate dependence

The increased risk of physical health problems in adult depressed patients has been shown in numerous studies. A recent study of the offspring of depressed parents found similar associations. The purpose of this study is to examine the strength and specificity of the association between depression and physical health problems in children and adolescents whose parents are dependent upon opiates. The sample consisted of offspring ages 6-17 (mean age 11 years) of opiate addicts who had a history of major depressive disorder (MDD; n = 28); other mood disorders (n = 31); no history of mood disorders but other psychiatric disorders (n = 92); or no history of psychiatric disorder (n = 127). Detailed psychiatric assessment and medical history of the offspring by direct interview with the offspring and an informant were obtained blind to parental diagnosis. After controlling for possible confounders, there was an increased risk of dermatological disorders, headache, other neurological/neuromuscular disorders, bronchitis, other respiratory disorders and hospitalizations for nonsurgical procedures in offspring with MDD, as compared to nonpsychiatrically ill controls. The offspring with other mood disorders had a slightly elevated risk. Major depression in children and adolescents whose parents are dependent on opiates is associated with increased risk of physical health problems. This finding is consistent with other reports and the timing of the physical health problems requires further study.     

Parental Depression as a Moderator of Secondary Deficits of Depression in Adult Offspring

This study examined whether having a depressed parent intensifies the secondary deficits that often co-occur with offspring’s depression symptoms. The sample was adult offspring of parents who had been diagnosed with depression 23 years earlier (N = 143) and demographically matched nondepressed parents (N = 197). Respondents completed mailed questionnaires. After controlling for demographic factors, offspring who were more depressed experienced more impairment: physical dysfunction, pain, and disability; anxiety, smoking, and drinking-related problems; poorer social resources; negative events and severe stressors; and reliance on emotional discharge coping. Parental status (depressed or not depressed) was not directly related to offspring impairment once offspring depression symptoms were controlled. However, parental status moderated associations between offspring’s depression severity and their impairment: relationships between depression and impairments were generally stronger for offspring of depressed parents than for offspring of nondepressed parents. Depressed individuals who are offspring of depressed parents may be at particular risk for the secondary deficits of depression.     

A high risk study of young children of parents with panic disorder and agoraphobia with and without comorbid major depression

Using family study methodology and psychiatric assessments by blind raters, this study tested hypotheses about patterns of familial association between anxiety and depressive disorders among high risk children of clinically referred parents. The study design contrasted five groups of children defined by the presence or absence in a parent of (1) panic disorder and agoraphobia (PDAG) without comorbid major depressive disorder (MDD) (n = 14); (2) comorbid PDAG plus MDD (PDAG + MDD) (n = 25); (3) MDD without comorbid PDAG (n = 12); (4) other psychiatric disorders (n = 23); and (5) normal comparisons (n = 47). While the PDAG and PDAG + MDD groups had similarly elevated rates of anxiety disorders and MDD, offspring of MDD parents had an elevated rate of MDD but not of anxiety disorders. Among children of parents with PDAG + MDD, the presence of an anxiety disorder did not significantly increase the risk for MDD in the same child. Thus, anxiety and MDD did not cosegregate among children of PDAG parents. These findings indicate that parental PDAG, either alone or comorbidly with MDD, increases the risk for both anxiety and depressive disorders in offspring. In the absence of PDAG, however, parental MDD does not appear to place children at risk for anxiety disorders. These findings are most consistent with the hypothesis that PDAG and PDAG + MDD share common familial etiologic factors while MDD alone is an independent disorder. More studies are needed to confirm these preliminary findings as well as to identify mediating factors that influence the transition from childhood to adult anxiety disorders.     

Temperament among offspring at high and low risk for depression

The purpose of this study was to examine relationships between parental depression, offspring temperament, and offspring major depressive disorder (MDD), and to determine whether difficult temperament, as measured by the Dimensions of Temperament Survey (DOTS), mediates the relation between parental MDD and offspring MDD. Offspring (n=169) of depressed or never depressed parents were followed over approximately 20 years and were blindly assessed up to 4 times (Waves 1 to 4) using semi-structured interviews. Offspring completed the DOTS at the time of first or second assessment. The results showed: (1) high-risk offspring with one or more depressed parent were significantly more likely than offspring with neither parent depressed to have a difficult temperament; (2) offspring with a difficult temperament were more than twice as likely as those with an easy temperament to develop a MDD; and (3) difficult temperament explained more than 10% of the association between parental depression and new onsets of MDD in offspring. The findings suggest that offspring temperament is associated with development of MDD and that difficult temperament at least partially mediates the relationship between parental depression and offspring depression. When identifying those at greatest risk for MDD, measures of temperament could serve as a useful supplement to family psychiatric history of MDD.     

Electroencephalographic measures of regional hemispheric activity in offspring at risk for depressive disorders.

BACKGROUND: Electroencephalographic (EEG) studies have found abnormal regional hemispheric asymmetries in depressive disorders, which have been hypothesized to be vulnerability markers for depression. In a longitudinal high-risk study, resting EEG was measured in primarily adult offspring of depressed or nondepressed probands. METHODS: Electroencephalograms from12 homologous sites over each hemisphere (digitally linked-ears reference) were analyzed in right-handed offspring for whom both parents (n = 18), one parent (n = 40), or neither parent (n = 29) had a major depressive disorder (MDD). RESULTS: Offspring with both parents having MDD showed greater alpha asymmetry at medial sites, with relatively less activity (more alpha) over right central and parietal regions, compared with offspring having one or no parent with MDD. Relatively less left frontal activity at lateral sites was associated with lifetime MDD in offspring but not with parental MDD. Offspring with both parents having a MDD also showed markedly greater anterior-to- posterior increase in alpha with eyes closed compared with those with one or no parent with a MDD. CONCLUSIONS: Alpha asymmetry indicative of right parietotemporal hypoactivity, previously reported for depressed adolescents and adults, and heightened anterior-to-posterior gradient of alpha are present in high-risk offspring having parents concordant for MDD.     

Memory deficits in children with and at risk for anxiety disorders

There are limited data on the neurocognitive correlates of childhood anxiety disorders. The objective of this study was to examine whether visual and verbal memory deficits of nonemotional stimuli are (1) a shared feature of three common childhood anxiety disorders (social phobia, separation anxiety disorder, and generalized anxiety disorder) or whether these deficits are restricted to specific anxiety disorders, and (2) present in offspring who possess at least one of the following established risk factors for anxiety disorders, parental history of panic disorder (PD), or major depressive disorder (MDD). One hundred and sixty offspring, ages 9-20 years, were recruited from parents with lifetime diagnoses of PD, MDD, PD plus MDD, or neither illness. Different clinicians blindly administered semistructured diagnostic interviews to offspring and parents. Verbal and visual memory subtests of the Wide Range Assessment of Memory and Learning were administered to offspring. The results showed that offspring with ongoing social phobia demonstrated reduced visual but not verbal memory scores compared to those without social phobia when controlling for offspring IQ, separation anxiety disorder, and generalized anxiety disorder. No other offspring anxiety disorder predicted memory performance. Neither parental PD nor parental MDD was associated with offspring memory performance. These findings are relevant to understanding the phenomenology of childhood anxiety disorders and may provide insights into the neural circuits underlying these disorders.     

Parental depression: animal models of an adverse life event

OBJECTIVE: This article reviews findings in preclinical research on the adverse impact of parental depression on the development of offspring, with emphasis on the relevance of this research for the psychiatric care of depressed parents. METHOD: The authors reviewed literature from the last 40 years reporting laboratory animal studies pertaining to the persistent effects of parental stress and parenting deficits on neurobehavioral and neurobiological development in offspring. RESULTS: Animal studies indicate that disrupted parenting produces a persistent, deleterious biobehavioral impact on offspring. Stressors, including maternal separation, variable foraging, and a variety of prenatal maternal challenges, produce offspring behaviors reminiscent of the cardinal features of anxiety and affective disorders. The stress paradigms also uniformly produce persistent hyperresponsivity in hypothalamic-pituitary-adrenal axis activity secondary to hypersecretion of corticotropin-releasing hormone. These findings bear striking similarities to findings for stress-related illnesses in humans, including major depression. CONCLUSIONS: Data from research on animal parenting reinforce the idea that parental mental illness may pose the first adverse life event for a child. A thorough risk-benefit assessment for the psychiatric care of parents of young children must consider the impact on the infant of exposure both to treatment and to parental illness. Preclinical data regarding the risk to offspring posed by untreated parental mental illness should be incorporated into clinical decision making in the treatment of parents with mental illness.     

Does major depressive disorder in parents predict specific fears and phobias in offspring?

Evidence suggests a relationship between parental depression and phobias in offspring as well as links between childhood fears and risk for major depression. This study examines the relationship between major depressive disorder (MDD) and anxiety disorders in parents and specific fears and phobias in offspring. Three hundred and eighteen children of parents with lifetime MDD, anxiety disorder, MDD+anxiety disorder, or neither were psychiatrically assessed via parent interview. Rates of specific phobias in offspring did not differ significantly across parental groups. Specific fears were significantly elevated in offspring of parents with MDD+anxiety disorder relative to the other groups (MDD, anxiety disorder, and controls, which did not differ). We failed to find increased phobias in offspring of parents with MDD without anxiety disorder. Elevated rates of specific fears in offspring of parents with MDD+anxiety disorder may be a function of more severe parental psychopathology, increased genetic loading, or unmeasured environmental influences.     

Maladaptative parenting and the association between parental and offspring psychiatric disorders

A longitudinal study was conducted to investigate the role of maladaptive parental behavior and the association between parent and offspring psychiatric disorders. Psychosocial and psychiatric interviews were carried out in a representative community sample of 593 biological parents and their offspring from two counties in the state of New York in 1975, 1983, 1985-86, and 1991-93. In 1975, the mean age of offspring was 6 years. Maladaptive parental behavior was assessed in 1975, 1983, and 1985-86. Parent and offspring psychiatric symptoms were assessed in 1983, 1985-86, and 1991-93. Maladaptive parental behavior substantially mediated a significant association between parental and offspring psychiatric symptoms. Parents with psychiatric disorders had higher levels of maladaptive behavior in the household than did parents without psychiatric disorders. Maladaptive parental behavior, in turn, was associated with increased offspring risk for psychiatric disorders during adolescence and early adulthood. Most of the youths that experienced high levels of maladaptive parental behavior during childhood had psychiatric disorders during adolescence or early adulthood, independent of whether or not their parents had psychiatric disorders. In contrast, the offspring of parents with psychiatric disorders were not at increased risk for psychiatric disorders unless there was a history of maladaptive parental behavior. Maladaptive parental behavior is associated with increased risk for the development of psychiatric disorders among the offspring of parents with and without psychiatric disorders. Maladaptive parental behavior appears to be an important mediator of the association between parental and offspring psychiatric symptoms.     

Incidence of psychiatric disorder in offspring at high and low risk for depression.

First onsets (incidence) of suicide attempts and DSM-III psychiatric disorders, including major depression, any anxiety disorder, conduct disorder, or substance abuse were determined in a 2-year longitudinal study of 174 offspring at high and low risk for major depression. All of the suicide attempts, the first onsets of major depression, and anxiety disorders were in offspring of depressed parents. Compared with asymptomatic offspring, offspring with subclinical manifestations of major depression, conduct disorder, and substance abuse at the initial interview were significantly more likely to become incident cases of the same disorder over the next 2 years. Either conduct disorder or substance abuse at initial interview were highly predictive of first onset of each other, but not of any other disorders 2 years later. Family risk factors (such as poor marital adjustment, parent-child discord, low cohesion, and affectionless control) at initial interview were associated with increased incidence of substance abuse, or conduct disorder, but not major depression or anxiety disorder. Combining both retrospective and prospective data, the overall suicide attempt rate was 7.8% in the offspring of depressed parents as compared with 1.4% in the offspring of nondepressed parents. By age 20, over 50% of the offspring of depressed patients reported a major depression.     

Association of maladaptive parental behavior with psychiatric disorder among parents and their offspring

BACKGROUND: A longitudinal study was conducted to investigate the role of maladaptive parental behavior in the association between parent and offspring psychiatric disorder. METHODS: Psychosocial and psychiatric interviews were administered to a representative community sample of 593 biological parents and their offspring from 2 counties in the state of New York in 1975, 1983, 1985 to 1986, and 1991 to 1993. In 1975, the offspring were a mean age of 6 years. Maladaptive parental behavior was assessed in 1975, 1983, and 1985 to 1986. Parent and offspring psychiatric symptoms were assessed in 1983, 1985 to 1986, and 1991 to 1993. RESULTS: Maladaptive parental behavior substantially mediated a significant association between parental and offspring psychiatric symptoms. Parents with psychiatric disorders had higher levels of maladaptive behavior in the household than did parents without psychiatric disorders. Maladaptive parental behavior, in turn, was associated with increased offspring risk for psychiatric disorders during adolescence and early adulthood. Most of the youths that experienced high levels of maladaptive parental behavior during childhood had psychiatric disorders during adolescence or early adulthood, whether or not their parents had psychiatric disorders. In contrast, the offspring of parents with psychiatric disorders were not at increased risk for psychiatric disorders unless there was a history of maladaptive parental behavior. CONCLUSIONS: Maladaptive parental behavior is associated with increased risk for the development of psychiatric disorders among the offspring of parents with and without psychiatric disorders. Maladaptive parental behavior appears to be an important mediator of the association between parental and offspring psychiatric symptoms.     

The course of major depression in the offspring of depressed parents. Incidence, recurrence, and recovery.

The 2-year course, first onset (incidence), recurrence, and recovery of major depression in 174 offspring at high and low risk for major depression were studied. A variety of predictors of course were examined, including parental diagnosis, demographic and clinical characteristics of the family and offspring, comorbidity and social functioning in offspring, and family risk factors. The 2-year incidence rate was 8.5%. All of the incident cases of major depression occurred in offspring of depressed parents. Additional predictors of incidence were a preceding diagnosis of conduct disorder and subclinical symptoms of depression. The recurrence rate results are tentative because of the small sample. The 2-year recurrence rate was 16.1%. Predictors of recurrence were a previous comorbid diagnosis of dysthymia or problems in social functioning. By the end of 2 years, the majority of offspring (87%) had recovered. The mean number of weeks to recovery was 54 in the offspring of depressed parents and 23 in the offspring of nondepressed parents. Offspring with an onset of major depression at age 13 years or younger, who were exposed to divorce in the family or who had been exposed to more than one parental depressive episode, had significantly more protracted times to recovery. We conclude that there are different predictors of incidence of major depression, its recurrence, and time to recovery in offspring, and that parental depression has an impact on the course in offspring.     

Psychopathology in offspring from multiplex alcohol dependence families with and without parental alcohol dependence: a prospective study during childhood and adolescence

Multiplex families ascertained through multiple alcohol dependent individuals appear to transmit alcohol and drug use disorders at higher rates than randomly selected families of alcoholics. Our goal was to investigate the risk of developing specific psychiatric diagnoses during childhood or adolescence in association with familial risk status (high-risk [HR] or low-risk [LR]) and parental diagnosis. Using a prospective longitudinal design, HR offspring from three generation multiplex alcohol dependence families and LR control families were followed yearly. Data analysis was based on consensus diagnoses from 1738 yearly evaluations conducted with the offspring and a parent using the K-SADS, and separately modeled the effects of familial susceptibility and exposure to parental alcohol dependence. Multiplex family membership and parental alcohol and drug dependence significantly increased the odds that offspring would experience some form of psychopathology during childhood or adolescence, particularly externalizing disorders. Additionally, parental alcohol dependence increased the odds that adolescent offspring would have major depressive disorder (MDD). While it is well known that parental substance dependence is associated with externalizing psychopathology, the increased risk for MDD seen during adolescence in the present study suggests the need for greater vigilance of these children.     

Developmental trajectories of anxiety disorders in offspring at high risk for panic disorder and major depression

The objective of this study was to evaluate the longitudinal course of psychiatric disorders in children of parents with and without panic disorder and major depression as they transition through the period of risk from early to late childhood. Over a 5-year follow-up, we compared the course of psychiatric disorders in offspring of parents with panic disorder, major depression, or neither disorder. Subjects consisted of 233 offspring (from 151 families) with baseline and follow-up assessments. Subjects were comprehensively assessed with structured diagnostic interviews. Anxiety disorders at baseline were used to predict anxiety disorders and major depression at follow-up using stepwise logistic regression. Separation anxiety disorder significantly increased the risk for the subsequent development of specific phobia, agoraphobia, panic disorder, and major depression, even after parental panic and depression were covaried. Agoraphobia significantly increased the risk for subsequent generalized anxiety disorder. These findings suggest that separation anxiety disorder is a major antecedent disorder for the development of panic disorder and a wide range of other psychopathological outcomes, and that it increases the risk for subsequent psychopathology even among children already at high familial risk for anxiety or mood disorder.