Psychopathology in the offspring of parents with bipolar disorder: a controlled study.

BACKGROUND: To examine the risk for psychopathology in offspring at risk for bipolar disorder and the course of psychiatric disorders in these youth. METHODS: Using structured diagnostic interviews (Structured Clinical Interview for DSM-IV [SCID] and Kiddie Schedule for Affective Disorders and Schizophrenia [K-SADS]), psychiatric diagnoses of 117 nonreferred offspring of parents with diagnosed bipolar disorder were compared with those of 171 age- and gender-matched offspring of parents without bipolar disorder or major depression. RESULTS: Compared with offspring of parents without mood disorders, high-risk youth had elevated rates of major depression and bipolar disorder, anxiety, and disruptive behavior disorders. High-risk offspring also had significantly more impaired Global Assessment of Functioning (GAF) scores, higher rates of psychiatric treatment, and higher rates of placement in special education classes. Disruptive behavior disorders, separation anxiety disorder, generalized anxiety disorder (GAD), social phobia, and depression tended to have their onset in early or middle childhood, whereas bipolar disorder, obsessive-compulsive disorder (OCD), panic disorder, and substance use disorder had onset most frequently in adolescence. CONCLUSIONS: These findings support the hypothesis that offspring of parents with bipolar disorder are at significantly increased risk for developing a wide range of severe psychiatric disorders and accompanying dysfunction. Early disruptive behavior and anxiety disorders, as well as early-onset depression, may be useful markers of risk for subsequent bipolar disorder in high-risk samples.     

Patterns of psychopathology and dysfunction in high-risk children of parents with panic disorder and major depression

OBJECTIVE: The purpose of the study was to evaluate 1) whether an underlying familial predisposition is shared by all anxiety disorders or whether specific risks are associated with specific disorders, and 2) whether panic disorder and major depression have a familial link. METHOD: The study compared four groups of children: 1) offspring of parents with panic disorder and comorbid major depression (N=179), 2) offspring of parents with panic disorder without comorbid major depression (N=29), 3) offspring of parents with major depression without comorbid panic disorder (N=59), and 4) offspring of parents with neither panic disorder nor major depression (N=113). RESULTS: Parental panic disorder, regardless of comorbidity with major depression, was associated with an increased risk for panic disorder and agoraphobia in offspring. Parental major depression, regardless of comorbidity with panic disorder, was associated with increased risks for social phobia, major depression, disruptive behavior disorders, and poorer social functioning in offspring. Both parental panic disorder and parental major depression, individually or comorbidly, were associated with increased risk for separation anxiety disorder and multiple (two or more) anxiety disorders in offspring. CONCLUSIONS: These findings confirm and extend previous results documenting significant associations between the presence of panic disorder and major depression in parents and patterns of psychopathology and dysfunction in their offspring.     

The child behavior checklist broad-band scales predict subsequent psychopathology: A 5-year follow-up

OBJECTIVE: To evaluate the utility of the Child Behavior Check list (CBCL) for identifying children of parents with panic disorder or major depression at high-risk for future psychopathology. METHODS: Baseline Internalizing and Externalizing CBCL T-scores were used to predict subsequent depressive, anxiety, and disruptive behavior disorders at a 5-year follow-up in children of parents with panic disorder, major depression, or neither disorder. RESULTS: The Internalizing scale predicted subsequent agoraphobia, generalized anxiety disorder, separation anxiety disorder, and social phobia. In contrast, the Externalizing scale predicted subsequent disruptive behavior disorders and major depression. CONCLUSIONS: The convergence of these results with previous findings based on structured diagnostic interviews suggests that the CBCL broad-band scales can inexpensively and efficiently help identify children at high risk for future psychopathology within a population of children already at risk by virtue of parental psychopathology.     

Psychopathology in the young offspring of parents with bipolar disorder: a controlled pilot study

Studies have suggested that the offspring of parents with bipolar disorder are at risk for a spectrum of psychopathology, but few have focused on children in the youngest age ranges or examined the impact of comorbid parental disorders. We utilized a pre-existing sample of young (mean age: 6.8 years) offspring of parents with bipolar disorder (n=34), of parents with panic or major depression (n=179), and of parents with neither mood or anxiety disorder (n=95). Children were assessed blindly to parental diagnoses using the Schedule for Affective Disorders and Schizophrenia-Epidemiologic version (K-SADS-E). Offspring of bipolar parents had significantly higher rates of disruptive behavior and anxiety disorders than offspring from both of the comparison groups, accounted for by elevated rates of ADHD and overanxious disorder. These comparisons were significant even when lifetime histories of the corresponding categories of comorbid disorders in the parents (disruptive behavior disorders and anxiety disorders) were covaried. In addition, offspring of bipolar parents had increased rates of bipolar I disorder, compared with psychiatric controls. Results support the hypotheses of elevated behavior, anxiety, and mood disorders among offspring at risk for bipolar disorder, and suggest that this psychopathology is already evident in early childhood.     

Lack of association between behavioral inhibition and psychosocial adversity factors in children at risk for anxiety disorders

OBJECTIVE: In a previous controlled study of offspring at risk for anxiety disorders, the authors found that parental panic disorder with comorbid major depression was associated with child behavioral inhibition, the temperamental tendency to be quiet and restrained in unfamiliar situations. To explore whether this association was mediated by environmental factors, the authors examined associations between psychosocial adversity variables and behavioral inhibition in this group of children. METHOD: Subjects included 200 offspring of parents with panic disorder and/or major depression and 84 comparison children of parents without mood or anxiety disorders. Behavioral inhibition was assessed through laboratory observations. The associations between behavioral inhibition and the following psychosocial factors were examined: socioeconomic status; an index of adversity factors found in previous studies to be additively associated with child psychopathology; family intactness, conflict, expressiveness, and cohesiveness; exposure to parental psychopathology; sibship size; birth order; and gender. RESULTS: The results showed no associations between behavioral inhibition and any of the psychosocial factors in the study group as a whole, despite adequate power to detect medium effect sizes. Among low-risk comparison children only, some definitions of behavioral inhibition were associated with low socioeconomic status, low family cohesion, and female gender. CONCLUSIONS: The results suggest that the psychosocial adversity factors examined in this study do not explain the previous finding that offspring of parents with panic disorder are at high risk for behavioral inhibition.     

Depression and anxiety disorders in parents and children. Results from the Yale family study

The children (aged 6 to 17 years) of probands with primary major depression, with and without various anxiety disorders, were compared with the children of a matched normal control group. The results from the study of these young children parallel our previous findings among the adult first-degree relatives of these probands. Depression in the proband increased the risk of depression in the children. Depression plus panic disorder or agoraphobia in the proband conferred an additional risk of depression and of an anxiety disorder in the children. Panic disorder in the parents conferred more than a threefold increased risk of separation anxiety in the children. Other factors that increased the risk to children were degree of familial loading for psychiatric illness, parental assortative mating, and parental recurrent depression. The findings suggest a relationship between depression and some of the anxiety disorders, and between adult panic disorder and agoraphobia and transmission of anxiety disorders to children.     

A controlled study of behavioral inhibition in children of parents with panic disorder and depression

OBJECTIVE: "Behavioral inhibition to the unfamiliar" has been proposed as a precursor to anxiety disorders. Children with behavioral inhibition are cautious, quiet, introverted, and shy in unfamiliar situations. Several lines of evidence suggest that behavioral inhibition is an index of anxiety proneness. The authors sought to replicate prior findings and examine the specificity of the association between behavioral inhibition and anxiety. METHOD: Laboratory-based behavioral observations were used to assess behavioral inhibition in 129 young children of parents with panic disorder and major depression, 22 children of parents with panic disorder without major depression, 49 children of parents with major depression without panic disorder, and 84 children of parents without anxiety disorders or major depression (comparison group). A standard definition of behavioral inhibition based on previous research ("dichotomous behavioral inhibition") was compared with two other definitions. RESULTS: Dichotomous behavioral inhibition was most frequent among the children of parents with panic disorder plus major depression (29% versus 12% in comparison subjects). For all definitions, the univariate effects of parental major depression were significant (conferring a twofold risk for behavioral inhibition), and for most definitions the effects of parental panic disorder conferred a twofold risk as well. CONCLUSIONS: These results suggest that the comorbidity of panic disorder and major depression accounts for much of the observed familial link between parental panic disorder and childhood behavioral inhibition. Further work is needed to elucidate the role of parental major depression in conferring risk for behavioral inhibition in children.     

Response to 5% carbon dioxide in children and adolescents: relationship to panic disorder in parents and anxiety disorders in subjects

BACKGROUND: Carbon dioxide (CO(2)) sensitivity is postulated to be a familial risk marker of panic disorder (PD). Exaggerated responses to CO(2) inhalation have been reported in adults with PD and their unaffected adult relatives, as well as in clinic-referred children with anxiety disorders. OBJECTIVE: To test in a family-based design whether CO(2) hypersensitivity is a familial risk marker for PD and associated with current anxiety disorders in children and adolescents. SETTING AND PARTICIPANTS: One hundred forty-two offspring (aged 9-19 years) of parents with PD, major depressive disorder, or no disorder. Forty-five (32%) had a current anxiety disorder, excluding specific phobia. DESIGN AND MAIN OUTCOME MEASURES: Parents and offspring received diagnostic assessments. Offspring underwent 5% CO(2) inhalation at home. Panic symptoms and panic attacks were rated with the Acute Panic Inventory at baseline, while anticipating CO(2) delivery ("threat"), and during CO(2) inhalation. Respiratory rate and volume were measured with spirometry. RESULTS: No group differences were found in Acute Panic Inventory ratings at baseline or in respiratory measures during threat. Risk for PD was not associated with CO(2) sensitivity (panic symptoms and respiratory physiologic response). During CO(2) inhalation, offspring with anxiety disorders, relative to offspring without anxiety disorders, experienced significantly more panic symptoms and panic attacks, as well as elevated respiratory rates. During threat, panic symptoms were significantly and independently associated with both parental PD and offspring anxiety disorders. CONCLUSIONS: No support was obtained for CO(2) hypersensitivity as a familial risk marker for PD in children and adolescents. Links between childhood anxiety disorders and CO(2) sensitivity were replicated. Familial risk for PD in children and adolescents may be associated with vulnerability to anticipatory anxiety.     

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.     

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.     

Further evidence of association between behavioral inhibition and social anxiety in children

OBJECTIVE: The authors sought to examine psychopathological correlates of behavioral inhibition in young offspring of parents with panic disorder and/or major depression. METHOD: Behavioral inhibition, determined by using standard laboratory observations, was assessed in four groups of children (age 2-6 years): 129 children of parents with both panic disorder and major depression, 22 children of parents with panic disorder alone, 49 children of parents with major depression alone, and 84 comparison children of parents with neither panic disorder nor major depression. Psychopathology in children > or =5 years was compared between children with behavioral inhibition (N=64) and without (N=152). RESULTS: Social anxiety disorder (social phobia or avoidant disorder) was significantly more likely to be found in the children with behavioral inhibition (17%) than in those without (5%). Noninhibited children were significantly more likely than inhibited children to have disruptive behavior disorders (20% versus 6%, respectively) and had higher scores on the attention problems scale of the Child Behavior Checklist (mean=52.1 versus 50.8). CONCLUSIONS: This study adds to the growing literature suggesting an association between behavioral inhibition and social anxiety disorder and an inverse relationship between inhibition and disruptive behavior disorders.     

Psychiatric correlates of behavioral inhibition in young children of parents with and without psychiatric disorders

Behavioral inhibition is a laboratory-based temperamental category by the tendency to constrict behavior in unfamiliar situations and assumed to reflect low thresholds of limbic arousal. We previously found behavioral inhibition prevalent in the offspring of parents with panic disorder and agoraphobia. In this report, we examined the psychiatric correlates of behavioral inhibition by evaluating the sample of offspring of parents with panic disorder and agoraphobia, previously dichotomized as inhibited and not inhibited, and an existing epidemiologically derived sample of children, followed by Kagan and colleagues and originally identified at 21 months of age as inhibited or uninhibited. A third group of healthy children was added for comparison. Our findings indicate that inhibited children had increased risk for multiple anxiety, overanxious, and phobic disorders. It is suggested that behavioral inhibition may be associated with risk for anxiety disorders in children.     

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.     

Parental predictors of pediatric panic disorder/agoraphobia: a controlled study in high-risk offspring

Our objective was to evaluate parental risk factors for pediatric-onset panic disorder/agoraphobia (PD/AG) in offspring at high risk for PD/AG. Comparisons were made between parents with PD who had a child with PD or AG (N = 27) and parents with PD without children with PD or AG (N = 79). Comparisons were also made between the spouses of these parents with PD. Separation anxiety disorder, social phobia, obsessive-compulsive disorder, and bipolar disorder in the parents with PD and their spouses accounted for the risk for childhood onset PD/AG in the offspring. This risk was particularly high if both parents were affected with social phobia. These findings suggest that psychiatric comorbidity with other anxiety disorders and with bipolar disorder in parents with PD and their spouses confer a particularly high risk in their offspring to develop PD/AG in childhood.     

Clinical outcomes of laboratory-observed preschool behavioral disinhibition at five-year follow-up.

BACKGROUND: Behavioral disinhibition refers to a temperamental tendency to exhibit boldness, approach, and spontaneity in unfamiliar situations. We previously found it to be associated with childhood disruptive behavior and mood disorders, as well as with parental bipolar disorder. In the present study, our objective was to examine the diagnostic outcome in middle childhood of behavioral disinhibition assessed at preschool age among offspring at risk for anxiety and mood disorders. METHODS: The sample consisted of 284 children, including offspring of parents with panic disorder or major depression and comparison offspring of parents without these disorders, who had been assessed with laboratory observations of temperament at ages 21 months to 6 years. We reassessed 215 of the children (77%) at 5-year follow-up (mean age 9.6 years) with structured diagnostic interviews. RESULTS: Compared with noninhibited, nondisinhibited control subjects, behaviorally disinhibited children had higher lifetime rates of comorbid mood plus disruptive behavior disorders and higher current rates of any disruptive behavior disorder and of oppositional defiant disorder. CONCLUSIONS: Behavioral disinhibition appears to be a temperamental antecedent of disruptive behavior disorders and their comorbidity with mood disorders in middle childhood, which may be targeted for preventive intervention.     

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.     

Attention deficit disorder in children at risk for anxiety and depression

The comorbidity between attention deficit disorder (ADD) and anxiety and/or depressive disorders was examined in the children of parents with panic disorder, major depressive disorder, or with no diagnosis. A child received a diagnosis by a self-report, parent report, and by consensus, using a best estimate procedure. The prevalence rates of ADD were significantly greater in offspring of parents with depressive and panic disorder by the parents' report and in children of depressed parents by consensus. A significant relationship between ADD and anxiety and/or depression was found for parent, child, and consensus diagnoses. Higher rates of ADD were reported by children (1% versus 13%), parents (8% versus 31%), and in the consensus diagnoses (13% versus 29%) when anxiety and/or depression was present. These results suggest that in children referred for evaluation of ADD, the possibility of a primary anxiety or depressive disorder should be considered.     

Influence of psychiatric comorbidity on recovery and recurrence in generalized anxiety disorder, social phobia, and panic disorder: a 12-year prospective study

OBJECTIVE: The authors sought to observe the long-term clinical course of anxiety disorders over 12 years and to examine the influence of comorbid psychiatric disorders on recovery from or recurrence of panic disorder, generalized anxiety disorder, and social phobia. METHOD: Data were drawn from the Harvard/Brown Anxiety Disorders Research Program, a prospective, naturalistic, longitudinal, multicenter study of adults with a current or past history of anxiety disorders. Probabilities of recovery and recurrence were calculated by using standard survival analysis methods. Proportional hazards regression analyses with time-varying covariates were conducted to determine risk ratios for possible comorbid psychiatric predictors of recovery and recurrence. RESULTS: Survival analyses revealed an overall chronic course for the majority of the anxiety disorders. Social phobia had the smallest probability of recovery after 12 years of follow-up. Moreover, patients who had prospectively observed recovery from their intake anxiety disorder had a high probability of recurrence over the follow-up period. The overall clinical course was worsened by several comorbid psychiatric conditions, including major depression and alcohol and other substance use disorders, and by comorbidity of generalized anxiety disorder and panic disorder with agoraphobia. CONCLUSIONS: These data depict the anxiety disorders as insidious, with a chronic clinical course, low rates of recovery, and relatively high probabilities of recurrence. The presence of particular comorbid psychiatric disorders significantly lowered the likelihood of recovery from anxiety disorders and increased the likelihood of their recurrence. The findings add to the understanding of the nosology and treatment of these disorders.     

Assortative mating and affective disorders: psychopathology in offspring

Familial aggregation has been frequently observed among probands with depression, anxiety disorders, and alcoholism (Gershon et al. 1976; Goodwin et al. 1973; Crowe et al. 1983). Because of the familial nature of these disorders, offspring of such probands have been identified to be at high risk for developing these illnesses themselves (Tarter 1983). Information regarding such risk has come from several sources: retrospective studies of patients with psychiatric disorders; studies of children whose parents are being treated for these disorders; and longitudinal follow-up studies of children with symptoms of the disorder.     

Pregnancy complications associated with childhood anxiety disorders

To determine whether perinatal complications predict childhood anxiety disorders independently of parental psychopathology, we systematically assessed pregnancy and delivery complications and psychopathology in a sample of children (mean age=6.8 years) at high risk for anxiety disorders whose parents had panic disorder with (n=138) or without (n=26) major depression, and in contrast groups of offspring of parents with major depression alone (n=47), or no mood or anxiety disorders (n=95; total N=306). Psychopathology in the children was assessed by structured diagnostic interviews (K-SADS), and pregnancy and delivery complications were assessed using the developmental history module of the DICA-P. Number of pregnancy complications predicted multiple childhood anxiety disorders independently of parental diagnosis (odds ratio=1.6 [1.4-2.0]). This effect was accounted for by heavy bleeding requiring bed-rest, hypertension, illness requiring medical attention, and serious family problems. Associations remained significant when lifetime child mood and disruptive behavior disorders were covaried. Results suggest that prenatal stressors may increase a child's risk for anxiety disorders beyond the risk conferred by parental psychopathology alone.