Daytime cortisol and stress reactivity in the offspring of parents with bipolar disorder

The hypothalamic-pituitary-adrenal (HPA) axis is compromised in major depression and bipolar disorder (BD). It is not known however whether HPA abnormalities predate the onset of these disorders. Preliminary data indicated that the adolescent offspring of parents with BD (high-risk), as compared to adolescents of parents with no mental disorder (low-risk), had higher levels of daytime salivary cortisol. The present study re-examined the cortisol increase after awakening and basal cortisol levels in a larger sample, and tested the hypothesis that high-risk offspring are more reactive to psychosocial stress than low-risk offspring. Saliva samples were collected from 58 adolescents, 29 high-risk (14 male/15 female, 16.8 years) and 29 (14 male/15 female, 16.6 years) low-risk, in their natural environment during at least two days. Twenty-five high-risk (13 male/12 female) and 25 low-risk (13 male/12 female) youth completed a child adaptation (15 years) or the standard version of the “Trier Social Stress Test”. Consistent with our previous finding, high-risk offspring had higher daytime levels of cortisol in their natural environment than low-risk offspring, and the difference was unrelated to clinical symptoms or other known confounds. Irrespective of risk status, female participants had higher daytime levels of cortisol than male participants. In contrast, there were no group differences in the cortisol response to the laboratory psychosocial stressor. The offspring of parents with BD show evidence of increased daytime basal HPA functioning with normal reactivity to psychosocial stress.     

High cortisol levels in the offspring of parents with bipolar disorder during two weeks of daily sampling

Ellenbogen MA, Santo JB, Linnen A‐M, Walker C‐D, Hodgins S. High cortisol levels in the offspring of parents with bipolar disorder during two weeks of daily sampling.
Bipolar Disord 2010: 12: 77–86. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives: The hypothalamic‐pituitary‐adrenal (HPA) axis is compromised in major depression, bipolar disorder (BD), and in the offspring of parents with major depression. Less is known about the offspring of parents with BD (FH+). The present project provides follow‐up to a previous study showing that the adolescent (mean age 16.7 years) FH+ offspring had higher salivary cortisol levels than the offspring of parents with no mental disorder (FH?) throughout the day in their natural environment, and that girls had higher cortisol levels than boys (Ellenbogen MA, Hodgins S, Walker C‐D, Adam S, Couture S. Daytime cortisol and stress reactivity in the offspring of parents with bipolar disorder. Psychoneuroendocrinology 2006; 31: 1164–1180). The goal of the present study was to determine whether FH+ offspring, approximately two years later, continued to exhibit elevated cortisol levels relative to FH? offspring during two weeks of daily sampling. Methods: The present study examined salivary cortisol levels in 24 (18.3 ± 2.6 years) FH+ and 22 (18.0 ± 2.3 years) FH? offspring who are part of the same longitudinal cohort as the previous study. Saliva was collected at 1300h and 1500h in the natural environment of the offspring during 14 consecutive days. Results: Multilevel modelling analyses indicated that FH+ offspring had higher afternoon levels of cortisol in their natural environment than FH? offspring, but group differences in slope and gender differences were not found. Conclusions: The FH+ offspring exhibited increased daytime secretion of cortisol that, at the level of the group, persisted into late adolescence and young adulthood. Perhaps this change in HPA functioning is associated with an increased vulnerability for the development of an affective disorder.     

Co-occurring manic symptomatology influences HPA axis alterations in depression

Although dysfunctioning of the HPA axis is considered to be a core pathophysiological process in mood disorders, the evidence with regard to depression remains conflicting. This could partly be due to the large heterogeneity within mood disorders, since HPA axis abnormalities may also be associated with the extent of co-occurring manic symptomatology as is seen in bipolar disorder. In this study, patients with depressive disorder and bipolar spectrum disorders were studied with regard to their HPA axis functioning. In 304 healthy controls, 1134 patients with pure unipolar depressive disorder (UP), and 133 bipolar spectrum disorder patients (BD spectrum), cortisol was measured in 7 saliva samples to determine the 1 h cortisol awakening response (CAR), evening cortisol levels and cortisol suppression after a 0.5 mg dexamethasone suppression test. Both patient groups had overall higher CAR levels compared to controls, but only UP patients showed a higher increase over time in the CAR. A linear association was found between increasing bipolarity and cortisol diurnal slope: BD spectrum patients had a significantly higher diurnal slope than UP patients. Dexamethasone suppression did not differ between mood disorder diagnoses. The heterogeneity in HPA axis functioning in patients with depression can partially be explained by co-existing manic symptomatology, since an increase in the CAR appears to be more specific for pure depression whereas the presence of bipolarity is associated with an increase in the diurnal slope of cortisol.     

Psychiatric phenomenology of child and adolescent bipolar offspring

OBJECTIVE: To establish prodromal signs of and risk factors for childhood bipolar disorder (BD) by characterizing youths at high risk for BD. METHOD: Structured diagnostic interviews were performed on 60 biological offspring of at least one parent with BD. Demographics, family histories, and parental history of childhood disruptive behavioral disorders were also assessed. RESULTS: Fifty-one percent of bipolar offspring had a psychiatric disorder, most commonly attention-deficit/hyperactivity disorder (ADHD), major depression or dysthymia, and BD. BD in offspring tended to be associated with earlier parental symptom onset when compared with offspring without a psychiatric diagnosis. Bipolar parents with a history of childhood ADHD were more likely to have children with BD, but not ADHD. Offspring with bilineal risk had increased severity of depressed and irritable mood, lack of mood reactivity, and rejection sensitivity, while severity of grandiosity, euphoric mood, and decreased need for sleep were not preferentially associated with such offspring. CONCLUSIONS: Bipolar offspring have high levels of psychopathology. Parental history of early-onset BD and/or childhood ADHD may increase the risk that their offspring will develop BD. Prodromal symptoms of childhood BD may include more subtle presentations of mood regulation difficulties and less presence of classic manic symptoms.     

Salivary cortisol secretion in remitted bipolar patients and offspring of bipolar parents

OBJECTIVES: It is generally believed that cortisol secretion normalizes during clinical remission in mood disorders. However, this assumption has been challenged by preliminary reports of enhanced cortisol secretion in remitted bipolar patients and in the offspring of bipolar parents. The purpose of this study is to replicate findings of increased cortisol secretion during clinical remission in bipolar patients and in the offspring of bipolar parents, rigorously controlling for known confounders. METHODS: We conducted intensive cortisol sampling (six samples per day for three test days, on three consecutive weekends) on 15 bipolar type I and type II patients and 28 unrelated offspring of bipolar parents. Offspring had a history of unipolar depression. Participation was restricted to cases in complete sustained remission. Controls were matched as closely as possible for age, sex, and education. Mood and sleep measures were recorded on each sampling day. RESULTS: In total, 743 samples were collected from the patient group and 576 from controls. Correcting for repeat measures, there was no statistically significant difference in cortisol secretion at any sampling time between remitted bipolar patients, remitted offspring of bipolar parents, and normal controls. The cortisol waking response did not differ between patients and controls. Covariates, including sex, age, Beck depression score and hours of sleep, were not statistically significant. CONCLUSIONS: Our observations are consistent with the view that complete sustained clinical remission is associated with normal salivary cortisol levels throughout the day. A personal or family history of bipolar disorder per se does not appear to confer added risk for increased salivary cortisol secretion during sustained clinical remission.     

Stress responsivity and HPA axis activity in juveniles: results from a home-based CO2 inhalation study

OBJECTIVE: A previous laboratory-based study found elevated cortisol levels in anxious children susceptible to CO(2)-induced panic, but the effects of parent diagnosis were not considered. The current home-based study tested the hypothesis that parental panic disorder and offspring response to CO(2) are associated with elevated cortisol levels in juvenile offspring. METHOD: A total of 131 offspring (ages 9-19) of parents with panic disorder, major depression, and no mental disorder underwent CO(2) inhalation. Parent and child diagnoses were assessed. Salivary cortisol was assayed before and after CO(2) inhalation. RESULTS: Neither parents with panic disorder, parents with major depression, or offspring anxiety predicted offspring cortisol levels. Independent of parent and child diagnoses, anxiety response to CO(2) predicted elevated cortisol levels in offspring. CONCLUSIONS: As in adults, anxiety response to CO(2) in juveniles is associated with elevated cortisol levels, but elevated cortisol levels are not related to parent or child diagnoses.     

Associations between HPA axis functioning and level of anxiety in children and adolescents with an anxiety disorder

The hypothalamus-pituitary-adrenal (HPA) axis becomes active in response to stress. Hence, increased levels of anxiety in children and adolescents may be associated with changes in HPA-axis functioning. The aim of this study was to test if level of anxiety or specific anxiety disorders were associated with basal HPA axis activity in children and adolescents with an anxiety disorder. In 99 8- to 16-year-olds with an anxiety disorder, basal cortisol levels were assessed. It was tested if (1) cortisol levels correlated with the level of self-reported anxiety and (2) if cortisol levels were different for individuals with different anxiety disorders. In girls, low levels of anxiety were associated with a stronger rise in early morning cortisol concentrations. In both boys and girls, harm avoidance predicted low cortisol concentrations after awakening. Separation anxiety and physical anxiety symptoms predicted cortisol concentrations at noon. Differences between individuals with different anxiety disorders were not found. More research is needed regarding mechanisms that explain the associations that were found, and to investigate if treatment may influence HPA axis functioning in children and adolescents with an anxiety disorder.     

The cortisol awakening response in bipolar illness: a pilot study.

OBJECTIVE: A growing body of data suggests that a significantly enhanced salivary cortisol response to waking may indicate an enduring tendency to abnormal cortisol regulation. Our objective was to apply the response test to a population already known to have long-term hypothalamo-pituitary-adrenocortical (HPA) axis dysregulation. We hypothesized that the free cortisol response to waking, believed to be genetically influenced, would be elevated in a significant percentage of cases, regardless of the afternoon Dexamethasone Suppression Test (DST) value. METHOD: Using the free cortisol response to waking and the short daytime profile, we tested 18 clinically stable, lithium-responsive subjects from our long-term naturalistic follow-up of monthly DSTs. These tests include salivary testing every 15 minutes during the first hour of waking, followed by samples taken at 3:00 PM and 8:00 PM. RESULTS: While clinically stable on lithium prophylaxis, patients with bipolar disorder (BD) showed a significantly enhanced salivary cortisol response to waking, compared with control subjects (P < 0.03). Cortisol levels 30 minutes after waking significantly exceeded those in the large normative data provided in the literature (P < 0.001). CONCLUSIONS: Our observations support the hypothesis that the free cortisol response to waking can reflect relatively enduring HPA dysregulation, even when lithium-responsive BD patients are clinically well and their DSTs are normal. Because the test is easy to administer, the free cortisol response to waking may hold promise as a marker in studies of high-risk families predisposed to, or at risk for, mood disorders.     

Five-year prospective outcome of psychopathology in the adolescent offspring of bipolar parents

OBJECTIVE: For nearly 5 years a prospective high risk cohort study was carried out in the Netherlands among adolescent offspring of parents with bipolar disorder (BD). The purpose of this study was to determine the prevalence of psychopathology, specifically mood disorders, in adolescents and young adults with a bipolar parent. METHOD: At first and second measurement 140 and 132 children of bipolar parents, respectively, were psychiatrically evaluated with a semi-structured psychiatric interview (K-SADS-PL). At follow up (third measurement), nearly 5 years later, lifetime DSM IV diagnoses were obtained from the SCID interview for 129 subjects (aged 16--26 years). RESULTS: Compared with the first measurement, the lifetime prevalence of BD increased from 3 to 10% at follow up. In addition, the lifetime prevalence of overall mood disorders increased to 40% and of overall psychopathology to 59%. All subjects except for one with BD, debuted with a unipolar mood disorder with a mean of 4.9 (SD 3.4) years prior to the first (hypo)manic episode. CONCLUSION: At follow up, we noticed an increase in BD onset, while a further increase could be expected. In addition, we found that a unipolar depression in bipolar offspring is a risk factor for, and at the same time the first sign of, the development of BD.     

The early manifestations of bipolar disorder: a longitudinal prospective study of the offspring of bipolar parents

OBJECTIVE: A major aim of this longitudinal high-risk study is to identify reliable early indicators of emerging bipolar disorder (BD) among offspring from well-characterized parents. METHODS: High-risk offspring were recruited from families in which one parent had BD diagnosed on the basis of the Schedule for Affective Disorders and Schizophrenia - Lifetime version (SADS-L) interviews and DSM-IV diagnostic criteria and the other parent was well. Bipolar parents were further subdivided on the basis of response or non-response to long-term lithium. A comparison group of offspring was recruited from well parents diagnosed on the basis of either SADS-L interviews or the family history method. All consenting offspring from high-risk and control families were assessed longitudinally with the Schedule for Affective Disorders and Schizophrenia for School-aged Children - Present and Lifetime version (KSADS-PL) interviews and DSM-IV diagnoses were made on a blind consensus review. The offspring were reassessed on average annually, as well as at any time symptoms developed. RESULTS: Antecedent conditions to BD in both high-risk groups included sleep and anxiety disorders, while attention-deficit hyperactivity disorder and pre-psychotic conditions were antecedents among the offspring of lithium non-responders only. Among those offspring developing BD, the index mood episode was almost always depressive. CONCLUSIONS: Despite a specific genetic risk, BD began with non-specific psychopathology and/or depressive disorders in a majority of offspring. Therefore, diagnosis based only on cross-sectional assessment of symptoms appears to be insufficient for the accurate early detection of emerging BD. Other parameters such as family history and associated antecedents should be taken into account.     

Cortisol response to clonidine in panic disorder: comparison with depressed patients and normal controls

Abnormalities in regulation of noradrenergic function have been proposed as part of the pathology of depressive and panic anxiety disorders. However, abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function have largely been limited to patients with depressive disorders. Using the cortisol response to clonidine, an alpha 2-adrenergic receptor agonist, this study examined the relationship between the noradrenergic system and the HPA axis in 10 patients with major depression (4 unipolar, 6 bipolar), 10 patients with panic disorder, and 10 normal controls. Baseline cortisol was significantly elevated in depressed as compared with panic patients, but not with controls. Depressed patients also tended to exhibit a greater absolute fall in plasma cortisol (5.2 +/- 4.0 micrograms/dl) compared with panic patients (1.7 +/- 2.4 micrograms/dl) (p less than 0.06, t-test). When expressed as a percentage of baseline, however, the cortisol response to clonidine did not differ significantly between diagnostic groups (p greater than 0.10). Basal levels of cortisol were highly correlated with the degree of decrease in cortisol induced by clonidine in the group of 30 subjects (r = -0.81, p less than 0.0001). These findings are discussed in the context of the utility of clonidine as a probe of the functional relatedness of the noradrenergic system and the HPA axis in these disorders.     

A pilot study of visual backward masking performance among affected versus unaffected offspring of parents with bipolar disorder

BACKGROUND: Cognitive dysfunction is evident in some euthymic patients with established bipolar disorder (BD), including deficits in visual backward masking (VBM) tasks which map to a specific neural pathway. A high-risk paradigm would clarify the temporal relation of cognitive dysfunction to clinical course. METHOD: We compared euthymic offspring (age range: 18-32 years) of lithium-responsive bipolar parents with and without a previous lifetime history of psychiatric illness to healthy comparison subjects with a negative family history, on a VBM task that requires target location. RESULTS: High-risk offspring with no lifetime psychiatric history performed the VBM task at levels of healthy controls. High-risk offspring with a previous history of a mood disorder, in complete remission, made significantly more errors at short target-mask intervals than control or never ill offspring. These higher error rates were not a consequence of faster response times. CONCLUSIONS: There is preliminary evidence of specific cognitive dysfunction early in the course of illness in affected offspring of parents with lithium responsive BD. VBM is ideal for future longitudinal studies addressing whether cognitive dysfunction in BD is a trait marker or a consequence of illness manifestation.     

Twenty-four-hour cortisol secretion patterns in prepubertal children with anxiety or depressive disorders.

BACKGROUND: Previous studies found few abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function in prepubertal children with anxiety or depressive disorders. In this study, we combined data from two independent, consecutive studies to achieve a larger sample size. Our goal was to identify potential alterations in the circadian pattern of cortisol secretion in anxious or depressed children. METHODS: A total of 124 prepubertal subjects from two independent samples (76 with major depressive disorder, 31 with anxiety disorders, and 17 healthy control subjects) were studied. Blood samples collected for cortisol at hourly intervals over a 24-hour period were examined. Analyses were performed aligning cortisol samples by clock-time. Additional analyses aligning samples by sleep-onset time were performed with a subsample of subjects. RESULTS: In the combined sample, significant findings emerged that were previously undetected. Anxious children exhibited significantly lower nighttime cortisol levels and an initially sluggish rise in cortisol during the nighttime when compared with depressed and healthy control children. In contrast, depressed children did not show a clear-cut pattern of differences compared with healthy control children. CONCLUSIONS: Anxious children seem to exhibit an altered pattern of nighttime cortisol secretion, with an initially sluggish or delayed nocturnal rise before reaching similar peak levels of cortisol near the time of awakening. These findings suggest subtle alterations in HPA axis function in prepubertal children with anxiety disorders.     

Salivary cortisol is associated with diagnosis and severity of late-life generalized anxiety disorder

Age-associated alterations in hypothalamic-pituitary-adrenal (HPA) axis functioning may make individuals more susceptible to HPA dysregulation in the context of mood and anxiety disorders. Little to no research has been done to examine HPA axis function in generalized anxiety disorder (GAD), particularly in late-life GAD, the most prevalent anxiety disorder in the elderly. The study sample consisted of 71 GAD subjects and 40 nonanxious comparison subjects over 60 years of age. We examined the hypotheses that elderly individuals with GAD will have elevated salivary cortisol levels compared to nonanxious subjects, and that elevated cortisol levels in GAD will be associated with measures of symptom severity. We report that late-life GAD is characterized by elevated basal salivary cortisol levels, with higher peak cortisol levels and larger areas under the curve, compared to nonanxious subjects. Additionally, severity of GAD as measured by the GAD Severity Scale and the Penn State Worry Questionnaire are positively correlated with cortisol levels. These data demonstrate HPA axis dysfunction in late-life GAD and suggest the need for additional research on the influence of aging on HPA axis function in mood and anxiety disorders.     

Parental posttraumatic stress disorder as a vulnerability factor for low cortisol trait in offspring of holocaust survivors

CONTEXT: Lower cortisol levels in posttraumatic stress disorder (PTSD) may reflect a preexisting vulnerability associated with developing the disorder after trauma exposure. Because offspring of trauma survivors with PTSD have a greater prevalence of PTSD after their own life events than offspring of trauma survivors without PTSD and offspring of nonexposed persons, examination of patterns of basal cortisol secretion in such offspring provides an opportunity to test this hypothesis. OBJECTIVE: To characterize the patterns of basal cortisol secretion in offspring of Holocaust survivors with and without parental PTSD and children of nonexposed parents. DESIGN: Cortisol secretion was measured every 30 minutes for 24 hours. The raw hormonal data were subjected to a chronobiological analysis by applying single-oscillator and multioscillator cosinor analyses, a nonlinear least squares curve-fitting program, to determine circadian and ultradian regulatory dynamics. SETTING: The study was conducted under controlled conditions at the General Clinical Research Center at the Mount Sinai School of Medicine. PARTICIPANTS: Twenty-three Holocaust offspring with parental PTSD and 10 without parental PTSD were compared with 16 children of nonexposed parents. No participant had PTSD. MAIN OUTCOME MEASURES: Mean cortisol levels during the 24-hour cycle and other chronobiological parameters (amplitude, acrophase, circadian quotient, and goodness-of-fit coefficient) derived from single-oscillator and multioscillator models. RESULTS: Offspring with parental PTSD displayed lower mean cortisol levels, reflected by the circadian mesor and reduced cortisol amplitude, compared with offspring without parental PTSD and children of nonexposed parents. This effect seemed to be specifically related to the presence of maternal PTSD. CONCLUSIONS: Low cortisol levels and other chronobiological alterations in offspring are associated with the risk factor of maternal PTSD, raising the possibility that these alterations are acquired via glucocorticoid programming either from in utero exposures or in response to maternal behaviors early in life.     

Low cortisol and risk for PTSD in adult offspring of holocaust survivors

OBJECTIVE: The study examined the association between cortisol and putative risk factors for posttraumatic stress disorder (PTSD) in a sample of subjects at increased risk for the development of PTSD. METHOD: Twenty-four-hour urinary cortisol excretion was measured in 35 adult offspring of Holocaust survivors and 15 healthy comparison subjects who were not offspring of Holocaust survivors. Subjects were also characterized with regard to clinical symptoms, presence or absence of psychiatric diagnoses including PTSD, and presence or absence of PTSD in their parents. RESULTS: Low cortisol levels were significantly associated with both PTSD in parents and lifetime PTSD in subjects, whereas having a current psychiatric diagnosis other than PTSD was relatively, but nonsignificantly, associated with higher cortisol levels. Offspring with both parental PTSD and lifetime PTSD had the lowest cortisol levels of all study groups. CONCLUSIONS: Parental PTSD, a putative risk factor for PTSD, appears to be associated with low cortisol levels in offspring, even in the absence of lifetime PTSD in the offspring. The findings suggest that low cortisol levels in PTSD may constitute a vulnerability marker related to parental PTSD as well as a state-related characteristic associated with acute or chronic PTSD symptoms.     

Amygdalar, hippocampal, and thalamic volumes in youth at high risk for development of bipolar disorder

Children of parents with bipolar disorder (BD), especially those with attention deficit hyperactivity disorder (ADHD) and symptoms of depression or mania, are at significantly high risk for developing BD. As we have previously shown amygdalar reductions in pediatric BD, the current study examined amygdalar volumes in offspring of parents (BD offspring) who have not yet developed a full manic episode. Youth participating in the study included 22 BD offspring and 22 healthy controls of comparable age, gender, handedness, and IQ. Subjects had no history of a manic episode, but met criteria for ADHD and moderate mood symptoms. MRI was performed on a 3 T GE scanner, using a 3D volumetric spoiled gradient echo series. Amygdalae were manually traced using BrainImage Java software on positionally normalized brain stacks. Bipolar offspring had similar amygdalar volumes compared to the control group. Exploratory analyses yielded no differences in hippocampal or thalamic volumes. Bipolar offspring do not show decreased amygdalar volume, possibly because these abnormalities occur after more prolonged illness rather than as a preexisting risk factor. Longitudinal studies are needed to determine whether amygdalar volumes change during and after the development of BD.     

Lifetime psychopathology in child and adolescent offspring of parents diagnosed with schizophrenia or bipolar disorder: a 2-year follow-up study

Having one parent diagnosed with a severe mental disorder is considered one of the main risk factors for developing that disorder in adulthood, and it also increases the risk of a wide range of mental disorders in the offspring. The aim of this study is to compare the prevalence of several psychopathological diagnoses, the presence of prodromal symptoms, and global functioning in offspring of parents with schizophrenia or bipolar disorder and in offspring of controls at baseline and 2-year follow-up. This study included 41 offspring of parents with schizophrenia, 90 offspring of parents with bipolar disorder, and 107 offspring of controls (mean age 11.7 ± 3.2 at baseline and 13.9 ± 3.2 at follow-up). The prevalence of psychopathology and comorbidity was higher in offspring of parents with schizophrenia and offspring of parents with bipolar disorder than in offspring of controls at baseline and at 2-year follow-up. Interestingly, mood disorders were more prevalent in offspring of parents with bipolar disorder and disruptive disorders were more prevalent in offspring of parents with schizophrenia. Prodromal symptoms were more frequent in offspring of parents with schizophrenia than in offspring of controls, while the offspring of parents with bipolar disorder showed an intermediate pattern. Finally, global functioning was lower in the offspring of parents with schizophrenia than the offspring of parents with bipolar disorder and the offspring of controls. Screening patients’ children is clinically relevant, since, as a group, they have an elevated risk of developing a psychiatric disorder and of experiencing their first symptoms during childhood and adolescence.

     

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.