Anxiety and major depression comorbidity in a family study of obsessive-compulsive disorder

To understand the familial relationship between obsessive-compulsive disorder (OCD), other anxiety disorders, and major depressive disorder (MDD), we examined the rates of anxiety disorders and MDD in first-degree relatives of OCD probands and controls, the association between age at onset of OCD and the occurrence of other anxiety disorders and major depressive disorder in relatives of probands, and the co-transmission of specific anxiety disorders, MDD, and OCD within families of probands. Recurrence risks were estimated from 466 first-degree relatives of 100 probands with OCD and 113 first-degree relatives of 33 non-psychiatric controls. Rates of non-OCD anxiety disorders and MDD were comparable in relatives of OCD probands and controls. Rates of anxiety disorders and MDD were higher among case relatives with OCD than among case relatives without OCD and control relatives. Fifty percent of case relatives with OCD had at least one comorbid anxiety disorder. Early age at onset (<10 years) in probands was associated with higher rates of anxiety and depression comorbidity among case relatives with OCD but not among case relatives without OCD. The occurrence of specific anxiety disorders and MDD in case relatives was independent of the same comorbid diagnosis in the OCD probands. OCD, panic disorder, generalized anxiety disorder, and MDD occurred together more often than expected by chance among individuals with OCD. Furthermore, age at onset in probands is associated with specific anxiety and affective comorbidity among case relatives. These findings support the hypothesis that early- and late-onset OCD represent different etiologic variants.     

First episode of depression in children at low and high familial risk for depression

OBJECTIVE: To examine the development of first-onset major depressive disorder (MDD) in children at high and low familial risk for depression in a prospective study. METHOD: High-risk children (n = 76) who were free of any lifetime affective disorder and had at least one first-degree and one second-degree relative with a lifetime history of childhood-onset, recurrent, bipolar, or psychotic depression were included. Low-risk children (n = 63) were included if they were free of any lifetime psychiatric disorder and had no first-degree relatives and fewer than 20% of their second-degree relatives with a lifetime affective disorder. Children and their parents were assessed in a prospective design using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic version (K-SADS-E). The average interval between follow-up interviews was 18 months, and the average follow-up period was 6 years. RESULTS: High-risk children had approximately a threefold increased risk of developing first-onset MDD compared with low-risk children (odds ratio = 3.21). The average age of new-onset MDD was 14.0 +/- 2.9 years (range 9.5-19.5 years). Above and beyond the familial loading for MDD, mother's lifetime anxiety disorder (odds ratio = 2.84) and lifetime behavioral disorder (odds ratio = 3.25) in the child significantly added to the risk of developing a first-onset MDD. CONCLUSIONS: Having high familial loading for affective disorders, a mother with and anxiety disorder, and a behavioral disorder in the child all significantly contributed to the risk of developing depression.     

Specificity of familial transmission of anxiety and comorbid disorders

This study examines the specificity and impact of comorbid disorders in probands on the familial transmission of panic and social anxiety disorders. It employs a contemporary family study design with 225 probands (with and without panic and social anxiety disorders) sampled from outpatient clinics and the local community. Their 1053 adult first-degree relatives were assessed for lifetime disorders, based on best estimate diagnoses derived from semi-structured psychiatric diagnostic interviews (Schedule for Affective Disorders and Schizophrenia), multi-informant family history information, and medical records. Generalized estimating equations were used to examine the familial aggregation of panic and social anxiety disorders, and the contributions of comorbid disorders. Results show specificity of familial aggregation of both panic disorder and social anxiety in probands and relatives (i.e., panic odds ratio=3.7, 95%CI 1.5-9.3; social anxiety odds ratio=1.8, 95%CI 1.1-2.9) after controlling for comorbid disorders. There was no contribution of common comorbid disorders (depression, alcoholism, generalized anxiety disorder and agoraphobia) in probands on the familial aggregation of either disorder. These findings confirm prior studies of specificity of familial transmission of panic and social anxiety disorders, and demonstrate that the association between these disorders in probands is not attributable to comorbid mood, anxiety or substance use disorders. Therefore, despite the high magnitude of co-occurrence of panic disorder and social anxiety, there may be distinct etiologic factors underlying each disorder. These findings have implications for studies of the etiology, genetics, and treatment of these disorders.     

Familial psychiatric illness and posttraumatic stress disorder: findings from a family study of substance abuse and anxiety disorders.

BACKGROUND: Aside from the possibility of a direct relationship between individual and familial posttraumatic stress disorder (PTSD), there is accumulating evidence that implicates a family history of psychiatric and substance use disorders as an important risk factor in the development of PTSD and associated symptoms. METHOD: The familial risk of DSM-III-R PTSD was examined within a family study of clinical- and community-ascertained probands (N = 263) and their 1206 adult first-degree relatives. RESULTS: Although PTSD among probands was not found to significantly elevate the risk of PTSD among first-degree relatives, an elevated rate of PTSD was found among the relatives of drug abusing probands compared with the relatives of probands with alcoholism, other anxiety disorders, and normal controls. Additionally, affective disorders were significantly associated with PTSD in relatives (p < .01). When these familial and individual associations were examined according to gender, drug disorders in probands were significantly associated with PTSD only among male relatives (p < .01), while the association between PTSD and comorbid affective disorders was seen primarily among female relatives (p < .01). CONCLUSION: Although probands in the present family study were not selected specifically for PTSD, the data afforded a unique opportunity to examine the profile of familial psychopathology as a part of the complex picture of susceptibility for PTSD. Future family study research will be able to determine the generalizability of the present findings through more complete measurement of diverse forms of trauma.     

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.     

Psychiatric disorders in the first-degree relatives of probands with bulimia nervosa

Data from a family study of psychiatric disorders showed higher rates of major affective disorders, eating disorders, and alcoholism in first-degree relatives of 40 bulimic probands than in first-degree relatives of 24 control subjects. More importantly, the data showed higher rates of major affective disorders in relatives of bulimic probands who themselves had no history of major affective disorders than in relatives of control subjects. This significant finding indicates a familial relationship between bulimia nervosa and major affective disorders, which suggests the possibility of a common diathesis.     

Early onset psychiatric disorder in high risk children and increased familial morbidity

The relationship between child psychopathology and familial morbidity in second degree relatives was examined for children considered at risk on the basis of parental affective illness. Second degree relatives in high-risk families with no child psychopathology were no different from low-risk families in their rates of depression and anxiety. Second degree relatives in high-risk families positive for child psychopathology had significantly higher rates of depression and anxiety than relatives of low-risk children and relatives of high-risk children with no disorder. The implications of these findings are discussed with respect to risk status, prepubertal onset of psychopathology, and familial morbidity for specific psychiatric disorders.     

A family study of major depressive disorder in a community sample of adolescents

BACKGROUND: Family studies provide a useful approach to exploring the continuities and discontinuities between major depressive disorder (MDD) in children and adolescents and MDD in adults. We report a family study of MDD in a large community sample of adolescents. METHODS: Probands included 268 adolescents with a history of MDD, 110 adolescents with a history of nonmood disorders but no history of MDD through age 18 years, and 291 adolescents with no history of psychopathology through age 18 years. Psychopathology in their 2202 first-degree relatives was assessed with semistructured direct and family history interviews, and best-estimate diagnoses were derived with the use of all available data. RESULTS: The relatives of adolescents with MDD exhibited significantly elevated rates of MDD (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.46-2.31), dysthymia (HR, 1.79; 95% CI, 1. 11-2.87), and alcohol abuse or dependence (HR, 1.29; 95% CI, 1.05-1. 53), but not anxiety disorders, drug abuse or dependence, or antisocial and borderline personality disorder. In contrast, anxiety, substance use, and disruptive behavior disorders in adolescents were not associated with elevated rates of MDD in relatives. However, the relatives of probands with anxiety and substance use disorders exhibited elevated rates of anxiety and substance use disorders, respectively. CONCLUSIONS: The results provide evidence of the familial aggregation of adolescent MDD, and also indicate that there is a considerable specificity in the pattern of familial transmission. In addition, we found preliminary evidence of the familial aggregation of adolescent anxiety and substance use disorders.     

Further evidence for family-genetic risk factors in attention deficit hyperactivity disorder. Patterns of comorbidity in probands and relatives psychiatrically and pediatrically referred samples.

We examined 140 probands with attention deficit hyperactivity disorder, 120 normal controls, and their 822 first-degree relatives using "blind" raters and structured diagnostic interviews. Compared with controls, probands with attention deficit hyperactivity disorder were more likely to have conduct, mood, and anxiety disorders. Compared with relatives of controls, relatives of probands with attention deficit hyperactivity disorder had a higher risk for attention deficit hyperactivity disorder, antisocial disorders, major depressive disorder, substance dependence, and anxiety disorders. Patterns of comorbidity indicate that attention deficit hyperactivity disorder and major depressive disorders may share common familial vulnerabilities, that attention deficit hyperactivity disorder plus conduct disorder may be a distinct subtype, and that attention deficit hyperactivity disorder and anxiety disorders are transmitted independently in families. These results extend previous findings indicating family-genetic influences in attention deficit hyperactivity disorder by using both pediatrically and psychiatrically referred proband samples. The distributions of comorbid illnesses in families provide further validation for subgrouping probands with attention deficit hyperactivity disorder by comorbidity.     

Psychopathology in drug abusers and their families

Demographic, clinical, and family pedigree data obtained on 350 hospitalized drug-dependent patients showed that 52% also met DSM-III criteria for alcohol abuse or dependence, while 37% met DSM-III criteria for a concurrent axis I psychiatric disorder other than substance abuse. Cyclothymic disorder was significantly more common among cocaine abusers, while generalized anxiety disorder and panic disorder were more common among sedative-hypnotic abusers. Data on 1,478 first-degree relatives revealed that the prevalence of alcoholism and affective disorder was highly correlated with the occurrence of similar psychopathology in the probands. These findings suggest a relationship between drug of choice and comorbid psychopathology, a role for familial factors in the transmission of these disorders, and the importance of diagnostic subtypes in the evaluation and treatment of substance abusers.     

Family aggregation of mental disorders in the nationwide Danish three generation study

Objective  The study of familial aggregation of major mental disorders in a national population. Method  Within a Danish register-based cohort study, aggregation of mental disorders was analysed in all case-probands with first psychiatric contact before the age of 19 years in the time period between 1 April 1969 and 29 June 2004 followed up until the age of 35 years, their first-degree relatives, and a matched group of control-probands including their first-degree relatives. Results  Hazard rate ratios were significantly elevated for cases as compared to controls for all diagnoses among probands, parents, and siblings. Among children of the probands, these ratios were significantly elevated for neurotic (anxiety) disorders, mental retardation, developmental disorders, behavioural and emotional disorders of childhood and adolescence, and miscellaneous disorders. Family aggregation of any diagnosis was significantly higher in probands with substance use disorder, schizophrenia, affective disorders, neurotic (anxiety) disorders, and miscellaneous disorders. There was specificity of familial transmission for affective and neurotic (anxiety) disorders. Conclusion  This large nationwide study found some differential patterns of familial aggregation of major mental disorders.     

The lifetime prevalence of psychopathology in men with multigenerational family histories of alcoholism

This paper reports the results of a pilot study of the lifetime prevalence of psychiatric disorders in a group of nonalcoholic men with multigenerational family histories of alcoholism (high-risk) in comparison with that of a control group (nonalcoholic men without multigenerational family histories of alcoholism). Diagnoses were given following the structured interview format of the Schedule for Affective Disorders and Schizophrenia, using the Research Diagnostic Criteria. The prevalence of psychopathology in the probands' first- and second-degree relatives was also determined using the Family History Research Diagnostic Criteria. The results showed a higher lifetime prevalence of psychopathology for the high-risk men compared with control subjects, with the diagnoses of major affective disorder and anxiety disorder predominating. In addition, the data obtained from first- and second-degree relatives indicated a significantly higher prevalence of nonalcoholic diagnoses in the high-risk families (depression in particular), suggesting that alcoholism and depression may be cosegregating in these families. The lifetime prevalence of these disorders is similar to that reported in chronic alcoholics.     

Familial relationship between mood disorders and alcoholism

Clinical and epidemiological studies have consistently revealed an association between alcohol use disorders and both bipolar and nonbipolar mood disorders. However, the evidence regarding the nature of these associations is unclear. The familial patterns of alcohol and affective disorders were examined using data from a controlled family study of probands with alcohol and anxiety disorders who were sampled from treatment settings and the community. The substantial degree of comorbidity between mood and anxiety disorders among probands allowed for the examination of comorbidity and familial aggregation of alcohol and mood disorders. The major findings are that (1) alcoholism was associated with bipolar and nonbipolar mood disorders in the relatives; (2) there was a strong degree of familial aggregation of alcohol dependence and both types of mood disorders were observed; and (3) there was no evidence of cross-aggregation (i.e., increase in mood disorders among probands with alcohol dependence, and vice versa) between alcoholism and mood disorders. The independent familial aggregation of bipolar disorder and alcoholism and the finding that the onset of bipolar disorder tended to precede that of alcoholism are compatible with a self-medication hypothesis as the explanation for the frequent co-occurrence of these disorders. In contrast, the independent familial aggregation and the tendency of an earlier onset of alcoholism than that of nonbipolar depression suggest that unipolar mood disorders are frequently secondary to alcoholism.     

Affective and impulsive personality disorder traits in the relatives of patients with borderline personality disorder

OBJECTIVE: This study tested the hypothesis that the risk for affective and impulsive personality disorder traits commonly found in patients with borderline personality disorder would be greater in the first-degree relatives of probands with borderline personality disorder than in two comparison groups. METHOD: Blind family history interviews were conducted with family informants to assess the extent to which first-degree relatives of 29 probands with borderline personality disorder, 22 probands with other personality disorders who met three or fewer of the criteria for borderline personality disorder, and 43 probands with schizophrenia fulfilled operationalized criteria for the two kinds of personality disorder traits and for other diagnostic categories. The crude proportions of adult relatives with each diagnosis, as well as the age-adjusted morbid risks, were assessed in the three groups of relatives. RESULTS: The risks for affective and impulsive personality disorder traits were independently greater in the 129 relatives of the borderline probands than in the 105 relatives of the probands with other personality disorders and the 218 relatives of the schizophrenic probands. There was no similarly greater risk for any other psychiatric disorder assessed, including major affective disorder. In addition, the relatives of borderline probands with current or past major depressive disorder showed a greater risk for major affective disorders than the relatives of never-depressed probands with other personality disorders but not the relatives of never-depressed borderline probands. CONCLUSIONS: These results suggest familial transmission of the hallmark borderline-related personality characteristics and raise the possibility that these familial traits may be partially independent.     

Children with prepubertal-onset major depressive disorder and anxiety grown up

BACKGROUND: The continuity in adulthood of major depressive disorder (MDD) first arising before puberty is largely unknown. This information could guide early treatment and clarify the appropriateness of including children with MDD in genetic studies. METHODS: Eighty-three subjects with onset of MDD, 44 subjects with anxiety disorder and no MDD, and 91 subjects with no evidence of past or current psychiatric disorders were assessed by two psychiatrists before puberty (Tanner stage < III) and were evaluated 10 to 15 years later as adults by an independent team without knowledge of the initial diagnosis. RESULTS: The clinical outcome of children with prepubertal-onset MDD in adulthood includes a high risk of suicide attempts (nearly 3-fold compared with normal controls and 2-fold compared with children with anxiety) and bipolar disorder. Compared with controls, both the children with MDD and those with anxiety went on to have increased risk of substance abuse and conduct disorder but not other disorders, increased use of longterm psychiatric and medical services, and overall impaired functioning. Children with prepubertal-onset MDD with a recurrence of MDD during follow-up had higher rates of MDD in their first-degree relatives. CONCLUSIONS: There is high morbidity in clinically referred children with prepubertal-onset MDD and anxiety, but continuity and specificity of MDD or anxiety disorder in adulthood is less clear. Caution is warranted in selecting clinically referred children with prepubertal-onset MDD for inclusion in genetic studies unless they have a family history of MDD and recurrence of MDD over time.     

Parsing the comorbidity between bipolar disorder and anxiety disorders: a familial risk analysis

BACKGROUND: A growing literature suggests that anxiety disorders (ANX) co-occur with bipolar disorder (BPD), but the nature of this overlap is unknown. Thus, we investigated the familial association between BPD and ANX among the first-degree relatives of children with BPD with and without comorbid ANX. METHODS: We compared relatives of four proband groups defined by the presence or absence of BPD and ANX in the proband: (1) BPD + ANX (n = 23 probands, 74 relatives), (2) BPD without ANX (n = 11 probands, 38 relatives), (3) ANX without BPD (n = 48 probands, 167 relatives), and (4) controls without BPD or ANX (n = 118 probands, 385 relatives). All subjects were evaluated with structured diagnostic interviews. Diagnoses of relatives were made blind to the diagnoses of probands. RESULTS: The results show high rates of both BPD and ANX in relatives of children with BPD + ANX. Moreover, BPD and ANX cosegregated among the relatives of children with BPD + ANX. Although relatives of both ANX proband groups (with and without BPD) had high rates of ANX, and relatives of both BPD proband groups (with and without ANX) had high rates of BPD, the combined condition BPD + ANX was the predominant form of BPD among relatives of probands with BPD + ANX. CONCLUSIONS: These family-genetic findings suggest that the comorbid condition BPD+ANX may be a distinct clinical entity. More work is needed to evaluate whether the presence of comorbid ANX may be a marker of very early onset BPD.     

Family study of affective spectrum disorder

BACKGROUND: Affective spectrum disorder (ASD) represents a group of psychiatric and medical conditions, each known to respond to several chemical families of antidepressant medications and hence possibly linked by common heritable abnormalities. Forms of ASD include major depressive disorder (MDD), attention-deficit/hyperactivity disorder, bulimia nervosa, cataplexy, dysthymic disorder, fibromyalgia, generalized anxiety disorder, irritable bowel syndrome, migraine, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder, and social phobia. Two predictions of the ASD hypothesis were tested: that ASD, taken as a single entity, would aggregate in families and that MDD would coaggregate with other forms of ASD in families. METHODS: Probands with and without MDD, together with their first-degree relatives, were interviewed using the Structured Clinical Interview for DSM-IV and a supplemental interview for other forms of ASD. The familial aggregation and coaggregation of disorders were analyzed using proband predictive logistic regression models, including a novel bivariate model for the presence or absence of each of 2 disorders in a relative as predicted by the presence or absence of each of 2 disorders in the associated proband. RESULTS: In the 178 interviewed relatives of 64 probands with MDD and 152 relatives of 58 probands without MDD, the estimated odds ratio (95% confidence interval) for the familial aggregation of ASD as a whole was 2.5 (1.4-4.3; P =.001) and for the familial coaggregation of MDD with at least one other form of ASD was 1.9 (1.1-3.2; P =.02). CONCLUSIONS: Affective spectrum disorder aggregates strongly in families, and MDD displays a significant familial coaggregation with other forms of ASD, taken collectively. These results suggest that forms of ASD may share heritable pathophysiologic features.     

Patterns of psychiatric comorbidity with attention-deficit/hyperactivity disorder

Attention deficit/hyperactivity disorder (ADHD) is frequently comorbid with a variety of psychiatric disorders. These disorders include oppositional defiant (ODD) and conduct disorders (CD), and affective, anxiety, and learning disorders. Studies which have examined the comorbidity of these disorders with ADHD are reviewed. ADHD and ADHD with CD seem to be distinct subtypes; children with ADHD/CD are at higher risk of antisocial personality as adults. Coexisting anxiety may attenuate impulsivity in ADHD. Studies examining stimulant response in children with ADHD/anxiety have recently yielded conflicting results. Anxiety and ADHD seem to be inherited independently. The prevalence of major depressive disorder (MDD) and bipolar disorder among children with ADHD is controversial, but there clearly exists a subgroup of severely emotionally labile children with ADHD who present serious management issues for the clinician. About 20% to 25% of children with ADHD meet criteria for a learning disorder (LD), but LD seems to be independent of ADHD.     

Familial transmission of depression and alcoholism

The familial transmission of major depression and alcoholism among probands who had depression and alcoholism was examined. Our findings indicated that depressives without alcoholism did not transmit alcoholism, and probands with depression and alcoholism tended to transmit both depression and alcoholism. This confirms the observation that depression and alcoholism are not manifestations of the same underlying disorder. An increased risk of anxiety disorders in the relatives of probands with alcoholism, which could specifically be attributed to the presence of alcoholism in addition to an anxiety disorder in the proband, was also observed. This suggested that the alcoholism in these probands may result from self-medication of anxiety symptoms. The results of this study underscore the importance of examining combinations of diagnoses in patients in decreasing the heterogeneity of diagnostic categories.     

Familiality of major depressive disorder and gender differences in comorbidity

Objective: Gender differences exist in the prevalence and psychiatric comorbidity of major depressive disorder (MDD). This study investigates whether familiality of MDD contributes to observed gender differences in comorbidity. Method: Familial (f‐MDD) and non‐familial (nf‐MDD) MDD cases from a population sample were assessed for comorbid dysthymia, anxiety disorders and alcohol‐related disorders using the Composite International Diagnostic Interview (CIDI). Logistic regression analyses were performed to examine the effect of f‐MDD on gender differences in comorbidity, adjusted for confounders. Results: Women with f‐MDD reported significantly more comorbid dysthymia and generalized anxiety disorder (GAD) than their male counterparts; women with nf‐MDD reported significantly more comorbid simple phobias and agoraphobia than their male counterparts. Gender differences in comorbid panic disorder and alcohol‐related disorders occurred independently of the familial load. Adjustment for age of onset, severity and recurrence of MDD did not change these results. Conclusion: Models to explain comorbidity patterns of MDD differ by gender. Familiality of MDD should be taken into account.