Evidence of familial association between attention deficit disorder and major affective disorders

With the use of family study methods and assessments by "blinded" raters, we tested hypotheses about patterns of familial association between DSM-III attention deficit disorder (ADD) and affective disorders (AFFs) among first-degree relatives of clinically referred children and adolescents with ADD (73 probands, 264 relatives) and normal controls (26 probands, 92 relatives). Among the 73 ADD probands, 24 (33%) met criteria for AFFs (major depression, n = 15 [21%]; bipolar disorder, n = 8 [11%]; and dysthymia, n = 1 [1%]). After stratification of the ADD sample into those with AFFs (ADD + AFF) and those without AFF (ADD), familial risk analyses revealed the following: (1) the relatives of each ADD proband subgroup were at significantly greater risk for ADD than were relatives of normal controls; (2) the age-corrected morbidity risk for ADD was not significantly different between relatives of ADD and ADD + AFF (27% vs 22%); however, these two risks were significantly greater than the risk to relatives of normal controls (5%); (3) the risk for any AFF (bipolar disorder, major depressive disorder, or dysthymia) was not significantly different between relatives of ADD probands and ADD + AFF probands (28% and 25%), but these two risks were significantly greater than the risk to relatives of normal controls (4%); (4) ADD and AFFs did not cosegregate within families; and (5) there was no evidence for nonrandom mating. These findings are consistent with the hypothesis that ADD and AFFs may share common familial vulnerabilities.     

Revisiting the association between attention-deficit/hyperactivity disorder and anxiety disorders: a familial risk analysis.

BACKGROUND: This study tested competing hypotheses about patterns of familial association between attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders using familial risk analysis methodology. METHODS: The risk for ADHD and anxiety disorders in first-degree relatives was examined after stratifying ADHD probands by the presence or absence of comorbid anxiety disorders. The presence of anxiety disorders in probands and relatives was defined as meeting DSM-III-R diagnostic criteria for > or = 2 anxiety syndromes in the same subject. RESULTS: Familial risk analyses revealed that 1) the risk for anxiety disorders was significantly higher in ADHD probands and their relatives than in control probands and their relatives; 2) the risk for anxiety disorders among the relatives of ADHD probands was limited to those families in which the proband had a diagnosis of ADHD; 3) the risk for anxiety disorders was significantly higher among the relatives of ADHD probands with anxiety disorders than in relatives of ADHD probands without anxiety disorders, but these two groups did not differ in the familial risk for ADHD; and 4) ADHD and anxiety disorders did not cosegregate within families, and there was no evidence for nonrandom (assortative) mating. CONCLUSIONS: These findings are most consistent with the hypothesis that ADHD and anxiety disorders segregate independently in families.     

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.     

A family study of patients with attention deficit disorder and normal controls

In a family study of Attention Deficit Disorder (ADD), we collected data on first-degree relatives of 22 children with ADD and 20 normal children. The morbidity risk for ADD was 31.5% in the first group. This was significantly higher than the rate of 5.7% in the control group. Relatives of ADD probands were also shown to be at higher risk for Oppositional Disorders and Major Depressive Disorder (MDD). The findings indicate that ADD is a familial disorder associated with increased familial risk of other psychiatric disorders.     

A family study of generalized anxiety disorder

The frequency of generalized anxiety disorder was higher among first-degree relatives of probands with generalized anxiety (N = 20) than among the relatives of control subjects (N = 20), but it was not higher among relatives of probands with panic disorder (N = 40) or agoraphobia (N = 40). Also, the frequency of panic disorder was higher among relatives of probands with panic disorder than among control relatives but was not higher among relatives of generalized anxiety probands. Relatives of probands with generalized anxiety who had the same disorder had a mild, stress-related illness. The results confirm the separation between generalized anxiety disorder and panic disorder but challenge the distinction between generalized anxiety and adjustment disorders.     

A controlled family history study of prepubertal major depressive disorder

First-degree (N = 195) and second-degree (N = 785) adult relatives of prepubertal children with major depression (N = 48), children with nonaffective psychiatric disorders (N = 20), and normal children (N = 27) were assessed by the Family History-Research Diagnostic Criteria method (FH-RDC), except for the adult informant (usually the mother), who was directly interviewed. Compared with normal controls, prepubertal children with major depressive disorder (MDD) had significantly higher familial rates of psychiatric disorders in both first- and second-degree relatives, especially MDD, alcoholism, and "other" (mostly anxiety) diagnoses. Relatives of children in the nonaffective psychiatric control (PC) group had low rates of alcoholism, high rates of other (anxiety) disorder diagnoses, and intermediate rates of MDD (accounted for by those children with separation anxiety). This suggests that prepubertal onset of major depression may be especially likely in families with a high aggregation of affective disorders when these families also have a high prevalence of alcoholism, and that a proportion of children without affective disorder but with separation anxiety disorder in this study were at high risk for the development of affective illness later in life. These results support the validity of prepubertal-onset depressive illness as a diagnostic category, and are consistent with high familial rates of MDD and other psychiatric disorders found in family studies of adolescent and early-onset adult probands with major affective disorders, and with studies of the offspring of parents with major affective disorders. Within the child MDD group substantial heterogeneity was found. Low familial rates of MDD were associated with suicidality and comorbid conduct disorder in the child probands. The highest familial rates of MDD, approximately threefold those in the normal controls, and all the bipolar relatives, were found in the families of prepubertal probands with MDD who never had a concrete suicidal plan or act and who were without comorbid conduct disorder. A useful nosological continuum in which to classify prepubertal MDD may be to place at one end those patients with comorbid conduct disorder and at the other end those patients with manifestations related to bipolarity, including hypomania, mania, and psychotic subtype.     

Gilles de la Tourette's syndrome and attention deficit disorder with hyperactivity. Evidence against a genetic relationship

Results of a family study of Gilles de la Tourette's syndrome (TS) suggest that TS and attention deficit disorder (ADD) with hyperactivity are genetically separate disorders transmitted independently in families at risk. Although the rate of TS among the relatives of the two proband groups was virtually the same (10.3% vs 11.1%), the rate of ADD among the relatives of probands with TS and ADD with hyperactivity was approximately eight times higher than the rate of ADD among the relatives of the probands with TS only. In those families where the proband had both TS and ADD, the two traits segregated independently. Therefore, there is no evidence to suggest that the two disorders are genetically related.     

Family history of suicidal behavior and mood disorders in probands with mood disorders

OBJECTIVE: First-degree relatives of persons with mood disorder who attempt suicide are at greater risk for mood disorders and attempted or completed suicide. This study examined the shared and distinctive factors associated with familial mood disorders and familial suicidal behavior. METHOD: First-degree relatives' history of DSM-IV-defined mood disorder and suicidal behavior was recorded for 457 mood disorder probands, of whom 81% were inpatients and 62% were female. Probands' lifetime severity of aggression and impulsivity were rated, and probands' reports of childhood physical or sexual abuse, suicide attempts, and age at onset of mood disorder were recorded. Univariate and multivariate analyses were carried out to identify predictors of suicidal acts in first-degree relatives. RESULTS: A total of 23.2% of the probands with mood disorder who had attempted suicide had a first-degree relative with a history of suicidal behavior, compared with 13.2% of the probands with mood disorder who had not attempted suicide (odds ratio=1.99, 95% CI=1.21-3.26). Thirty percent (30.8%) of the first-degree relatives with a diagnosis of mood disorder also manifested suicidal behavior, compared with 6.6% of the first-degree relatives with no mood disorder diagnosis (odds ratio=6.25, 95% CI=3.44-11.35). Probands with and without a history of suicide attempts did not differ in the incidence of mood disorder in first-degree relatives (50.6% versus 48.1%). Rates of reported childhood abuse and severity of lifetime aggression were higher in probands with a family history of suicidal behavior. Earlier age at onset of mood disorder in probands was associated with greater lifetime severity of aggression and higher rates of reported childhood abuse, mood disorder in first-degree relatives, and suicidal behavior in first-degree relatives. CONCLUSIONS: Risk for suicidal behavior in families of probands with mood disorders appears related to early onset of mood disorders, aggressive/impulsive traits, and reported childhood abuse in probands. Studies of such clinical features in at-risk relatives are under way to determine the relative transmission of these clinical features.     

Schizoaffective disorder and affective disorders with mood-incongruent psychotic features: keep separate or combine? Evidence from a family study.

OBJECTIVE: This study investigated whether the distinction between schizoaffective disorder and affective disorders with mood-incongruent psychotic features as described in DSM-III-R is reflected by aggregation of schizophrenia in the families of probands with the former disorder and aggregation of affective disorders mainly among the relatives of probands with the latter type of disorders. METHOD: The probands were 118 inpatients with definite lifetime diagnoses of DSM-III-R schizoaffective disorder or a major mood disorder with incongruent psychotic features according to structured clinical interviews. Diagnostic information on 475 of the probands' first-degree relatives was gathered through direct interviews (with 80% of the living first-degree relatives) or the family history approach. The rates of affective and psychotic disorders among these relatives were then compared with those among the relatives of a comparison group of 109 interviewed individuals from the general population who were matched on sociodemographic factors to the inpatient probands. RESULTS: With regard to the familial aggregation of schizophrenia, the DSM-III-R distinction emerged as valid. However, the risk of unipolar affective disorders was enhanced in the families of all of the subgroups of patients studied. The unipolar/bipolar distinction in both DSM-III-R diagnostic groups was reflected by distinct patterns of bipolar disorders in the relatives. CONCLUSIONS: The results partly support the DSM-III-R dichotomy of schizoaffective disorder and affective disorders with mood-incongruent psychotic features. Although the differences between these two diagnostic groups were significant, the magnitude of the differences remained relatively modest.     

Morbidity risk for obsessive-compulsive spectrum disorders in first-degree relatives of patients with eating disorders

OBJECTIVE: A hypothesis that eating disorders are a phenomenological variant of obsessive-compulsive disorder (OCD) has been proposed. This study was conducted to determine whether anorexia nervosa and bulimia, the two main eating disorders, are familial and whether the risk for obsessive-compulsive spectrum disorders (OCD and tic disorders) is higher in families of patients with eating disorders. METHOD: The morbidity risk for obsessive-compulsive spectrum disorders in first-degree relatives of 136 female probands with eating disorders (84 with anorexia nervosa, 52 with bulimia) was compared to that for first-degree relatives of 72 female comparison subjects. RESULTS: The morbidity risk for obsessive-compulsive spectrum disorders was significantly higher among the 436 relatives of the eating disorder probands than among the 358 relatives of the comparison subjects (9.69% versus 0%). This finding was independent of any comorbid diagnosis of an obsessive-compulsive spectrum disorder in the eating disorder probands. The eating disorder group and the comparison group did not differ in familial risk for eating disorders and tic disorders. CONCLUSIONS: To better understand the genetic components of eating disorders, these disorders should be considered as part of the obsessive-compulsive spectrum of disorders.     

A family study of juvenile obsessive-compulsive disorder.

OBJECTIVES: To determine whether juvenile obsessive-compulsive disorder (OCD) is familial and whether the rate of Tourette syndrome (TS) and tic disorders is higher among relatives of patients with OCD than among relatives of controls subjects. METHOD: We assessed first-degree relatives of 35 juvenile OCD probands (aged 16 years or less) and 34 matched, psychiatrically unaffected control subjects, using the Diagnostic Interview for Children and Adolescents-Revised (DICA-R) (unpublished), a Questionnaire for tic disorders, the Children's Version of Leyton's Obsessional Inventory (CV-LOI), and the Children's Version of the Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Similarly, we assessed adult relatives, using the Schedule for Clinical Assessment in Neuropsychiatry (SCAN), Leyton's Obsessional Inventory (LOI), the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), and a Questionnaire for tic disorders. The diagnoses were determined by consensus, using DSM-III-R criteria. We calculated age-corrected morbid risk, using Weinberg's method. RESULTS: The morbid risk for OCD among the relatives of OCD probands was 4.96%, while none of the relatives of unaffected control subjects had OCD. We did not diagnose TS in any of the relatives of either OCD probands or control subjects. We diagnosed chronic motor tic disorders in only 1 of the relatives of OCD probands, while none of the relatives of control subjects had any tic disorder. CONCLUSION: Most juvenile cases of OCD are nonfamilial and unrelated to tic disorders, while only a few are familial. There is a need to re-examine the issue of familiality in cases of OCD, as well as its relation to TS, using larger community samples to better understand the hypotheses of familial transmission and comorbidity with tic disorders.     

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 family history study of binge-eating disorder

Family studies of anorexia nervosa and bulimia nervosa have yielded important information about the etiologies of these eating disorders. By contrast, little is known about familial factors of etiologic importance for binge-eating disorder (BED). The purpose of the current family history study was to assess the prevalence of comorbid psychopathology in a non-treatment seeking female sample of 31 probands with BED, 32 control probands without BED, and their 283 first-degree relatives. In-person semistructured clinical interviews were conducted with the probands, who also served as informants for all of their first-degree relatives. Significantly higher lifetime rates of major depressive disorder, dysthymic disorder, and social phobia were found among women with BED compared with control women. Significantly higher lifetime rates of bipolar (I or II) disorder, any depressive disorder, nearly all anxiety disorders, anorexia nervosa, and BED were reported among the first-degree relatives of women with BED compared with the first-degree relatives of control women. Furthermore, female relatives of women with BED were reported to have higher rates of substance use disorders and dysthymic disorder compared with female relatives of control women without BED. Nearly all disorders that were elevated in relatives of women with BED followed a pattern of independent transmission from BED. The primary exception was substance use disorder among female relatives, whose transmission pattern was consistent with that of a shared etiology with BED. Thus, BED and substance use disorder may share a common mechanism of familial transmission among women.     

Schizoaffective illness,schizophrenia and affective disorders: morbidity risk and genetic transmission

Data on schizoaffective illness, schizophrenia and affective disorders were gathered on first-degree relatives of schizoaffective probands and matched controls (bipolars, unipolars and schizophrenics). The familial pattern of affective and schizophrenic subtypes of schizoaffective disorder resembled the familial pattern of affective and schizophrenic probands, respectively. The overall risk for the spectrum of schizoaffective and affective disorders was higher among relatives of schizoaffective-manic as compared to relatives of schizoaffective-depressive probands, although the difference fell short of significance. When tested for consistency with multiple threshold hypotheses of genetic transmission, schizoaffective illness did not qualify as either a more extreme form of affective illness nor as a disorder that occupies an intermediate position between bipolar and unipolar disorders or is genetically milder than affective disorder. The implications of diagnostic subtyping for genetic research in the major psychoses were discussed.     

Attention-deficit disorder and conduct disorder in girls: evidence for a familial subtype.

BACKGROUND: The frequent comorbidity between attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) raises the possibility that ADHD+CD is a distinct and separate condition. METHODS: We tested hypotheses about patterns of familial association between ADHD, CD, oppositional defiant disorder (ODD) and adult antisocial personality disorder (ASPD). Using family study methodology in a sample of girls, we found 11 children with diagnoses of ADHD+ CD, 39 with ADHD+ODD, and 90 with ADHD only. These were compared with 122 non-ADHD, non-CD control probands. Familial risk analysis was utilized. RESULTS: Relatives of each ADHD proband subgroup were at significantly greater risk for ADHD, and the relatives of ADHD-only subjects were at a greater risk of ODD than relatives of control subjects. Also, rates of CD were elevated among relatives of ADHD+CD probands only, and the coaggregation of ADHD and the antisocial disorders could not be accounted for by marriages between ADHD and antisocial spouses. Both ADHD and antisocial disorders occurred in the same relatives more often than expected by chance. CONCLUSIONS: These findings suggest that ADHD with and without antisocial disorders may be etiologically distinct disorders and provide evidence for the nosologic validity of ICD-10 hyperkinetic conduct disorder.     

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.     

Family-genetic and psychosocial risk factors in DSM-III attention deficit disorder

Using family study methodology and assessments made by blind raters, this study evaluated family-genetic and psychosocial risk factors for DSM-III attention deficit disorder (ADD) among the 457 first-degree relatives of clinically referred children and adolescents with ADD (N = 73), compared with psychiatric (N = 26) and normal controls (N = 26). Relatives of ADD probands had a higher morbidity risk for ADD (25.1% versus 5.3% versus 4.6%, ps less than 0.00001), antisocial disorders (25.3% versus 6.9% versus 4.2%, ps less than 0.00001), and mood disorders (27.1% versus 13.9%, p = 0.038 and 27.1% versus 3.6%, p = 0.00001) than did relatives of psychiatric and normal controls. The increased risk for ADD could not be accounted for by gender or generation of relative, the age of proband, social class, or the intactness of the family. These results confirm and extend previous findings indicating important family-genetic risk factors in ADD.     

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.     

Relationship between panic disorder and agoraphobia. A family study

A family study of patients with agoraphobia (n = 40), panic disorder (n = 40), and nonanxious controls (n = 20) showed that the morbidity risk for panic disorder was increased among the relatives of agoraphobics (8.3%) and the relatives of patients with panic disorder (17.3%). The morbidity risk for agoraphobia was also increased among the relatives of agoraphobics (11.6%) but not the relatives of panic disorder patients (1.9%). Male relatives of agoraphobics were shown to be at higher risk for alcohol disorders (30.8%). No greater risk for primary affective disorders was found among the relatives of agoraphobic or panic disorder patients or among the relatives of probands with secondary depression compared with relatives of probands without secondary depression. Probands and relatives with agoraphobia reported an earlier onset of illness, more persistent and disabling symptoms, more frequent complications, and a less favorable outcome than probands and relatives with panic disorder. The findings suggest that agoraphobia is a more severe variant of panic disorder. They also lend support to the separation between anxiety disorders and affective disorders.     

Familial transmission of simple phobias and fears. A preliminary report

Preliminary data from a blind direct interview family study indicate a significantly higher risk for simple phobia among first-degree relatives (n = 49) of simple phobic probands (who had no other anxiety disorder) as compared with first-degree relatives (n = 119) of never mentally ill controls (31% vs 11%, relative risk = 3.3). Female relatives were more likely to be affected than male relatives (48% vs 13%), though this difference did not reach conventional significance in an age-corrected analysis. Significant between-group differences were not found in risks for (1) other anxiety, affective, and substance abuse disorders, and (2) simple irrational fears that did not meet disorder criteria. The results suggest that simple phobia is a highly familial disorder that does not transmit increased risk for other phobic or anxiety disorders. The specificity of increased risk among the relatives of simple phobics is consistent with the distinction between simple phobia, social phobia, and agoraphobia. However, complete delineation of the transmissional relationship between these illnesses requires assessment of the extent to which risk for simple phobia can be transmitted by individuals with other phobic or anxiety disorders. Replication of these preliminary findings in larger clinically and epidemiologically selected samples is needed.