Familial association between attention deficit disorder and anxiety disorders

BACKGROUND AND METHOD: This study tested hypotheses about patterns of familial association between attention deficit disorder (ADD) and anxiety disorders among 356 first-degree relatives of 73 clinically referred children with ADD and 26 normal comparison children. Through structured diagnostic interviews with trained raters, relatives were assessed for adult and childhood psychopathology. After stratifying the sample of ADD probands into those with anxiety disorders and those without, the authors examined patterns of aggregation of ADD and anxiety disorders in the relatives of these probands as well as in the relatives of the normal comparison subjects. RESULTS: Familial risk analyses revealed that 1) familial risk for anxiety disorders was higher among all ADD probands than among the normal subjects; 2) familial risk for ADD was similar in the relatives of the ADD probands and of the probands with ADD and anxiety disorder; 3) the relatives of the ADD probands with and without anxiety disorders were at greater risk for ADD than the relatives of the normal subjects; 4) the risk for anxiety disorders was two times higher in the relatives of the probands who had ADD with anxiety disorder than in those of the ADD probands without anxiety disorders; and 5) there was a tendency for ADD probands' relatives who themselves had ADD to have a higher risk for anxiety disorders than ADD probands' relatives who did not have ADD (cosegregation). CONCLUSIONS: The results were most consistent with the hypotheses indicating that ADD and anxiety disorders segregate independently in families.     

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.     

Parsing the association between bipolar, conduct, and substance use disorders: a familial risk analysis.

BACKGROUND: Bipolar disorder has emerged as a risk factor for substance use disorders (alcohol or drug abuse or dependence) in youth; however, the association between bipolar disorder and substance use disorders is complicated by comorbidity with conduct disorder. We used familial risk analysis to disentangle the association between the three disorders. METHODS: We compared relatives of four proband groups: 1) conduct disorder + bipolar disorder, 2) bipolar disorder without conduct disorder, 3) conduct disorder without bipolar disorder, and 4) control subjects without bipolar disorder or conduct disorder. All subjects were evaluated with structured diagnostic interviews. For the analysis of substance use disorders, Cox proportional hazard survival models were utilized to compare age-at-onset distributions. RESULTS: Bipolar disorder in probands was a risk factor for both drug and alcohol addiction in relatives, independent of conduct disorder in probands, which was a risk factor for alcohol dependence in relatives independent of bipolar disorder in probands, but not for drug dependence. The effects of bipolar disorder and conduct disorder in probands combined additively to predict the risk for substance use disorders in relatives. CONCLUSIONS: The combination of conduct disorder + bipolar disorder in youth predicts especially high rates of substance use disorders in relatives. These findings support previous results documenting that when bipolar disorder and conduct disorder occur comorbidly, both are validly diagnosed disorders.     

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.     

Familial rates of affective disorder. A report from the National Institute of Mental Health Collaborative Study

We examined familial rates of affective disorder and related illness in a cohort of 955 probands studied at five centers in the National Institute of Mental Health Collaborative Study of the Psychobiology of Depression: Boston, Chicago, Iowa City, New York, and St. Louis. Six hundred sixteen of these probands were entered into a family study, and 3423 of their first-degree relatives were evaluated. The probands were divided into five diagnostic groups: schizoaffective-bipolar (n = 37), schizoaffective-depressed (n = 18), bipolar I (n = 151), bipolar II (n = 76), and unipolar (n = 330). The relatives of bipolar I probands had a higher rate of bipolar I illness than the relatives of unipolar probands, but the relatives of unipolar probands did not have a higher rate of unipolar illness than the relatives of bipolar I probands. The relatives of probands with schizoaffective disorder, depressed subtype, had a higher rate of schizophrenia than the relatives of schizoaffective-bipolar probands, suggesting that bipolar schizoaffective disorder may be closer to pure affective disorder while schizoaffective depression may be closer to schizophrenia. An increase in bipolar II illness was also observed in the relatives of bipolar II probands. Overall, these data support the widely accepted distinction between bipolar and unipolar affective disorders.     

Increased morbid risk for schizophrenia in families of in-patients with bipolar illness

BACKGROUND: It has been reported that relatives of probands with severe, psychotic forms of bipolar illness have increased rates of schizophrenia but not the relatives of individuals with milder, non-psychotic forms of disorder. In this study, we examined the prevalence of psychiatric disorders in the first degree relatives of a sample of 103 inpatients with bipolar disorder and in a matched control sample of 84 healthy individuals. METHOD: Relatives of cases and controls were interviewed using the FH-RDC to determine familial morbid risk for schizophrenia and bipolar disorder. Age- and sex-adjusted morbidity risks were calculated in both samples according to the method of Str?mgren. RESULTS: The morbid risks for both bipolar disorder (4.9%) and schizophrenia (2.8%) were higher in relatives of patients than in relatives of controls (0.3% and 0.6% respectively). The relative risks were 14.2 [95% confidence interval (CI)=3.1-64.2] for bipolar disorder and 4.9 (95% CI=1.3-18.8) for schizophrenia. Relatives of women with early onset of bipolar illness had the highest morbid risks for both bipolar illness and schizophrenia. The presence of more than one patient with bipolar disorder in a family increased the risk for schizophrenia nearly fourfold (RR=3.5, 95% CI=1.2-10.2). There was no additional effect of presence of psychotic features. CONCLUSION: Our results suggest that the transmission of psychosis is not disorder-specific. Bipolar illness characterised by a high familial loading is associated with increased risk of schizophrenia in the relatives.     

A family study of nailfold plexus visibility in psychotic disorders.

It has been proposed that the nailfold subpapillary plexus visibility score (PVS) may be a marker of susceptibility to schizophrenia. To further investigate this hypothesis, we evaluated plexus visibility in a sample of 61 chronic schizophrenics, a large sample of first-episode psychotic patients and their first-degree relatives (50 with schizophrenia, and 51 of their relatives; 29 with schizophreniform disorder, 30 of their relatives; 32 with major depression with psychotic features, 35 of their relatives; 33 with a bipolar disorder with psychotic features, 32 of their relatives), and 169 normal control subjects. Group comparisons demonstrated that (1) the probands with chronic schizophrenia, first episode schizophrenia, and schizophreniform disorder did not differ from one another on PVS; (2) these subjects combined had higher PVS ratings than the other two proband groups and normal subjects combined (who did not differ); and (3) none of the relative groups significantly differed from either one another or the normal subjects. On the other hand, relatives of schizophrenia spectrum probands with high PVS (greater than or equal to 10.0) had higher PVS ratings than the relatives of such probands with low PVS. Patterns of familial correlations suggested that PVS was moderately heritable (0.40). There was no evidence that nonadditive genetic variation influenced the trait.     

Association of bipolar and substance use disorders in parents of adolescents with bipolar disorder.

BACKGROUND: We have previously shown that juvenile bipolar disorder (BPD) is a risk for substance use disorders (SUD). Here we examine the expression of both disorders in families of youth with BPD to evaluate the familial risk mechanism. METHODS: We studied 108 adolescent BPD probands with 187 parents (34 with SUD and 58 parents) and 96 control probands with 177 parents with structured interviews. We compared the prevalence of BPD and SUD with Cox proportional hazards models with time to onset of BPD or SUD as the dependent variable and proband diagnosis (Control, BPD, or BPD+SUD) as the independent variable. RESULTS: The parents of the proband youth with BPD (without SUD) and BPD+SUD were more likely to develop BPD than the parents of control subjects [omnibus test chi2=10.18, p=.006]; we found no differences between the two bipolar groups. Parents of proband youth with BPD and with BPD+SUD were more likely than relatives of control subjects to develop SUD [omnibus test chi2=14.69, p<.001]; however, we found no differences between the parents of the two proband bipolar groups. Within the parents of proband youth with BPD+SUD, we found higher risk of SUD in parents with BPD than in those without BPD [chi2=8.39, p=.004], although the frequency of BPD was low in this group of parents. CONCLUSIONS: Bipolar disorder and SUD are prevalent in the first-degree relatives of adolescents with BPD. Adults with BPD were more likely to manifest SUD with preliminary evidence of BPD and SUD cosegregation.     

Family history study of major psychiatric disorders and syndromes

The family history of major psychiatric disorders was examined among relatives of 193 in-patients fulfilling the Research Diagnostic Criteria (RDC) for Schizophrenia, Unspecified Functional Psychoses, Schizoaffective Disorder, Manic Disorder or Major Depressive Disorder. The morbid risk (MR) for schizophrenia was greater among the relatives of probands with non-affective psychoses whereas the MR for mania was greater among the relatives of probands with affective bipolar disorder. When major psychiatric syndromes were examined, only manic syndrome showed familial aggregation.     

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.     

Familial transmission of schizotypal and borderline personality disorders

The authors determined the risk for psychiatric disorders in the first-degree relatives of 36 probands with schizotypal personality disorder (13 definite, 23 probable), 17 probands with borderline personality disorder (two definite, 15 probable), and 90 normal control probands. The relatives of probands with schizotypal personality disorder without a concurrent diagnosis of borderline personality disorder had a significantly greater risk for schizotypal personality disorder than the relatives of normal control probands, borderline probands, or schizotypal probands with coexisting borderline personality disorder. The relatives of borderline probands had a significantly greater risk for definite and probable borderline personality disorder than the relatives of normal control probands.     

Affective disorders in first-degree relatives of adolescent onset bipolars, unipolars, and normal controls

Two hundred and fifty-nine first-degree relatives of 23 adolescent bipolars (81 relatives); 26 unipolars (95 relatives); and 24 normal controls (83 relatives) were assessed for the presence of affective disorders, using the family history method. First-degree relatives of bipolar probands were significantly more likely to have a bipolar illness than those of unipolar probands (p = 0.03) and normal controls (p = 0.001). Rates of unipolar depression in first-degree relatives of bipolars and unipolars were not significantly different but differed significantly between bipolars and normals (p = 0.002) and unipolars and normals (p = 0.006). The implications of these findings for clinical work, diagnosis, and research in adolescents with affective disorders are discussed.     

Comorbid bipolar disorder and panic disorder in families with a high prevalence of bipolar disorder.

OBJECTIVE: Panic attacks are a common complication of affective disorder, although the etiologic relationship of panic and affective symptoms has not been determined. Evidence from a family study suggests that panic attacks and panic disorder may be related genetically to bipolar disorder. This study used diagnostic data from the NIMH Bipolar Disorder Genetics Initiative to assess in a separate, larger family set the familiality of panic combined with bipolar disorder. METHOD: First-degree relatives (N=966) of probands with bipolar I disorder (N=192) and schizoaffective disorder, bipolar type, (N=11) were included in the study. All subjects were interviewed directly and were assigned best-estimate diagnoses for major affective and other psychiatric disorders. The risk of a family member being diagnosed with panic disorder if the proband with bipolar disorder had panic attacks or panic disorder was calculated with logistic regression analysis with generalized estimating equations that controlled for sex and affective disorder subdiagnosis. RESULTS: More than 90% of the probands and first-degree relatives with panic disorder also had an affective disorder diagnosis. Panic disorder was present in 17% of the relatives with recurrent major affective disorder and in 3% of the relatives without recurrent major affective disorder. Risk of panic disorder in relatives with bipolar disorder was increased significantly if the proband had panic attacks or panic disorder. CONCLUSIONS: Risk for panic disorder with familial bipolar disorder appears to be inherited. Inherited risk for panic disorder with bipolar disorder may indicate a shared genetic etiology for both disorders in some families. The patterns of bipolar disorder and panic disorder comorbidity observed in families imply a complex genetic etiology, which may be elucidated by using endophenotypes.     

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.     

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 rates of affective illness in Sardinia with special reference to schizoaffective disorder

Summary Familial rates of psychiatric disorders were studied in southern Sardinia and showed an increase in relatives of probands with the following research diagnostic criteria (RDC) diagnoses: normal, unipolar depression, schizoaffective depressive, schizoaffective bipolar, bipolar with mania and bipolar with hypomania. A significantly higher risk for bipolar schizoaffective disorder was observed in relatives of bipolar schizoaffectives compared with relatives of normal probands.Supported by a grant from Regione Autonoma della Sardegna, Assessorato all'Igiene e Sanità     

Executive function in parents of patients with familial versus sporadic bipolar disorder

ObjectiveStudies investigating the cognitive function of healthy relatives of patients with bipolar disorder are conflicting, and the neurocognitive profile of relatives of bipolar disorder probands is still unclear. We aimed to evaluate executive function in unaffected parents of familial and sporadic patients with bipolar disorder.MethodsThe study included 24 unaffected familial parents (FP) of patients with bipolar disorder, 26 unaffected sporadic parents (SP) of patients with bipolar disorder and 26 controls matched with the parents for gender, age and duration of education (76 subjects in total). All of the subjects were interviewed with the Structured Clinical Interview for DSM-IV-Axis I. Executive function was assessed using the California Verbal Learning Test (CVLT), the Trail Making Test (TMT), the Wisconsin Card Sorting Test (WCST) and the Stroop test.ResultsIn comparison to their respective matched controls, FP performed significantly worse on the CVLT, TMT, WCST and Stroop test, whereas SP performed significantly worse only on WCST perseverative errors and Stroop color test. FP performed significantly worse than SP on the CVLT, TMT, and WCST.ConclusionThe present study investigated relatives with and without a family history of bipolar disorder separately and found that executive function was impaired in parents with a positive family history of bipolar disorder. These findings bring more evidence suggesting that deficits in prefrontal executive function and verbal memory are associated with familial vulnerability to bipolar disorder and that executive function and verbal memory impairments may represent a potential endophenotype of bipolar disorder.     

No evidence for physical anhedonia as a candidate symptom or an endophenotype in bipolar affective disorder

OBJECTIVES: Bipolar affective disorder (BPAD) is clinically and genetically heterogeneous and the affected phenotype is poorly defined, hampering studies of its genetic basis. Studies of specific, familial, clinical indicators of BPAD may be useful for identifying heritable forms. Homogeneous forms of the disease may be identified in patients (candidate symptom approach) and some vulnerability markers may be sought in unaffected relatives of patients (intermediate traits or endophenotypes). Physical anhedonia (PA) is considered a possible candidate symptom and endophenotype in schizophrenia, but has never been specifically investigated in BPAD. METHODS: Physical anhedonia scores (measured using Chapman's Physical Anhedonia Scale) were compared in 351 euthymic bipolar patients, 130 of their first-degree relatives and 170 healthy controls with no personal or familial history of schizophrenia, mood disorders or suicidal behavior. We investigated intrafamilial resemblance of PA and compared the progressive and clinical characteristics of hedonic and anhedonic bipolar probands. RESULTS: Physical anhedonia was a stable trait in normothymic bipolar patients and significant intrafamilial correlation of PA scores was observed in bipolar families. However, PA scores were similar in unaffected relatives and controls and the clinical characteristics of anhedonic and hedonic patients did not differ significantly. Physical anhedonia was not associated with an increased familial risk for bipolar disorder. CONCLUSIONS: Physical anhedonia is a stable, familial dimension in BPAD families. It cannot be considered an endophenotype because unaffected relatives of bipolar patients and healthy controls have similar PA scores. It also cannot be considered a candidate symptom because it does not identify a homogeneous clinical and familial sub-group of bipolar patients. Given the results of previous studies, PA might be a specific candidate symptom (and endophenotype) to schizophrenia. However, the validation of this hypothesis requires replication studies in bipolar disorder and schizophrenia and further investigations in other psychiatric diseases (in particular across the mood disorder spectrum).     

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 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.