The effects on children of depressed mothers' remission and relapse over 9 months.

BACKGROUND: The high rate of depression among children of depressed mothers is well known. Suggestions that improvement in maternal acute depression has a positive effect on the child have emerged. However, data on the mechanisms of change have been sparse. The aim was to understand how remission and relapse in the mother might explain the changes in the child's outcome. METHOD: Participants were 76 depressed mothers who entered into a medication clinical trial for depression and 135 of their eligible offspring ages 7-17 years. The mothers and children were assessed at baseline and periodically over 9 months by independent teams to understand the relationship between changes in children's symptoms and functioning and maternal remission or relapse. The main outcome measures were, for mothers, the Hamilton Depression Rating Scale (HAMD), the Social Adjustment Scale (SAS) and the Parental Bonding Instrument (PBI) and, for children, the Children's Depression Inventory (CDI), the Columbia Impairment Scale (CIS), the Multidimensional Anxiety Scale for Children (MASC) and the Children's Global Assessment Scale (CGAS). RESULTS: Maternal remission was associated with a decrease in the child's depressive symptoms. The mother's subsequent relapse was associated with an increase in the child's symptoms over 9 months. The effect of maternal remission on the child's improvement was partially explained by an improvement in the mother's parenting, particularly the change in the mother's ability to listen and talk to her child, but also reflected in her improvement in parental bonding. These findings could not be explained by the child's treatment. CONCLUSIONS: A depressed mother's remission is associated with her improvement in parenting and a decrease in her child's symptoms. Her relapse is associated with an increase in her child's symptoms.

Depression and cognition are associated with lipid dysregulation in both a multigenerational study of depression and the National Health and Nutrition Examination Survey.

Chronic dysregulation of peripheral lipids has been found to be associated with depression and cognition, but their interaction has not been investigated. Growing evidence has highlighted the association between peripheral lipoprotein levels with depression and cognition with inconsistent results. We assessed the association between peripheral lipids, depression, and cognition while evaluating their potential interactions using robust clinically relevant predictors such as lipoprotein levels and chronic medical disorders that dysregulate lipoproteins. We report an association between peripheral lipids, depression, and cognition, suggesting a common underlying biological mechanism driven by lipid dysregulation in two independent studies. Analysis of a longitudinal study of a cohort at high or low familial risk for major depressive disorder (MDD) (n = 526) found metabolic diseases, including diabetes, hypertension, and other cardiovascular diseases, were associated with MDD and cognitive outcomes. Investigating a cross-sectional population survey of adults in the National Health and Nutrition Examination Survey 2011-2014 (NHANES) (n = 2377), depression was found to be associated with high density lipoprotein (HDL) and cognitive assessments. In the familial risk study, medical conditions were found to be associated with chronic lipid dysregulation and were significantly associated with MDD using the structural equation model. A positive association between chronic lipid dysregulation and cognitive scores was found in an exploratory analysis of the familial risk study. In a complementary study, analysis of NHANES revealed a positive association of HDL levels with cognition. Further analysis of the NHANES cohort indicated that depression status mediated the interaction between HDL levels and cognitive tests. Importantly, the protective effect of HDL on cognition was absent in those with depressive symptoms, which may ultimately result in worse outcomes leading to cognitive decline. These findings highlight the potential for the early predictive value of medical conditions with chronic lipid dyshomeostasis for the risk of depression and cognitive decline.

Religiosity and resilience in persons at high risk for major depression.

BACKGROUND: Few studies have examined religiosity as a protective factor using a longitudinal design to predict resilience in persons at high risk for major depressive disorder (MDD). METHOD: High-risk offspring selected for having a depressed parent and control offspring of non-depressed parents were evaluated for psychiatric disorders in childhood/adolescence and at 10-year and 20-year follow-ups. Religious/spiritual importance, services attendance and negative life events (NLEs) were assessed at the 10-year follow-up. Models tested differences in relationships between religiosity/spirituality and subsequent disorders among offspring based on parent depression status, history of prior MDD and level of NLE exposure. Resilience was defined as lower odds for disorders with greater religiosity/spirituality in higher-risk versus lower-risk offspring. RESULTS: Increased attendance was associated with significantly reduced odds for mood disorder (by 43%) and any psychiatric disorder (by 53%) in all offspring; however, odds were significantly lower in offspring of non-depressed parents than in offspring of depressed parents. In analyses confined to offspring of depressed parents, those with high and those with average/low NLE exposure were compared: increased attendance was associated with significantly reduced odds for MDD, mood disorder and any psychiatric disorder (by 76, 69 and 64% respectively) and increased importance was associated with significantly reduced odds for mood disorder (by 74%) only in offspring of depressed parents with high NLE exposure. Moreover, those associations differed significantly between offspring of depressed parents with high NLE exposure and offspring of depressed parents with average/low NLE exposure. CONCLUSIONS: Greater religiosity may contribute to development of resilience in certain high-risk individuals.

The course of major depression in the offspring of depressed parents. Incidence, recurrence, and recovery.

The 2-year course, first onset (incidence), recurrence, and recovery of major depression in 174 offspring at high and low risk for major depression were studied. A variety of predictors of course were examined, including parental diagnosis, demographic and clinical characteristics of the family and offspring, comorbidity and social functioning in offspring, and family risk factors. The 2-year incidence rate was 8.5%. All of the incident cases of major depression occurred in offspring of depressed parents. Additional predictors of incidence were a preceding diagnosis of conduct disorder and subclinical symptoms of depression. The recurrence rate results are tentative because of the small sample. The 2-year recurrence rate was 16.1%. Predictors of recurrence were a previous comorbid diagnosis of dysthymia or problems in social functioning. By the end of 2 years, the majority of offspring (87%) had recovered. The mean number of weeks to recovery was 54 in the offspring of depressed parents and 23 in the offspring of nondepressed parents. Offspring with an onset of major depression at age 13 years or younger, who were exposed to divorce in the family or who had been exposed to more than one parental depressive episode, had significantly more protracted times to recovery. We conclude that there are different predictors of incidence of major depression, its recurrence, and time to recovery in offspring, and that parental depression has an impact on the course in offspring.

Familial aggregation and phenomenology of 'early'-onset (at or before age 20 years) panic disorder.

BACKGROUND: While early age at onset has been associated with increased familial risk, increased clinical severity, and distinctive patterns of comorbidity in a range of psychiatric disorders, it has received limited attention in panic disorder, both in family studies and with respect to clinical presentation. METHODS: A family study of 838 adult first-degree relatives of 152 probands in 3 diagnostic groups (panic disorder with or without major depression, subdivided by age at onset at or before 20 and after 20 years, and screened normal controls) was used to examine familial aggregation of panic disorder by proband age at panic disorder onset. Phenomenology of panic disorder in ill probands and their affected adult first-degree relatives was investigated as a function of proband panic disorder onset at or before 20 vs after 20 years of age. RESULTS: Compared with adult first-degree relatives of normal controls, the risks of panic disorder in adult first-degree relatives of probands with panic disorder onset at or before 20 and after 20 years of age were increased 17-fold and 6-fold, respectively. These findings were not explained by the numerous potential confounding factors that we tested. Age at panic disorder onset did not appear to be specifically transmitted within families. The clinical presentation of panic disorder differed little in either probands or affected relatives by proband age at onset. CONCLUSION: The strikingly elevated risk of panic disorder in relatives of probands with panic disorder onset at or before 20 years of age suggests that age at onset may be useful in differentiating familial subtypes of panic disorder and that genetic studies of panic disorder should consider age at onset.

Offspring of depressed parents. 10 Years later.

BACKGROUND: There have been numerous studies that have shown that offspring of depressed parents are at a high risk for major depressive disorder (MDD) and impairment. None have followed up the offspring into adulthood to obtain more precise estimates of risk. METHOD: One hundred eighty-two offspring from 91 families, in which 1 or more parents had MDD (high risk) or in which neither parent was depressed (low risk), were blindly reassessed in the third follow-up, using a structured diagnostic instrument 10 years after their initial identification. RESULTS: Compared with the offspring for whom neither parent was depressed, the offspring of depressed parents had increased rates of MDD, particularly before puberty, and phobias (both at approximately a 3-fold risk), panic disorder, alcohol dependence (at a 5-fold risk), and greater social impairment. The peak age at onset for MDD in both high- and low-risk offspring ranged from 15 to 20 years. The peak age at onset for anxiety disorder was considerably earlier, especially in female offspring in the high-risk group. The onset of alcohol dependence in the offspring in the high-risk group peaked in adolescence and then after the age of 25 years. The depressed offspring of depressed parents, compared with nondepressed parents, had more serious and impairing depressions during the follow-up period but were less likely to go for treatment. CONCLUSIONS: The offspring of depressed parents are a high-risk group for onset of anxiety disorder and MDD in childhood, MDD in adolescence, and alcohol dependence in adolescence and early adulthood. The findings support the potential value of early detection in the offspring of depressed parents.

Family-genetic studies of psychiatric disorders. Developing technologies.

During the past decade new concepts and technologies have improved the conduct of family-genetic studies in psychiatry. We compiled and critically evaluated these advances, including study design, pedigree collection, diagnostic procedures in adults and children, and epidemiologic and genetic approaches to data analysis. These approaches have improved the collection of accurate information on the nature and patterns of psychiatric illness in families. The data generated from well-designed and well-conducted family studies are useful for the identification of homogeneous subgroups of psychiatric disorders, for understanding the spectrum of psychiatric disorders, for examining the associations between psychiatric disorders, and for studying the continuity between adult and childhood manifestations of psychiatric disorders. Findings from these studies also may enhance our capacity to identify the mode of transmission of the psychiatric disorders and to select potentially informative families for future genetic linkage studies using the new recombinant DNA techniques. The adaptation of these methods to routine clinical practice and new directions in the application of family-genetic studies employing more refined assessments and analytic methods are also discussed.

Brief screening for family psychiatric history: the family history screen.

BACKGROUND: Brief screens to collect lifetime family psychiatric history are useful in clinical practice and for identifying potential families for genetic studies. METHODS: The Family History Screen (FHS) collects information on 15 psychiatric disorders and suicidal behavior in informants and their first-degree relatives. Since each question is posed only once about all family members as a group, the administrative time is 5 to 20 minutes, depending on family size and illness. Data on the validity against best-estimate (BE) diagnosis based on independent and blind direct interviews on 289 probands and 305 relatives and test-retest reliability across 15 months in 417 subjects are presented. RESULTS: Agreement between FHS and BE diagnosis for proband and relative self-report had median sensitivity (SEN) of 67.6 and 71.1 respectively; median specificity (SPC) was 87.6 and 89.4, respectively. Marked decrease in SEN occurred when a single informant (the proband) reported on a relative (median, 37.5); however, median SPC was 95.8. Use of more than 1 informant substantially improved SEN (median, 68.2), with a modest reduction in SPC (median, 86.8). Test-retest reliability across 15 months resulted in a median kappa of 0.56. CONCLUSIONS: The FHS is a promising brief screen for collecting lifetime psychiatric history on an informant and/or first-degree relatives. Its validity is best demonstrated for major depression, anxiety disorders, substance dependence (alcohol and drug dependence), and suicide attempts. It is not a substitute for more lengthy family history if more detail on diagnosis is required.

The relationship between panic disorder and major depression. A new family study.

OBJECTIVE: The comorbidity between panic disorder and major depression (MDD) in individuals has been amply documented. However, data from family studies to determine whether panic disorder and MDD aggregate separately or together in families have been inconclusive, in part because of the absence of studies with the full range of proband groups. This report presents results from a family study with the necessary mutually exclusive groups: panic disorder without MDD, panic disorder with MDD, MDD without panic disorder, and normal controls. METHODS: Diagnostic information was obtained from 193 probands and 1047 of their adult relatives with the Schedule for Affective Disorders and Schizophrenia--Lifetime Version for Anxiety Disorders by direct interview, and/or from multiple informants, without knowledge of proband diagnoses. Best-estimate diagnoses were based on all available information by clinicians independently of data collection and without knowledge of probands' and other relatives' status. RESULTS: Findings indicated the specific and independent transmission of panic disorder and MDD, the separation of panic disorder from MDD, and the nonfamilial nature of late-onset MDD. The pattern of results was unaffected by the use of different diagnostic criteria, number of informants, interview status of relatives, presence of substance abuse or agoraphobia or the sequence of MDD and panic disorder in probands, or whether probands were selected from treatment clinics or community sample. CONCLUSIONS: We conclude that panic disorder and MDD are separate disorders with substantial co-occurrence in individuals, and that panic comorbid with MDD is not a single, distinct disorder. Finally, we illustrate an approach to examining comorbidity in family data through analysis of mutually exclusive, parallel diagnoses in probands and relatives.

Assessing psychiatric disorders in children. Discrepancies between mothers' and children's reports.

Results were compared from independent interviews using the Schedule for Affective Disorders and Schizophrenia for School-aged Children-Epidemiologic Version and DSM-III with 220 subjects (ages 6 to 23 years) and their parent informants. In agreement with results from studies using a variety of structured diagnostic interviews or symptom scales, considerable discrepancies were found between parents' and children's reports on the degree and nature of the child's psychopathology. The children reported more illness about themselves than their parents reported about them. The parents' reports were primarily a subset of the children's reports. Various factors that might affect agreement, including demography, parental clinical status, severity of illness, and treatment, were also explored. The findings that parents under-report psychiatric disorders in their children are comparable with those reported in studies of adults when family informants are used to obtain diagnostic information. Until these parent-child discrepancies can be resolved by longitudinal, family, and other research, diagnostic assessment of children should include direct interviews with them. An independent assessment of the child's diagnosis based on information from multiple informants, including the child, may be the best estimate.

Understanding the clinical heterogeneity of major depression using family data.

For major depression, putative subgroups have been defined by age at onset, clinical severity, symptom patterns, or the presence of other disorders (comorbidity), yet the high degree of overlap in clinical presentation makes it difficult to determine which combination of criteria for defining subgroups best predicts familial aggregation. In dealing with this overlap, we found that only early age at onset, or major depression with an anxiety disorder or secondary alcoholism, were independently related to increased risk of major depression in relatives. Once the effects of these proband factors had been taken into account, endogenous, delusional, melancholic, or autonomous symptom patterns, recurrent depression, history of hospitalization, and suicidal ideation or attempts in probands were not associated with increased risk of major depression in relatives.

Psychiatric disorders in relatives of probands with panic disorder and/or major depression.

BACKGROUND: Panic disorder and major depression (MDD) are both highly familial disorders that co-occur in individuals but do not cosegregate in families. Evidence concerning their familial aggregation with other psychiatric disorders, including phobias, substance abuse, and antisocial personality, has been contradictory. In part, the contradictory findings may be due to failure to account for the effects of proband comorbidity on risks in relatives. METHODS: A family study of 1047 adult first-degree relatives of 193 probands in four diagnostic groups (panic disorder without MDD, panic disorder plus MDD, early-onset MDD, and screened normal controls) was used to determine the range of psychiatric disorders associated with panic disorder and MDD and the effects of proband comorbidity on the rates of disorders in relatives. RESULTS: Compared to relatives of normal controls, relatives of probands with panic disorder or panic disorder and MDD showed significantly increased risks of panic disorder, but relatives of probands with early-onset MDD did not. After proband comorbidity was controlled for, relatives of probands with panic disorder were also at a significantly increased risk for social phobia but not for any other psychiatric disorders. Relatives of probands with early-onset MDD were at significantly increased risk for MDD, dysthymia, abuse of or dependence on alcohol and other drugs, and antisocial personality disorders but not for any other psychiatric disorders. CONCLUSIONS: We conclude that panic disorder is a specific familial entity that is not associated with a broad range of other anxiety or other psychiatric disorders, with the possible exception of social phobia. Dysthymia, substance abuse, and antisocial personality appear to be on the spectrum of early-onset MDD.

Is the comorbidity between social phobia and panic disorder due to familial cotransmission or other factors?

BACKGROUND: We previously reported significantly elevated rates of social phobia in relatives of probands with panic disorder compared with relatives of other proband groups. This study further investigates the relationship between social phobia and panic disorder. METHOD: This sample is from a family study that included 193 probands from four mutually exclusive groups (patients with panic disorder, patients with panic disorder and major depression, patients with early-onset major depression, and normal controls) and 1047 of their adult first-degree relatives. Best-estimate diagnoses were completed using DSM-III-R criteria. RESULTS: Social phobia and agoraphobia aggregate in the families of probands with panic disorder without major depression. Social phobia frequently co-occurs with panic disorder in relatives, but the risk for comorbidity does not vary across proband groups. CONCLUSIONS: The familial aggregation of social phobia with panic disorder may be explained by the aggregation of panic disorder in relatives of probands with panic disorder combined with the tendency for panic disorder to occur comorbidly with social phobia in individuals.

Onset of major depression in early adulthood. Increased familial loading and specificity.

In a family study of 133 probands with major depression and 82 normal control subjects, and 1,518 of their first-degree relatives, we found a substantial inverse relationship between the age of onset of major depression in the probands and the risk of major depression in their relatives. The relatives of probands whose onset of major depression occurred when they were younger than 20 years of age had the highest risk of major depression, compared with the relatives of probands who had later ages of onset or with the relatives of normal subjects. Probands with an age of onset of 40 years or more had familial loading that was only slightly higher than the families of normal control subjects. Our statistical methods enabled us to examine the relationship of the ages of onset in the probands and their relatives while accounting for possible confounding factors. More studies will be needed to sort out secular changes in the rates of the occurrence of major depression among young persons (cohort effect) from the high familial loading of major depression that has its onset in childhood and adolescence, and to determine whether the specificity of transmission of early-onset depression is the result of a single homogeneous disorder.

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.

The cross-national epidemiology of panic disorder.

BACKGROUND: Epidemiological data on panic disorder from community studies from 10 countries around the world are presented to determine the consistency of findings across diverse cultures. METHOD: Data from independently conducted community surveys from 10 countries (the United States, Canada, Puerto Rico, France, West Germany, Italy, Lebanon, Taiwan, Korea, and New Zealand), using the Diagnostic Interview Schedule and DSM-III criteria and including over 40,000 subjects, were analyzed with appropriate standardization for age and sex differences among subjects from different countries. RESULTS: The lifetime prevalence rates for panic disorder ranged from 1.4 per 100 in Edmonton, Alberta, to 2.9 per 100 in Florence, Italy, with the exception of that in Taiwan, 0.4 per 100, where rates for most psychiatric disorders are low. Mean age at first onset was usually in early to middle adulthood. The rates were higher in female than male subjects in all countries. Panic disorder was associated with an increased risk of agoraphobia and major depression in all countries. CONCLUSIONS: Panic disorder is relatively consistent, with a few exceptions, in rates and patterns across different countries. It is unclear why the rates of panic and other psychiatric disorders are lower in Taiwan.

Delusional depression and bipolar spectrum: evidence for a possible association from a family study of children.

Recent pedigree studies demonstrating a possible linkage of bipolar disorder to markers on different chromosomes have included family members with major depression and cyclothymia as affected. There is general agreement that cyclothymia is related to bipolar disorder and that major depression is heterogenous. It is unclear which subtype of major depression is related to bipolar disorder. Data suggesting a relationship between delusional subtype of major depression and bipolar spectrum are presented. The data derive from a direct-interview study of 220 offspring (ages 6 to 23 years) of probands with either delusional or nondelusional major depression and normal controls. The children of delusional as contrasted with nondelusional probands had nearly a threefold increase in cyclothymia, were more often described by health professionals as hyperactive, and had increased school and social impairments. These findings in children replicate earlier findings in adults on the possible relationship between delusional depression and bipolar disorder and its spectrum. The findings must be considered tentative, however, because of the small sample of children in the subgroups of interest.

Selecting early onset MDD probands for genetic studies: results from a longitudinal high-risk study.

Recent studies have found high rates of familial aggregation of major depression (MDD) in relatives of depressed children coming for treatment, leading investigators to suggest that probands for genetic studies of MDD should be selected from samples of depressed children being brought for treatment. Implicit in this recommendation is the assumption that childhood and adult depression are similar disorders. This assumption in turn implies that children with prepubertal or adolescent onset depression are at high risk for having recurrent episodes of MDD that continue into adulthood. The data supporting this latter hypothesis, however, is limited and contradictory. In this article we report results from a high-risk longitudinal family study in which we explored the recurrence and continuity into adulthood of prepubertal or adolescent onset MDD in offspring who were at high or low risk for MDD, by virtue of their parental depression status. One hundred eighteen offspring from 55 families in which one or more parents had MDD and 50 offspring from 21 families in which neither parent had MDD were followed for more than 10 years (all offspring were 20 years or older at the end of follow-up time) and blindly reassessed using a semistructured diagnostic instrument. Offspring with childhood/adolescent onset MDD were at significantly greater risk for recurrence in adulthood (after age 25) as compared with offspring without an onset of childhood/adolescent MDD, if they had a history of parental MDD. In contrast, among offspring without a history of parental MDD, those with childhood/adolescent onset MDD were at no greater risk for continuing to have MDD in adulthood (after age 25) than those without childhood/adolescent onset MDD. Moreover, there was a trend for offspring with childhood/adolescent onset MDD to be at greater risk for recurrence after age 25 if they had a history of parental MDD, as compared with offspring without a history of parental MDD (60 vs. 18%). We conclude that childhood/adolescent onset MDD is a heterogeneous disorder, with family history of MDD appearing to define a subtype of childhood/adolescent onset MDD that is recurrent and continues into adulthood. Our findings suggest that caution should be exercised in selecting depressed children and adolescents brought for treatment as probands in genetic studies of early onset MDD. A conservative strategy would be to select only those depressed children and adolescents with a family history of MDD and reassess the treated sample as they mature, ensuring that they go on to have MDD in adulthood. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:93-101, 2000

Association studies in the presence of comorbidity: design and analysis.

Methods for the design and analysis of allelic association studies in the presence of two comorbid disorders are discussed. These methods are applicable to population-based (i.e., case-control) designs. We first develop probability models that represent pathways to the comorbidity of two disorders when it is hypothesized that at least one of the two disorders is associated with a specific allele. These potential pathways are illustrated with the specific example of the association of the human leptin (OB) gene with obesity and major depressive disorders in humans. We then discuss methods of design and analysis using the well-known methods of log-linear analysis [Bishop et al., 1975: "Discrete Multivariate Analysis." M.I.T. Press, Cambridge, MA] to differentiate between these pathways. With the increasing focus in psychiatric genetics on both association studies and pathways to comorbidity we anticipate that these methods will have wide applications.

The cross national epidemiology of obsessive compulsive disorder. The Cross National Collaborative Group.

Data on the epidemiology of psychiatric disorders from different parts of the world using similar methods and diagnostic criteria have previously not been available. This article presents data on lifetime and annual prevalence rates, age at onset, symptom profiles, and comorbidity of obsessive compulsive disorder (OCD), using DSM-III criteria, from community surveys in seven countries: the United States, Canada, Puerto Rico, Germany, Taiwan, Korea, and New Zealand. The OCD annual prevalence rates are remarkably consistent among these countries, ranging from 1.1/100 in Korea and New Zealand to 1.8/100 in Puerto Rico. The only exception is Taiwan (0.4/100), which has the lowest prevalence rates for all psychiatric disorders. The data for age at onset and comorbidity with major depression and the other anxiety disorders are also consistent among countries, but the predominance of obsessions or compulsions varies. These findings suggest the robustness of OCD as a disorder in diverse parts of the world.