Executive functioning in offspring at risk for depression and anxiety.

BACKGROUND: Executive functioning deficits (EFDs) have been found in adults with major depression and some anxiety disorders, yet it is unknown whether these deficits predate onset of disorder, or whether they reflect acute symptoms. Studies of at-risk offspring can shed light on this question by examining whether EFDs characterize children at high risk for depression and anxiety who are not yet symptomatic. METHODS: This study examined neuropsychological functioning in a sample of 147 children, ages 6-17 years (M age=9.16, SD=1.82), of parents with major depression (MDD) and/or panic disorder (PD) and of controls with neither disorder. Children were assessed via structured diagnostic interviews and neuropsychological measures. RESULTS: Although parental MDD and PD were not associated with neuropsychological impairments, presence of current offspring MDD was associated with poorer performance on several executive functioning and processing speed measures. Children with current generalized anxiety showed poorer verbal memory, whereas children with social phobia had more omissions on a continuous performance task. CONCLUSIONS: Findings suggest that EFDs do not serve as trait markers for developing anxiety or depression but appear to be symptomatic of current disorder.

Disruptive behavior disorders in offspring of parents with major depression: associations with parental behavior disorders.

OBJECTIVE: Although the offspring of parents with major depressive disorder (MDD) are at increased risk to develop disruptive behavior disorders (DBD) in addition to MDD, it remains unclear whether this heightened risk is due to MDD or to comorbid DBD in the parents. METHOD: In a secondary analysis of longitudinal data from offspring at risk for MDD and panic disorder and comparison children, we stratified 169 children of parents who had been treated for MDD based upon presence (n=50) or absence (n=119) of parental history of DBD (ADHD, oppositional disorder, and conduct disorder) and contrasted them with children of parents with DBD but without MDD (n=19) and children whose parents had neither MDD nor DBD (n=106). The children had been assessed in middle childhood using structured diagnostic interviews. RESULTS: Offspring of parents with MDD + DBD had significantly higher rates of MDD, DBD in general, and ADHD in particular, compared with offspring of parents with MDD alone. Offspring of parents with MDD + DBD also had higher rates of mania than controls. Both parental MDD and DBD conferred independent risk for MDD and DBD in the offspring. However, only parental DBD conferred independent risk for conduct disorder and ADHD and only parental MDD conferred independent risk for oppositional defiant disorder. CONCLUSION: Elevated rates of DBD in the offspring of parents with MDD appear to be due in part to the presence of DBD in the parents. Further studies of samples not selected on the basis of parental panic disorder are needed to confirm these results.

The child behavior checklist broad-band scales predict subsequent psychopathology: A 5-year follow-up.

OBJECTIVE: To evaluate the utility of the Child Behavior Check list (CBCL) for identifying children of parents with panic disorder or major depression at high-risk for future psychopathology. METHODS: Baseline Internalizing and Externalizing CBCL T-scores were used to predict subsequent depressive, anxiety, and disruptive behavior disorders at a 5-year follow-up in children of parents with panic disorder, major depression, or neither disorder. RESULTS: The Internalizing scale predicted subsequent agoraphobia, generalized anxiety disorder, separation anxiety disorder, and social phobia. In contrast, the Externalizing scale predicted subsequent disruptive behavior disorders and major depression. CONCLUSIONS: The convergence of these results with previous findings based on structured diagnostic interviews suggests that the CBCL broad-band scales can inexpensively and efficiently help identify children at high risk for future psychopathology within a population of children already at risk by virtue of parental psychopathology.

Clinical outcomes of laboratory-observed preschool behavioral disinhibition at five-year follow-up.

BACKGROUND: Behavioral disinhibition refers to a temperamental tendency to exhibit boldness, approach, and spontaneity in unfamiliar situations. We previously found it to be associated with childhood disruptive behavior and mood disorders, as well as with parental bipolar disorder. In the present study, our objective was to examine the diagnostic outcome in middle childhood of behavioral disinhibition assessed at preschool age among offspring at risk for anxiety and mood disorders. METHODS: The sample consisted of 284 children, including offspring of parents with panic disorder or major depression and comparison offspring of parents without these disorders, who had been assessed with laboratory observations of temperament at ages 21 months to 6 years. We reassessed 215 of the children (77%) at 5-year follow-up (mean age 9.6 years) with structured diagnostic interviews. RESULTS: Compared with noninhibited, nondisinhibited control subjects, behaviorally disinhibited children had higher lifetime rates of comorbid mood plus disruptive behavior disorders and higher current rates of any disruptive behavior disorder and of oppositional defiant disorder. CONCLUSIONS: Behavioral disinhibition appears to be a temperamental antecedent of disruptive behavior disorders and their comorbidity with mood disorders in middle childhood, which may be targeted for preventive intervention.

Developmental trajectories of anxiety disorders in offspring at high risk for panic disorder and major depression.

The objective of this study was to evaluate the longitudinal course of psychiatric disorders in children of parents with and without panic disorder and major depression as they transition through the period of risk from early to late childhood. Over a 5-year follow-up, we compared the course of psychiatric disorders in offspring of parents with panic disorder, major depression, or neither disorder. Subjects consisted of 233 offspring (from 151 families) with baseline and follow-up assessments. Subjects were comprehensively assessed with structured diagnostic interviews. Anxiety disorders at baseline were used to predict anxiety disorders and major depression at follow-up using stepwise logistic regression. Separation anxiety disorder significantly increased the risk for the subsequent development of specific phobia, agoraphobia, panic disorder, and major depression, even after parental panic and depression were covaried. Agoraphobia significantly increased the risk for subsequent generalized anxiety disorder. These findings suggest that separation anxiety disorder is a major antecedent disorder for the development of panic disorder and a wide range of other psychopathological outcomes, and that it increases the risk for subsequent psychopathology even among children already at high familial risk for anxiety or mood disorder.

Behavioral inhibition in preschool children at risk is a specific predictor of middle childhood social anxiety: a five-year follow-up.

OBJECTIVE: Behavioral inhibition (BI) to the unfamiliar represents the temperamental tendency to exhibit fearfulness, reticence, or restraint when faced with unfamiliar people or situations. It has been hypothesized to be a risk factor for anxiety disorders. In this prospective longitudinal study, we compared the psychiatric outcomes in middle childhood of children evaluated at preschool age for BI. METHOD: The baseline sample consisted of 284 children ages 21 months to 6 years, including offspring at risk for anxiety (children of parents with panic disorder and/or major depression) and comparison offspring of parents without mood or major anxiety disorders. They had been assessed for BI using age-specific laboratory protocols. We reassessed 215 of the children (76.5%) at 5-year follow-up at a mean age of 9.6 years using structured diagnostic interviews. RESULTS: BI specifically predicted onset of social anxiety. The rate of lifetime social anxiety (DSM-IV social phobia or DSM-III-R avoidant disorder) was 28% versus 14% (odds ratio [OR] = 2.37; 95% confidence interval [CI]: 1.10-5.10) in inhibited versus noninhibited children. BI significantly predicted new onset of social phobia among children unaffected at baseline (22.2% vs 8.0% in inhibited versus noninhibited children (OR = 3.15, 95% CI: 1.16-8.57). No other anxiety disorders were associated with BI. CONCLUSION: BI appears to be a temperamental antecedent to subsequent social anxiety in middle childhood. Children presenting with BI should be monitored for symptoms of social anxiety and may be good candidates for preventive cognitive behavioral strategies.

Posttraumatic stress disorder symptoms following media exposure to tragic events: impact of 9/11 on children at risk for anxiety disorders.

With the extensive media coverage on September 11, 2001, adults and children indirectly witnessed the terrorist attacks leading to the deaths of almost 3,000 people. An ongoing longitudinal study provided the opportunity to examine pre-event characteristics and the impact of this media exposure. We assessed symptoms of PTSD in 166 children and 84 mothers who had no direct exposure to the 9/11 attacks. The sample included children who had parents with or without anxiety and mood disorders, and who had been assessed for the presence or absence of temperamental behavioral inhibition (BI). We found a 5.4 percent rate of symptomatic PTSD in response to 9/11 in children and 1.2 percent in their mothers. Children's identification with victims of the attack, and for younger children, the amount of television viewing predicted increased risk of PTSD symptoms. Parental depression was associated with higher symptoms, and pre-event levels of family support was associated with a lower risk for PTSD symptoms. BI in children was also linked to lower rates of PTSD symptoms, suggesting that a cautious and fearful approach to novelty may offer protection against exposure to media-based traumatic images. Media viewing of tragic events is sufficient to produce PTSD symptoms in vulnerable populations such as children. Given the links between PTSD symptoms and viewing habits, parental monitoring of media exposure may be important for younger children.

Laboratory-observed behavioral disinhibition in the young offspring of parents with bipolar disorder: a high-risk pilot study.

OBJECTIVE: This study tested whether behavioral disinhibition is more prevalent among offspring of parents with bipolar disorder than among offspring of parents without bipolar disorder. METHOD: The authors conducted a secondary analysis of data from a preexisting high-risk study of offspring at risk for panic disorder and depression (N=278) that had included some children with parents who had bipolar disorder (N=34). Children (ages 2-6) had been classified as behaviorally inhibited, disinhibited, or neither in laboratory assessments. RESULTS: Offspring of bipolar parents had significantly higher rates of behavioral disinhibition than offspring of parents without bipolar disorder. Behavioral inhibition did not differ between groups. Differences were not accounted for by parental panic disorder or major depression or by parental history of attention deficit hyperactivity disorder, conduct disorder, antisocial personality, or substance use disorders. CONCLUSIONS: Results suggest a familial link between bipolar disorder in parents and behavioral disinhibition in their offspring. Behavioral disinhibition may be a familially transmitted predisposing factor for dysregulatory distress later in life.

Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report.

OBJECTIVE: This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. METHOD: A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of or=11 (HRSD(17)>or=14) defined relapse. RESULTS: The QIDS-SR(16) remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps. CONCLUSIONS: When more treatment steps are required, lower acute remission rates (especially in the third and fourth treatment steps) and higher relapse rates during the follow-up phase are to be expected. Studies to identify the best multistep treatment sequences for individual patients and the development of more broadly effective treatments are needed.

Report by the ACNP Task Force on response and remission in major depressive disorder.

This report summarizes recommendations from the ACNP Task Force on the conceptualization of remission and its implications for defining recovery, relapse, recurrence, and response for clinical investigators and practicing clinicians. Given the strong implications of remission for better function and a better prognosis, remission is a valid, clinically relevant end point for both practitioners and investigators. Not all depressed patients, however, will reach remission. Response is a less desirable primary outcome in trials because it depends highly on the initial (often single) baseline measure of symptom severity. It is recommended that remission be ascribed after 3 consecutive weeks during which minimal symptom status (absence of both sadness and reduced interest/pleasure along with the presence of fewer than three of the remaining seven DSM-IV-TR diagnostic criterion symptoms) is maintained. Once achieved, remission can only be lost if followed by a relapse. Recovery is ascribed after at least 4 months following the onset of remission, during which a relapse has not occurred. Recovery, once achieved, can only be lost if followed by a recurrence. Day-to-day functioning and quality of life are important secondary end points, but they were not included in the proposed definitions of response, remission, recovery, relapse, or recurrence. These recommendations suggest that symptom ratings that measure all nine criterion symptom domains to define a major depressive episode are preferred as they provide a more certain ascertainment of remission. These recommendations were based largely on logic, the need for internal consistency, and clinical experience owing to the lack of empirical evidence to test these concepts. Research to evaluate these recommendations empirically is needed.

Antecedents to panic disorder in nonreferred adults.

OBJECTIVE: Previous work has shown that childhood anxiety disorders are unique antecedents for panic disorder. The current study examined both childhood and adult comorbid disorders as potential antecedent disorders to panic disorder in a large sample of nonreferred adults. METHODS: Subjects were 1018 adults with (N = 58) and without (N = 960) panic disorder who were derived from a sample originally ascertained through family studies of probands with and without attention-deficit/hyperactivity disorder (ADHD); data were obtained from 1988 to 1996. Classification and regression trees (CART) analysis was used to examine anxiety and nonanxiety disorders antecedent to panic disorder. RESULTS: CART analysis showed that separation anxiety disorder, social phobia, and simple phobia were unique predictors of subsequent panic disorder. CONCLUSION: These results support and expand previously reported findings in referred samples documenting that comorbid anxiety disorders are unique antecedent risk factors for panic disorder.

Effects of parental anxiety disorders in children at high risk for panic disorder: a controlled study.

BACKGROUND: To examine the association between anxiety disorders in parents and offspring in a sample of children at risk for panic disorder. We hypothesized that individual anxiety disorders will breed true in offspring. METHODS: Comparisons were made between offspring of parents with PD+MD (N=136), PD (N=27), MD (N=27), and Controls (N=103). All subjects were assessed with structured diagnostic interviews. Individual anxiety disorders in the offspring were used as dependent variables in logistic regression models where parental PD status, parental MD, and the same parental anxiety diagnosis were used as independent binary variables. RESULTS: Social phobia and separation anxiety disorder in the offspring were accounted for by the same disorders in the parent, whereas agoraphobia and OCD in the offspring were accounted for by parental panic disorder. CONCLUSIONS: These findings suggest that differing risk factors underlie the expression of individual anxiety disorders in children at risk for panic disorder.

Psychopathology in the young offspring of parents with bipolar disorder: a controlled pilot study.

Studies have suggested that the offspring of parents with bipolar disorder are at risk for a spectrum of psychopathology, but few have focused on children in the youngest age ranges or examined the impact of comorbid parental disorders. We utilized a pre-existing sample of young (mean age: 6.8 years) offspring of parents with bipolar disorder (n=34), of parents with panic or major depression (n=179), and of parents with neither mood or anxiety disorder (n=95). Children were assessed blindly to parental diagnoses using the Schedule for Affective Disorders and Schizophrenia-Epidemiologic version (K-SADS-E). Offspring of bipolar parents had significantly higher rates of disruptive behavior and anxiety disorders than offspring from both of the comparison groups, accounted for by elevated rates of ADHD and overanxious disorder. These comparisons were significant even when lifetime histories of the corresponding categories of comorbid disorders in the parents (disruptive behavior disorders and anxiety disorders) were covaried. In addition, offspring of bipolar parents had increased rates of bipolar I disorder, compared with psychiatric controls. Results support the hypotheses of elevated behavior, anxiety, and mood disorders among offspring at risk for bipolar disorder, and suggest that this psychopathology is already evident in early childhood.

Stratifying Risk for Renal Insufficiency Among Lithium-Treated Patients: An Electronic Health Record Study.

Although lithium preparations remain first-line treatment for bipolar disorder, risk for development of renal insufficiency may discourage their use. Estimating such risk could allow more informed decisions and facilitate development of prevention strategies. We utilized electronic health records from a large New England health-care system between 2006 and 2013 to identify patients aged 18 years or older with a lithium prescription. Renal insufficiency was identified using the presence of renal failure by ICD9 code or laboratory-confirmed glomerular filtration rate below 60 ml/min. Logistic regression was used to build a predictive model in a random two-thirds of the cohort, which was tested in the remaining one-third. Risks associated with aspects of pharmacotherapy were also examined in the full cohort. We identified 1445 adult lithium-treated patients with renal insufficiency, matched by risk set sampling 1 : 3 with 4306 lithium-exposed patients without renal insufficiency. In regression models, features associated with risk included older age, female sex, history of smoking, history of hypertension, overall burden of medical comorbidity, and diagnosis of schizophrenia or schizoaffective disorder (p<0.01 for all contrasts). The model yielded an area under the ROC curve exceeding 0.81 in an independent testing set, with 74% of renal insufficiency cases among the top two risk quintiles. Use of lithium more than once daily, lithium levels greater than 0.6 mEq/l, and use of first-generation antipsychotics were independently associated with risk. These results suggest the possibility of stratifying risk for renal failure among lithium-treated patients. Once-daily lithium dosing and maintaining lower lithium levels where possible may represent strategies for reducing risk.

The corticotropin-releasing hormone gene and behavioral inhibition in children at risk for panic disorder.

BACKGROUND: Behavioral inhibition to the unfamiliar (BI) is a heritable temperamental phenotype involving the tendency to display fearful, avoidant, or shy behavior in novel situations. BI is a familial and developmental risk factor for panic and phobic anxiety disorders. We previously observed an association between BI and a microsatellite marker linked to the corticotropin releasing hormone (CRH) gene in children at risk for panic disorder. To evaluate this further, we genotyped additional families for this marker and a panel of markers encompassing the CRH locus. METHODS: Sixty-two families that included parents with panic disorder and children who underwent laboratory-based behavioral observations were studied. Family-based association tests and haplotype analysis were used to evaluate the association between BI and polymorphisms spanning the CRH locus. RESULTS: We examined a set of markers which we found to reside in a block of strong linkage disequilibrium encompassing the CRH locus. The BI phenotype was associated with the microsatellite marker (p=.0016) and three single nucleotide polymorphisms (SNPs), including a SNP in the coding sequence of the gene (p=.023). Haplotype-specific tests revealed association with a haplotype comprising all of the markers (p=.015). CONCLUSIONS: These results suggest that the CRH gene influences inhibited temperament, a risk factor for panic and phobic anxiety disorders. Genetic studies of anxiety-related temperament represent an important strategy for identifying the genetic basis of anxiety disorders.

Attitudes toward benzodiazepines over the years.

Benzodiazepines have been used extensively for the treatment of anxiety and related disorders since the 1960s. Although they have been proven to be effective as first-line treatment for anxiety disorders, during the 1980s public perception and concern for abuse liability and physical dependence with long-term use gave rise to a great deal of controversy. Negative perceptions toward the use of benzodiazepines for treating anxiety not only caused severely ill patients to go untreated or under-treated but also called into question whether the illness itself was worthy of treatment. Although new pharmacologic and psychological treatments for anxiety are available, psychopharmacologists continue to endorse benzodiazepines as primary or adjunct treatment for anxiety disorders. The intent of this article is to provide a historic overview of these issues and to offer some general clinical principles to help minimize the risk of abuse and dependence with benzodiazepine use.