Reward-related neural activity and structure predict future substance use in dysregulated youth.

BACKGROUND: Identifying youth who may engage in future substance use could facilitate early identification of substance use disorder vulnerability. We aimed to identify biomarkers that predicted future substance use in psychiatrically un-well youth. METHOD: LASSO regression for variable selection was used to predict substance use 24.3 months after neuroimaging assessment in 73 behaviorally and emotionally dysregulated youth aged 13.9 (s.d. = 2.0) years, 30 female, from three clinical sites in the Longitudinal Assessment of Manic Symptoms (LAMS) study. Predictor variables included neural activity during a reward task, cortical thickness, and clinical and demographic variables. RESULTS: Future substance use was associated with higher left middle prefrontal cortex activity, lower left ventral anterior insula activity, thicker caudal anterior cingulate cortex, higher depression and lower mania scores, not using antipsychotic medication, more parental stress, older age. This combination of variables explained 60.4% of the variance in future substance use, and accurately classified 83.6%. CONCLUSIONS: These variables explained a large proportion of the variance, were useful classifiers of future substance use, and showed the value of combining multiple domains to provide a comprehensive understanding of substance use development. This may be a step toward identifying neural measures that can identify future substance use disorder risk, and act as targets for therapeutic interventions.

Predicting clinical outcome from reward circuitry function and white matter structure in behaviorally and emotionally dysregulated youth.

Behavioral and emotional dysregulation in childhood may be understood as prodromal to adult psychopathology. Additionally, there is a critical need to identify biomarkers reflecting underlying neuropathological processes that predict clinical/behavioral outcomes in youth. We aimed to identify such biomarkers in youth with behavioral and emotional dysregulation in the Longitudinal Assessment of Manic Symptoms (LAMS) study. We examined neuroimaging measures of function and white matter in the whole brain using 80 youth aged 14.0 (s.d.=2.0) from three clinical sites. Linear regression using the LASSO (Least Absolute Shrinkage and Selection Operator) method for variable selection was used to predict severity of future behavioral and emotional dysregulation measured by the Parent General Behavior Inventory-10 Item Mania Scale (PGBI-10M)) at a mean of 14.2 months follow-up after neuroimaging assessment. Neuroimaging measures, together with near-scan PGBI-10M, a score of manic behaviors, depressive behaviors and sex, explained 28% of the variance in follow-up PGBI-10M. Neuroimaging measures alone, after accounting for other identified predictors, explained ~1/3 of the explained variance, in follow-up PGBI-10M. Specifically, greater bilateral cingulum length predicted lower PGBI-10M at follow-up. Greater functional connectivity in parietal-subcortical reward circuitry predicted greater PGBI-10M at follow-up. For the first time, data suggest that multimodal neuroimaging measures of underlying neuropathologic processes account for over a third of the explained variance in clinical outcome in a large sample of behaviorally and emotionally dysregulated youth. This may be an important first step toward identifying neurobiological measures with the potential to act as novel targets for early detection and future therapeutic interventions.

Behavioral and emotional dysregulation trajectories marked by prefrontal-amygdala function in symptomatic youth.

BACKGROUND: Neuroimaging measures of behavioral and emotional dysregulation can yield biomarkers denoting developmental trajectories of psychiatric pathology in youth. We aimed to identify functional abnormalities in emotion regulation (ER) neural circuitry associated with different behavioral and emotional dysregulation trajectories using latent class growth analysis (LCGA) and neuroimaging. METHOD: A total of 61 youth (9-17 years) from the Longitudinal Assessment of Manic Symptoms study, and 24 healthy control youth, completed an emotional face n-back ER task during scanning. LCGA was performed on 12 biannual reports completed over 5 years of the Parent General Behavior Inventory 10-Item Mania Scale (PGBI-10M), a parental report of the child's difficulty regulating positive mood and energy. RESULTS: There were two latent classes of PGBI-10M trajectories: high and decreasing (HighD; n=22) and low and decreasing (LowD; n=39) course of behavioral and emotional dysregulation over the 12 time points. Task performance was >89% in all youth, but more accurate in healthy controls and LowD versus HighD (p<0.001). During ER, LowD had greater activity than HighD and healthy controls in the dorsolateral prefrontal cortex, a key ER region, and greater functional connectivity than HighD between the amygdala and ventrolateral prefrontal cortex (p's<0.001, corrected). CONCLUSIONS: Patterns of function in lateral prefrontal cortical-amygdala circuitry in youth denote the severity of the developmental trajectory of behavioral and emotional dysregulation over time, and may be biological targets to guide differential treatment and novel treatment development for different levels of behavioral and emotional dysregulation in youth.

A systematic review of interventions in the early course of bipolar disorder I or II: a report of the International Society for Bipolar Disorders Taskforce on early intervention.

BACKGROUND: Given the likelihood of progressive illness in bipolar disorder (BD), it is important to understand the benefits and risks of interventions administered early in illness course. We conducted a systematic review of the effectiveness of interventions in the early course of BD I or II. METHODS: We completed a systematic search on MEDLINE, PsycINFO, EMBASE, the Cochrane Central Register of Controlled Trials, CINAHL and Google Scholar from 1/1/1979 till 14/9/2022. We included controlled trials examining intervention effects on symptomatic, course, functional and tolerability outcomes of patients in the 'early course' of BD I or II. We classified patients to be in early course if they (a) were seeking help for the first time for a manic episode, (b) had a lifetime history of up to 3 manic episodes, or (c) had up to 6 lifetime mood episodes. Evidence quality was assessed using the GRADE approach. RESULTS: From 4135 unique publications we included 25 reports representing 2212 participants in 16 randomized studies, and 17,714 participants from nine non-randomized studies. Available evidence suggested that in early illness course, lithium use was associated with lower recurrence risk compared with other mood stabilizers. Mood stabilizers were also associated with better global functioning, compared with the use of antipsychotics in the medium term. While summative findings regarding psychological therapies were limited by heterogeneity, family-focused and cognitive-behavioral interventions were associated with reduced recurrence risk or improved symptomatic outcomes. There was some evidence that the same pharmacological interventions were more efficacious in preventing recurrences when utilized in earlier rather than later illness course. CONCLUSIONS AND RECOMMENDATIONS: While there are promising initial findings, there is a need for more adequately powered trials to examine the efficacy and tolerability of interventions in youth and adults in early illness course. Specifically, there is a compelling need to compare the relative benefits of lithium with other pharmacological agents in preventing recurrences. In addition to symptomatic outcomes, there should be a greater focus on functional impact and tolerability. Effective pharmacological and psychological interventions should be offered to those in early course of BD, balancing potential risks using shared decision-making approaches.

Diffusion imaging markers of bipolar versus general psychopathology risk in youth at-risk.

Bipolar disorder (BD) is highly heritable. Thus, studies in first-degree relatives of individuals with BD could lead to the discovery of objective risk markers of BD. Abnormalities in white matter structure reported in at-risk individuals could play an important role in the pathophysiology of BD. Due to the lack of studies with other at-risk offspring, however, it remains unclear whether such abnormalities reflect BD-specific or generic risk markers for future psychopathology. Using a tract-profile approach, we examined 18 major white matter tracts in 38 offspring of BD parents, 36 offspring of comparison parents with non-BD psychopathology (depression, attention-deficit/hyperactivity disorder), and 41 offspring of healthy parents. Both at-risk groups showed significantly lower fractional anisotropy (FA) in left-sided tracts (cingulum, inferior longitudinal fasciculus, forceps minor), and significantly greater FA in right-sided tracts (uncinate fasciculus and inferior longitudinal fasciculus), relative to offspring of healthy parents (P < 0.05). These abnormalities were present in both healthy and affected youth in at-risk groups. Only offspring (particularly healthy offspring) of BD parents showed lower FA in the right superior longitudinal fasciculus relative to healthy offspring of healthy parents (P < 0.05). We show, for the first time, important similarities, and some differences, in white matter structure between offspring of BD and offspring of non-BD parents. Findings suggest that lower left-sided and higher right-sided FA in tracts important for emotional regulation may represent markers of risk for general, rather than BD-specific, psychopathology. Lower FA in the right superior longitudinal fasciculus may protect against development of BD in offspring of BD parents.

Comparison of fluorescent polarization immunoassay and radioimmunoassay in measuring cortisol levels in prepubertal depressed children.

Cortisol levels of 21 hospitalized prepubertal depressed children given the dexamethasone suppression test (DST) were measured by radioimmunoassay and by fluorescent polarization immunoassay, a new assay method. Correlation analyses demonstrated a highly significant linear relationship between the two methods of measuring cortisol. Thus, it may be possible to use fluorescent polarization immunoassay to measure cortisol levels in children undergoing the DST.

Psychosocial functioning in children after the death of a parent.

Eight weeks after the death of a parent, children from stable families (N = 38) were compared to depressed inpatients (N = 38) and normal children (N = 19). School behavior, interest in school, peer involvement, peer enjoyment, and self-esteem were similar for bereaved and normal children. Bereaved children functioned significantly better than depressed inpatients. As a group, the bereaved children from stable families did not experience significant, acute psychosocial dysfunction.

Depression in recently bereaved prepubertal children.

OBJECTIVE: The purpose of this study was to ascertain depressive symptoms in recently bereaved prepubertal children and compare these symptoms with those of depressed prepubertal children. METHOD: The subjects were 38 children who had recently experienced the death of one but not both of their parents. They had to meet strict inclusion criteria so that the effects of bereavement per se, rather than other significant stressors, could be assessed. The comparison group consisted of 38 hospitalized, depressed children individually matched to each bereaved subject for age, sex, and socioeconomic status. All of the children underwent systematic and comprehensive evaluation. They and their parents were independently evaluated by trained interviewers using the parent and child versions of the Diagnostic Interview for Children and Adolescents. Family histories and basic demographic information were also obtained. RESULTS: The recently bereaved children endorsed many depressive symptoms. Thirty-seven percent of them met the DSM-III-R criteria for a major depressive episode. The depressed children, however, had more depressive symptoms on average than the bereaved children. The factors associated with increased depressive symptoms in the bereaved children were 1) the mother as the surviving parent, 2) preexisting untreated psychiatric disorder in the child, 3) family history of depression, and 4) high socioeconomic status. CONCLUSIONS: A considerable number of the bereaved children developed the clinical symptoms of a major depressive episode immediately after the death of a parent. The relation of these symptoms to the subsequent course of grief and to major depressive disorder remains unknown and should be studied further.

Dexamethasone suppression test and clinical outcome in prepubertal depressed children.

Hospitalized prepubertal depressed children with abnormal dexamethasone suppression test (DST) results were treated and given repeat DSTs at 6 weeks (N = 21) and 5 months (N = 14). DST results were significantly correlated with clinical status at 5 months but not at 6 weeks.

Lithium treatment of manic episodes with psychotic features in prepubertal children.

The authors describe the manic symptoms, family psychiatric histories, and psychotic symptoms of 10 prepubertal children 6-12 years old who had a DSM-III diagnosis of manic episode with psychotic features. All of the children improved when treated with lithium alone. Improvement in both manic and psychotic symptoms was noted an average of 11 days after lithium administration was started.

The dexamethasone suppression test in hospitalized prepubertal depressed children.

The dexamethasone suppression test was performed on 20 hospitalized prepubertal children who met DSM-III criteria for major depressive disorder. Fourteen children (70%) did not suppress cortisol secretion at either 8:00 a.m. or 4:00 p.m. The 4:00 p.m. value alone predicted 93% of the nonsuppressors.

A comparison of the cortisol suppression index and the dexamethasone suppression test in prepubertal children.

Results of the dexamethasone suppression test (DST) and the cortisol suppression index (CSI) were compared in 50 depressed prepubertal children and 36 control subjects. The 4:00 p.m. DST, the two-point DST, and the 8:00 a.m. revised criterion CSI yielded the best results and had similar clinical utility and diagnostic confidence values.

The dexamethasone suppression test in prepubertal depressed children.

The dexamethasone suppression test (DST) was performed in 50 hospitalized prepubertal children who met DSM-III criteria for major depressive episode, 18 hospitalized controls with a psychiatric disorder, and 18 nonhospitalized normal controls. Baseline and post-DST cortisol levels were measured at 8 a.m. and 4 p.m. The depressed children had consistently higher cortisol levels than the controls at baseline and post-DST. The DST was positive in 82% of depressed children, 28% of psychiatric controls, and 11% of normal controls. The results indicate that prepubertal depressed children may have abnormalities in the hypothalamic-pituitary-adrenal axis similar to those in adults with a major depressive illness.

Scaling structured interview data: a comparison of two methods.

OBJECTIVE: Although structured interviews are currently considered essential assessment strategies for conducting research, the data they generate are typically not used for purposes beyond making categorical determinations about diagnoses. Because of the need for dimensional scales to be used in conjunction with categorical data, two dimensional scales constructed from structured interviews are presented and examined. One scale, Behavior, Anxiety, Mood, and Other (BAMO), provides an overall score by summing the percentage of symptoms endorsed for each of 20 behavior, anxiety, mood, and other disorders found in the Diagnostic Interview for Children and Adolescents-Revised (DICA-R, DSM-III-R version). Another scale, DICA-SUM, is constructed by summing all endorsed symptoms on the interview. In this study the psychometric and pragmatic characteristics of BAMO and DICA-SUM are compared. METHOD: Data were obtained from 570 children (331 bereaved, 110 depressed, 129 community) aged 5 to 18 years (mean +/- SD = 11.3 +/- 3.2) who were interviewed as part of an ongoing longitudinal childhood bereavement study from 1987 to 1996. RESULTS: Discriminant and convergent validity with other child psychopathology measures are comparable for BAMO and DICA-SUM. However, BAMO more clearly conveys information regarding the approximate number of diagnoses endorsed. CONCLUSION: This study identified two methods of creating dimensional scales from structured interviews. Use of such dimensional scales might allow for improved comparison of results across studies.

The Mania Rating Scale: can it be used in children? A preliminary report.

The Mania Rating Scale (MRS) was evaluated for use in prepubertal children. Eleven manic and 11 matched controls with attention-deficit hyperactivity disorder were examined. MRS scores were significantly higher in manic versus ADHD children (p less than 0.0001), while scores on hyperactivity rating scales (Conners-Parent and Teacher Forms) did not differ between groups. Most individual MRS item scores differed significantly between groups (p less than 0.05). MRS scores correlated significantly with severity of mania (Clinical Global Impression--Mania, r = 0.84; p less than 0.0001). Age, race, and sex were not correlated with MRS scores. The MRS may be useful in differentiating mania from ADHD and determining the severity of mania in prepubertal children.

Bipolar disorder in children: misdiagnosis, underdiagnosis, and future directions.

Bipolar disorder has not been well studied in prepubertal children, despite its potentially debilitating effects on growth and development. However, there have been case reports of mania in this age group dating back to Esquirol in the mid-19th century. Despite anecdotal case reports, explicit criteria to diagnose mania in children were not used until 1960. Since 1980 the DSM-III/DSM-III-R criteria have indicated adult criteria can be used to diagnose childhood mania, with some modifications to adjust for age differences. Bipolar disorder has not been frequently considered in the psychiatric differential diagnosis of children. However, if a diagnosis of mania is made, clinical rating scales can be used to rate the severity of manic symptoms and to monitor treatment. A manic child should be treated using a biopsychosocial approach. To date, lithium carbonate has been the most commonly used psychopharmacological treatment, but results have been variable. Additional research is needed, including double-blind, placebo-controlled studies to document the beneficial effects of mood-stabilizing medications. Also, diagnostic instruments should be refined to improve their utility. Finally, children at high risk for developing mania should be studied to identify predictors of bipolar disorder in children.

Suicide-bereaved children and adolescents: II. Parental and family functioning.

OBJECTIVE: The current study extends the authors' earlier examination of suicide-bereaved (SB) children from the Grief Research Study, a longitudinal study of childhood bereavement after parental death, by examining the children's family history of psychopathology and family environment before and after death. METHOD: Twenty-six SB children, aged 5 to 17 years, and their 15 surviving parents were compared with 332 children bereaved from parental death not caused by suicide (NSB) and their 201 surviving parents in interviews 1, 6, 13, and 25 months after the death. RESULTS: Suicide completers evidenced more psychopathology than parents who died from reasons other than suicide. Contrary to expectations, surviving SB parents were not more impaired than NSB parents. Before the death, SB families were less stable than NSB families and relationships with the decreased SB parent were compromised. However, no differences were detected between groups in children's relationships with their surviving parents. Likewise, few differences were found in social support or changes in religious beliefs. CONCLUSIONS: SB children generally come from families with a history of psychopathology and substantial family disruption. However, surviving SB parents do not exhibit higher rates of psychopathology than other bereaved parents and many have positive relationships with their children.

Suicide-bereaved children and adolescents: a controlled longitudinal examination.

OBJECTIVE: The current study examined emotional and behavioral sequelae in children who have experienced parental suicide by completing a secondary analysis of data from the Grief Research Study, a longitudinal study of childhood bereavement. METHOD: Twenty-six suicide-bereaved (SB) children, aged 5 to 17 years, were compared with 332 children bereaved from parental death not caused by suicide (NSB) in interviews 1, 6, 13, and 25 months after the death. Children's emotional reactions to the death, psychiatric symptomatology, and psychosocial functioning after the parent's death were determined. RESULTS: Grief emotions were common in both groups. SB children were more likely to experience anxiety, anger, and shame than NSB children. SB children were more likely to have preexisting behavioral problems and more behavioral and anxiety symptoms throughout the first 2 years compared with NSB children. Indices of depression, suicidality, and psychosocial functioning differed minimally between groups. CONCLUSIONS: SB children experience some "common" elements of bereavement. In addition, they demonstrate some lifetime risk factors as well as subsequent pathology that suggests a negative behavioral trajectory. As these cohorts have not yet passed through the age of risk, long-term follow-up is critical.

Children's Interview for Psychiatric Syndromes (ChIPS).

OBJECTIVE: To describe the development and summarize the psychometric properties of the Children's Interview for Psychiatric Syndromes (ChIPS). METHOD: ChIPS is a highly structured interview designed for use by trained lay interviewers in children aged 6-18 years. It screens for 20 Axis I disorders as well as psychosocial stressors. Questions use simple language and short sentence structure to enhance subject comprehension and cooperation. The interview is based on DSM-IV and results are presented in a concise, easy-to-interpret manner. There are both child and parent versions. The psychometric properties of each version were studied. RESULTS: A series of 5 studies has demonstrated the validity of the DSM-III, DSM-III-R, and DSM-IV versions of the ChIPS as well as the validity of the P-ChIPS (parent version). Administration time is relatively brief, averaging 49 minutes for inpatients, 30 minutes for outpatients, and 21 minutes for a community-based sample. CONCLUSIONS: ChIPS can be used as a screening instrument to maximize a clinician's efficiency, as a diagnostic instrument in clinical research, and as a training instrument to help mental health professionals learn psychiatric diagnosis. It can also be used in epidemiological research.

Comparison of lithium dosage methods for preschool- and early school-age children.

OBJECTIVE: Lithium may be useful in the treatment of prepubertal children with bipolar disorder or aggressive conduct disorder. However, there are few dosage guidelines. This study compares two dosage methods reported for prescribing lithium to prepubertal children: (1) a weight-based dosing schedule and (2) a single-dose, kinetics-based method. METHOD: Lithium doses were calculated using each method and then compared with doses actually used in the clinical care of hospitalized children. RESULTS: No statistically significant differences were found between mean lithium dose estimates calculated by the two methods. Average lithium dose estimates for both kinetic and weight-based methods were less than the observed discharge doses. Differences were seen between the two methods for children weighing between 25 and 30 kg. CONCLUSIONS: The weight-based dosing schedule and the single-dose, kinetics-based methods for calculating lithium dose result in similar dosage estimates when applied to young children.