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.

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.

Suicidal behavior and parental psychopathology in hospitalized depressed children.

This study describes the suicidal behavior of hospitalized depressed children and assesses its relationship to psychopathology and suicidal behavior in their parents. Subjects were 58 consecutively hospitalized prepubertal children with a primary diagnosis of major depressive disorder (MDD), and 58 age- and gender-matched children hospitalized for psychiatric diagnoses other than a mood disorder. Clinical interviews and structured diagnostic instruments were reviewed to determine the children's suicidal behavior and their parents' history of psychopathology. Suicidal ideation, suicidal intent, suicidal plans, and suicide attempts were more frequent in MDD children compared to nondepressed children. When MDD and control samples were stratified as to presence of suicidal behavior in the child, psychopathology was high in parents from all subgroups. Intensity of suicidal behavior in the depressed and non-depressed children was not associated with an altered pattern of psychopathology in their parents. Hospitalized MDD children had increased suicidal behavior compared to inpatient psychiatric control children. However, suicidal behavior in the children was not associated with increased psychopathology or an altered pattern of psychopathology in their parents.

Psychosocial interventions for suicidal children and adolescents.

This paper discusses the role of psychosocial intervention in the treatment of suicidal youth, summarizes the existing relevant literature, describes model programs for treating suicidal youth, and discusses efficacy-to-effectiveness issues in working with this population.

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.

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.

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.

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.

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.

Study I: development and criterion validity of the Children's Interview for Psychiatric Syndromes (ChIPS).

OBJECTIVE: To test the psychometric properties of the Children's Interview for Psychiatric Syndromes (ChIPS), a second-generation structured diagnostic interview designed to improve on the methodology provided by first-generation structured interviews, which have increased diagnostic reliability over unstructured clinical interviews. METHOD: Forty-two children hospitalized on a children's inpatient unit were administered the ChIPS and the Diagnostic Interview for Children and Adolescents (DICA). The level of agreement regarding syndrome presence or absence of 15 diagnoses according to the two instruments was assessed using a standard kappa coefficient or a rare kappa coefficient and percentage agreement. RESULTS: Agreement between the two instruments was significant (p < 0.05) for 13 of 14 diagnoses for which either kappa coefficient could be calculated. Percentage agreement was 98% and 100% for the remaining two diagnoses. ChIPS and DICA results also were compared with a psychiatrist's diagnoses. Sensitivity was 80% for ChIPS and 61% for DICA. Specificity was 78% for ChIPS and 87% for DICA. CONCLUSION: ChIPS is proposed as a valid measure of child psychopathology that offers advantages over existing interviews.

Study III: development and concurrent validity of the Children's Interview for Psychiatric Syndromes--parent version (P-ChIPS).

OBJECTIVE: To assess concurrent validity for the newly developed parent version of the Children's Interview for Psychiatric Syndromes (P-ChIPS). METHOD: ChIPS and P-ChIPS were administered to 36 children 6 to 13 years of age and their parents. P-ChIPS results were compared with clinicians' diagnoses for 21 of those children. Either a standard or rare kappa coefficient and percentage agreement were used to assess concordance. Questions on P-ChIPS have a one-to-one correspondence with questions on the ChIPS, with the only change being from first to third person (e.g. "Have you ever . ." is replaced by "Has your child ever . . ."). RESULTS: There were moderate levels of agreement between the parent and child versions of the instrument, consistent with other reports of parent and child concordance on structured interviews in the literature. Likewise, there were moderate levels of agreement between the parent interview and clinician diagnoses, again consistent with other reports of parent and clinician concordance in the literature. Sensitivity averaged 87% across diagnostic categories, and average specificity was 76%. CONCLUSION: P-ChIPS has adequate psychometric properties for use in clinical settings.

Study II: concurrent validity of the DSM-III-R Children's Interview for Psychiatric Syndromes (ChIPS).

OBJECTIVE: To test the concurrent validity of the Diagnostic and Statistical Manual of Mental Disorders (3rd ed., revised) (DSM-III-R) revised Children's Interview for Psychiatric Syndromes (ChIPS). METHOD: In this study, the DSM-III-R revised ChIPS, the DSM-III-R revised Diagnostic Interview for Children and Adolescents (DICA-R-C), and clinicians' diagnoses were compared in 71 inpatients and outpatients 6 to 13 years of age using a standard kappa coefficient or a rare kappa coefficient and percentage agreement. RESULTS: High levels of agreement were found between the two interviews on all 14 syndromes analyzed (p < 0.05). ChIPS and DICA also had high levels of agreement with clinicians' diagnoses. When DSM-III-R revised ChIPS and DICA-R-C results were discrepant, ChIPS results were somewhat more likely than DICA-R-C results (48 % versus 38%) to agree with the clinician's diagnoses. CONCLUSION: ChIPS appears to be a valid assessment for screening children in inpatient and outpatient mental health facilities. It has the added benefit of being brief, with average administration time of 46 minutes for an inpatient sample and 36 minutes for an outpatient sample.

Study IV: concurrent validity of the DSM-IV revised Children's Interview for Psychiatric Syndromes (ChIPS).

OBJECTIVE: To determine validity of the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) (DSM-IV) revised Children's Interview for Psychiatric Syndromes (ChIPS) in inpatient children and adolescents. METHOD: Participants were 47 psychiatric inpatients 6-12 (n = 23) and 12 to 18 years of age (n = 24). ChIPS was administered to all participants. The Diagnostic Interview for Children and Adolescents-Revised-Child Version (DICA-R-C) was administered to 40 participants. Discharge diagnoses were recorded for all participants. Kappas, low base rate kappas, and percentage agreement were used to assess diagnostic agreement between sources for 18 disorders. RESULTS: ChIPS/DICA-R-C kappas could not be calculated for two disorders because of 100% agreement on their absence. Fourteen of 16 kappas were significant (p < 0.05). The remaining 2 of 16 disorders had 98% agreement (kappax = 0.494, p < 0.157). When ChIPS results were compared with discharge diagnoses, sensitivity for each disorder averaged 70%, whereas specificity averaged 84%. When disagreements occurred between all three sources, ChIPS was somewhat more likely than DICA-R-C to agree with discharge diagnoses (27% versus 22%). Analysis were repeated for children and adolescents, then for boys and girls. Boys and children had fewer significant ChIPS and DICA-R-C kappa coefficients compared with girls and adolescents; this appeared to be related to the fewer number of diagnoses they endorsed. ChIPS/clinician agreement was similar for boys and girls as well as for children and adolescents. Administration time was less for ChIPS than for DICA-R-C (p < 0.08). CONCLUSION: Psychometric properties of the DSM-IV revised ChIPS compare favorably with that of other structured interviews. ChIPS appears to work well for adolescents as well as children.

Study V: Children's Interview for Psychiatric Syndromes (ChIPS): psychometrics in two community samples.

OBJECTIVE: To determine sensitivity and specificity of the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) (DSM-IV) revised Children's Interview for Psychiatric Syndromes (ChIPS) in nonclinical samples. METHOD: Participants were 40 children 6 to 18 years of age from a community sample (n = 22) or a bereaved sample 1 to 2 years following the death of a parent (n = 18). ChIPS and the Diagnostic Interview for Children and Adolescents (DICA-R-C) were administered in a Latin Square design. A consensus conference (CC) of child psychopathology experts determined presence or absence of syndromes or symptoms after reviewing assessment materials not including ChIPS. RESULTS: Sensitivity is commensurate with epidemiologic base rates (17.5% of participants endorsed at least one syndrome). Low base rate kappas and percentage agreement were calculated to determine agreement on symptom or syndrome endorsement for 20 disorders. For syndrome analyses, over half the kappas could not be calculated due to 100% agreement on absence. For symptom analyses, 3 of 20 kappas could not be calculated (100% agreement on absence). Eleven of ChIPS/DICA-R-C symptom kappas were significant (p < 0.04), 2 of 17 had 95% agreement (kappas, p < 0.08), and 4 of 17 had 97.5% agreement (kappas, p < 0.16). Thirteen of 17 ChIPS/CC symptom kappas were significant (p < 0.04), and 4 of 17 had 97.5% agreement (kappas, p < 0.16). CONCLUSION: ChIPS' psychometrics in nonclinical samples compares favorably with that of other structured interviews.

Use and abuse of the Children's Depression Inventory.

This study investigated current uses of the Children's Depression Inventory (CDI), a frequently cited self-report measure for children's depressive symptomatology. Recently published studies of "childhood depression" were reviewed: Half of them used the CDI. Of these studies, 68% did not use a clinical or structured interview to determine diagnostic status. When the CDI was used alone to assess depressive symptoms, 44% of studies referred to high CDI scorers as "depressed" without providing a clear cautionary statement (i.e., either stating that the CDI cannot be used to diagnose depression or clarifying limitations regarding generalization of findings from a nonclinical to a clinical sample). These results are similar to those previously published regarding the Beck Depression Inventory, and they suggest a need for caution in the administration and interpretation of results from self-report inventories for children's depressive symptoms.

Untoward effects of lithium treatment in children aged four through six years.

OBJECTIVE: To explore the relationship between lithium dose and serum lithium level on the occurrence of untoward or toxic effects of lithium in the treatment of 20 hospitalized aggressive and/or mood-disordered children aged 4 through 6 years. METHOD: Clinical and research records of 20 children treated with lithium according to an established inpatient protocol were reviewed. Side effects as reported by psychiatric staff were categorized by organ system affected and severity. RESULTS: During the initial 2 weeks of lithium treatment, 60% of the children manifested one or more types of side effects, most commonly central nervous system effects. Side effects were seen at doses of 25.6 to 52.1 mg/kg per day and at serum levels from 0.65 to 1.37 mEq/L. In general, adverse effects were associated with higher lithium doses and lithium levels and were most common during the first week of treatment. A potential interaction between concurrent infection and more severe side effects was seen. CONCLUSIONS: Side effects occur frequently in children aged 6 years and younger during the initiation phase of lithium treatment; are related to higher milligram per kilogram doses, higher serum lithium levels, and phase of treatment; and may be related to concurrent medical illness.