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.

Comorbid anxiety and substance use disorders associated with a lower use of mood stabilisers in patients with rapid cycling bipolar disorder: a descriptive analysis of the cross-sectional data of 566 patients.

OBJECTIVE: To study mood stabiliser treatment in patients with bipolar disorder with or without anxiety disorders (ADs) and/or substance use disorders (SUDs). METHODS: Extensive clinical interview and Mini-International Neuropsychiatric Interview were used to ascertain DSM-IV diagnoses of rapid cycling bipolar I (RCBDI) or II (RCBDII), SUDs and ADs. Previous treatment statuses with a mood stabiliser after the first onset of mania/hypomania (unmedicated, mismedicated and correctly medicated) were retrospectively determined in patients enrolled into four similar clinical trials. T-test and chi-square/Fisher's exact were used wherever appropriate. RESULTS: Of 566 patients (RCBDI n = 320, RCBDII n = 246), 46% had any lifetime AD, 67% had any lifetime SUD and 40% had any recent SUD. Overall, 12% of patients were unmedicated, 37% were mismedicated at the onset of first mania/hypomania and 51% were correctly medicated. Presence of lifetime ADs and recent SUDs was associated with fewer mood stabiliser treatments. Patients with RCBDI were more likely correctly medicated than those with RCBDII (OR = 3.64) regardless of the presence (OR = 2.6) or absence (OR = 4.2) of ADs, or the presence (OR = 2.8) or absence (OR = 3.13) of recent SUDs. Presence of lifetime ADs and recent SUDs increased the risk for mismedicated in RCBDI with odds ratios of 1.8 and 1.9, respectively, but not in RCBDII. CONCLUSION: In this multi-morbid cohort of patients with RCBD, 51% of patients (64% of RCBDI and 33% with RCDBII) were correctly medicated with a mood stabiliser after the onset of first mania/hypomania. The presence of ADs and SUDs was associated with an increased risk of mismedicated in patients with RCBDI, but not with RCBDII.

Altered prefrontal lobe oxygenation in bipolar disorder: a study by near-infrared spectroscopy.

BACKGROUND: Previous studies have reported prefrontal cortex (PFC) pathophysiology in bipolar disorder. METHOD: We examined the hemodynamics of the PFC during resting and cognitive tasks in 29 patients with bipolar disorder and 27 healthy controls, matched for age, verbal abilities and education. The cognitive test battery consisted of letter and category fluency (LF and CF), Sets A and B of the Raven's Colored Progressive Matrices (RCPM-A and RCPM-B) and the letter cancellation test (LCT). The tissue oxygenation index (TOI), the ratio of oxygenated hemoglobin (HbO2) concentration to total hemoglobin concentration, was measured in the bilateral PFC by spatially resolved near-infrared spectroscopy. Changes in HbO2 concentration were also measured. RESULTS: The bipolar group showed slight but significant impairment in performance for the non-verbal tasks (RCPM-A, RCPM-B and LCT), with no significant between-group differences for the two verbal tasks (LF and CF). A group x task x hemisphere analysis of variance (ANOVA) on the TOI revealed an abnormal pattern of prefrontal oxygenation across different types of cognitive processing in the bipolar group. Post hoc analyses following a group x task x hemisphere ANOVA on HbO2 concentration revealed that the bipolar group showed a greater increase in HbO2 concentration in the LCT and in RCPM-B, relative to controls. CONCLUSIONS: Both indices of cortical activation (TOI and HbO2 concentration) indicated a discrepancy in the PFC function between verbal versus non-verbal processing, indicating task-specific abnormalities in the hemodynamic control of the PFC in bipolar disorder.

New data on the use of lithium, divalproate, and lamotrigine in rapid cycling bipolar disorder.

The rapid cycling variant of bipolar disorder is defined as the occurrence of four periods of either manic or depressive illness within 12 months. Patients suffering from this variant of bipolar disorder have an unmet need for effective treatment. This review examines two major studies in an attempt to update understanding of the current therapies available to treat rapid cycling patients. The first trial compares lamotrigine versus placebo in 182 patients studied for 6 months. The second is a recently completed, 20-month trial comparing divalproate and lithium in 60 patients. Both trials had a double-blind, randomized parallel-group design. The data from the latter study indicate that there are no large differences in efficacy between lithium and divalproate in the long-term treatment of rapid cycling bipolar disorder. In addition, lamotrigine has the potential to complement the spectrum of lithium and divalproate through its greater efficacy for depressive symptoms.

Rapid, continuous cycling and psychiatric co-morbidity in pediatric bipolar I disorder.

OBJECTIVES: The primary purpose of this study was to describe the clinical presentation of bipolar I disorder (BP-I) as it occurs in children and adolescents and to assess whether the manifestations of BP-I were similar in both age groups. METHOD: Ninety youths between the ages of 5 and 17 years meeting full diagnostic symptom criteria for BP-I were included in this study. The diagnosis of BP-I was established for these youths based on the results of a semi-structured diagnostic interview and a clinical assessment by a child and adolescent psychiatrist. The course of a subset of these youngsters' illnesses was assessed using the Life Charting Method (LCM). Data regarding the clinical presentation, longitudinal history, psychiatric co-morbidities and parental psychopathology were also obtained. RESULTS: The clinical presentation of BP-I was similar in children and adolescents. Youths meeting diagnostic criteria for BP-I developed an average of approximately 5.8 of the 7 symptoms of mania during periods of elevated or irritable mood. BP-I was found to be a cyclic disorder characterized by high rates of rapid cycling (50%) with almost no inter-episode recovery. Almost 75% of these subjects also met diagnostic symptom criteria for a disruptive behavior disorder. High rates of mood disorders were found in fathers. CONCLUSIONS: These data suggest that the presentation of juvenile BP-I is a cyclic and valid clinical condition with manifestations on a continuum with the later-onset forms of this illness.

Discriminative validity of parent report of hypomanic and depressive symptoms on the General Behavior Inventory.

It often is difficult clinically to differentiate bipolar disorder from other mental health conditions in young people. This study evaluated a parent report measure of depressive and hypomanic/biphasic symptoms. Parents of 196 youths, who were 5 to 17 years old and presented at an outpatient research center, completed an adapted General Behavior Inventory (GBI). Factor analyses suggested two dimensions, depression (alpha = .97) and biphasic/hypomania (alpha = .95). Logistic regressions using these scales discriminated mood disorder versus disruptive behavior disorder or no diagnosis, unipolar versus bipolar disorder, and bipolar versus disruptive behavior disorder based on structured interviews. Classification rates exceeded 80%, and receiver operating characteristic analyses showed good diagnostic efficiency for the scales, with areas under the curve greater than .80. Results indicate that clinicians can use the parent-completed GBI to derive clinically meaningful information about mood disorders in youths.

Short-term cardiovascular effects of methylphenidate and adderall.

OBJECTIVE: The primary purpose of this study was to examine the cardiovascular effects of Adderall (ADL) in a clinic-based group of youths with attention-deficit/hyperactivity disorder ranging in age from 4 to 17 years. METHOD: One hundred thirty-seven patients were treated with either methylphenidate (MPH) or ADL. Youths prescribed MPH were given medication twice daily, and youths treated with ADL received medication once daily. Patients were evaluated under five conditions: baseline, placebo, 5 mg/dose, 10 mg/dose, or 15 mg/dose. Resting pulse, diastolic blood pressure, and systolic blood pressure were examined after 1 week at each treatment condition. Changes from baseline on these parameters were examined. RESULTS: The short-term cardiovascular effects of both ADL and MPH were modest. No patients experienced any clinically significant change in these cardiovascular measures during the course of this brief trial. CONCLUSION: Since the short-term cardiovascular effects of ADL appear minimal, specific cardiovascular monitoring during short-term ADL treatment at doses of 15 mg/day or less does not appear to be indicated. In addition, under similar conditions, using similar methods, both medication treatments led to changes in blood pressure and pulse that were clinically insignificant.

Paediatric psychopharmacology: closing the gap between science and practice.

Children and adolescents do not always respond to treatment with psychotropic agents in a similar fashion to adults. Differences in safety and therapeutic response may occur across the life cycle. For example, despite the fact that tricyclic antidepressants are traditionally the 'gold standards' of pharmacotherapy for depressed adults, it does not seem that youths with depression benefit from treatment with these agents [1]. Similarly, it appears that earlier age at onset is associated with a reduced propensity to respond to neuroleptics for patients with schizophrenia [2]. In addition, young patients have been noted to be at higher risk for developing neuroleptic-induced extrapyramidal side effects when compared to adults [3]. Simply put, what is known about the safety and effectiveness of psychotropic compounds in adults cannot necessarily be presumed to be applicable to teenagers or children.

Prevention of recurrent postpartum depression: a randomized clinical trial.

BACKGROUND: Women who have suffered one episode of postpartum-onset major depression (PPMD) comprise a high-risk group for subsequent episodes. We conducted a double-blind, randomized clinical trial to test the efficacy of nortriptyline in the prevention of recurrent PPMD. METHOD: Nondepressed women who had at least one past episode of PPMD (Research Diagnostic Criteria) were recruited during pregnancy. Subjects were randomly assigned to nortriptyline or placebo. Treatment began immediately postpartum. Each subject was assessed for 20 sequential weeks with the Hamilton Rating Scale for Depression and Research Diagnostic Criteria for recurrence of major depression. RESULTS: No difference was found in the rate of recurrence in women treated with nortriptyline compared with those treated with placebo. Of 26 subjects who took nortriptyline preventively, 6 (0.23, 95% exact confidence interval [CI] = 0.09 to 0.44) suffered recurrences. Of 25 subjects who took placebo, 6 (0.24, 95% exact CI = 0.09 to 0.45) suffered recurrence (Fisher exact p = 1.00). CONCLUSION: Nortriptyline did not confer additional preventive efficacy beyond that of placebo. The rate of recurrence of PPMD (one fourth of women) was unacceptably high.

Developmental aspects of psychostimulant treatment in children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVES: To examine the relationship between age and short-term clinical response to psychostimulant treatment in youths with attention-deficit/hyperactivity disorder (ADHD) and to examine whether weight-corrected doses of optimized psychostimulant therapy varied as a function of patient age. METHOD: One hundred seventy-seven patients were treated with either methylphenidate (MPH) or Adderall (ADL). Sixty-six youths received ADL and 111 patients were treated with MPH. All youths were evaluated at baseline and after receiving a week of treatment at each blinded, randomized dose level (placebo, 5, 10, or 15 mg). A "best dose" for each patient was assigned before the medication blind was broken. Behavioral ratings by both teachers and parents were examined for dose and medication effects. RESULTS: The medications had similar efficacy in children and teenagers. Older youths, however, benefited from a smaller weight-adjusted dose of medication than did the younger children. Similar efficacy was observed between the medications. CONCLUSIONS: These data suggest that psychostimulants are equally effective in treating children and adolescents with ADHD. Adolescents with ADHD may not necessarily require more medication than younger children to achieve a similar therapeutic response.

Nefazodone pharmacokinetics in depressed children and adolescents.

OBJECTIVE: To describe the pharmacokinetics and safety of nefazodone (NFZ) in depressed children and adolescents. METHOD: Depressed youths aged 7 to 17 years were eligible to participate. Intensive sampling for pharmacokinetic analyses of NFZ and 3 of its active metabolites was performed after single and multiple dose administration. Treatment was continued for 6 more weeks and titrated to maximize clinical response. RESULTS: Twenty-eight patients were enrolled. Systemic exposure to NFZ and 3 metabolites was generally higher in children than adolescents. NFZ and metabolite disposition profiles showed high intra- and interpatient variability. Compared to published data in adults, the half-life of NFZ and 2 of its metabolites appears shorter in children and adolescents. Meta-chlorphenylpiperazine pharmacokinetic parameters were different in 5 patients determined to be poor metabolizers of cytochrome P450 2D6 (CYP2D6). NFZ was well tolerated, and administration was associated with significant reductions (p < .001) in depressive symptoms. CONCLUSIONS: The pharmacokinetics of NFZ in pediatric patients is highly variable. NFZ appears to be safe in this small, short-term study. Pediatric patients who are poor metabolizers of CYP2D6 do not appear to be at increased risk for NFZ-associated adverse events. Open-label treatment of NFZ is associated with reductions in depressive symptoms.

A double-blind pilot study of risperidone in the treatment of conduct disorder.

OBJECTIVE: To examine whether risperidone is superior to placebo in the treatment of youths with conduct disorder. METHOD: This was a 10-week, randomized, double-blind, placebo-controlled study with 2 parallel arms. Ten youths were randomly assigned to receive placebo and 10 youths were randomly assigned to receive risperidone. Patients were seen weekly throughout the trial. Medications could be increased at weekly intervals during the first 6 weeks of the study from an initial dose of 0.25 mg or 0.50 mg each morning, depending on patient weight. Patients weighing less than 50 kg had a maximum total daily dose of risperidone of 1.5 mg. Patients weighing 50 kg or greater had a maximum total daily dose of risperidone of 3.0 mg. The primary outcome measure was the Rating of Aggression Against People and/or Property Scale. RESULTS: Risperidone was superior to placebo in ameliorating aggression on most measures. Risperidone was reasonably well tolerated, with none of the risperidone-treated patients developing extrapyramidal side effects. CONCLUSIONS: These data provide preliminary evidence that risperidone may have efficacy in the treatment of youths with conduct disorder. Because of the small sample size and the brief length of this study, further research is necessary to confirm these findings.

Paediatric uses of atypical antipsychotics.

Antipsychotics are commonly prescribed to children and adolescents. With the relatively recent availability of the atypical antipsychotics, physicians have begun prescribing these agents to young people in the hope of finding safe, effective alternatives to the typical antipsychotics. This report reviews what is currently known about the use of the atypical antipsychotics in young people. Most of the currently available data are based on case reports and case series. The results of only a handful of prospective trials pertaining to the use of the atypical antipsychotics in youths have been reported. Based on the available information, it appears that clozapine has a role in juvenile treatment resistant schizophrenia. When considered as a group, the 'first-line' atypical antipsychotics risperidone, olanzapine and quetiapine appear to have promise as treatments for several neuropsychiatric disorders in young people. These conditions include psychotic, mood, disruptive, movement and pervasive developmental disorders. Unfortunately, as has historically been the case, the demand to address the clinical needs of young patients with neuropsychiatric disorders has outpaced empirically based information. This is particularly important because significant side effects can occur when children or adolescents are treated with atypical antipsychotics. Since there is a paucity of short-term and almost no long-term safety data pertaining to these agents in young people, careful consideration must be made prior to initiating atypical antipsychotic treatment for a child or teenager. Based upon what is known about these agents, a rational approach to the use of these drugs in juveniles is offered.

The rationale, design, and progress of two novel maintenance treatment studies in pediatric bipolarity.

INTRODUCTION: There are no definitively established acute or maintenance treatments for juvenile bipolar disorder. METHOD: Two randomized, blind, maintenance clinical trials in children and adolescents with bipolar disorders are ongoing at the University Hospitals of Cleveland/Case Western Reserve University Stanley Clinical Research Center for bipolar disorder. The first is comparing the safety and effectiveness of lithium carbonate (Li+) to divalproex sodium (VPA) for up to 76 weeks in youths with stabilized bipolar illness (type 1 or 2). The second study is designed to compare the efficacy of VPA to placebo in the acute management of subsyndromal symptoms of bipolar disorder ('cyclotaxia') and the prevention of the full syndrome in children at risk. Both studies use the prospective life-chart method as an outcome measure. RESULTS: Sixty-six youths have received study medication as part of the trial that is comparing Li+ to VPA as a maintenance therapy. In addition, 32 youths have received blinded treatment as part of the 'cyclotaxia' prevention study. Combination Li+A/PA treatment appears generally well tolerated and seems to have robust anti-manic and antidepressant effects. DISCUSSION: Since the blind has not been broken on either of these clinical trials, conclusions about the maintenance effectiveness of either VPA or Li+ in youths with bipolar disorder type 1 or 2 cannot be made yet. Similarly, it is unclear whether VPA is superior to placebo in genetically high-risk youths with cyclotaxia. The final results of these trials should provide valuable information about the treatment of juvenile bipolar disorders.