Lower orbital frontal white matter integrity in adolescents with bipolar I disorder.

ABSTRACT Objective: To examine white matter microstructure, as assessed via diffusion tensor imaging (DTI), in adolescents with bipolar I disorder compared with control volunteers. Method: Twenty-six (12 male and 14 female subjects) adolescents (mean age, 16.0 years) with bipolar I disorder and 26 (14 male and 12 female subjects) control volunteers (mean age, 15.3 years) completed structural and DTI examinations. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) maps were compared between groups in the brain white matter using a voxelwise analysis after intersubject registration to Talairach space. Exploratory analyses were performed to assess structureYfunction correlations in a subgroup of 11 patients with available neuropsychological measures. Results: Compared with the control volunteers, the patients demonstrated abnormalities in white matter regions predicted to differ a priori between groups, including lower FA in the right orbital frontal lobe and higher ADC in the right and left subgenual region (p < .005, uncorrected; cluster size Q 100). There were no areas of higher FA or lower ADC in patients compared with control volunteers. Lower FA across regions that differed significantly between groups correlated significantly with slower visuomotor speed among patients with bipolar disorder. Conclusions: Abnormalities involving the orbital frontal and subgenual white matter in adolescents with bipolar disorder are consistent with neurobiological models that implicate dysregulation of affective systems and impulsivity in the pathophysiology of the disorder. Preliminary findings suggest that white matter abnormalities in pediatric bipolar disorder have functional correlates and may be useful in constructing neurobiological models of the disorder

Type and duration of subsyndromal symptoms in youth with bipolar I disorder prior to their first manic episode

Objectives: The aim of the present study was to systematically evaluate the prodrome to mania in youth. Methods: New-onset/worsening symptoms/signs of \u3e= moderate severity preceding first mania were systematically assessed in 52 youth (16.2 +/- 2.8 years) with a research diagnosis of bipolar I disorder (BD-I). Youth and/or caregivers underwent semi-structured interviews, using the Bipolar Prodrome Symptom Scale-Retrospective. Results: The mania prodrome was reported to start gradually in most youth (88.5%), with either slow (59.6%) or rapid (28.8%) deterioration, while a rapid-onset-and-deterioration prodrome was rare (11.5%). The manic prodrome, conservatively defined as requiring \u3e= 3 symptoms, lasted 10.3 +/- 14.4 months [95% confidence interval (CI): 6.3-14.4], being present for \u3e= 4 months in 65.4% of subjects. Among prodromal symptoms reported in \u3e= 50% of youth, three were subthreshold manic in nature (irritability: 61.5%, racing thoughts: 59.6%, increased energy/activity: 50.0%), two were nonspecific (decreased school/work functioning: 65.4%, mood swings/lability: 57.7%), and one each was depressive (depressed mood: 53.8%) or subthreshold manic/depressive (inattention: 51.9%). A decreasing number of youth had \u3e= 1 (84.6%), \u3e= 2 (48.1%), or \u3e= 3 (26.9%) \u27specific\u27 subthreshold mania symptoms (i.e., elation, grandiosity, decreased need for sleep, racing thoughts, or hypersexuality), lasting 9.5 +/- 14.9 months (95% CI: 5.0-14.0), 3.5 +/- 3.5 months (95% CI: 2.0-4.9), and 3.0 +/- 3.2 months (95% CI: 1.0-5.0) for \u3e= 1, \u3e= 2, or \u3e= 3 specific symptoms, respectively. Conclusions: In youth with BD-I, a relatively long, predominantly slowonset mania prodrome appears to be common, including subthreshold manic and depressive psychopathology symptoms. This suggests that early clinical identification and intervention may be feasible in bipolar disorder. Identifying biological markers associated with clinical symptoms of impending mania may help to increase chances for early detection and prevention before full mania

Post-Acute Effectiveness of Lithium in Pediatric Bipolar I Disorder

This study examined the long-term effectiveness of lithium for the treatment of pediatric bipolar disorder within the context of combination mood stabilizer therapy for refractory mania and pharmacological treatment of comorbid psychiatric conditions

Lithium in Paediatric Patients with Bipolar Disorder: Implications for Selection of Dosage Regimens via Population Pharmacokinetics/Pharmacodynamics

BACKGROUND: Lithium is a well-established treatment for bipolar I disorder in adults. However, there is a paucity of information on its pharmacokinetics/pharmacodynamics in children and adolescents. We aimed to develop the first lithium dosage regimens based on population pharmacokinetics/pharmacodynamics for paediatric patients. METHODS: Lithium concentrations, Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Improvement (CGI-I) scores over 24 weeks were available from 61 paediatric patients with bipolar I disorder. The population pharmacokinetics/pharmacodynamics were co-modelled. Concentrations and clinical effects following several dosage regimens were predicted by Monte Carlo simulations. RESULTS: The pharmacokinetics were well characterised by a two compartment model with linear elimination. Including the effect of total body weight (TBW) or lean body weight (LBW) on clearance and volume of distribution decreased the unexplained inter-individual variability by up to 12 %. The population mean (inter-individual variability) clearance was 1.64 L/h/53 kg LBW0.75 (19 %) and central volume of distribution 23.6 L/53 kg LBW (6.8 %). The average lithium concentration over a dosing interval required for a 50 % reduction in YMRS was 0.711 mEq/L (59 %). A maintenance dose of 25 mg/kg TBW/day lithium carbonate in two daily doses was predicted to achieve a \u3e /=50 % reduction in YMRS in 74 % of patients, while ~8 % of patients would be expected to have trough concentrations above the nominal safety threshold of 1.4 mEq/L. Therefore, therapeutic drug monitoring will still be required even with these dosing strategies. CONCLUSIONS: When accounting for body size, the pharmacokinetic parameters in paediatric patients were within the range of estimates from adults. Pharmacokinetic/pharmacodynamic modelling supported development of practical scientifically-based dosage regimens for paediatric patients