Ema Saito

Lower Orbital Frontal White Matter Integrity in Adolescents With Bipolar I Disorder

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 structure-function 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 >or= 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

The aim of the present study was to systematically evaluate the prodrome to mania in youth.

A placebo-controlled pilot study of adjunctive olanzapine for adolescents with anorexia nervosa.

OBJECTIVE The objective of this study was to explore whether the addition of olanzapine versus placebo increases weight gain and improves psychological symptoms in adolescents with anorexia nervosa-restricting type who are participating in a comprehensive eating disorders treatment program. METHODS Twenty underweight females participated in this 10-week, double-blind, placebo-controlled pilot study of olanzapine. The primary efficacy measure was change in percentage of median body weight measured at baseline and weeks 5 and 10. Secondary efficacy measures included clinician-rated and self-reported measures of psychological functioning measured at 2-week intervals and eating disorder symptoms measured at baseline and weeks 5 and 10 as well as laboratory assessments (including indirect calorimetry), which were also performed at baseline and weeks 5 and 10. A mixed models approach to repeated measures analysis of variance was utilized to detect any treatment-by-time interaction. RESULTS Fifteen of 20 enrolled females (median age, 17.1 years; range, 12.3-21.8 years; mean body mass index, 16.3) completed this 10-week pilot study. Change in % median body weight did not differ between the treatment groups at midpoint or end of study. Both groups gained weight at a similar rate and had similar improvements in eating attitudes and behaviors, psychological functioning, and resting energy expenditure. A trend of increasing fasting glucose and insulin levels was found only in the olanzapine group at week 10. CONCLUSIONS These preliminary findings do not support a role for adjunctive olanzapine for underweight adolescent females with anorexia nervosa-restricting type who are receiving standard care in an eating disorder treatment program (clinical trials.gov; no. NCT00592930).

Lack of Effect of Stimulant Combination with Second-Generation Antipsychotics on Weight Gain, Metabolic Changes, Prolactin Levels, and Sedation in Youth with Clinically Relevant Aggression or Oppositionality

BACKGROUND Second-generation antipsychotics (SGAs) are associated with weight gain, metabolic abnormalities, sedation/sleep disturbance, and prolactin abnormalities, especially in youths. Although stimulants have opposing dopamine receptor and adverse effects, it is unclear whether stimulant co-treatment counteracts the therapeutic or side effects of antipsychotics. METHODS This was a naturalistic cohort study including 153 antipsychotic trials in youths aged 4-19 (mean, 11.3 +/- 3.0) years, started on an SGA for clinically significant aggression or oppositionality associated with oppositional defiant disorder, conduct disorder, disruptive behavior disorder not otherwise specified (NOS), impulse control disorder NOS, intermittent explosive disorder, Tourettes disorder, autistic disorder, and pervasive developmental disorder NOS. Patients underwent fasting assessments of body composition, lipids, glucose, insulin, prolactin, sedation, and general efficacy at baseline, weeks 4, 8, and 12, comparing patients co-prescribed stimulants (n = 71) with those not co-prescribed stimulants (n = 82). RESULTS Patients received risperidone (33.3%), aripiprazole (29.4%), quetiapine (18.4%), olanzapine (11.8%), ziprasidone (5.9%), or clozapine (0.7%). With and without adjustment for differences in baseline variables (sex, prior stimulant use, primary Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition [DSM-IV] disorders, co-morbid attention-deficit/hyperactivity disorder [ADHD], present in 46.3% of youths not receiving stimulants, and some body composition parameters), patients on versus off stimulants did not differ on any of the assessed outcomes (all p values > or = 0.1). CONCLUSIONS In contrast to guidelines, stimulant use did not precede or accompany antipsychotic use during the current episode of aggression/oppositionality in almost half of those youths who had aggressive/oppositional behavior and a DSM-IV diagnosis of ADHD. At the clinically prescribed doses, stimulant co-treatment of SGAs did not seem to significantly reduce antipsychotic effects on body composition, metabolic parameters, prolactin, sedation, and broad efficacy.

Pharmacoepidemiology of antipsychotic use in youth with ADHD: trends and clinical implications.

Although concern has been raised about antipsychotic prescribing to youth with attention-deficit/hyperactivity disorder (ADHD), the available database is limited to individual studies. Therefore, in order to provide a synthesis of prevalence and time trends, we conducted a systematic review and pooled analysis of pharmaco-epidemiologic data on antipsychotic use in ADHD youth. Of 1806 hits, 21 studies (N) were retained that reported analyzable data for three separate populations: 1) antipsychotic-treated youth (N = 15, n = 341,586); 2) ADHD youth (N = 9, n = 6,192,368), and 3) general population youth (N = 5, n = 14,284,916). Altogether, 30.5 ± 18.5 % of antipsychotic-treated youth had ADHD. In longitudinal studies, this percentage increased over time (1998–2007) from 21.7 ± 7.1 % to 27.7 ± 7.7 %, ratio = 1.3 ± 0.4. Furthermore, 11.5 ± 17.5 % of ADHD youth received antipsychotics. In longitudinal studies, this percentage also increased (1998–2006) from 5.5 ± 2.6 % to 11.4 ± 6.7 %, ratio = 2.1 ± 0.6. Finally, 0.12 ± 0.07 % of youth in the general population were diagnosed with ADHD and received antipsychotics. Again, in longitudinal studies, this percentage increased over time (1993–2007): 0.13 ± 0.09 % to 0.44 ± 0.49 %, ratio = 3.1 ± 2.2. Taken together, these data indicate that antipsychotics are used by a clinically relevant and increasing number of youth with ADHD. Reasons for and risk/benefit ratios of this practice with little evidence base require further investigation.

Can Diabetes Mellitus Be Induced by Medication

The possible relation between diabetes mellitus and the use of psychotropic medications in adult psychiatric patients has been discussed in the literature. In child and adolescent psychiatry, however, there have been only two previous case reports of an adolescent who developed diabetes mellitus while receiving psychotropic medications. We present three adolescents who developed diabetes mellitus after combined treatment with divalproex sodium and atypical antipsychotics. All were African American, obese, and had a family history of diabetes mellitus. We discuss each case and examine the possibility of psychotropic medication-induced diabetes mellitus in adolescents.

Prevalence and correlates of antipsychotic polypharmacy in children and adolescents receiving antipsychotic treatment.

Antipsychotic polypharmacy (APP), which is common in adults with psychotic disorders, is of unproven efficacy and raises safety concerns. Although youth are increasingly prescribed antipsychotics, little is known about APP in this population. We performed a systematic PubMed search (last update 26 January 2013) of studies reporting the prevalence of APP in antipsychotic-treated youth. Summary statistics and statistical tests were calculated at the study level and not weighted by sample size. Fifteen studies (n = 58 041, range 68-23 183) reported on APP in youth [mean age = 13.4 ± 1.7 yr, 67.1 ± 10.2% male, 77.9 ± 27.4% treated with second-generation antipsychotics (SGAs)]. Data collected in these studies covered 1993-2008. The most common diagnoses were attention-deficit hyperactivity disorder (ADHD; 39.9 ± 23.5%) and conduct disorder/oppositional defiant disorder (CD/ODD; 33.6 ± 24.8). In studies including predominantly children (mean age = <13 yr, N = 5), the most common diagnosis were ADHD (50.6 ± 25.4%) and CD/ODD (39.5 ± 27.5%); while in studies with predominantly adolescents (mean age = ⩾13 yr, N = 7) the most common diagnoses were schizophrenia-spectrum disorders (28.6 ± 23.8%), anxiety disorders (26.9 ± 14.9%) and bipolar-spectrum disorders (26.6 ± 7.0%), followed closely by CD/ODD (25.8 ± 17.7). The prevalence of APP among antipsychotic-treated youth was 9.6 ± 7.2% (5.9 ± 4.5% in child studies, 12.0 ± 7.9% in adolescent studies, p = 0.15). Higher prevalence of APP was correlated with a bipolar disorder or schizophrenia diagnosis (p = 0.019) and APP involving SGA+SGA combinations (p = 0.0027). No correlation was found with APP definition [⩾1 d (N = 10) vs. >30-⩾90 d (N = 5), p = 0.88]. Despite lacking safety and efficacy data, APP in youth is not uncommon, even in samples predominantly consisting of non-psychotic patients. The duration, clinical motivations and effectiveness of this practice require further study.

Frequency, characteristics and management of adolescent inpatient aggression.

BACKGROUND Inpatient aggression is a serious challenge in pediatric psychiatry. METHODS A chart review study in adolescent psychiatric inpatients consecutively admitted over 24 months was conducted, to describe aggressive events requiring an intervention (AERI) and to characterize their management. AERIs were identified based on specific institutional event forms and/or documentation of as-needed (STAT/PRN) medication administration for aggression, both recorded by nursing staff. RESULTS Among 408 adolescent inpatients (age: 15.2±1.6 years, 43.9% male), 1349 AERIs were recorded, with ≥1 AERI occurring in 28.4% (n=116; AERI+). However, the frequency of AERIs was highly skewed (median 4, range: 1-258). In a logistical regression model, the primary diagnosis at discharge of disruptive behavior disorders and bipolar disorders, history of previous inpatient treatment, length of hospitalization, and absence of a specific precipitant prior to admission were significantly associated with AERIs (R(2)=0.32; p<0.0001). The first line treatment of patients with AERIs (AERI+) was pharmacological in nature (95.6%). Seclusion or restraint (SRU) was used at least once in 59.4% of the AERI+ subgroup (i.e., in 16.9% of all patients; median within-group SRU frequency: 3). Treatment and discharge characteristics indicated a poorer prognosis in the AERI+ (discharge to residential care AERI+: 22.8%, AERI-: 5.6%, p<0.001) and a greater need for psychotropic polypharmacy (median number of psychotropic medications AERI+: 2; AERI-: 1, p<0.001). CONCLUSIONS Despite high rates of pharmacological interventions, SRU continue to be used in adolescent inpatient care. As both of these approaches lack a clear evidence base, and as adolescents with clinically significant inpatient aggression have increased illness acuity/severity and service needs, structured research into the most appropriate inpatient aggression management is sorely needed.

Changes in white matter microstructure predict lithium response in adolescents with bipolar disorder

To investigate whether response to lithium treatment in pediatric bipolar disorder can be predicted by changes in white matter microstructure in key cortico‐limbic tracts involved in emotion regulation.

Outcome of Youth with Early-Phase Schizophrenia-Spectrum Disorders and Psychosis Not Otherwise Specified Treated with Second-Generation Antipsychotics: 12 Week Results from a Prospective, Naturalistic Cohort Study

OBJECTIVES The purpose of this study was to assess differences in the outcomes of youth with schizophrenia-spectrum disorders (SCZ-S) and psychotic disorder not otherwise specified (PsyNOS) during early antipsychotic treatment. METHODS The study was a prospective, naturalistic, inception cohort study of youth ≤19 years old with SCZ-S (schizophrenia, schizoaffective disorder, schizophreniform disorder) or PsyNOS (PsyNOS, brief psychotic disorder) and ≤24 months of lifetime antipsychotic treatment receiving clinicians choice antipsychotic treatment. Baseline demographic, illness and treatment variables, and effectiveness outcomes were compared at 12 weeks last-observation-carried-forward across SCZ-S and PsyNOS patients, adjusting for significantly different baseline variables. RESULTS Altogether, 130 youth with SCZ-S (n=42) or PsyNOS (n=88), mostly antipsychotic naïve (76.9%), were prescribed risperidone (47.7%), olanzapine (19.2%), aripiprazole (14.6%), quetiapine (11.5%), or ziprasidone (6.9%). Compared with those with PsyNOS, SCZ-S youth were older (16.4±2.1 vs. 14.8±3.2, p=0.0040), and less likely to be Caucasian (19.1% vs. 42.5%, p=0.009). At baseline, SCZ-S patients had significantly higher Clinical Global Impressions-Severity (CGI-S) scores (6.0±0.9 vs. 5.5±0.8, p=0.0018) and lower Childrens Global Assessment Scale (CGAS) scores (29.6±9.2 vs. 36.1±8.9, p=0.0002) and were more likely to be in the severely ill CGAS group (i.e., CGAS≤40). SCZ-S and PsyNOS patients did not differ regarding all-cause discontinuation (40.5 vs. 40.3%. p=0.49), discontinuation because of adverse effects (12.2% vs. 12.4%, p=0.97), or nonadherence (29.3% vs. 30.9%, p=0.88), but somewhat more SCZ-S patients discontinued treatment for inefficacy (19.5% vs. 7.4%, p=0.063). CGI-S and CGAS scores improved significantly in both diagnostic groups (p=0.0001, each). Adjusting for baseline differences, PsyNOS patients experienced significantly better CGI-I improvement (CGI-I) scores (p=0.012) and more frequently reached higher categorical CGAS group status (p=0.021) than SCZ-S patients. CONCLUSIONS Both youth with SCZ-S and those with PsyNOS experienced significant improvements with clinicians choice antipsychotic treatment. However, treatment discontinuation was common within 12 weeks, with greater inefficacy-related discontinuation in the SCZ-S group, whereas CGI-I and CGAS score-based improvements were greater in the PsyNOS group.