The Motivational Determinants of Human Action, Their Neural Bases and Functional Impact in Adolescents With Obsessive-Compulsive Disorder.

Background: Establishing the motivational influences on human action is essential for understanding choice and decision making in health and disease. Here we used tests of value-based decision making, manipulating both predicted and experienced reward values to assess the motivational control of goal-directed action in healthy adolescents and those with obsessive-compulsive disorder (OCD). Methods: After instrumental training on a two action-two outcome probabilistic task, adolescents (n = 21) underwent Pavlovian conditioning using distinct stimuli predicting either the instrumental outcomes, a third outcome, or nothing. We then assessed functional magnetic resonance imaging during choice tests in which we varied the predicted value, using specific and general Pavlovian-instrumental transfer, and the experienced value, using outcome devaluation. To establish functional significance, we tested a matched cohort of adolescents with OCD (n = 20). Results: In healthy adolescents, both predicted and experienced values influenced the performance of goal-directed actions, mediated by distinct orbitofrontal-striatal circuits involving the lateral orbitofrontal cortex (OFC) and medial OFC, respectively. However, in adolescents with OCD, choice was insensitive to changes in either predicted or experienced values. These impairments were related to hypoactivity in the lateral OFC and hyperactivity in the medial OFC during specific Pavlovian-instrumental transfer and hypoactivity in the anterior prefrontal cortex, caudate nucleus, and their connectivity in the devaluation test. Conclusions: We found that predicted and experienced values exerted a potent influence on the performance of goal-directed actions in adolescents via distinct orbitofrontal- and prefrontal-striatal circuits. Furthermore, the influence of these motivational processes was severely blunted in OCD, as was the functional segregation of circuits involving medial and lateral OFC, producing dysregulated action control.

Bipolar disorder subtypes in children and adolescents: demographic and clinical characteristics from an Australian sample.

BACKGROUND: Bipolar disorder (BD) phenomenology in children and adolescents remains contentious. The study investigated Australian children and adolescents with bipolar I disorder (BD-I), bipolar II disorder (BD-II), or BD not otherwise specified (BD-NOS). METHODS: Index episode demographics, symptomatology, functioning and diagnostic data were compared for 88 participants (63 female) aged 8-18 years (M=14.8, SD=2.5) meeting DSM-IV-TR criteria for BD-I (n=24), BD-II (n=13) or BD-NOS (n=51). RESULTS: BD-I had higher rates of previous episodes, psychotropic medication (compared to BD-II but not BD-NOS), rates of inpatient admissions (compared to BD-NOS), and number of inpatient admissions (compared to BD-II). BD-II had lower rates of lifetime depression and anxiety disorders, higher frequency of hypomania, shorter duration of illness, and fewer previous episodes. BD-NOS had younger age of onset, chronic course, irritability and mixed presentation. All BD subtypes had high rates of self-harm (69.3%), suicidal ideation (73.9%), suicide attempts (36.4%), psychiatric admission (55.7%), and psychosis (36.4%). LIMITATIONS: There were relatively small numbers of BD-I and BD-II. Diagnoses were based on retrospective recall. CONCLUSIONS: All BD subtypes had high levels of acuity and clinical risk. In accord with previous results, BD-I and BD-II participants' phenomenology was consistent with classical descriptions of these subtypes. BD-NOS participants were younger, with less euphoric mania but otherwise phenomenologically on a continuum with BD-I, suggesting that child and adolescent BD-NOS may be an early and less differentiated phase of illness of BD-I or BD-II and hence a target for early intervention.

How oppositionality, inattention, and hyperactivity affect response to atomoxetine versus methylphenidate: a pooled meta-analysis.

OBJECTIVE: To assess how threshold oppositional defiant disorder (ODD), inattention, and hyperactivity-impulsivity affect the response to atomoxetine versus methylphenidate. METHOD: Systematic review of randomized controlled trials (RCTs; ≥6 weeks follow-up). The primary measure was core symptom response-≥40% reduction in ADHD Rating Scale-IV-Parent Version: investigator administered and scored total or domain subscores, as appropriate. RESULTS: Data from 1,391 children and adolescents (823 atomoxetine, 568 methylphenidate; 7 RCTs) were meta-analyzed. The mean difference in response rates for patients with ODD was 0.6% (95% confidence interval [CI] = -11.9%-13.1%). The "without ODD" patient group showed significant between-trial heterogeneity (p < .001). Response rate differences for patients meeting the threshold for inattention or hyperactivity-impulsivity were -3.1% (95% CI = -11.5%-5.3%) and -4.9% (95% CI = -14.3%-4.4%), respectively. CONCLUSIONS: Meeting the threshold criteria for oppositionality, inattention, or hyperactivity-impulsivity did not alter core ADHD symptom response to atomoxetine versus methylphenidate, which was equivalent.

Core ADHD symptom improvement with atomoxetine versus methylphenidate: a direct comparison meta-analysis.

OBJECTIVE: Previous studies comparing atomoxetine and methylphenidate to treat ADHD symptoms have been equivocal. This noninferiority meta-analysis compared core ADHD symptom response between atomoxetine and methylphenidate in children and adolescents. METHOD: Selection criteria included randomized, controlled design; duration 6 weeks; and assessment of ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS) scores. Six-week response rates, defined as ≥40% reduction in ADHDRS total score, were compared using a noninferiority margin of -15%. RESULTS: Seven studies met inclusion criteria (N = 1,368). After 6 weeks, 53.6% (95% confidence interval [CI] 48.6%-58.4%) of atomoxetine-treated patients (n = 811) had responded compared with 54.4% (47.6%-61.1%) for methylphenidate (n = 557), with atomoxetine demonstrating noninferiority to methylphenidate (absolute difference -0.9%, 95% CI -9.2%-7.5%). CONCLUSION: After 6 weeks of treatment atomoxetine and methylphenidate had comparable efficacy in reducing core ADHD symptoms in children and adolescents.

Self-injury in Australia: a community survey.

OBJECTIVE: To understand self-injury and its correlates in the Australian population. DESIGN, PARTICIPANTS AND SETTING: Cross-sectional survey, using computer-assisted telephone interview, of a representative sample of 12,006 Australians from randomly selected households. MAIN OUTCOME MEASURES: Data on demographics, self-injury, psychiatric morbidity, substance use, suicidality, disclosure and help-seeking. RESULTS: In the 4 weeks before the survey, 1.1% of the sample self-injured. For females, self-injury peaked in 15-24-year-olds; for males, it peaked in 10-19-year-olds. The youngest self-injurers were nine boys and three girls in the 10-14-year age group, and the oldest were one female and one male in the 75-84-year age group. Mean age of onset was 17 years, but the oldest age of onset was 44 years for males and 60 years for females. No statistically significant differences existed between those who did and did not self-injure on sex, socioeconomic status or Indigenous status. Most common self-injury method was cutting; most common motivation was to manage emotions. Frequency of self-injury during the 4-week period ranged from 1 to 50 instances (mean, 7). Self-injurers were significantly more psychologically distressed, and also more likely to use substances. Adults who self-injured were more likely to have received a psychiatric diagnosis. Self-injurers were more likely to have experienced recent suicidal ideation (OR, 11.56; 95% CI, 8.14-16.41), and have ever attempted suicide (OR, 8.51; 95% CI, 5.70-12.69). Most respondents told someone about their self-injury but fewer than half sought help. CONCLUSION: The prevalence of self-injury in Australia in the 4 weeks before the survey was substantial and self-injury may begin at older ages than previously reported. Self-injurers are more likely to have mental health problems and are at higher risk of suicidal thoughts and behaviour than non-self-injurers, and many self-injurers do not seek help.

Group therapy for repeated deliberate self-harm in adolescents: failure of replication of a randomized trial.

OBJECTIVE: To replicate a study, which found group therapy superior to routine care in preventing the recurrence of self-harming behavior in adolescents who had deliberately harmed themselves on at least two occasions. METHOD: Single blind study with parallel randomized groups undertaken in three sites in Australia. The primary outcome measure was repetition of self-harm, assessed on average after 6 and 12 months. Secondary outcome measures included suicidal ideation, psychiatric disorder, and service use. RESULTS: Seventy-two adolescents aged 12 to 16 years (91% female subjects) were randomized to group therapy or routine care. Primary outcome data were available for 68 of the 72 randomized participants. More adolescents randomized to group therapy than those randomized to routine care had self-harmed by 6 months (30/34 versus 23/34, chi = 4.19, p =.04), and there was a statistically nonsignificant trend for this pattern to be repeated in the interval of 6 to 12 months (30/34 versus 24/34, chi = 3.24, p =.07). There were few differences between the treatment groups on secondary outcome measures, other than a trend for greater improvement over time on global symptom ratings among the experimental group compared with the control group. CONCLUSIONS: Our findings contradict those of the original study. Some differences in participant characteristics between the studies, along with less experience at the Australian sites in delivering the intervention, may have accounted for the different outcome. The benefit of group therapy for deliberate self-harm is unproven outside the environment in which it was originally developed.

Long-chain omega-3 polyunsaturated fatty acids in the blood of children and adolescents with juvenile bipolar disorder.

Reduced long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been reported in adult patients suffering from depression and bipolar disorder (BD). LCn-3PUFA status has not previously been examined in children and adolescents with BD compared with healthy controls. Fifteen children and adolescents (9-18 years, M +/- SD = 14.4 +/- 3.48) diagnosed with juvenile bipolar disorder (JBD) and fifteen healthy age and sex-matched controls were assessed for dietary intake and fasting red blood cell (RBC) membrane concentrations of LCn-3PUFA. Fatty acid concentrations were compared between participants diagnosed with JBD and controls after controlling for dietary intake. RBC membrane concentrations of EPA and DHA were not significantly lower in participants diagnosed with JBD compared with healthy controls (M +/- sem EPA = 3.37 +/- 0.26 vs. 3.69 +/- 0.27 microg/mL, P = 0.458; M +/- sem DHA = 22.08 +/- 2.23 vs. 24.61 +/- 2.38 microg/mL, P = 0.528) after controlling for intake. Red blood cell DHA was negatively (r = -0.55; P = 0.044) related to clinician ratings of depression. Although lower RBC concentrations of LCn-3PUFA were explained by lower intakes in the current study, previous evidence has linked reduced LCn-3PUFA to the aetiology of BD. As RBC DHA was also negatively related to symptoms of depression, a randomised placebo-controlled study examining supplementation with LCn-3PUFA as an adjunct to standard pharmacotherapy appears warranted in this patient population.

Long chain omega-3 polyunsaturated fatty acids in the treatment of psychiatric illnesses in children and adolescents.

OBJECTIVE: Long chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) are in increasing use in the general population to treat health problems. The objective of the current article is to review the evidence for the rationale and benefit of LCn-3PUFA in the treatment of common psychiatric disorders in children and adolescents. METHODS: A search of Psychlit, PubMed and Cochrane Databases was conducted using the terms child, adolescent, bipolar, depression, psychosis, first-episode psychosis, schizophrenia, attention deficit hyperactivity disorder (ADHD), autism, psychiatric, omega-3, n-3, docosahexaenoic acid and eicosapentaenoic acid. Further studies were identified from the bibliographies of published reviews. RESULTS: One small randomized controlled trial with LCn-3PUFA supplementation in depression in children found a small beneficial effect over placebo. Four placebo-controlled trials showed uncertain benefit of LCn-3PUFA for ADHD. Single placebo-controlled trials showed no benefit in autism or bipolar disorder. There is an absence of studies examining benefit for first-episode psychosis or schizophrenia in children and adolescents. CONCLUSIONS: While children and adolescents are receiving LCn-3PUFA for a range of psychiatric indications, there is only evidence of likely benefit for unipolar depression.

A comparison of North American versus non-North American ADHD study populations.

Few large, prospective clinical studies in Europe have assessed the validity and applicability of research methods used to study ADHD in North America. To assess comparability of study populations, we examined baseline patient characteristics from a group of North American studies against those of a large European/African/Australian study. All studies used identical diagnostic assessments and inclusion criteria, with ADHD diagnosis and the presence of comorbid psychiatric conditions confirmed using the KSADS-PL. Raters were trained and assessed to ensure uniform diagnostic and symptom severity rating standards. Six hundred and four patients (mean age = 10.2 years) enrolled in the non-North American study, and 665 patients (mean age = 10.4 years) enrolled in the North American study. The proportion of girls was higher in the North American studies (29.2% vs. 10.4%, p < 0.001). In both groups, most patients had a positive family history of ADHD and previous stimulant treatment. Fewer had the inattentive subtype of ADHD, and mean severity was slightly higher in the non-North American study. Results demonstrate that, when a uniform set of rigorous, standardized diagnostic criteria are used by skilled clinicians, the patient populations identified are generally similar. This supports the practice of generalizing results from treatment studies across geographies.

A randomized controlled trial of clonidine added to psychostimulant medication for hyperactive and aggressive children.

OBJECTIVE: To compare clonidine with placebo added to ongoing psychostimulant therapy for the treatment of attention-deficit/hyperactivity disorder with comorbid oppositional defiant disorder or conduct disorder. METHOD: Children 6 to 14 years of age recruited through 2000 to 2001 were randomized to receive clonidine syrup 0.10 to 0.20 mg/day (n = 38) or placebo (n = 29) for 6 weeks. Primary outcome measures were the Conduct and Hyperactive Index subscales of the parent-report Conners Behavior Checklist. Side effects were monitored using physiological measures and the Barkley Side Effect Rating Scale. RESULTS: Evaluable patient analysis showed that significantly more clonidine-treated children than controls were responders on the Conduct scale (21 of 37 versus 6 of 29; chi2(1) = 8.75, p <.01) but not the Hyperactive Index (13 of 37 versus 5 of 29). Compared with placebo, clonidine was associated with a greater reduction in systolic blood pressure measured standing and with transient sedation and dizziness. Clonidine-treated individuals had a greater reduction in a number of unwanted effects associated with psychostimulant treatment compared with placebo. CONCLUSIONS: The findings support the continued use of clonidine in combination with psychostimulant medication to reduce conduct symptoms associated with attention-deficit/hyperactivity disorder. Treatment is well tolerated and unwanted effects are transient.

Manic symptoms in young males with ADHD predict functioning but not diagnosis after 6 years.

OBJECTIVE: To compare the outcome in early adulthood of males who met criteria for attention-deficit/hyperactivity disorder (ADHD) and mania, ADHD alone, or no psychiatric disorder when aged 9-13 years. METHOD: Males who met criteria at baseline assessment conducted in the period 1992-1994 for mania+ADHD (n = 15), ADHD without mania (n = 65), or no psychiatric diagnosis (n = 17) were reevaluated after 6 years using computer-assisted structured interviews for Axis I and Axis II disorders, questionnaires about functioning and service utilization, and a clinician-rated assessment of global functioning. RESULTS: There were no group differences in the prevalence of Axis I or Axis II disorders, with the exception of alcohol abuse, which was higher in controls. Manic symptoms persisted in only one mania+ADHD subject, while three (5%) of the ADHD subjects had new-onset manic symptoms. There were no clear cases of bipolar disorder. The groups were not distinguished on levels of service utilization or criminal behavior, but global functioning was significantly lower at follow-up in the mania+ADHD group compared with controls. CONCLUSIONS: Although a pilot study in scope, the findings cast doubt on a link between mania symptoms associated with ADHD in childhood and later bipolar disorder.

Clinical practice guidelines for depression in young people: are the treatment recommendations outdated?

The 1997 NHMRC clinical practice guidelines for depression in young people included recommendations for treatment that need to be modified in light of more recent research. Changes to the guidelines should include the findings that selective serotonin reuptake inhibitors and some forms of psychotherapy are effective in treating adolescent depression. It is increasingly recognised that depression in adolescents often recurs and that prevention of recurrences should be a priority for research and practice.

Health-related quality of life of children and adolescents with mental disorders.

OBJECTIVE: To compare the health-related quality of life (HRQL) between children aged 6-17 years with one of three mental disorders (attention-deficit/hyperactivity disorder, major depressive disorder, or conduct disorder), a physical disorder, and those with none of these disorders. METHOD: Parent reports describing the HRQL, mental disorders, and physical disorders of a national sample of 3,597 children and adolescents in Australia, aged 6-17 years (response rate = 70%), were obtained by means of a structured diagnostic interview and questionnaires. RESULTS: After controlling for age, gender, and family structure, children with mental disorders were reported to have a significantly worse HRQL in several domains than children with no disorder. In many areas they were reported to have a worse HRQL than children with physical disorders. Parents also reported that the problems of children with mental disorders interfered significantly with the daily lives of children, parents, and families. CONCLUSIONS: The findings are consistent with previous studies which have reported that adults with mental disorders have substantial impairment in their HRQL. The findings suggest that children with a mental disorder require help in many areas of their lives. Achieving this will require an integrated approach to health care delivery rather than the current distinction between physical and mental health services.