Corticotropin releasing hormone increases apparent potency of adrenocorticotropic hormone stimulation of cortisol secretion.

HYPOTHESIS: Corticotropin releasing hormone (CRH) has a regulatory effect on cortisol secretion in addition to its classic effect of stimulating adrenocorticotropic hormone (ACTH) secretion. REVIEW: There is growing evidence of "long-loop" and paracrine adrenal stimulation by CRH. Data from a study of the ovine-corticotropin releasing hormone (oCRH) stimulation test in 13 sexually abused girls and 13 normal controls was used in Montecarlo simulations of the hypothalamic-pituitary-adrenal axis, to get estimates of adrenal sensitivity to ACTH and cortisol elimination kinetics before and after oCRH administration. In both controls and sexually abused girls, ACTH had an apparent greater effect on cortisol secretion after administration of oCRH compared to its effect during the baseline period. This lends support to the hypothesis and suggests that it should be tested experimentally.

Increased orbitofrontal cortex levels of choline in depressed adolescents as detected by in vivo proton magnetic resonance spectroscopy.

BACKGROUND: The frontal lobe has been implicated in the pathology of depression in adults. Through the use of magnetic resonance spectroscopy, altered brain choline levels have also been linked to the pathophysiology of affective disorders. METHODS: To identify possible alterations in orbitofrontal cortex levels of cytosolic choline in adolescents with and without depression, 22 depressed and 43 control adolescents were recruited. Of those recruited, usable proton magnetic resonance spectra were acquired from a voxel in the left anterior medial frontal lobe of 17 depressed (mean age 15.8+/-1.6) and 28 healthy adolescents (mean age 14.5+/-1.7). RESULTS: Orbitofrontal cytosolic choline/creatine (Cho/Cr) ratios (p =.032) and cytosolic choline/N-acetyl aspartate (Cho/NAA) ratios (p =.043) were significantly higher in the depressed subjects than in the control subjects. There were no significant differences between depressed and control subjects in gray or white matter content within the voxel. CONCLUSIONS: These findings suggest that brain cytosolic choline may be increased in depressed adolescents in comparison with control subjects and independent of a corresponding structural change. These results are consistent with similar, previously reported findings in adults and suggest that depression in adolescents is associated with alterations in orbitofrontal metabolism.

Implementation of an electronic medical record system in a pediatric psychopharmacology program.

The design, implementation, and utilization of an electronic medical record system (EMRS) in a pediatric psychopharmacology clinic is described. The EMRS is a relational database with information entered directly by the clinician during a patient visit. It has been used during more than 2590 patient visits with 805 patients. Complete clinical documentation and simultaneous data entry as well as computer generated prescriptions for the patient were accomplished 75% of the time within a 20-min medication management session. One hundred consecutive parents of patients were asked to fill out a five-question survey to begin to assess the impact of the application. Of the 87 parents who responded, all (100%) noted that the doctor paid attention to their concerns. Between 88 and 90% of the parents reported that the use of the computer is a 'good' thing, made it easier to work with the doctor, and that they understood why the computer was being used. The findings support that the development and implementation of an EMRS with direct clinician information entry within pediatric psychopharmacology clinic, is feasible.

Using MRI to examine brain-behavior relationships in males with attention deficit disorder with hyperactivity.

OBJECTIVE: The relationship between neuropsychological measures of inhibition and sustained attention and structural brain differences in the regions of the caudate and the frontal region was examined in males with attention deficit disorder with hyperactivity (ADD/H). METHOD: Ten males with ADD/H (aged 8-17) and 11 male controls (aged 9-18) participated in a neuropsychological evaluation and had a magnetic resonance imaging scan. RESULTS: As had been reported previously by these authors, the children with ADD/H were found to have reversed asymmetry of the head of the caudate, smaller volume of the left caudate head, and smaller volume of the white matter of the right frontal lobe. Children with ADD/H were found to score more poorly on measures of inhibition and sustained attention but not on measures of IQ, achievement, or motor speed. Comparison of neuropsychological measures and brain structure measures indicated a significant relationship between reversed caudate asymmetry and measures of inhibition and externalizing behavior; i.e., children with reversed caudate asymmetry performed more poorly on measures of inhibition regardless of group membership. Poorer performance on sustained attention tasks was related to smaller volume of the right-hemispheric white matter. CONCLUSIONS: There is emerging evidence that compromised brain morphology of selected regions is related to behavioral measures of inhibition and attention.

Perinatal complications and abnormal proton metabolite concentrations in frontal cortex of adolescents seen on magnetic resonance spectroscopy.

OBJECTIVE: The relation of perinatal complications to metabolism of orbitofrontal cortex was studied in 12 normal adolescents aged 13 to 17 years. BACKGROUND: Perinatal complications are associated with both (a) behavioral signs of frontal lobe dysfunction and (b) increased risk for mood disorders and schizophrenia. Perinatal complications are not usually sufficient to produce these disorders, however, suggesting an etiologic model in which perinatal complications interact with a second, familial, liability factor. The present study tested a key prediction of this "two-factor" model, namely, that perinatal complications will be associated with physiologic signs of frontal dysfunction, even in persons who have no personal or family history of these psychiatric disorders. METHODS: Subjects were screened by structured interviews with the Kiddie Schedule for Affective Disorders and Schizophrenia and had no personal or family history of psychiatric disorder. Ratios of choline and N-acetyl aspartate to creatine in orbitofrontal cortex were measured using proton magnetic resonance spectroscopy. Perinatal complications were scored with the examiners blinded to magnetic resonance spectroscopy data, applying published scales to hospital records on subjects' gestations and births. RESULTS: Perinatal complications were significantly correlated with reduced concentrations of choline and N-acetyl aspartate. CONCLUSIONS: Our results complement earlier findings of significant relations between perinatal complications and signs of frontal lobe dysfunction, as well as elevated rates of these two types of variables in mood disorders and schizophrenia.

The neuroscience of depression in adolescence.

The neuroscience of depression in children and adolescents has only recently become a focus of research. Initially, techniques previously used for adult investigations were employed, such as endocrine studies and sleep studies. Endocrine studies have indicated that, as in adult depression, a dysregulation of the serotonin (5-HT) axis is involved in childhood depression. However, both of these techniques are difficult to perform in children and have yielded some inconsistent results. The more recently developed neuroimaging techniques should enable the greatest advances in our understanding of the pathophysiology of depression. These techniques have already implicated the frontal lobes in the pathogenesis of depression in children and adolescents, and further research is ongoing.

Prevalence of errors in a pediatric hospital medication system: implications for error proofing.

The purpose of this study was to determine the prevalence of errors in the medication system of a pediatric teaching hospital. Error was defined broadly to capture all deviations in the process from medication order through administration of the dose. The long-term goal was to provide direction to efforts to error-proof the system. The sample was 3,312 medication orders written during 669 patient-days for which a total of 11,978 doses were passed. Errors were categorized as intercepted errors (intercepted through the normal processes of the medication system) or administration errors (errors that involve the patient with or without adverse sequelae). Errors were also categorized as errors in primary activities (e.g., prescribing or preparing the medication for administration) or supporting activity (e.g., transferring the order to another record). A total of 784 errors were identified; 98% were intercepted and 2% were administration errors. More errors (71%) occurred in supporting activities than in primary activities. Medication systems are complex processes. Errors are imbedded in the medication system and are typically intercepted before patients are involved. Intercepting errors involves additional work that adds to an already cumbersome process. Error proofing will be different for errors in primary activities and for supporting activities.

Using 'off the shelf', computer programs to mine additional insights from published data: diurnal variation in potency of ACTH stimulation of cortisol secretion revealed.

We describe the use of available computer programs to mine additional insights from published data. Graphs from four studies of ACTH and cortisol plasma levels collected throughout the 24 h day in humans were scanned into digital form and the data points extracted. To investigate the magnitude of ACTH stimulation of cortisol secretion across the 24 h, Monte Carlo methods were used to fit the parameters of a computer model of the ACTH-adrenal axis to the extracted data. ACTH was found to have a greater effect on cortisol secretion during the peaks of the cycle than at the nadir. This finding could not be explained by previously published dose response curves of ACTH effect. This implies that other modulators influence the effect of ACTH on the adrenal. This study also demonstrates how available computer programs can be used to examine models of physiologic regulation using data already available in the literature.

Functional magnetic resonance imaging of facial affect recognition in children and adolescents.

OBJECTIVE: To examine further the role of the amygdala in the recognition of facial expression in adolescents. METHOD: Twelve healthy adolescents were studied using functional magnetic resonance imaging technology during a task of facial affect recognition and a visual control task. RESULTS: All subjects demonstrated a significant increase in signal intensity in the amygdala for the facial expression recognition task. CONCLUSIONS: The data are consistent with previous work in healthy adult subjects implicating the amygdala as essential for the recognition of fearful facial expression.

Tricyclic antidepressants and cardiac autonomic control in children and adolescents.

OBJECTIVE: To elucidate the effects of tricyclic antidepressants on sympathetic and vagal modulation of heart rate variability. METHOD: Seventy-five children and adolescents (mean age 10.5 years, SD 2.0) from therapeutic and regular schools underwent challenges of paced breathing and orthostatic postural change, while heart rate was continuously recorded. Teachers completed dimensional ratings of behavior to quantity anxiety and conduct disorder. Spectral analysis of heart rate variability was utilized to decompose the postural (sympathetic) and respiratory (vagal) contributions to beat-to-beat variations in heart rate. RESULTS: Under conditions in which cardiac vagal effects were expected to predominate, subjects medicated with tricyclic antidepressants (n = 13) showed significantly reduced vagal modulation of heart rate variability (F[5,69] = 5.23, p < .003), higher heart rates (F[5,69] = 5.54, p < .002), and higher relative sympathovagal balance (F[5,69] = 5.51, p < .002) than nonmedicated (n = 42) and medicated comparison groups (n = 20), even after controlling for the effects of age and psychopathology. CONCLUSIONS: The relative loss of cardiac vagal control in young subjects medicated with tricyclic antidepressants, considered in the context of factors known to be associated with the development of tachyarrhythmias, presents as yet another risk, especially when coupled with factors such as maturational effects and psychopathology.

Basic neuroscience: critical issues for understanding psychiatric disorders.

Recent scientific advances in understanding the function and plasticity of the central nervous system have opened fundamental insights into the pathophysiology of various mental disorders. This chapter reviews the basic physiology of the central nervous system, and further focuses on the applications of the new knowledge to clinical psychiatry.

An update on adolescent psychopharmacology.

Adolescent pediatricians are being asked to assume a larger role in the management of psychiatric disorders. Therefore, dissemination of the knowledge base regarding the use of psychotropic medications to treat these disorders in children and adolescents is critical. This chapter is an update to the previous "Primer on Adolescent Psychopharmacology" by Bailey and Hendren. Many of the disorders that occur in adolescence are associated with significant morbidity and functional impairment. While the evaluation of adolescents involves a careful assessment of the psychosocial milieu and the implementation of an intervention that involves the use of multiple modalities, pharmacotherapy can diminish symptom severity and thereby assist in the process of recovery. Successful pharmacotherapy begins with the development of an active and reciprocal alliance with the patient and family that allows for sharing of critical information and provision of support. The initiation of treatment should include a clear definition of target symptoms, the potential risks and benefits of the proposed intervention, and a discussion that includes a review of the current treatment experiences in both adult and child psychiatry. The establishment of a method that allows for adequate monitoring of both response and side effects is critical. Clearly, this is a field in its infancy. Thus, practitioners must be acutely aware of both the extent and limitations of the existing knowledge base as well as critical need for more controlled studies of these interventions in adolescence.

Case study: seizure disorder presenting as panic disorder with agoraphobia.

Seizure disorders can produce anxiety that is almost indistinguishable from psychiatric disorders. There are few reports of adolescents with seizure disorders that produce fear. The first case of an adolescent female who presented with panic disorder and agoraphobia which was a consequence of seizure activity is reported. Careful diagnostic evaluation and correlation with video electroencephalography were important in distinguishing seizure activity from panic disorder.

Sertraline treatment of transition-associated anxiety and agitation in children with autistic disorder.

The intolerance of children with autistic disorder to changes in their routine or environment is well known, typically presenting with acute symptoms of anxiety, panic, irritability, or agitation. In a clinical sample of children (6-12 years old) with autistic disorder and transition-induced behavioral deterioration, 8 of 9 patients showed a clinically significant improvement in response to sertraline treatment. Only one child was taking concurrent psychotropic medication. Therapeutic doses were surprisingly low in all cases (25-50 mg daily), with a clinical response appearing generally in 2-8 weeks. Adverse effects were minimal (one child developed stomachaches), except for apparent sertraline-induced behavioral worsening in 2 children when their doses were raised to 75 mg daily. In 3 children, an initial satisfactory clinical response appeared to diminish after 3-7 months of treatment, despite steady or increased doses. In 6 patients, the beneficial effects persisted throughout the several-month follow-up period. Only four of the children's families were identified as having mood and/or anxiety disorders. This open-label study suggests that short-term sertraline treatment may reduce the behavioral reactions seen in association with situational transitions or environmental changes in children with autistic disorder, though the beneficial effect may be only temporary in some children. Our experience suggests that small doses of sertraline may be effective and that some children may require divided doses of sertraline during the day. Controlled studies are needed to determine the efficacy, safety, and pharmacokinetics of sertraline in treating this "need for sameness," both in short-term and long-term studies of children with autistic disorder.

Volumetric MRI analysis comparing subjects having attention-deficit hyperactivity disorder with normal controls.

OBJECTIVE: To test by MRI-based morphometry the a priori hypotheses that developmental anomalies exist in attention-deficit hyperactivity disorder (ADHD) in left caudate and right prefrontal/frontal/ and/or posterior parietal hemispheric regions, in accord with neurochemical, neuronal circuitry and attentional network hypotheses, and prior imaging studies. DESIGN: Case-control study. SETTING: Academic medical center. PARTICIPANTS: Fifteen male subjects with ADHD without comorbid diagnoses (aged 12.4 +/- 3.4 years) and 15 male normal controls (aged 14.4 +/- 3.4), group-matched for age, IQ, and handedness. MAIN OUTCOME MEASURES: Global and hemispheric regional volumes (in cm3) of cerebral hemispheres, cortex, white matter, ventricles, caudate, lenticulate, central gray nuclei, insula, amygdala, and hippocampus. RESULTS: Despite similar hemispheric volumes, ADHD subjects had smaller volumes of (1) left total caudate and caudate head (p < 0.04), with reversed asymmetry (p < 0.03); (2) right anterior-superior (frontal) region en bloc (p < 0.03) and white matter (p < 0.01); (3) bilateral anterior-inferior region en bloc (p < 0.04); and (4) bilateral retrocallosal (parietal-occipital) region white matter (p < 0.03). Possible structural correlates of ADHD response to stimulants were noted in an exploratory analysis, with the smallest and symmetric caudate, and smallest left anterior-superior cortex volumes found in the responders, but reversed caudate asymmetry and the smallest retrocallosal white matter volumes noted in the nonresponders. CONCLUSIONS: This study is the first to report localized hemispheric structural anomalies in ADHD, which are concordant with theoretical models of abnormal frontal-striatal and parietal function, and with possible differing morphologic substrates of response to stimulant medication.

A clinical approach to the pharmacotherapy of aggression in children and adolescents.

Overt aggression in its various forms is the most prevalent symptom presenting to pediatric mental health providers, regardless of setting. It is a behavior with a heterogeneous etiology and requires a comprehensive approach to evaluation and treatment. Evaluation of the aggressive child must assess medical, neurologic, psychiatric, psychosocial, familial, and/or educational contributions to behavioral dyscontrol. Multimodal treatment is generally required. At present, there is no single medication to recommend for the treatment of aggressive behavior. Multiple medications have clinically been used in a nonspecific fashion to target excessive childhood aggression. Although successful for some, this approach increases risk for ineffective interventions accompanied by side effects. Until a scientific understanding of the developmental neurobiology of aggression leads to more specific treatment, this review suggests the use of a diagnostic-based approach to the pharmacology of aggression (FIG. 1). Descriptive diagnostic techniques should be used to define the presence of any primary or comorbid psychiatric disorder that presents with aggression as an associated symptom. Treating aggression in the context of these psychiatric syndromes appears to be the most direct approach. Aggression occurring in the context of a medication-responsive psychiatric diagnosis appears most sensitive to pharmacologic intervention. Presently, evidence for efficacy is strongest for aggression in the context of ADHD, psychotic disorder, adolescent-onset bipolar disorder, and ictal aggression It remains less clear that medication can help aggression when it occurs independently of a pharmacologically treatable comorbid psychiatric disorder. Aggression may respond to a target symptom approach where discrete behavioral symptoms that contribute to aggression, such as irritability, explosiveness, fear, or impulsivity, may be modified by medication intervention (FIG. 1). When treatment is approached in this fashion, it is standard practice to use the least toxic and safest intervention first. Behavioral treatment based on contingency management principles could be initially recommended. Medication trials should first use medications that have demonstrated empiric efficacy in reducing aggression (TABLE 1) and that have a favorable safety profile. Neuroleptics to treat aggression in nonpsychotic psychiatrically referred youth should be kept to a minimum, secondary to their significant adverse risk profile. Alternative medications, such as selective serotonin reuptake-inhibiting antidepressants, buspirone, lithium, anticonvulsants, opiate blocking agents, propranolol, nadolol, and clonidine, deserve more clinical research in pediatric aggression. These medications may offer effective and less toxic alternatives in the pharmacologic treatment of inappropriate excessive childhood aggression.

Use of risperidone in psychotic disorder following ischemic brain damage.

Risperidone, a novel atypical neuroleptic agent, was used to treat a psychotic disorder secondary to ischemic brain damage in a 19-year-old adolescent, who had been treatment-refractory to two conventional antipsychotic agents and valproate. Clinically significant reductions in behavioral agitation and psychotic thinking initially appeared within the first 4 days of treatment with risperidone 3 mg twice daily. Risperidone was well tolerated despite this adolescent's severe cardiac and pulmonary illnesses. There was no evidence of increased neurotoxic symptoms in the presence of the ischemic brain damage. With its favorable side effect profile, risperidone may hold promise in the treatment of patients with psychotic disorders due to general medical conditions.

Structural abnormalities in brain magnetic resonance images of depressed children.

OBJECTIVE: Brain magnetic resonance images (MRIs) of 65 children and adolescents who were hospitalized with depressive disorders (DD) were compared with the brain MRIs of 18 hospitalized psychiatric controls (PC) without a depressive disorder. METHOD: Volumetric analyses were used to measure frontal lobe volumes (FLV), lateral ventricular volumes (VV), and total cerebral volumes (CV) for all subjects. To correct for differences in absolute cerebral volume associated with different body and head size, the ratios of FLV/CV and VV/CV were used to compare differences between the two groups. A multivariate analysis was used to control for the effects of several independent variables (age, sex, diagnosis). RESULTS: Significant differences were seen in the FLV/CV ratio and the VV/CV ratio when the results were compared between the two groups (DD versus PC). The DD group had a significantly smaller FLV/CV ratio (t = 2.148, df = 79, p = .035) and a significantly larger VV/CV ratio (t = -2.093, df = 79, p = .040). CONCLUSION: The findings are consistent with previous reports in depressed adults and may implicate the frontal lobes in the pathogenesis of early-onset depressive disorders.

Behavioral side effects of gabapentin in children.

We report 7 children who received gabapentin (GBP) as adjunctive medic ation and subsequently developed behavioral side effects. These behavioral changes consisted of intensification of baseline behaviors as well as new behavioral problems. Behaviors that parents considered most troublesome were tantrums, aggression directed toward others, hyperactivity, and defiance. All behavioral changes were reversible and were managed by dose reduction or discontinuation of GBP. All children had baseline attention deficit hyperactivity disorder and developmental delays.

Case study: behavioral symptoms of pediatric HIV-1 encephalopathy successfully treated with clonidine.

There are few reports of the behavioral manifestations in the pediatric population infected with human immunodeficiency virus type 1 (HIV-1). We report a case of a 4-year-old child with acquired immunodeficiency syndrome, whose initial manifestation of central nervous system involvement consisted of sudden onset of impulsivity, hyperactivity, initial insomnia, and aggressive behavior. This clinical picture may suggest an initial presentation of HIV-1 encephalopathy. Clonidine was helpful in ameliorating these behaviors.