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Aim: The emotional consequences of elective surgery to children and to their parents have not been sufficiently studied. The aim of the present study was to prospectively assess the prevalence and severity of post-traumatic, anxiety and depressive symptoms in this population., Methods: Forty children and adolescents consecutively admitted for elective surgery in a general hospital participated in the study. Their parents were also assessed. The assessments were made on the day of admission and surgery, and 1 and 6 months after the surgery., Results: Minor post-traumatic symptoms of the children were noted at the first and second assessments, decreasing significantly at the 6-month assessment. Further, the prevalence of children with elevated post-traumatic symptoms decreased significantly between the first and second assessments. Parents scored highest for anxiety and depression at the first assessment. Their symptoms, however, decreased significantly within 1 month. A significant decrease between the first and second assessments was also noted in the prevalence of parents with elevated anxiety symptoms. At the 1- and 6-month follow-up assessments, there was a significant correlation between the children's symptoms and their parents'., Conclusion: Mild post-traumatic symptoms may accompany paediatric elective surgery and persist for at least 1 month. Parents may also manifest anxiety and depressive symptoms, which may diminish earlier, that is, immediately after the surgery or within 1 month.

This study evaluated symptoms, risk, and protective factors of adolescents from six Israeli schools exposed to continuous terrorism. All children in the grades selected at each school (7, 9, and 11) were administered anonymous assessment materials measuring posttraumatic, grief, and dissociative symptoms, as well as traumatic exposure, personal resilience, and family factors. A high number of risk factors increased the likelihood of negative symptoms. Perceived personal resilience served as a protective factor against symptom development, perhaps enforced by ideology. Girls living on the West Bank had less severe posttrauma and were more willing to make personal sacrifices for their country. Proactive interventions aimed at enhancing a child's personal resilience and ability to cope with continuous stress may help protect against later symptomatology following traumatic events. Facing terrorism, political ideology may serve a double edge sword: protecting against symptom development as well as contributing to the toxic cycle of violence.

Objective: The authors compared the effects of maintenance versus withdrawal of risperidone treatment in children and adolescents with symptoms of disruptive behavior disorder., Method: Patients with disruptive behavior disorder (5-17 years of age and a range of intellect) who had responded to risperidone treatment over 12 weeks were randomly assigned to 6 months of double-blind treatment with either risperidone or placebo. The primary efficacy measure was time to symptom recurrence, defined as sustained deterioration on either the Clinical Global Impression severity rating (/2 points) or the conduct problem subscale of the Nisonger Child Behavior Rating Form (/7 points). Secondary efficacy measures included rates of discontinuation due to symptom recurrence, disruptive behavior disorder symptoms, and general function. Safety and tolerability were also assessed. Risperidone dosage was based on weight (patients <50 kg: 0.25-0.75 mg/day; patients /50 kg: 0.5-1.5 mg/day)., Results: Treatment was initiated in 527 patients, with 335 randomly assigned to a double-blind maintenance condition. Time to symptom recurrence was significantly longer in patients who continued risperidone treatment than in those switched to placebo. Symptom recurrence in 25% of patients occurred after 119 days with risperidone and 37 days with placebo. Secondary efficacy measures also favored risperidone over placebo. Weight increased over the initial 12 weeks of treatment (mean weight z score change=0.2, SD=2.7, N=511), after which it plateaued., Conclusions: This study is the first placebo-controlled maintenance versus withdrawal trial of its kind in disruptive behavior disorder and provides evidence that patients who respond to initial treatment with risperidone would benefit from continuous treatment over the longer term.

Gemfibrozil more potently inhibits CYP2C9 than CYP2C8 in vitro, and yet the opposite inhibitory potency is observed in the clinic. To investigate this apparent paradox, we evaluated both gemfibrozil and its major metabolite, an acyl-glucuronide (gemfibrozil 1-O-beta-glucuronide) as direct-acting and metabolism-dependent inhibitors of the major drug-metabolizing cytochrome P450 enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) in human liver microsomes. Gemfibrozil most potently inhibited CYP2C9 (IC50 of 30 microM), whereas gemfibrozil glucuronide most potently inhibited CYP2C8 (IC50 of 24 microM). Unexpectedly, gemfibrozil glucuronide, but not gemfibrozil, was found to be a metabolism-dependent inhibitor of CYP2C8 only. The IC50 for inhibition of CYP2C8 by gemfibrozil glucuronide decreased from 24 microM to 1.8 microM after a 30-min incubation with human liver microsomes and NADPH. Inactivation of CYP2C8 by gemfibrozil glucuronide required NADPH, and proceeded with a K(I) (inhibitor concentration that supports half the maximal rate of enzyme inactivation) of 20 to 52 microM and a k(inact) (maximal rate of inactivation) of 0.21 min(-1). Potent inhibition of CYP2C8 was also achieved by first incubating gemfibrozil with alamethicin-activated human liver microsomes and UDP-glucuronic acid (to form gemfibrozil glucuronide), followed by a second incubation with NADPH. Liquid chromatography-tandem mass spectrometry analysis established that human liver microsomes and recombinant CYP2C8 both convert gemfibrozil glucuronide to a hydroxylated metabolite, with oxidative metabolism occurring on the dimethylphenoxy moiety (the group furthest from the glucuronide moiety). The results described have important implications for the mechanism of the clinical interaction reported between gemfibrozil and CYP2C8 substrates such as cerivastatin, repaglinide, rosiglitazone, and pioglitazone.

The research was designed to determine whether the purported hemispheric asymmetries that are associated with attention deficit/hyperactivity disorder (ADHD) affect performance on a selective attention visual search task, and whether any obtained asymmetry will be modulated by methylphenidate. Two groups of children (8-15 years) with ADHD, one with methylphenidate treatment (ADHD+) and one without (ADHD+), were compared to matched controls on a two-stage visual search task. The task assessed right-left visual field asymmetries and the effects of changing a previous distractor into a target. Such a procedure, related to latent inhibition (LI; poorer performance to a previously irrelevant stimulus than to a novel one), can provide evidence for dysfunctional processing of irrelevant stimuli. All three groups exhibited the LI effect. The ADHD group, however, exhibited less LI for left- than right-side targets, an effect absent in the control and ADHD+ groups, suggesting a lateralized attentional deficit for ADHD+ that was normalized by methylphenidate.

Objective: This open-label study assessed the effectiveness of reboxetine, a selective norepinephrine reuptake inhibitor, in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) resistant to a previous methylphenidate trial., Method: Thirty-one child and adolescent outpatients, aged 8 to 18 (mean age, 11.7; SD = 2.87) years, diagnosed with ADHD were enrolled in a 6-week open-label study. Assessments included rater-administered scales (DSM-IV ADHD Scale; Clinical Global Impressions Scale), parent-administered scales (the Abbreviated Conners Rating Scale), and self-administered-scales for the evaluation of depressive (Children's Depression Inventory) and anxiety (the Revised Children's Manifest Anxiety Scale) symptoms. Reboxetine was initiated and maintained at a dose of 4 mg/day., Results: A significant decrease in ADHD symptoms, on all scales measured, was noted. Adverse effects were relatively mild and transient. The most common adverse effects were drowsiness/sedation and gastrointestinal complaints., Conclusions: The results of the current open-label study suggest the effectiveness of reboxetine in the treatment of ADHD in methylphenidate-resistant children and adolescents. Double-blind, placebo-, and active comparator-controlled studies are indicated to rigorously test the efficacy of reboxetine in ADHD.

Objective: The aim of the present study was to evaluate the efficacy of ondansetron, a selective 5-HT(3) antagonist, in the treatment of Tourette's disorder., Method: Participants (N = 30) aged 12 to 46 years, diagnosed with DSM-IV Tourette's disorder and resistant to previous haloperidol treatment, were enrolled in a 3-week, randomized, double-blind, placebo-controlled outpatient study. Assessments were conducted at baseline and once a week during the study period. Scales used included the Tourette's Syndrome Global Scale (TSGS), the Yale Global Tic Severity Scale (YGTSS), and the Yale-Brown Obsessive Compulsive Scale. Ondansetron dose was 8, 16, and 24 mg/day in the first, second, and third weeks, respectively., Results: A significant positive effect of ondansetron on tic severity, as assessed by the TSGS, was noted (baseline vs. endpoint: mean +/-SD = 29.62 +/-20.33 vs. 20.58 +/-12.82, p = .002 vs. placebo). However, no significant effect was detected upon assessing ondansetron/ placebo effect on tic severity with the YGTSS (baseline vs. endpoint: mean +/-SD = 24.04 +/-9.44 vs. 17.50 +/-9.48, p = .15 vs. placebo). No change in obsessive-compulsive symptoms was noted in either group. Adverse effects included mild and transient abdominal pain., Conclusions: Ondansetron may have antitic effects in patients with Tourette's disorder. Large-scale, double-blind studies should further assess the antitic efficacy of ondansetron.

The aim of the present study was to assess vesicular monoamine transporter (VMAT2) density in attention deficit/hyperactivity disorder (ADHD), a disorder involving monoaminergic dysregulation. It was hypothesized that the hypoactivity of monoaminergic neurotransmission related to ADHD could be associated with an under-expression of VMAT2. We assessed high affinity [3H]dihydrotetrabenazine [TBZOH] binding to platelet VMAT2 in untreated male ADHD children and adolescents (n=11) as compared to age-matched controls (n=14), as well as the correlation between VMAT2 density and the severity of ADHD symptoms as measured by the clinician-administered DSM-IV ADHD Scale (DAS) and the parent-administered Abbreviated Conners' Rating Scale (ACPRS). The [3H]TBZOH binding capacity (Bmax) was significantly lower (17%) in the ADHD group as compared to the controls. There was no difference between the two groups in the affinity (Kd value) of [3H]TBZOH to its binding site. An inverse correlation was found between the ADHD symptom scales and the Bmax values. It remains unclear whether the under-expression of platelet VMAT2 in ADHD children is reflective of a parallel change in the brain, and whether it is primary or an epiphenomenon of ADHD.

Unlabelled: Reboxetine is a selective norepinephrine reuptake inhibitor., Objectives: To evaluate the antienuretic effect of reboxetine in children with attention deficit and mood disorders., Methods: Six children aged 12-15 years with primary nocturnal enuresis and with attention deficit/hyperactivity disorder with or without other comorbid disorders were treated with reboxetine (4-8 mg/day). Monitoring of enuretic frequency was recorded at baseline and once a week for 6 weeks., Results: A statistically significant decrease in bedwetting was noted along the assessment points (p < 0.001), with the maximal change noted in the first week of treatment (p = 0.004). Reboxetine was well tolerated with minimal and transient side effects., Conclusions: reboxetine may possess an antienuretic effect in some children with the attention deficit/hyperactivity disorder., (Copyright (c) 2005 S. Karger AG, Basel.)

Recent improvements in prognosis necessitate considering the emotional responses of children with malignant diseases and of their parents. This prospective study assessed 20 children and adolescents and their 36 parents within 2 weeks of diagnosis and after 1 and 6 months. Fifty-three percent exhibited moderate to severe posttraumatic symptoms right after diagnosis that decreased significantly after 1 month. Children with high-risk disease reported the most severe symptoms. Unexpectedly, children with low-risk disease exhibited more severe symptoms than those with moderate risk. Depressive symptoms decreased significantly during the period, but anxiety symptoms did not. Moreover, quality of life did not change. Twenty percent of parents exhibited posttraumatic symptoms on initial evaluation. Mothers' symptoms did not change, but fathers' symptoms decreased with those of their children. Several procedures and experiences were identified as causes of traumatic stress responses.

Evidence on the efficacy and safety of atypical antipsychotics in children and adolescents with schizophrenia is limited. The purpose of this review is to assess the published data on the use of atypical antipsychotics in children and adolescents with schizophrenia alone and with comorbid disorders, and to establish benefit-risk guidelines for clinicians.Risperidone, olanzapine and clozapine were found to be effective in the treatment of aggression and mania. Risperidone, and possibly also olanzapine, may be the drugs of choice in children with comorbid tic disorders. Ziprasidone has some monoamine reuptake inhibition properties and may be administered as an augmenting agent in children and adolescents with schizophrenia and comorbid anxiety and mood disorders. Compared with the typical antipsychotics, the atypical drugs seem to be more effective, better tolerated and lead to better patient adherence. Importantly, the atypical antipsychotics have a lower propensity to induce extrapyramidal symptoms and a potential (shown so far only in adults) to improve cognitive function and inhibit suicidal behaviour (especially clozapine). Yet, the adverse effects associated with these agents, especially weight gain, which may also have long-term effects, can lead to non-compliance in the young population. In children and adolescents receiving clozapine, olanzapine and quetiapine (but not ziprasidone, which does not have a pro-appetite effect), particularly those with obesity or a family history of diabetes mellitus, fasting blood glucose and lipid levels must be monitored frequently. Weight gain might be better controlled when the children and their parents are properly informed about this adverse effect and diet is regulated. Another major disadvantage of the atypical antipsychotics, especially risperidone, is their association with hyperprolactinaemia, which can lead to hypogonadism-induced osteoporosis, galactorrhoea, gynaecomastia, irregular menstruation and sexual dysfunction, all seen also with typical antipsychotics. Other atypical antipsychotics, namely olanzapine and ziprasidone, have been reported to be prolactin sparing in adults, but may not be completely devoid of hyperprolactinaemic effects in children and adolescents. Thus, prolactin levels should be assessed routinely in young patients treated with atypical antipsychotics. Further, children and adolescents with hyperprolactinaemia-related effects should be switched to a prolactin-sparing agent, such as quetiapine. All atypical antipsychotics may induce sedation and they are not devoid of extrapyramidal symptoms (especially risperidone). The use of typical antipsychotics has been limited to patients who are resistant to atypical antipsychotics, intolerant to their adverse effects, or require injections or depot preparations. Further double-blind, placebo-controlled trials and long-term safety assessments are needed before definitive conclusions can be reached about the place of atypical antipsychotics in the therapeutic armamentarium of childhood-onset schizophrenia.

Objective: Most of the data supporting the use of atypical antipsychotics (AA) is based on studies in young adult patients. The present study is an open-label naturalistic follow-up study of olanzapine treatment vs. haloperidol for elderly chronic schizophrenia patients. MEHTOD: 20 patients (mean age 72.7+/-5.9 years, mean disease duration 33.1+/-12.0 years) who met the DSM-IV criteria for schizophrenia were randomly assigned to olanzapine (n=10) or haloperidol (n=10) treatment during acute exacerbation. Primary outcome measure was rating on the Clinical Global Impression (CGI) scale and the Positive and Negative Symptom Scale (PANSS)., Results: Between-group differences were computed using analysis of covariance. PANSS Total score decreased from 84 at baseline to 65 after treatment with olanzapine while decreased only from 79 to 74 with haloperidol treatment (F= 6.66, P=.02). PANSS Negative subscale decreased from 19 at baseline to 15 with olanzapine treatment while increased (deteriorated) from 18 to 20 with haloperidol treatment (F=23.37, P=.0003). CGI decreased from baseline with both olanzapine and haloperidol treatments (1.1 vs. 0.4) but the decrease in the olanzapine group was significantly greater (F=4.63, P=.05). Mean weight increased in both groups but without statistical difference between groups., Conclusions: In elderly chronic schizophrenia patients, olanzapine treatment is superior to haloperidol in reducing negative symptoms as well as less induction of extrapyramidal symptoms (EPS).

Tricyclic antidepressants possess established antienuretic properties. The selective serotonin reuptake inhibitors (SSRIs) have similar antidepressant properties to the tricyclic antidepressants and a safer side effect profile. The aim of the present study was to evaluate the antienuretic efficacy of one SSRI, fluvoxamine. Nine children aged 9 to 14 years with primary enuresis which was resistant to behavioral therapy participated in the study. All received fluvoxamine, 75-100 mg per day. In four, the enuresis was the only focus of clinical attention, and five received fluvoxamine for other primary indications. Enuresis was monitored daily, and mean voiding frequency was compared between three phases: baseline, on treatment and off treatment. Fluvoxamine had no statistically significant effect on enuresis. Fluvoxamine does not seem to possess significant antienuretic properties. We suggest that the combination of serotonergic with anticholinergic activity is a major factor in the antienuretic activity. In the treatment of children or adolescents with obsessive-compulsive disorder and comorbid enuresis, clomipramine may be preferred over SSRIs. Copyright 2001 John Wiley & Sons, Ltd.

This study examined the behavioral effects of agents active at the gamma-aminobutyric acid (GABA(A)) receptor complex in the mouse staircase paradigm. The neuroactivesteroids dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) were compared with the benzodiazepine agonist clonazepam, the non-benzodiazepine hypnotic compound zopiclone, and the antiepileptic agent gabapentin. Clonazepam, zopiclone and gabapentin reduced rearing activity at doses that did not affect climbing. The rearing-suppression effect of clonazepam and zopiclone, but not of gabapentin, was blocked by the benzodiazepine antagonist flumazenil, suggesting that the added effect of gabapentin is not mediated by the benzodiazepine receptor on the GABA complex. DHEA suppressed rearing behavior at doses that did not reduce climbing, but analysis with the Bonferroni post hoc test yielded no statistically significant difference. This inhibitory effect was attenuated by flumazenil. By contrast, DHEA-S suppressed, in a dose-dependent manner, both rearing and climbing behavior to the same extent. The findings support the potential value of the mouse staircase paradigm for demonstrating behaviorally relevant anxiolysis of test compounds shown to interact in vitro with the GABA(A) receptor complex.

Objective: To report on a brief parent-child group therapy program for children with anxiety disorders., Method: Twenty-four children with an anxiety disorder and their parents participated in a 10-session treatment. Children were evaluated at pretreatment (T1), posttreatment (T2), 12-month follow-up (T3), and 36-month follow-up (T4). Ten children were also assessed on entering a waiting period (T0)., Results: There were no significant symptomatic changes between T0 and T1. Anxiety symptoms decreased significantly during the treatment and follow-up periods. Depressive symptoms changed only during the follow-up period. The percentage of children with no current anxiety disorder was 71% at T2 and 91% at T4. Children of mothers with an anxiety disorder improved more than children of nonanxious mothers, whereas the anxiety level of anxious mothers remained stable., Conclusions: Brief parent-child group psychotherapy may serve as a time-limited, cost-effective, and efficient intervention.

Children with anxiety disorders have been suggested to possess a specific cognitive scheme that underscores negative information and leads to the formation of a negative view of themselves and of the world. The aim of the present study was to assess the neuropsychological processes of children and adolescents with anxiety disorders, as compared to healthy matched controls. Nineteen children (6-18 years) with anxiety disorders and 14 age-matched healthy controls participated in the study. Both groups scored within normal range on the Wechsler Intelligence Scale for Children-Revised (WISC-R). All children underwent neuropsychological assessment with the California Verbal Learning Test (CVLT) (Verbal Processing), the Rey-Osterrieth Complex Figure test (ROCF) (Nonverbal Processing), and the Wisconsin Card Sorting Test (WCST) (Executive Functions). The anxiety group scored lower than the control group on all measures of the CVLT and had a significantly greater number of errors, perseverative responses, and incorrect answers after negative feedback on the WCST. No differences were detected for the ROCF. We conclude that in children and adolescents, anxiety disorders may be associated with lowered linguistic abilities and cognitive flexibility, as measured by neuropsychological paradigms. Anxiety does not appear to be associated with nonverbal processes.

Children and adolescents (ages 6-17 years) diagnosed as having an anxiety disorder were compared to matched controls on a two-stage serial visual search task in which they identified presence or absence of a unique shape presented with homogeneous distractors. Response time was examined as a function of prior experience with either target, distractor, or both, allowing for a within-subject assessment of latent inhibition (LI: slower responding to a target that was formerly a distractor against a background of distractors that were formerly targets as compared to a novel target with distractors that were formerly targets) and novel pop-out effects (NPO: faster responding to a novel target against a background of familiar former targets as compared to the condition in which both the target and distractors were novel). There were robust LI and NPO effects for both anxious and control children. However, the predicted interaction between diagnosis and LI condition was not obtained. In general, the results suggest that children with diagnosed anxiety disorder do not differ from controls on basic information processing as assessed by this visual search task.

Despite the devastating impact of affective dysregulation in posttraumatic stress disorder (PTSD), there has been little research on how trauma relates to affect regulation. This study examines the relationship between the cognitive capacity to control mental images and symptoms of individuals with (N = 23) and without (N = 23) PTSD after exposure to SCUD missile attacks during the Gulf War. The capacity to control mental images, symptoms of posttrauma, anxiety, and anger were assessed. PTSD subjects with a high image control reported a higher capacity to control anger, lower levels of anger state and expression, and lower levels of intrusive symptoms compared with PTSD subjects with low image control. In individuals without PTSD, results show that the better the image control, the lower the control of anger and the higher the expression of anger. Image control seems to play different functions in the emotional regulation of normal subjects (facilitatory) and PTSD patients (protective).

Ondansetron, a selective 5-HT3 antagonist, may lower mesolimbic dopaminergic hyperactivity. The present open-label pilot study evaluated the effect of ondansetron in Tourette's syndrome. Six Tourette's syndrome men aged 14-48 years resistant to haloperidol participated in the study. Assessments included the Yale Global Tic Severity Scale (YGTSS), Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and Tourette's syndrome-Clinical Global Impression (TS-CGI) scale. The maximal ondansetron dosage (8-16 mg per day) was given for 3 weeks. Ondansetron treatment was associated with a significant decrease in the severity of tics. Two patients showed a definite response (score improvement of 40% or more), and two showed a probable response (> 25%). Two patients did not improve. Side-effects were transient and included abdominal pain (n = 5) and constipation (n = 2). Ondansetron may possess anti-tic effects in some Tourette's syndrome patients.

Despite the recognized importance of imagery use by children as well as the developmental relevance for maturity and health of imagery properties such as vividness and control, only a few studies have investigated imagery of children. The aim of the present study was to examine the development of control of mental images in a sample of boys and girls aged 7 to 17 years. Children were assessed on two aspects of mental imagery, vividness and control, and teachers were asked to rate the children's intellectual and socioemotional performance. Analysis showed that the capacity for image control increased in adolescence and that children characterized by vivid and uncontrolled imagery received the lowest ratings from teachers, whereas those with nonvivid and controlled imagery received the highest ratings. The implications of these results were discussed in relation to normal and abnormal development as well as suggestions for research.

Studies in adults have suggested a comorbidity of mitral valve prolapse and anxiety disorders, especially panic disorder. The nature of the association between these disorders is yet unclear. In the last years, case studies have appeared, reporting on the comorbidity of anxiety disorders and mitral valve prolapse in children. The present study evaluated the prevalence of mitral valve prolapse in children with anxiety disorders as compared to normal controls. The study group consisted of 52 children, 6-18 years old, with a diagnosis of panic disorder (9.6%), separation anxiety disorder (65.4%) and/or overanxious disorder (61.5%). Fifty-one normal age- and gender-matched healthy children served as controls. All participants were evaluated for the presence of mitral valve prolapse by cardiac auscultation and echocardiography. None of the 52 children with anxiety disorder and one of the 51 control children (1.96%) had mitral valve prolapse. There appears to be no association between childhood anxiety disorders and mitral valve prolapse. Whether children with panic disorder proper show a greater prevalence of mitral valve prolapse remains an open question. Implications to the association of mitral valve prolapse and panic disorder are discussed.

This study examined the relationship between image vividness and psychophysiological responses to trauma-related stimuli in participants with Posttraumatic Stress Disorder (PTSD). An auditory stimulus related to a shared trauma was presented to participants with and without PTSD and physiological parameters (heart rate and blood pressure) were measured concurrently. A negative correlation was noted in the PTSD group between image vividness and the level of physiological response. When the PTSD group was divided into high and low vividness, the physiological response was higher than that of the non-PTSD controls only when image vividness was low. The results are discussed in the context of Lang' s theoretical model, emphasizing the role of image vividness in the mediation and regulation of psychophysiology.

Background: This article reviews the published clinical experience with atypical neuroleptics in children and adolescents., Method: A computerized literature search was conducted (MEDLINE, 1974-1998) to retrieve all reports on the use of atypical neuroleptics in children and adolescents. A hand search was performed as well. All relevant clinical data were collated by type of drug., Results: We found 5 blind placebo-controlled clinical trials (105 patients), 24 open-label clinical trials (387 patients), and 33 case series (115 patients) describing the use of the atypical neuroleptics clozapine, risperidone, olanzapine, sulpiride, tiapride, amisulpride, remoxipride, and clothiapine in children and adolescents. Some of these agents, especially clozapine, risperidone, and olanzapine, were found to be efficacious in the treatment of schizophrenia, bipolar disorders, and pervasive developmental disorders. The role of atypical neuroleptics as augmenters of serotonin reuptake inhibitors in obsessive-compulsive disorder is unclear. Risperidone appears to possess anti-tic properties in patients with Tourette's disorder., Conclusion: The most convincing evidence of the efficacy of atypical neuroleptics in children and adolescents concerns clozapine in the treatment of schizophrenia. Data on other atypical neuroleptics in other disorders are still sparse, and further research is needed. Some of the atypical neuroleptics may become the first-line treatment for childhood schizophrenia and pervasive developmental disorders.

Rifapentine is a cyclopentyl derivative of rifampin under development for the treatment of Mycobacterium tuberculosis and Mycobacterium avium complex infections. These studies were designed to investigate the disposition and biotransformation of single iv and oral doses of 14C-rifapentine in mice, bile duct-cannulated and uncannulated rats, and monkeys. Mass balance studies included 14C analyses of urine, feces, bile, cage wash, carcasses, and cage air collected for up to 120 hr postdose. Separation of radioactive compounds extracted from urine, bile, and feces was conducted using high-performance liquid chromatography and radioisotope detection. The mass spectra of selected chromatographic peaks were obtained. Disposition results were similar for all three species. Less than 5% of the radioactive dose of 14C-rifapentine was recovered in urine, indicating that renal excretion is a minor route of elimination in these species. The major route of elimination of radioactivity was into the feces, where more than 75% of the radioactivity was recovered. Biliary excretion was the major route of elimination of radioactivity in bile duct-cannulated rats dosed either po or IV. Radiochromatograms were similar for fecal samples from animals dosed by IV or orally. Ten regions of radioactivity were observed in mouse and rat fecal sample radiochromatograms, and seven regions of radioactivity were observed in monkey fecal sample radiochromatograms. The most abundant compound identified in feces was usually intact rifapentine (27%-41% of dose in mouse, 3%-35% of dose in rat, and 17%-29% of dose in monkey). Other peaks identified or characterized in feces based on liquid chromatography/ultraviolet/14C and/or liquid chromatography/mass spectrometry methods included 25-desacetyl-rifapentine, 3-formyl-25-desacetyl-rifapentine, and 3-formyl-rifapentine. The compounds rifapentine, 25-desacetyl-rifapentine, and 3-formyl-rifapentine were present in rat bile samples. These studies show that the metabolism and disposition of rifapentine in mice, rats, and monkeys were similar.

Rifapentine is a long-acting cyclopentyl-derivative of rifampin. This study was designed to investigate the mass balance and biotransformation of 14C-rifapentine in humans. Four healthy male volunteers received a single 600-mg oral dose of 14C-rifapentine in a hydroalcoholic solution. Whole blood, urine, and fecal samples were collected before and at frequent intervals after drug administration. Amount of radioactivity recovered in urine and feces was assessed for up to 18 days postdose. Metabolite characterization in urine and feces was conducted using high-performance liquid chromatography with radiometric detection and liquid chromatography/mass spectroscopy. The total recovery of radioactive dose was 86.8%, with the majority of the radioactive dose recovered in feces (70.2%). Urine was a minor pathway for excretion (16.6% of the dose recovered). More than 90% of the excreted radioactivity was profiled as 14C chromatographic peaks and 50% was structurally characterized. These characterized compounds found in feces and urine were rifapentine, 25-desacetyl-rifapentine, 3-formyl-rifapentine, and 3-formyl-25-desacetyl-rifapentine. The 25-desacetyl metabolite, formed by esterase enzymes found in blood, liver, and other tissues, was the most abundant compound in feces and urine, contributing 22% to the profiled radioactivity in feces and 54% in urine. The 3-formyl derivatives of rifapentine and 25-desacetyl-rifapentine, formed by nonenzymatic hydrolysis, were also prominent in feces and, to a lesser extent, in urine. In contrast to the feces and urine, rifapentine and 25-desacetyl-rifapentine accounted for essentially all of the plasma radioactivity (99% of the 14C area under the concentration-time curve), indicating that 25-desacetyl-rifapentine is the primary metabolite in plasma. It appears, therefore, that the nonenzymatic hydrolysis of rifapentine to 3-formyl byproducts occurs primarily in the gut and the acidic environment of the urine.

Both oxidized low density lipoprotein (ox-LDL) and platelet-derived growth factor (PDGF) have been implicated in the genesis of various inflammatory responses, including atherosclerosis. We demonstrate here a novel interaction between specific oxidized lipids derived from ox-LDL and PDGF. The lipid moieties of ox-LDL caused concentration-dependent inactivation of PDGF as measured by loss of its mitogenic activity and its binding to high affinity receptors. Reverse-phase and normal-phase HPLC were used to purify the inactivating component in the lipid mixture. By fast atom bombardment mass spectrometry and infrared spectroscopy, we identified the inactivating lipids as the 9- and 13-hydroperoxy derivatives of cholesteryl linoleate, cholesteryl hydroperoxyoctadecadienoate. When a series of cholesteryl esters were subjected to oxidizing conditions, only those containing two or more double bonds caused inactivation of PDGF; the extent of inactivation increased with increased levels of oxidation. Exposing PDGF to cumene hydroperoxide, t-butyl hydroperoxide, or hydrogen peroxide did not affect the activity of the mitogen. The oxidized lipid had no effect on the mitogenic activity of epidermal growth factor but did abolish the mitogenic activity of basic fibroblast growth factor and the antiproliferative activity of transforming growth factor beta1. The inactivation of PDGF and other cytokines by lipid hydroperoxides may occur in such processes as vascular disease, inflammation, and wound healing.

Pathological laughter and crying is a well known clinical phenomenon which in most cases appears in association with diverse neurological and psychiatric symptoms and signs. It is not a disturbance of affectivity but rather of the motor concomitant of affective expression. Its main clinical characteristics are: absence of voluntary control and absence of the corresponding change in mood. It is not accompanied by the emotional lability of the organic brain syndromes, it does not present the inappropriate jocularity of the patients with frontal lobe disturbance, it is not due to the intoxicating effect of alcohol or addictive drugs and there are no typical symptoms of manic syndromes (such as grandiose self-esteem, flight of ideas, hyperactivity, etc.). In this paper three cases of pathological laughter are presented, two of these associated with organic brain conditions. The discussion will deal in particular with aetiological considerations and psychopathology of the third case which was unusual because it was a monosymptomatic condition and seemed to be the expression of a posttraumatic stress disorder.

Background: Studies performed with schizophrenic adults who were resistant to classical neuroleptics showed improvement in 30% of the patients when treated with clozapine. Very early onset schizophrenic patients benefit only partially from conventional antipsychotics and are at increased risk of developing extrapyramidal symptoms; clozapine may offer an alternative treatment for these patients., Methods: Eleven neuroleptic-resistant children (< 13 years) with schizophrenia were treated with clozapine. Improvement was monitored during the first 16 weeks using the Brief Psychiatric Rating Scale, Positive and Negative Syndrome Scale and Clinical Global Impression. The mean clozapine dosage was 227.3 (s.d. 34.4 mg/day at the end of the 16 weeks., Results: There was an overall statistically significant reduction in all parameters, especially positive symptoms, implying a favourable outcome. Most of the improvement occurred during the first 6 to 8 weeks. The major side-effects were somnolence and drooling (no agranulocytosis)., Conclusion: Clozapine may be a promising drug for the treatment of resistant childhood-onset schizophrenia.

The aim of this study was to assess the growth hormone (GH) axis in methylphenidate (MPH)-treated and untreated boys with attention-deficit and hyperactivity disorder (ADHD), by evaluating serum GH, GH-binding protein (GHBP) activity, and insulin-like growth factor I (IGF-I) levels as compared to age-matched normal controls. Blood samples were taken from 42 boys (aged 6-16 years) diagnosed as having ADHD according to DSM-III-R criteria and confirmed by using the Schedule for Affective Disorder and Schizophrenia for school-age children (K[Kiddle]-SADS). A total of 21 patients were treated with MPH (5-20 mg/day; 0.15-0.77 mg/kg/day), on a drug holiday protocol, for 1-36 months, and 21 were drug naive. A total of 46 age-matched normal boys at height and weight within normal range served as controls. No significant differences were detected between the MPH-treated ADHD children, the untreated ADHD children, and the control children on fasting serum GH levels, GHBP activity, or IGF-I levels. Active treatment with MPH, in ADHD children on a drug holiday protocol, does not cause changes in GH axis as manifested by normal values of GH, GHBP, and IGF-I.

In view of the recent conflicting findings regarding the causative role of thyroid abnormalities in attention deficit hyperactivity disorder (ADHD), we performed a replication study to clarify the issue and establish clinical guidelines. Thyroid tests were performed in 43 ADHD children and 28 age- and gender-matched controls. Sixteen ADHD children showed total triiodothyronine (TT3) levels which were slightly above the upper limit of normal, but no significant difference in TT3 values was noted between the ADHD and the control groups. Moreover, none of the ADHD subjects had abnormal levels of total thyroxine, free thyroxine, thyroid stimulating hormone or total triiodothyronine reuptake. The present study supplies additional evidence for the lack of an association between thyroid function and ADHD, and counters the suggestion that thyroid function be routinely screened for in ADHD children.

The effect of pretreatment with the gonadotropin releasing hormone (GnRH) agonist D-Trp6-LHRH (Decapeptyl) on platelet serotonin transporter in women undergoing assisted reproductive treatment (ART) was investigated and compared with women treated with human menopausal gonadotropin (Pergonal). The study group (n = 10) was exposed for 12 days to 3.2 mg Decapeptyl C.R. while a comparison group (n = 9) was exposed to 11 days of human meno-pausal gonadotropin (Pergonal). All patients were assessed with the Hamilton depression and anxiety scales before and after treatment, and platelet and plasma samples were collected at the same time points. Plasma levels of estradiol, progesterone. FSH and LH were determined by radioimmunoassay (RIA). Platelet serotonin transporter was labeled using high affinity [3H]imipramine binding. The GnRH analogue induced ovarian suppression as reflected by low plasma estradiol levels, while Pergonal administration induced ovarian stimulation. An elevation in the Hamilton depression and anxiety scale scores was observed in the Decapeptyl treated group; this mood alteration was associated with a significant decrease (19%, P < 0.05) in the density (Bmax) of platelet [3H]imipramine binding sites. No significant change was observed in the Bmax of the Pergonal treated group. These results indicate that ovarian suppression (menopausal-like state) in young women is associated with depressed and anxious mood and decreased serotonin transporter density.

Stress can produce immunosuppression leading to increased susceptibility to infection, tumor growth or autoimmune disease. It has been recently noted, however, that certain kinds of stress need not increase the risk of immune pathology. The present study looked for immune pathology in an anxiety-related disorder. Acute exacerbation of obsessive-compulsive disorder (OCD), an anxiety spectrum disorder, served as a model for stress. Seven OCD subjects in acute exacerbation, and 9 healthy age-matched control subjects participated in the study. T cell subsets were determined at baseline in both OCD and control groups, and after 6 weeks on clomipramine in the OCD group. No statistically significant changes in lymphocyte subsets were found between the control and the untreated patient groups. Likewise, no statistically significant changes were found in patients before and after treatment. The negative findings of the present study supports the view that stress need not compromise immunologic function. Various aspects of stress, which may turn the immune system vulnerable, are discussed as well.

Serotonergic dysregulation in obsessive-compulsive disorder has been repeatedly demonstrated. Recent reports on the emergence of obsessive-compulsive symptoms in patients treated with clozapine support a hyposerotonergic hypothesis of obsessive-compulsive disorder. The authors report the emergence of de novo compulsive symptoms in a drug-naive 8-year-old schizophrenic child, shortly after the initiation of treatment with clothiapine. Clothiapine, an atypical antipsychotic agent, shares with clozapine its strong antiserotonergic properties. It seems that antagonistic activity of atypical neuroleptics at postsynaptic serotonergic receptors might be responsible for the development of iatrogenic obsessive-compulsive symptoms.

MDL 100,240 ([4S-[4 alpha,7 alpha(R*), 12b beta]]-7-[[2- (acetylthio)-1-oxo-3-phenylpropyl]amino]-1,2,3,4,6,7,8,12b-octahyd ro-6-oxo- pyrido[2,1-a][2]benzazepine-4-carboxylic acid, I) is the thioacetyl prodrug of the active thiol, MDL 100,173 (II), a dual inhibitor of angiotensin-I converting enzyme (ACE) and neutral endopeptidase (NEP). A drug which simultaneously inhibits both ACE and NEP may provide a unique therapy for hypertension and congestive heart failure. Methods based on high-performance liquid chromatography with UV absorbance detection at 200 nm were developed to support preclinical pharmacokinetic investigations. One method is used to measure unchanged I and free II, while the second method is used to quantify the total level of the thiol II after the plasma is incubated with the disulfide reducing agent, dithiothreitol. By either method, the analytes are quantified over the range of 25-1000 ng/ml with good accuracy and precision. The overall extraction efficiencies of unchanged I and free II in dog plasma were 79% and 86%, respectively, while the extraction efficiency of total II averaged 75%. Described in this report are the results obtained in validating the assay methods for measuring the compounds in plasma. Pharmacokinetic data are presented which were obtained by applying these methods to plasma collected from dogs dosed with I.

The effects of a calcium channel blocker (verapamil, 160-320 mg/day for 4 weeks) were studied in seven unipolar major-depressed patients resistant to treatment with tricyclic antidepressants. This regimen of verapamil did not alter either the Hamilton rating scales for depression and anxiety or the Beck depression inventory score in these patients. Thus, verapamil appears devoid of antidepressant properties in patients resistant to tricyclic antidepressants.

Very early onset schizophrenic patients only partially benefit from conventional antipsychotic treatment and are at increased risk for developing tardive dyskinesia (TD). Clozapine, which lacks extrapyramidal side effects including TD, has been proved effective for adult schizophrenic patients who are resistant to other neuroleptics. Clozapine, therefore, may offer an alternative treatment for these patients. The authors report four successful trials of clozapine in children aged 10 to 12 years old with schizophrenia, the youngest group reported on to date, who were unresponsive to conventional neuroleptic treatment.

The psychiatric evaluation of the testamentary capacities of a delusional person may be hindered by (a) the cognitive, emotional and situational factors affecting the evaluator during the execution of her or his task, and (b) the sometimes very difficult challenge of proving testament invalidity due to the presence of delusions. As an illustration, this article presents a specific case which was recently brought to court in Israel.

Nineteen children with circulating anticoagulants or anticardiolipin antibodies and negative or only weakly positive antinuclear factors were reviewed for their clinical manifestations. The relationship between these antibodies and the morbidity in the pediatric age group will be discussed.

One hundred and six staff members and 150 patients of three psychiatric hospitals in Israel were administered a smoking habit and attitudes questionnaire. Upon analyzing the data, staff members and patients made up a very high percentage of smokers, 48.1 and 76%, respectively. The staff was not knowledgeable enough about the hazards of smoking. Nurses generously used cigarettes in order to appease the patients. Furthermore, the patients admitted being encouraged to smoke by the staff. According to these findings, a patient hospitalized in the psychiatric hospitals surveyed is significantly exposed to the pro-smoking atmosphere and the hazards of smoking.

Aspartate129 in porcine somatotropin was converted into a cyclic imide residue (succinimide) under acidic solution conditions. Reversed-phase high performance liquid chromatography was utilized to isolate and quantitate this altered species, which accounted for approximately 30% of the total protein. The molecular mass of this modified species was determined by electrospray mass spectrometry to be 18 Da less than normal porcine somatotropin, indicative of a loss of 1 H2O molecule. Tryptic peptide mapping demonstrated that the peptide composed of residues 126-133 was altered in this modified protein. Amino acid analysis, amino acid sequencing, mass spectrometry, and capillary zone electrophoresis were used to demonstrate that aspartate129 in this peptide had been converted into a succinimide residue. Further confirmation that this peptide contained a succinimide was obtained by hydrolyzing the modified peptide at pH 9.0, which yielded both the aspartate and isoaspartate peptides.

A rapid method for determining the three disulfide bond pairings in bovine transforming growth factor-alpha (bTGF-alpha) was developed by digesting bTGF-alpha with thermolysin followed by separation of the generated peptides by reversed-phase HPLC. The disulfide-bonded peptides were identified by amino acid sequencing and fast atom bombardment mass spectrometry. The disulfide bond pairings in bTGF-alpha were determined to be homologous to those in the human and mouse TGF-alpha molecules. A species of low bioactivity isolated from the folding/oxidation mixture of chemically synthesized bTGF-alpha was demonstrated to contain two incorrect disulfide bonds. These results indicate that mispairing of disulfide bonds in bTGF-alpha significantly reduces the activity of this molecule.

Asparagine 99 in bovine (BST) and porcine somatotropins (PST) was converted to an isoaspartate residue during incubation at neutral or alkaline pH. Isoaspartate 99 BST or isoaspartate 99 PST was resolved from the normal somatotropin by reversed-phase high-performance liquid chromatography (HPLC). The altered peptide of residues 96-108 which contains isoaspartate 99 was detected by tryptic peptide mapping of the modified BST or PST. Amino acid sequencing, amino acid analysis, mass spectrometry, and co-elution with a chemically synthesized peptide containing isoaspartate 99 were used to demonstrate the existence of isoaspartate in the modified peptides. Peptide bond cleavage between Asn 99 and Ser 100 also occurred during incubation of BST and PST at neutral or alkaline pH. This chemically cleaved product was resolved on reversed-phase HPLC from both the isoaspartate 99 and normal somatotropin molecules.

Negative-ion fast atom bombardment mass spectrometry is quite useful for the identification of products and by-products formed during the synthesis of nucleoside 3'-phosphoramidites. The data show that detritylation and oxidation are side reactions which occur during the synthesis of monomeric units used in the construction of oligodeoxyribonucleotides by the phosphite triester method.

New methodology for identifying and locating crosslinkages in peptides is described. Pepsin is used to cleave insulin and B-chain dimers of insulin into fragments under conditions which retain the original peptide crosslinkages. After partial separation by HPLC, the peptides are analyzed by fast atom bombardment mass spectrometry (FABMS) to determine their molecular weights. The molecular weights of peptide fragments expected from the pepsin digests of human insulin and related model compounds are calculated from the amino acid sequence of the intact peptide. Digestion products are identified by matching their molecular weights, as determined by FABMS, with calculated molecular weights. Locations of interchain crosslinkages are deduced after the peptide fragments have been assigned to specific segments of the parent peptide. The validity of the method has been established by correctly identifying structurally important products in the pepsin digests of model compounds such as human, bovine, and porcine insulins. Procedures developed with the model compounds were used to identify crosslinkages in peptides of unknown structure isolated from an insulin A-chain/B-chain combination reaction mixture. Evidence is presented for formation of three different types of crosslinkages, disulfide, lanthionine, and sulfoxide.

To determine the effect of transcutaneous electrical stimulation on the rabbit joint, we studied skin and intraarticular temperatures and pressure both before and following the stimulation in nine rabbits. An elevation in skin temperature by a mean of 0.6 degrees C (p less than 0.05) and increase in intraarticular temperature by a mean of 0.8 degrees C (p less than 0.01) was noted following the electrical stimulation. Intraarticular pressure in the stimulated joints has only a trend to increase, but not significantly. In four other rabbits, synovial tissue of the stimulated joint showed blood vessels congestion and interstitial edema. These results suggest that the analgetic effect produced by electrical stimulation on joints may partially involve intraarticular temperature and pressure alterations.

Sulfation of human alpha 2-antiplasmin, the major plasma inhibitor of fibrinolysis, was examined using both protein isolated from human plasma and protein synthesized and biosynthetically labeled with [35S]sulfate by a human hepatoma-derived cell line. Linkage of sulfate to tyrosine was demonstrated by recovery of labeled tyrosine sulfate after base hydrolysis of sulfate-labeled alpha 2-antiplasmin. Analysis by reverse-phase high performance liquid chromatography of peptides released from alpha 2-antiplasmin by cleavage with trypsin or cyanogen bromide indicated that sulfate is linked to a single segment of the protein. A cyanogen bromide peptide corresponding to the sulfate-labeled peptide was prepared from alpha 2-antiplasmin isolated from human plasma. Consistent with the presence of tyrosine sulfate in this peptide, its chromatographic elution was altered by treatment with acid under conditions which release sulfate from a tyrosine residue. No peptide in the total digest of alpha 2-antiplasmin by cyanogen bromide eluted at the position of the peptide following desulfation, suggesting that all of the protein is in a sulfated form. The sequence of the sulfate-containing cyanogen bromide peptide as determined by sequential Edman degradation, amino acid composition, and fast atom-bombardment-mass spectrometry was: Glu-Glu-Asp-Tyr(SO4)-Pro-Gln-Phe-Gly-Ser-Pro-Lys-COOH. This peptide is a segment of the previously identified plasmin-binding domain of alpha 2-antiplasmin.