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Extended-release guanfacine (Intuniv) is a novel long-acting, once-daily formulation of guanfacine indicated for attention deficit hyperactivity disorder (ADHD) in 6 to 17 year old children and adolescents. In doses 1 to 4 mg/day, guanfacine extended release (GXR) significantly improves the symptoms of inattention and hyperactivity-impulsivity in ADHD youngsters compared with placebo. Because of different pharmacokinetics, GXR is not substitutable on a mg-for-mg basis with immediate release guanfacine. Although extended release guanfacine does not demonstrate clinically significant ECG changes, mild slowing of the heart rate and some lowering of SBP and DBP does occur and requires vital sign monitoring during treatment. Children with a clinically significant cardiovascular history are not eligible for GXR therapy. Future research is exploring GXR effectiveness in ADHD complicated by oppositional defiant symptoms, ADHD complicated by tic disorders, posttraumatic stress disorders, and impulsive aggression in ADHD youngsters., (Copyright (c) 2010 Prous Science, S.A.U. or its licensors. All rights reserved.)

Repeated low-dose cocaine treatment (0.5 mg/kg/day) during adolescence induces offensive aggression in male Syrian hamsters (Mesocricetus auratus). This study examines the hypothesis that adolescent cocaine exposure predisposes hamsters to heightened levels of aggressive behavior by increasing the activity of the anterior hypothalamic-vasopressinergic neural system. In a first experiment, adolescent male hamsters were treated with low-dose cocaine and then scored for offensive aggression in the absence or presence of vasopressin receptor antagonists applied directly to the anterior hypothalamus. Adolescent cocaine-treated hamsters displayed highly escalated offensive aggression that could be reversed by blocking the activity of vasopressin receptors within the anterior hypothalamus. In a second set of experiments, adolescent hamsters were administered low-dose cocaine or vehicle, tested for offensive aggression, and then examined for differences in vasopressin innervation patterns and expression levels in the anterior hypothalamus, as well as the basal- and stimulated-release of vasopressin in this same brain region. Aggressive, adolescent cocaine-treated hamsters showed no differences in vasopressin afferent innervation and/or peptide levels in the anterior hypothalamus compared with non-aggressive, saline-treated littermates. Conversely, significant increases in stimulated, but not basal, vasopressin release were detected from the anterior hypothalamus of aggressive, cocaine-treated animals compared with non-aggressive, saline-treated controls. Together, these data suggest that adolescent cocaine exposure increases aggression by increasing stimulated release of vasopressin in the anterior hypothalamus, providing direct evidence for a causal role of anterior hypothalamic-vasopressin activity in adolescent cocaine-induced offensive aggression. A model for how alterations in anterior hypothalamic-vasopressin neural functioning may facilitate the development of the aggressive phenotype in adolescent-cocaine exposed animals is presented.

Background: Few studies have investigated the comparative risk of neuroleptic-related dyskinesias in children and adolescents receiving typical versus newer, atypical antipsychotics. This prospective study was completed to test whether clinical use of atypical antipsychotics is associated with less risk for developing neuroleptic-related dyskinesias than clinical use of typical neuroleptics in an unselected heterogeneous population of seriously emotionally disturbed youths admitted to acute residential treatment. We also tested a novel model of predictive risk for neuroleptic-related dyskinesias in children and adolescents., Method: 102 children and adolescents receiving typical neuroleptics, atypical antipsychotics, or the combination were studied. Youths developing neuroleptic-related dyskinesias were compared with youths free of dyskinesias over a 3-month study period on demographic, diagnostic, and treatment variables. Logistic regression was utilized to develop a novel model of predictive risk., Results: Of neuroleptic-treated youths, 5.9% had probable tardive dyskinesia, a rate less than the prevalence of tardive dyskinesia in chronic neuroleptic-treated adults. Use of typical neuroleptics was significantly (p = .03) associated with dyskinesia compared with use of atypical antipsychotics. Four variables including IQ, initial Abnormal Involuntary Movement Scale score, type of antipsychotic, and cumulative number of risk factors accounted for 35.8% of the variance when predicting dyskinetic status., Conclusion: Use of atypical antipsychotics appears to be associated with less dyskinesia risk than typical neuroleptics in an unselected group of seriously emotionally disturbed children and adolescents. Results support a cumulative risk model of neuroleptic-related dyskinesia in youths.

Cocaine abuse during adolescence represents a significant health risk due to the potential for both acute and long-term negative physical and psychological sequelae, including increased aggressive behavior. This study examined the effect of adolescent cocaine treatment on flank marking (i.e., a stereotypic motor behavior that is part of the response pattern of offensive aggression) in female and male Syrian hamsters (Mesocricetus auratus). Adolescent cocaine treatment activated flank marking in female hamsters when animals were measured upon return to their home cage immediately following drug treatment. Sex differences were observed in cocaine-induced flank marking, as males failed to flank mark when returned to the home cage. In females, the behavioral response was most marked on Day 11 of cocaine treatment in all doses tested. Yet, animals treated with low-dose cocaine (0.5 mg/kg/day) showed the most significant increase in flank marking on and from Day 11 forward as compared to medium- and high-dose cocaine-treated animals and controls. In addition, the response of cocaine-treated animals was vigorous and nearly immediate, as >75% of the flank marks scored were performed within the first 2 min of the behavioral test in >85% of animals examined. Measures of locomotion showed that cocaine had stimulatory effects on motor activity in adolescent female hamsters at all doses tested. Cocaine-treated animals did not differ in body weight gain from controls, suggesting no dramatic physiological effects of adolescent cocaine exposure on body growth at the doses tested.

A pilot comparison of the safety and efficacy of methylphenidate (MPH) combined with clonidine, clonidine monotherapy, or MPH monotherapy in 6- to 16-year-old children diagnosed with attention deficit hyperactivity disorder (ADHD) and comorbid aggressive oppositional defiant disorder or conduct disorder was completed. Study design was a 3-month, randomized, blinded, group comparison with eight subjects per group. No placebo comparison was used. All three treatment groups showed significant improvements in attention deficits, impulsivity, oppositional, and conduct disordered symptoms as assessed by parent and teacher rating scales and laboratory measures. Significant differences among treatment groups were found only on a few measures. Only the clonidine monotherapy group showed significantly decreased fine motor speed. These results suggest the safety and efficacy of clonidine alone or in combination with MPH for the treatment of ADHD and aggressive oppositional and conduct disorders.

Objective: Meta-analysis was used to review the literature on the clinical use of clonidine to treat symptoms of attention-deficit hyperactivity disorder (ADHD)., Method: A review of the literature from 1980 to 1999 revealed 39 studies that reported clonidine's efficacy and side effects for symptoms of ADHD and comorbid conditions. Of these, 11 reports provided sufficient information to be included in a meta-analysis., Results: Meta-analysis using weighted variables revealed clonidine demonstrates a moderate effect size of 0.58 +/- 0.16 (95% confidence interval = 0.27-0.89) on symptoms of ADHD in children and adolescents with ADHD and ADHD comorbid with conduct disorder, developmental delay, and tic disorders., Conclusions: Clonidine may be an effective second-tier treatment for symptoms of ADHD, but it has an effect size less than that of stimulants. Clinical use of clonidine is associated with many side effects.

Drug induced acute pancreatitis is an uncommon cause for acute pancreatitis. To make this diagnosis confidently, certain criteria should be fulfilled. The patient should be receiving the drug when acute pancreatitis develops and the pancreatitis should resolve with cessation of the drug. Also, other causes need to be excluded, and while the patient should ideally have recurrence of the pancreatitis if the drug is recommenced, as a confirmatory test this is not usually performed. A case is reported of severe acute necrotising pancreatitis associated with the use of sodium valproate. Sixteen years previously a similar but milder episode of possible acute pancreatitis occurred in this patient, resulting in cessation of sodium valproate. On the present occasion the patient required aggressive resuscitation, inotropic and ventilatory support, antibiotics and enteral feeding for a prolonged period before making a complete recovery.

Dissection of the internal carotid artery is often caused by trauma to the face or neck. It usually has a delayed onset neurological presentation, a partial middle cerebral artery territory syndrome, 'normal' early CT scan, MRI evidence of middle cerebral artery occlusion, progressive partial or complete neurological recovery, and duplex scan evidence of a reestablished lumen in the internal carotid artery after 10 weeks. A case is reported of a dissection of the right internal carotid artery in a patient with severe facial trauma. The patient presented with a left sided hemiplegia 8 hours after a motor vehicle accident. A cerebral CT scan performed 16 hours after the accident revealed a small wedge shaped area of cerebral infarction within the right temporo-parietal region. An MRI angiogram performed four days after the accident revealed a right carotid artery dissection with an occlusive thrombus of the dissected portion of the right internal carotid artery and right middle cerebral artery and a haemorrhagic infarct of the right parieto-occipital lobe. The patient was anticoagulated and over the next two weeks made a slow recovery, using her left hand effectively and walking unaided. Four months after the accident a duplex scan revealed that the right carotid artery lumen was patent with normal arterial flows. Five months after the accident the patient had returned to work.

Objective: To investigate descriptive and predictive correlates of aggression in children and adolescents who exhibit a high frequency of daily physical assault after admission to a structured residential treatment program and to examine correlations between subcategories of overt categorical aggression (OCA) in the same population., Method: Fifty-one admissions to a residential treatment program were assessed for frequency of physical assault after admission; analyses were corrected for length of stay. Patients with a high frequency of daily assault were compared with patients with a low frequency of daily assault on variables assessing demographics, history, family, concurrent behavior, treatment, and outcome., Results: A high prevalence of OCA was found in this sample. Variables assessing history and concurrent behavior were significantly associated and predictive of subjects exhibiting a high frequency of daily physical assault after admission. Physical assault was significantly correlated with verbal aggression, property destruction, and self-injurious behavior., Conclusions: These findings support the distinctiveness of OCA as a separate subtype of aggression encompassing four subcategories. Further research on treatment, outcome, and associated comorbidity of OCA is warranted.

The prevalence and patterns of use of psychiatric and anticonvulsant medications were studied in 83 seriously emotionally disturbed children and adolescents at the time of their admission to a residential treatment facility. Youths (aged 5-19, mean = 13.6 years), consecutively admitted over 17 months, were assessed for the prevalence and patterns of use of psychotropic and anticonvulsant treatments. At admission, 76% of the youths were receiving psychiatric pharmacotherapy, 40% with more than one psychiatric agent, and 15% with a combination of psychotropic and anticonvulsant medications. Frequently prescribed medications were neuroleptics (35 % of the medicated youths), sedative-hypnotics (26 %), and anticonvulsants (15%). Psychostimulants (16%) and antidepressants (22%) were under-prescribed relative to their diagnostic indications. Over 50 different medication combinations were used. The neuroleptic + lithium combination was most common (25 % of the polypharmacological treatments). Neuroleptics were the most commonly prescribed medication and mostly used for nonpsychotic, nontic, and nonbipolar indications (55% of neuroleptic trials). Neuroleptics were used primarily for aggression regardless of diagnosis. Neuroleptics were used more in symptomatic treatments than in treatments for indicated diagnoses. The high prevalence of psychiatric and antiepileptic medication use in children and adolescents admitted to a residential treatment facility, and especially the pattern of their use, raises questions about prescribing practices for youths entering residential treatment and about pediatric psychopharmacotherapy in general.

Objective: The aim of this preliminary pilot study was to investigate the safety and efficacy of open-label nadolol as an adjunctive pharmacological treatment for aggression and/or inattention/overactivity in a developmentally delayed child, adolescent, and young adult population., Method: Twelve subjects enrolled and completed (mean age 13.8 years, range 9 through 24) a 5-month, open, prospective protocol of nadolol (mean dose 109 mg, range 30 through 220 mg) with systematic baseline and outcome evaluations and weekly clinical assessment., Results: All subjects were developmentally delayed and most were cognitively delayed. Ten subjects (83%) showed clinical improvement while receiving nadolol. Significant improvements were noted on observer-rated overt categorical aggression, severity of illness, and global impressions of improvement. No significant effects were found for inattention/overactivity. Nadolol was well tolerated, with few side effects., Conclusions: Overt categorical aggression presenting in developmentally delayed children, adolescents, and young adults may respond to nadolol treatment.

The use of clonidine alone and in combination to treat a variety of problems has increased in child and adolescent patients. Four cases of adverse experiences with clonidine are described. Clinical guidelines for the use of clonidine in particular and the use of polypharmacy in general are presented.

Objective: To investigate characteristics of children and adolescents with a history of combined pharmacotherapy (CPT) and compare them with a group with no history of CPT., Method: Eighty-three consecutive admissions to a residential treatment center were divided into a CPT and a no-CPT group based on treatment history and compared by chart review. Prevalence of lifetime psychiatric medication use and CPT exposure were assessed. Demographic, diagnostic, treatment, behavioral, and medication variables were compared across the two groups., Results: Medication use was present in the treatment history for 89.2% and a history of CPT was found for 60.3% of subjects. Admission to current placement from inpatient psychiatry, lifetime number of psychiatric placements, lifetime number of psychiatric diagnoses, and nonseizure neuropsychiatric comorbidity were significantly associated with CPT. Aggression and neuroleptic use were also significantly associated with CPT. Admission psychiatric diagnostic comorbidity was not associated with CPT., Conclusions: A high prevalence of psychiatric medication use and CPT was found in this population. Variables assessing illness severity, aggressive behavior, and nonseizure neuropsychiatric comorbidity may identify youths in psychiatric treatment settings with a high prevalence of past or current CPT exposure. Further research on the CPT of aggression is warranted.

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.

Risk factors for neuroleptic withdrawal dyskinesia in children have not been well studied. The authors present a case of a child who had been treated with a combination of neuroleptics and stimulants for nonpsychotic aggressive behavior. A severe withdrawal dyskinesia precipitated by neuroleptic tapering was ameliorated by discontinuation of the psycho-stimulant. Although stimulants have been reported to increase certain involuntary movement disorders, this is the first known report of psychostimulant exacerbation of withdrawal dyskinesia.

ABSTRACT beta-Adrenergic blocking agents have been used successfully to treat intractable aggression in adult psychiatric patients. A review of the adult literature and a summary of the pediatrie treatment experience are presented. There are no double-blind placebo-controlled studies in child or adolescent psychiatric patients. Open studies have reported high improvement rates (75-85%), but actual improvement rates may be lower than the generally uncontrolled reports in the literature suggest to date. Future controlled studies should take advantage of statistical methods that allow determination of meaningful changes within subjects in addition to the more typically analyzed changes within groups. Though these medications may be effective as adjunctive treatments in a multidisciplinary approach to aggression, beta blockers cannot at present be considered to be indicated in the treatment of any child or adolescent psychiatric disorder. There is not enough available information to know whether aggression that is associated with any specific psychiatric diagnosis is predictive of response to beta blockers in children or adolescents, and no other predictors of treatment response have been consistently identified. Judging from the experience in adults, treatment duration may be more important than dose level in attaining a therapeutic response with beta blockers. Empirical clinical and research trials of beta blockers for psychiatric symptoms or disorders should probably be run for a minimum of 12 weeks.