Risk Factors and Modifiers for Cardiovascular Disease Assessment of Patients with Heterozygous Familial Hypercholesterolaemia.

Background: The assessment of the risk of cardiovascular disease (CVD) in patients with heterozygous familial hypercholesterolemia (HeFH) is determined by conventional risk factors. However, factors modifying CVD, or risk modifiers, beyond conventional risk factors may inform their CVD risk assessment and the subsequent use of new therapies. This work identifies and characterises patients within a lipid clinic cohort with regards to conventional CVD risk factors and risk modifiers with a focus on those with HeFH. Methods: A study of consecutive adult patients attending our specialist lipid clinic was performed over a six-month period. The patient data recorded included demographics, clinical characteristics, risk factors and risk modifiers, biochemical profiles and genetic testing results. Risk modifiers were identified based on ESC/EAS guidance, and those with HeFH were compared to those without. Results: A total of 370 patients were included. Of these, 98 HeFH patients were identified (26%). Then, 52% of HeFH patients were stratified into the very-high risk category due to the presence of CVD risk factors. Risk modifiers were present in 73%. These included a family history of premature CVD (56%), obesity (28%), a sedentary lifestyle (13%) and a major psychiatric disorder (12%). Compared to the rest of the cohort, those with HeFH were less likely to have hypertension and more likely to have a family history of premature CVD. Conclusions: Half of patients with HeFH are categorised as having very high CV risk. Consideration of risk modifiers, particularly a family history of premature CV disease, increases this very-high-risk category further. This may have implications for the clinical application and access to novel treatments.

The role of antipsychotics in the management of behavioural symptoms in children and adolescents with autism.

Autistic disorder or autism is a serious childhood-onset disorder that affects all areas of development, particularly in the areas of language, communication and reciprocal social interaction. Patients with autistic disorder typically demonstrate repetitiveness and a restricted repertoire of behaviour. Additionally, they also have a number of disruptive symptoms that may be reduced by drug treatment, including severe tantrums, hyperactivity and lability. Antipsychotic drugs are the agents that are the most critically studied as treatments for reducing symptoms. Both first- and second-generation antipsychotics have shown safety and efficacy in short- and long-term studies in autism. The most studied antipsychotic drugs include haloperidol and risperidone, although studies of other antipsychotic drugs are underway. Safety concerns associated with treatment include the risk of drug-related dyskinesias, which is greater with the first-generation drugs, and the risk of weight gain and associated metabolic problems (i.e. increases in glucose and lipids), which is greater with second-generation agents. Prescription of antipsychotic drugs requires careful monitoring because of these safety risks and the likelihood of long-term use. Drug administration should be initiated at low dosages and subsequent dosage changes should be based on tolerability and clinical response.

The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) Protocol: a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.

BACKGROUND: Sepsis accounts for 30% to 50% of all in-hospital deaths in the United States. Other than antibiotics and source control, management strategies are largely supportive with fluid resuscitation and respiratory, renal, and circulatory support. Intravenous vitamin C in conjunction with thiamine and hydrocortisone has recently been suggested to improve outcomes in patients with sepsis in a single-center before-and-after study. However, before this therapeutic strategy is adopted, a rigorous assessment of its efficacy is needed. METHODS: The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial. It will enroll patients with sepsis causing respiratory or circulatory compromise or both. Patients will be randomly assigned (1:1) to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 h or matching placebos until a total of 16 administrations have been completed or intensive care unit discharge occurs (whichever is first). Patients randomly assigned to the comparator group are permitted to receive open-label stress-dose steroids at the discretion of the treating clinical team. The primary outcome is consecutive days free of ventilator and vasopressor support (VVFDs) in the 30 days following randomization. The key secondary outcome is mortality at 30 days. Sample size will be determined adaptively by using interim analyses with pre-stated stopping rules to allow the early recognition of a large mortality benefit if one exists and to refocus on the more sensitive outcome of VVFDs if an early large mortality benefit is not observed. DISCUSSION: VICTAS is a large, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial that will test the efficacy of vitamin C, thiamine, and hydrocortisone as a combined therapy in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. Because the components of this therapy are inexpensive and readily available and have very favorable risk profiles, demonstrated efficacy would have immediate implications for the management of sepsis worldwide. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03509350 . First registered on April 26, 2018, and last verified on December 20, 2018. Protocol version: 1.4, January 9, 2019.

Consensus report on impulsive aggression as a symptom across diagnostic categories in child psychiatry: implications for medication studies.

OBJECTIVE: To determine whether impulsive aggression (IA) is a meaningful clinical construct and to ascertain whether it is sufficiently similar across diagnostic categories, such that parallel studies across disorders might constitute appropriate evidence for pursuing indications. If so, how should IA be assessed, pharmacological studies designed, and ethical issues addressed? METHOD: Experts from key stakeholder communities, including academic clinicians, researchers, practicing clinicians, U.S. Food and Drug Administration, National Institute of Mental Health, industry sponsors, and patient and family advocates, met for a 2-day consensus conference on November 4 and 5, 2004. After evaluating summary presentations on current research evidence, participants were assigned to three workgroups, examined core issues, and generated consensus guidelines in their areas. Workgroup recommendations were discussed by the whole group to reach consensus, and then further iterated and condensed into this report postconference by the authors. RESULTS: Conference participants agreed that IA is a substantial public health and clinical concern, constitutes a key therapeutic target across multiple disorders, and can be measured with sufficient precision that pharmacological studies are warranted. Additional areas of consensus concerned types of measures, optimal study designs, and ethical imperatives. CONCLUSION: Derived from scientific evidence and clinical experience, these consensus-driven recommendations can guide the design of future studies.

Ziprasidone in adolescents with autism: an open-label pilot study.

INTRODUCTION: The antipsychotic drugs are the best-studied agents shown to reduce symptoms in autism, including hyperactivity, aggression, self-abusive behavior, temper tantrums, lability, irritability, social withdrawal, and stereotypical behaviors. However, significant weight gain has been associated with use of many atypical agents. Ziprasidone has been weight neutral in adult populations, but data from adolescents and patients with autism are sparse. However, ziprasidone administration has been associated with increases in the QTc. The purpose of this study was to collect pilot data on the efficacy and safety of ziprasidone in adolescents with autism, focusing on safety issues of weight gain and QTc. METHODS: Twelve adolescents with autism (mean age 14.5 +/- 1.8 years) were treated in a 6-week open pilot study. Ziprasidone dosage ranged from 20 to 160 mg/day (mean, 98.3 +/- 40.4 mg/day). The primary efficacy measure was the Clinical Global Impressions-Improvement item (CGI-I); other efficacy measures included the Aberrant Behavior Checklist and the Children's Psychiatric Rating Scale. RESULTS: Based on the CGI-I, 9 of 12 (75%) patients were treatment responders. Ziprasidone was weight neutral, and the QTc increased by a mean of 14.7 msec. Two subjects had acute dystonic reactions. Cholesterol decreased and prolactin remained the same. CONCLUSIONS: Ziprasidone shows promise as a treatment for adolescents with autism. More definitive trials are needed.

Juvenile maladaptive aggression: a review of prevention, treatment, and service configuration and a proposed research agenda.

OBJECTIVE: To review prevention programs, psychosocial and psychopharmacologic treatments, and service delivery configurations for children and adolescents with maladaptive aggression. To propose a research agenda for disorders of aggression in child and adolescent psychiatry. DATA SOURCES: Recent empirical studies were reviewed using searches of MEDLINE and PsycINFO (text terms: aggression, antisocial, violence, conduct, oppositional, psychosocial treatment, psychopharmacology, and prevention), relevant books, review articles, and bibliographies. DATA EXTRACTION: Articles met the following criteria: published in an English-language, peer-reviewed journal between 1980 and 2005, included a focus on individuals < 18 years old, and included an outcome measure of relevant significance. STUDY SELECTION: Results of 154 randomized, controlled psychosocial treatment trials, 20 controlled psychopharmacology studies, 4 open-label medication studies, and 2 psychopharmacology meta-analyses were reviewed. RESULTS: Prevention programs show promise for reducing future aggression in at-risk populations. Empirical support is available for the effectiveness of multifocused psychosocial treatments in reducing aggression in children and adolescents. Atypical antipsychotics, lithium, divalproex sodium, and stimulants for conduct problems associated with attention-deficit/hyperactivity disorder have empirical support for reducing aggression in selected patient populations. CONCLUSIONS: Therapeutic nihilism in the treatment of aggressive children and adolescents with conduct problems is no longer warranted. Multifocused psychosocial interventions given early in life to at-risk children have the most support for effectiveness. However, treatments for children who routinely present to the child psychiatrist with already well-established disorders of aggression are neither robust nor well-established. Further research into maladaptive aggression in referred children and adolescents within and across psychiatric diagnoses is important for the field of child and adolescent psychiatry.

Impersistence of depression in youth: Implications for drug study design.

Food and Drug Administration data show that most anti-depressant studies in youth do not show drug effect. The few positive studies used rigorous diagnostic screening procedures, suggesting major depressive disorder (MDD) may not be a persistent condition in a subgroup of youth. To investigate persistence of MDD, we serially assessed a cohort of inpatients admitted to the hospital with a clinical diagnosis of MDD. Assessments included a structured diagnostic interview, the Diagnostic Interview for Children and Adolescents-Revised (DICA-R), and measures of depressive symptomatology. Of 66 subjects (40 girls; mean age, 14.4 +/- 2.2 years), 34 (51.5%) met DICA-R criteria for MDD at the initial postadmission assessment. Of these, only 8 (23.5%) met DICA-R criteria for MDD at any subsequent assessment. Similar reductions were found on other ratings of depression. In conclusion, MDD did not persist in this sample. The findings suggest a multigated assessment procedure should be employed before randomization in antidepressant clinical trials.

Advances in drug treatments for children and adolescents with autism and other pervasive developmental disorders.

Autism is a disorder characterised by abnormalities in language and social development, and repetitive behaviours. Antipsychotics, including haloperidol and risperidone, are the most widely studied drugs for reducing symptoms in children and adolescents with autism. When administered at relatively low dosages, antipsychotics have been shown to reduce repetitive behaviours (stereotypies) and social withdrawal, as well as a number of related symptoms, such as hyperactivity, aggression, self-abusive behaviour, temper tantrums, lability of mood and irritability. Adverse effects of antipsychotics include sedation, dizziness, increased appetite, weight gain, changes in the electrocardiogram parameters, drooling, hyperprolactinemia and a risk of drug-related dyskinesias. Other agents have been less well studied for the treatment of autism, but there are suggestive data regarding their safety and efficacy. Of these agents, a number have been investigated, based on theories about the aetiology of autism, including SSRIs and naltrexone, although the efficacy of these agents has been limited. Stimulant drugs have been shown to reduce hyperactivity and improve focus, but they may cause behavioural worsening, weight loss and stereotypies de novo. Secretin is a treatment that has received much media attention after reports of efficacy from small open studies, but all controlled studies have failed to show any benefit. In autism, alternative treatments have also been used, but none have shown benefit in well-designed studies.

Risperidone treatment in children and adolescents with autism: short- and long-term safety and effectiveness.

OBJECTIVE: Atypical neuroleptics, including risperidone, are used to treat children with autism, despite limited efficacy and safety data. Many clinicians believe that risperidone will not induce dyskinesias in children. The authors investigated open risperidone treatment in children with autism and included findings on dyskinesias. METHOD: The sample included 22 outpatients (mean age = 7.1 years) diagnosed with autism (DSM-IV). Treatment consisted of a 1-month short-term phase followed by a 6-month long-term phase. At the end of the long-term phase, drug was discontinued, and the need for further drug treatment and the occurrence of withdrawal dyskinesias were assessed. Measures included the Clinical Global Impressions (CGI), Children's Psychiatric Rating Scale (CPRS), and the Abnormal Involuntary Movement Scale. RESULTS: The mean risperidone dosage was 1.2 mg/day. Overall, the children had significant clinical improvement as assessed by the CPRS and CGI. Untoward effects included sedation, increased appetite, and weight gain. Two of 13 (15.4%) children treated long-term developed mild, reversible withdrawal dyskinesias when risperidone was discontinued. No child developed dyskinesias on risperidone. CONCLUSIONS: Risperidone shows promise as a treatment in autism. However, withdrawal dyskinesias were noted. Further assessment of the risk of risperidone-related dyskinesias is indicated.

Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part I: a review.

OBJECTIVES: To review the evidence for the safety and efficacy of nonpharmacological and pharmacological treatments for aggression in children and adolescents. METHOD: and searches (1990-present) were conducted for double-blind, placebo-controlled studies of atypical antipsychotics for aggression and for literature on the use of other pharmacological agents and psychosocial interventions for aggression. Case reports and adult literature regarding the safety of atypical antipsychotics were used where controlled data for youth were lacking. RESULTS: Controlled data on the treatment of aggression in youth is scarce. Psychosocial interventions may be effective alone or in combination with pharmacological treatments. Psychotropic agents (e.g., stimulants, mood stabilizers, beta-blockers) have also been shown to have limited efficacy in reducing aggression. Antipsychotics, particularly the atypical antipsychotics, show substantial efficacy in the treatment of aggression in selected pediatric populations. Atypical antipsychotics are generally associated with fewer extrapyramidal symptoms than are typical antipsychotics. CONCLUSIONS: Psychosocial interventions and atypical antipsychotics are promising treatments for aggression in youth. Double-blind studies should examine the safety and efficacy of atypical antipsychotics compared to each other and to medications from other classes, the efficacy of specific medications for different subtypes of aggression, combining various psychotropic medications, optimal dosages, and long-term safety.

Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part II.

OBJECTIVE: To develop treatment recommendations for the use of antipsychotic medications for children and adolescents with serious psychiatric disorders and externalizing behavior problems. METHOD: Using a combination of evidence- and consensus-based methodologies, recommendations were developed in six phases as informed by three primary sources of information: (1) current scientific evidence (published and unpublished), (2) the expressed needs for treatment-relevant information and guidance specified by clinicians in a series of focus groups, and (3) consensus of clinical and research experts derived from a formal survey and a consensus workshop. RESULTS: Fourteen treatment recommendations on the use of atypical antipsychotics for aggression in youth with comorbid psychiatric conditions were developed. Each recommendation corresponds to one of the phases of care (evaluation, treatment, stabilization, and maintenance) and includes a brief clinical rationale that draws upon the available scientific evidence and consensus expert opinion derived from survey data and a consensus workshop. CONCLUSION: Until additional research from controlled trials becomes available, these evidence- and consensus-based treatment recommendations may be a useful approach to guide the use of antipsychotics in youth with aggression.