Safety methodology in pediatric psychopharmacology trials.

In recent years, there has been an increase in pediatric clinical trials as the result of an identified need for greater research with this population. Given the potential risks, and the vulnerability of the population, there has also been an identified need for greater safety elicitation and monitoring in pediatric psychopharmacology trials, for example, through the use of a data and safety monitoring board (DSMB). However, research indicates that pediatric trials and psychiatric trials are less likely to use a DSMB. The rationale for the current study was to determine what safety methodologies have been reported in pediatric psychopharmacology trials over the past 10 years. A literature review was conducted of all pediatric psychopharmacology trials published since 2001. Results indicated that the most common elicitation method was collecting laboratory information and vital signs. Six percent of trials solely relied on spontaneous reporting of adverse events, and only 11.8% reported using a DSMB. These results suggest that elicitation methods and use of DSMBs are still low. Practical considerations, affected stakeholders, and barriers are discussed. Recommendations for moving forward include the use of multiple elicitation methods and automatic requirement of a DSMB for pediatric psychopharmacology trials, required completion of a standardized safety reporting form, and engaging multiple interested parties in these processes.

Evidence review and clinical guidance for the use of ziprasidone in Canada.

While indicated for schizophrenia and acute mania, ziprasidone's evidence base and use in clinical practice extends beyond these regulatory approvals. We, an invited panel of experts led by a working group of 3, critically examined the evidence and our collective experience regarding the effectiveness, tolerability and safety of ziprasidone across its clinical uses. There was no opportunity for manufacturer input into the content of the review. As anticipated, ziprasidone was found to be effective for its indicated uses, although its utility in mania and mixed states lacked comparative data. Beyond these uses, the available data were either unimpressive or were lacking. An attractive characteristic is its neutral effect on weight thereby providing patients with a non-obesogenic long-term treatment option. Key challenges in practice include the need for dosing on a full stomach and managing its early onset adverse effect of restlessness. Addressing these issues are critical to its long-term success.

A review of escitalopram and citalopram in child and adolescent depression.

OBJECTIVE: To review the basic pharmacology and published literature regarding escitalopram and citalopram in child and adolescent depression. METHODS: A LITERATURE REVIEW WAS CONDUCTED USING THE SEARCH TERMS: 'escitalopram', 'citalopram', 'depression', 'randomized controlled trial', 'open label trial' and limits set to: Human trials, English Language and All Child (Age 0-18). Additional articles were identified from reference information and poster presentation data. RESULTS: Three prospective, randomized controlled trials (RCT) were found for escitalopram in pediatric depression, and two RCTs were found for citalopram. One RCT each for escitalopram and citalopram showed superiority over placebo on the primary out come measure. Adverse effects in escitalopram and citalopram trials were generally mild to moderate. Suicidality was not assessed systematically in all RCTs reviewed, but did not appear to be elevated over placebo in escitalopram RCTs. One trial reported numerically higher suicide related events for citalopram compared to placebo (14 vs. 5, p=0.06). CONCLUSION: At present, escitalopram and citalopram should be considered a second-line option for adolescent depression. The US Food and Drug Administration approval of escitalopram for treatment of adolescent depression was based on a single positive RCT. This is less evidence than typically required for approval of a drug for a new indication.

Focus on ziprasidone: a review of its use in child and adolescent psychiatry.

OBJECTIVE: To review published literature regarding ziprasidone in child and adolescent psychiatry. METHODS: A literature review was conducted using the medline search term: 'ziprasidone' with limits: Human trials, English language, All Child (Age 0-18). Additional articles were identified from reference information and poster presentation data. RESULTS: Two randomized controlled trials and five prospective open-label studies have been conducted with ziprasidone. Additionally, several case reports and case series are reviewed. Ziprasidone has a greater propensity for QT(c) prolongation and risk for fatal arrhythmias compared to other atypical antipsychotics. Careful history taking regarding presence of congenital long QT syndrome is essential. Given limited clinical experience, electrocardiogram monitoring at baseline and following attainment of ziprasidone target dosage is warranted. No deaths from overdose have been reported in children and adolescents. Ziprasidone has a low potential for extrapyramidal side effects. Prolactin changes are small and transient. Lethargy, drowsiness, agitation and tachycardia were the most common adverse effects in randomized trials. Body weight changes with ziprasidone were comparable to placebo-treated subjects. CONCLUSION: At present, ziprasidone should be considered a second or third-line option for a limited set of conditions. A role may exist for ziprasidone in patients who have experienced significant metabolic adverse effects with other atypical antipsychotics.

Delirium and isolated angiitis of the central nervous system: a case report and review.

Central nervous system (CNS) vasculitis is a rare entity, especially when it occurs in isolation; it is seen more commonly as part of a multisystem vasculitis. Common presenting symptoms include persistent headache, encephalopathy, and multifocal signs. We discuss the case of a 68-year-old female who presented twice in 1 month with confusion and choreaform movements. Extensive workup was negative for a connective tissue disease or other conditions in the differential, including neurosarcoidosis, Creutzfeldt-Jakob disease, and neurosyphilis. The only significant findings were elevated erythrocyte sedimentation rate, inflammatory signs in the CNS, and diffuse slowing of the electroencephalogram. A presumptive diagnosis of isolated angiitis of the central nervous system (IACNS) was made and the patient was successfully treated with steroids. She recovered fully with no residual symptoms. The diagnosis of IACNS is often difficult given there are no definitive laboratory investigations or pathognomonic presentation. However, a series of signs, symptoms, and laboratory findings have been proposed that are helpful in making the diagnosis. To our knowledge, IACNS presenting primarily with delirium has not been previously reported in the literature. The diagnosis of IACNS is purely speculative for this case, as the gold standard for diagnosis, a leptomeningeal cortical biopsy, was not performed.

Metyrosine in psychosis associated with 22q11.2 deletion syndrome: case report.

This report describes the use of metyrosine (Demser) in an adolescent male with psychosis associated with the 22q11.2 deletion syndrome (velocardiofacial syndrome; VCFS), diagnosed by fluorescence in situ hybridization (FISH). He presented with multiple features of 22q11.2 deletion syndrome, including ventricular septal defect, palatal abnormalities, speech and motor delays, attention deficits, mood lability, and psychosis. After a failed trial of an atypical antipsychotic to address the psychosis, metyrosine was initiated, with significant reduction of psychotic symptoms and mood lability. Metyrosine treatment allowed this youth to live at home and to attend school, after months of recurrent psychiatric hospitalizations. The successful treatment of metyrosine for psychosis associated with VCFS represents a first in psychiatry, where a known biochemical abnormality in a psychiatric disorder was corrected by a treatment that targets the biochemical pathway, leading to reduction of psychiatric symptoms and improvement of functioning.

Acute dystonic reaction in an adolescent on risperidone when a concomitant stimulant medication is discontinued.

This report describes an acute dystonic reaction that occurred after dexamphetamine was discontinued from a drug regimen that included risperidone. This is the second report that has revealed a possible rebound dystonia when a stimulant medication is withdrawn from a patient taking risperidone. We also discuss the neurophysiological hypotheses and implications for treatment.

Lamotrigine in adolescent mood disorders: a retrospective chart review.

INTRODUCTION: Treatment nonresponse in adolescent mood disorders is a major public health problem, as mood disorders in youth are associated with significant mortality by suicide, protracted course of illness, and recurrence into adulthood. Three studies with small sample sizes exist for lamotrigine in youth mood disorders. However, the risk of serious rash has limited its use in youth mood disorders. OBJECTIVE: The aims of this study are to evaluate the preliminary effectiveness and safety of lamotrigine in adolescent mood disorders. METHODS: Medical charts were retrospectively reviewed at three clinical sites for 42 adolescents treated with lamotrigine for a mood disorder. The Clinical Global Impression (CGI) Severity and Improvement scores were obtained at baseline and last visit. Treatment-emergent adverse effects were also obtained. RESULTS: Improvement was seen in 22 subjects (52%). The mean daily lamotrigine dose was 114.8mg (SD 75.6), and the average duration of lamotrigine treatment was 29.1+/-31.8 weeks. The mean CGI-S score decreased from 4.9+/-1.0 at baseline to 3.5+/-1.4 at endpoint (z=3.204, p<0.002). Four subjects (10%) developed benign rash. CONCLUSIONS: This study provides preliminary data that lamotrigine may be effective in adolescents with mood disorders. However, this study revealed that lamotrigine might be associated with a significant risk of benign rash.