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FDA Approves Risperidone Long-Acting Injection for the Treatment of Schizophrenia

The Food and Drug Administration approved risperidone long-acting injection (Risperdal Consta, Janssen) for the treatment of schizophrenia in late October. The first long-acting atypical to receive FDA approval, risperidone injection releases consistent amounts of medication over a 2-week period.

Risperidone long-acting injection uses the Medisorb drug-delivery technology; active medication is encapsulated into polymer-based microspheres that are injected into the body, where they degrade slowly and release the drug at a controlled rate. The new formulation provides an alternative for schizophrenic patients who have trouble taking oral medication on a regular basis. In addition, the continuous-release properties of the drug eliminates many symptom fluctuations that some patients experience between doses of short-acting formulations.

Clinical trials with risperidone long-acting injection involved 400 adult inpatients and outpatients with schizophrenia randomized to risperidone injection (25 or 50 mg) or placebo for 12 weeks. Of patients taking risperidone injection 25 mg, 47% experienced greater improvement (20% reduction in score) on the Positive and Negative Syndrome Scale compared to 17% of those taking placebo. The most common side effects experienced by patients taking risperidone injection were headache, agitation, psychosis, insomnia, dizziness, rhinitis, and pain. Overall, percentage of adverse events reported were similar in the risperidone injection and placebo groups and serious adverse events were more common in the placebo group. Treatment discontinuation due to side effects was 12% in both groups.

Pain upon injection was reported to be low upon first injection and decreased on subsequent injections. Less than 5% of patients experienced redness, swelling, or indurations following injection. –DH

Citalopram Treatment of Abdominal Pain in Children and Adolescents

In an exploratory 12-week, open-label trial, citalopram (Celexa) was shown to be effective in the treatment of recurrent abdominal pain and comorbid psychiatric disorders in children and adolescents. Recurrent abdominal pain is defined as at least three episodes of abdominal pain occurring over 3 months that are severe enough to impair normal functioning. The condition affects 7% to 25% of school-aged youths and usually cannot be explained by a physical disease.

“We were especially interested in recurrent abdominal pain because of the high rates of comorbid anxiety and depressive disorders, and low rates of mental health treatment and referral,” said John V. Campo, MD, lead researcher of the study. “The disorder defies simplistic classification as physical or mental, with affected children often falling through the cracks between traditional medical and mental health services; many patients, families, and physicians bristle at the implication that the child’s physical suffering may be caused by a mental disorder.”

Campo and colleagues at the University of Pittsburgh Medical Center evaluated 25 clinically referred children and adolescents 7–18 years of age who were suffering from recurrent abdominal pain. Citalopram was initiated at 10 mg/day, increased to 20 mg/day at week 2 and 40 mg/day at week 4 depending on individual response and tolerability. Positive response to treatment was defined as a score of 1 (very much improved) or 2 (much improved) on the Clinical Global Impression Scale for Improvement. Reports of abdominal pain (Abdominal Pain Index), anxiety (Screen for Child Anxiety-Related Emotional Disorders), depression (Children’s Depression Inventory), functional impairment (Functional Disability Inventory, Columbia Impairment Scale), and somatic symptoms (Children’s Somatization Inventory) were obtained from both patients and their parents. Adverse events were assessed using the Side Effects for Children Assessment. Medical and psychiatric history were assessed at baseline.

Eighty-four percent (n=21) of patients completed the 12-week study, with 68% taking the maximum 40 mg/day dose by study endpoint. As shown in the Figure, 80% of patients responded by week 8 and 84% responded by week 12. Both children and parents reported significant improvement in abdominal pain by week 2. Child-reported symptoms of anxiety and depression were significantly improved by weeks 1 and 2 respectively. Both child and parent ratings of all symptoms were significantly improved at study endpoint compared to baseline.

“We were impressed by the magnitude of benefit in selected children,” Dr. Campo said. “In addition, four of the five children who did not meet criteria for a comorbid psychiatric disorder showed a clinically significant response to treatment with a ‘psychoactive’ medication.”

Campo and colleagues point to the importance of examining the potential role of anxiety and depression as mediators of treatment response in children with functional gastrointestinal disorders, such as recurrent abdominal pain. They note that placebo-controlled trials of citalopram in the treatment of such disorders are warranted.

Funding for this research was provided by Forest Laboratories. –DH
(Abstract B23, AACAP 2003)

Metabolic Effects of Atypical Antipsychotics in Youths

Preliminary results of an open-label naturalistic study suggest that the three most commonly used atypical antipsychotics are associated with significant increases in weight and metabolic problems, particularly in antipsychotic-naive youths. To evaluate the risk of weight gain and metabolic abnormalities in children and adolescents taking atypicals, Christoph U. Correll, MD, at the Zucker Hillside Hospital in Glen Oaks, New York, and colleagues, treated 100 aggressive and psychotic patients with olanzapine (Zyprexa), risperidone (Risperdal), or quetiapine (Seroquel) for 12 weeks.

“The aim was to carefully evaluate the potential health risks of these agents in order to more accurately weigh benefits and risks as well as the effect of adverse events on compliance,” Dr. Correll said.

The study included inpatients and outpatients 5–19 years of age with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for psychotic, mood, and/or aggressive disorders. Exclusion criteria included history of (or active) eating disorder, thyroid problems, mental retardation, or severe medical disorder; pregnancy; >7 days of newly initiated treatment with the atypicals under study; and treatment with more than one antipsychotic at study entry. Fasting glucose, lipids, insulin, leptin, and prolactin measures were obtained at baseline, 4 weeks, and 12 weeks. Weight, height, and body mass index (BMI) were measured at baseline and monthly thereafter.

Weight and BMI were significantly increased (P<.0001) in all 60 patients who completed 8 weeks of treatment. The weight was due to an increase in body fat rather than a natural result of growth. Weight gain 7% occurred in approximately 77% of those taking olanzapine (n=22), 75% of those taking risperidone (n=20), and 33% of those taking quetiapine (n=18). Patients who were new to antipsychotic treatment (n=35) were most vulnerable to weight gain, showing significant elevations of trigylcerides, low-density lipoproteins, and insulin; this subgroup showed no improved metabolic effects with quetiapine over the other two atypicals. New-onset dyslipidemia occurred in approximately 27%, 40%, and 39% of patients in the olanzapine, risperidone, and quetiapine groups, respectively. Two premorbidly obese patients developed hyperglycemia.

“We did not expect to see this degree of short-term metabolic effects in kids,” Dr. Correll said. “Weight gain and metabolic adverse effects of novel antipsychotics need to be taken seriously; weight and height should be monitored at each visit and age- and sex-adjusted BMI should be calculated and tracked.” (Growth charts can be downloaded at http://www.cdc.gov/growthcharts/).

Correll and colleagues are conducting a longitudinal phase of the study consisting of 3-monthly assessments in children and adolescents who continue on the antipsychotic. –DH

(Abstract 17C, AACAP 2003)

 

Use of Electronic Diaries to Monitor Treatment Adherence

Adherence to a strict dosing schedule is important for achieving the maximum benefit of a prescribed medication. Certain long-acting stimulants like ostomotic release oral system methylphenidate (OROS MPH, Concerta), used to treat attention-deficit/hyperactivity disorder (ADHD), can somewhat relieve the need for strict monitoring since they are taken once daily, but advanced methods for tracking treatment would be beneficial for both physicians and patients.

James McGough, MD, and Suzanne Lamerand, BS, of the University of California Neuropsychiatric Institute in Los Angeles, proposed regulating patients’ dosing through the use of an electronic diary, which could record the date, time, and dosage of medication taken. To test whether this approach could compete with current methods of dosing, such as tablet counting, McGough and Lamerand studied 177 ADHD adolescents 13–18 years of age. The patients were culled from a double-blind, controlled phase of the investigation determining the safety and efficacy of OROS MPH among adolescents.

Each patient was given either a once-daily OROS MPH tablet or a placebo, and a personal digital assistant (PDA) with eCaselink™ e-Patient software, with which to record his or her data. Patients visited a clinic weekly, where they returned unused tablets from the previous week and were instructed how to enter pertinent information in their electronic diaries. Between visits to the clinic, relevant information was submitted to the investigators by PDA connection to a phone line. Data from the electronic diary submissions and the tablet counts at the clinic were compiled at the end of the 2-week study to determine adherence to the dosing schedule.

McGough and Lamerand found a high level of subject adherence to the medication according to both tablet counts and diary submissions. According to the tablet counts, 92% of OROS MPH patients and 94% of placebo patients were 80% adherent. Similar data were drawn from the electronic diaries, with 94% of the drug-treated group and 97% of the placebo group showing adherence of 80%. Furthermore, the two types of assessment were highly correlated.

McGough and Lamerand’s evidence suggests that electronic diaries are a valuable and novel means of determining patient adherence to treatment. They propose that electronic submissions could replace time-consuming tablet counting as a method for collecting data about adherence, thus increasing the effectiveness of stimulant therapy.

Funding for this research was provided by McNeil Pharmaceuticals. –EJR
(Abstract A30, AACAP 2003)

Impact of Comorbid ADHD on Treatment Compliance

Most adolescents in treatment for substance use disorders (SUD) have comorbid mental disorders including conduct disorder (CD), attention-deficit/hyperactivity disorder (ADHD), and major depression (MDD). Although comorbid psychiatric disorders in general is associated with poor treatment outcomes for substance abuse, it has been suggested that ADHD may be particularly damaging.

Michelle Lohman, RN, Paula Riggs, MD, and colleagues at the University of Colorado School of Medicine in Denver, evaluated 50 adolescents 13–19 years of age with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for MDD, CD, and SUD. The subjects were part of an ongoing 16-week, double-blind, placebo-controlled trial of fluoxetine (Prozac) for treatment of depression.

“We wanted to know whether the subsample of patients who also had ADHD had similar outcomes and substance treatment compliance,” Dr. Riggs said.

The researchers determined that 42% of the subjects met criteria for ADHD. All ADHD and non-ADHD subjects were given the option of attending free individual weekly cognitive-behavioral therapy (CBT) sessions targeting substance abuse. Participants were paid $25/week to attend weekly medication follow-up assessments regardless of their compliance with treatment.

While both subjects with and without ADHD were >90% compliant with the paid weekly medication follow up visits, those with ADHD had poorer compliance with treatment components for which they were not paid. ADHD?patients were 70% compliant with weekly CBT therapy attendance and 66% compliant in taking medications as prescribed. In contrast, these rates were 85% and 83% respectively, in patients without ADHD (Figure).

“Preliminary data from this ongoing study indicate that treatment compliance may be poorer for adolescents in treatment for SUDs who also have ADHD,” Dr. Riggs said. “However, pilot data indicate that treatment compliance may be improved when incentives are given or can be earned for treatment compliance.”

The researchers note that future studies are needed to confirm these results and refine treatment interventions for dually diagnosed adolescents. –DH
(Abstract C21, AACAP 2003)

Trauma Symptoms Expressed as Functioning Deficits in Children

Posttraumatic stress disorder (PTSD) and other psychiatric disorders are highly prevalent in children exposed to abuse at very young ages. According to researchers at Dartmouth Medical School, symptoms of PTSD and anxiety may be expressed as executive functioning deficits in such children.

“Inhibitory control, emotional modulation, and cognitive flexibility are basic elements of executive functioning that support higher level metacognitive abilities such as problem solving and deferral of gratification,” said Robert J. Racusin, MD, lead author of the study. “When younger, anxiety is expressed more directly. As maltreated children enter adolescence, it is expressed as poor executive functioning and takes the form of disruptive behavior disorders, such as attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD).”

To investigate this hypothesis, Racusin and colleagues recruited 25 foster children 9–18 years of age with histories of early trauma and their foster parents. Foster parents completed the Behavior Rating Inventory of Executive Function (BRIEF), the Behavior Assessment System for Children, the Children’s Global Assessment Scale, and the Computerized Diagnostic Interview for Children (C-DISC); children completed the Trauma Symptom Checklist for Children and the C-DISC.

The researchers found that 68% of the children met criteria for 1 psychiatric disorders: 15% had an anxiety disorder, 15% had ADHD or ODD, 32% has both, 4% had depression, and 4% had PTSD. Abused children were also shown to have significantly greater executive functioning difficulties, such as ability to inhibit impulses, shift flexibly, modulate emotions, sustain attention, and plan and organize problem solving than their peers. These problems reached clinically significant levels in 60% to 70% of the children. In addition, internalizing and externalizing problems were more frequent in abused children and severity of these problems were related to degree of executive functioning deficits.

“Relationships between executive functioning, anxiety, disruptive behaviors, and adversity are as yet unknown; however, it may be that abuse and neglect is causally linked with anxiety, and that the ability to regulate behavior and emotions is disrupted in these children,” Dr. Racusin said.

According to Dr. Racusin, studies have shown that children with histories of early abuse and neglect have executive functioning problems similar to those seen in children with traumatic brain injuries and ADHD.

“These phenomenologic similarities may reflect similarities in underlying pathophysiology,” Dr. Racusin said. “Exposure to repeated and/or severe stress may result in structural and/or functional central nervous system changes, particularly in the same areas putatively involved with the behavioral changes seen in children with brain trauma.”

Although nearly 70% of foster children with histories of trauma exhibited criteria for anxiety and disruptive behaviors in this study, only one child met criteria for PTSD?diagnosis. The researchers speculate that in the context of stable foster care, the aftermath of early trauma may be expressed as substantial executive functioning deficits observed in the study.

“Given the high frequency of undiagnosed anxiety disorders and the prevalence of anxiety symptoms in this study, clinicians working with maltreated children should explore the possibility that underlying anxiety disorders are expressed as, or masked by, disruptive behavior disorders,” Dr. Racusin said. “Treatment choices may change depending on the presence of underlying anxiety disorders in children who demonstrate disruptive behavior disorders such as ADHD, ODD, or CD.”

Racusin and colleagues note that future studies should examine whether interventions and supports for children with poor executive function can help mediate the expression of anxiety and disruptive behaviors. –DH

(Abstract B6, AACAP 2003)

Combination Lithium and Divalproex Effective in Juveniles with Bipolar Disorder

In a large prospective study of bipolar children and adolescents, combination lithium and divalproex (Depakote)?showed efficacy rates double those observed in adult studies. The study researchers note that, although monotherapy with several mood-stabilizing agents appear to be associated with beneficial effects in young people with bipolar disorder, most of these youths do not achieve full syndromal remission with monotherapy. 

“For that reason, we wished to explore combination therapy with two commonly used mood stabilizers in young people,” said study author Robert L. Findling, MD, of the University Hospitals of Cleveland in Ohio.

Findling and colleagues studied 139 bipolar I or II outpatients 5–17 years of age who had suffered a hypomanic or manic episode within 3 months of study initiation. Subjects were treated for 20 weeks with both lithium and divalproex. Symptoms improvement was assessed with the Children’s Depression Rating Scale-revised (CDRS-R), Young Mania Rating Scale (YMRS), and the Children’s Global Assessment Scale (CGAS).

“Our rates of remission were almost twice as great as the remission rates seen in an analogous study in adults,” Dr. Findling said. “It is generally accepted that pediatric bipolarity is a treatment-resistant condition. Our data suggest that when proper agents are used, it is in fact a more responsive condition than adult bipolarity.”

Subjects showed significant improvement on all outcome scales by week 4. Fifteen percent were withdrawn from the study due to side effects. Common comorbid diagnoses were attention-deficit/hyperactivity disorder (68%), oppositional defiant disorder (28.1%), and conduct disorder (12.2%).

“The combination was very well tolerated. Among those youths who adhered to study-related procedures and tolerated the medication well, very few had residual affective symptomatology,” Dr. Findling said. “The most common reason youths did not achieve remission was due to lack of adherence with study-related procedures, not residual symptoms or medication intolerance.”

Dr. Findling also pointed out while previous studies in bipolar adults have shown increased depressive symptomatology, the treatment-resistant mood state in youths was mania, rather than depression. Thus, an antidepressant may not be needed in most children and adolescents with bipolar disorder who are treated with an effective mood-stabilizer strategy.

In a follow-up study, subjects meeting a priori response criteria (CDRS-R 40, YMRS 12.5, CGAS 51) for 4 consecutive weeks (n=60) were entered into a double-blind trial and randomized to either lithium or divalproex. Lithium and divalproex monotherapy appeared similar in efficacy for maintenance treatment of remitted bipolar children and adolescents. DH

Funding for this research was provided by The Stanley Medical Research Institute. PP


 

(Abstracts C24 and C25, AACAP 2003)

Psychiatric Dispatches is written and compiled by Deborah Hughes and
Emil J.
Ross.