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1.  Lack of Efficacy of Citalopram in Children With Autism Spectrum Disorders and High Levels of Repetitive Behavior 
Archives of general psychiatry  2009;66(6):583-590.
Selective serotonin reuptake inhibitors are widely prescribed for children with autism spectrum disorders.
To determine the efficacy and safety of citalopram hydrobromide therapy for repetitive behavior in children with autism spectrum disorders.
National Institutes of Health–sponsored randomized controlled trial.
Six academic centers, including Mount Sinai School of Medicine, North Shore–Long Island Jewish Health System, University of North Carolina at Chapel Hill, University of California at Los Angeles, Yale University, and Dartmouth Medical School.
One hundred forty-nine volunteers 5 to 17 years old (mean [SD] age, 9.4 [3.1] years) were randomized to receive citalopram (n = 73) or placebo (n = 76). Participants had autistic spectrum disorders, Asperger disorder, or pervasive developmental disorder, not otherwise specified; had illness severity ratings of at least moderate on the Clinical Global Impressions, Severity of Illness Scale; and scored at least moderate on compulsive behaviors measured with the Children's Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders.
Twelve weeks of citalopram hydrobromide (10 mg/5 mL) or placebo. The mean (SD) maximum dosage of citalopram hydrobromide was 16.5 (6.5) mg/d by mouth (maximum, 20 mg/d).
Main Outcome Measures
Positive response was defined by a score of much improved or very much improved on the Clinical Global Impressions, Improvement subscale. An important secondary outcome was the score on the Children's Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders. Adverse events were systematically elicited using the Safety Monitoring Uniform Report Form.
There was no significant difference in the rate of positive response on the Clinical Global Impressions, Improvement subscale between the citalopram-treated group (32.9%) and the placebo group (34.2%) (relative risk, 0.96; 95% confidence interval, 0.61-1.51; P> .99). There was no difference in score reduction on the Children's Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders from baseline (mean [SD], −2.0 [3.4] points for the citalopram-treated group and −1.9 [2.5] points for the placebo group; P=.81). Citalopram use was significantly more likely to be associated with adverse events, particularly increased energy level, impulsiveness, decreased concentration, hyperactivity, stereotypy, diarrhea, insomnia, and dry skin or pruritus.
Results of this trial do not support the use of citalopram for the treatment of repetitive behavior in children and adolescents with autism spectrum disorders.
Trial Registration Identifier: NCT00086645
PMCID: PMC4112556  PMID: 19487623
2.  Effects of risperidone and parent training on adaptive functioning in children with pervasive developmental disorders and serious behavioral problems 
Children with Pervasive Developmental Disorders (PDDs) have deficits in social interaction, delayed communication and repetitive behavior as well as impairments in adaptive functioning. Many children actually show decline in adaptive skills compared to age mates over time.
This 24-week, three-site, controlled clinical trial randomized 124 children (4 through 13 years of age) with PDDs and serious behavior problems to medication alone (MED; N=49; risperidone 0.5 to 3.5 mg/day (if ineffective, switch to aripiprazole was permitted) or medication plus parent training (PT) (COMB; N=75). Parents of children in COMB received an average of 11.4 PT sessions. Standard scores and Age Equivalent scores on Vineland Adaptive Behavior Scales were the outcome measures of primary interest.
Seventeen subjects did not have a post-randomization Vineland. Thus, we used a mixed model with outcome conditioned on the baseline Vineland scores. Both groups showed improvement over the 24-week trial on all Vineland domains. Compared to MED, Vineland Socialization and Adaptive Composite Standard scores showed greater improvement in the COMB group (p = 0.01 and 0.05; effect sizes = 0.35.and 0.22, respectively). On Age Equivalent scores, Socialization and Communication domains showed greater improvement in COMB versus MED (p=0.03, 0.05; effect sizes = 0.33 and 0.14 respectively). Using logistic regression, children in the COMB group were twice as likely to make at least 6 months gain (equal to the passage of time) in the Vineland Communication Age Equivalent score compared to MED (p = 0.02). After controlling for IQ, this difference was no longer significant.
Reduction of serious maladaptive behavior promotes improvement in adaptive behavior. Medication plus PT shows modest additional benefit over medication alone.
PMCID: PMC3941712  PMID: 22265360
risperidone; parent training; Pervasive Developmental Disorders; children; adaptive behavior
3.  Predictors of Spontaneous and Systematically Assessed Suicidal Adverse Events in the Treatment of SSRI Resistant Depression in Adolescents (TORDIA) Study 
The American journal of psychiatry  2009;166(4):418-426.
The authors sought to identify predictors of self-harm adverse events in treatment-resistant, depressed adolescents during the first 12 weeks of treatment.
Depressed adolescents (N=334) who had not responded to a previous trial with an SSRI antidepressant were randomized to a switch to either another SSRI or venlafaxine, with or without cognitive behavior therapy. Self-harm events, i.e., suicidal and non-suicidal self-injury adverse events were assessed by spontaneous report for the first 181 participants, and by systematic weekly assessment for the last 153 participants.
Higher rates of suicidal (20.8% vs. 8.8%) and nonsuicidal self-injury (17.6% vs. 2.2%), but not serious adverse events (8.4% vs. 7.3%) were detected with systematic monitoring. Median time to a suicidal event was 3 weeks, predicted by high baseline suicidal ideation, family conflict, and drug and alcohol use. Median time to nonsuicidal self-injury was 2 weeks, predicted by previous history of nonsuicidal self-injury. While there were no main effects of treatment, venlafaxine treatment was associated with a higher rate of self-harm adverse events in those with higher suicidal ideation. Adjunctive use of benzodiazepines, while in a small number of participants (N=10) was associated with higher rate of both suicidal and nonsuicidal self-injury adverse events.
Since predictors of suicidal adverse events also predict poor response to treatment, and many of these events occurred early in treatment, improving the speed of response to depression, by targeting of family conflict, suicidal ideation, and drug use may help to reduce their incidence. The relationship of venlafaxine and of benzodiazepines to selfharm events requires further study and clinical caution.
PMCID: PMC3593721  PMID: 19223438
4.  Out of the Black Box: Treatment of Resistant Depression in Adolescents and the Antidepressant Controversy 
The purpose of this article is to describe the effects of the pediatric antidepressant controversy on the Treatment of Serotonin-Selective Reuptake Inhibitor (SSRI) Resistant Depression in Adolescents (TORDIA) trial.
Adolescents, ages 12–18 years, with SSRI resistant depression were randomized to one of four treatments for a 12 week trial: Switch to different SSRI, switch to an alternate antidepressant (venlafaxine), switch to an alternate SSRI plus cognitive behavior therapy (CBT), or switch to venlafaxine plus CBT.
The health advisories and “black box” warnings regarding suicidality and antidepressants in adolescents occurred during the course of the TORDIA trial. Revisions to the protocol, multiple-consent form changes, and re-consenting of patients were necessary. Recruitment of participants was adversely affected.
Despite a cascade of unforeseen events that delayed the completion of the study, the TORDIA trial resulted in clinically important information about treatment-resistant depression in adolescents.
PMCID: PMC3281287  PMID: 22251022
5.  Double-blind maintenance safety and effectiveness findings from the Treatment of Early-Onset Schizophrenia Spectrum Study (TEOSS) 
To examine the long-term safety and efficacy of three antipsychotics in early-onset schizophrenia spectrum disorders (EOSS).
Patients (age 8–19 years) who had improved during an 8-week, randomized double-blind acute trial of olanzapine, risperidone, or molindone (plus benztropine) were eligible to continue on the same medication for up to 44 additional weeks under double-blind conditions. Adjunctive medications were allowed following defined algorithms. Standardized symptom, safety, and functional assessments were conducted every 4 weeks.
Of the 116 youth randomized in the acute trial, 54 entered maintenance treatment (molindone, N=20; olanzapine, N=13; risperidone, N=21). Fourteen (26%) completed 44 weeks of treatment. Adverse effects (N=15), inadequate efficacy (N=14), or study non-adherence (N=8) were the most common reasons for discontinuation. The three treatment arms did not significantly differ in symptom reduction or time to discontinuation. Akathisia was more common with molindone and elevated prolactin concentrations more common with risperidone. Although weight gain and metabolic adverse events had occurred more often with olanzapine and risperidone during the acute trial, no significant between-drug differences emerged in most of these parameters during maintenance treatment.
Only 12 % of youth with EOSS continued on their originally randomized treatment at 52 weeks. No agent demonstrated superior efficacy, and all were associated with side effects, including weight gain. Improved treatments are needed for EOSS.
PMCID: PMC2882800  PMID: 20494268
adolescent; schizophrenia; schizoaffective disorder; antipsychotic; treatment
6.  Possible Influence of Variant of the P-Glycoprotein Gene (MDR1/ABCB1) on Clinical Response to Guanfacine in Children with Pervasive Developmental Disorders and Hyperactivity 
Guanfacine has been shown to reduce hyperactive behaviors in children with attention-deficit/hyperactivity disorder (ADHD) and possibly in children with pervasive developmental disorder (PDD) and hyperactivity. The aim of this exploratory study was to examine whether gene variants encoding the multidrug resistance protein (MDR1 or ABCB1) , a drug transporter at the blood–brain barrier, are associated with variability in the efficacy of guanfacine in children with PDD and hyperactivity.
Children with PDD who participated in an 8-week open-label trial of guanfacine were genotyped for the C3435T single-nucleotide polymorphism (SNP) variant of the MDR1 gene, a variant reported to alter function of the transporter. The decrease from baseline to 8 weeks in parent-rated Aberrant Behavior Checklist (ABC) hyperactivity and Swanson, Nolan, and Pelham (SNAP) scores were analyzed by MDR1 genotype. Response was compared between subjects homozygous for the minor allele T of the C34535T MDR1 variant (T/T) versus other genotypes (C/T and C/C).
Disruptive behavior decreased during guanfacine treatment as assessed by several end points in the 25 enrolled children (23 boys and 2 girls). Genotype data were available from 22 children. Subjects with either C/T or C/C (n = 16) genotypes showed a three-fold greater improvement than T/T MDR1 C3435T genotype (n = 6) (mean decrease of 15.1 ± 12.6, or 50.7% from baseline, versus 4.5 ± 5.1, or 15.6% from baseline) in parent-rated ABC Hyperactivity scores over 8 weeks (p = 0.03). Parent-rated ADHD SNAP scores also differed by genotype (p = 0.05).
Gene variants in MDR1 may influence guanfacine response on hyperactive-impulsive behaviors via altered membrane transport. If replicated in larger samples, additional studies would be important to clarify the mechanisms underlying this effect and to determine its clinical significance.
PMCID: PMC2835389  PMID: 20166790
7.  Gender Differences in Depression Symptoms in Treatment-Seeking Adults: STAR*D Confirmatory Analyses 
Comprehensive psychiatry  2008;49(3):238-246.
While epidemiologic research consistently reports greater prevalence of major depressive disorder in women, small sample sizes in many studies do not allow for full elaboration of illness characteristics. This paper examines gender differences in terms of illness attributes in a cohort of 2541 outpatients from across the United States who enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.
Confirmatory analyses were performed in 2541 outpatients comparing men and women with regard to socio-demographic features, comorbid Axis I and Axis III conditions, and illness characteristics. Results were compared to those of our previous report on the initial population of the first 1500 individuals enrolled in STAR*D.
In both samples, nearly two-thirds of the sample (62.5%) were women. Women had greater symptom severity, but men had more episodes of major depression, despite no difference in the length of illness. No differences in age of onset emerged. As in the first cohort, women showed greater rates of an anxiety disorder, bulimia and somatoform disorder, as well as more past suicide attempts, while men showed more alcohol and substance abuse. Women reported more appetite, weight, hypersomnia, interpersonal sensitivity, gastrointestinal and pain complaints, and less suicidal ideation. Irritability was equally common in men and women.
This large analysis confirmed most of the clinical features and co-morbidities found to be more prevalent in the first cohort of women. Additionally, this analysis corroborated previous research suggesting higher rates of atypical and anxious depression in women, but refuted the notion of an “irritable depression” found in men. The report confirmed the 1.7:1 ratio for depression seen across genders in the National Comorbidity Survey.
PMCID: PMC2759282  PMID: 18396182
Women; Depression; Prevalence; Gender
8.  Treatment of Selective Serotonin Reuptake Inhibitor–Resistant Depression in Adolescents: Predictors and Moderators of Treatment Response 
To advance knowledge regarding strategies for treating selective serotonin reuptake inhibitor (SSRI)–resistant depression in adolescents, we conducted a randomized controlled trial evaluating alternative treatment strategies. In primary analyses, cognitive-behavioral therapy (CBT) combined with medication change was associated with higher rates of positive response to short-term (12-week) treatment than medication alone. This study examines predictors and moderators of treatment response, with the goal of informing efforts to match youths to optimal treatment strategies.
Youths who had not improved during an adequate SSRI trial (N = 334) were randomized to an alternative SSRI, an alternative SSRI plus CBT, venlafaxine, or venlafaxine plus CBT. Analyses examined predictors and moderators of treatment response.
Less severe depression, less family conflict, and absence of nonsuicidal self-injurious behavior predicted better treatment response status. Significant moderators of response to CBT + medication (combined) treatment were number of comorbid disorders and abuse history; hopelessness was marginally significant. The CBT/combined treatment superiority over medication alone was more evident among youths who had more comorbid disorders (particularly attention-deficit/hyperactivity disorder and anxiety disorders), no abuse history, and lower hopelessness. Further analyses revealed a stronger effect of combined CBT + medication treatment among youths who were older and white and had no nonsuicidal self-injurious behavior and longer prestudy pharmacotherapy.
Combined treatment with CBT and antidepressant medication may be more advantageous for adolescents whose depression is comorbid with other disorders. Given the additional costs of adding CBT to medication, consideration of moderators in clinical decision making can contribute to a more personalized and effective approach to treatment.
PMCID: PMC2754157  PMID: 19182688
depression; adolescents; treatment-resistant; cognitive-behavioral therapy
9.  Cognitive Effects of Risperidone in Children with Autism and Irritable Behavior 
The objective of this research was to explore the effects of risperidone on cognitive processes in children with autism and irritable behavior.
Thirty-eight children, ages 5–17 years with autism and severe behavioral disturbance, were randomly assigned to risperidone (0.5 to 3.5 mg/day) or placebo for 8 weeks. This sample of 38 was a subset of 101 subjects who participated in the clinical trial; 63 were unable to perform the cognitive tasks. A double-blind placebo-controlled parallel groups design was used. Dependent measures included tests of sustained attention, verbal learning, hand-eye coordination, and spatial memory assessed before, during, and after the 8-week treatment. Changes in performance were compared by repeated measures ANOVA.
Twenty-nine boys and 9 girls with autism and severe behavioral disturbance and a mental age ≥18 months completed the cognitive part of the study. No decline in performance occurred with risperidone. Performance on a cancellation task (number of correct detections) and a verbal learning task (word recognition) was better on risperidone than on placebo (without correction for multiplicity). Equivocal improvement also occurred on a spatial memory task. There were no significant differences between treatment conditions on the Purdue Pegboard (hand-eye coordination) task or the Analog Classroom Task (timed math test).
Risperidone given to children with autism at doses up to 3.5 mg for up to 8 weeks appears to have no detrimental effect on cognitive performance.
PMCID: PMC2935828  PMID: 18582177
10.  Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-Resistant Depression 
Only about 60% of adolescents with depression will show an adequate clinical response to an initial treatment trial with a selective serotonin reuptake inhibitor (SSRI). There are no data to guide clinicians on subsequent treatment strategy.
To evaluate the relative efficacy of 4 treatment strategies in adolescents who continued to have depression despite adequate initial treatment with an SSRI.
Design, Setting, and Participants
Randomized controlled trial of a clinical sample of 334 patients aged 12 to 18 years with a primary diagnosis of major depressive disorder that had not responded to a 2-month initial treatment with an SSRI, conducted at 6 US academic and community clinics from 2000–2006.
Twelve weeks of: (1) switch to a second, different SSRI (paroxetine, citalopram, or fluoxetine, 20–40 mg); (2) switch to a different SSRI plus cognitive behavioral therapy; (3) switch to venlafaxine (150–225 mg); or (4) switch to venlafaxine plus cognitive behavioral therapy.
Main Outcome Measures
Clinical Global Impressions-Improvement score of 2 or less (much or very much improved) and a decrease of at least 50% in the Children’s Depression Rating Scale-Revised (CDRS-R); and change in CDRS-R over time.
Cognitive behavioral therapy plus a switch to either medication regimen showed a higher response rate (54.8%; 95% confidence interval [CI], 47%–62%) than a medication switch alone (40.5%; 95% CI, 33%–48%; P=.009), but there was no difference in response rate between venlafaxine and a second SSRI (48.2%; 95% CI, 41%–56% vs 47.0%; 95% CI, 40%–55%; P=.83). There were no differential treatment effects on change in the CDRS-R, self-rated depressive symptoms, suicidal ideation, or on the rate of harm-related or any other adverse events. There was a greater increase in diastolic blood pressure and pulse and more frequent occurrence of skin problems during venlafaxine than SSRI treatment.
For adolescents with depression not responding to an adequate initial treatment with an SSRI, the combination of cognitive behavioral therapy and a switch to another antidepressant resulted in a higher rate of clinical response than did a medication switch alone. However, a switch to another SSRI was just as efficacious as a switch to venlafaxine and resulted in fewer adverse effects.
PMCID: PMC2277341  PMID: 18314433

Results 1-10 (10)