Henrietta L. Leonard

Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-Resistant Depression: The TORDIA Randomized Controlled Trial

CONTEXT 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. OBJECTIVE 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. INTERVENTIONS 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 Childrens Depression Rating Scale-Revised (CDRS-R); and change in CDRS-R over time. RESULTS 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. CONCLUSIONS 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. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00018902.

Case Study: A New Infection-Triggered, Autoimmune Subtype of Pediatric OCD and Tourette's Syndrome

A review of clinical observations and literature reports leads to the hypothesis that, via a process analogous to Sydenhams chorea, infections with group A beta-hemolytic streptococci, among others, may trigger autoimmune responses that cause or exacerbate some cases of childhood-onset obsessive-compulsive disorder (OCD) or tic disorders (including Tourettes syndrome). If this hypothesis is correct, then immunological treatments should lead to decreased symptoms in some cases. Four cases with abrupt, severe onset or worsening of OCD or tics are presented from an open treatment study. All were boys aged 10 to 14 years. One had OCD, one had Tourettes syndrome, and two had both OCD and Tourettes syndrome. Clinically and on standardized rating scales, their symptoms were in the moderate to very severe range. Two had evidence of recent group A beta-hemolytic streptococci infections, and the others had histories of recent viral illnesses. Two were treated with plasmapheresis, one with intravenous immunoglobulin, and one with immunosuppressive doses of prednisone. All had a clinically significant response immediately after treatment. Diagnostic criteria are provided that describe these cases of pediatric, infection-triggered, autoimmune neuropsychiatric disorders (PITANDs). Suggestions are made regarding the evaluation and management of patients who may have this condition.

A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections

BACKGROUND Some children with obsessive-compulsive disorder (OCD) and tic disorders appear to have symptom exacerbations triggered by group A beta-hemolytic streptococcal infections in a manner that is similar to rheumatic fever and its neurologic variant, Sydenhams chorea. Because penicillin prophylaxis has proven to be effective in preventing recurrences of rheumatic fever, it was postulated that it might also prevent streptococcal-triggered neuropsychiatric symptom exacerbations in children with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS). These children are identified by five clinical characteristics: presence of OCD or tic disorder, prepubertal onset, episodic symptom course, neurologic abnormalities (i.e., choreiform movements) and streptococcal-triggered symptom exacerbations. METHODS Thirty-seven children with PANDAS were enrolled in an 8 month, double-blind, balanced cross-over study. Patients were randomized to receive either 4 months of the active compound (twice daily oral 250 mg penicillin V) followed by 4 months of placebo, or placebo followed by penicillin V. Tic, OCD, and other psychiatric symptoms were monitored monthly. Throat cultures and streptococcal antibody titers were also obtained. RESULTS There were an equal number of infections in both the active and placebo phases of the study. There was no significant change seen in either the obsessive-compulsive or tic symptom severity between the two phases. CONCLUSIONS Because of the failure to achieve an acceptable level of streptococcal prophylaxis, no conclusions can be drawn from this study regarding the efficacy of penicillin prophylaxis in preventing tic or OCD symptom exacerbations. Future studies should employ a more effective prophylactic agent, and include a larger sample size.

Sydenham's chorea Magnetic resonance imaging of the basal ganglia

Analysis of cerebral magnetic resonance images of 24 subjects with Sydenhams chorea and 48 age-, height-, weight-, gender-, and handedness-matched controls demonstrated increased sizes of the caudate, putamen, and globus pallidus in the Sydenhams chorea group. In contrast, neither total cerebral, prefrontal, or midfrontal volumes or thalamic area were increased. These results indicate the selective involvement of the basal ganglia in Sydenhams chorea. NEUROLOGY 1995;45: 2199-2203

Obsessions and Compulsions across Time in 79 Children and Adolescents with Obsessive-Compulsive Disorder

Individual symptoms of 79 children and adolescents with severe obsessive-compulsive disorder were obtained from chart review of at least two in-persons evaluations and recorded across an average of 7.9 years (range, 2 to 16). Symptoms were grouped according to the categories of the Yale-Brown Symptom Checklist. No significant age related trends were found with any one type of symptom, although patients with a very early onset of illness (less than 6 years old) were more likely to have compulsions than obsessions. Across the study period, patients reported symptoms from many different symptom categories, with 47% of the patients displaying both washing and checking compulsions at some time during their illness. No patient maintained the same constellation of symptoms from presentation to follow-up. These data support the concept of obsessive-compulsive disorder as an illness with varied clinical manifestations that individually change over time.

Practice Parameters for the Assessment and Treatment of Children and Adolescents With Obsessive-Compulsive Disorder

These practice parameters describe the assessment and treatment of obsessive-compulsive disorder based on a detailed literature review and expert consultation. Obsessive-compulsive disorder is a disorder of heterogeneous origin characterized by intrusive thoughts or compulsive urges or behaviors that are distressing, time-consuming, or functionally impairing. In children and adolescents, the disorder often is accompanied by a wide range of comorbidity, including mood, anxiety, attentional, and learning difficulties, and/or tic disorder. These parameters describe the relevant areas of assessment, especially symptomatology, onset, and course, other associated psychopathology, and developmental, family, and medical history (including postinfectious onset or exacerbations). Two modalities have been systematically assessed and empirically shown to ameliorate core symptoms: cognitive-behavioral therapy (primarily exposure/response prevention) and serotonin reuptake inhibitor medication. Data regarding the indications, efficacy, and implementation of these modalities are reviewed. Because OCD frequently occurs in the context of other psychopathology and adaptive difficulties, additional individual and family psychotherapeutic, pharmacological, and educational interventions often are necessary. Treatment planning guidelines are provided.

Case Study: Acute Basal Ganglia Enlargement and Obsessive-Compulsive Symptoms in an Adolescent Boy

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAs) may arise when antibodies directed against invading bacteria cross-react with basal ganglia structures, resulting in exacerbations of obsessive-compulsive disorder (OCD) or tic disorders. This is a report of severe worsening of obsessive-compulsive symptoms in an adolescent boy following infection with group A beta-hemolytic streptococci for whom serial magnetic resonance imaging scans of the brain were acquired to assess the relationship between basal ganglia size, symptom severity, and treatment with plasmapheresis. These data provide further support for basal ganglia-mediated dysfunction in OCD and the potential for immunological treatments in PANDAs patients.

Tics Moderate Treatment Outcome with Sertraline but not Cognitive-Behavior Therapy in Pediatric Obsessive-Compulsive Disorder

BACKGROUND The presence of a comorbid tic disorder may predict a poorer outcome in the acute treatment of pediatric obsessive-compulsive disorder (OCD). METHODS Using data from the National Institute of Mental Health (NIMH)-funded Pediatric OCD Treatment Study (POTS) that compared cognitive-behavior therapy (CBT), medical management with sertraline (SER), and the combination of CBT and SER (COMB), to pill placebo (PBO) in children and adolescents with OCD, we asked whether the presence of a comorbid tic disorder influenced symptom reduction on the Childrens Yale-Brown Obsessive Compulsive Scale (CY-BOCS) after 12 weeks of treatment. RESULTS Fifteen percent (17 of 112) of patients exhibited a comorbid tic disorder. In patients without tics, results replicated previously published intent-to-treat outcomes: COMB > CBT > SER > PBO. In patients with a comorbid tic disorder, SER did not differ from PBO, while COMB remained superior to CBT and CBT remained superior to PBO. CONCLUSIONS In contrast to CBT outcomes, which are not differentially impacted, tic disorders appear to adversely impact the outcome of medication management of pediatric OCD. Children and adolescents with obsessive-compulsive disorder and a comorbid tic disorder should begin treatment with cognitive-behavior therapy alone or the combination of cognitive-behavior therapy plus a serotonin reuptake inhibitor.

Early Childhood OCD : Preliminary Findings From a Family-Based Cognitive-Behavioral Approach

OBJECTIVE To examine the relative efficacy of family-based cognitive-behavioral therapy (CBT) versus family-based relaxation treatment (RT) for young children ages 5 to 8 years with obsessive-compulsive disorder (OCD). METHOD Forty-two young children with primary OCD were randomized to receive 12 sessions of family-based CBT or family-based RT. Assessments were conducted before and after treatment by independent raters blind to treatment assignment. Primary outcomes included scores on the Childrens Yale-Brown Obsessive Compulsive Scale and Clinical Global Impressions-Improvement. RESULTS For the intent-to-treat sample, CBT was associated with a moderate treatment effect (d = 0.53), although there was not a significant difference between the groups at conventional levels. For the completer sample, CBT had a large effect (d = 0.85), and there was a significant group difference favoring CBT. In the intent-to-treat sample, 50% of children in the CBT group achieved remission as compared to 20% in the RT group. In the completer sample, 69% of children in the CBT group achieved a clinical remission compared to 20% in the RT group. CONCLUSIONS Results indicate that children with early-onset OCD benefit from a treatment approach tailored to their developmental needs and family context. CBT was effective in reducing OCD symptoms and in helping a large number of children achieve a clinical remission.

Predictors of Spontaneous and Systematically Assessed Suicidal Adverse Events in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) Study

OBJECTIVE The authors sought to identify predictors of self-harm adverse events in treatment-resistant, depressed adolescents during the first 12 weeks of treatment. METHOD 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. RESULTS 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. CONCLUSIONS 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 self-harm events requires further study and clinical caution.