The use of antibody D8/17 to identify B cells in adults with obsessive-compulsive disorder.

Compared with healthy control subjects, individuals with childhood-onset obsessive-compulsive disorder (OCD) have been reported to have a higher percentage of B cells that react with the monoclonal antibody D8/17, a marker for rheumatic fever. This study sought to replicate these findings in adults with OCD. Double-blind analyses of blood samples from 29 consecutive adults with primary OCD and 26 healthy control subjects were conducted to determine the percentage of B cells identified by D8/17. Using a standard criterion of > or =12% labeled B cells to denote positivity, rates of D8/17 positive individuals did not significantly differ between the OCD (58.6%) and control (42.3%) groups. Early age of onset was not a predictor of D8/17 positivity in the OCD group. The percentage of B cells identified by the monoclonal antibody marker D8/17 did not distinguish adults with OCD from control subjects, nor did it distinguish a sub-group of adults with OCD who described pre-pubertal onset of their OCD symptoms.

Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS).

The evidence to date, both published and unpublished, which addresses the validity of the proposed unique subgroup of children with early and abrupt onset of obsessive--compulsive disorder (OCD) and/or tic disorders subsequent to streptococcal infections was reviewed. The aetiology of OCD and tic disorders is unknown, although it appears that both disorders may arise from a variety of genetic and environmental factors. Post-streptococcal autoimmunity has been postulated as one possible mechanism for some. The acronym PANDAS (for paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) has been given to a subgroup of paediatric patients who meet five inclusionary criteria: presence of OCD and/or tic disorder, pre-pubertal symptom onset, sudden onset or episodic course of symptoms, temporal association between streptococcal infections and neuropsychiatric symptom exacerbations, and associated neurological abnormalities. The proposed model of pathophysiology provides for several unique treatment strategies, including the use of antibiotic prophylaxis to prevent streptococcal-triggered exacerbations, and the use of immunomodulatory interventions (such as intravenous immunoglobulin or therapeutic plasma exchange) in the treatment severe neuropsychiatric symptoms. For the latter study group, long-term (2--5 yr) follow-up revealed continued symptom improvement for the majority of patients, particularly when antibiotic prophylaxis had been effective in preventing recurrent streptococcal infections. In addition, the episodic nature of the subgroup's illness provides for opportunities to study brain structure and function during health and disease, as well as allowing for investigations of the aetiologic role of anti-neuronal antibodies and neuroimmune dysfunction in both OCD and tic disorders. Although much research remains to be done, an increasing body of evidence provides support for the postulate that OCD and tic disorders may arise from post-streptococcal autoimmunity. The unique clinical characteristics of the PANDAS subgroup, the presence of volumetric changes in the basal ganglia, and the dramatic response to immunomodulatory treatments, suggest that symptoms arise from a combination of local, regional and systemic dysfunction. Ongoing research is directed at understanding the nature of the abnormal immune response, as well as identifying at-risk children, in order to provide for novel strategies of prevention and treatment.

The PANDAS subgroup: recognition and treatment.

A subgroup of patients with childhood-onset obsessive-compulsive disorder (OCD) has been identified who share a common clinical course characterized by dramatic symptom exacerbations following Group A beta-hemolytic streptococcal (GABHS) infections. The term PANDAS has been applied to the subgroup, to indicate the postulated etiology of their symptoms: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections. Five clinical characteristics define the PANDAS subgroup: presence of OCD and/or tic disorder, prepubertal symptom onset, sudden onset or abrupt exacerbations (sawtooth course), association with neurological abnormalities (presence of adventitious movements or motoric hyperactivity during exacerbations), and temporal association between symptom exacerbations and GABHS infections. Post-streptococcal symptom exacerbations are typically quite dramatic, with patients reporting that their symptoms "...came on overnight" or "...appeared all of a sudden a few days after I had a sore throat." The post-streptococcal inflammatory nature of the neuropsychiatric symptoms provides novel opportunities for treatment and prevention, including immunomodulatory therapies such as therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIG). A recently completed placebo-controlled trial revealed that both IVIG and TPE were effective in reducing neuropsychiatric symptom severity (40% to 55% reductions, respectively) for a group of severely ill children with OCD and/or tic disorders. Further research is required to determine why the treatments are helpful, as well as to ascertain whether or not antibiotic prophylaxis can help prevent post-streptococcal symptom exacerbations.

Risk-benefit decision making for treatment of depression during pregnancy.

OBJECTIVE: The Committee on Research on Psychiatric Treatments of the American Psychiatric Association identified treatment of major depression during pregnancy as a priority area for improvement in clinical management. The goal of this article was to assist physicians in optimizing treatment plans for childbearing women. METHOD: The authors' work group developed a decision-making model designed to structure the information delivered to pregnant women in the context of the risk-benefit discussion. Perspectives of forensic and decision-making experts were incorporated. RESULTS: The model directs the psychiatrist to structure the problem through diagnostic formulation and identification of treatment options for depression. Reproductive toxicity in five domains (intrauterine fetal death, physical malformations, growth impairment, behavioral teratogenicity, and neonatal toxicity) is reviewed for the potential somatic treatments. The illness (depression) also is characterized by symptoms of somatic dysregulation that compromise health during pregnancy. The patient actively participates and provides her evaluation of the acceptability of the various treatments and outcomes. Her capacity to participate in this process provides evidence of competence to consent. Included in the decision-making process are the patient's significant others and obstetrical physician. The process is ongoing, with the need for incorporation of additional data as the pregnancy and treatment response progress. CONCLUSIONS: The conceptual model provides structure to a process that is frequently stressful for both patients and psychiatrists. By applying the model, clinicians will ensure that critical aspects of the risk-benefit discussion are included in their care of pregnant women.

Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood.

BACKGROUND: In children, exacerbations of tics and obsessive symptoms may occur after infection with group A beta-haemolytic streptococci. If post-streptococcal autoimmunity is the cause of the exacerbations, then children might respond to immunomodulatory treatments such as plasma exchange or intravenous immunoglobulin (IVIG). We studied whether plasma exchange or IVIG would be better than placebo (sham IVIG) in reducing severity of neuropsychiatric symptoms. METHODS: Children with severe, infection-triggered exacerbations of obsessive-compulsive disorder (OCD) or tic disorders, including Tourette syndrome, were randomly assigned treatment with plasma exchange (five single-volume exchanges over 2 weeks), IVIG (1 g/kg daily on 2 consecutive days), or placebo (saline solution given in the same manner as IVIG). Symptom severity was rated at baseline, and at 1 month and 12 months after treatment by use of standard assessment scales for OCD, tics, anxiety, depression, and global function. FINDINGS: 30 children entered the study and 29 completed the trial. Ten received plasma exchange, nine IVIG, and ten placebo. At 1 month, the IVIG and plasma exchange groups showed striking improvements in obsessive-compulsive symptoms (mean improvement on children's Yale-Brown obsessive compulsive scale score of 12 [45%] and 13 [58%], respectively), anxiety (2.1 [31%] and 3.0 [47%] improvement on National Institute of Mental Health anxiety scale), and overall functioning (2.9 [33%] and 2.8 [35%] improvement on National Institute of Mental Health global scale). Tic symptoms were also significantly improved by plasma exchange (mean change on Tourette syndrome unified rating scale of 49%). Treatment gains were maintained at 1 year, with 14 (82%) of 17 children "much" or "very much" improved over baseline (seven of eight for plasma exchange, seven of nine for IVIG). INTERPRETATION: Plasma exchange and IVIG were both effective in lessening of symptom severity for children with infection-triggered OCD and tic disorders. Further studies are needed to determine the active mechanism of these interventions, and to determine which children with OCD and tic disorders will benefit from immunomodulatory therapies.

Postinfectious and other forms of obsessive-compulsive disorder.

The search for subtypes of OCD has led to increased appreciation of the importance of distinguishing early (prepubertal) versus later on-set, and of tic-related versus non-tic related subtypes, as well as postinfectious forms of the disorder. How these apparent typologies relate to each other remains to be elucidated. Careful longitudinal clinical descriptive studies, as well as the ongoing application of genetic, neuroimaging, and immunologic techniques, promise to advance our understanding of how genotype and environmental factors interact to produce the diverse clinical forms of OCD and to point the way to more effective treatment.

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, Sydenham's 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.

Critical review of tricyclic antidepressant use in children and adolescents.

OBJECTIVE: To provide a critical review of the role of tricyclic antidepressant (TCA) medications in children and adolescents. METHOD: Multiple resources including a Medline search (1966-1998) were used. RESULTS: There were few double-blind, placebo-controlled studies of TCAs, and even fewer with positive results. Also, potentially serious cardiovascular side effects have been described. CONCLUSIONS: The future therapeutic role of TCAs for children and adolescents needs to be seriously weighed against lethality of overdose, the unresolved issue of possible sudden unexplained death, and the availability of safer and easier to monitor medications. Ongoing future research on heart rate variability and epidemiology of psychotropic medication-related deaths will address developmental aspects of TCA use.

Anxiolytics, adrenergic agents, and naltrexone.

OBJECTIVE: To review extant data on the efficacy and safety of anxiolytic medications (benzodiazepines, buspirone, and other serotonin 1A agonists), adrenergic agents (beta-blockers and alpha 2-adrenergic agonists clonidine and guanfacine), and the opiate antagonist naltrexone that have been used to treat various psychopathologies in children and adolescents. To identify critical gaps in our current knowledge about these agents and needs for further research. METHOD: All available controlled trials of these medications in children and adolescents published in English through 1997 were reviewed. In addition, selected uncontrolled studies are included. RESULTS: The major finding, that there are virtually no controlled data that support the efficacy of most of these drugs for the treatment of psychiatric disorders in children and adolescents, is both surprising and unfortunate. For some drugs, e.g., buspirone and guanfacine, this is because no controlled studies have been carried out in children and/or adolescents. For other drugs, e.g., clonidine and naltrexone, most of the placebo-controlled studies have failed to demonstrate efficacy. CONCLUSIONS: The strongest recommendations for controlled studies of safety and efficacy in children and adolescents can be given for the following drugs: benzodiazepines for acute anxiety; buspirone (and newer serotonin 1A agonists as they become available) for anxiety and depression; beta-blockers for aggressive dyscontrol; guanfacine for attention-deficit/hyperactivity disorder; and naltrexone for hyperactivity, inattention, and aggression in autistic disorder.

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases.

OBJECTIVE: The purpose of this study was to describe the clinical characteristics of a novel group of patients with obsessive-compulsive disorder (OCD) and tic disorders, designated as pediatric autoimmune neuropsychiatric disorders associated with streptococcal (group A beta-hemolytic streptococcal [GABHS]) infections (PANDAS). METHOD: The authors conducted a systematic clinical evaluation of 50 children who met all of the following five working diagnostic criteria: presence of OCD and/or a tic disorder, prepubertal symptom onset, episodic course of symptom severity, association with GABHS infections, and association with neurological abnormalities. RESULTS: The children's symptom onset was acute and dramatic, typically triggered by GABHS infections at a very early age (mean = 6.3 years, SD = 2.7, for tics; mean = 7.4 years, SD = 2.7, for OCD). The PANDAS clinical course was characterized by a relapsing-remitting symptom pattern with significant psychiatric comorbidity accompanying the exacerbations; emotional lability, separation anxiety, nighttime fears and bedtime rituals, cognitive deficits, oppositional behaviors, and motoric hyperactivity were particularly common. Symptom onset was triggered by GABHS infection for 22 (44%) of the children and by pharyngitis (no throat culture obtained) for 14 others (28%). Among the 50 children; there were 144 separate episodes of symptom exacerbation; 45 (31%) were associated with documented GABHS infection, 60 (42%) with symptoms of pharyngitis or upper respiratory infection (no throat culture obtained), and six (4%) with GABHS exposure. CONCLUSIONS: The working diagnostic criteria appear to accurately characterize a homogeneous patient group in which symptom exacerbations are triggered by GABHS infections. The identification of such a subgroup will allow for testing of models of pathogenesis, as well as the development of novel treatment and prevention strategies.

Pharmacology of the selective serotonin reuptake inhibitors in children and adolescents.

OBJECTIVE: To review the pharmacology of a new class of medications, the potent selective serotonin reuptake inhibitors (SSRIs), what is known about their metabolism in children and adolescents, and the practical clinical implications of such. METHOD: Articles were retrieved through index Medicus searches for articles published during the past 10 years on the SSRIs and on pediatric pharmacology. RESULTS: More than 300 articles were reviewed. Pharmacological data, derived from relevant adult literature, were summarized and extrapolated to children and from the limited pediatric literature. The SSRIs represent a new class of antidepressants with distinct advantages in their side effect profile and their broad therapeutic index over that seen with the tricyclic antidepressants. Their advantage of few anticholinergic side effects and limited cardiovascular toxicities are particularly relevant for the pediatric population. The SSRIs are metabolized via the hepatic cytochrome isoenzyme P450 system, and potential drug-drug interactions are reviewed. CONCLUSIONS: The SSRIs appear to offer advantages over the tricyclic antidepressants. Unfortunately, pharmacokinetic data are lacking, and systematic studies of safety and efficacy in the pediatric age group are limited. Preliminary reports are encouraging, but further study is required.

Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever.

OBJECTIVE: The authors' goal was to determine whether a trait marker of rheumatic fever susceptibility (labeled D8/17) could identify children with pediatric autoimmune neuropsychiatric disorders (obsessive-compulsive disorder and tic disorders) associated with streptococcal infections (PANDAS). METHOD: Blood samples obtained from 27 children with PANDAS, nine children with Sydenham's chorea, and 24 healthy children were evaluated for D8/17 reactivity. Individuals were defined as D8/17 positive if they had 12% or more D8/17+ cells. RESULTS: The frequency of D8/17-positive individuals was significantly higher in both patient groups than it was among the healthy volunteers: 85% of the children with PANDAS and 89% of the children with Sydenham's chorea, compared with 17% of the healthy children, were D8/17 positive. Further, the mean number of D8/17+ cells was similar in the two patient groups and was significantly higher in these groups than in the group of healthy children. CONCLUSIONS: These results suggest that there may be a subgroup of D8/17-positive children who present with clinical symptoms of obsessive-compulsive disorder and Tourette's syndrome, rather than Sydenham's chorea, but who have similar poststreptococcal autoimmunity.

New developments in the treatment of obsessive-compulsive disorder.

The treatment of obsessive-compulsive disorder (OCD) has changed dramatically in the last 10 years. Currently, the serotonin reuptake inhibitors (SRIs) and the serotonin selective reuptake inhibitors (SSRIs) are considered the "first choice" agents for pharmacologic treatment of OCD, although few head-to-head comparisons exist between any two specific agents. Strategies for nonresponders and partial responders to the SRI/SSRIs are reviewed. The only agents that have shown significant improvement as augmenting agents to an SRI/SSRI in systematic trials have been clonazepam and haloperidol. Predictors of response to pharmacotherapy have been limited, but several reports have found that an early age at onset of OCD has been associated with a poorer response to medications. Long-term maintenance medication may be necessary for some, although behavioral therapy may improve the need for extended pharmacotherapy. Cognitive behavioral therapy, specifically exposure with response prevention, still remains an effective and important component of treatment for many. One of the newest developments is the identification of a pediatric subtype of OCD characterized by prepubertal acute onset after group A beta-hemolytic streptococcal pharyngitis. Investigation trials with these children include immunomodulatory therapies and penicillin treatment and prophylaxis. If a unique subgroup of children with OCD can be identified, then novel treatments may prove effective and have a role in long-term prophylaxis.

Autonomic activity in relation to cerebrospinal fluid neurochemistry in obsessive and disruptive children and adolescents.

Electrodermal activity and heart rate were recorded during rest, simple tones, and a reaction time task in 43 male and female adolescents and children with obsessive compulsive disorder and 30 male adolescents and children with disruptive behavior disorders who had lumbar cerebrospinal fluid drawn during the same week. Partial correlations controlling for age and sex showed that in the obsessive group metabolites of serotonin and dopamine, but not of norepinephrine, were positively correlated with electrodermal responsivity, most consistently in the reaction time task. This result was not replicated in disruptive boys. Adrenocorticotropic hormone was positively related to electrodermal activity and heart rate throughout the session. The results for the obsessive adolescents suggest that nigrostriatal dopamine turnover and central serotonin turnover affect electrodermal activity, generally confirming and extending conclusions from pharmacological studies. Diagnosis may affect these relationships.

Obsessive-compulsive disorder in children and adolescents: a review of the past 10 years.

OBJECTIVE: To review the literature on pediatric obsessive-compulsive disorder (OCD) from the perspective of information relevant to American Board of Psychiatry and Neurology recertification in child and adolescent psychiatry. METHOD: The clinical and research literatures were systematically searched or articles that address the diagnosis and treatment of pediatric OCD. RESULTS: Drawing from the literature and their own clinical experience, the authors note that (1) OCD is a common neuropsychiatric disorder; (2) comorbidity is common, especially with tic, attention-deficit, anxiety, and affective disorders; (3) OCD following group A beta-hemolytic streptococcal infection may define an autoimmune sub-grouping calling for immunomodulatory treatments; and (4) OCD-specific cognitive-behavioral psychotherapy and pharmacotherapy with a serotonin reuptake inhibitor define the psychotherapeutic and pharmacotherapeutic treatments of choice, respectively. CONCLUSION: Child psychiatrists should be familiar with the differential diagnosis and treatment of OCD.

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.

Autonomic activity in children and adolescents with obsessive-compulsive disorder.

Electrodermal activity and heart rate were recorded from 55 children and adolescents with obsessive-compulsive disorder (OCD) and 58 normal subjects in a protocol that included rest and mild stress periods, and nonsignal and signal stimuli, to determine if autonomic activity might be involved in the pathogenesis of OCD or might be related to important clinical differences. Few differences were observed between OCD and normal subjects despite adequate power to detect small differences due to the large number of subjects. Thus, autonomic activity appears not to be an important etiological factor in childhood OCD. However, electrodermal activity showed consistent positive correlations with ratings of the severity of OCD symptoms (but not with anxiety or depression ratings), suggesting that severely afflicted cases are autonomically sensitive to OCD-related stimuli or, conversely, that low electrodermal activity may be protective of symptom severity. Patients with a coexisting tic disorder (not Tourette's syndrome) had larger electrodermal responses to a novel stimulus and higher heart rate variability than those without tics but did not differ from normal subjects. These few differences seem insufficient to support the hypothesis of a separate etiology of OCD cases with a coexisting tic disorder.