A double-blind comparison of clomipramine and desipramine treatment of severe onychophagia (nail biting).

Twenty-five adult subjects with severe morbid onychophagia (nail biting) and no history of obsessive-compulsive disorder were enrolled in a 10-week double-blind cross-over trial of clomipramine hydrochloride and desipramine hydrochloride. For the 14 subjects who completed the study, clomipramine hydrochloride (mean +/- SD dose, 120 +/- 48 mg/d) was superior to desipramine hydrochloride (mean +/- SD dose, 135 +/- 53 mg/d) in decreasing nail biting as measured by a repeated-measures analysis of variance on the Nail Biting Severity, Nailbiting Impairment, and Clinical Progress scales. The high dropout rate at every stage of the study was in sharp contrast to that seen with psychiatric populations. From a neuroethologic perspective, similar biologic systems are hypothesized to mediate a spectrum of grooming behaviors, including onychophagia, trichotillomania, and obsessive-compulsive disorder.

A 2- to 7-year follow-up study of 54 obsessive-compulsive children and adolescents.

OBJECTIVE: Due to the generally poor prognosis previously reported for patients with obsessive-compulsive disorder (OCD), this report systematically assessed the outcome of patients who had had access to new psychopharmacologic treatments to determine whether there had been any long-term gains and if there were any predictors of outcome. DESIGN: Prospective follow-up study of a cohort of consecutive pediatric patients with OCD who had participated in controlled treatment (clomipramine hydrochloride) trials and then received a variety of interim treatments. PATIENTS: Fifty-four children and adolescents were reevaluated 2 to 7 years (mean, 3.4 +/- 1.0 years) after initial clomipramine treatment. Information for 48 (89%) of the patients was from direct interview and for the remaining six (11%) from at least two sources. RESULTS: On follow-up, 23 of the subjects (43%) still met diagnostic criteria for OCD, and only three (6%) could be considered in true remission. Thirty-eight subjects (70%) were taking psychoactive medication at the time of follow-up. Although OCD symptoms continued, the group as a whole was significantly improved at follow-up, with only 10 subjects (19%) rated as unchanged or worse. A worse OCD outcome score at follow-up was predicted in a stepwise multiple regression by (1) more severe OCD symptoms score after 5 weeks of clomipramine therapy, (2) lifetime history of a tic disorder, and (3) presence of parental Axis I psychiatric diagnosis (R2 = .31, P < .01). CONCLUSIONS: With new treatments available, most patients with pediatric OCD can expect significant longterm improvements but not complete remission. This study supports previous reports of the chronicity and intractability of the disorder, as there still remained a significant subgroup of subjects who exhibited continued morbidity despite multiple interventions.

A double-blind desipramine substitution during long-term clomipramine treatment in children and adolescents with obsessive-compulsive disorder.

Twenty-six children and adolescents with severe primary obsessive-compulsive disorder receiving long-term clomipramine hydrochloride maintenance treatment (mean +/- SD, 17.1 +/- 8.3 months; range, 4 to 32 months) entered an 8-month double-blind desipramine hydrochloride substitution study to assess the necessity of continued drug treatment. All patients received clomipramine for the first 3 months, then half continued with clomipramine therapy (nonsubstituted group) and half had desipramine blindly substituted for the next 2 months; all subjects again received clomipramine for the last 3 study months. Eight (89%) of nine of the substituted and only two (18%) of 11 of the nonsubstituted group subjects relapsed during the 2-month comparison period. Long-term clomipramine treatment seems necessary for this population of children and adolescents with obsessive-compulsive disorder. However, even patients receiving maintenance clomipramine treatment throughout the entire study had continued obsessive-compulsive symptoms, which varied in severity over time.

Regional cerebral glucose metabolism of women with trichotillomania.

Positron emission tomography and 18-F-fluorodeoxyglucose were used to study resting cerebral glucose metabolism in 10 adult women with trichotillomania and 20 age-matched female controls. As a group, the patients with trichotillomania showed significantly increased global (mean gray matter) and normalized right and left cerebellar and right superior parietal glucose metabolic rates. Contrary to expectation, this pattern differed from that seen in our previous investigation of obsessive-compulsive disorder. Clomipramine hydrochloride-induced improvement was negatively correlated with anterior cingulate and orbital frontal metabolism, of particular interest because similar results had been obtained for obsessive-compulsive disorder.

Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder. Revisualization during pharmacotherapy.

To investigate the effects of drug treatment in childhood-onset obsessive-compulsive disorder (OCD), we repeated positron emission tomographic scans in 13 adults with OCD (eight taking clomipramine, two taking fluoxetine, and three taking no drug) after at least 1 year of pharmacotherapy. As a group, the patients had a significant improvement on all OCD and anxiety ratings. Positron emission tomography revealed a significant decrease in normalized orbitofrontal regional cerebral glucose metabolism (relative to global metabolism) bilaterally. Among the treated patients, the decrease in right orbitofrontal metabolism was directly correlated with two measures of OCD improvement. These results extend previous positron emission tomographic findings of regional dysfunction in OCD and suggest involvement of the orbitofrontal regions in the pathophysiology of OCD.

Treatment of obsessive-compulsive disorder with clomipramine and desipramine in children and adolescents. A double-blind crossover comparison.

Forty-eight children and adolescents with severe primary obsessive-compulsive disorder completed a 10-week double-blind crossover trial of clomipramine hydrochloride (mean dose [+/- SD], 150 +/- 53 mg/d) and desipramine hydrochloride (mean dose [+/- SD], 153 +/- 55 mg/d). Clomipramine was clearly superior to desipramine in significantly reducing obsessive-compulsive symptoms. Age at onset, duration and severity of illness, type of symptom, and plasma drug concentrations did not predict clinical response to clomipramine. Sixty-four percent of patients who received clomipramine as their first active treatment showed at least some sign of relapse during desipramine treatment. We further document the specificity of the antiobsessional effect of clomipramine and the need for maintenance treatment.

Changes in cerebrospinal fluid neurochemistry during treatment of obsessive-compulsive disorder with clomipramine.

BACKGROUND: This study examined the effect of long-term (mean, 19 months) treatment with clomipramine hydrochloride on cerebrospinal fluid (CSF) levels of several neuropeptides and monoamine metabolites in children and adolescents with obsessive-compulsive disorder. METHODS: The CSF levels of corticotropin-releasing hormone, vasopressin, somatostatin, and oxytocin and of the monoamine metabolites 5-hydroxyindoleacetic acid, homovanillic acid, and 3-methoxy-4-hydroxyphenylglycol were measured in 17 children and adolescents with obsessive-compulsive disorder before and after long-term treatment with clomipramine. RESULTS: Treatment resulted in significant decreases in CSF levels of corticotropin-releasing hormone (mean +/- SD, 175 +/- 32 vs 152 +/- 25 pmol/L, P < .03) and vasopressin (mean +/- SD, 1.30 +/- 0.57 vs 0.86 +/- 0.54 pmol/L, P < .02) and a trend toward a decrease in somatostatin levels (mean +/- SD, 21.3 +/- 8.5 vs 15.3 +/- 9.8 pmol/L, P < .06). Treatment also significantly increased CSF oxytocin levels (mean +/- SD, 6.05 +/- 1.60 vs 6.70 +/- 1.44 pmol/L, P < .01). Significant changes in CSF monoamine metabolite levels with treatment included significant decreases in CSF levels of 5-hydroxyindoleacetic acid (mean +/- SD, 109 +/- 31 vs 77 +/- 23 pmol/mL, P < .001), CSF homovanillic acid (mean +/- SD, 273 +/- 111 vs 237 +/- 101 pmol/mL, P < .04), and 3-methoxy-4-hydroxyphenylglycol (mean +/- SD, 42.4 +/- 10.2 vs 36.1 +/- 4.8 pmol/L, P < .02) and a significant increase in the homovanillic acid-5-hydroxyindoleacetic acid ratio (mean +/- SD, 2.44 +/- 0.46 vs 3.42 +/- 0.84, P < .0001). CONCLUSIONS: These neuropeptide results coupled with evidence that central administration of corticotropin-releasing hormone, vasopressin, and somatostatin to laboratory animals increases arousal and acquisition of conditioned behaviors whereas central administration of oxytocin has opposite behavioral effects are consistent with a role for these neuropeptides in the pathophysiologic processes and pharmacologic treatment of obsessive-compulsive disorder.

Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder.

The cerebral metabolic rate for glucose was studied in 18 adults with childhood-onset obsessive-compulsive disorder (OCD) and in age- and sex-matched controls using positron emission tomography and fludeoxyglucose F 18. Both groups were scanned during rest, with reduced auditory and visual stimulation. The group with OCD showed an increased glucose metabolism in the left orbital frontal, right sensorimotor, and bilateral prefrontal and anterior cingulate regions as compared with controls. Ratios of regional activity to mean cortical gray matter metabolism were increased for the right prefrontal and left anterior cingulate regions in the group with OCD as a whole. Correlations between glucose metabolism and clinical assessment measures showed a significant relationship between metabolic activity and both state and trait measurements of OCD and anxiety as well as the response to clomipramine hydrochloride therapy. These results are consistent with the suggestion that OCD may result from a functional disturbance in the frontal-limbic-basal ganglia system.

Cerebrospinal fluid neurochemistry in children and adolescents with obsessive-compulsive disorder.

Cerebrospinal fluid hormones, monoaminergic metabolites, and dynorphin A (1-8 sequence) were examined in 43 children with severe, primary obsessive-compulsive disorder. Cerebrospinal fluid levels of 5-hydroxyindoleacetic acid were positively correlated with one of eight obsessive-compulsive disorder severity ratings and three of seven measures of improvement following 5 weeks of treatment with clomipramine hydrochloride. Arginine vasopressin concentration was significantly and negatively correlated with several ratings of obsessive-compulsive disorder symptom severity, while oxytocin concentration was positively correlated with depressive symptoms. The ratio of arginine vasopressin to oxytocin was also negatively correlated with obsessive-compulsive disorder and depressive symptoms. Comorbid affective disorder was associated with decreased arginine vasopressin concentrations, while concomitant anxiety disorder was associated with increased oxytocin. Dynorphin A (1-8 sequence), homovanillic acid, corticotropin, 3-methoxy-4-hydroxyphenylglycol, and corticotropin releasing hormone were not significantly related to obsessive-compulsive disorder symptoms. These results seem to indicate that arginine vasopressin may be related to obsessive-compulsive disorder symptom severity, while 5-hydroxyindoleacetic acid might be associated with drug response.

Individual differences in cerebral metabolic patterns during pharmacotherapy in obsessive-compulsive disorder: a multiple regression/discriminant analysis of positron emission tomographic data.

A multiple regression/discriminant analysis of positron emission tomographic cerebral metabolic (rCMRglc) data in 10 obsessive-compulsive disorder (OCD) patients before and during pharmacotherapy was carried out to see if rCMRglc interdependencies distinguished OCD patients from controls. Before therapy, a discriminant function reflecting parietal, sensorimotor, and midbrain rCMRglc interdependencies correctly classified eight (80%) of the 10 patients as OCD; after therapy, six (70%) were classified as controls, most of whom were responders. Before therapy, rCMRglc interdependencies involving basal ganglia, thalamus, limbic, and sensory and association cortical regions distinguished 67% of patients who clinically responded to drug (RESP, n = 6) and 75% of patients who did not (NRESP, n = 4) from controls. After therapy, all RESP were classified as controls; classification of NRESP remained unchanged. The results suggest the conjunctive utility of this method to assess individual differences in rCMRglc during pharmacotherapy, and to explore the neurobiology of OCD.

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.

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.

Tics and Tourette's disorder: a 2- to 7-year follow-up of 54 obsessive-compulsive children.

OBJECTIVE: This study examined a hypothesized etiologic relationship between Tourette's disorder and obsessive-compulsive disorder. METHOD: Fifty-four children who had initially participated in treatment protocols for obsessive-compulsive disorder (Tourette's disorder was an exclusionary criterion) were reevaluated 2-7 years later with a neurological examination and a structured interview to establish the presence or absence of tics and Tourette's disorder. The children's first-degree relatives (N = 171) were also screened for tic disorders. RESULTS: At baseline, 57% (N = 31) of the patients had lifetime histories of tics. At follow-up, 59% (N = 32) had lifetime histories of tics; eight of these (all males) met the criteria for Tourette's disorder (six had developed the disorder, and two, it could be argued in retrospect, might have met the criteria at baseline). The patients with lifetime histories of tics had greater anxiety, a higher ratio of CSF 5-hydroxyindoleacetic acid to homovanillic acid, and a younger age at onset of obsessive-compulsive disorder than those without tics. The patients with Tourette's disorder differed from other male patients only in having an earlier age at onset of obsessive-compulsive disorder. Of the first-degree relatives, 1.8% (N = 3) had Tourette's disorder, and 14% (N = 24) had a tic disorder. CONCLUSIONS: Except for their earlier age at onset of obsessive-compulsive disorder, the patients with Tourette's disorder were indistinguishable from those without. The apparent high rate of tics and Tourette's disorder in the subjects and their relatives is consistent with the hypothesis that in some cases, obsessive-compulsive disorder and Tourette's disorder may be alternative manifestations of the same underlying illness.

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.

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.

High prevalence of obsessive-compulsive symptoms in patients with Sydenham's chorea.

The 20-item Leyton Obsessional Inventory--Child Version was completed by children and adolescents who had had Sydenham's chorea (N = 23) or rheumatic fever without chorea (N = 14). The Sydenham's chorea subjects had significantly more obsessive thoughts and compulsive behaviors and significantly greater interference from these behaviors. Three Sydenham's chorea patients but no rheumatic fever patients had substantial obsessional interference and met criteria for obsessive-compulsive disorder when interviewed by telephone. This suggests that obsessive-compulsive disorder, at least in some patients, may be due to basal ganglia dysfunction.

Sydenham's chorea: magnetic resonance imaging of the basal ganglia.

Analysis of cerebral magnetic resonance images of 24 subjects with Sydenham's chorea and 48 age-, height-, weight-, gender-, and handedness-matched controls demonstrated increased sizes of the caudate, putamen, and globus pallidus in the Sydenham's 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 Sydenham's chorea.

Sydenham's chorea: physical and psychological symptoms of St Vitus dance.

Eleven children with Sydenham's chorea (8 girls and 3 boys, mean age = 8.4 +/- 2.2 [SD] years) underwent comprehensive physical, neuropsychologic, and psychiatric examination. The chorea was manifested as dysarthria, gait disturbances, and frequent adventitious movements of the face, neck, trunk, and extremities. Antineuronal antibodies were present in 10 of 11 children. All children exhibited concomitant psychologic dysfunction, specifically obsessive-compulsive symptomatology, increased emotional lability, motoric hyperactivity, irritability, distractibility, and age-regressed behavior. Obsessive-compulsive symptoms were observed in 9 (82%) children, 4 of whom met diagnostic criteria for obsessive-compulsive disorder. These behavioral symptoms began several days to weeks before the chorea was observed, and they waxed and waned in severity along with the motoric abnormalities. These results suggest that psychologic, particularly obsessive-compulsive, symptoms are accompanying manifestations of Sydenham's chorea which may require medical attention.

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.

Childhood movement disorders and obsessive compulsive disorder.

Recent investigations of childhood-onset obsessive compulsive disorder (OCD) and pediatric movement disorders such as tics, Tourette's syndrome (TS), and Sydenham's chorea suggest that these disorders may be related. Although comorbid obsessive-compulsive symptoms have long been recognized in individuals with TS, more recent studies have demonstrated that tics and TS are surprisingly common in children with primary OCD, and further, that the two disorders seem to have a common genetic vulnerability. Obsessive-compulsive symptoms are also manifest in Sydenham's chorea, a neurologic variant of rheumatic fever in which antistreptococcal antibodies are thought to cross-react with neuronal tissue, particularly within the basal ganglia, and cause inflammatory changes resulting in neuropsychiatric symptomatology. The frequent comorbidity of OCD and Sydenham's chorea and similar postulates of basal ganglia dysfunction for both disorders suggest that Sydenham's chorea may serve as a medical model for OCD. Of note, however, is that the medications (e.g., neuroleptics) that are effective in treating this and other movement disorders are distinctly different from those that are efficacious for OCD (e.g., serotonin reuptake blockers). Examinations of the similarities and differences among these various neuropsychiatric conditions may lead to greater understanding of the pathophysiology of OCD and offer further insights into the etiology and treatment of this troubling disorder.