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 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.

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.

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.

Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison.

BACKGROUND: Childhood-onset schizophrenia is a rare but severe form of the disorder that is often treatment-refractory. In this study, the efficacy and adverse effects of clozapine and haloperidol were compared for children and adolescents with early-onset schizophrenia. METHODS: Twenty-one patients (mean [+/-SD] age, 14.0 +/- 2.3 years) with onset of Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition-defined schizophrenia that began by age 12 years and who had been nonresponsive to typical neuroleptics participated in the study. Patients were randomized to a 6-week double-blind parallel comparison of clozapine (mean [+/-SD] final dose, 176 +/- 149 mg/d), or haloperidol, (16 +/- 8 mg/d). RESULTS: Clozapine was superior to haloperidol on all measures of psychosis (P = .04-.002). Positive and negative symptoms of schizophrenia improved. However, neutropenia and seizures were major concerns. To date, one third of the group has discontinued using clozapine. CONCLUSIONS: Clozapine has striking superiority for positive and negative symptoms in treatment-refractory childhood-onset schizophrenia. However, due to possibly increased toxic effects in this pediatric population, close monitoring for adverse events is essential.

Brain anatomic magnetic resonance imaging in childhood-onset schizophrenia.

BACKGROUND: Early-onset schizophrenia (first psychotic symptoms by age 12 years) has been the subject of a small number of studies, and its biological continuity with later-onset disorder has not been established. In this study quantitative anatomic brain magnetic resonance images of children and adolescents with early-onset schizophrenia were compared with those of matched controls. Brain abnormalities in childhood-onset schizophrenia were examined in relation to those reported for later-onset schizophrenics. METHODS: Anatomic brain magnetic resonance imaging scans were obtained for 21 patients (mean +/- SD age, 14.6 +/- 2.1 years; range, 10 to 18 years) with childhood-onset schizophrenia (13 males, eight females) and 33 age-, sex-, height-, and weight-matched normal controls. Quantitative measurements were obtained for the cerebrum, anterior frontal region, lateral ventricles, thalamus, caudate, putamen, and globus pallidus. RESULTS: Total cerebral volume and midsagittal thalamic area were smaller in the patients (analysis of variance, P = .002, and analysis of covariance, P = .03, respectively); the caudate, putamen, and globus pallidus were larger in the patients (analysis of covariance, P = .05, P = .007, and P < .001, respectively); and the lateral ventricles tended to be larger in the patients (analysis of covariance, P = .06). Globus pallidus enlargement correlated with neuroleptic exposure and with age of onset of psychosis. The magnitude of abnormalities compared with controls was similar to that reported in adult studies, although there was a trend toward relatively smaller cerebral volumes for the childhood-onset group compared with controls. CONCLUSION: Brain anatomic abnormalities in childhood-onset schizophrenia are similar to those reported for adult populations, indicating overall continuity between these rare childhood cases and the adult schizophrenia populations.

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.

Childhood-onset schizophrenia: brain MRI rescan after 2 years of clozapine maintenance treatment.

OBJECTIVE: The effect of clozapine on striatal morphology was examined in adolescents with childhood-onset schizophrenia. METHOD: Eight adolescent patients with onset of psychosis before age 12 and eight matched comparison subjects had initial and 2-year follow-up brain magnetic resonance imaging scans. Basal ganglia and lateral ventricle volumes were measured. The patients were on a clozapine regimen during the 2-year interim. RESULTS: Caudate volume was larger in the patients at the initial scanning, decreased in the patients between scans, and did not differ significantly between the patients and the comparison subjects at the second scanning. CONCLUSIONS: Caudate enlargement in patients with childhood-onset schizophrenia who are taking typical neuroleptics appears to be secondary to medication exposure. Rescanning to examine basal ganglia morphology is indicated for these patients when they are taking an atypical neuroleptic.

Progressive reduction of temporal lobe structures in childhood-onset schizophrenia.

OBJECTIVE: A previous cross-sectional study of brain morphology in childhood-onset schizophrenia indicated sparing of the temporal lobes from processes reducing total cerebral volume in this population. In the present study, subjects with childhood-onset schizophrenia and healthy subjects were rescanned at 2-year follow-up to determine whether this pattern of temporal lobe sparing persists with ongoing illness. METHOD: Anatomic brain magnetic resonance imaging scans were acquired for 10 adolescent patients with average onset of schizophrenia at 10.4 years (SD = 1.7) and 17 healthy adolescents. Scans were obtained on initial admission and at 2-year follow-up by using identical equipment and measurement methodology. RESULTS: Schizophrenic subjects showed significantly greater decreases than healthy subjects in right temporal lobe, bilateral superior temporal gyrus and posterior superior temporal gyrus, right anterior superior temporal gyrus, and left hippocampal volumes during the follow-up interval. Decline in right posterior superior temporal gyrus was associated with high total scores on the Scale for the Assessment of Positive Symptoms at baseline and at follow-up. CONCLUSIONS: Progressive reduction of temporal lobe structures occurs with ongoing illness in childhood-onset schizophrenia.

Cerebrospinal fluid monoamine metabolites in childhood-onset schizophrenia.

OBJECTIVE: Pediatric studies of cerebrospinal fluid (CSF) monoamine metabolites in childhood-onset schizophrenia may help to elucidate both pathophysiology and treatment response in early-onset psychosis. METHOD: CSF homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) and serum prolactin were measured during drug-free and antipsychotic medication conditions in 18 patients (mean age = 14.2 years, SD = 1.7) who had onset of schizophrenia by age 12 (mean age at onset = 9.9 years, SD = 1.8). Relationships between changes in CSF monoamines and serum prolactin and clinical outcome were examined, and the degree of change in CSF monoamines in response to clozapine treatment was compared with that for 16 patients with later-onset schizophrenia. RESULTS: Despite patients' significant clinical improvement with treatment, CSF monoamine concentrations and ratios of HVA/5-HIAA and HVA/MHPG did not significantly change with 6 weeks of either haloperidol or clozapine treatment. Serum prolactin levels increased during haloperidol treatment. Clozapine had similar effects on CSF monoamines in patients with childhood- and later-onset schizophrenia. CONCLUSIONS: While these data are compatible with continuity between childhood- and later-onset schizophrenia, they also highlight the complexity of the biochemical events mediating clinical changes in schizophrenia.

Temporal lobe morphology in childhood-onset schizophrenia.

OBJECTIVE: Neurodevelopmental models of schizophrenia imply that a more severe early brain lesion may produce earlier onset of psychotic symptoms. The medial temporal lobes have been proposed as possible locations for such a lesion. The authors tested this hypothesis in a group of children and adolescents with childhood-onset schizophrenia who had severe, chronic symptoms and who were refractory to treatment with typical neuroleptics. METHOD: Anatomic brain magnetic resonance imaging scans were acquired with a 1.5-T scanner for 21 patients (mean age=14.6 years, SD=2.1) who had onset of schizophrenia by age 12 (mean age at onset=10.2, SD=1.5) and 41 normal children. Volumes of the temporal lobe, superior temporal gyrus, amygdala, and hippocampus were measured by manually outlining these structures on contiguous 2-mm thick coronal slices. RESULTS: Patients with childhood-onset schizophrenia had significantly smaller cerebral volumes. With no adjustment for brain volume, no diagnostic differences were observed for any temporal lobe structure. Unexpectedly, with adjustment for total cerebral volume, larger volumes of the superior temporal gyrus and its posterior segment and a trend toward larger temporal lobe volume emerged for the patients with schizophrenia. These patients lacked the normal (right-greater-than-left) hippocampal asymmetry. CONCLUSIONS: These findings do not indicate a more severe medial temporal lobe lesion as the basis of very early onset schizophrenia.

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.

Chromosome 22q11.2 interstitial deletions among childhood-onset schizophrenics and "multidimensionally impaired".

Since its first description almost a century ago schizophrenia with childhood onset, a rare yet devastating disorder, has been diagnosed in children as young as age 5. Recently, the velocardiofacial syndrome, whose underlying cause is interstitial deletions of 22q11.2, was found in 2 of 100 cases of schizophrenics with adult onset [Karayiorgou et al., Proc Natl Acad Sci USA 92: 7612-7616, 1995]. No study has documented the prevalence of velocardiofacial syndrome and the 22q11.2 deletion in a population of schizophrenics with childhood onset. Here we describe the result of such a study in a sample originally selected for a trial of atypical antipsychotic drugs. A separate group of patients was also included in the study; they can best be accounted for as a variant of childhood-onset schizophrenia (COS) and had been provisionally termed "multidimensionally impaired." Fluorescent in situ hybridization screening of 32 COS and 21 multidimensionally impaired patients revealed 1 COS patient with an interstitial deletion spanning at least 2.5 megabases.

Childhood-onset schizophrenia/autistic disorder and t(1;7) reciprocal translocation: identification of a BAC contig spanning the translocation breakpoint at 7q21.

Childhood-onset schizophrenia (COS) is defined by the development of first psychotic symptoms by age 12. While recruiting patients with COS refractory to conventional treatments for a trial of atypical antipsychotic drugs, we discovered a unique case who has a familial t(1;7)(p22;q21) reciprocal translocation and onset of psychosis at age 9. The patient also has symptoms of autistic disorder, which are usually transient before the first psychotic episode among 40-50% of the childhood schizophrenics but has persisted in him even after the remission of psychosis. Cosegregating with the translocation, among the carriers in the family available for the study, are other significant psychopathologies, including alcohol/drug abuse, severe impulsivity, and paranoid personality and language delay. This case may provide a model for understanding the genetic basis of schizophrenia or autism. Here we report the progress toward characterization of genomic organization across the translocation breakpoint at 7q21. The polymorphic markers, D7S630/D7S492 and D7S2410/D7S646, immediately flanking the breakpoint, may be useful for further confirming the genetic linkage for schizophrenia or autism in this region. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:749-753, 2000. Published 2000 Wiley-Liss, Inc.

Obsessive compulsive disorder in children and adolescents: issues in management.

Clinical experience with children and adolescents with obsessive compulsive disorder (OCD) suggests the need for long-term care. In addition to maintenance drug treatment, behavior therapy and family counseling are usually indicated. Family counseling can help prevent the avoidant behavior that is a serious complication of OCD. The outcome for OCD in children and adolescents has been improved by the use of these active long-term therapies.

Normal controls and biological reference values in child psychiatry: defining normal.

About half of adults volunteering as normal control research subjects may be rejected because of significant psychopathology, but no parallel study has been done to date for pediatric subjects. Of 152 applicants (ages 6 to 18) for participation as paid normal controls, 44% were found ineligible and at least 31.8% of the child volunteers had probable or certain psychiatric disorders. Successive screenings, including rating scales and structured interviews, were necessary to obtain controls meeting a defined standard of psychiatric health. Careful scrutiny of child volunteers in biological psychiatric research is needed to assure meaningful comparisons.

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.

Psychiatric disorders in first degree relatives of children and adolescents with obsessive compulsive disorder.

One hundred and forty-five first-degree relatives (89 parents [96%] and 56 siblings [98%]) of 46 children and adolescents with severe primary obsessive compulsive disorder (OCD) were personally interviewed with clinical and structured psychiatric interviews. Parent interviews were scored by a rater blind to proband diagnosis. Thirty percent of probands had at least one first-degree relative with OCD: 25% of fathers and 9% of mothers received this diagnosis. Forty-five percent of fathers and 65% of mothers received one or more other psychiatric diagnoses. The increased familial rate of OCD over that expected from a general population, and over that found in parents of conduct disordered patients, is consistent with a genetic factor in OCD. Presenting obsessive compulsive symptoms of probands and their parents were usually dissimilar, arguing against any simple social or cultural transmission.

An open trial of clozapine in 11 adolescents with childhood-onset schizophrenia.

OBJECTIVE: To review the response of 11 adolescents with childhood-onset schizophrenia to a 6-week open clozapine trial. METHOD: Eleven children meeting DSM-III-R criteria for schizophrenia had a 6-week open trial of clozapine (mean sixth week daily dose 370 mg). Behavioral ratings included the Brief Psychiatric Rating Scale and Children's Global Assessment Scale. RESULTS: More than half showed marked improvement in Brief Psychiatric Rating Scale ratings by 6 weeks of clozapine therapy compared to admission drug rating and compared to a systematic 6-week trial of haloperidol. CONCLUSIONS: This open trial indicates that clozapine may be a promising treatment for children and adolescents with schizophrenia who do not respond well to typical neuroleptics. A double-blind placebo-controlled study is ongoing.

Childhood-onset schizophrenia: the severity of premorbid course.

OBJECTIVE: To review the premorbid histories of 23 children meeting DSM-III-R criteria for schizophrenia with onset before age 12 years and to compare these with childhood data of later-onset schizophrenics. METHOD: Premorbid features up to 1 year before onset of first psychotic symptoms were rated from hospital and clinic records, clinical interviews, rating scales, and tests. RESULTS: In keeping with previous studies, specific developmental disabilities and transient early symptoms of autism, particularly motor stereotypies, were common. Comparison with the childhood of later-onset schizophrenics showed greater delay in language development, and more premorbid speech and language disorders, learning disorders, and disruptive behavior disorders. (Sixty percent had received or were estimated to meet criteria for one or more clinical diagnoses.) CONCLUSIONS: Childhood-onset schizophrenia may represent a more malignant form of the disorder, although selection and ascertainment bias cannot be ruled out. The presence of prepsychotic language difficulties focuses attention on the importance of early temporal and frontal lobe development; early transient motor stereotypies suggest developmental basal ganglia abnormalities and extend previous findings seen in the childhood of later-onset patients.