Blink rate in pediatric complex partial seizure disorder

This study examined spontaneous blink rate, a putative measure of dopamine function, in 30 children with complex partial epilepsy and 61 normal children. The children with epilepsy had significantly lower blink rates than the normal children in a conversation and a verbal recall task, particularly if they had a schizophrenia-like psychosis, EEG evidence for left focal epileptic activity, illogical thinking, discourse deficits, and distractibility. They modulated their blink rates across a listening, a conversation, and a verbal recall task like the normal children. Given previously reported low blink rates in schizophrenic children, these findings suggest that children with complex partial epilepsy or schizophrenia might have similar biological features.     

Value of beat-to-beat blood pressure changes, detected by pulse transit time, in the management of the obstructive sleep apnoea/hypopnoea syndrome

BACKGROUND: Previous studies of oculomotor dysfunction in schizophrenia have tended to concentrate on abnormalities of smooth pursuit eye tracking in chronic medicated patients. We report the results of a study of smooth pursuit, reflexive and antisaccade performance in drug naive and antipsychotic treated first-episode schizophrenic patients. METHODS: Smooth pursuit and saccadic eye movements were recorded in 36 first-episode schizophrenic patients and 36 controls matched for age and estimated IQ. The schizophrenic patients were divided into drug-naive (N = 17) and antipsychotic treated groups (N = 19). RESULTS: Smooth pursuit velocity gain was significantly lower than controls only in the drug-naive patients. The treated patients did not differ significantly from either the controls or the untreated group. In an antisaccade paradigm both treated and drug-naive schizophrenic patients demonstrated an increased number of errors, but only drug-naive patients also demonstrated an increased latency in initiating correct antisaccades. CONCLUSIONS: These impairments are unlikely to be due to a generalized deficit in oculomotor function in the schizophrenic groups, as there were no differences between the groups in saccadic metrics on a reflexive saccade task. The results show that both smooth pursuit and saccadic abnormalities are present at the onset of schizophrenia and are integral to the disorder.     

A Psychophysical Measure of Attention Deficit in Children With Attention-Deficit/Hyperactivity Disorder.

The authors explored the temporal mechanism of attention deficit in children with attention-deficit/hyperactivity disorder (ADHD). In rapid serial visual presentation tasks in which two targets (T? and T?) were presented in close temporal proximity among distractors, participants tried to identify T? and detect T? in one (dual-task) experiment and only to detect T? in a second control (single-task) experiment. The sensitivity of T? detection was analyzed using signal detection theory. The attentional blink--the impairment in T? detection following the identification of T?--was increased in magnitude and protracted in the patients. Moreover, some ADHD children appeared to have a blink largely normal in magnitude but temporally displaced toward a later time. The authors hypothesize that a slower closing of the attention gate may mediate this specific attention impairment in ADHD children. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Saccadic eye movements in families multiply affected with schizophrenia: the Maudsley Family Study

OBJECTIVE: Family studies have shown that abnormalities of smooth pursuit eye movement are increased in the adult relatives of schizophrenic probands as well as in the probands themselves. More recently, an inability of schizophrenic subjects to inhibit reflexive saccades reliably has been shown. This study aimed to test the hypothesis that the latter dysfunction is part of the extended schizophrenia phenotype. METHOD: With the use of infrared oculography, measurements of reflexive saccades and antisaccades were undertaken in 29 probands with schizophrenia, 50 of their nonpsychotic first-degree relatives, and 38 unrelated healthy volunteers. RESULTS: Probands, relatives, and healthy subjects showed no overall differences in the generation of reflexive saccades. However, in the antisaccade task, probands showed more saccadic distractibility when they were required to inhibit reflexive saccades. Analysis of corrective saccades showed that this was not due to failed comprehension or motivation. Relatives of the probands with high saccadic distractibility showed a higher distractibility rate than relatives of the probands with normal distractibility. Across all subjects, females showed a higher rate of distractibility errors than males. CONCLUSIONS: The ability to suppress reflexive saccades is an objective neurocognitive measure that is impaired in schizophrenic patients and in a proportion of their biological relatives. This antisaccade abnormality may be a vulnerability marker in a subset of schizophrenic patients and their families.     

Clinical and neurocognitive effects of clozapine and risperidone in treatment-refractory schizophrenic patients: a prospective study

BACKGROUND: Few controlled studies have compared the efficacy of clozapine and risperidone in treatment-refractory schizophrenic patients. The present study investigates the efficacy of both clozapine and risperidone on psychopathologic and neurocognitive measures in a prospective 12-week open-label trial in treatment-refractory schizophrenic patients from state psychiatric hospitals. METHOD: Thirty-five DSM-IV schizophrenic patients with a documented history of nonresponse to typical neuroleptics were treated with either clozapine or risperidone. Response was assessed every 2 weeks by independent raters with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions (CGI) scale, neurologic rating scales, and plasma drug levels. Neurocognitive tests were administered at baseline and week 12. RESULTS: Both clozapine and risperidone brought about significant (p < .003) overall improvement in psychopathology. However, clozapine was numerically superior to risperidone on PANSS total scores and PANSS positive, negative, excitement, and cognitive factors. Extrapyramidal side effects were minimal for clozapine, whereas some were present for risperidone. Patients taking risperidone improved significantly in the beginning stages of the study and remained stable thereafter. Patients taking clozapine showed a gradual improvement that occurred over the entire length of the trial. Neurocognitive measures showed minimal improvement and did not differentiate between the 2 medication groups. CONCLUSION: Both clozapine and risperidone were comparably effective across a wide spectrum of psychopathologic measures. While the efficacy of clozapine was only numerically superior to that of risperidone, it was associated with fewer extrapyramidal side effects and with progressive improvement over the 12-week treatment period, suggesting that in longer trials clozapine may prove to be superior to risperidone in neuroleptic-refractory patients.     

A new taxane diterpenoid from Taxus mairei

OBJECTIVE: The authors examined the effect of prolonged clozapine treatment on central serotonergic (5-HT) function in schizophrenia. METHOD: Prolactin responses to the 5-HT releasing agent d-fenfluramine were measured in two groups of 10 schizophrenic subjects. The first group was tested twice, before and after a mean of 10 weeks of clozapine treatment. The second group was tested after a mean of 20 months of clozapine treatment. RESULTS: The prolactin response was significantly blunted in these 20 patients treated with clozapine. There was a significant positive correlation between d-fenfluramine-evoked prolactin release and the overall positive symptom score and the hallucination and delusion subscores of the Scale for the Assessment of Positive Symptoms. CONCLUSIONS: Blunted 5-HT-mediated prolactin responses in schizophrenic patients receiving clozapine monotherapy for up to 20 months were correlated with reductions in positive symptoms. This suggests that 5-HT antagonism is relevant to clozapine's efficacy in alleviating hallucinations and other positive schizophrenic symptoms.     

Risperidone as an adjunct to clozapine therapy in chronic schizophrenics

BACKGROUND: Some treatment-resistant schizophrenic patients improve enough to remain out of the hospital but continue to have significant positive or negative symptoms. METHOD: The goal of this study was to assess the safety and potential efficacy of risperidone as an adjunct for schizophrenic patients treated with clozapine. In an open 4-week trial involving 12 DSM-III-R-diagnosed patients, the addition of risperidone to clozapine was well tolerated and did not affect serum clozapine concentrations significantly. RESULTS: Total Brief Psychiatric Rating Scale (BPRS) scores and subscales measuring positive symptoms, negative symptoms, and depressive symptoms were significantly reduced from baseline. Ten of 12 participants had a 20% or greater reduction in the total BPRS score. CONCLUSION: In this open trial, the addition of risperidone to clozapine was well tolerated and produced significant reduction of symptoms, suggesting that this may be a useful clinical approach. Because this was an open trial, the improvement we observed must be replicated in a controlled trial.     

Effect of clozapine on motor function in schizophrenic patients

It is well established that clozapine is less likely than typical antipsychotic drugs to cause clinically discernible extrapyramidal side-effects. There is a paucity of data, however, on clozapine's motor effects. In this report we compare normal controls to groups of chronic schizophrenic patients treated with either typical antipsychotic drugs or with clozapine. Motor function was measured with a target-matching task, a test relying on submaximal sustained force control. Results indicated that patients on clozapine performed with significantly lower accuracy (greater variability) of force control. Even though the clozapine patients were treatment resistant to typical antipsychotic drugs, and many had a history of tardive dyskinesia, we postulate that the observed deficit is likely due to clozapine treatment rather than to earlier treatments or other factors. The observed force control deficit may be the result of an increase in myoclonus and a generally lower level of overall motor activity.     

Eye movement impairment and schizotypal psychopathology

OBJECTIVE: Eye movement dysfunction in relation to a smooth pursuit task has been documented in schizophrenic patients and in patients with the related personality disorder, schizotypal personality disorder. To investigate which quantitative measures are associated with the eye movement dysfunction and whether the dysfunction is more related to the psychotic-like or the deficit-like symptoms of schizotypal personality disorder, ratings of eye movements in several groups of subjects were compared. METHOD: The study groups consisted of 26 patients with schizotypal personality disorder, 42 patients with other personality disorders (22 who also had two or more schizotypal personality traits and 20 who had fewer than two), and 37 normal comparison subjects. Smooth pursuit eye tracking of sinusoidal and constant velocity targets was recorded by an infrared eye tracking system. Two raters evaluated pursuit gain and large and small saccades in the direction of the target and in the direction opposite to that of the target (quantitative ratings) and constant velocity (qualitative rating). RESULTS: Patients with schizotypal personality disorder and patients with other personality disorders and two or more schizotypal traits, but not those with fewer than two schizotypal traits, had significantly poorer qualitative ratings of tracking than the normal comparison subjects. Neither gain nor any of the saccadic measures significantly differed between groups. The number of large saccades in the direction of the target was the only quantitative variable that predicted low qualitative ratings. Qualitatively poor tracking was associated with the deficit-like, but not the psychotic-like, symptoms of schizotypal personality disorder. CONCLUSIONS: Patients with schizotypal personality disorder demonstrate qualitatively poorer tracking than comparison groups, and the impaired tracking is associated with deficit-like symptoms.     

Serotonin function and treatment response to clozapine in schizophrenic patients

OBJECTIVE: Clozapine is the only compound proven to be effective in the 20% of schizophrenic patients refractory to treatment with conventional neuroleptics. Although its mechanism of action has not been elucidated, clozapine appears, in contrast to most conventional neuroleptics, to be a potent serotonin (5-HT) antagonist. This study hypothesized that 5-HT function is increased in patients who benefit from clozapine treatment relative to patients who fail to improve on it. METHOD: The 5-HT receptor agonist m-chlorophenylpiperazine (MCPP) was used as a probe to examine 5-HT function. MCPP (0.35 mg/kg p.o.) was administered in a placebo-controlled design after a 3-week drug-free period to 19 schizophrenic patients. ACTH, prolactin, body temperature, behavior, and MCPP blood level were measured. Patients were then treated with a conventional neuroleptic, and, having failed to respond to it, were treated with clozapine for 5 weeks (up to 600 mg/day). RESULTS: Patients who responded to clozapine had significantly higher ACTH responses to MCPP during the drug-free state than the patients who failed to benefit from clozapine. Moreover, the degree of improvement with clozapine, particularly the improvement in psychotic symptoms, was strongly correlated with the magnitude of MCPP-induced ACTH release. Other MCPP-induced responses and MCPP blood level were similar for the two groups and did not correlate with the degree of symptomatic improvement with clozapine. CONCLUSIONS: Results of this study suggest that MCPP-induced ACTH release, and by inference 5-HT receptor function, may be increased in patients who benefit from treatment with clozapine relative to patients who fail to improve on this drug.     

Relationship between clinical efficacy and clozapine concentrations in plasma in schizophrenia: effect of smoking

Concentrations in plasma of clozapine and norclozapine, the major metabolite of clozapine, were measured in 59 treatment-resistant schizophrenic patients at a random time period during the course of treatment. A lower sum of the concentrations of clozapine and norclozapine or either alone predicted less improvement in the Brief Psychiatric Rating Scale (BPRS) Total and Positive symptoms in a multivariate analysis that controlled for baseline BPRS rating and dose. The mean doses of clozapine after 6 months of treatment and at the time of blood sampling were not significantly different in 30 responders and 29 nonresponders to clozapine, on the basis of the decrease in BPRS Total scores, whereas the concentrations in plasma in clozapine of norclozapine and the sum of their concentrations were significantly higher in responders. Clozapine and norclozapine concentrations in plasma correlated both with dose at the time of sampling and with dose at 6 months. A clozapine concentration of 370 ng/ml was the optimal cutoff for distinguishing responders from nonresponders. Clozapine and norclozapine concentrations did not differ in male smokers and nonsmokers.     

Concept of "pathogenesis" in parents of schizophrenic and normal children.

Administered the TAT to 5 pairs of parents of normal and schizophrenic children in a cross-validation study. Parents by diagnostic category were matched on age, education, and social class. Each story was judged pathogenic, benign, or unscorable and a pathogenic score was tabulated for each S from the formula: pathogenic/pathogenic plus benign. Mothers of the normal children told significantly fewer pathogenic stories than mothers of the schizophrenic children. Although fathers did not differ significantly, their mean pathogenic scores were distributed according to the hypotheses of the study. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Econazole, miconazole and SK & F 96365 inhibit depolarization-induced and receptor-operated contraction of guinea-pig isolated trachea in vitro

Recently, there have been some reports that schizophrenia is accompanied by an immune-inflammatory response, characterized by increased secretion of interleukin-6 (IL-6), soluble IL-2 receptor (sIL-2) and lower plasma levels of CC16 (Clara cell protein), an endogenous anti-cytokine. It was shown that clozapine, an atypical antipsychotic drug, may increase the plasma levels of sIL-2R and pro-inflammatory cytokines. This study was carried out in order to examine serum IL-6, IL-6R, CC16, IL-1R antagonist (IL-1RA), transferrin receptor (TfR) and sCD8 antigen, both before and after treatment with clozapine in schizophrenic subjects versus normal controls. Schizophrenic patients showed significantly higher plasma IL-6R and IL-1RA and lower plasma CC16 than normal controls. Treatment with clozapine significantly increased plasma sCD8, IL-6, CC16 and IL-1RA concentrations. The clozapine-induced increments in plasma IL-6 and CC16 appeared during the first 2 weeks of treatment, whereas the increases in plasma sCD8 and IL-1RA appeared after 5 weeks. Clozapine appears to have complex in vivo immunomodulatory effects.     

Attentional versus motor inhibition in adults with attention-deficit/hyperactivity disorder.

Faulty inhibition is theorized to be a central feature in attention-deficit/hyperactivity disorder (ADHD), but it remains unclear whether inhibitory impairments encompass both motoric and attentional domains. Further, characterization of inhibitory deficits in adults with ADHD is needed. We experimentally assessed adults who met diagnostic criteria for ADHD and a subgroup who had partially remitted. Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994) subtype effects were also examined. Motoric inhibition was assessed with the antisaccade task, and attentional inhibition was assessed with the attentional blink (AB) task. Antisaccade results replicated prior findings of extended latencies and increased anticipatory saccades in ADHD. Errors, however, appeared to be epiphenomenal to ADHD as they were absent when symptoms had partially remitted. Anticipatory saccades appeared as potential core problems that remained even when symptoms had improved. Differential response patterns were found for predominantly inattentive and combined subtypes, with the latter showing increasing anticipatory movements with increasing fixation time. In the AB task, ADHD groups committed more errors but showed no convincing evidence of an abnormal blink. These results demonstrate clear effects on motoric inhibition but not attentional inhibition in adults with ADHD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Licking behavior in the rat: measurement and situational control of licking frequency

OBJECTIVE: In a preliminary report, the authors observed that clozapine was superior to haloperidol in the treatment of positive and negative symptoms in stable outpatients with schizophrenia. In this final report, they examine the effects of clozapine on positive and negative symptoms in patients with and without the deficit syndrome to determine which patients receive the positive symptom advantage of clozapine and the extent of clozapine's therapeutic effects on negative symptoms. In addition, they examine the long-term effects of clozapine on positive, negative, and affective symptoms, social and occupational functioning, and quality of life. METHOD: Seventy-five outpatients with schizophrenia, who met retrospective and prospective criteria for residual positive or negative symptoms, were entered into a 10-week double-blind, parallel-groups comparison of clozapine and haloperidol. Patients who completed the double-blind study were then entered into a 1-year open-label clozapine study. RESULTS: For patients who completed the 10-week double-blind study, clozapine was superior to haloperidol in treating positive symptoms. This effect was not observed in the intent-to-treat analyses. There was no evidence of any superior efficacy or long-term effect of clozapine on primary or secondary negative symptoms. Long-term clozapine treatment was associated with significant improvements in social and occupational functioning but not in overall quality of life. CONCLUSIONS: For schizophrenic patients who are able to tolerate clozapine therapy, clozapine has superior efficacy for positive symptoms but not negative symptoms and is associated with long-term improvements in social and occupational functioning for patients with and without the deficit syndrome.     

Clozapine blunts N-methyl-D-aspartate antagonist-induced psychosis: a study with ketamine

Several lines of evidence suggest that the glutamatergic N-methyl-D-aspartate (NMDA) receptor is involved in the antipsychotic efficacy of the atypical antipsychotic agent clozapine. Clinical data on the interaction between clozapine's mechanism of action and NMDA receptor function have been lacking secondary to a paucity of pharmacologic probes of the NMDA system. We have utilized a double-blind, placebo-controlled infusion paradigm with subanesthetic doses of the NMDA antagonist ketamine to test the hypothesis that clozapine would blunt ketamine-induced psychotic symptoms in schizophrenic patients. Ten schizophrenic patients underwent ketamine infusions while antipsychotic drug free and also during treatment with clozapine. Antipsychotic drug-free patients experienced increases in ratings of positive and negative symptoms. Clozapine treatment significantly blunted the ketamine-induced increase in positive symptoms. These data suggest that NMDA receptor function may be involved in the unique antipsychotic efficacy of clozapine.     

Diagnostic pearls in the management of vitreomacular disorders

Pharmacokinetic interactions of clozapine and its metabolites N-desmethylclozapine and clozapine N-oxide with the selective serotonin reuptake inhibitors (SSRIs) fluvoxamine and paroxetine were investigated in a prospective study in schizophrenic patients under steady-state conditions. Thirty patients were treated with clozapine at a target dose of 2.5 to 3.0 mg/kg of body weight. After gradual dose escalation, serum concentrations of clozapine and two metabolites were determined twice at 7-day intervals after steady-state conditions had been reached. Then, fluvoxamine (50 mg/day) or paroxetine (20 mg/day) was added in 16 and 14 patients, respectively. Serum concentrations of clozapine and its metabolites were measured after 1, 7, and 14 days of coadministration with the SSRI. Mean trough concentrations of steady-state serum concentrations of clozapine, N-desmethylclozapine, and clozapine N-oxide were markedly elevated under fluvoxamine by about threefold of baseline concentrations whereas paroxetine induced only minor, nonsignificant changes. Estimation of the mean elimination half-life of clozapine 2 weeks after start of fluvoxamine comedication revealed an increase from 17 hours to about 50 hours whereas there was no change under paroxetine coadministration. The N-desmethylclozapine/clozapine ratio did not change significantly with either SSRI. Under monotherapy, clozapine mean serum concentrations in smokers were significantly lower by 32% compared with nonsmokers. Similarly, N-demethylation ratios were about 20 to 50% higher in smokers. Thus, in all patients, fluvoxamine induced relevant increases in serum concentrations of clozapine and its metabolites, probably by the inhibition of enzymes catalyzing the degradation of clozapine and N-desmethylclozapine, whereas paroxetine, at a usual clinically effective dosage of 20 mg/day, did not cause significant pharmacokinetic interactions.     

Smooth pursuit eye movements to extraretinal motion signals: deficits in relatives of patients with schizophrenia

BACKGROUND: Although mounting evidence supports the idea that smooth pursuit abnormality marks the genetic liability to schizophrenia, the precise ocular motor mechanism underlying the abnormality remains unknown. Based on recent findings in schizophrenia, we hypothesize that subtle deficits in the ability to hold online and/or use extraretinal motion information underlie the pursuit abnormality in vulnerable individuals. METHODS: The hypothesis was tested in 69 first-degree, biological relatives of probands with schizophrenia; 26 relatives had schizophrenia spectrum personalities (SSP). Subjects recruited from the community (n=71; 29 with SSP), without a known family history of psychosis, constituted the comparison groups. The traditional smooth pursuit gain measure, which is a ratio of smooth pursuit eye velocity in response to both retinal and extraretinal motion signals and the target velocity, was obtained. In addition, newly developed measures of predictive smooth pursuit (ie, in the presence of only extraretinal motion signals) were obtained. The latter measures were evaluated after the current retinal motion signals were made unavailable by briefly making the target invisible. RESULTS: Relatives, particularly those with SSP, showed significantly poorer predictive pursuit response to extraretinal motion signals (F(2,136)=6.51, P<.005), compared with the community subjects. However, the traditional smooth pursuit gain in response to both retinal and extraretinal motion signals was not different between groups. CONCLUSIONS: These results suggest that relatives of patients with schizophrenia, particularly those with SSP, have specific deficits in predictive pursuit based on only extraretinal motion signals. Normal smooth pursuit gain in response to both retinal and extraretinal motion signals is likely due to compensation based on retinal motion information. The latter suggests normal retinal motion processing and smooth pursuit motor output.     

Intellectual performance and school failure in children with attention deficit hyperactivity disorder and in their siblings.

Made psychiatric and intellectual assessments of 140 children with attention deficit hyperactivity disorder (ADHD), 120 normal controls, and their 303 siblings. The index children were White, non-Hispanic boys. ADHD children were more likely to have had learning disabilities, repeated grades, been placed in special classes, and received academic tutoring. They also did worse on the Wechsler Intelligence Scale for Children—Revised (WISC—R). Among ADHD probands, comorbid conduct, major depressive, and anxiety disorders predicted school placement more than school failure or WISC—R scores. However, the neuropsychological disability of all ADHD children could not be attributed to comorbid disorders because those without comorbidity had more school failure and lower WISC—R scores than normal controls. Intellectual impairment was also increased among siblings of ADHD children. This provides converging evidence that the ADHD syndrome is familial. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Magnetic resonance imaging correlates of attention-deficit/hyperactivity disorder in children.

This study compared magnetic resonance imaging size differences in several brain regions and neurocognitive function in a group of male and female children with attention-deficit/hyperactivity disorder (ADHD) with no comorbid learning disorders with a normal control group of children. The ADHD group demonstrated smaller total brain, superior prefrontal, and right superior prefrontal volumes, as well as significantly smaller areas for cerebellar lobules I-V and VIII-X, total corpus callosum area, and splenium. No group differences were observed for the inferior prefrontal, caudate, or cerebellar volumes, or for the area of cerebellar lobules VI-VII. In the ADHD group but not in the control group, greater right superior prefrontal volume predicted poorer performance on a test of sustained attention. Patterns of brain abnormality did not differ in male and female children with ADHD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)