The impact of parent socio-economic status on executive functioning and cortical morphology in individuals with schizophrenia and healthy controls.

BACKGROUND: Relatively lower executive functioning is characteristic of individuals with schizophrenia. As low socio-economic status (SES) early in life (i.e. parent SES) has been linked with lower executive skills in healthy children, we hypothesized that parental SES (pSES) would be more strongly related to executive functioning in individuals with schizophrenia than in controls and have a greater impact on prefrontal cortical morphology. METHOD: Healthy controls (n = 125) and individuals with schizophrenia (n = 102) completed tests assessing executive functioning and intelligence. The groups were matched on pSES, which was evaluated with the Hollingshead-Redlich scale. A principal components analysis (PCA) was conducted on 10 variables from six executive tests, yielding three specific components (fluency, planning and response inhibition). Voxel-based morphometry (VBM) was used to evaluate effects of pSES on gray matter (GM) concentration. RESULTS: Lower pSES was associated with lower scores across the three executive functioning components, and a significant group by pSES interaction was observed such that low pSES, in particular, affected individuals with schizophrenia. These effects remained significant when intellectual ability, education and self-SES (sSES) were added as covariates. VBM revealed that lower pSES was associated with reduced GM volume in several anterior brain regions, especially the superior frontal gyrus, in patients but not in controls. CONCLUSIONS: These findings suggest that individuals with schizophrenia may be particularly vulnerable to the adverse impact of low pSES, in terms of both lower executive skills and reduced anterior GM volumes.

Striatal function in relation to negative symptoms in schizophrenia.

BACKGROUND: Previous studies have suggested that motivational aspects of executive functioning, which may be disrupted in schizophrenia patients with negative symptoms, are mediated in part by the striatum. Negative symptoms have been linked to impaired recruitment of both the striatum and the dorsolateral prefrontal cortex (DLPFC). Here we tested the hypothesis that negative symptoms are associated primarily with striatal dysfunction, using functional magnetic resonance imaging (fMRI). METHOD: Working-memory load-dependent activation and gray matter volumes of the striatum and DLPFC were measured using a region-of-interest (ROI) approach, in 147 schizophrenia patients and 160 healthy controls. In addition to testing for a linear relationships between striatal function and negative symptoms, we chose a second, categorical analytic strategy in which we compared three demographically and behaviorally matched subgroups: patients with a high burden of negative symptoms, patients with minimal negative symptoms, and healthy subjects. RESULTS: There were no differences in striatal response magnitudes between schizophrenia patients and healthy controls, but right DLPFC activity was higher in patients than in controls. Negative symptoms were inversely associated with striatal, but not DLPFC, activity. In addition, patients with a high burden of negative symptoms exhibited significantly lower bilateral striatal, but not DLPFC, activation than schizophrenia patients with minimal negative symptoms. Working memory performance, antipsychotic exposure and changes in gray matter volumes did not account for these differences. CONCLUSIONS: These data provide further evidence for a robust association between negative symptoms and diminished striatal activity. Future work will determine whether low striatal activity in schizophrenia patients could serve as a reliable biomarker for negative symptoms.

Dialysis in schizophrenia: a double-blind evaluation.

Eight chronic schizophrenia patients completed a research program consisting of ten weekly sessions of active hemodialysis and ten weekly sessions of sham dialysis in a double-blind design. Previous reports of therapeutic efficacy were not substantiated. None of the patients improved during active dialysis; four patients worsened.

Catching up on schizophrenia. The Fifth International Congress on Schizophrenia Research, Warm Springs, Va, April 8-12, 1995.

It is axiomatic that the diversity and ingenuity of strategies in the study of schizophrenia bear testimony to the complexity of this disorder. Accordingly, the opportunity for investigators of diverse interests to share their latest findings and be informed of developments in key areas of science is critical to advance our understanding of schizophrenia. Nearly 700 investigators from around the world gathered at Warm Springs, Va, to present their data at the Fifth International Congress on Schizophrenia Research (April 8-12, 1995). This 5-day conference, held every other year alternating with the European Winter Workshop on Schizophrenia, is co-organized by S. Charles Schulz, MD, Case Western Reserve University, Cleveland, Ohio, and Carol Tamminga, MD, Maryland Psychiatric Research Center, University of Maryland at Baltimore. Drs Schulz and Tamminga first held the Congress in 1987 in Clearwater, Fla, with 170 investigators presenting. The Congress has flourished since then and is now the largest research meeting devoted solely to schizophrenia. The Congress organizers, the program coordinator (Jeffrey Lieberman, MD, Hillside Hospital, Glen Oaks, NY), and the Congress coordinator (Susan Nusbaum, Maryland Psychiatric Research Center) are congratulated on the success of this event and its contribution to fostering initiatives and collaborations within schizophrenia research.

Lack of behavioral supersensitivity to d-amphetamine after pimozide withdrawal. A trial with schizophrenic patients.

The dopamine hypothesis of schizophrenia claims that increased dopamine activity underlies psychotic behavior. This hypothesis gets major support from the reported d-amphetamine-induced worsening of psychosis, because amphetamine increases dopamine activity in the brain. Dopamine receptor supersensitivity has been shown to be present in animals during the postneuroleptic period. In this study the postulated relationships between psychotic decompensation as observed after d-amphetamine infusion and the dopamine receptor supersensitivity expected to be present during the neuroleptic withdrawal period were examined. Twenty milligrams of d-amphetamine administered intravenously did not cause a stronger psychotogenic effect in 12 schizophrenic patients. One week after discontinuation of pimozide treatment, the d-amphetamine-induced change as indicated by the Brief Psychiatric Rating Scale (BPRS) paranoid disturbance cluster score, was not significantly different from the response to a similar infusion during the drug-free state. Unexpectedly, the increase in the BPRS mannerisms and posturing item and in the pulse rate response to d-amphetamine were decreased. These results raise questions about the role of dopamine in d-amphetamine effects and suggest postneuroleptic dopamine receptor subsensitivity. They challenge a simple dopamine hypothesis of schizophrenia.

Borderline and schizotypal personality disorders treated with low-dose thiothixene vs placebo.

Fifty outpatients with borderline and/or schizotypal personality disorder were randomly allocated to thiothixene (Navane) or placebo treatment that was continued for 12 weeks. The mean daily dosage of thiothixene hydrochloride in the final week of the study was 8.7 mg, a lower dosage than is used in outpatient schizophrenics. Significant drug-placebo differences were found, regardless of diagnosis, on "illusions," "ideas of reference," "psychoticism," "obsessive-compulsive symptoms," and "phobic anxiety," but not on "depression." Thiothixene seems to have more than an antipsychotic effect. Since response to treatment studies are a means for reformulating diagnostic concepts, we suggest a subdiagnosis defined by those symptoms that are drug-responsive, some of which are not included in current diagnostic criteria. Patients with borderline and schizotypal disorder without the foregoing symptoms probably would not profit from thiothixene and might needlessly be placed at risk for adverse drug effects.

Antipsychotic effects of pimozide in schizophrenia. Treatment response prediction with acute dextroamphetamine response.

Acute behavioral response to 20 mg of dextroamphetamine (intravenous) predicted fourth-week antipsychotic response to double-blind pimozide treatment. Patients whose psychotic condition improved with dextroamphetamine administration showed more antipsychotic response to pimozide therapy than those whose condition worsened or did not change. Multiple regression analysis indicated amphetamine-induced response predicted pimozide response after four weeks for fifth-week pimozide response was more accurately predicted by prepimozide psychosis ratings. Our study provides some evidence that mechanisms underlying early and late pimozide response are not necessarily identical. Because patients who did not respond to dextroamphetamine administration still improved with pimozide therapy, our data do not support the concept that schizophrenia can be divided into two groups (dopamine-sensitive or dopamine-insensitive) but, rather, that dopamine responsiveness changes over time. Clinical application is not warranted until studies with larger samples have replicated our findings.

Changes in EEG mean frequency associated with anxiety and with amphetamine challenge in BPD.

Recent authors have hypothesized that cerebral dysfunction, as reflected in an abnormal EEG, may play an important role in the behavioral symptoms of patients with borderline personality disorder (BPD). Spectral analysis and amphetamine challenge testing are two promising methods for probing the clinical symptomatology of this disorder. In this study, we evaluated the relationship between clinical symptoms and computerized EEG spectral analysis in BPD patients both before and after amphetamine challenge. We found that mean frequency values on spectral analysis consistently correlated with anxiety levels in our patients, but did not correlate with a wide variety of other important symptoms, such as depression or transient psychosis. This result, coupled with our previous negative findings concerning EEG abnormalities in patients with BPD, casts doubt on the etiological relationship of cerebral dysrhythmias to the behavioral pathology of this disorder, but raises interesting questions concerning the relationship of anxiety and mean frequency.

The neuroendocrine and behavioral response to dextroamphetamine in normal individuals.

Dextroamphetamine 30 mg and placebo were administered by mouth in a double-blind randomized cross-over trial to ten subjects. Behavior was assessed and blood samples analyzed for growth hormone (GH), prolactin (PRL), homovanillic acid (HVA), and amphetamine. There was a statistically significant increase in well-being following d-amphetamine as compared to baseline and placebo on both the Amphetamine Interview Rating Scale and the Hopkins Mood Scale. No subject became psychotic. There was a statistically significant increase in GH from baseline to peak following d-amphetamine ingestion. When compared to placebo, the increase in GH was invariable and statistically significant for the 90-min sampling. PRL decreased from baseline following both d-amphetamine and placebo and there was no significant drug-placebo difference. Serum HVA was measured at baseline and 120 min, for eight subjects. Six subjects had an increase in HVA following d-amphetamine but there was no significant drug effect.

Olanzapine safety and efficacy in patients with borderline personality disorder and comorbid dysthymia.

BACKGROUND: Numerous medications have been tested in patients with borderline personality disorder (BPD) and/or schizotypal personality disorder (SPD). Although many of the medications tested have been demonstrated to be useful, no clear main treatment for BPD has emerged. Despite the efficacy of some of the medicines, acceptability and side effects have proven to be barriers to the use of medication. Therefore, an open-label olanzapine trial utilizing objective ratings was performed. METHODS: Patients suffering from BPD and dysthymia were included in an 8-week, open-label study of olanzapine monotherapy. The first 4 weeks of the trial allowed for flexible dosing; during the last 4 weeks, olanzapine dose was held constant. Patients were rated on Hopkins Symptoms Checklist 90 (SCL-90), Brief Psychiatric Rating Scale (BPRS), Global Assessment of Function (GAF), Barratt Impulsivity Scale (BIS 11), and Buss-Durkee Hostility Inventory (BDHI). RESULTS: Eleven patients completed at least 2 weeks; nine of the patients finished the entire trial. There was a robust and statistically significant reduction in the five global ratings. Within the global ratings, symptoms of psychoticism, depression, interpersonal sensitivity, and anger were among the symptoms to be reduced. No movement disorder symptoms were noted for any of the patients. CONCLUSIONS: In this open-label pilot study, patients treated with olanzapine showed statistically significant reduction in self-rated and clinician-rated scales. Symptoms associated with BPD and dysthymia were among those to be substantially reduced. Further studies to explore olanzapine's efficacy versus placebo, as well as comparison to other potential treatments for BPD, are important next steps.

An MRI study of adolescent patients with either schizophrenia or bipolar disorder as compared to healthy control subjects.

BACKGROUND: There are few imaging studies in adolescent patients with either schizophrenia or bipolar disorder. Such studies are of interest because adolescents may have a more severe illness and neurodevelopmental events may have a greater role in their pathophysiology. METHODS: We compared 20 patients with schizophrenia and 15 patients with bipolar disorder (10 to 18 years) to 16 normal adolescents on magnetic resonance imaging (MRI) measures of intracranial volume and ventricular and sulcal enlargement. Two planned comparison contrasts were employed, one comparing the two patient groups to each other (contrast 1), and one comparing both patient groups combined to control subjects (contrast 2). RESULTS: None of the contrast 1 comparisons (schizophrenia vs bipolar) were statistically significant. Contrast 2 comparisons (control subjects vs patients) were statistically significant for intracranial volume (reduced in patients) as well as frontal and temporal sulcal size (increased in patients). CONCLUSIONS: The patient groups were not statistically significantly different from each other on any measure. The combined patient groups were different from control subjects on intracranial volume and frontal and temporal sulcal size. Also, there was evidence for ventricular enlargement, after removal of a control subject with an extreme value. These findings indicate that the same abnormalities noted in adult populations are present in adolescents.

The amphetamine challenge test in patients with borderline disorder.

The authors used amphetamine as a psychopharmacological probe to investigate the hypothesis that patients with borderline personality disorder are prone to psychosis following ingestion of a dopamine agonist. Sixteen patients with borderline personality disorder participated in the study. Significant increases in the mean total Brief Psychiatric Rating Scale scores and in activation and thought disturbance factors after amphetamine administration were noted in the sample. Patients with diagnoses of both schizotypal and borderline personality disorders worsened transiently with amphetamine administration, but patients with only the borderline diagnosis improved. These results indicate the usefulness of pharmacological probes to further understand DSM-III axis II disorders.

Fluoxetine in the treatment of borderline and schizotypal personality disorders.

Twenty-two patients meeting the criteria for borderline or schizotypal personality disorder or both participated in a prospective, nonblind 12-week trial of fluoxetine. There were significant reductions in self-injury and in scores on the Hopkins Symptom Checklist regardless of diagnosis. The results suggest that controlled trials of fluoxetine and investigations of the serotonergic system in these disorders would be useful.

Contrasts between patients with affective disorders and patients with schizophrenia on a neuropsychological test battery.

OBJECTIVE: This study was designed to ascertain the degree and specificity of cognitive impairments in patients with schizophrenia and patients with affective disorders. METHOD: Cognitive function was assessed with a neuropsychological test battery in consecutively admitted patients with schizophrenia (N = 57), unipolar depression (N = 29), and bipolar disorder (N = 16). RESULTS: The performance of the schizophrenic group was significantly below that of the groups with affective disorders on measures of attention and psychomotor speed, verbal and visual memory, and problem solving and abstraction. IQ was lower in the schizophrenic group and appeared to have deteriorated from a normal premorbid level that was not different from that of the affective disorder groups, as determined by the Wide Range Achievement Test--Revised reading test, a putative measure of premorbid intelligence. When IQ was controlled, differences between the groups in problem solving and visual memory remained. Psychiatric symptoms had a larger impact on test performance in the affective disorder groups than in the schizophrenic group. CONCLUSIONS: These results suggest that patients with schizophrenia perform systematically worse on cognitive measures than patients with affective disorders, which is consistent with their generally poorer outcome. The results also indicate that schizophrenia and affective disorders are qualitatively distinguishable in neuropsychological terms, given differences in apparent intellectual deterioration, profiles of cognitive impairment, and associations between cognitive performance and psychopathology.

Ventricular enlargement in teenage patients with schizophrenia spectrum disorder.

Recent research has demonstrated statistically significant differences between the ventricular-brain ratios (VBRs) of schizophrenic patients and control subjects. In this study the VBRs of teenage schizophrenic/schizophreniform patients (N = 15) and borderline patients (N = 8) were measured and compared with those of controls of similar ages (N = 18). The schizophrenic group had significantly larger ventricles than the other two groups (p less than .0001). These findings support the hypothesis of previous investigators that ventricular enlargement is present early in the course of schizophrenia.

Cognitive impairment in adolescents with schizophrenia.

OBJECTIVE: The purpose of this study was to determine whether adolescent schizophrenia is characterized by neuropsychological deficits. METHOD: The performance on a battery of neuropsychological tests of 17 adolescents with schizophrenia (mean age = 15.71 years) was compared with that of 17 normal adolescents (mean age = 15.12 years). RESULTS: Compared with the normal subjects, the patients were impaired on 10 of the 13 measures; larger effect sizes were shown for measures involving working memory and attention than for those involving secondary memory, generative naming, and executive functions. CONCLUSIONS: Adolescents with schizophrenia have generalized cognitive dysfunction, which is most apparent on tests of attention and working memory.

Behavioral and biological effects of acute beta-endorphin injection in schizophrenic and depressed patients.

In this double-blind study, beta-endorphin, 4-15 mg, was administered intravenously to 6 schizophrenic and 4 depressed patients. There were neither significant differences in behavioral ratings between beta-endorphin and placebo for the overall group nor for either the schizophrenic or depressed subgroup. Clinical worsening and improvement were observed in individual schizophrenic patients. There was no evidence of late-appearing therapeutic effects in 4 schizophrenic patients rated for 5 consecutive days after placebo and drug infusions. In 1 patient 10 mg of beta-endorphin produced neuroendocrine effects comparable to those produced by 5 mg of intravenously administered methadone; in 2 other patients it produced large increases in circulating opioid activity as determined by radioreceptor assay. These biological data support the notion that parenterally administered beta-endorphin exerts significant opiate-like activity in vivo.

Positron-emission tomography and personality disorders.

This study used positron-emission tomography to examine cerebral metabolic rates of glucose (CMRG) in 17 patients with DSM III-R diagnoses of personality disorder. Within the group of 17 personality disorder patients, there was a significant inverse correlation between a life history of aggressive impulse difficulties and regional CMRG in the frontal cortex of the transaxial plane approximately 40 mm above the canthomeatal line (CML) (r = -.56, p = 0.17). Diagnostic groups included antisocial (n = 6), borderline (n = 6), dependent (n = 2), and narcissistic (n = 3). Regional CMRG in the six antisocial patients and in the six borderline patients was compared to a control group of 43 subjects using an analysis of covariance with age and sex as covariates. In the borderline personality disorder group, there was a significant decrease in frontal cortex metabolism in the transaxial plane approximately 81 mm above the CML and a significant increase in the transaxial plane approximately 53 mm above the CML (F[1,45] = 8.65, p = .005; and F[1,45] = 7.68, p = .008, respectively.

PET measurement of neuroreceptor occupancy by typical and atypical neuroleptics.

UNLABELLED: The goal of this study was to use PET and 11C-N-methylspiperone (11C-NMSP) to measure the difference in relative occupancy of serotonin (5-hydroxytryptamine-2 or 5-HT2A) and dopamine-2 (D2) neuroreceptors in subjects being treated with typical or atypical antipsychotic drugs. METHODS: We used PET and single-dose 11C-NMSP to measure receptor indices and relative receptor occupancy of 5-HT2A receptors in frontal cortex and D2 receptors in basal ganglia in five subjects who were neuroleptic free, five subjects who were being treated with typical antipsychotic drugs and five subjects who were being treated with clozapine, an atypical antipsychotic drug. RESULTS: Among the three groups, there were significant differences in 5-HT2A indices, D2 indices and the ratio of 5-HT2A to D2 indices. With no overlap, the 5-HT2A index separated all subjects who received clozapine and the D2 index separated the remaining two groups. CONCLUSION: Typical antipsychotic and atypical antipsychotic subjects do have differing patterns of 5-HT2A and D2 relative receptor occupancy when measured with a single PET scan, single 11C-NMSP radiotracer dose and no separately injected "cold" pharmaceutical.

Screening for tardive dyskinesia.

A program of routine Abnormal Involuntary Movement Scale (AIMS) examinations is contrasted with a referral system for detection of tardive dyskinesia in an outpatient schizophrenia clinic. Routine clinical use of the AIMS examination may have improved the early detection of tardive dyskinesia, which could result in a decrease in the morbidity associated with this disorder. Routine AIMS examinations also facilitated repeat discussions with patients about tardive dyskinesia, which provide an opportunity to obtain ongoing informed consent for treatment with neuroleptics.