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.

Cognitive deficits in recent-onset and chronic schizophrenia.

Although cognitive dysfunction is a primary characteristic of schizophrenia, only recently have investigations begun to pinpoint when the dysfunction develops in the individual afflicted by the disorder. Research to date provides evidence for significant cognitive impairments prior to disorder onset. Less is known about the course of cognitive dysfunction from onset to the chronic phase of schizophrenia. Although longitudinal studies are optimal for assessing stability of cognitive deficits, practice effects often confound assessments, and large and representative subject samples have not been followed over long periods of time. We report results of a cross-sectional study of cognitive deficits early and late in the course of schizophrenia carried out at four different geographic locations to increase sample size and generalizability of findings. We examined a broad set of cognitive functions in 41 recent-onset schizophrenia patients and 106 chronic schizophrenia patients. The study included separate groups of 43 matched controls for the recent-onset sample and 105 matched controls for the chronic schizophrenia sample in order to evaluate the effects of cohort (i.e., age) and diagnosis (i.e., schizophrenia) on cognitive functions. All measures of cognitive function showed effects of diagnosis; however, select time-based measures of problem solving and fine motor dexterity exhibited interactions of diagnosis and cohort indicating that these deficits may progress beyond what is expected with normal aging. Also, worse recall of material in episodic memory was associated with greater length of illness. Nevertheless, findings indicate that nearly all cognitive deficits are comparably impaired across recent-onset and chronic schizophrenia.

First-episode psychosis: a clinical approach.

BACKGROUND: Psychotic illnesses, such as schizophrenia and bipolar illness, are relatively common and clearly devastating diseases. Most scientific literature focuses on research and care of patients suffering from psychotic illnesses in the middle age-group; subsequently, the first episode or early stages of psychotic illnesses have been relatively ignored, especially the issues of early diagnosis and intervention. The purpose of this article is to highlight issues of first-episode schizophrenia for the family physician and to discuss (1) diagnosis, (2) neuropsychiatry research, (3) new medications, and (4) family issues. METHODS: To approach the issues of first-episode schizophrenia, we describe a case of a young woman who suffered her first episode of psychosis. Relevant literature related to the early stages of psychosis, including new pharmacologic treatments, is addressed. RESULTS: This report of our patient, a 19-year-old woman, illustrates the problems of a long prodromal phase of her illness, the use of medications that might have worsened her condition, and the successful use of new antipsychotic medications. Her family's issues as the patient went through this phase of her illness and recovery are reviewed. CONCLUSIONS: Patients at the outset of a psychotic illness are frequently first seen by a family physician. Familiarity with current diagnostic criteria and effectiveness of new treatments can lead to improved detection and overall outcome.

Schizophrenia research: a progress report, summarizing proceedings of the 1999 International Congress on Schizophrenia Research.

The Seventh International Congress on Schizophrenia Research was held in Santa Fe, New Mexico, in April 1999. This was the largest Congress meeting to date, with almost 1,000 presentations that covered all aspects of schizophrenia research. This article provides an account of the Congress proceedings. Several research areas received extensive coverage, including early detection of illness through the use of cognitive and behavioral precursors of schizophrenia and the etiology and treatment of childhood-onset and first episode schizophrenia. The etiopathophysiological hypothesis of schizophrenia as a disorder of neural dysconnectivity was promoted across cognitive, neurochemical, neuroimaging, and postmortem domains. The importance of cognition as a major outcome measure and the impact of new antipsychotics on the treatment and conceptualization of schizophrenia were also major topics. Overall, the conference was noteworthy for the convergence of findings across research domains.

Higher brain blood flow at amygdala and lower frontal cortex blood flow in PTSD patients with comorbid cocaine and alcohol abuse compared with normals.

Posttraumatic stress disorder (PTSD) patients with histories of cocaine and alcohol abuse (CA-PTSD) were compared with normal volunteers. Positron emission tomography (PET) scans with 15O-butanol were used to compare regional cerebral blood flow (rCBF) between the groups during rest and during an auditory continuous performance task (ACPT). CA-PTSD patients had significantly higher rCBF in right amygdala and left parahippocampal gyrus than normals during the ACPT. Normals had higher rCBF at frontal cortex during the resting scan and during the ACPT. The role of the amygdala in attention and fear conditioning suggests that increased amygdala rCBF may be related to clinical features of PTSD. Cocaine use may be associated with increased amygdala rCBF in PTSD patients. Amygdala and frontal cortex attention system components may be reciprocally related and their relative contributions to processing of neutral stimuli perturbed in CA-PTSD.

New antipsychotic medications: more than old wine and new bottles.

Four new antipsychotic medications--clozapine, risperidone, olanzapine, and quetiapine--have been introduced in the United States during the past decade. These new medications now account for the majority of antipsychotic prescriptions. The author reviews specific issues related to the use of traditional antipsychotic medications and then highlights the emerging clinical research data regarding the new medications, which have all been shown to be efficacious in the treatment of schizophrenia. Clinical research data indicate that they are also more useful for a broader array of symptoms associated with schizophrenia than traditional compounds. Furthermore, movement disorder side effects are substantially decreased--a property that leads to higher acceptability. Surprisingly, there has been little relationship between the pivotal trials designed for FDA approval and current dosing strategies in broader clinical settings. These dosing issues are described. New uses, including treatment of mood disorders and conduct disorder, are also discussed. These medicines offer substantial hope for improved treatment of schizophrenia.

If patients with schizophrenia have small brains, why don't they have small heads?

Although patients with schizophrenia have reduced brain size, there is no conclusive evidence that they have reduced head size. This begs the question: 'What is the precise relationship between head size and brain size?' We used a unique osteological collection to explore the relationship between external head measures and cranial capacity. The external measures accounted for, at most, 60% of the variance in cranial capacity - a value low enough to question the oft-assumed tight relationship between head measures and brain size. Obviously, various tissues and spaces [skull, sinus, muscle (frontalis, temporalis and occipitalis), subcutaneous fat and epidermal layers] contribute to head size without contributing to brain volume. The contribution of these other tissues and spaces tends to decrease the signal and increase the noise in the estimation of brain volume. Thus, it is understandable that patients with schizophrenia can have reduced cranial capacity and not reduced head size.

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.

Lithium augmentation fails to reduce symptoms in poorly responsive schizophrenic outpatients.

BACKGROUND: Nearly one third of patients suffering from schizophrenia do not fully respond to antipsychotic medication. Safe, effective, and cost-efficient methods to reduce symptoms are clearly needed; therefore, lithium as an adjunct to fluphenazine decanoate was tested in a placebo-controlled trial in outpatients who were part of the Treatment Strategies of Schizophrenia (TSS) study. METHOD: Forty-one patients with DSM-III schizophrenia or schizoaffective disorder were assigned to either adjunctive lithium or placebo after at least 6 months of fluphenazine decanoate treatment to stabilize symptoms had failed. The trial was designed for 8 weeks of treatment, and patients assigned to placebo could afterward be administered lithium in an 8-week, open-label study. RESULTS: Assessment of the intent-to-treat analysis revealed no significant differences in demographic variables between the lithium and placebo groups. Although both groups showed significant (p = .00135) improvement as measured by total scores on the Brief Psychiatric Rating Scale (BPRS), there were no significant differences in response between the lithium and placebo groups. Patients originally treated with placebo added to neuroleptic did not have significantly greater improvement when receiving open-label adjunctive lithium. CONCLUSION: Although success with lithium augmentation therapy for persistent psychosis has been reported in the past, this study of well-characterized patients showed no benefit for this common strategy, thus indicating that care be used in utilizing lithium augmentation.

Meta-analysis of brain size in bipolar disorder.

A recent meta-analysis concluded that patients with schizophrenia have reduced cerebral volume, and this finding has been used to implicate neurodevelopmental events in the etiology of this disorder. Since bipolar-disorder patients and schizophrenia patients have some similar brain abnormalities, it was of interest to meta-analytically review the literature on brain size in bipolar disorder. Only seven studies met the inclusion/exclusion criteria for our meta-analysis, but none reported the brain size differences between the bipolar patients and the controls to be statistically significant. The composite effect size was a negligible 0.04 (95% CI: -0.17 to 0.25) and statistically not significantly different from 0.0 (no effect). Thus, it appears that bipolar disorder is not associated with the same cerebral volume reductions noted in schizophrenia. Implications for hypotheses regarding the etiology of the two disorders are discussed.

A magnetic resonance imaging study of thalamic area in adolescent patients with either schizophrenia or bipolar disorder as compared to healthy controls.

The purpose of this study was to compare thalamic size in adolescent patients with either schizophrenia or bipolar disorder and healthy controls. T2-weighted axial magnetic resonance images were used to manually define the area of the thalamus for 20 schizophrenia patients, 15 bipolar patients and 16 normal control subjects, all of whom were adolescents. Two orthogonal planned contrasts were tested: Contrast 1, patients with schizophrenia vs. patients with bipolar disorder; and Contrast 2, both patient groups taken as a single group compared to controls. Contrast 1 was not statistically significant for right or left thalamic area. Contrast 2 was statistically significant and indicated reductions in thalamic area in the patients as compared to controls. The same pattern of results emerged after adjustment for total brain volume. Our results indicate that thalamic abnormalities reported in adult schizophrenic and bipolar patients are also observed in adolescent patients. Our findings also add to the evidence implicating the thalamus in the pathophysiology of schizophrenia and bipolar disorder.

Schizophrenia research: a biennium of progress. Proceedings from the Sixth International Congress on Schizophrenia Research. Colorado Springs, CO, April 12-16, 1997.

The Sixth International Congress on Schizophrenia Research (ICOSR) took place in Colorado Springs, Colorado, April 12-16, 1997, where over 1,000 scientists presented and listened to the latest developments in the search for the cause and treatment of schizophrenia. The ICOSR is sponsored by Maryland Psychiatric Research Center, Case Western Reserve University, and the William K. Warren Foundation. The National Institute of Mental Health and several pharmaceutical companies contributed generously to the meeting. The ICOSR is co-organized by Dr. Carol A. Tamminga, Maryland Psychiatric Research Center, University of Maryland at Baltimore, and Dr. S. Charles Schulz, Case Western Reserve University, Cleveland, Ohio. The William K. Warren Research Award is given to a senior investigator, who has made outstanding contributions to our understanding of schizophrenia. The fifth William K. Warren Research Award was presented to Dr. Philip S. Holzman in recognition of his contributions to the identification of eye-tracking abnormalities as a potential phenotypic marker of the illness and also in recognition of his work as a lifelong mentor for schizophrenia researchers. The ICOSR Young Investigator Awards are presented to junior investigators who have demonstrated the potential to make significant contributions to research on schizophrenia. These awards promote scientific development by enabling these young researchers to attend the meeting. There were 30 Young Investigator Award winners. The ICOSR meeting is organized into four sessions: (1) a morning plenary session; (2) a plenary lecture; (3) a poster session; and (4) concurrent afternoon oral sessions. The morning plenary sessions are comprised of a set of 30-minute lectures, which provide an overview of a particular topic area relevant to schizophrenia research. The plenary lecture is an invited lecture on a basic topic related to current research efforts in schizophrenia. The poster sessions provide a forum for the presentation of prepublication reports of basic and clinical science projects. The afternoon sessions are a collection of approximately 10 focused presentations on current research projects related to a specific topic area. The purpose of this report is to provide an account of the proceedings from the plenary and afternoon oral sessions.

Child and adolescent schizophrenia.

Until only very recently, the occurrence of schizophrenia in childhood and early adolescence had been largely neglected. Improved diagnostic formulations have resulted in clarification of the boundaries between childhood schizophrenia, other psychotic disorders, and pervasive developmental disorder. The study of schizophrenia in childhood or adolescence provides a unique opportunity to examine illness characteristics in the absence of the confounds of substance abuse illness, chronicity, and medication effects. Additionally, current etiopathologic models of schizophrenia can be tested in this patient subgroup.

Treatment and outcomes in adolescents with schizophrenia.

The pharmacologic treatment and assessment of outcomes in adolescents with schizophrenia have been inadequately addressed. Structural brain imaging and brain function studies both point to a continuity between adolescent and adult stages of schizophrenia. Because the teenage population seems to be less tolerant of physical side effects, the advent of atypical antipsychotic medications may offer increased safety and efficacy. Studies support the notion that adolescent illness is associated with a more severe form of schizophrenia and that length of illness before treatment is correlated with long-term outcome. As a consequence, the authors recommend assertive pharmacologic intervention in adolescents with schizophrenia and future research focused on the issues of treatment and outcome in teenagers suffering a psychotic disorder.

The antipsychotics. A pediatric perspective.

As can be discerned from this article, antipsychotics are commonly prescribed, and they are not used to treat only psychosis. Although some data support the use of typical antipsychotics in pediatric patients with a variety of psychiatric syndromes, concerns about the safety and tolerability of these agents often complicated their use and probably even interfered with case identification. A fundamentally new group of medications, the atypicals, have now become available and may not only have improved tolerability but also may have greater ability to reduce some target symptoms. Because of their superior side-effect profile in adults, some of these atypical treatments probably will be commonly prescribed despite a relative paucity of data about their use in the young. Moreover, although frequently prescribed in this age group, the overall prescription rate for antipsychotics will probably increase because of the putative improved safety profile of the newer agents. However, it is possible that serious side effects, such as tardive dyskinesia or neuroleptic malignant syndrome, may occur with these atypical agents. For this reason, the enthusiasm for prescribing these newer treatments should be tempered with the understanding that these agents, although they may in some ways be superior to their predecessors, still possess the potential for significant adverse events. Four atypical antipsychotics are currently marketed in the United States (see Table 2). One additional agent, ziprasodone, is undergoing clinical investigation. Ziprasodone has been shown to be superior to placebo in adults suffering from schizophrenia. Ziprasodone will probably be marketed in the United States in the near future. Whether all of these atypical drugs will have a place in the clinical armamentarium of the pediatric psychopharmacologist remains to be determined. Because the receptor binding profile of the atypical agents differ, it is not possible to assume that what is true for one of these agents is true for the others. Although results from most preliminary studies with atypical antipsychotics indicate that these are promising agents for pediatric patients, further research is needed to define just how these medications may be most judiciously used.

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.

Comparing the mental health needs of female and male incarcerated juvenile delinquents.

The present study was undertaken to survey the prevalence of mental disorder in juvenile justice facilities and to compare the mental health needs for females and males. Girls displayed significantly more mental health needs than boys. The estimated prevalence of mental disorder for boys was 27%, compared with 84% for girls. The difference is highly significant and is discussed in terms of service system issues in juvenile justice that affect males and females differently.