Neuropsychological deficits in the early course of first episode schizophrenia.
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Adult↗
Biomedical subjects
J A Lieberman
Publications and source records attributed to J A Lieberman.
A selective review of biological markers in schizophrenia.
Through previous research, promising biological markers for schizophrenia have been identified. Abnormalities in eye movement, electrodermal activity, event-related brain potentials, attention and informational processing, and brain imaging have been reported. Studies of potential trait markers suffer from the lack of a standardized methodology, which makes comparisons of their results difficult. No one possible marker appears specific for schizophrenia. Additional studies in high-risk children and adults are needed using multiple measurements to define biologic similarities and differences between psychiatric syndromes in order to develop definitive trait markers for schizophrenia. Sufficient evidence does not exist to support the inclusion of biological markers among the DSM-IV criteria for schizophrenia, although some are sufficiently robust to merit mention among the associated features discussed in the text.
Arousal↗
Update on the clinical efficacy and side effects of clozapine.
Clozapine (CLOZ) is an atypical antipsychotic drug being used with increasing frequency throughout the world and has recently been commercially marketed in the United States. Its unique properties make it a promising but challenging drug to use in the treatment of schizophrenia. In order to use CLOZ most effectively and efficiently, clinicians must be aware of its potential benefits and risks. This report is a review and critical evaluation of current knowledge regarding the clinical efficacy and side effects of CLOZ. Although CLOZ has proven to be effective in some treatment-refractory schizophrenic patients and to produce relatively few extrapyramidal side effects compared to classical neuroleptic drugs, several issues require further investigation including what defines neuroleptic intolerance, the optimal dose range, and the appropriate duration of a CLOZ treatment trial. Similarly, studies are needed to determine what role CLOZ should have in the treatment of patients with predominantly negative symptoms and those patients who are only partially responsive to standard neuroleptics. In addition, important questions remain as to what other conditions might be indications for CLOZ, for example, schizoaffective disorder, affective psychoses, and idiopathic Parkinson's disease.
Agranulocytosis↗
The effects of clozapine on tardive dyskinesia.
This article reviews eight published studies that describe clozapine's effects on TD and examines the outcome of 30 patients with TD treated with clozapine for up to 36 months. These data indicate that TD response to clozapine is variable but that approximately 43% of cases, particularly those with dystonic features, improved after clozapine treatment. Methodological limitations of the studies described, however, preclude definitive conclusions, which must await appropriately controlled trials.
Adult↗
The prevalence of tardive dyskinesia.
A total of 2250 subjects from psychiatric and geriatric settings was examined for abnormal involuntary movements by the same team of trained raters employing a standard examination technique and rating scale. "Spontaneous" dyskinesia rates were 1.3% among 400 healthy elderly people surveyed at senior citizens centers, 4.8% among medical geriatric inpatients and ranged from 0 to 2% among psychiatric patients never exposed to neuroleptics. For samples of neuroleptic-treated patients, prevalence rates ranged from 13.3% among patients at a voluntary psychiatric hospital to 36.1% among state hospital patients. Logistic regression analyses revealed a large effect of age on tardive dyskinesia prevalence and an interaction of age with sex. Among younger subjects, men had higher rates; among subjects over age 40, rates were higher for women. Edentulousness and presence of other neurological disorders were possible contributors to high rates for the elderly. Even with control for age, sex and duration of neuroleptic exposure, prevalence differed markedly across study site.
Adult↗
A case report of cimetidine-induced clozapine toxicity.
Cimetidine may decrease concomitant medication clearance by inhibiting the oxidative system of cytochrome P-450. The authors report increased serum clozapine levels and adverse side effects during clozapine and cimetidine treatment but not during clozapine and ranitidine treatment in a patient with chronic paranoid schizophrenia.
Adult↗
CSF 5-hydroxyindoleacetic acid levels and suicide attempts in schizophrenia.
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Adult↗
HLA-B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia.
Agranulocytosis develops in approximately 1% of patients with chronic schizophrenia treated with the atypical neuroleptic drug clozapine. Previous studies have not identified the mechanism or risk factors for this adverse reaction. Because of an observed association between Jewish ethnic background and the development of agranulocytosis in our patient sample treated with clozapine for refractory symptoms, HLA typing was performed in 31 patients (19.4% of whom had developed agranulocytosis). The HLA-B38 phenotype was found in 83% of patients who developed agranulocytosis and in 20% of clozapine-treated patients who did not develop agranulocytosis. Because B38 is part of a haplotype known to occur frequently in the Ashkenazi Jewish population, the frequencies of the combined alleles HLA-B38, DR4, and DQw3 were examined. The incidence of HLA-B38, DR4, DQw3 was significantly increased in patients with agranulocytosis (five of five patients) compared with control patients of Ashkenazi Jewish ancestry (two of 17 patients). These findings indicate that genetic factors marked by major histocompatibility complex haplotypes may be associated with the susceptibility of Jewish schizophrenic patients treated with clozapine to develop agranulocytosis. We postulate that gene products contained in the haplotype may be involved in mediating drug toxicity.
Agranulocytosis↗
Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia.
Pathomorphology of the limbic system has been described in post-mortem studies of schizophrenia. To determine whether this could be detected in living patients and was not secondary to the treatment or the chronicity of the disease itself, we measured the volumes of the hippocampus-amygdala complex and adjoining temporal horns of 34 patients in their first episode of schizophrenia and 25 normal volunteers using T1 weighted contiguous coronal magnetic resonance images of 3.1 mm width. The results demonstrate abnormal medial temporal lobe morphology in a subgroup of patients at the onset of their illness. There were clear laterality effects and sex differences: hippocampal tissue was significantly smaller only in the left hemisphere of male patients, whereas enlargement of the whole temporal horn or its anterior portion was present on the left side in both sexes. Dysfunction of the limbic mesiotemporal structures might explain some of the clinical features of the disease.
Adolescent↗
Dopaminergic mechanisms in idiopathic and drug-induced psychoses.
Stimulant drugs such as cocaine and amphetamine are among the most commonly abused substances by schizophrenic patients. This may be due in part to aspects of the illness and treatment side effects that impel patients to use dopamine agonist drugs. Dopaminergic neural systems have been shown to mediate both stimulant drug effects and schizophrenia. Because of the hypothesized overlap in the pathophysiology of schizophrenia and the neurobiological effects of chronic stimulant use, the potential for serious complication of the primary disease by substance abuse exists. This article reviews the neurobiological mechanisms of behavioral sensitization and neurotoxicity associated with chronic stimulant administration in the context of pathophysiological theories of schizophrenia. Discussion focuses on the potential impact of stimulant use on the disease process as well as the manifest phenomenology and course of schizophrenia.
Amphetamine↗
Computerized volume measurement of brain structure.
Morphometric analysis of brain structures recently has become a main focus of interest in studies of some neuropsychiatric diseases. Limitations in imaging and mensuration methodology that is available currently for quantitative measurement of anatomic structures have prompted the development of a computerized system to study brain morphometry. A menudriven semi-automated computer system has been developed to assess in vivo brain morphometry using three-dimensional (3-D) magnetic resonance (MR), gradient echo, contiguous images of the whole brain. Accuracy of the system was tested with phantoms creating white on black contrast to simulate the brain tissue surrounded by subarachnoid cerebrospinal fluid (CSF), and a second set of phantoms creating black on white contrast to simulate the ventricular system in the brain tissue. The first set of phantoms was composed of three water-filled balloons (spherical, elliptical, and multiform) and a fresh postmortem brain. The second set of phantoms consisted of three rods of different diameters from a simple geometric plexiglass rod phantom and a life size cast of a human ventricular phantom. System accuracy was generally within 2.0% of the true volumes. System reliability was evaluated in three patient populations; 12 patients with Alzheimer's disease, nine with schizophrenia and nine healthy controls age-matched to the patients with Alzheimer's disease. Two independent observers measured the ventricular systems of these patients. Reliability of the system was addressed by the correlation between the two sets of measurements. For the sample as a whole, and each of the subgroups, the correlation between the two observers was 0.99. This system compares favorably with other morphometric methods reported.
Cerebral Ventricles↗
Growth hormone response to growth hormone-releasing hormone in schizophrenic patients.
Ten schizophrenic patients and five normal control subjects were challenged with growth hormone-releasing hormone in a pilot study investigating growth hormone secretion from the pituitary. The results suggest suprapituitary dysfunction in schizophrenia, but replication in a larger study is needed.
Adult↗
A single estimate of separate within-individual correlations: applications in psychopharmacology.
Simple procedures are proposed to describe relationships between sets of repeated measures within study subjects. An example is the association between blood levels of prolactin and a drug (e.g., methylphenidate) measured at multiple time-points across study subjects. These procedures consist of (a) estimating Pearson product moment correlation coefficients (rs) within individuals using all the observations available per individual; (b) estimating an average r that pools the information across study subjects; (c) testing whether these rs are homogenous using a simple chi-square test; and (d) testing the average r for statistical significance. If these individual rs are found to be homogeneous, the average r is taken as representative of the individual rs. Testing rs for homogeneity and pooling them across individuals are relatively old procedures (Snedecor 1956). Recent applications can be found in the meta-analytic literature (Rosenthal 1983). Applications are demonstrated using actual data. We recommend using these procedures because they are simple and easily applied and interpreted.
Humans↗
Behavioral response to methylphenidate and treatment outcome in first episode schizophrenia.
In order to examine the relationship of behavioral response to psychostimulants and acute treatment response, we administered methylphenidate (0.5 mg/kg i.v.), an indirect dopamine (DA) agonist, to 38 patients who met Research Diagnostic Criteria (RDC) for definite or probable schizophrenia or schizoaffective disorder, were experiencing their first acute episode of psychosis, and had received less than 12 weeks or no prior lifetime neuroleptic exposure. Following baseline methylphenidate infusions, patients received a standardized regimen of acute neuroleptic treatment. Methylphenidate produced an increase in psychopathology reflected by a worsening of both positive and negative symptoms. Using a priori criteria, 61 percent of patients exhibited psychotic symptom activation, and 39 percent showed no change. Activation during methylphenidate infusion during the initial acute phase of illness was not correlated with time to achieve antipsychotic treatment response but was associated with side-effect vulnerability.
Adolescent↗
Gonadal hormones, sex and behavior.
Gender differences have been demonstrated in several regions of the central nervous system (CNS) in animals and humans. These differences change with development and aging and are probably influenced by hormones. Gender differences have been demonstrated clinically in the prevalence of some mental disorders and responses to psychotropic medications. Gonadal hormones might be involved in these differences as well as in differential cognitive functions. The two genders also differ in the aging process. While it is well known that changes in the pituitary gonadal system influence the aging process in women, preliminary data described here demonstrate the association between pituitary-gonadal hormones and the aging process of sexual desire and activity in men. The changes in levels of gonadal hormones might contribute to the pathophysiology of dysphoric cyclic disorders and increased vulnerability to affective disorders in women. This vulnerability might be related to hormonal fluctuations over time as well as to alteration in internal oscillators and time-related functions.
Aging↗
Substance abuse comorbidity in schizophrenia: editors' introduction.
Substance abuse is a pervasive problem in American society that extends to persons with mental illness. Despite the fact that substance abuse in the mentally ill is a major clinical problem, there have been very few systematic investigations of the dimensions, nature, and treatment of this problem. This issue of the Schizophrenia Bulletin attempts to examine the problem of substance abuse in schizophrenia from various perspectives by reviewing the published literature, presenting original data, and identifying areas and approaches for future scientific investigation.
Humans↗
Treatment of tardive dyskinesia with bromocriptine. A test of the receptor modification strategy.
Pathophysiologic theories postulate that tardive dyskinesia arises from the development of chemical denervation supersensitivity of dopamine receptors produced by chronic long-term neuroleptic treatment. To test a dopamine receptor modification strategy, 16 patients with tardive dyskinesia were assigned to treatment with a neuroleptic plus bromocriptine (a dopamine agonist) or placebo for 10 weeks in a rising-dose design. Patients were evaluated weekly during the 10-week treatment period and for 8 weeks after medication withdrawal. No significant treatment effect was found in tardive dyskinesia response in the overall sample. When patients were classified by tardive dyskinesia subtype, patients with choreoathetoid symptoms exhibited only slight improvement with active treatment, which persisted after drug withdrawal; patients with dystonic symptoms showed moderate improvement that was drug and dose dependent. The sustained administration of substantial doses of a dopamine agonist did not produce significant adverse effects, including behavioral toxic effects. These results, although not statistically significant, are of clinical and heuristic interest.
Adolescent↗
Depression in hemodialysis patients.
Psychiatric evaluation of depression in medically ill patients using DSM-III-R or Research Diagnostic Criteria (RDC) is difficult because these diagnostic systems have not been validated for this population. Diagnosis of depression has been especially problematic in patients with end-stage renal disease (ESRD). This study found a 17.7% prevalence of RDC-defined minor depression and a 6.5% prevalence of major depression in 124 ESRD patients treated with hemodialysis. Vegetative symptoms of depression were less useful for discriminating between those with and without depression than were the psychological symptoms of suicidal ideation, depressed mood, and discouragement.
Depressive Disorder↗