Roger A. Boshes

The CATIE Schizophrenia Trial: Results, Impact, Controversy

&NA; The CATIE (Clinical Antipsychotic Trials for Intervention Effectiveness) Schizophrenia Trial was designed to examine fundamental issues about second‐generation antipsychotic (SGA) medications (olanzapine, risperidone, quetiapine, and ziprasidone)—their relative effectiveness and their effectiveness compared to a first‐generation antipsychotic (FGA), perphenazine. This article reviews these and other findings from this important trial and offers a perspective regarding their meaning for practice and their significance for the advancement of research in psychiatry. The primary outcome measure, time to discontinuation, served as an index of effectiveness and was remarkably short; only 26% of subjects completed the 18‐month trial on the medicine to which they were initially randomized. Subjects receiving olanzapine experienced a slightly longer time to discontinuation. Based on this single criterion, olanzapine showed greater effectiveness than the other agents despite its association with significant metabolic disturbance, especially weight gain. Perphenazine unexpectedly showed comparable levels of effectiveness and produced no more extrapyramidal side effects than the other agents. Despite modest prolactin elevation, risperidone was the best‐tolerated medication. Ziprasidone was associated with weight loss and with positive impact on lipids and blood glucose. In Phase 2, clozapine demonstrated better effectiveness compared to other SGAs for subjects who discontinued their Phase 1 medication because of efficacy. Olanzapine and risperidone showed greater effectiveness in the tolerability pathway. CATIE secondary outcomes are currently being examined. Improvements in cognition were modest among all the agents in Phase 1, and perphenazine was no less effective in improving cognitive performance than the SGAs. Cost‐effectiveness analysis revealed a significant advantage for perphenazine, due to the impact of the high‐priced, brand‐name SGAs on overall health care costs.

Haloperidol response and plasma catecholamines and their metabolites

Eleven acutely psychotic patients with schizophrenia or schizoaffective disorder underwent a 5-7 day drug-washout period (with lorazepam allowed) prior to participating in a 6-week controlled dose haloperidol trial. Patients were evaluated longitudinally with clinical ratings and with plasma measures of the catecholamines dopamine (pDA) and norepinephrine (pNE) and their metabolites, homovanillic acid (pHVA) and 3-methoxy-4-hydroxyphenylglycol (pMHPG). All patients exhibited clinical improvement with haloperidol; the decrease in their Brief Psychiatric Rating Scale (BPRS) scores ranged from 32 to 89%. Measures of pHVA increased within the first week of treatment and returned to baseline by week 5. The pattern of change of pDA resembled that of pHVA. The pattern of change of pNE and pMHPG revealed a decrease over the course of treatment. The early increase and the subsequent decrease in pHVA were strongly correlated with improvement in positive symptoms on the BPRS. These data are consistent with previous reports on the change in pHVA and pMHPG during clinical response to haloperidol. The data on change of pDA and pNE further describe the nature of the biochemical response to this drug.

Leukemia in a black child with Bloom's syndrome: somatic recombination as a possible mechanism for neoplasia.

A 5 1/2‐year‐old black child with Blooms syndrome developed acute lymphocytic leukemia (ALL). Blooms syndrome is associated with chromosomal aberrations, and affected individuals have an increased incidence of leukemia and solid tumors. The skin on our patient had adjacent areas of decreased and increased pigmentation similar to the “twin‐spots” seen in Drosophila. “Twin‐spots” are the manifestation of somatic cell DNA recombination and provide evidence that clones of cells in Blooms syndrome have become homozygous for a particular gene. Somatic cell recombination is proposed as a mechanism to explain the increased incidence of neoplasia in Blooms syndrome and supports the hypothesis that cancer may be a recessive disorder at the cellular level.

Longitudinal consent-related abilities among research participants with schizophrenia: Results from the CATIE study

OBJECTIVE Research participants must have adequate consent-related abilities to provide informed consent at the time of study enrollment. We sought to determine if research participants with schizophrenia maintain adequate consent-related abilities during a longitudinal study. If participants lose abilities during a trial they may not be able to judge and protect their interests. If reduced abilities are common or can be predicted, special protections can be targeted appropriately. METHOD We examined longitudinal consent-related abilities of participants in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study using the MacArthur Competence Assessment Tool-Clinical Research (MacCAT-CR) at protocol-specified times over 18 months. RESULTS Of 1158 research participants in this analysis, most (n=650, 56%) had a stable pattern of MacCAT-CR Understanding scores, 235 (20%) improved substantially with no evidence of decline, 273 (24%) had at least one assessment with substantial worsening. During the course of the trial, 43 (4%) fell below the initial threshold for adequate capacity, which was predicted by lower Understanding scores, more severe positive symptoms, and poorer neurocognitive functioning at baseline, and by increases in negative symptoms and deteriorating global status. CONCLUSIONS Most participants in this long-term study had stable or improved consent-related abilities, but almost one-fourth experienced substantial worsening and 4% of participants fell below the studys capacity threshold for enrollment. Clinical investigators should monitor with special care individuals with marginal capacity or higher levels of psychotic symptoms at study entry and those who exhibit clinical worsening during a study.

Initiation of clozapine therapy in a patient with preexisting leukopenia: A discussion of the rationale of current treatment options

Clozapine remains the most effective agent for diminishing or eliminating psychotic symptoms in treatment-resistant patients. However, among such patients, a small percentage (<3.0%) develops clozapine-induced granulocytopenia (CIG). In spite of the fact that lithium and granulocyte colony stimulating factor (G-CSF) have been shown to reverse CIG, many such patients are consigned to treatment with antipsychotic agents that have failed in the past. Apparently, their physicians are not aware that these patients can be salvaged for ongoing clozapine treatment. We report the effectiveness of lithium in reversing CIG in a young man with preexisting mild granulocytopenia. The rapidity of onset of leukocyte depletion is discussed in light of previously hypothesized autoimmune mechanisms of CIG. This case dramatizes the importance of lithium (or G-CSF) augmentation in those patients to maintain clozapine treatment so that their neutropenia can be reversed, and they can continue to benefit from the unique antipsychotic qualities of clozapine.

HISTOCHEMICAL DEMONSTRATION OF 5-NUCLEOTIDASE IN THE CENTRAL NERVOUS SYSTEM. EFFECTS OF MANGANOUS ION AND pH

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Genetics of the Schizophrenias: A Model Accounting for Their Persistence and Myriad Phenotypes

This article addresses the classic enigma about schizophrenia (SZ). The disease occurs with a lifetime prevalence of 1%, 80% of which is attributable to genetic factors. Females with SZ produce 50% as many children as normals, and males with SZ produce 25%. Genetic factors responsible for SZ should behave like lethal genes. Yet the prevalence of SZ remains around 1% throughout the world. How can that be? Additionally, CATIE concluded that the response of each individual with SZ to treatment with antipsychotic agents (effectiveness, side-effect profile, or long-term prognosis) cannot be predicted. Every case seems to be unique. Several recent publications have reported increased frequencies of single-nucleotide polymorphisms (SNPs) and of copy-number variants (CNVs) containing large regions of DNA in patients with SZ. These genetic perturbations often include neurodevelopmental genes. The overwhelming majority of SNPs and CNVs are post-fertilization mutations, occurring in somatic tissue, not germinal tissue. These mutations are a normal aspect of somatic cell division but occur more frequently in patients with SZ. Somatic mutations are not passed on to subsequent generations and therefore cannot account for the inheritance of SZ. Our speculation is that the genetic platform for SZ is the gene or genes that increase the number of de novo mutations in patients with SZ. We argue that balanced polymorphism is the most plausible hypothesis to account for the preservation of non-adaptive genes in nature-and, in particular, in SZ. Maladaptive genes in different combinations can confer increased fitness to the entire population, thus insuring their preservation in the gene pool. Somatic mutations explain both the sporadic occurrence of SZ within families and the wide variations in phenotypic expression of SZ. Increased frequency of somatic mutations may confirm greater overall fitness via balanced polymorphism to explain the maintenance of the SZ gene or genes within the human population.

An RNA polymerase from Drosophila

Abstract RNA polymerase was isolated and partially purified from two types of cells of Drosophila melanogaster. Only one species of polymerase, which appeared to be the same in both cell types, was detected. The enzyme can transcribe, in addition to Drosophila DNA, various other template DNAs, including calf thymus, bacteriophage T4, SV40 virus, and poly(dAT). The RNA molecules produced by the enzyme are small, sedimenting at about the same rate as 4S transfer RNA. The molecular size of the enzyme is about 470,000 daltons. Phosphocellulose chromatography separates the enzyme into two components, both of which are required for full enzymatic activity.

Treatment of Meige's syndrome with ECT.

A 62-year-old woman with Meiges syndrome failed to respond to several pharmacologic interventions. Her dystonias improved significantly after treatment with bilateral electroconvulsive therapy (ECT). However, the effect was not durable, lasting < or = 72 h. ECT is an effective treatment for many movement disorders including dystonias of differing etiologies. Its efficacy for Meiges syndrome is questionable.

A Neuropsychological Perspective on Dual Diagnosis

The purpose of this study was to investigate whether patients experiencing both a major psychiatric disorder and a concurrent substance abuse problem (dual diagnosis) manifest greater neuropsychological dysfunctions than patients experiencing a major psychiatric disorder alone. Differences in diagnostic variability and fluidity between dual diagnosis and non-dual diagnosis patients and the occurrence of polysubstance abuse among the dual diagnosis patients were also investigated. The hypotheses were tested by retrospectively reviewing the psychiatric records of 50 dual diagnosis patients and comparing them to 36 chronically hospitalized non-dual diagnosis psychiatric patients. Results revealed that dual diagnosis patients manifested significantly greater neuropsychological impairments than non-dual diagnosis patients and that dual diagnosis patients showed a greater range of diagnoses and diagnostic fluidity than non-dual diagnosis patients. Results also revealed that over one-half of the dual diagnosis patients abused a variety of different substances. An etiological role of neuropsychological dysfunction in the development of the dual diagnosis syndrome in at least a subgroup of dual diagnosis patients is suggested. More specifically, it is suggested that the neuropsychological dysfunctional pattern that is described may represent an organic substrate of a nonspecific vulnerability to developing both (atypical) psychoses and (poly) substance abuse.