Less is more Redux: Scheduled intermittent dosing to protect/prevent cognitive deterioration in schizophrenia.

We propose a strategy of scheduled intermittent dosing in place of daily administration of antipsychotic medications for the treatment of patients with schizophrenia. Intermittent (extended) dosing has already been demonstrated to be at least equally effective as daily administration of antipsychotic medications. It is increasingly appreciated that remission of positive symptoms is not the same as recovery: a resumption of a productive and socially gratifying life. Our field has focused on positive symptoms to the exclusion of cognitive deterioration and emotional blunting. Dopamine is the primary neurotransmitter responsible for the accumulation and processing of new information as well as the expression of emotions modulated via the nucleus accumbens. Data suggests that patients receiving less accumulated antipsychotic agents do better over the years in achieving meaningful recoveries. In addition to clinical improvement, there is the financial benefit in giving less medication, which is often costly, over several decades. Finally, there is the possibility, albeit not yet demonstrated, that less accumulated antipsychotic agents might reduce the occurrence of significant weight gain, the metabolic syndrome, with its accompanying medical complications which not only impacts the quality of life and life expectancy of those who suffer from it, but also increases the financial burden to society.

Impaired motor performance in adolescents at familial high-risk for schizophrenia.

BACKGROUND: The Harvard Adolescent Family High Risk (FHR) Study examined multiple domains of function in young relatives of individuals diagnosed with schizophrenia to identify precursors of the illness. One such area is motor performance, which is deviant in people with schizophrenia and in children at risk for schizophrenia, usually offspring. The present study assessed accuracy of motor performance and degree of lateralization in FHR adolescents and young adults. METHODS: Subjects were 33 non-psychotic, first-degree relatives of individuals diagnosed with schizophrenia, and 30 non-psychotic comparison subjects (NpC), ranging in age from 13 to 25 who were compared using a line-drawing task. RESULTS: FHR individuals exhibited less precise and coordinated line drawing but greater degree of lateralization than controls. Performance on the linedrawing task was correlated with degree of genetic loading, a possible predictor of higher risk for schizophrenia in the pedigree. CONCLUSIONS: The observation of increased motor deviance and increased lateralization in FHR can be utilized in identification and initiation of the treatment in those at high risk in order to prevent or delay the full manifestation of this devastating condition. The use of a rigorously quantified measure is likely to add to the sensitivity of measuring motor performance, especially when impairments may be subtle.

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.

Treatment of Meige's syndrome with ECT.

A 62-year-old woman with Meige's 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 Meige's syndrome is questionable.

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.

MAO inhibition and clinical response in depressed patients treated with phenelzine.

The authors studied clinical response in 47 depressed inpatients treated with the monoamine oxidase (MAO) inhibitor phenelzine. Improvement on ratings for depression at Week 2 of treatment was correlated with percent MAO inhibition at Week 2 (r = .35, p less than .03), and the modest positive correlation that was found remained after the authors adjusted for the effects of baseline scores on the Hamilton Rating Scale for Depression, dose (mg/kg), and psychosis (partial correlation = .49, p less than .002). Further, the 23 patients ultimately classified as responders had a significantly greater percent MAO inhibition at Week 2 than did the 24 nonresponders (t = 3.02, p less than .005). Thus, the rate of MAO inhibition at Week 2 was significantly correlated with clinical improvement at Week 2 and final response status. These findings could not be explained by other potentially moderating variables such as sex, age, endogenicity, recurrence, and incapacitation.

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

A 5 1/2-year-old child with Bloom's syndrome developed acute lymphocytic leukemia (ALL). Bloom's 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 Bloom's syndrome have become homozygous for a particular gene. Somatic cell recombination is proposed as a mechanism to explain the increased incidence of neoplasia in Bloom's syndrome and supports the hypothesis that cancer may be a recessive disorder at the cellular level.

Nuclear nonhistone proteins in murine melanoma cells: II. changes following exposure to MSH.

Murine melanoma cells provide an excellent system for studying the proposed role of nuclear nonhistone proteins (NHP's) as regulators of gene expression. Cloudman mouse melanoma cells (S91, NCTC 3960, CCL 53), grown in culture, are normally lightly pigmented, but in the presence of melanocyte stimulating hormone (MSH) show a large increase in melanin content. Cells were grown in medium with and withoug MSH and labeled with either 14C- or 3H-leucine, respectively. Following 48 hr of incubation, the cells were harvested, combined, and nuclei isolated. The NHPs were extracted from these nuclei in a series of steps which yielded 4 major fractions. Each fraction was further separated on DEAE cellulose columns into a total of 40 subfractions, each of which was electrophoresed on SDS gels. Each gel was sliced and counted and the 14C/3H ratio was determined for each slice. A number of differences in 14C/3H ratios were observed between the NHPs isolated from MSH-treated and control cells which reflect changes in the synthesis and/or transport of NHPs in MSH-treated cells.

Nuclear nonhistone proteins in murine melanoma cells. I. Quantitative isolation and fractionation.

Nuclear nonhistone proteins (NHP's) have been implicated as regulatory agents involved in controlling genetic expression. Utilizing murine melanoma cells, we describe a method for isolating and fractionating NHP's which greatly increases the yield of these proteins as well as the level of resolution required for detecting small differences in particular NHP's. Mouse melanoma cells were grown in medium labeled with [(3)H]leucine. Following 48 hr of incubation, the cells were harvested and nuclei isolated. The NHP's were extracted from the nuclei in a series of steps which yielded four major fractions: NHP(1), NHP(2), NHP(3), NHP(4). This method solubilized 80-90% of the protein from the nuclear homogenate. The NHP fractions were then separated on DEAE-cellulose columns in a series of salt steps increasing in concentration from 0.05 to 0.50 M NaCl, followed by steps of 2 M NaCl and 4 and 7 M guanidine-hydrochloride. The 40 NHP fractions eluted from these columns were further separated on polyacrylamide-SDS gels and ranged in molecular weight from 9000 to 110,000 daltons. Differences were observed in the electrophoretic pattern of each of these 40 fractions. The high resolution of these fractionation procedures greatly enhances the possibility of observing small changes in proteins which may play a role in gene regulation.

Drosophila polyribosomes. The characterization of two populations by cell fractionation and isotopic labeling with nucleic acid and protein precursors.

Two populations of polyribosomes have been isolated from third instar larvae of D. melanogaster. One population appeared to be soluble while the second seemed membrane-bound. Short-term labeling of the two RNP fractions with radioactive nucleic acid and protein precursors was achieved by using a feeding stimulant. RNA was extracted from both polyribosomal fractions following 25, 40, and 60 min of in vivo uridine-(3)H incorporation. Soluble polyribosomes exhibited more rapid uptake of uridine into ribosomal and heterogeneous RNA fractions than did membrane-bound polyribosomes at comparable time periods. In vivo amino acid incorporation into the two polyribosomal populations was examined after 10, 20, 40, 60, and 80 min of incubation in leucine-(3)H. In this case, the membrane-bound polyribosomes reached a higher specific activity than did the soluble ones. These functional differences confirmed the observation, based on cellular fractionation studies, that the two classes of polyribosomes represented functionally distinct populations. These data have been compared with those from studies on other metazoan systems. In addition, dithiothreitol has been demonstrated to be a powerful ribonuclease inhibitor.