Risperidone: an analysis of the first three years in general use.

Since the introduction in 1993 of the novel serotonin-dopamine antagonist antipsychotic risperidone, over 12 million patient-months of exposure to the drug have been accumulated. Further studies have confirmed the efficacy of risperidone across a broad range of patients with schizophrenia who were not represented in the two pivotal clinical trials. Two studies confirm the efficacy of risperidone in first-episode schizophrenia and subanalyses of these studies suggest that the dose in these patients should be lower than in patients with chronic schizophrenia. In addition, a prospective comparison with risperidone and clozapine and a subanalysis of the North American Trial of risperidone show that risperidone is effective in treatment-resistant schizophrenia. The efficacy of risperidone against negative symptoms has been confirmed by a meta-analysis of seven clinical trials comparing risperidone with active control medication, and by further analyses of the North American Trial (analysis of covariance and path analysis). A long-term open study of risperidone has shown that the benefits of the drug extend well beyond the 8 weeks of the double-blind trials, and the low liability of risperidone for extrapyramidal side effects suggests that patients will be more likely to be compliant with risperidone treatment than with conventional neuroleptic treatment. Relapse rates can therefore be expected to be lower. Evidence from over 1100 patients, 503 of whom had taken risperidone for at least 1 year, suggests that the annual incidence of tardive dyskinesia in patients taking risperidone (7.6-9.4 mg/day) is 0.3%, compared to an annual incidence in patients taking conventional neuroleptics of 5-10%. Studies also suggest that risperidone reduces the number of days that patients with chronic schizophrenia spend as inpatients. It is concluded that mental health-care workers will need to raise their expectations about the treatment outcome of schizophrenia as a result of the introduction of risperidone.

Alzheimer beta/A4 amyloid precursor protein in human brain: aging-associated increases in holoprotein and in a proteolytic fragment.

Alzheimer beta/A4 amyloid precursor protein (APP) has been suggested to play a central role in the pathogenesis of Alzheimer disease. We have measured the content of different species of APP holoprotein and carboxyl-terminal fragments in human brains from young individuals, nondemented aged individuals, and aged individuals with Alzheimer disease. By using an antibody directed against the cytoplasmic domain of APP, five species were resolved. Three of these, of molecular masses 106, 113, and 133 kDa, represent presumptive immature and mature isoforms of APP holoprotein. Two smaller proteins, of molecular masses 15 and 19 kDa, represent presumptive proteolytic carboxyl-terminal fragments of APP. The 133-, 113-, 106-, and 15-kDa species were found in both grey and white matter, whereas the 19-kDa species was found only in grey matter. Total APP immunoreactivity (sum of all five species) and the levels of the 113-, 106-, and 15-kDa species were not significantly different in brain samples from young individuals, nondemented aged individuals, and aged individuals with Alzheimer disease. In contrast, the levels of the 133- and 19-kDa species increased 2- to 3-fold with age. A correlation was observed between the levels of the 133- and 19-kDa species, suggesting a possible precursor-product relationship. The size of the 19-kDa fragment indicated that it might have an intact beta/A4 domain and therefore be amyloidogenic. The age-dependent increase either in a mature APP isoform and/or in a putative amyloidogenic fragment could explain why Alzheimer disease is associated with advanced age.

An analysis of synapsin II, a neuronal phosphoprotein, in postmortem brain tissue from alcoholic and neuropsychiatrically ill adults and medically ill children and young adults.

Synapsin II (formerly known as protein III) is a synaptic vesicle-associated neuronal phosphoprotein that may be involved in the regulation of neurotransmitter release. Synapsin II was studied in postmortem brain samples from 132 individuals with various neuropsychiatric and medical diagnoses. Molecular weight variants of synapsin II were present in 73% of samples from alcoholic individuals but in only 31% of samples from non-diseased individuals, thus confirming our two previous reports of an association between synapsin II variants and alcoholism. The presence of synapsin II variants was not correlated with age or nutritional state. Synapsin II variants were also present in 56% of samples from individuals with schizophrenia and 41% of samples from individuals with Huntington's disease. Synapsin II variants were present in samples from children and young adults, consistent with the possibility that synapsin II variants may reflect a genetically inherited trait. Synapsin II variants were not found in any of 18 rodent models of alcoholism, aging, or vitamin B deficiency, suggesting that synapsin II variants may be a uniquely human trait.

General assay for phosphoproteins in cerebrospinal fluid: a candidate marker for paraneoplastic cerebellar degeneration.

The components of protein phosphorylation systems (protein kinases, protein phosphatases, and their phosphoprotein substrates) are highly enriched in neuronal cells compared with other cell types. We exploited this relative neuronal enrichment of protein phosphorylation system components to develop a general assay technique for putative protein kinase substrates (phosphoproteins) in human cerebrospinal fluid. Using this cerebrospinal fluid phosphoprotein assay, we have detected a putative protein kinase C substrate protein of apparent Mr 60 kd in 6 of 14 patients with paraneoplastic cerebellar degeneration but not in any of 55 patients with a variety of other neurological diseases. Phosphoproteins in cerebrospinal fluid may provide novel and unique markers for the diagnosis or staging of neuronal diseases as well as offer potential insights into the biochemical characterization of affected neuronal populations.

Chronic treatment of rats with SCH-23390 or raclopride does not affect the concentrations of DARPP-32 or its mRNA in dopamine-innervated brain regions.

DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein, Mr = 32,000, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis) is a neuronal phosphoprotein that is enriched in neurons which possess dopamine D1 receptors, particularly striatonigral neurons. In rat brain slices, the phosphorylation state of DARPP-32 is regulated by dopamine, acting through the dopamine D1 receptor and the adenylyl cyclase system. This study reports that chronic blockade (21 days) of either dopamine D1 receptors by SCH-23390 or dopamine D2 receptors by raclopride does not affect the concentrations of DARPP-32 in specific rat brain regions (striatum, thalamus, hippocampus, frontal cerebral cortical pole). Northern blot analysis indicates that the steady-state level of DARPP-32 mRNA in striatum is also unchanged by these treatments.

An analysis of postmortem brain samples from 32 alcoholic and nonalcoholic individuals for protein III, a neuronal phosphoprotein.

Protein phosphorylation is a primary mechanism of intracellular signal transduction, and abnormalities in protein phosphorylation have been implicated in the pathogenesis of several specific diseases. Protein III is a neuronal phosphoprotein that is associated with synaptic vesicles and is probably involved in the regulation of neurotransmitter release. Analysis of 32 postmortem brains has confirmed our previous report that variant forms of protein III with higher apparent molecular weights are found frequently in the brains of alcoholic individuals but rarely in the brains of nonalcoholic individuals who did not suffer from any other medical or neuropsychiatric disorders. Eight of 14 (57%) brain samples from alcoholic individuals and four of eight (50%) brain samples from suspected alcoholic individuals had variant forms, while none of 10 samples from nonalcoholic individuals had variant forms. Previous data indicate that variant forms of protein III are also associated with other neurodegenerative conditions, including various dementias, and, possibly, normal aging.

Induction of seizures in mice by intracerebroventricular administration of the calcium channel agonist BAY k 8644.

The calcium channel agonist BAY k 8644 was used to investigate the role of the calcium ion (Ca2+) in epileptogenesis. Intracerebroventricular administration of the compound induced murine seizures that were reversed by calcium channel inhibitors (CCIs) but not by anticonvulsants such as carbamazepine, pentobarbital, and diazepam. The seizures were exacerbated by phenytoin and valproic acid. Chronic administration of CCI's, previously shown to produce down-regulation of the binding of the CCI [3H]nitrendipine, resulted in augmentation of BAY k 8644-induced seizures.

Diltiazem or verapamil prevents haloperidol-induced apomorphine supersensitivity in mice.

Chronic thioridazine treatment in animals has been reported to produce less dopaminergic supersensitivity than other neuroleptics. This difference may be due to the potent calcium channel inhibitory effect of thioridazine. To test this hypothesis Swiss-Webster mice were treated chronically (28 d) with calcium channel inhibitors (CCI's) - diltiazem, nifedipine or verapamil - with or without haloperidol. Following three days of drug withdrawal, mice were tested for amphetamine-induced locomotion and apomorphine-induced cage climbing. Co-administration of diltiazem or verapamil (but not nifedipine) prevented the development of haloperidol-induced behavioral supersensitivity to apomorphine. Co-administration of CCI's with haloperidol did not affect the development of amphetamine supersensitivity. These data support the hypothesis that co-administration of haloperidol and a CCI (verapamil or diltiazem, but not nifedipine) would mimic the effects of thioridazine treatment alone.

Nifedipine and flunarizine block amphetamine-induced behavioral stimulation in mice.

Sixteen calcium channel inhibitors (CCI's) were tested in a model utilizing amphetamine-induced behavioral stimulation in mice. Nifedipine, flunarizine and possibly PY 108-068 were effective in blocking amphetamine-induced locomotor stimulation. Verapamil, diltiazem and many other CCI's were ineffective in this experimental paradigm.

Evidence for down-regulation of 3H-nitrendipine recognition sites in mouse brain after long-term treatment with nifedipine or verapamil.

Mice were fed powdered food which contained nifedipine, verapamil or diltiazem for 28 days. Long lasting treatment with nifedipine (0.28 mg/g b.w./day) or verapamil (0.27 mg/g b.w./day), but not with diltiazem (0.38 mg/g b.w./day) reduced the number of 3H-nitrendipine recognition sites in membranes prepared from cerebral cortex, caudate nucleus, and hippocampus. In addition, the veratridine-elicited stimulation of 45Ca-uptake in slices of the same brain areas was decreased in mice which were fed nifedipine or verapamil for 28 days.

Differences between calcium channel inhibitors in their effects on phencyclidine-induced behavioral stimulation in mice.

Sixteen calcium channel inhibitors (CCI's) were tested in a model utilizing phencyclidine (PCP)-induced behavioral stimulation in mice. There were marked differences in the effects of CCI's both within subclasses and between subclasses of CCI's. All of the dihydropyridines and possibly flunarizine were effective in blocking PCP-induced behavioral stimulation. Papaverine derivatives, including verapamil, and several other CCI's, were ineffective.