A comparison of the effect of clozapine with typical neuroleptics on cognitive function in neuroleptic-responsive schizophrenia

Clozapine has been reported to improve selected aspects of cognitive function in neuroleptic-resistant schizophrenia. In this study, we report the first direct comparison of the effect of clozapine and typical neuroleptic drugs on cognitive function in neuroleptic-responsive schizophrenia. Sixty-four patients with recent onset, neuroleptic-responsive schizophrenia or schizoaffective disorder were randomly assigned to either clozapine (n = 35) or typical neuroleptics (n = 29) and followed for 12 months. They were administered a comprehensive cognitive test battery at baseline and at 6 weeks, 6 months and 12 months after initiating drug treatment. Treatment with clozapine improved psychomotor speed and attention [Digit Symbol Substitution Test (DSST)] and verbal fluency [Category Instance Generation and Controlled Word Association Test (CWAT)] at 6 weeks. The improvement in these measures was maintained throughout the 12-month period. Treatment with typical neuroleptics produced no sustained improvement in any cognitive measure, except for a tendency to improve delayed recall memory (Verbal List Learning Test). The improvement in the DSST and CWAT was significantly greater with clozapine treatment compared to that with typical neuroleptics. These improvements were not related to improvement in psychopathology. These results suggest that clozapine is superior to typical neuroleptics in improving specific types of cognitive function in recent onset, neuroleptic-responsive schizophrenia.     

Reactive astrocytes express p53 in the spinal cord of transgenic mice expressing a human Cu/Zn SOD mutation

In a previous study, we reported increased NOS expression in the astrocytes in the spinal cord of SOD mutant transgenic mice that are used as ALS animal model. Recently, Messmer and Brune suggested that nitric oxide-induced apoptosis is intimately related with p53-dependent signaling pathway, and de la Monte et al. reported increased p53-immunoreactivity in the spinal cord of ALS patients. In the present study, we performed immunocytochemical studies to investigate the changes of p53-immunoreactivity in the brains of the mutant transgenic mice expressing a human Cu/Zn SOD mutation. Immunocytochemistry showed intensely stained p53-IR glial cells with the appearance of astrocytes in all levels of the spinal cord of the mutant transgenic mice, but no p53-IR glial cells were observed in the spinal cord of the control mice. P53-IR astrocytes were also detected in the brain stem of the mutant transgenic mice. In the medulla, they were observed in the medullary reticular formation, hypoglossal nucleus, vestibular nucleus, dorsal motor nucleus of the vagus and nucleus ambiguus. In the pons, their presences were noted in the pontine reticular formation, and trigeminal and facial nuclei. In the midbrain, astrocytes were detected in the mesencephalic reticular formation, red nucleus and periaqueductal gray matter. In the cerebellum, intensely stained p53-IR astrocytes were detected in the intracerebellar nuclei. In contrast to the mutant transgenic mice, no p53-IR astrocytes were detected in the brain stem and spinal cord of the control mice. Further multidisciplinary investigations involving p53-mediated cellular damage and pathogenesis of ALS are needed to clarify the importance of these results.     

Hemiballismus-hemichorea in older diabetic women: a clinical syndrome with MRI correlation

Eight older women from two different continents, all with nonketotic hyperglycemia, presented with hemiballismus-hemichorea (HB-HC) and high signal intensity in the contralateral striatum on T1-weighted MRI scans. Correction of underlying hyperglycemia and supportive care resulted in resolution within days to weeks. This characteristic clinicoradiologic picture suggests a clinical syndrome with benign outcome.     

The expression of alpha-, beta-, and gamma-synucleins in olfactory mucosa from patients with and without neurodegenerative diseases

A family of homologous proteins known as alpha-, beta-, and gamma-synuclein are abundantly expressed in brain, especially in the presynaptic terminal of neurons. Although the precise function of these proteins remains unknown, alpha-synuclein has been implicated in synaptic plasticity associated with avian song learning as well as in the pathogenesis of Parkinson's disease (PD), dementia with LBs (DLB), some forms of Alzheimer's disease (AD), and multiple system atrophy (MSA). Since olfactory dysfunction is a common feature of these disorders and the olfactory receptor neurons (ORNs) of the olfactory epithelium (OE) regenerate throughout the lifespan, we used antibodies specific for alpha-, beta-, and gamma-synucleins to examine the olfactory mucosa of patients with PD, DLB, AD, MSA, and controls without a neurological disorder. Although antibodies to alpha- and beta-synucleins detected abnormal dystrophic neurites in the OE of patients with neurodegenerative disorders, similar pathology was also seen in the OE of controls. More significantly, we show here for the first time that alpha-, beta-, and gamma-synucleins are differentially expressed in cells of the OE and respiratory epithelium and that alpha-synuclein is the most abundant synuclein in the olfactory mucosa, where it is prominently expressed in ORNs. Moreover, alpha- and gamma-synucleins also were prominent in the OE basal cells, which include the progenitor cells of the ORNs in the OE. Thus, our data on synuclein expression within the OE may signify that synuclein plays a role in the regeneration and plasticity of ORNs in the adult human OE.     

Physics and the quandaries of contemporary psychiatry: review and research

Although in physics, quantum mechanical principles have long replaced Newtonian ones, we continue to apply the latter in models of the mind and its diseases. This article discusses the possible theoretical application of quantum principles to mind-brain function. Empirically, this study tested which of these principles practicing psychiatrists found more applicable in clinical practice. Psychiatrists (N = 382) at universities around the United States were asked to answer a questionnaire that contained clinical scenarios reflecting mental, interpersonal, or therapeutic processes corresponding to quantum or classical physical principles. Respondents (N = 191) were significantly more likely to rate scenarios reflecting quantum principles as being consistent with their experience than they were those reflecting classical principles (p < .0005). This effect was significantly greater in more experienced psychiatrists. Quantum physics, a powerful tool in understanding properties of both micro- and macro-level phenomena, may have implications at the human level, invoking the roles of observer, interpersonal relationships, and resources such as resiliency and creativity.     

Autism and Congenital Blindness

The nature of autism in congenitally blind children has long been a source of interest and perplexity. A group of nine congenitally blind children with an autism-like syndrome were closely matched on chronological age and verbal mental age with nine sighted autistic children, and were compared on the Childhood Autism Rating Scale (Schopler, Reichler, & Renner, 1986) and the Behavior Checklist for Disordered Preschoolers, together with the Play Items for Disordered Preschoolers (Sherman, Shapiro, & Glassman, 1983). A checklist of clinical features characteristic of autism (derived from DSM-III-R) was also completed through an interview with teachers. There was substantial similarity between the groups, but also suggestive evidence of possible group differences, specifically in the domain of social-emotional responsiveness. Research on the psychological development of congenitally blind children promises to yield insights into the nature of autism itself.     

Spontaneous oscillations of cerebral blood flow velocity in the middle cerebral arteries of normal subjects and schizophrenic patients

Although many regional cerebral blood flow (rCBF) studies of schizophrenic patients have been carried out, only a few studies have investigated real-time hemodynamic changes in schizophrenic patients. In the present study, we used long-term monitoring of the middle cerebral artery (MCA) by non-invasive transcranial Doppler ultrasonography to obtain real-time CBF data in 55 schizophrenic patients and 20 normal comparison subjects. The mean blood flow velocity and pulsatility index (PI) of the MCA were not constant during long-term monitoring. They showed sinusoidal oscillations similar to those described in previous reports. The amplitude variations of these oscillations in both drug-naive and medicated schizophrenic patients were significantly decreased compared with findings in normal control subjects. The averaged PI values were found to be decreased in patients with illness durations of more than 10 years. After withdrawal of antipsychotic medication, both the amplitude variations of oscillations and the PI values in the drug-withdrawn patients were significantly decreased relative to findings in normal control subjects. Our results show a decreased adjustment ability of cerebral vessel resistance not only in neuroleptic-naive schizophrenic patients but also in patients with longer illness duration. Neuroleptics could affect the adjustment ability of vessel resistance.     

Regulation of striatal dopamine release through 5-HT1 and 5-HT2 receptors

Dopamine (DA) release in the striatum is regulated by 5-hydroxytryptamine (5-HT, serotonin) through putative heteroreceptors. However, the effect of 5-HT is controversial. The present study investigated the effects of different 5-HT receptor ligands on DA release in the rat striatum by using in vivo microdialysis in conscious and freely moving rats. Perfusion with 5-carboxamidotryptamine, anpirtoline, pindobind-5-HT1A, and isamoltane demonstrated the involvement of 5-HT1A and 5-HT1B receptors in facilitating DA release. In contrast, 5-HT2 receptors mediated inhibition of DA efflux, as shown by experiments with DOI [R-(-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] and ketanserin. A 5-HT3 agonist (1-(m-chlorophenyl)-biguanide hydrochloride) did not have any effect. None of the agonists used affected DA uptake into striatal synaptosomes. Unilateral 6-hydroxydopamine lesioning of the nigrostriatal DA pathway led to a selective decrease in 5-HT2 receptors. It is concluded that there are 5-HT2 heteroreceptors at the dopaminergic terminals that mediate inhibition of DA release. Further investigation is required to clarify the localization of the 5-HT1 receptors in the striatum.     

Increased expression of prion protein is associated with changes in dopamine metabolism and MAO activity in PC12 cells

Prion diseases of humans and animals occur following infection with infectious agents containing PrP(Sc) or in situations in which there is a mutation of the prion protein (PrP) gene. The cellular prion protein (PrP(C)) is a sialoglycoprotein that is expressed predominantly in neurons. PrP(C) is converted into a pathogenic form of PrP (PrP(Sc)), which is distinguishable from PrP(C) by its relative resistance to protease digestion. A number of postulates have been advanced for the function of normal PrP (PrP(C)), but this issue has not been resolved. To investigate the function(s) of PrP(C), we established clonal PC12 cell lines, which have elevated PrP(C) expression. The results show that there were alterations in dopamine metabolism and in monoamine oxidase (MAO) activity in transfected PC12 cells that overexpress PrP(C). There was an increase in concentration of DOPAC, a metabolite of dopamine, and in MAO activity in cells overexpressing PrP(C). MAO is involved in oxidative degradation of dopamine (DA). Our data suggest that PrP(C) plays a role in DA metabolism by regulating MAO activity.