Effective adjunctive use of pergolide with quetiapine for cognitive impairment and negative symptoms in schizophrenia.
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Biomedical subjects
Publications and source records attributed to Nori Takei.
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Several lines of evidence suggest that increased generation of auto-oxidized dopamine (DA) o-quinone is associated with the neurotoxicity of methamphetamine (MAP) in the brain, and that, as a cellular defenses against DA-derived quinines, glutathione S-transferase (GST) detoxifies auto-oxidized DA o-quinone in the brain. Glutathione S-transferase M1 (GSTM1) of the mu-class of GSTs catalyzes reaction between glutathione and catecholamine o-quinones under physiological conditions. This study was undertaken to investigate the role of the GSTM1 gene deletion polymorphism in the neuropathology of MAP abuse. One hundred fifty-seven MAP abusers and 200 healthy comparison subjects were tested for a genetic polymorphism of GSTM1. The difference in the frequency of deletion (D)/non-deletion (N) alleles between the female abusers and female controls was close to statistical significance (P = 0.071), although there was no statistical difference (P = 0.651) between male abusers and male controls. Furthermore, the number of female abusers with deletion alleles was significantly (P = 0.007, odds ratio: 2.77, 95% CI 1.30-5.89) higher than that of male abusers with deletion alleles. These findings suggest that GSTM1 gene deletion may contribute to a vulnerability to MAP abuse in female subjects, but not in male subjects.
Milnacipran, one of the serotonin noradrenaline reuptake inhibitors (SNRIs) to which venlafaxine and duloxetine belong, is a new antidepressant that has recently become available in many countries. Despite the advances in pharmacotherapy, almost one third of patients with depressive illness respond inadequately to monotherapy with such an antidepressant. We herein describe five patients with major depression who responded partially, but not fully, to milnacipran alone and remarkably improved with an adjunct of risperidone. In addition, milnacipran plus risperidone was found to be a useful augmentation for treatment-refractory depression in 3 of the 5 patients. The minimum dose of risperidone, 0.5 or 1 mg/d, was efficacious. The time of response after addition of risperidone was within 4 d. Our experience suggests that an augmentation therapy of milnacipran plus risperidone is useful for treating patients with depression who only partially respond to various types of antidepressants and for treatment-refractory depression.
Long-term toluene abuse causes a variety of psychiatric symptoms. However, little is known about abnormalities at the neurochemical level in the living human brain after long-term exposure to toluene. To detect neurochemical changes in the basal ganglia of subjects with a history of long-term toluene use, proton magnetic resonance spectroscopy (1H MRS) was performed in 12 abstinent toluene users and 13 healthy comparisons with no history of drug abuse. N-acetylaspartate (NAA), creatine plus phosphocreatine (Cr + PCr), choline-containing compounds (Cho), and myo-inositol (MI) levels were measured in the left and right basal ganglia. The Cho/Cr + PCr ratio, a marker of membrane metabolism, was significantly increased in the basal ganglia of toluene users in comparison to that of the control subjects. Furthermore, the increase in the Cho/Cr + PCr ratio was significantly correlated with the severity of residual psychiatric symptoms. These findings suggest that long-term toluene use causes membrane disturbance in the basal ganglia, which is associated with residual psychiatric symptoms that persist even after long-term abstinence from toluene use.
BACKGROUND: The need to achieve is common to all societies, and failure to do so may have a highly detrimental psychological impact. For those on the margins of mainstream society, especially migrants or descendants of migrants, the impact of failed or poor achievements may increase their vulnerability to mental illness. AIMS: In a prospective study of schizophrenia in three ethnic groups (White, Indian and African-Caribbean) we studied the impact of goal striving and investigated whether the gap between the poor achievement and the high aspirations of members of some minority ethnic groups was potentially a factor contributing to the development of the illness. METHODS: The patients and age- and sex-matched controls from their respective communities were asked to rate their perceived current levels of achievement and their past and future expectations in five domains--social standing, housing, education, employment and financial status on a 10-point scale. RESULTS: The control subjects from the three ethnic groups scored similarly in most areas, supporting the validity of inter-ethnic comparisons. The gap between achievement and expectations did not appear to cause high disappointment levels in any group, and in fact only in the domain of housing did the African-Caribbean patients assess their current achievement as being significantly lower than that of their matched controls. CONCLUSIONS: Poor housing conditions may be one of the risk factors contributing to the high incidence of schizophrenia in African-Caribbeans.
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Basic fibroblast growth factor (bFGF) is a multifunctional growth factor that has been implicated in a variety of neurodevelopmental processes. The aim of the present study was to examine whether bFGF contributes to the pathophysiology of schizophrenia. Serum bFGF levels in 40 patients with schizophrenia (15 drug-naive and 25 medicated patients) and in 40 age- and sex-matched healthy normal controls were measured. Serum bFGF levels were significantly higher in the medicated patients than in the normal controls. Analysis of partial correlation coefficients showed that the increased bFGF levels might not be attributable to antipsychotic medication. Although there was no significant overall difference in bFGF levels between drug-naive patients and normal controls, the bFGF levels in these patients significantly correlated with the severity of negative symptoms. Furthermore, we found a significant negative correlation between serum bFGF levels and the age of onset in the entire patient group. Our finding of elevated bFGF levels in the serum of patients with schizophrenia, especially in earlier age-of-onset cases considered to have more neurodevelopmental insults, suggests that bFGF abnormalities may be involved in the pathophysiology of schizophrenia.
Autistic disorder is associated with deficits in social function. The disorder may be related to dysfunction in the brain regions that are involved in the process of recognising facial expressions of other persons. Using fMRI, we investigated whether autistic patients with relatively high IQ would have different brain activation on the tasks of recognition of facial expressions (i.e. faces expressing disgust, fear, and happiness) compared with normal control subjects. In disgust and fear recognition tasks, there were different patterns of brain activation in the cortico-limbic neural circuits qbetween autistic and normal groups. Patients with autistic disorder may have difficulty in grasping facially expressed qemotions in others, and thereby cannot manipulate the interpersonally derived information.
Schizophrenic patients with an onset before age 16 years (early-onset schizophrenia, EOS) would be a rare but attractive subpopulation for genetic studies. This study explored the relationship between the polymorphism of four dopamine-regulating-enzymes (tyrosine hydroxylase, dopamine-beta-hydroxylase, catechol-O-methyltransferase, monoamine oxidase-A) genes, four dopamine-receptors (dopamine D1, D2, D3, D4 receptors) genes and susceptibility to EOS in a Japanese sample. Subjects comprised 51 Japanese patients who met DSM-IV criteria for schizophrenia with an onset before age 16 (by age 15) and 148 Japanese healthy controls. DNA was extracted from whole blood and genotyping was carried out by PCR-RELP using each restriction endonuclease. No significant difference was found in the allele frequencies or genotype distributions of any of the eight genes examined between EOS and the control groups. We did not find the relationship between the polymorphism of eight dopamine-related genes and susceptibility to EOS in a Japanese sample.
In this study, we examined the effect of the s.c. administration of (+/-) 3,4-methylenedioxymethamphetamine (MDMA) or saline on locomotor activity and Fos expression following the bilateral destruction of hippocampal dentate granule cells by colchicine in rats. The lesioned animals, when administered s.c. saline, showed a significantly greater increase in locomotor activity compared to the intact animals, and revealed a marginally significant level of increased locomotor activity compared to the sham-lesioned animals. In addition, when the lesioned animals were given s.c. saline or MDMA, there was a significant increase in Fos expression in the nucleus accumbens core, but not in the medial prefrontal cortex, dorsolateral prefrontal cortex, anterior cingulate cortex, piriform cortex, dorsal striatum, or nucleus accumbens shell, compared to the intact and sham-lesioned animals. Overall, these results suggest that the nucleus accumbens core may be involved in the enhancement of locomotor activity induced by the injection of saline alone (stress loading) or MDMA following bilateral destruction of hippocampal dentate granule cells by colchicine.
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OBJECTIVE: The authors examined dopamine transporter density in the orbitofrontal cortex, dorsolateral prefrontal cortex, and amygdala in methamphetamine users and assessed the relationship of these measures to the subjects' clinical characteristics. METHOD: Positron emission tomography with [(11)C]WIN 35,428 was used to examine the regions of interest in 11 methamphetamine users and nine healthy comparison subjects. Psychiatric symptoms were evaluated with the Brief Psychiatric Rating Scale. RESULTS: Dopamine transporter density in the three regions studied was significantly lower in the methamphetamine users than in the comparison subjects. The lower dopamine transporter density in the orbitofrontal and dorsolateral prefrontal cortex was significantly correlated with the duration of methamphetamine use and the severity of psychiatric symptoms. CONCLUSIONS: Chronic methamphetamine use may cause dopamine transporter reduction in the orbitofrontal cortex, dorsolateral prefrontal cortex, and amygdala in the brain. Psychiatric symptoms in methamphetamine users may be attributable to the decrease in dopamine transporter density in the orbitofrontal cortex and the dorsolateral prefrontal cortex.
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We investigated, using proton magnetic resonance spectroscopy (1H-MRS), whether the tardive dyskinesia (TD) often seen in schizophrenic patients is associated with cellular abnormalities in the basal ganglia system. The subjects in this study included schizophrenic patients with TD (TD group, n=7), schizophrenic patients without TD (non-TD group, n=7), and healthy volunteers (N group, n=7). We examined the 1H-MRS peaks of N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) in the regions of the left and right lenticular nucleus. In the left lenticular nucleus, the Cho/Cr ratio was significantly greater in the TD and non-TD groups than in the N group (Mann-Whitney U test; p<0.007 and p<0.006, respectively). Further, a significant linear trend was observed in the means of the ratio across the three groups (p<0.005); the TD group was the highest, the N group the lowest, and the non-TD group intermediate. No significant difference in the NAA/Cr ratio was found among groups. These results indicate that neural abnormalities in the basal ganglia may be linked with the neuroleptic medications and the process of the fundamental illness per se, and that more excessive damage to this neural substrate may lead to development of TD. However, as this is a preliminary study, further studies with a large number of subjects are required to verify our findings.