Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuroleptics were the first modern class of pharmacotherapeutic agents available for the treatment of schizophrenia. Although they were effective in reducing florid psychotic symptoms, up to 90% of treated individuals subsequently developed extrapyramidal symptoms (EPS) (akathisia, dystonia, or parkinsonism), and about 20% developed tardive dyskinesia (TD). When clozapine became commercially available for treatment-resistant and treatment-intolerant (i.e., prone to EPS and TD) schizophrenic individuals, it became apparent that an antipsychotic need not induce motor side effects to be efficacious in reducing the symptomatology of schizophrenia. Sociodemographic, behavioral, and clinical predictors of TD are useful in identifying a subset of schizophrenic individuals who would benefit from treatment with clozapine, the prototype atypical antipsychotic whose efficacy and motor side effect profile are superior to those of chlorpromazine. This favorable motor side effect profile of clozapine contributes to improved patient outcomes by reducing noncompliance, substance abuse, and suicide, resulting in improved quality of life and savings on health care costs.
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PMID:Effects of clozapine therapy in schizophrenic individuals at risk for tardive dyskinesia. 954 36

Five autopsy cases of sudden death caused by intestinal obstruction are reported. The causes of death of the cases were duodenal obstruction of impacted food stuff, ileocaecal obstruction caused by Crohn's disease, incarceration of inguinal hernia, intestinal obstruction caused by heterotopic pancreas and paralytic ileus. In three cases, the patient was in cardiopulmonary arrest on arrival at hospital, and in the remaining cases the patient died within 12 hours from the beginning of treatment; therefore, a correct clinical diagnosis was not made before the death in all cases. All the patients had from one to three days history of nausea and abdominal pain, major complications of intestinal obstruction. Among all cases, the duration from the onset to death was the shortest in the case of a patient complicated with schizophrenia. It is characteristic that the patients of all cases died suddenly and resuscitation was not successful. Regarding the laboratory data of a hospitalized patient, marked hemoconcentration and an increased level of BUN/Cr ratio and blood sugar were shown. The patient who died from duodenal obstruction caused by impacted food-stuff had suffered from depression for six years, and the patient who died from paralytic ileus had suffered from schizophrenia for about 23 years. In both cases, it is characteristic that the complaints of the patient were poorer than what would be expected. Furthermore, these patients had been taking medication of psychotic, anti-depressant and anti-parkinsonism drugs; therefore the combination of these drugs was thought to be reflected in the bowel movement.
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PMID:[Analysis of sudden death caused by intestinal obstruction]. 954 55

Tyrosine hydroxylase (TH) gene is the rate-limiting enzyme in the synthesis of catecholamines. Functional polymorphisms of the TH gene may be involved in the pathogenesis of neuropsychiatric diseases such as schizophrenia, affective disorders, and Parkinsonism. This study examined a possible association of two polymorphisms, both of which result in an amino acid change of the TH protein, with schizophrenia and Parkinson's disease (PD). The Val81Met polymorphism is a common variation, although its effect on the enzyme expression is unclear. Leu205Pro polymorphism is a rare mutation that is reported to cause Parkinsonism in infancy for individuals who are homozygous for the mutated type. We genotyped a Japanese sample of 194 schizophrenics, 99 patients with PD, and 161 controls for the Val81Met polymorphism by using mis-match PCR and digestion by the restriction enzyme BalI. There was no significant allelic or genotypic association of the Val81Met polymorphism with schizophrenia or PD. The Leu205Pro polymorphism was examined by using PCR and digestion by AluI; however, there was no individual who carried the mutated type of Pro205 among 50 schizophrenics or 50 patients with PD. Thus we obtained no evidence for the involvement of the two structural mutations of the TH gene in the pathogenesis of schizophrenia or PD.
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PMID:Association study of structural mutations of the tyrosine hydroxylase gene with schizophrenia and Parkinson's disease. 961 51

Anhedonia and psychomotor slowing in schizophrenia have been attributed to a dysfunction of dopaminergic neurotransmission. To differentiate between disease and drug-induced negative symptoms, we examined eight drug-free and eight neuroleptic-treated schizophrenic patients. Positive and negative symptoms and extrapyramidal side effects were assessed using standardized rating scales (PSAS, AMDP, SANS). 'Reaction time' and 'motor speed' were measured using a computer-aided system and striatal dopamine D2/D3 receptor availability was assessed using [I-123]IBZM SPECT. Psychomotor reaction time, parkinsonism, affective flattening and avolition were increased in treated patients relative to the untreated cohort and were negatively correlated with dopamine D2/D3 receptor availability. Significant positive correlations were found between parkinsonism and affective flattening and between psychomotor slowing and avolition. Positive symptoms were not significantly associated with striatal IBZM binding. These findings support the hypothesis that neuroleptic-induced dopamine D2/D3 blockade in the striatum can mimic certain negative symptoms, such as affective flattening and avolition, and indicates that psychomotor testing may be helpful in differentiating between disease and drug-induced negative symptoms.
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PMID:Psychomotor slowing, negative symptoms and dopamine receptor availability--an IBZM SPECT study in neuroleptic-treated and drug-free schizophrenic patients. 963 33

Schizophrenia is a lifelong illness, with symptoms beginning in late adolescence/early adulthood and persisting throughout the rest of the patient's life. Positive psychotic symptoms may fluctuate during the course of the illness, but negative symptoms, especially primary negative symptoms, and cognitive dysfunction are relatively constant. The negative symptoms of schizophrenia are both primary (associated with the illness) and secondary (due to depression, neuroleptic-induced parkinsonism or acute psychosis). While secondary negative symptoms may be reduced by treating the causative agent, primary negative symptoms are viewed as enduring, persisting between psychotic episodes. Conventional antipsychotics treat the positive symptoms of schizophrenia, but they have little effect on primary negative and cognitive symptoms. Primary negative symptoms are often associated with poor premorbid function, the male sex, and low IQ (Intelligence Quotient). In addition, most studies find that negative symptoms are associated with a poor overall outcome. Several studies, including our own, have suggested that primary negative symptoms are functionally localized to the frontal and parietal cortices. These kinds of data raise the possibility that primary negative symptoms may have a pathophysiological basis distinct from positive psychosis. Cognitive impairment also appears to be a relatively independent aspect of schizophrenia. Impairment may be evident in a subtle form from early childhood, and often precedes the development of psychotic symptoms. Additional impairment accrues with the onset of psychotic illness with little evidence, in the vast majority of cases, of progression over the course of the illness. Cognitive impairment is only modestly related to psychotic symptom severity and type. However, the extent, and perhaps specific types of cognitive impairment, appear to be predictive of functional outcome.
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PMID:The role of negative symptoms and cognitive dysfunction in schizophrenia outcome. 969 Sep 66

This 4-week, double-blind, randomized study was undertaken to determine the dose-response relationship of amisulpride in 319 patients with acute exacerbation of schizophrenia. Fixed doses of amisulpride (400, 800 and 1200 mg/day) and haloperidol (16 mg/day) were compared to amisulpride, 100 mg/day, as a potentially subtherapeutic dose. Efficacy data (BPRS total score and PANSS positive subscale) in the amisulpride groups generated a bell-shaped dose-response curve, with 400 mg/day and 800 mg/day being the most effective treatments for positive symptoms. Parkinsonism did not increase significantly between baseline and endpoint with amisulpride 400, 800 and 1200 mg/day compared to the amisulpride 100 mg/day group, whereas the difference was significant for haloperidol (P<0.05). It is concluded that amisulpride 400 mg and 800 mg/day is highly effective in treating the positive symptoms of schizophrenia, with less extrapyramidal side-effects than haloperidol 16 mg/day.
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PMID:Amisulpride, and atypical antipsychotic, in the treatment of acute episodes of schizophrenia: a dose-ranging study vs. haloperidol. The Amisulpride Study Group. 969 17

The aetiology and treatment of Parkinsonism is currently conceptualised within a dopamine (DA) deficiency-repletion framework. Loss of striatal DA is thought to cause motor impairment of which tremor, bradykinaesia and rigidity are prominent features. Repletion of deficient DA should at least minimise parkinsonian signs and symptoms. In Section 2, based on extensive pre-clinical and clinical findings, the instability of this approach to Parkinsonism is scrutinised as the existing negative findings challenging the DA deficiency hypothesis are reviewed and reinterpreted. In Section 3 it is suggested that Parkinsonism is due to a DA excess far from the striatum in the area of the posterior lateral hypothalamus (PLH) and the substantia nigra (SN). This unique area, around the diencephalon/mesencephalon border (DCMCB), is packed with many ascending and descending fibres which undergo functional transformation during degeneration, collectively labelled 'orphan neurones'. These malformed cells remain functional resulting in pathological release of transmitter and perpetual neurotoxicity. Orphan neurone formation is commonly observed in the PLH of animals and in man exhibiting Parkinsonism. The mechanism by which orphan neurones impair motor function is analogous to that seen in the diseased human heart. From this perspective, to conceptualise orphan neurones at the DCMCB as 'Time bombs in the brain' is neither fanciful nor unrealistic [E.M. Stricker, M.J. Zigmond, Comments on effects of nigro-striatal dopamine lesions, Appetite 5 (1984) 266-267] as the DA excess phenomenon demands a different therapeutic approach for the management of Parkinsonism. In Section 4 the focus is on this novel concept of treatment strategies by concentrating on non-invasive, pharmacological and surgical modification of functional orphan neurones as they affect adjacent systems. The Orphan neurone/DA excess hypothesis permits a more comprehensive and defendable interpretation of the interrelationship between Parkinsonism and schizophrenia and other related disorders.
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PMID:Orphan neurones and amine excess: the functional neuropathology of Parkinsonism and neuropsychiatric disease. 972 69

We investigated the availability of dopamine reuptake sites in the striata of two patients with productive symptoms and neuroleptic therapy as well as progressive parkinsonism using the new dopamine transporter ligand [123I]N-(3-iodopropen-2-yl)-2beta-carbo-methoxy-3beta- (4-chlorophenyl)tropane (IPT) and single photon emission computed tomography (SPECT). Normal specific binding in the caudate nucleus was 8.6 +/- 1.2 and in the putamen 6.5 +/- 1.3 (mean +/- S.D.; n = 8; mean age, 56.7 years; range 41-67 years). Patient 1 (age 43) was admitted to our clinic at age 38 because of left-sided parkinsonism. At age 40, she developed paranoid psychosis without change after cessation of L-DOPA and lisuride treatment for 3 months. She was diagnosed as a schizophrenic, paranoid subtype (DSM-III-R). IPT-SPECT showed a loss of dopaminergic nerve terminals (right caudate/putamen, 5.16/2.0; left caudate/putamen, 5.92/2.66). Patient 2 (age, 61 years) had a history of paranoid psychosis for approx. 30 years. He experienced progressive right-sided parkinsonism since age 57 when treated with clozapine. IPT-SPECT showed a marked reduction of striatal dopamine transporter binding (right caudate/putamen, 5.06/1.65; left caudate/putamen, 3.8/1.12). Our findings indicate that patients may suffer contemporaneously from Parkinson's disease and schizophrenia. In these patients, the proof of a nigrostriatal dopaminergic deficit justifies treatment with neuroleptics and dopaminergic drugs. Imaging of dopamine transporters with SPECT and IPT or a related compound represents an attractive alternative to the more complex measurements of fluorodopa uptake with positron emission tomography (PET).
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PMID:Reduced striatal dopaminergic innervation shown by IPT and SPECT in patients under neuroleptic treatment: need for levodopa therapy? 975 2

Behavioral paradigms applicable for use in both human and nonhuman subjects for investigating aspects of working/short-term memory are presented with a view towards exploring their strengths, weaknesses, and utility in a variety of experimental situations. Such procedures can be useful in teasing out specific aspects of mnemonic processes including discrimination, encoding, and retention. Delayed matching-to-position, delayed matching-to-sample (DMTS), and titrating matching-to-sample procedures are highlighted. Additionally, the application of DMTS tasks in preclinical and clinical settings is presented: drug effects on memory processes can be explored preclinically in animal models; normative data have been developed in human populations where they have been used in adults to explore the relationships between mnemonic processes and specific clinical entities such as Parkinsonism, senile dementia of the Alzheimer's type, schizophrenia, and depression. Studies in children indicate that encoding and retention processes improve rapidly in the early years, plateauing prior to puberty. Noninvasive imaging techniques such as positron emission tomography (PET) indicate that activity in specific brain areas is associated with DMTS task performance and may serve to confirm roles for such structures in mnemonic processes.
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PMID:Symposium overview: the use of delayed matching-to-sample procedures in studies of short-term memory in animals and humans. 976 87

Neuroleptics have revolutionized the treatment of schizophrenia and other psychoses since the early 1950s. Several adverse neurobiological effects are, however, associated with the long-term use of these agents. This article will review human and animal studies of these adverse effects, and also present some new data. Tardive dyskinesia (TD) is the most widely studied potentially persistent movement disorder resulting from long-term neuroleptic treatment, and several risk factors for TD development have been identified. Although drug-induced parkinsonism (DIP) usually disappears after the offending agent is withdrawn, a small portion of patients may have persistent parkinsonism. It is however, unclear if this is an aging-related effect. Persistent cognitive impairment associated with long-term use of typical neuroleptics has not been well documented. Atypical antipsychotics may produce improvement in cognitive performance in patients with chronic schizophrenia. MRI changes that are secondary to neuroleptics are possible, but have not yet been studied adequately. There is one unconfirmed report of neurofibrillary tangles associated with long-term neuroleptic use. A number of investigators have reported vacuous chewing movements, and neuropathologic changes following prolonged administration of neuroleptics in animals. We discuss the implications of the various reported adverse effects of long-term use of neuroleptics.
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PMID:Adverse neurobiological effects of long-term use of neuroleptics: human and animal studies. 979 74


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