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)

Haloperidol (HAL), a potent typical antipsychotic, continues to be a frequently prescribed medication for behavioral disturbances associated particularly with schizophrenia despite well-documented adverse effects associated with its chronic use. Animal experiments have even indicated that HAL can damage cholinergic pathways and thus could be especially deleterious to those experiencing cognitive deficits. However, several recent clinical studies indicate that atypical antipsychotics may actually improve cognitive function in some patients, although this assertion requires further investigation. The purpose of this study was to compare the effects of prior chronic (45- or 90-day) oral exposure to HAL and the atypical antipsychotics risperidone (RISP) and clozapine (CLOZ) on cognitive performance and central cholinergic markers in rats. All analyses were done after 4 days of drug washout in order to minimize direct drug effects. Learning performance and choline acetyltransferase (ChAT) levels were assessed in a water maze task and with immunofluorescence staining, respectively. HAL significantly impaired learning performance after 90 but not after 45 days of treatment when compared to both vehicle controls and the atypical agents, while RISP slightly improved task performance. Both 45 and 90 days of previous HAL exposure reduced ChAT staining in several brain regions, including the cortex, caudate-putamen, and hippocampus. ChAT staining in the caudate-putamen and hippocampus was also decreased after 90 days of RISP exposure, raising the possibility of deleterious cognitive effects after exposure to this dosage for longer periods of time. The results suggest that antipsychotic drugs exert differential and temporally dependent effects on central cholinergic neurons and learning performance.
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PMID:Differential effects of haloperidol, risperidone, and clozapine exposure on cholinergic markers and spatial learning performance in rats. 1258 83

The effect of acute treatment with clozapine, risperidone and haloperidol on cardiovascular response to open field novelty stress was investigated in rats using radio-telemetry and video-tracking analysis. Pretreatment with clozapine dose-dependently inhibited the pressor response, tachycardia and increase in dP/dt and caused a marked reduction of exploratory locomotor activity. Similar effects were observed after risperidone treatment. Haloperidol treatment markedly reduced locomotor activity but its cardiovascular effects were limited to a more rapid return of heart rate towards baseline levels. These data suggest that particularly the atypical antipsychotic drugs, clozapine and risperidone, but not the typical antipsychotic, haloperidol, reduce cardiovascular stress responses, an effect that could reflect their anxiolytic action. Such anxiolytic effects could contribute to the beneficial clinical effects of atypical antipsychotic drugs in patients with schizophrenia.
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PMID:Acute effects of antipsychotic drugs on cardiovascular responses to stress. 1260 Jun 95

There are some reports describing concurrent changes in lymphocytic and monocytic activities in schizophrenia. In this study we investigated T cell activity in schizophrenic patients by measuring the release of interleukin-2 (IL-2) and soluble interleukin-2 receptor (sIL-2R) by T cells and the percentages of CD4+ and CD8+ cells in blood. The release of IL-2 and sIL-2R by T cells was evaluated in dilute whole blood after in-vitro stimulation with phytohemagglutinin. IL-2 levels and the percentage of CD4-cells tended to decrease and sIL-2R levels decreased significantly in schizophrenic patients. Haloperidol and perazine significantly decreased IL-2 levels and increased sIL-2R levels and the percentage CD4-cells. IL-2 and sIL-2R levels were lower in patients with a predominance of positive symptoms. The neuroleptic-induced increase in sIL-2R levels was higher in patients with a predominance of positive symptoms compared with those in whom both positive and negative symptoms were severe. The study has shown that T-cell activity is reduced in schizophrenia and that neuroleptics may have immunomodulatory properties.
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PMID:In-vitro immunomodulatory effects of haloperidol and perazine in schizophrenia. 1260 15

Aripiprazole is a novel antipsychotic with a unique mechanism of action. Presented here is a pooled analysis of safety and tolerability data from all completed short-term, placebo-controlled trials in schizophrenia from the aripiprazole clinical development program. Data were analyzed from five 4- to 6-week double-blind multicenter studies of patients hospitalized with acute relapse of schizophrenia or schizoaffective disorder randomized to aripiprazole (n=932), placebo (n=416), or haloperidol (n=201). Daily aripiprazole doses ranged from 2 to 30 mg. Safety assessments included adverse event (AE) reports, EPS scales, ECGs, weight, and prolactin, glucose and cholesterol levels. Aripiprazole was well tolerated, with similar AE incidence rates to placebo, and lower rates than haloperidol for akathisia, extrapyramidal syndrome and somnolence. Objective EPS assessments demonstrated no significant differences between aripiprazole and placebo on Simpson-Angus Scale (SAS) scores, no dose-dependent effects on Barnes Akathisia scores, and significant reductions in Abnormal Involuntary Movement Scale (AIMS) scores from baseline vs. placebo (p</=0.01). Haloperidol showed increased SAS and Barnes Akathisia scores over placebo (p</=0.01). There was minimal mean weight change with aripiprazole (+0.71 kg) and haloperidol (+0.56 kg), and a lack of QT(c) prolongation. Serum prolactin increased with haloperidol, but not aripiprazole. In conclusion, aripiprazole shows a favorable safety and tolerability profile with low potential for EPS, weight gain, prolactin elevation, QT(c) prolongation, and sedation. Aripiprazole's safety profile may offer benefits in schizophrenia treatment.
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PMID:Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials. 1272 64

The present study examined the effects of the atypical antipsychotic drugs clozapine, olanzapine, quetiapine and risperidone, on N-methyl-4-phenylpyridinium ion-induced apoptosis and DNA damage in PC12 cells, and explored the molecular mechanisms underlying these effects. Haloperidol, a typical antipsychotic drug, was used for comparison. Exposure of PC12 cells to 50 micro m N-methyl-4-phenylpyridinium ion for 24 h resulted in a 35-45% loss of cells in culture. Pretreatment with the aforementioned atypical antipsychotic drugs significantly reduced the N-methyl-4-phenylpyridinium ion-induced cell loss, whereas haloperidol (10-100 micro m) did not have this protective effect. Hoechst 33258 staining revealed the apoptotic nuclear features of the N-methyl-4-phenylpyridinium ion-induced cell death, and showed that the atypical antipsychotic drugs, but not haloperidol, effectively prevented PC12 cells from this N-methyl-4-phenylpyridinium ion-induced apoptosis. DNA fragmentation assays further confirmed the N-methyl-4-phenylpyridinium ion-induced nuclear fragmentation. Pretreatment with the atypical antipsychotic drugs completely prevented this nuclear fragmentation, whereas haloperidol only partially prevented it. In vitro oligonucleotide assays indicated an activation of a specific glycosylase that recognizes and cleaves bases (at the 8-hydroxyl-2-deoxyguanine site) that were damaged by N-methyl-4-phenylpyridinium ion. Pretreatment with the atypical antipsychotic drugs more effectively attenuated this N-methyl-4-phenylpyridinium ion-induced activation than did haloperidol. Northern blot analyses showed that the atypical antipsychotic drugs, but not haloperidol, blocked the N-methyl-4-phenylpyridinium ion-induced substantial increase of copper/zinc superoxide dismutase mRNA in PC12 cells. Atypical antipsychotic drugs slightly up-regulated the expression of copper/zinc superoxide dismutase mRNA, whereas haloperidol strongly increased the expression of copper/zinc superoxide dismutase mRNA. These data may account for the different therapeutic effects and side-effect profiles of typical and atypical antipsychotic drugs in schizophrenia.
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PMID:The ability of atypical antipsychotic drugs vs. haloperidol to protect PC12 cells against MPP+-induced apoptosis. 1275 74

Antipsychotic drugs require a treatment regimen of several weeks before clinical efficacy is achieved in patient populations. While the biochemical mechanisms underlying the delayed temporal profile remain unclear, molecular adaptations in specific neuroanatomical loci are likely involved. Haloperidol-induced changes in gene expression in various brain regions have been observed; however, alterations in distinct neuronal populations have remained elusive. The present study examined changes in gene expression profiles of ventral tegmental area (VTA) and substantia nigra (SN) tyrosine hydroxylase immunopositive neurons following 1, 10 or 21 days of haloperidol administration (0.5 mg/kg/day). Macroarrays were used to study the expression of receptors, signaling proteins, transcription factors and pre- and post-synaptic proteins. Data were analyzed using conventional statistical procedures as well as self-organizing maps (SOM) to elucidate conserved patterns of expression changes. Results show statistically significant haloperidol-induced and time-dependent alterations in 17 genes in the VTA and 25 genes in the SN, including glutamate and GABA receptor subunits, signaling proteins and transcription factors. SOMs revealed distinct patterns of gene expression changes in response to haloperidol. Understanding how gene expression is altered over a clinically relevant time course of haloperidol administration may provide insight into the development of antipsychotic efficacy as well as the underlying pathology of schizophrenia.
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PMID:Time-dependent changes in gene expression profiles of midbrain dopamine neurons following haloperidol administration. 1296 67

We used a psychophysiological marker of visual attention (the visual scanpath) to investigate the effects of atypical (risperidone) vs. typical (haloperidol) antipsychotic medication on facial emotion perception in schizophrenia (n=28) and healthy control (n=28) groups. Of the schizophrenia subjects, 15 were prescribed risperidone. Visual scanpaths to 'happy', 'sad' and 'neutral' faces were recorded using video-oculography, and concurrent emotion-recognition accuracy was assessed using multiple-option tasks. Compared to control subjects, both schizophrenia subgroups showed a restriction in visual scanning (reduced total fixation number and decreased scanpath length). Haloperidol-treated schizophrenia subjects exhibited an additional and consistent pattern of reduced attention (fixation) to salient features for neutral and happy. By contrast, risperidone-treated subjects showed a relatively greater attention to salient features for these expressions, in which they did not differ from controls. Recognition accuracy for happy and neutral showed a similar lack of impairment. These findings suggest that risperidone may play a specific role in schizophrenia in the ability to attend to salient features, and to integrate this information into an accurate percept for neutral and positive expressions in particular.
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PMID:Emotion perception in schizophrenia: an eye movement study comparing the effectiveness of risperidone vs. haloperidol. 1450 Jan 10

Schizophrenia is marked by pronounced cognitive impairments in addition to the hallmark psychotic symptoms like hallucinations. Antipsychotic drugs can effectively reduce these hallucinations; however, the drugs have not resolved the cognitive impairment. Interestingly, nicotine, a drug commonly self-administered by people with schizophrenia, has been shown to significantly improve cognitive function of people with schizophrenia. The current study was conducted to determine the effect of typical (haloperidol) and atypical (clozapine and risperidone) antipsychotic drug treatment on sustained attention in rats performing a visual signal detection task. In addition, the interaction of haloperidol with chronic nicotine administration was assessed. Female Sprague-Dawley rats were injected subcutaneously with clozapine (0, 0.6, 1.25 and 2.5 mg/kg), risperidone (0, 0.025, 0.05 and 0.1 mg/kg) or haloperidol (0, 0.01, 0.02 and 0.04 mg/kg). In the second part of the study, the interaction of acute haloperidol (0, 0.005, 0.01 and 0.02 mg/kg) and chronic nicotine (5 mg/kg/day, for 4 weeks via osmotic minipump) was characterized. Clozapine, risperidone and haloperidol all caused dose-related impairments in percent hit performance. There was a significant linear dose-related impairment in percent hit caused by risperidone. All the doses of clozapine caused a significant impairment in percent hit at the higher luminance intensities in the visual signal detection task. The 0.01 and 0.02 mg/kg haloperidol doses caused significant decreases in percent hit. The 0.04 mg/kg haloperidol dose impaired performance of the task to the point that reliable choice accuracy measurements could not be made. Chronic nicotine infusion significantly diminished the impairing effects of haloperidol on performance during weeks 1-2. In summary, both typical and atypical antipsychotic drugs significantly impaired sustained attention in rats. Haloperidol was more detrimental than clozapine and risperidone. Chronic nicotine diminished the adverse effects of haloperidol on performance. This study establishes a paradigm to reliably determine the attentional impairment caused by antipsychotic drugs.
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PMID:Nicotine-antipsychotic drug interactions and attentional performance in female rats. 1497 6

Presently there is no established treatment for antipsychotic drugs-induced tardive dyskinesia (TD), which remains a major clinical issue in psychiatry. Based on the principles of the glutamatergic hypothesis of schizophrenia, the amino acid glycine (GLY) and the antituberculosis drug D-cycloserine (DCS) have been assessed, during the last decade, as adjuvants to antipsychotic drugs. Observations stemming from these studies suggest that, in addition to improving schizophrenia symptoms, these compounds may also be beneficial against drug-induced dyskinesias. In order to investigate this hypothesis, GLY and DCS effects were studied using the putative TD analogue vacuous chewing movements (VCM) rat model. Following 24 weeks of treatment with haloperidol decanoate (0.38 mg/kg/4 weeks) rats (N=40) were randomized to receive one intraperitoneal injection with 1.6 g/kg GLY, 10 mg/kg ("low dose") DCS; 100 mg/kg ("high dose") DCS or saline ("placebo"), respectively. Behavior was videotaped at intervals during the experiment and all VCM, rearing, grooming and immobility episodes were analyzed and scored. A control group (N=9) received saline for 24 weeks. Haloperidol administration decreased motor activity and significantly induced VCM. High dose DCS significantly reduced VCM without affecting other motor parameters. GLY treatment resulted in significantly less VCM but also reduced rearing, grooming and mobility. In contrast, low dose DCS and placebo did not significantly affect any of these parameters. These findings indicate that the use of GLY and DCS results in attenuation of VCM in rats and may have an effect on TD in humans. Clinical trials with this type of compounds for patients suffering from TD are warranted.
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PMID:Glycine and D-cycloserine attenuate vacuous chewing movements in a rat model of tardive dyskinesia. 1503 29

The neurotoxicity of conventional antipsychotic drugs has emerged as a potential pathogenic event in extrapyramidal side effects (EPS) and in their limited efficacy for negative-cognitive symptoms in schizophrenic patients. The atypical antipsychotics, recently developed, have superior therapeutic efficacy to treat not only positive symptoms but negative symptoms and cognitive dysfunctions with much lower potentials of side effects, although the influence of atypical antipsychotics on the regulation of neuronal survival has been less investigated. It is important to clarify the effects of typical and atypical antipsychotics on neuronal survival and their contributions to the therapeutic development and understanding of the pathophysiology of schizophrenia. We measured the neurotoxicity of two antipsychotic drug treatments, haloperidol and risperidone, in primary cultured rat cortical neurons. Immunoblotting and pharmacological agent analyses were used to determine the signal transduction changes implicated in the mechanisms of the neurotoxicity. Haloperidol induced apoptotic injury in cultured cortical neurons, but risperidone showed weak potential to injure the neurons. Treatment with haloperidol also led the reduction of phosphorylation levels of Akt, and activated caspase-3. The D2 agonist bromocriptine and 5-HT2A antagonist, ketanserin attenuated the haloperidol-induced neuronal toxicity. Moreover, brain-derived neurotrophic factor (BDNF) reduced the caspase-3 activity and protected neurons from haloperidol-induced apoptosis. BDNF also reversed the reduced levels of phosphorylation of Akt caused by treatment with haloperidol. Haloperidol but not risperidone induces caspase-dependent apoptosis by reducing cellular survival signaling, which possibly contributes to the differential clinical therapeutic efficacy and expression of side effects in schizophrenia.
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PMID:Neurotoxic potential of haloperidol in comparison with risperidone: implication of Akt-mediated signal changes by haloperidol. 1516 14


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