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)

The concentrations of neuropeptide Y (NPY) and somatostatin (SS) have been said to be altered in the brain and cerebrospinal fluid of schizophrenic patients. This alteration could result from the neuroleptic treatment. Therefore, it is of interest to evaluate effects of long-term treatment with neuroleptics on the peptide concentrations in the brain. Haloperidol (HPD) is one of the most frequently used neuroleptics for the treatment of schizophrenia. We determined regional brain levels of NPY and SS following HPD administration in the rat. A single intraperitoneal injection of HPD, at a dose of 1 mg/kg, did not affect peptide levels in the brain regions studied. Four weeks after an intramuscular deposit injection of HPD decanoate, 50 mg/kg, NPY concentrations were increased in a number of areas of the cerebral cortex. SS content was also significantly increased in the lateral prefrontal cortex and anterior cingulate cortex. Both peptide levels were decreased in the striatum. These results suggest that the reduction found in these peptides' levels in the cerebral cortex of the brain from schizophrenic patients may not be the consequence of HPD treatment and that these peptides' levels might be increased in the cerebral cortex of the brain of schizophrenic patients following the treatment with HPD.
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PMID:Increases in cortical neuropeptide Y and somatostatin concentrations following haloperidol-depot treatment in rats. 853 77

1. Immobility induced by forced swimming is well known as an animal model of depression. To develop an animal model for the negative symptoms of schizophrenia, in particular the depressive symptoms, the effect of phencyclidine (PCP) on immobility in the forced swimming test was investigated in mice, since PCP produces such negative symptoms in humans. 2. Repeated treatment with PCP (10 mg kg-1 day-1, s.c., once a day for 14 days) prolonged the immobility time in the forced swimming test 24 h after the final injection compared with saline treatment; the effect was not obtained by single or 5 treatments with PCP (10 mg kg-1, s.c.), or by repeated treatment with methamphetamine (0.5 and 1 mg kg-1 day-1, s.c., once a day for 14 days). 3. The enhancing effect of PCP (10 mg kg-1 day-1, s.c.) on the immobility persisted for at least 21 days after the withdrawal of the drug. 4. Haloperidol (0.3 and 1 mg kg-1, p.o.), ritanserin (3 and 10 mg kg-1, p.o.), risperidone (0.1-1 mg kg-1, p.o.), and clozapine (3 and 10 mg kg-1, p.o.) failed to attenuate the immobility induced by the forced swimming in mice repeatedly treated with saline when the drugs were administered 1 h before the forced swimming test. However, ritanserin (30 mg kg-1) and clozapine (30 mg kg-1) did attenuate this immobility. 5. The enhancing effect of PCP on the immobility was attenuated by ritanserin (3 and 10 mg kg-1, p.o.), risperidone (0.3 mg kg-1, p.o.), and clozapine (3 and 10 mg kg-1, p.o.), whereas haloperidol (0.3 and 1 mg kg-1, p.o.) had no effect. 6. These results suggest that the enhancement of immobility in the forced swimming test brought about by repeated PCP treatment could be used as a model of the negative symptoms, particularly the depression, of schizophrenia. This effect of PCP appeared to be mediated, at least in part, via 5-HT2A receptors.
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PMID:Enhancement of immobility in a forced swimming test by subacute or repeated treatment with phencyclidine: a new model of schizophrenia. 858 Dec 95

There are now more than 50 studies concerning neuroleptic blood levels and clinical outcome relationships. Haloperidol, the most studied, is the only antipsychotic permitting some conclusions. A number of authors suggest that the striking lack of agreement between different studies results from heterogeneity of their quality. Here, we have used a scoring system for assessing the quality of those studies. According to this system, none (0/14) of the studies having a score < 0.60 was able to show a therapeutic window, as compared to 53% (10/19) of those having a score > or = 0.60 (p = 0.002, Fisher exact test). Also, the studies able to identify the presence of a therapeutic window during haloperidol treatment were those having sample size > 20 (p = 0.06) and those whose patients were treated with fixed doses (p = 0.02). The diagnosis of schizophrenia in the studies seems not to be an exclusive condition, as compared with those also including schizophreniform and schizoaffective disorders (p = 0.12). Our qualitative analysis of haloperidol blood level publications seem to indicate that an upper limit may exist for haloperidol efficacy; values above this limit seem not to provide any supplementary clinical improvement and may even reduce therapeutic effect.
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PMID:Is there a relationship between antipsychotic blood levels and their clinical efficacy? An analysis of studies design and methodology. 861 13

Haloperidol (HAL) is a widely used and clinically effective neuroleptic. Its metabolism differs in various animal species. In humans, reduced haloperidol (RHAL), a hydroxy metabolite of HAL, is produced by a cytosolic ketone reductase. Interconversion is known to occur whereby HAL is found in the plasma after administration of RHAL in vivo. Interconversion of HAL and RHAL has been observed in man. However, the capacity for reductive HAL is greater than its oxidation back from RHAL. RHAL, the resulting metabolite of HAL, is reported to be about 10-25% as active as HAL in an animal model. Large intersubject variation has been observed in the pharmacokinetics of HAL and RHAL. A wide variation in reductive drug-metabolizing has been observed in schizophrenic patients treated with HAL. Both high and low RHAL/HAL ratios or RHAL levels were reported to be linked to poor response in HAL-treated patients and might be correlated with the therapeutic window effect of HAL treatment. It is conceivable, therefore, that subjects with high reductive capacity relative to oxidative capacity may have less therapeutic response from the same dose of HAL than those with a low reductive capacity relative to oxidative capacity. This aim of this study was to investigate the HAL reduction among a sample of HAL-treated schizophrenic patients. Because ketone reductases are generally not tissue specific, we investigate the reductase activity in Red blood cells (as described by Inaba), before and during the treatment. Steady-state plasma drug levels during 2 weeks of treatment were quantified. We examined the relationships between fixed doses of HAL treatment, Red blood cells ketone reductase activity, plasma HAL and RHAL levels and the percentage of change of the Positive and Negative Syndrome Scale for Schizophrenia. The participants in this study were 15 inpatients consecutively being treated in the adult psychiatric wards of the University of Lille. All subjects met DSM III-R criteria for schizophrenia (paranoid form). Upon induction subjects were evaluated clinically by trained raters using the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). Subjects were required to score 40 or higher on the general psychopathology subscale of the PANSS to continue participation. All subjects were drug free. Haloperidol was administered orally at three times daily dose. Patients were randomized to treatment at three orally fixed doses: 6 mg per day, 10 mg per day and 15 mg per day. Patients were treated for 2 periods of one week. At the end of each period, dosages could be modified according to the clinic evolution of the patient. PANSS was repeated by the same raters blinded to the haloperidol dosage, plasma concentration and Rbc haloperidol ketone reductase activity, at the beginning and at the end of each period. Blood samples were collected on the same day that clinical assessment were made. Multiple regression analysis (forward stepwise) revealed that Red blood cells reductase activity at D0 is an important variable predicting haloperidol plasma levels at week 2. Similarly Red blood cells reductase activity at D0 and D7 predicted Reduced haloperidol plasma concentrations at week 2. In this sample, no parameter was found to be consistency predicted the percentage change in the PANSS positive subscale from baseline, at week 2. Nevertheless, Red blood cells reductase activity at D0, Reduced haloperidol/haloperidol ratio at week 2, haloperidol plasma levels at week 2 and the dose of haloperidol at week 1 were important variables predicting the percentage change in the PANSS general subscale from baseline at week 2. These results suggest that the knowledge of reductase activity could predict the treatment response in acute schizophrenic patients.
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PMID:[Erythrocyte ketone reductase activity, total plasma haloperidol and acute psychoses]. 867 66

Results of recent studies in pharmacotherapy in autism are presented. Haloperidol, fenfluramine and naltrexone have been the most extensively studied drugs in systematic research. Haloperidol appeared to decrease levels of hyperactivity, stereotypies, emotional lability but also abnormal object relations and social withdrawal. However, the therapeutic effect was generally modest and long term administration was associated with dyskinesias in autistic children. The frequent hyperserotonemia in autism has suggested the use of fenfluramine, an antiserotoninergic agent. Although the initial reports were optimistic, more recent carefully designed studies often failed to show that fenfluramine was superior to placebo. Naltrexone, a potent opiate antagonist, was explored following the opioid hypothesis based on the similarity between autistic symptomatology and abnormal behaviors observed in opiate addicts and in laboratory animals administered opiates and on the abnormalities of endogenous opioids that exit in a subgroup of autistic children. However, the current studies do not concur and no definite conclusions can be made of the efficacy of naltrexone at present time. Low doses of amisulpride which have been shown to improve negative symptoms in schizophrenia and serotoninergic antidepressants, which have proven effective in repetitive and ritualized behaviors, have recently began to be evaluated in controlled studies. At present time, no medication has shown to alter the course or the symptoms of autism, but some seem to be effective in reducing severe aberrant behaviors.
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PMID:[Psychopharmacology of autism]. 876 48

Increasing evidence suggests an important role of 5-HT, and 5-HT2A receptors in particular, in the etiology and treatment of schizophrenia. The prepulse inhibition paradigm is used as a model for sensorimotor gating processes that are disrupted in schizophrenia. The present study used the selective serotonin2A (5-HT2A) antagonist and putative antipsychotic agent MDL 100,907 to evaluate the contribution of 5-HT2A receptors to the disruptions of prepulse inhibition produced by several 5-HT agonists. The D2 antagonist haloperidol was used to evaluate a possible interaction with dopamine neurons. Sound or light prepulses were used to measure the generality of these drug effects on cross-modal prepulse inhibition. In the first study, MDL 100,907 antagonized the disruptions of auditory prepulse inhibition produced by the 5-HT releasing agents fenfluramine and 3,4-methylenedioxymethamphetamine (MDMA). These effects on prepulse inhibition were modality-specific in that MDL 100,907 did not reverse the effects of the 5-HT releasers on visual prepulse inhibition. Haloperidol did not alter the disruptive effects of MDMA or fenfluramine on either auditory or visual prepulse inhibition. In the second study, the direct acting 5-HT2A/2C receptor agonist/hallucinogen (+)1-4-iodo-2,5-dimethoxyphenyl-2-aminopropane (DOI) consistently disrupted auditory prepulse inhibition, and this effect was blocked by MDL 100,907 but not by haloperidol. A dose-response analysis demonstrated that MDL 100,907 potently antagonized DOI disrupted auditory prepulse inhibition, with an ED50 of 0.04 mg/kg, IP. DOI did not consistently disrupt visual prepulse inhibition. In summary, these data indicate that, at least under the conditions of the present studies, the disruptions of auditory prepulse inhibition produced by fenfluramine, MDMA, and DOI result from stimulation of 5-HT2A receptors. Furthermore, these disruptions do not involve direct or indirect stimulation of D2 receptors. The identity of the 5-HT receptor(s) underlying the disruptive effects of fenfluramine or MDMA on visual prepulse inhibition has not yet been identified. MDL 100,907 may be generally useful in CNS disorders in which excessive 5-HT2A receptor tone disrupts sensory gating processes.
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PMID:5-HT modulation of auditory and visual sensorimotor gating: II. Effects of the 5-HT2A antagonist MDL 100,907 on disruption of sound and light prepulse inhibition produced by 5-HT agonists in Wistar rats. 893 5

Several reports have suggested that the frequency of Alzheimer's disease (AD) neuropathology is significantly reduced in elderly individuals with schizophrenia (SZ), and it has been proposed that medications used for treatment of SZ may be responsible. A central event in AD pathology is the formation of beta-amyloid (A beta) peptide, which is derived by enzymatic processing of its precursor protein. Haloperidol, an antipsychotic medication commonly used in the treatment of SZ, can act as an inhibitor of select proteinases; hence, we examined the ability of this compound to inhibit A beta formation by cultured cells. Haloperidol and, to a lesser extent, droperidol inhibited A beta in a dose-dependent manner. These results may explain the apparent reduction of AD neuropathological changes in elderly patients with SZ as well as provide a possible mechanism for this difference.
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PMID:Inhibition of beta-amyloid formation by haloperidol: a possible mechanism for reduced frequency of Alzheimer's disease pathology in schizophrenia. 897 43

The benzamide derivative amisulpride shows a unique therapeutic profile being antipsychotic, at high doses, and disinhibitory, at low doses, while giving rise to only a low incidence of extrapyramidal side effects. In vitro, amisulpride has high affinity and selectivity for the human dopamine D2 (Ki = 2.8 nM) and D3 (Ki = 3.2 nM) receptors. Amisulpride shows antagonist properties toward D3 and both pre- and postsynaptic D2-like dopamine receptors of the rat striatum or nucleus accumbens in vitro. At low doses (< or = 10 mg/kg) amisulpride preferentially blocks presynaptic dopamine autoreceptors that control dopamine synthesis and release in the rat, whereas at higher doses (40-80 mg/kg) postsynaptic dopamine D2 receptor occupancy and antagonism is apparent. In contrast, haloperidol is active in all of these paradigms within the same dose range. Amisulpride preferentially inhibits in vivo binding of the D2/D3 antagonist [3H]raclopride to the limbic system (ID50 = 17 mg/kg) in comparison to the striatum (ID50 = 44 mg/kg) of the rat, increases striatal and limbic tissue 3,4-dihydroxyphenylacetic acid levels with similar potency and efficacy, and preferentially increases extracellular 3,4-dihydroxyphenylacetic acid levels in the nucleus accumbens when compared to the striatum. Haloperidol shows similar potency for the displacement of in vivo [3H]raclopride binding in striatal and limbic regions and preferentially increases striatal tissue 3,4-dihydroxyphenylacetic acid levels. The present data characterize amisulpride as a specific dopamine receptor antagonist with high and similar affinity for the dopamine D2 and D3 receptor. In vivo, it displays a degree of limbic selectivity and a preferential effect, at low doses, on dopamine D2/D3 autoreceptors. This atypical profile may explain the therapeutic efficacy of amisulpride in the treatment of both positive and negative symptoms of schizophrenia.
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PMID:Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. 899 85

Haloperidol (HAL) has been widely used in the elderly. Little is known about the phenomenology of schizophrenia in late life or the response to antipsychotic treatment. We prospectively studied 19 elderly patients treated with HAL for 25 days. They ranged in age from 55 to 83 (mean age = 67.5 +/- 6.4 years). After a washout period in 15 patients (4 patients had been noncompliant with medication for at least 1 month), patients were rated before treatment and at the end of the assessment period with the Positive and Negative Syndrome Scale (PANSS) and Simpson-Angus extrapyramidal side effects rating scale (SA). Baseline PANSS scores were associated with change in SA scores (r = .52, p = .02) and with SA baseline score (r = .45, p = .05). Age was negatively associated with baseline positive subscale (r = -.42, p = .07) and endpoint positive subscale scores of PANSS (r = -.48, p = .04). Age was positively associated with improvement in negative symptoms (r = .53, p = .02). Haloperidol dose was negatively associated with improvement in positive symptoms (r = -.46, p = .04). Although studies with larger samples sizes are needed, these findings may indicate that elderly schizophrenics do not respond to treatment in the same manner as do younger schizophrenics.
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PMID:Symptom change and extrapyramidal side effects during acute haloperidol treatment in chronic geriatric schizophrenics. 913 62

The rabbit classical eyeblink conditioning paradigm was used to assess the effects of haloperidol on hippocampal function. Haloperidol disrupted hippocampal activity and conditioned responses (CRs) at low but not high conditioned stimulus (CS) intensities. The observed relationship of hippocampal activity and the CR suggested that the hippocampus encoded sensory features associated with the learned response. Sensory processing by the hippocampus appeared to be altered by haloperidol through attenuation of the ability of a CS to evoke a learned response. Results are discussed in terms of the role of the hippocampus in sensory processing and possible mechanisms for the beneficial effects of haloperidol in schizophrenia. Classical eyeblink conditioning may provide a model system for studying behavioral and biological issues relevant to the etiology and treatment of schizophrenia.
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PMID:Effects of haloperidol on sensory processing in the hippocampus during classical eyeblink conditioning. 915 60


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