UMLS:C0036341 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Social withdrawal is the first sign and key component of the negative symptoms of schizophrenia. The efficacy of risperidone, an atypical antipsychotic, on the symptom is practically limited by dose-dependent side effects in clinical trials, therefore there is the need for adjuvant treatments. In the present study, we aimed to investigate the synergistic effect and mechanism of risperidone and galantamine, which is a nicotinic acetylcholine receptor (nAChR)-allosteric modulator and a modest cholinesterase inhibitor, on phencyclidine (PCP)-treated mouse model of social withdrawal. At non-effective doses by themselves, co-administration of galantamine (0.05mg/kg) and risperidone (0.05mg/kg) showed synergistic effects on PCP-induced impairments of social interaction and dopamine release in the medial prefrontal cortex (mPFC). The behavioral synergistic effect was abolished by the administration of a dopamine-D(1) receptor antagonist, SCH 23390 (0.02mg/kg, systemic; or 0.02microg/0.5microL/mouse, intra-mPFC), and a nAChR antagonist, mecamylamine (3mg/kg), but not a muscarinic receptor antagonist, scopolamine (0.1mg/kg). Mecamylamine (3mg/kg) also abolished the synergistic effect on dopamine release in the mPFC. We conclude that galantamine may have synergistic effect with risperidone on the negative symptom of social withdrawal in schizophrenia, which is mediated by dopamine-D(1) receptors in the mPFC through nAChR activation-increased dopamine release.
...
PMID:Synergistic effect of galantamine with risperidone on impairment of social interaction in phencyclidine-treated mice as a schizophrenic animal model. 1731 62

Thirteen outpatients with chronic but stable schizophrenia received donepezil and placebo augmentation of their maintenance antipsychotic medication regimen. Each subject received in a randomized, counterbalanced order 1) donepezil 5 mg for 6 weeks then donepezil 10 mg for six weeks and 2) placebo donepezil for 12 weeks. Serial ratings of the Positive and Negative Symptom Scale (PANSS) [Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13(2): 261-276] were performed by a trained rater blind to the donepezil order and condition: at baseline, 12 weeks and 24 weeks. On donepezil as compared to baseline or placebo, there was a significant improvement in PANSS negative scores (p=.018, n=13). These results are discussed with respect to other studies using cholinesterase inhibitors as an augmentation strategy in schizophrenia.
...
PMID:Double-blind donepezil-placebo crossover augmentation study of atypical antipsychotics in chronic, stable schizophrenia: a pilot study. 1739 30

Altered expression of central muscarinic and nicotinic acetylcholine receptors in hippocampal and cortical regions may contribute to the cognitive impairment exhibited in patients with schizophrenia. Increasing cholinergic activity through the use of a cholinesterase inhibitor (ChEI) therefore represents a possible strategy for cognitive augmentation in schizophrenia. We examined the efficacy and safety of the ChEI donepezil as cotreatment for mild to moderate cognitive impairment in schizophrenia or schizoaffective disorder in a prospective, 12-week, placebo-controlled, double-blind, parallel-group study. In total, 250 patients (18-55 years) with schizophrenia or schizoaffective disorder who were clinically stabilized on risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole, alone or in combination, were enrolled at 38 outpatient psychiatric clinics in the United States. Patients were randomized to donepezil 5 mg q.d. for 6 weeks then 10 mg q.d. for 6 weeks, or placebo administered as oral tablets. The primary outcome measure was the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) neurocognitive battery composite score. In the intent-to-treat sample (donepezil, n=121; placebo, n=124), both treatments showed improvement in the composite score from baseline to week 12. At week 12, cognitive improvement with donepezil was similar to that with placebo (last-observation-carried-forward effect size, 0.277 vs 0.411; p=0.1182) and statistically significantly inferior for the observed-cases analysis (0.257 vs 0.450; p=0.044). There was statistically significant improvement in the Positive and Negative Syndrome Assessment Scale negative symptoms score for placebo compared with donepezil, while total and positive symptom scores were similar between both treatments. Statistically significant improvements in positive symptoms score and Clinical Global Impression-Improvement for donepezil compared with placebo were noted at Week 6. Treatment-emergent adverse events (AEs) were observed for 54.5% of donepezil- and 61.3% of placebo-treated patients; most AEs were rated as mild to moderate in severity. Donepezil was safe and well-tolerated but was not effective compared with placebo as a cotreatment for the improvement of cognitive impairment in this patient population. A significant and surprisingly large placebo/practice effect was observed among placebo-treated patients, and is a serious consideration in future clinical trial study designs for potential cognitive enhancing compounds in schizophrenia.
...
PMID:Efficacy and safety of donepezil in patients with schizophrenia or schizoaffective disorder: significant placebo/practice effects in a 12-week, randomized, double-blind, placebo-controlled trial. 1762 2

The clinically achievable efficacy of the atypical antipsychotics on cognitive symptoms of schizophrenia is practically limited by their dose-dependent side effects. Thus, there is the need for adjuvant treatments or strategies for the cognitive impairments. Further, human autopsy and genetic data in schizophrenia have indicated the existence of the abnormality of nicotinic acetylcholine receptors (nAChR). In the present study, we aimed to investigate the synergistic effect and mechanisms of a combined treatment with an atypical antipsychotic risperidone and galantamine, which is a nAChR-allosteric modulator and a modest cholinesterase inhibitor, on the impairment of latent visuospatial learning and memory in mice resembling the cognitive impairment of schizophrenia. Repeated treatment with phencyclidine (PCP, 10 mg/kg, 14 days)-induced cognitive impairment in mice in a one trial water-finding test was used as a model of the cognitive impairment of schizophrenia. In vivo microdialysis was used to investigate the extracellular concentration of dopamine in the medial prefrontal cortex (mPFC). Combined treatment with galantamine and risperidone, at low, ineffective doses (both at 0.05 mg/kg) showed a synergistic effect to reverse cognitive impairment and increase extracellular concentration of dopamine in the mPFC. The synergistic behavioral effect was abolished by a dopamine-D1 receptor antagonist, SCH 23390, and a nAChR antagonist, mecamylamine, but not a muscarinic AChR (mAChR) antagonist, scopolamine. Mecamylamine also blocked the synergistic effect on dopamine release in the mPFC of PCP-treated mice. The study indicates that galantamine and risperidone may have synergistic effect on the cognitive impairments in schizophrenia patients by synergistically promoting the nAChR activation-dependent increase of dopamine D1 receptor-mediated neurotransmission.
...
PMID:Synergistic effect of combined treatment with risperidone and galantamine on phencyclidine-induced impairment of latent visuospatial learning and memory: Role of nAChR activation-dependent increase of dopamine D1 receptor-mediated neurotransmission. 1763 85

Atypical antipsychotics will continue to be prescribed for the behavioral symptoms of dementia in the absence of more effective, better tolerated, and safer alternatives. The evidence base, although incomplete, suggests that modest treatment effect sizes are offset by risk of considerable adverse effects. How might this information be best applied to clinical practice? Non-pharmacologic strategies should be implemented in routine clinical practice. Placebo-controlled clinical trials of individual antipsychotic agents have historically reported high placebo response rates; CATIE-AD reported that the sum total of the risk/benefit equation of atypical antipsychotic therapy was no greater than that achieved by placebo. CATIE-AD was designed to study the effectiveness of atypical antipsychotic treatment in community dwelling patients with AD. It is uncertain whether the results can be generalized to the populations of dementia patients residing in nursing homes with more severe cognitive and behavioral impairment. There is some suggestion that nursing home patients with dementia complicated by severe behavioral symptoms, particularly agitation and aggression without accompanying psychosis, might achieve greater benefit from atypical antipsychotic treatment than patients with milder behavioral symptoms. The finding that dementia patients without psychosis may respond more robustly to antipsychotic treatment seems counterintuitive, but may support the hypothesis that the neurobiology of the "psychosis of AD" differs from the psychosis of schizophrenia or bipolar disease. Adverse effects associated with antipsychotic therapy should be aggressively monitored throughout therapy. Treatment-emergent sedation was associated with all of the atypical antipsychotics in CATIE-AD and is probably an important mediator of mortality risk in patients with dementia. Sedation exacerbates pre-existing cognitive impairment and increases the risk of complications such as aspiration pneumonia, so concomitant use of benzodiazepines should be discouraged or limited to short periods with careful observation.' Once initiated, the effectiveness and tolerability of antipsychotic therapy should be evaluated routinely. In Alzheimer's disease, the severity and frequency of behavioral symptoms often decreases as illness progresses. In a stable patient, it is prudent to attempt to taper and discontinue the antipsychotic after 2-8 months of therapy. Better understanding of the potential adverse effects of antipsychotic therapy has increased interest in the effects of the dementia-specific medications on behavioral symptoms. Reductions in neuropsychiatric symptoms have been reported from trials of individual cholinesterase inhibitors, memantine monotherapy, and memantine combined with donepezil in AD patients. Studies of small numbers of patients in open trials of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and one double-blind placebo controlled trial (rivastigmine) have reported varying degrees of improvement of behavioral symptoms and psychosis of dementia with Lewy bodies (DLB). Delusions, hallucinations, apathy, and agitation/aggression are cited as the symptom categories most likely to show significant improvement. Since few of these studies were prospectively designed to study behavioral symptoms, results must be interpreted cautiously. Treatment of behavioral symptoms in AD and other dementias is challenging. The limitations of current approaches drive the search for effective, well tolerated therapies.
...
PMID:Atypical antipsychotics for the treatment of dementia-related behaviors: an update. 1763 94

Nicotinic acetylcholine receptor (nAChR) dysfunction occurs in individuals with schizophrenia (SZ) and may also affect individuals with bipolar disorder (BP). The molecular mechanisms for these disease-associated cholinergic deficits are not known. In vitro, the protein RIC-3 (resistance to inhibitors of cholinesterase-3) aids the assembly and trafficking of alpha7-nAChRs but has unclear action on the biogenesis of alpha4/beta2-nAChRs. To evaluate RIC-3/nAChR dynamics in diseased and normal human brain tissue, we measured RIC-3, alpha7-, alpha4- and beta2-nAChRs transcript levels in postmortem prefrontal cortex of individuals with SZ (n=31), BP (n=28) and unaffected controls (NC, n=33). Of the 28 individuals with BP, 20 had a history of psychotic symptoms. We compared relative message abundances between diagnostic groups and tested correlations of RIC-3 with each nAChR message subtype. RIC-3 and alpha4 messages were significantly increased in BP compared with NC (RIC-3, P< or =0.002; alpha4, P< or =0.04). RIC-3 message was also upregulated in SZ (P< or =0.04). In BP with psychoses, RIC-3 and alpha4 levels were increased compared with BP without psychoses (both P< or =0.02) and compared with NC (RIC-3, P< or =0.0003; alpha4, P< or =0.004). In correlation regression analyses, RIC-3 expression was very highly correlated to alpha7, alpha4 and beta2 in NC (alpha7, P< or =2.5e-05; alpha4, P< or =2.5e-09; beta2, P< or =0.003) and in SZ (alpha7, P< or =1e-07; alpha4, P< or =7e-07; beta2, P< or =3e-09). RIC-3 also strongly correlated with alpha7 and alpha4 in BP (alpha7, P< or =0.003; alpha4, P< or =3.5e-07). RIC-3 was modestly correlated with beta2 in BP overall (P< or =0.04), but showed no significant correlation in BP with psychoses (P< or =0.31) compared with a significant correlation in BP without psychoses (P< or =0.007). In conclusion, coordinated RIC-3/alpha4 upregulation and discordant RIC-3/beta2 levels suggest that alpha4/beta2 nAChR deficits in BP may occur from dysregulated RIC-3 chaperoning of the beta2 nAChR subunit in a subset of patients affected by psychotic features.
...
PMID:Lack of RIC-3 congruence with beta2 subunit-containing nicotinic acetylcholine receptors in bipolar disorder. 1764 Aug 15

Patients with schizophrenia suffer from cognitive deficits which are important predictors of functional outcome. Alterations such as reduced muscarinic and nicotinic receptors in the central cholinergic system in patients with schizophrenia may contribute to these cognitive impairments. Because such deficits do not respond to neuroleptic treatment, different approaches have been developed regarding pharmacological treatments that enhance central cholinergic transmission, e.g. with acetylcholinesterase inhibitors. In this review the pathophysiology of cognitive impairment in schizophrenia, results of studies using acetylcholinesterase inhibitors (donepezil, rivastigmine, physostigmine, and galantamine), and future research strategies are presented. Till now randomized, placebo-controlled studies exist only for donepezil and rivastigmine, and none could replicate the positive results of previous trials with open designs. More trials with higher numbers of patients are needed, particularly for substances with more complex mechanisms of action (e.g. galantamine).
...
PMID:[Therapy of cognitive deficits in schizophrenia with acetylcholinesterase inhibitors. A systematic overview]. 1796 Mar 54

NT69L is a novel neurotensin (8-13) analog that produces atypical antipsychotic-like effects in animal models. Because atypical antipsychotic drugs increase dopamine (DA) and acetylcholine (ACh) efflux in the medial prefrontal cortex and DA efflux in the nucleus accumbens, the present study sought to further evaluate the putative antipsychotic-like effects of NT69L by assessing DA and ACh efflux in these regions. Dual probe microdialysis was conducted in awake freely moving male rats, without using an acetylcholinesterase inhibitor in the perfusion medium. NT69L (1.0 and 3.0 mg/kg) produced significant increases in extracellular DA and ACh efflux in the medial prefrontal cortex. NT69L (1.0 mg/kg, but not 3.0 mg/kg) produced a significant increase of DA, but not ACh, efflux in the nucleus accumbens. Pretreatment with the serotonin (5-HT)(1A) receptor antagonist WAY100635 (0.2 mg/kg) significantly attenuated the 3.0 mg/kg NT69L-induced increase in medial prefrontal cortical DA efflux. Pretreatment with NT69L (1.0 mg/kg) significantly potentiated the effects of the atypical antipsychotic drug risperidone (0.1 mg/kg) on DA, but not ACh, efflux in the medial prefrontal cortex, while pretreatment with NT69L 1.0 mg/kg failed to alter the effects of haloperidol (0.1 mg/kg) on DA or ACh efflux in either region. These findings further suggest that NT analogs may be useful alone or adjunctively for the treatment of schizophrenia.
...
PMID:The neurotensin analog NT69L enhances medial prefrontal cortical dopamine and acetylcholine efflux: potentiation of risperidone-, but not haloperidol-, induced dopamine efflux. 1798 54

(-)-Galanthamine is a selective, reversible competitive acetylcholinesterase inhibitor that has been recently approved for the symptomatic treatment of Alzheimer's disease. Galanthamine is a natural product belonging to the Amaryllidaceae family of alkaloids. The pharmacological history of galanthamine shows that the bioactive compound was discovered accidentally in the early 1950s, and the plant extracts were initially used to treat nerve pain and poliomyelitis. In addition, galanthamine had since been tested for use in anesthesiology, from facial nerve paralysis to schizophrenia. Galanthamine is a long-acting, selective, reversible and competitive AChE inhibitor that has recently been tested in AD patients and found to be readily absorbed, to be a performance enhancer on memory tests in some patients, and to be well tolerated, although some cholinergic side effects were observed. A number of total synthetic approaches have been reported, and a method for the industrial scale-up preparation of galanthamine is now being developed and patented. A variety of galanthamine derivatives have also been synthesized aiming to develop an agent free from cholinergic adverse effects. Galanthamine is a natural product that complements other synthetic drugs for the management of AD. In this account we will review the recent patent literature showing the most important advance on the chemistry of galanthamine.
...
PMID:Galanthamine, a natural product for the treatment of Alzheimer's disease. 1822 Nov 96

The alpha7 subtype of the nicotinic acetylcholine receptor (nAChR) is a target of considerable interest in CNS drug discovery, in part due to its implication in diseases of unmet medical need such as schizophrenia and Alzheimer's disease. Pharmacological distinction of this subtype from other nAChRs is exemplified by antagonists such as alpha-bungarotoxin and methyllycaconitine, and more recently by agonists that have emerged from various structural classes. Increasing evidence, both preclinical and clinical, has also demonstrated that alpha7 nAChR agonists and partial agonists can lead to improvements in cognitive performance. An attractive alternative approach to modulating alpha7 nAChR function is to enhance the effects of the endogenous neurotransmitter acetylcholine (ACh) through positive allosteric modulation (PAM). This class of compounds - positive allosteric modulators (PAMs) - could selectively modulate the activity of ACh at alpha7 nAChRs in a manner that may have significant advantages over indiscriminate and direct activation of nAChRs by nicotine/nicotinic agonists or by acetylcholinesterase inhibitors. Validation of the alpha7 nAChR-selective PAM approach requires the identification of potent and selective compounds. Initially identified nAChR allosteric modulators, including 5-hydroxyindole (5-HI), galantamine, bovine serum albumin, and SLURP-1, are weak and nonselective. More recently, potent and alpha7 nAChR-selective PAMs belonging to diverse chemotypes have emerged and are beginning to be optimized as tools for concept validation in preclinical models and in the clinic. This review summarizes the current status of nAChR-selective PAMs, from patents and published literature, and their potential for the treatment of cognitive deficits associated with neuropsychiatric and neurodegenerative disorders and other diseases.
...
PMID:Advances in the discovery of novel positive allosteric modulators of the alpha7 nicotinic acetylcholine receptor. 1822 Dec 20

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>