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

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Query: EC:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Delusions are commonly encountered symptoms in patients with Alzheimer's disease and may lead to significant morbidity. The purpose of this article is to review all clinical trials to date focusing on the management of delusions in patients with Alzheimer's disease to determine the level of evidence for treatment. To achieve this objective, Medline was searched using the key words delusions, dementia, Alzheimer's disease and psychosis. Three main categories of treatment were identified: atypical antipsychotics, cholinesterase inhibitors, and other miscellaneous treatments. It was concluded that all forms of treatment were effective although the greatest burden of evidence existed for risperidone and donepezil. Side effects were noted in all forms of treatment and included somnolence and extrapyramidal effects for antipsychotic medications, whereas gastrointestinal effects were more prevalent in studies involving cholinesterase inhibitors. Further large scale, double-blind, randomized, controlled studies are required before a definitive conclusion can be reached. To our knowledge this is the only systematic review of this area.
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PMID:Treatment of delusions in Alzheimer's disease--response to pharmacotherapy. 1690 81

The fact that muscarinic antagonists may evoke a psychotic state ('antimuscarinic psychosis'), along with findings of cholinergic alterations in schizophrenia, have kindled an interest in the involvement of the cholinergic system in this disorder. Latent inhibition (LI) is a cross-species phenomenon manifested as a poorer conditioning of a stimulus seen when the stage of conditioning is preceded by a stage of repeated nonreinforced pre-exposure to that stimulus, and is considered to index the capacity to ignore irrelevant stimuli. Amphetamine-induced LI disruption and its reversal by antipsychotic drugs (APDs) is a well-established model of positive symptoms of schizophrenia. Here, we tested whether the muscarinic antagonist scopolamine would disrupt LI and whether such disruption would be reversed by APDs and by the acetylcholinesterase inhibitor physostigmine. The results showed that scopolamine at doses of 0.15 and 0.5 mg/kg disrupted LI, and that this effect was due to the action of the drug in the pre-exposure stage, suggesting a role of muscarinic transmission in attentional processes underlying LI. Both the typical and the atypical APDs, haloperidol and clozapine, reversed scopolamine-induced LI disruption when given in conditioning or in both stages, but not in pre-exposure, indicating that the mechanism of antipsychotic action in this model is independent of the mechanism of action of the propsychotic drug. Scopolamine-induced LI disruption was reversed by physostigmine (0.05 and 0.15 mg/kg), which was ineffective in reversing amphetamine-induced LI disruption, pointing to distinct mechanisms underlying LI disruption by these two propsychotic drugs. The latter was further supported by the finding that unlike amphetamine, the LI-disrupting doses of scopolamine did not affect activity levels. We propose scopolamine-induced LI disruption as a model of cholinergic-related positive symptoms in schizophrenia.
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PMID:Scopolamine induces disruption of latent inhibition which is prevented by antipsychotic drugs and an acetylcholinesterase inhibitor. 1697 98

Parkinson's disease dementia (PDD) ultimately develops in about 80% of patients with Parkinson's disease (PD), and cross-sectional studies have found that some 30% of these patients will experience neuropsychiatric symptoms, such as visual hallucinations and psychosis. The most consistently reported risk factors for dementia in PD are age, severe parkinsonism and mild cognitive impairment. In PDD, both subcortical cognitive and cortical cognitive profiles are described. Specific disorders of sleep, such as rapid eye movement sleep behaviour disorder, excessive daytime sleepiness and sleep attacks, occur frequently. Alzheimer and Lewy body pathology coexist, but the Lewy body pathology in limbic and cortical areas seems to be the main cause of dementia. Neurochemical changes in the biogenic amines and acetylcholine are common, and magnetic resonance imaging studies have shown cortical atrophy in wide cortical areas, including the hippocampus. All PD patients should be screened for mild cognitive impairment and dementia. A large randomised clinical trial showed that the cholinesterase inhibitor rivastigmine has desirable effects on cognition and neuropsychiatric symptoms in PDD patients. Atypical antipsychotic agents may improve psychosis in PDD, but the evidence for this is poor and adverse effects from such therapy are common and may be severe. Non-pharmacological interventions can also be effective but require further study.
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PMID:Management of Parkinson's disease dementia : practical considerations. 1706 84

Cholinergic receptors (AChR) are reported altered in brains from schizophrenic patients, and a growing body of evidence suggests that muscarinic receptor agonists exhibit antipsychotic potential. Centrally acting selective muscarinic receptor agonists are currently not available for clinical use, but acetylcholinesterase (AChE) inhibitors, which indirectly stimulate AChR by blocking the breakdown of acetylcholine by AChE, are widely used in the clinic against Alzheimer's disease. AChE inhibitors have been reported to exhibit antipsychotic efficacy in Alzheimer's disease patients, and these compounds have also been investigated as adjunctive treatment to antipsychotic medication in schizophrenic patients with varying results. However, monotherapy with AChE inhibitors in schizophrenic patients has not been evaluated. We wanted to investigate the antipsychotic potential of the AChE inhibitor galantamine, which also allosterically potentiates nicotinic receptor stimulation. To this end, we investigated its ability to antagonize d-amphetamine-induced psychotic-like behavior in extrapyramidal side effects (EPS)-primed Cebus monkeys. Galantamine inhibited d-amphetamine-induced unrest, arousal, and stereotypy. Side effects such as emesis, sedation, and EPS were minor or not existing. The results indicate that AChE inhibitors have antipsychotic potentials and suggest that clinical trials investigating antipsychotic effects of AChE inhibitors as monotherapy would be of interest.
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PMID:The acetylcholinesterase inhibitor galantamine inhibits d-amphetamine-induced psychotic-like behavior in Cebus monkeys. 1737 45

Parkinson's disease (PD) is a chronic, neurodegenerative disease with degeneration of the central dopaminergic neurons in the substantia nigra, leading to a depletion of dopamine (DA) in the striatum. This depletion causes the clinical hallmarks of this disease: bradykinesia, hypokinesia, rigidity, tremor and postural instability. Besides these well known motor symptoms, non-motor symptoms may develop, such as hyposmia, sleep disorders, autonomic disturbances, depression, cognitive impairment and psychosis. Pathophysiological mechanisms underlying these symptoms not only comprise Lewy body pathology in the central dopaminergic system, but also in the noradrenergic, serotinergic and cholinergic transmittersystems. Indeed, in Parkinson's disease, about 30-40% of the patients suffers fluctuating psychotic symptoms, mainly paranoid delusions and/or visual or acoustic hallucinations, symptoms considered to represent major contributors to patient and caregiver distress and nursing home placement. Endogenous (related to the disease process itself) as well as exogenous (related to therapeutical interventions) psychotogenic factors may contribute to the development of psychotic symptoms in PD. Therapeutical strategies, therefore, are aimed to reduce both endogenous and exogenous factors. To reduce endogenous psychotogenic factors, cholinesterase inhibitors, suggested to reduce cognitive deterioration, now seem to be the drugs of choice. In exogenously induced psychotic symptoms, atypical antipsychotics are considered the most effective. However, as psychotic symptoms in PD are often influenced by both endogenous and exogenous factors, a combination of both strategies may be preferred.
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PMID:PD-related psychosis: pathophysiology with therapeutical strategies. 1744 13

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.
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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.
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PMID:Lack of RIC-3 congruence with beta2 subunit-containing nicotinic acetylcholine receptors in bipolar disorder. 1764 Aug 15

Alzheimer's disease (AD) is the most common cause of dementia affecting nearly 18 million people around the world and 4.5 million in the US. It is a progressive neurodegenerative condition that is estimated to dramatically increase in prevalence as the elderly population continues to grow. As the cognitive and neuropsychiatric signs and symptoms of AD progresses in severity over time, affected individuals become increasingly dependent on others for assistance in performing all activities of daily living. The burden of caring for someone affected by the disorder is great and has substantial impact on a family's emotional, social and financial well-being. In the US, the currently approved medications for the treatment of mild to moderate stages of AD are the cholinesterase inhibitors (ChEIs). Cholinesterase inhibitors have shown modest efficacy in terms of symptomatic improvement and stabilization for periods generally ranging from 6 to 12 months. There are additional data that have emerged, which suggest longer-term benefits. For the moderate to severe stages of AD, memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist is in widespread use and has shown modest benefit as monotherapy and in combination with ChEIs. The cost effectiveness of the currently available therapeutic agents for AD has undergone great scrutiny and remains controversial, especially outside the US. Neuropsychiatric symptoms such as agitation and psychosis are common in AD. Unfortunately, in the US there are no Food and Drug Administration (FDA)-approved agents for the treatment of these symptoms, although atypical antipsychotics have shown some efficacy and have been widely used. However, the use of these agents has recently warranted special caution due to reports of associated adverse effects such as weight gain, hyperlipidemia, glucose intolerance, cerebrovascular events, and an increased risk for death. Alternative agents used to treat neuropsychiatric symptoms include serotonergic antidepressants, benzodiazepines, and anticonvulsant medications.
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PMID:Treatment of Alzheimer's disease across the spectrum of severity. 1804 10

The authors review current literature on hallucinations in Parkinson's disease (PD). Recent neuropathological studies showed that hallucinations occur in synucleinopathies and are a significant predictor of Lewy Body depositions. Therefore, hallucinations are a hallmark of PD and of dementia with Lewy Bodies. Visual hallucinations are mostly complex and kinematic; preserved or disturbed insight on the nature of hallucinations is a major prognostic factor, although eventually all hallucinators will present with reduced insight. Current theories on the origin of hallucinations point to visual dysfunction, dream overflow and cognitive impairment, yet objection can be raised on each one of the putative models of hallucinations. Understanding of the origin of hallucinations is required in order to develop treatments: all treatment evaluations were focused in general on psychosis, and only clozapine obtained positive evidence-based ratings on efficacy. However, it is likely that cholinesterase inhibitors, antipsychotics and anti-5-hydroxytryptamine(3) agents and drugs acting on sleep regulation will have different and perhaps opposite effects on different types of hallucinations, whether they are accompanied by disturbed insight, sleep disorders or other psychotic features. Further studies will try to separate phenomenology and responses to treatment and will investigate the relevance of concomitant sleep disorders and abnormality of frontoparietal networks involved in the attention process.
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PMID:New approaches to understanding hallucinations in Parkinson's disease: phenomenology and possible origins. 1805 66

Diagnosis and treatment of dementia in nursing homes and assisted living facilities remains challenging since response to treatment and disease course varies for the common degenerative dementias. Four cholinesterase inhibitors and an N-methyl-D-aspartate glutamate receptor antagonist are approved by the US Food and Drug Administration for the treatment of Alzheimer's disease (AD). Treatment with AD medications is clinically efficacious and associated with reduced caregiver burden. Some controlled trials have reported that cholinesterase inhibitors and memantine ameliorate dementia-related behavioral symptoms. Antipsychotic therapy is often used for intractable behavioral symptoms or psychosis not responding to nonpharmacologic interventions and antidementia medications; however, the risk/benefit ratio for each patient should be critically evaluated, because treatment with atypical antipsychotics has been associated with serious adverse events, including increased risk for death in older adults with dementia.
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PMID:Current issues in dementia pharmacotherapy. 1809 83


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