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)

Although there have been several case reports suggesting the beneficial effect of acetylcholinesterase inhibitors in the cognitive deficits seen in schizophrenia, controlled studies have revealed contradictory results. The aim of this study was to investigate if donepezil could improve cognitive functions in schizophrenia. Twelve schizophrenic patients, who were diagnosed according to DSM-IV criteria and who had been on a stable dose of a high-potency typical antipsychotic for a minimum period of 3 months, participated in this 12-wk double-blind, placebo controlled, cross-over study of donepezil adjunctive treatment. Patients were randomly assigned under double-blind conditions to receive 5 mg/d donepezil or placebo for 6 wk, and then were crossed over to the alternate condition for 6 additional weeks. At baseline, 6 and 12 wk, patients were evaluated with the Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, the Wechsler Memory Scale Revised (WMS-R), a test for Verbal Fluency, Trail Making Test, Parts A and B, and Wisconsin Card Sorting Test (WCST). Treatment effect was not significant in any of the cognitive measures. There were also no significant changes in the PANSS and depression scores. Nicotinic receptor desensitization may cause non-responsiveness to acetylcholine as previously suggested, but the most likely explanation appears to be that defects in other neurotransmitter systems account for the cognitive deficits seen in schizophrenic patients.
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PMID:A double-blind, placebo controlled, cross-over trial of adjunctive donepezil for cognitive impairment in schizophrenia. 1474 Oct 60

Comorbid schizophrenia and dementia is becoming an increasingly common phenomenon. Because rivastigmine, a reversible acetylcholinesterase inhibitor, appears to delay the progression of Alzheimer's disease, it may also improve or delay the cognitive and behavioural disturbances evident in elderly chronic schizophrenia patients with comorbid cognitive decline. The aim of this study was to investigate augmentative rivastigmine administration in this population and to determine any effect on cognition, behaviour and 'activity of daily living' (ADLs) capabilities. Thirteen subjects with comorbid schizophrenia and dementia were administered open-label oral rivastigmine (9 mg/day) for a period of 12 weeks. The results indicated improvement in Mini-Mental State Examination scores (P<0.01), Alzheimer's Disease Assessment Scale-cognitive subscale scores (P<0.001), ADL scores (P<0.01) and Positive and Negative Syndrome Scale scores (P<0.01). Study observations indicate beneficial effects of rivastigmine administration in this subpopulation of schizophrenia patients. Following on from other studies of cholinesterase inhibitor agents, clinical improvement in this patient subpopulation may extend to the class of cholinesterase inhibitor agents in general and not necessarily be a specific effect of any of the medications. The effects noted may be specific to the subpopulation of comorbid schizophrenia and dementia rather than schizophrenia in general. Although speculative, these effects may be related to cholinergic dysfunction, which has been hypothesized to be present in some patients with schizophrenia.
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PMID:Rivastigmine augmentation in the management of chronic schizophrenia with comorbid dementia: an open-label study investigating effects on cognition, behaviour and activities of daily living. 1548 16

This review presents data showing that apathy is common across a number of disorders. Apathy is not only common, but is also associated with significant problems: reduced functional level, decreased response to treatment, poor illness outcome, caregiver distress, and chronicity. Preliminary evidence of treatment efficacy exists for dopaminergic drugs and for amphetamines. Strong evidence of efficacy exists for acetylcholinesterase inhibitors in Alzheimer's disease, and for atypical antipsychotics in schizophrenia. Frontal-subcortical system(s) dysfunction is implicated in the causation of apathy; apathy subtypes based on the various frontal-subcortical loops may thus exist. Further research involving diagnosis, pathophysiology, and treatment is suggested.
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PMID:Apathy: why care? 1574 78

Enhancing cholinergic function has been suggested as a possible strategy for ameliorating the cognitive deficits of schizophrenia. The purpose of this study was to examine the effects of acetylcholinesterase (AChE) inhibitors in mice treated with the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, which has been suggested as an animal model of the cognitive deficits of schizophrenia. Three separate experiments were conducted to test the effects of physostigmine, donepezil, or galantamine on deficits in learning and memory induced by MK-801. In each experiment, MK-801 (0.05 or 0.10 mg/kg) or saline was administered i.p. 20 min prior to behavioral testing over a total of 12 days. At 30 min prior to administration of MK-801 or saline, one of three doses of the AChE inhibitor (ie physostigmine-0.03, 0.10, or 0.30 mg/kg; donepezil-0.10, 0.30, or 1.00 mg/kg; or galantamine-0.25, 0.50, or 1.00 mg/kg) or saline was administered s.c. Behavioral testing was performed in all experimental animals using the following sequence: (1) spatial reversal learning, (2) locomotion, (3) fear conditioning, and (4) shock sensitivity. Both doses of MK-801 produced impairments in spatial reversal learning and in contextual and cued memory, as well as hyperlocomotion. Physostigmine and donepezil, but not galantamine, ameliorated MK-801-induced deficits in spatial reversal learning and in contextual and cued memory in a dose-dependent manner. Also, physostigmine, but not donepezil or galantamine, reversed MK-801-induced hyperlocomotion. Galantamine, but not physostigmine or donepezil, altered shock sensitivity. These results suggest that AChE inhibitors may differ in their capacity to ameliorate learning and memory deficits produced by MK-801 in mice, which may have relevance for the cognitive effects of cholinomimetic drugs in patients with schizophrenia.
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PMID:Cholinesterase inhibitors ameliorate behavioral deficits induced by MK-801 in mice. 1595 97

The goal of the present study was to determine whether the architectonic criteria used to identify the core, lateral belt, and parabelt auditory cortices in macaque monkeys (Macaca fascicularis) could be used to identify homologous regions in humans (Homo sapiens). Current evidence indicates that auditory cortex in humans, as in monkeys, is located on the superior temporal gyrus (STG), and is functionally and structurally altered in illnesses such as schizophrenia and Alzheimer's disease. In this study, we used serial sets of adjacent sections processed for Nissl substance, acetylcholinesterase, and parvalbumin to identify the distinguishing cyto- and chemoarchitectonic features of the core, lateral belt, and parabelt in monkey. These criteria were evaluated in postmortem tissue from a human subject, leading to the identification of additional criteria specific to human. The criteria were validated in an additional set of eight human subjects. Regions were delineated and their volumes estimated using the Cavalieri method in these subjects, and the sources of methodologic contribution to variability of the estimates was assessed. Serial reconstructions of the auditory cortex in humans were made showing the location of the lateral belt and parabelt with respect to gross anatomical landmarks. Architectonic criteria for the core, lateral belt, and parabelt were readily adapted from monkey to human. Additionally, we found evidence for an architectonic subdivision within the parabelt, present in both species. Variability of regional volume estimates was readily constrained using a multifaceted approach to reduce potential sources of variability in regional delineation.
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PMID:Mapping auditory core, lateral belt, and parabelt cortices in the human superior temporal gyrus. 1613 38

Facilitation of central cholinergic activity may form a potential treatment strategy for cognitive impairment in schizophrenia. In a randomized, placebo-controlled, double-blind, parallel-group design, we investigated the neural correlates of cognitive effects of rivastigmine, an acetylcholinesterase inhibitor, given as an add-on therapy to antipsychotic-treated schizophrenia patients. Thirty-six chronic schizophrenia patients with mild cognitive impairment took part. After 1 week on placebo (baseline), all patients entered a double-blind protocol; 18 were allocated to receive rivastigmine and 18 placebo for the next 12 weeks (final sample with usable imaging data: 11 patients on rivastigmine, 10 on placebo). All patients underwent functional magnetic resonance imaging during a parametric 'n-back' task, involving monitoring of dots in particular locations on a screen at a given delay from the original occurrence, twice: at baseline and 12 weeks post-rivastigmine/placebo treatment. Compared to placebo, rivastigmine produced only a small and non-significant improvement in task accuracy across all conditions with no change in response latency, and increased activity in the extrastriate visual cortex in areas associated with visual and spatial attention but not in any region within the working memory network. Our observations suggest that cholinergic enhancement with rivastigmine at doses known to be effective in Alzheimer's disease does not produce strong and clinically meaningful cognitive and neural changes in schizophrenia patients treated with atypical antipsychotics although the neural effects in terms of enhanced neuronal activity in regions associated with visual and spatial attention are consistent with those reported previously with cholinergic enhancement in healthy subjects.
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PMID:Neural correlates of adjunctive rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo-controlled, double-blind fMRI study. 1618 92

The present study compared the effects of two selective dopamine (DA) D(3) receptor antagonists, SB-277011A (3, 10 and 30 mg/kg i.p.) and SB-414796A (3, 10 and 30 mg/kg i.p.) on extracellular levels of acetylcholine (ACh) in the rat medial prefrontal cortex (mPFC) by using a LC/MS-MS analytical method that permitted the detection of ACh without the necessity of adding acetylcholinesterase inhibitors to the perfusate. Furthermore, the present LC/MS-MS method permitted the simultaneous measurement of the respective concentrations of SB-277011A and SB-414796A in the same extracellular samples from the mPFC. The systemic administration of both selective DA D(3) receptor antagonists produced a significant increase in extracellular levels of Ach compared to vehicle-treated animals, which was associated with increases in extracellular concentrations of SB-277011A and SB-414796. Overall, the present findings further strengthen the likelihood of a modulation of cortical cholinergic function through a DA D(3)-mediated mechanism and suggest that selective DA D(3) receptor antagonism may be beneficial in the treatment of psychiatric diseases, such as schizophrenia, which are characterized by cognitive dysfunction.
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PMID:Selective dopamine D3 receptor antagonists enhance cortical acetylcholine levels measured with high-performance liquid chromatography/tandem mass spectrometry without anti-cholinesterases. 1669 46

In cholinergic neurons, the presynaptic choline transporter (CHT) mediates high-affinity choline uptake (HACU) as the rate-limiting step in acetylcholine (ACh) synthesis. It has previously been shown that HACU is increased by behaviorally and pharmacologically-induced activity of cholinergic neurons in vivo, but the molecular mechanisms of this change in CHT function and regulation have only recently begun to be elucidated. The recent cloning of CHT has led to the generation of new valuable tools, including specific anti-CHT antibodies and a CHT knockout mouse. These new reagents have allowed researchers to investigate the possibility of a presynaptic, CHT-mediated, molecular plasticity mechanism, regulated by and necessary for sustained in vivo cholinergic activity. Studies in various mouse models of cholinergic dysfunction, including acetylcholinesterase (AChE) transgenic and knockout mice, choline acetyltransferase (ChAT) heterozygote mice, muscarinic (mAChR) and nicotinic (mAChR) receptor knockout mice, as well as CHT knockout and heterozygote mice, have revealed new information about the role of CHT expression and regulation in response to long-term alterations in cholinergic neurotransmission. These mouse models highlight the capacity of CHT to provide for functional compensation in states of cholinergic dysfunction. A better understanding of modes of CHT regulation should allow for experimental manipulation of cholinergic signaling in vivo with potential utility in human disorders of known cholinergic dysfunction such as Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's disease, and dysautonomia.
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PMID:The high-affinity choline transporter: a critical protein for sustaining cholinergic signaling as revealed in studies of genetically altered mice. 1672 48

Cognitive impairment has the greatest impact on illness outcome in schizophrenia. The most significant challenge in schizophrenia therapeutics, thus, is to develop an efficacious treatment for cognitive impairments. Acetylcholinesterase inhibitors, such as Physostigmine and Rivastigmine, are considered effective treatments for cognitive decline in Alzheimer's Disease, where the loss of cholinergic neurons is thought to be responsible for various cognitive deficits. The current study investigated the cognitive effects of Rivastigmine given as an add-on therapy to antipsychotic-treated schizophrenia patients in a placebo-controlled double-blind design. The study initially involved 40 patients, of which 21 patients (11 assigned to Rivastigmine and 10 assigned to placebo) agreed to continued participation, remained on the study drug, and underwent assessment of executive functioning, verbal skills, verbal and spatial working memory, attention and psychomotor speed on three occasions: (i) at baseline, and then (ii) after 12 weeks and (iii) 24 weeks of treatment with placebo or Rivastigmine. The results failed to reveal significant improvement on any cognitive measure with Rivastigmine treatment, compared with the placebo treatment. Some cognitive variables showed significant practice effects in both the placebo and Rivastigmine groups. No effects were noted in symptoms or side effects ratings. The beneficial cognitive effects of Rivastigmine seen in an open-label preliminary study are not substantiated by this study. Future studies should investigate the effects of other procholinergic drugs, such as Galantamine, which also act on the nicotine receptors and may produce stronger cognitive effects in schizophrenia.
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PMID:Cognitive effects of adjunctive 24-weeks Rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo-controlled, double-blind investigation. 1679 63

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


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