Showing papers by "Alasdair M. Barr published in 2012"

Cognitive reserve, presynaptic proteins and dementia in the elderly

Abstract: Differences in cognitive reserve may contribute to the wide range of likelihood of dementia in people with similar amounts of age-related neuropathology. The amounts and interactions of presynaptic proteins could be molecular components of cognitive reserve, contributing resistance to the expression of pathology as cognitive impairment. We carried out a prospective study with yearly assessments of N=253 participants without dementia at study entry. Six distinct presynaptic proteins, and the protein–protein interaction between synaptosomal-associated protein 25 (SNAP-25) and syntaxin, were measured in post-mortem brains. We assessed the contributions of Alzheimer's disease (AD) pathology, cerebral infarcts and presynaptic proteins to odds of dementia, level of cognitive function and cortical atrophy. Clinical dementia was present in N=97 (38.3%), a pathologic diagnosis of AD in N=142 (56.1%) and cerebral infarcts in N=77 (30.4%). After accounting for AD pathology and infarcts, greater amounts of vesicle-associated membrane protein, complexins I and II and the SNAP-25/syntaxin interaction were associated with lower odds of dementia (odds ratio=0.36–0.68, P<0.001 to P=0.03) and better cognitive function (P<0.001 to P=0.03). Greater cortical atrophy, a putative dementia biomarker, was not associated with AD pathology, but was associated with lower complexin-II (P=0.01) and lower SNAP-25/syntaxin interaction (P<0.001). In conclusion, greater amounts of specific presynaptic proteins and distinct protein–protein interactions may be structural or functional components of cognitive reserve that reduce the risk of dementia with aging.

Differential effects of 3 classes of antidiabetic drugs on olanzapine-induced glucose dysregulation and insulin resistance in female rats.

Abstract: Background: The second-generation antipsychotic drug olanzapine is an effective pharmacological treatment for psychosis. However, use of the drug is commonly associated with a range of metabolic side effects, including glucose intolerance and insulin resistance. These symptoms have been accurately modelled in rodents. Methods: We compared the effects of 3 distinct classes of anti dia betic drugs, metformin (100 and 500 mg/kg, oral), rosiglitazone (6 and 30 mg/kg, oral) and glyburide (2 and 10 mg/kg, oral), on olanzapineinduced metab olic dysregulation. After acutely treating female rats with lower (7.5 mg/kg) or higher (15 mg/kg) doses of olanzapine, we assessed glucose intolerance using the glucose tolerance test and measured insulin resistance using the homeostatic model assess ment of insulin resist ance equation. Results: Both doses of olanzapine caused pronounced glucose dysregulation and insulin resist ance, which were significantly reduced by treatment with metformin and rosiglitazone; however, glucose tolerance did not fully return to control levels. In contrast, glyburide failed to reverse the glucose intolerance caused by olanzapine despite increasing insulin levels. Limitations: We evaluated a single antipsychotic drug, and it is unknown whether other antipsychotic drugs are similarly affected by anti diabetic treatments. Conclusion: The present study indicates that oral hypoglycemic drugs that influence hepatic glucose metab olism, such as metformin and rosiglitazone, are more effective in regulating olanzapine-induced glucose dysregulation than drugs primarily affecting insulin release, such as glyburide. The current model may be used to better understand the biological basis of glucose dysregulation caused by olanzapine and how it can be reversed.

Pharmacological Risk Factors for Delirium after Cardiac Surgery: A Review

Abstract: Purpose: The objective of this review is to evaluate the literature on medications associated with delirium after cardiac surgery and potential prophylactic agents for preventing it.

Antipsychotic medications: linking receptor antagonism to neuropsychological functioning in first episode psychosis.

Abstract: Antipsychotic medications can contribute to neurocognitive and motor impairments, but specific links to individualized pharmacological treatment regimens are unclear. In 68 participants with stabilized first-episode psychosis (FEP), we investigated the links between neuropsychological functions and an established anticholinergic potency index and a new D2 antagonist potency index developed in our lab. Each participant's psychiatric medication regimen was converted into estimated receptor antagonist loads based upon specific medication dosage(s) and reported in vitro brain muscarinic cholinergic and D2 receptor antagonism. In addition to the global neuropsychological impairments of FEP participants, the findings supported the hypothesized links between receptor antagonist loads and specific deficits. Higher anticholinergic load was associated with poorer delayed verbal memory but was not related to motor functioning. In contrast, higher D2 load was associated with poorer motor functioning but not verbal memory. These selective antagonist load associations explained 19% of the variance in motor functioning and 17% of the variance in delayed verbal memory. Evidently, some of the neuropsychological impairments found in persons with FEP are selectively related to the specific pharmacodynamics and the dosing of their medication regimens. Moreover, these effects can be readily estimated from practical and inexpensive indices. (JINS, 2012, 18, 1–11)

Adverse events associated with switching antipsychotics.

Abstract: Antipsychotics are the first-line agents for managing schizophrenia and related disorders. As with other chronic illnesses, clinicians must often decide whether to switch a patient’s current medication to try to improve treatment response, reduce intolerable side effects and improve quality of life and functioning. Unfortunately, guidance for switching among antipsychotics is lacking, as minimal clinical research on switching strategies exists. During a switch, patients often experience adverse events that require monitoring. These events are the result of a complex pharmacology in which antipsychotics target various receptor subtypes (e.g., D2, 5-HT2A, M1, α1, H1) with varying degrees of affinity. Often, long-term antagonism of these receptors results in physiologic counter-adaptations, such as receptor upregulation. For example, if a patient switches too quickly from an antipsychotic with high affinity for a given receptor to one with low affinity, rebound and withdrawal symptoms can develop. Conversely, switching too quickly from an antipsychotic with low receptor affinity to one with high affinity can exceed the body’s ability to adapt to the medication and result in receptor-related adverse events. It is recommended that clinicians switch medications gradually to avoid adverse effects. The method (e.g., cross-taper) and duration of switching depend on many variables, including the receptor profile, receptor affinity and the pharmacokinetic parameters of each antipsychotic.1,2 In cases of a significant adverse event, the only option may be to abruptly switch antipsychotics. Overstimulation of mesolimbic D2 receptors likely contributes to the expression of psychosis. Switching from low- to high-affinity D2 antagonists (e.g., quetiapine to haloperidol) can result in dyskinesias, parkinsonism, akathisia and acute dystonias. In these cases, clinicians should decrease the dose of the high-affinity agent and titrate more slowly. If akathisia persists, β-blockers or benzodiazepines may improve symptoms. Conversely, when switching from high- to low-affinity D2 antagonist, patients may experience breakthrough psychosis, withdrawal dyskinesias and akathisia that may be indistinguishable from agitation. Tapering of the high-affinity agent should be slowed to allow more time for receptor adaptation. Second-generation antipsychotics also exert their effects in part through the 5-HT2A receptor. When switching from a drug with high affinity for 5-HT2A to one with low affinity (e.g., olanzapine to quetiapine), rebound effects can include agitation, diaphoresis, fever, tremor and confusion. Slow titration over a few weeks should mitigate the occurrence of these adverse events. Cholinergic M1 receptors control salivation, smooth muscle contractions in the digestive and urinary tracts, memory and cognition. Switching from a low to a high-affinity M1 antagonist (e.g., risperidone to olanzapine) can result in memory and cognitive impairment, dry mouth, constipation and urinary retention. Sugarless, hard candy may alleviate dry mouth, and increasing water and fibre may relieve constipation. Switching from a high- to a low-affinity drug can result in a cholinergic rebound with malaise, nausea, vomiting, diarrhea, sialorrhea, extra-pyramidal symptoms and akathisia. A low-dose anticholinergic may be necessary to control such effects during a switch. Adrenergic α1 receptors control vascular smooth muscle contraction. Orthostatic hypotension may be a concern when switching from a low- to a high-affinity α1 antagonist (e.g., olanzapine to clozapine). Conversely, switching from a high- to a low-affinity drug may result in rebound hypertension, tachycardia, tremor and restlessness. Blood pressure should be monitored regularly during the switch. Many antipsychotics block H1 receptors, and switching to a high-affinity drug (e.g., ziprasidone to clozapine) may result in sedation, increased appetite and weight gain. Patients should be informed of these potential effects and the importance of a balanced diet and physical activity. Switching from a high- to a low-affinity H1 blocker may result in insomnia, agitation, anxiety, and akathisia. A sedative and/or anxiolytic may alleviate these effects. Owing to the diverse receptor profile of antipsychotics, many adverse events may be observed when switching medications. Clinicians should be cautious and closely monitor patients for potential adverse events during the switch. There is a strong need for more clinical research on this topic and for additional resources to help clinicians implement optimal switching strategies to reduce patient discomfort.

Attention Deficits in Chronic Methamphetamine Users as a Potential Target for Enhancing Treatment Efficacy

Abstract: Received: 19 May 2012 First Revision: 26 June 2012 Accepted: 10 July 2012