Persistence of metabolic monitoring for psychiatry inpatients treated with second-generation antipsychotics utilizing a computer-based intervention.

WHAT IS KNOWN AND OBJECTIVE: Monitoring and intervention for metabolic abnormalities secondary to second-generation antipsychotics (SGAs) remain weak areas of performance in mental health care. This study evaluated the sustained impact of a computerized physician order entry (CPOE) pop-up alert designed to improve rates of laboratory metabolic monitoring of patients treated with SGAs in an inpatient psychiatry unit. Interventions carried out by the psychiatry team to manage metabolic abnormalities found on screening were also identified. METHODS: A retrospective chart review of patients treated with scheduled SGAs at a large Midwestern academic medical centre's inpatient adult psychiatry unit was conducted nearly 4 years after the initial implementation of a pop-up alert. Rates of laboratory monitoring (blood glucose level, haemoglobin A1C [HbA1c], lipid panel) were compared to those following the initial implementation. Medical charts of patients with abnormal laboratory results were also reviewed to summarize interventions made by the psychiatry team to manage identified abnormalities. RESULTS AND DISCUSSION: Patient demographics in the current study population (n = 129) were similar to those in the initial test cohort (n = 157). There was no significant decrease in monitoring of glucose levels and lipid panels (fasting or random). Nine patients with abnormally elevated laboratories were identified. Interventions by the psychiatry team included referrals to appropriate healthcare professionals and initiation of medication. WHAT IS NEW AND CONCLUSIONS: The rate of metabolic monitoring for inpatients on SGA therapy did not significantly change over time with the continued use of the CPOE pop-up alert. Optimal monitoring utilizing a CPOE pop-up alert may allow the psychiatry team, including psychiatric pharmacists, to better manage metabolic conditions.

Evaluation of a computer-based intervention to enhance metabolic monitoring in psychiatry inpatients treated with second-generation antipsychotics.

WHAT IS KNOWN AND OBJECTIVE: Second-generation antipsychotics (SGAs) play an important role in the pharmacologic management of various psychiatric conditions. Use of these medications has been associated with metabolic complications. Adherence to guideline-recommended monitoring is suboptimal. We evaluated the effect of a computerized physician order entry (CPOE) pop-up alert designed to improve rates of laboratory metabolic monitoring of patients treated with SGAs on a University Hospital inpatient psychiatry unit. METHODS: A single-centre, retrospective chart review was performed in which patient demographics and SGA drug and laboratory data were extracted from the CPOE database. We assessed the number of orders for appropriate metabolic monitoring data for patients admitted within a 6-month period before or after the alert implementation. RESULTS AND DISCUSSION: Pre-alert (n = 171) and post-alert (n = 157) groups were similar with respect to age, length of stay, sex, race and comorbidities. Following alert implementation, significant increases in monitoring both random (92.4% vs. 100%) and fasting (46.8% vs. 70%) glucose levels as well as random (28.7% vs. 74.5%) and fasting (18.7% vs. 59.9%) lipid panels (all P ≤ 0.001) were observed. The number of patients with both a fasting glucose level and fasting lipid panel available for monitoring increased from 12.9% to 47.8% (P < 0.0001). Significantly more post-alert laboratory orders were submitted at the same time as the SGA drug order (P < 0.0001), suggesting that the alert itself had a direct influence on the ordering of metabolic monitoring labs. WHAT IS NEW AND CONCLUSIONS: Implementation and use of an electronic pop-up alert in an inpatient psychiatric unit significantly improved rates of ordering fasting blood glucose and lipid levels for inpatients treated with SGAs. Overall rates remain suboptimal, suggesting a need for additional strategies to further improve metabolic monitoring.

Amino alcohol modulation of hippocampal acetylcholine release.

The synthesis and release of 3H-acetylcholine was measured in hippocampal slices of adult rat brain following acute in vitro exposure to ethanolamine. Evoked release of 3H-acetylcholine was elevated by 60-70% but 3H-acetylcholine synthesis was unaffected. Other amino alcohols were also found to significantly increase evoked 3H-acetylcholine release. The effect may be stereochemically mediated since only one of four possible propanolamine configurations, R-alaninol, was active. The most potent compound tested was R-prolinol which showed an EC50 nearly 10-fold lower than that of either R-alaninol or ethanolamine; S-prolinol was inactive. Slices taken from adult rats which had been fed active compounds for two weeks also exhibited enhancements in evoked 3H-acetylcholine release. These results indicate that amino alcohols modulate acetylcholine release in the rat hippocampus.

Modulation of acetylcholine release in rat hippocampus by amino alcohols and Bay K 8644.

The amino alcohols ethanolamine, R-alaninol and R-prolinol were shown to enhance high potassium evoked release of [3H]acetylcholine from hippocampal slices by monitoring fractional release of tritium during superfusion. This action appeared to be unique to hippocampal cholinergic nerve terminals because R-prolinol did not modulate evoked release of acetylcholine from cortical or striatal slices, dopamine from striatal slices or norepinephrine from hippocampal slices. Bay K 8644, a dihydropyridine activator of calcium L-channels, exhibited a similar specificity profile. Bay K 8644 decreased the EC50 of R-prolinol without changing the maximal response, indicating that the actions of these two compounds converge through a common cellular mechanism. The effect of R-prolinol was blocked by the L-channel antagonists diltiazem and verapamil but not by nifedipine. In contrast, nifedipine only and not diltiazem or verapamil, blocked the enhancement induced by Bay K 8644. It appears then that amino alcohols can modulate the release of acetylcholine in the hippocampus possibly by enhancing calcium entry into nerve terminals through a specific activation of presynaptic L-channels at a site other than that which interacts with dihydropyridines.

Distinct influences of nerve growth factor and a central cholinergic trophic factor on medial septal explants.

A central cholinergic trophic factor (C-CTF), previously reported in hippocampal extracts, enhances acetylcholine synthesis (ACh) and to a lesser extent choline acetyltransferase (ChAT) activity in cultured explants of the rat medial septal nucleus. Nerve growth factor (NGF) has been reported to enhance ChAT in several systems in vitro and in vivo, and clearly stimulates septal explants. At optimal concentrations of NGF and C-CTF, there is an additive effect on ChAT activity. The effects of NGF on ACh synthesis are minimal. Antibodies to NGF block effects of added NGF but have no effects on C-CTF activity. The ability of C-CTF to enhance ACh synthesis appears related to its ability to enhance the acetylation of the choline that has been taken up by a sodium dependent, high affinity transport system. Thus, actions of NGF and C-CTF appear qualitatively and quantitatively distinct, yet both can influence the cholinergic activity of the developing medial septal nucleus.

Use of [3H]-GBR12935 to measure dopaminergic nerve terminal growth into the developing rat striatum.

In this study we determined the temporal association between the appearance of the dopamine transporter, measured by 1-[2-(diphenyl-methoxy)ethyl]-4-(3- phenylpropyl)-piperazine ([3H]-GBR12935), a potent and selective inhibitor of dopamine uptake, and other biochemical markers of dopaminergic nerve terminal growth into the developing striatum. [3H]-GBR12935 binding was minimally detected in the rudimentary striatum of embryonic day 14 rat brains, increased to 23% of the adult level by birth, and reached the adult level during the fifth postnatal week. This finding contrasts with a slower developmental increase in [3H]-dopamine uptake, a functional measure of the transporter. Tyrosine hydroxylase activity levels followed a developmental curve similar to that of [3H]-GBR12935 binding but did not reach adult levels until the 7th postnatal week. Dopamine content increased at a slower rate, being only 10% and 92% of the adult level at birth and postnatal week 8, respectively. These results indicate that the appearance of a structural, but not optimally functional, dopamine transporter may be the earliest detectable biochemical index of dopaminergic nerve terminal growth into the striatum during development.

Detergent solubilization and hydrophobic chromatography of rat brain phosphatidylinositol kinase.

Rat brain microsomal phosphatidylinositol kinase activity was maximally activated in the presence of either 3 mM sodium deoxycholate, 2% Triton-X-100, or 30-40 mM octylglucoside. Among these detergents, 1% Triton-X-100 was most effective in solubilizing the enzyme, and after treatment with this agent, 100% of the activity was recovered in the high speed supernatant. Octylglucoside solubilized 40% of the enzyme at concentrations below its critical micelle concentration of 25 mM and up to 80% at higher levels. Solubilized phosphatidylinositol kinase failed to absorb to adenosine nucleotide affinity resins. However, when the Triton-X-100 extract was chromatographed on an uncharged hydrophobic resin, consisting of dodecyl chains attached to Sepharose 4B by ether bonds, nearly all the enzyme activity was retained, and from 44-85% could be eluted with 8 mM sodium deoxycholate. Solubilization followed by hydrophobic chromatography resulted in several-fold purification of phosphatidylinositol kinase and may have disrupted interactions of the enzyme with other hydrophobic proteins sufficiently to allow its substantial purification by conventional or affinity chromatography techniques.

A tyrosine hydroxylase assay in microwells using coupled nonenzymatic decarboxylation of dopa.

A radiometric assay for tyrosine hydroxylase employing a coupled nonenzymatic decarboxylation of L-[14C]Dopa formed from L-[14C]tyrosine has been adapted for performance in a 96 microwell culture plate. The method uses an easily manufactured plate holder to compress blotting paper impregnated with methylbenzethonium hydroxide against the top rim of each well. This forms isolated, airtight compartments in which 14CO2 is evolved and quantitatively absorbed into the blotting paper. The method is sensitive enough to detect the production of less than 5 pmol of 14CO2. A major advantage of this system is that cells can be grown in tissue culture and subsequently assayed for tyrosine hydroxylase activity in the same well. The method is more facile than previously devised procedures, allowing for the simultaneous assay of up to 96 samples totally contained in a single, compact, portable unit.

Phosphoethanolamine enhances high-affinity choline uptake and acetylcholine synthesis in dissociated cell cultures of the rat septal nucleus.

Dissociated rat septal nucleus cells cultured in defined medium exhibited twofold increases in the maximal rates of sodium-dependent, high-affinity choline uptake and acetylcholine formation when grown in the presence of phosphoethanolamine. The effect was concentration-dependent (EC50 = 15 microM) and appeared to be associated with in vitro maturation of cholinergic neurons rather than with enhanced survival. Choline acetyltransferase, acetylcholinesterase, and choline kinase activities were unaffected by this treatment. The effect of phosphoethanolamine was specific for cholinergic neurons, because treatment with this compound did not alter the kinetic constants for high-affinity neuronal uptake of gamma-aminobutyric acid or dopamine. The action appeared to be mediated primarily through activation of the sodium-dependent, high-affinity transport mechanism for choline as opposed to alterations in the storage and release of acetylcholine.

Purification and characterization of a central cholinergic enhancing factor from rat brain: its identity as phosphoethanolamine.

A compound that can enhance the apparent synthesis of acetylcholine in cultured explants of the medial septal nucleus has been purified from rat brain and identified as phosphoethanolamine. Acetylcholine synthesis is stimulated two- to threefold in cultures grown for 5 days in the presence of phosphoethanolamine, ethanolamine, or cytidine 5'-diphosphoethanolamine at concentrations above 100 microM. This effect appears to result from an increase in the accumulation of choline via the high-affinity, sodium-dependent uptake mechanism. The development of choline acetyltransferase activity is not affected. Phosphoethanolamine and ethanolamine seem to enhance the ability of developing cholinergic neurons to utilize choline accumulated via the sodium-dependent high-affinity choline uptake mechanism for the preferential production of acetylcholine without increasing the general metabolism of the cultures. Choline itself and its related derivatives are not stimulatory for these effects.

Regulation of plasma membrane Ca2+ ATPases by lipids of the phosphatidylinositol cycle.

When the erythrocyte plasma membrane Ca2+ pump is reconstituted into phosphatidylcholine liposomes, the inclusion of small amounts of phosphatidic acid or phosphatidylinositol 4,5-bisphosphate stimulates the enzyme's activity. Other lipids of the phosphatidylinositol cycle (diacylglycerol, phosphatidylinositol) have little effect. The stimulatory effect of phosphatidylinositol 4,5-bisphosphate is greater than that of calmodulin; this lipid also stimulates the plasma membrane Ca2+ ATPase from rat brain.