Implementing evidence-based continuous quality improvement strategies in an urban Aboriginal Community Controlled Health Service in South East Queensland: a best practice implementation pilot.

BACKGROUND: The Institute for Urban Indigenous Health believes that continuous quality improvement (CQI) contributes to the delivery of high-quality care, thereby improving health outcomes for Aboriginal and Torres Strait Islander people. The opening of a new health service in 2015 provided an opportunity to implement best practice CQI strategies and apply them to a regional influenza vaccination campaign. OBJECTIVE: The aim of this project was to implement an evidence-based CQI process within one Aboriginal Community Controlled Health Service in South East Queensland and use staff engagement as a measure of success. METHOD: A CQI tool was selected from the Joanna Briggs Institute Practical Application of Clinical Evidence System (PACES) to be implemented in the study site. The study site was a newly established Aboriginal and Torres Strait Islander Community Controlled Health Service located in the northern suburbs of Brisbane. This project used the evidence-based information collected in PACES to develop a set of questions related to known variables resulting in proven CQI uptake. A pre implementation clinical audit, education and self-directed learning, using the Plan Do Study Act framework, included a total of seven staff and was conducted in April 2015. A post implementation audit was conducted in July 2015. RESULTS: There were a total of 11 pre- and post-survey respondents which included representation from most of the clinical team and medical administration. The results of the pre implementation audit identified a number of possible areas to improve engagement with the CQI process including staff training and support, understanding CQI and its impacts on individual work areas, understanding clinical data extraction, clinical indicator benchmarking, strong internal leadership and having an external data extractor. There were improvements to all audit criteria in the post-survey, for example, knowledge regarding the importance of CQI activity, attendance at education and training sessions on CQI, active involvement with CQI activity and a multidisciplinary team approach to problem solving within the CQI process. CONCLUSION: The study found that the implementation of regular, formally organized CQI strategies does have an immediate impact on clinical practice, in this case, by increasing staff awareness regarding the uptake of influenza vaccination against regional targets. The Plan Do Study Act cycle is an efficient tool to record and monitor the change and to guide discussions. For the CQI process to be effective, continued education and training on data interpretation is pivotal to improve staff confidence to engage in regular data discussions, and this should be incorporated into all future CQI sessions.

Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder.

The synthesis and structure-activity relationship of a novel series of compounds with combined effects on 5-HT(3A) and 5-HT(1A) receptors and on the serotonin (5-HT) transporter (SERT) are described. Compound 5m (Lu AA21004) was the lead compound, displaying high affinity for recombinant human 5-HT(1A) (K(i) = 15 nM), 5-HT(1B) (K(i) = 33 nM), 5-HT(3A) (K(i) = 3.7 nM), 5-HT(7) (K(i) = 19 nM), and noradrenergic ß(1) (K(i) = 46 nM) receptors, and SERT (K(i) = 1.6 nM). Compound 5m displayed antagonistic properties at 5-HT(3A) and 5-HT(7) receptors, partial agonist properties at 5-HT(1B) receptors, agonistic properties at 5-HT(1A) receptors, and potent inhibition of SERT. In conscious rats, 5m significantly increased extracellular 5-HT levels in the brain after acute and 3 days of treatment. Following the 3-day treatment (5 or 10 (mg/kg)/day) SERT occupancies were only 43% and 57%, respectively. These characteristics indicate that 5m is a novel multimodal serotonergic compound, and 5m is currently in clinical development for major depressive disorder.

Relevance of dorsal raphe nucleus firing in serotonin 5-HT(2C) receptor blockade-induced augmentation of SSRIs effects.

Selective serotonin reuptake inhibitors are the most widely prescribed antidepressant drugs. However, they exhibit a slow onset of action, putatively due to the initial decrease in serotonin cell firing mediated via somato-dendritic autoreceptors. Interestingly, blockade of 5-HT(2C) receptors significantly potentiates the effect of citalopram, a selective serotonin reuptake inhibitor, on serotonin efflux in the hippocampus and prefrontal cortex (Cremers, T.I.F.H., Giorgetti, M., Bosker, F.J., Hogg, S., Arnt, J., Mork, A., Honig, G., Bøgesø, K.P., Westerink, B.H.C., den Boer, J.A., Wikstrøm, H.V., Tecott, L.H., 2004. Inactivation of 5-HT(2C) receptors potentiates consequences of serotonin reuptake blockade. Neuropsychopharmacology 29, 1782-1789; Cremers, T.I.F.H., Rea, K., Bosker, F.J., Wikström, H.V., Hogg, S., Mørk, A., Westerink, B.H.C., 2007. Augmentation of SSRI effects on serotonin by 5-HT(2C) antagonists: mechanistic studies. Neuropsychopharmacology 32, 1550-1557.). Using in vivo electrophysiology, we show in the present study that the purported selective 5-HT(2C) receptor antagonist, SB242,084, dose-dependently counteracts citalopram-induced inhibition of serotonin cell firing. Even though the effect of SB242,084 is significant at a dose found in vivo to also partially occupy 5-HT(2A) receptors, indicating a possible contribution of a partial blockade of 5-HT(2A) receptors together with 5-HT(2C) receptors, we suggest that high occupancy at 5-HT(2C) receptors is essential for the blockade of the inhibitory effect of citalopram on 5-HT cell firing. Using microdialysis, we also show that the potentiation by SB242,084 on serotonin efflux requires an action of citalopram outside the terminal, most likely at the somato-dendritic level (i.e., on serotonin cell firing). Further experiments using local 5-HT(2C) receptor blockade indicate a role of 5-HT(2C) receptors located in the prefrontal cortex. Modulation of short or long feedback loops originating in the prefrontal cortex by 5-HT(2C) receptors could directly inhibit serotonin efflux, or alternatively, regulate serotonin cell firing in the dorsal raphe nucleus, thereby modulating serotonin efflux indirectly.

Augmentation of SSRI effects on serotonin by 5-HT2C antagonists: mechanistic studies.

The treatment of depression may be improved by using an augmentation approach involving selective serotonin reuptake inhibitors (SSRIs) in combination with compounds that focus on antagonism of inhibitory serotonin receptors. Using microdialysis coupled to HPLC, it has recently been shown that the systemic co-administration of 5-HT(2C) antagonists with SSRIs augmented the acute effect of SSRIs on extracellular 5-HT. In this paper, we have investigated the mechanism through which this augmentation occurs. The increase in extracellular 5-HT was not observed when both compounds were locally infused. However, varying the route of administration for both compounds differentially revealed that an augmentation took place when the 5-HT(2C) antagonist was locally infused into ventral hippocampus and the SSRI given systemically, but not when systemic 5-HT(2C) antagonist was co-administered with the local infusion of citalopram. This suggests that the release of extracellular serotonin in ventral hippocampus may be controlled by (an)other brain area(s). As 5-HT(2C) receptors are not considered to be autoreceptors, this would implicate that other neurotransmitter systems are involved in this process. To investigate which neurotransmitter systems were involved in the interaction, systemic citalopram was challenged with several glutamatergic, GABA-ergic, noradrenergic, and dopaminergic compounds to determine their effects on serotonin release in ventral hippocampus. It was determined that the involvement of glutamate, norepinephrine, and dopamine in the augmentation did not seem likely, whereas evidence implicated a role for the GABA-ergic system in the augmentation.

Antidepressant effects of citalopram and CRF receptor antagonist CP-154,526 in a rat model of depression.

Due to the interest in the antidepressant potential of nonpeptide corticotropin-releasing factor (CRF)(1) receptor antagonists, the present investigation examined the antidepressant-like effects of the CRF(1) receptor antagonist CP-154,526 on the exaggerated swim test immobility in the Flinders Sensitive Line (FSL) rat, a genetic animal model of depression. Chronic treatment with CP-154,526 (10 mg/kg; 2x day) for 14 days increased swimming in the Flinders Sensitive Line rats. Citalopram (5 and 10 mg/kg; 2x day) and desipramine (5 mg/kg; 1x day) also significantly increased swimming in the Flinders Sensitive Line rats, as expected. However, neither CP-154,526 nor citalopram (10 mg/kg) altered swimming times in the control Flinders Resistant Line (FRL) rats. Citalopram (10 mg/kg) and CP-154,526 also increased the abnormally low level of social interaction behavior in the Flinders Sensitive Line rats. These findings indicate that citalopram and CP154,526, a CRF(1) receptor antagonist, have both antidepressant and anxiolytic effects that can be detected in an experimental model of depression only and not in "normal" control animals.

Inactivation of 5-HT(2C) receptors potentiates consequences of serotonin reuptake blockade.

The enhancement of central serotonin system function underlies the therapeutic effects of selective serotonin reuptake inhibitors (SSRIs), which have become the most commonly used class of antidepressant agents. However, many individuals experience depressive episodes that are resistant to SSRI treatment. Homeostatic mechanisms that limit the extent to which SSRIs enhance serotonergic neurotransmission have been implicated in this phenomenon. Here, we report a novel strategy for enhancing the efficacy of SSRIs. Using in vivo microdialysis methods in rats, the nonselective 5-HT2 receptor antagonist ketanserin was observed to produce a robust augmentation of citalopram-, fluoxetine-, and sertraline-induced elevations of hippocampal extracellular serotonin levels. Similar effects were also observed in cortex. The potentiation of SSRI-induced increases in hippocampal serotonin levels was reproduced by the 5-HT(2C) receptor-selective antagonists SB 242084 and RS 102221, but not by the 5-HT(2A) receptor-selective antagonist MDL 100 907. Although 5-HT(2C) receptor antagonists augmented the actions of SSRIs, they had no effect on extracellular serotonin levels or tail suspension responses when administered alone. These results were in strong accord with independent findings using a line of 5-HT(2C) receptor-null mutant mice. Although this mutation did not affect baseline extracellular serotonin levels or tail suspension test (TST) behavior, it enhanced fluoxetine effects on serotonin levels and immobility in the TST. These findings reveal an unanticipated pharmacological action of 5-HT(2C) receptors that warrants consideration in the development of novel strategies for the treatment of depression.