Reactions to treatment debriefing among the participants of a placebo controlled trial

BACKGROUND: A significant proportion of trial participants respond to placebos for a variety of conditions. Despite the common conduct of these trials and the strong emphasis placed on informed consent, very little is known about informing participants about their individual treatment allocation at trial closure. This study aims to address this gap in the literature by exploring treatment beliefs and reactions to feedback about treatment allocation in the participants of a placebo-controlled randomized clinical trial (RCT). METHODS: Survey of trial participants using a semi-structured questionnaire including close and open-ended questions administered as telephone interviews and postal questionnaires. Trial participants were enrolled in a double-blind placebo-controlled RCT evaluating the effectiveness of corticosteroid for heel pain (ISRCTN36539116). The trial had closed and participants remained blind to treatment allocation. We assessed treatment expectations, the percentage of participants who wanted to be informed about their treatment allocation, their ability to guess and reactions to debriefing. RESULTS: Forty-six (73%) contactable participants responded to our survey. Forty-two were eligible (four participants with bilateral disease were excluded as they had received both treatments). Most (79%) participants did not have any expectations prior to receiving treatment, but many 'hoped' that something would help. Reasons for not having high expectations included the experimental nature of their care and possibility that they may get a placebo. Participants were hopeful because their pain was so severe and because they trusted the staff and services. Most (83%) wanted to be informed about their treatment allocation and study results. Over half (55%) said they could not guess which treatment they had been randomized to, and many of those who attempted a guess were incorrect. Reactions to treatment debriefing were generally positive, including in placebo responders. CONCLUSION: Our study suggests that most trial participants want to be informed about their treatment allocation and trial results. Further research is required to develop measure of hope and expectancy and to rigorously evaluate the effects of debriefing prospectively

Creation of an open-access, mutation-defined fibroblast resource for neurological disease research.

Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community

Apomorphine-induced yawning in rats is abolished by bilateral 6-hydroxydopamine lesions of the substantia nigra.

Apomorphine-induced yawning was studied in male rats with bilateral 6-hydroxydopamine lesions of the substantia nigra. Apomorphine 10, 20 and 50 micrograms/kg SC induced dose-dependent yawning in unoperated controls and animals with sham lesions. In the lesioned animals (in which the mean striatal dopamine depletion was 67%), the maximum yawning response rate was greatly attenuated with no evidence that the dose response curve was shifted in either direction. Furthermore, blockade of yawning in the lesioned animals was not simply due to suppression by other stereotyped behaviours, since there was no evidence of increased sniffing or chewing in these animals. These data provide further support for the hypothesis that apomorphine-induced yawning is mediated by dopamine autoreceptors and requires intact nigrostriatal projections

Pharmacological characterization of the behavioural syndrome induced by the NK-3 tachykinin agonist senktide in rodents: evidence for mediation by endogenous 5-HT.

The effects of various manipulations of brain 5-HT mechanisms on the behavioural responses induced by the selective NK-3 tachykinin agonist senktide in rodents were assessed. Senktide elicited wet dog shakes in the rat which were attenuated by the 5-HT1C/2 antagonist mianserin and the selective 5-HT2 antagonist altanserin. Senktide-induced forepaw treading was stereospecifically attenuated by the 5-HT1A + B antagonist (-)-alprenolol. Senktide also elicited chewing mouth movements and yawning, which were unaffected by mianserin, altanserin, (+)- or (-)-alprenolol, or the selective 5-HT3 antagonist ICS 205-930, but attenuated by the muscarinic antagonist scopolamine. Penile grooming elicited by senktide was attenuated by mianserin, but was unaffected by the other antagonists. Senktide-induced wet dog shakes were enhanced by the 5-HT reuptake inhibitors citalopram and fluoxetine, suppressed by the monoamine oxidase (MAO)-B inhibitor pargyline, but unaffected by the MAO-A inhibitor clorgyline. Forepaw treading was potentiated by citalopram and clorgyline, but not significantly altered by fluoxetine or pargyline. Depletion of 5-HT by p-chlorophenylalanine (PCPA) in the rat attenuated senktide-induced wet dog shakes and forepaw treading. Neither PCPA nor 5,7-dihydroxytryptamine affected senktide-induced behaviours in the mouse, but the degree of brain 5-HT depletion caused by these treatments in mice was relatively small. These findings indicate that stimulation of NK-3 tachykinin receptors by senktide results in a complex behavioural syndrome which is mediated by multiple 5-HT receptors, and dependent upon intact stores of endogenous 5-HT. Independent stimulation of brain cholinergic mechanisms by senktide is also confirmed

The NK-3 tachykinin agonist senktide elicits yawning and chewing mouth movements following subcutaneous administration in the rat. Evidence for cholinergic mediation.

The selective NK-3 tachykinin receptor agonist senktide elicited yawning, chewing mouth movements and sexual arousal following subcutaneous administration (0.1-1.0 mg/kg) in the rat. These responses were not significantly affected by the dopamine antagonist haloperidol (0.03 mg/kg) or by 6-hydroxydopamine lesions of the nigrostriatal projection. In contrast, the behaviours were markedly attenuated by the peripheral and central muscarinic antagonist scopolamine (1 mg/kg), but not by the peripheral muscarinic antagonist N-methylscopolamine (1 mg/kg). These findings suggest that stimulation of NK-3 receptors produces yawning, chewing and sexual arousal by directly activating central cholinergic neurons

Chronic neuroleptic-induced mouth movements in the rat: suppression by CCK and selective dopamine D1 and D2 receptor antagonists.

Fluphenazine decanoate (25 mg/kg IM every 3 weeks x 6) resulted in spontaneous vacuous chewing mouth movements and jaw tremor in male Sprague-Dawley rats. These movements could be suppressed by the selective D1 or D2 dopamine antagonists SCH 23390 (0.5 mg/kg) and raclopride (0.5 mg/kg), respectively, and by CCK-8S (50 micrograms/kg). Fluphenazine-induced mouth movements were unaffected by the selective CCK antagonist MK-329, and by a dose of physostigmine (50 micrograms/kg) sufficient to stimulate mouth movements in placebo treated rats. Scopolamine (0.1 mg/kg) suppressed spontaneous mouth movements in placebo-treated rats, but the effect on fluphenazine-induced mouth movements was not significant. A higher dose of scopolamine (0.5 mg/kg) did suppress the neuroleptic-induced mouth movements, but also induced hyperactivity, characterized by increased sniffing and grooming. These findings indicate that mouth movements resulting from the chronic administration of neuroleptics to the rat may serve as a useful pharmacological model of tardive dyskinesia in the human, and suggest that a relative increase of D1 activity as well as impaired CCK function may contribute to the pathogenesis of this disorder