Psychological, behavioral and social effects of disclosing Alzheimer's disease biomarkers to research participants: a systematic review.

BACKGROUND: Current Alzheimer's disease (AD) research initiatives focus on cognitively healthy individuals with biomarkers that are associated with the development of AD. It is unclear whether biomarker results should be returned to research participants and what the psychological, behavioral and social effects of disclosure are. This systematic review therefore examines the psychological, behavioral and social effects of disclosing genetic and nongenetic AD-related biomarkers to cognitively healthy research participants. METHODS: We performed a systematic literature search in eight scientific databases. Three independent reviewers screened the identified records and selected relevant articles. Results extracted from the included articles were aggregated and presented per effect group. RESULTS: Fourteen studies met the inclusion criteria and were included in the data synthesis. None of the identified studies examined the effects of disclosing nongenetic biomarkers. All studies but one concerned the disclosure of APOE genotype and were conducted in the USA. Study populations consisted largely of cognitively healthy first-degree relatives of AD patients. In this group, disclosure of an increased risk was not associated with anxiety, depression or changes in perceived risk in relation to family history. Disclosure of an increased risk did lead to an increase in specific test-related distress levels, health-related behavior changes and long-term care insurance uptake and possibly diminished memory functioning. CONCLUSION: In cognitively healthy research participants with a first-degree relative with AD, disclosure of APOE ε4-positivity does not lead to elevated anxiety and depression levels, but does increase test-related distress and results in behavior changes concerning insurance and health. We did not find studies reporting the effects of disclosing nongenetic biomarkers and only one study included people without a family history of AD. Empirical studies on the effects of disclosing nongenetic biomarkers and of disclosure to persons without a family history of AD are urgently needed. TRIAL REGISTRATION: PROSPERO international prospective register for systematic reviews CRD42016035388 . Registered 19 February 2016.

Communication of socioeconomic research findings.

Socioeconomics is research that identifies, measures and compares the costs and the clinical, economic and humanistic consequences of diseases and healthcare interventions. Research findings must be communicated to be valuable. Publication moves research findings into the public domain and exposes hard won ideas to critical appraisal. The analyst or researcher informs the decision process by defining an answerable question, applying standard economic methodology, developing a credible study, and using appropriate analytical and communication tools. The decision-maker is more likely to listen if the message is relevant, clear, simple and timely, and if he/she has influence over the relevant budget. Traditional print media provide a standardised process for quality control, whereas electronic media can provide speed of publication and wide access, usually at the expense of quality. The quality of both published medical and socioeconomic research articles varies widely. Published checklists can greatly assist in determining the structural quality of a study, but they cannot guarantee that the content of an article is useful to a decision-maker. Barriers to communication include perceived lack of study credibility, lack of relevance to the decision under consideration, suspicion of bias and inadequate training of the readers. Journal editors aim to improve the readability and clarity of articles and to bring them into conformance with journal policies. Recommendations for effective communication include the following: determine the target audience(s) and develop the appropriate perspective; set the study in its clinical context; keep the language simple where possible and use multiple communication media. Well conducted and well communicated studies can influence policy and outcomes.

A predictive model of the health benefits and cost effectiveness of celiprolol and atenolol in primary prevention of cardiovascular disease in hypertensive patients.

This study compares the antihypertensive and lipid modifying effects of treatment of mild to moderate hypertension with celiprolol or atenolol. It also models the 5-year cardiovascular risk reduction and the cost effectiveness of monotherapy from a partial societal perspective. The effects of celiprolol and atenolol on systolic blood pressure (SBP), total serum cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) were obtained from a pooled analysis of published studies. Although celiprolol and atenolol had similar effects on SBP, celiprolol reduced the ratio of TC to HDL-C by 10.2% [95% confidence intervals (95% CI) -16.4%, -4.0%) but atenolol increased the ratio by 7.7% (95% CI of 3.4%, 12.0%). The 5-year absolute risks of an initial coronary or cerebrovascular event or cardiovascular death were computed for cohorts of patients treated with either agent or remaining untreated, using an accelerated failure time (AFT) model, based on Framingham Heart Study data. Inputs to the model were age, gender, smoking status, SBP, TC and HDL-C. The change in absolute risk was estimated using the changes in SBP and TC: HDL-C obtained from the pooled analysis. Average life-months gained by therapy were computed as differences between the Kaplan-Meier survival curves estimated from the model plus differences in 5-year cardiovascular death rates multiplied by average life expectancy obtained from life tables. Direct medical costs included drug treatment, and the costs of acute care for initial coronary and cerebrovascular events deferred by therapy over the 5-year treatment period. The model shows that in the lowest-risk base case (60-year-old men who are nondiabetic and nonsmokers with SBP of 160 mm Hg and a 5-year absolute cardiovascular risk of 12%), celiprolol (271 mg/day) is 2-fold more effective than atenolol (77.4 mg/day) in reducing coronary event risk, and equally effective in reducing cerebrovascular event risk. The number of individuals that would have to be treated for 5 years to avoid 1 coronary event is about 30 for celiprolol versus 70 for atenolol. Therapy with celiprolol yields more life-months and at current prices, the cost per life-year gained by therapy is significantly lower. Both drugs are cost effective by international standards in the treatment of patients with 5-year absolute cardiovascular risk greater than 10%, and are more cost effective in those patients at higher levels of absolute cardiovascular risk. The direct medical costs of treatment for 5 years with celiprolol are the same or slightly less than treatment with atenolol at the dosages used in the clinical trials, despite a 19% higher tablet price. Both drugs are more cost effective in patients at higher levels of absolute cardiovascular risk. These findings are sensitive to the drug dosages, tablet prices and the discount rate. Based on epidemiological and clinical data, replacing atenolol with celiprolol in patients with mild to moderate hypertension, but without overt cardiovascular disease, is predicted to have similar effects on stroke risk, but to be substantially more effective in reducing the risk of coronary events at no additional direct medical cost over a 5-year treatment period.

Costs, innovation and efficiency in anti-infective therapy.

This paper provides an overview of issues related to the emerging discipline of pharmacoeconomics and its relationship to the outcomes movement. The focus is upon the evolving Management Care Organisation (MCO) and the demands placed upon the pharmaceutical industry as it attempts to provide new innovative anti-infective treatments. Similarly, the challenge is to meet the ever increasing requirements for approval and reimbursement of new anti-infective pharmaceutical products. Outcomes research is playing an increasingly important role in such decisions throughout the world, including the United States. Unfortunately, most decisions and analysis at the national level and within MCOs regarding the adoption and utilisation of pharmaceuticals are rather unsophisticated in terms of the proper utilisation of pharmacoeconomic data. There is a prevalent need to better utilise this information to develop cost-effective disease and therapy intervention models and guidelines. Also, information on the application of pharmacoeconomics for the evaluation of pharmaceutical care services that enhance the cost effectiveness of drug therapy needs to be seriously considered. Specifically, this should include a consideration of the economic consequences of drug-related problems and the potential impact of pharmaceutical care on drug-related morbidity/mortality associated with the treatment of infectious disease.

Evaluation of the pharmacoeconomic literature.

Pharmacoeconomics identifies, measures, and compares the costs and consequences of pharmaceutical products and services. The cost effectiveness of a pharmacotherapy in a particular indication depends on the molecular configuration of the drug, its safety and efficacy, and local market factors such as the acquisition cost of the drug, the cost of a hospital bed, physician fees and nursing time. The types of study include cost minimisation, cost effectiveness, cost utility, cost benefit and cost of illness. Modelling studies are used to predict long term economic consequences of therapy. Retrospective studies apply local costs to clinical trials that may be international in scope. Full prospective pharmacoeconomic studies provide more complete information but are rare and expensive to perform. The principles of pharmacoeconomics are illustrated by 2 retrospective case studies from the literature. In the first study, ondansetron was compared with metoclopramide on the basis of efficacy and tolerability inferred from a previous well controlled clinical trial. A range of economic outputs provided answers from several perspectives. In the second study, a sound pharmacoeconomic analysis of corticosteroids in paediatric asthma used a comparator therapy that is now deemed clinically inappropriate. The case studies illustrate how conclusions from pharmacoeconomic studies must be interpreted with caution before they can be applied in a particular clinical setting.

Ondansetron: a pharmacoeconomic and quality-of-life evaluation of its antiemetic activity in patients receiving cancer chemotherapy.

Ondansetron is more effective than high-dose metoclopramide in the prevention of acute nausea and vomiting due to highly emetogenic chemotherapy, and, unlike metoclopramide, is rarely associated with extrapyramidal effects. Pharmacoeconomic analyses have demonstrated that, in specified clinical settings, ondansetron (8mg 4-hourly for 3 doses or 8mg followed by 1 mg/h for 24 hours) is equally cost-effective as high-dose metoclopramide (3 mg/kg followed by 0.5 mg/kg/h for 8 hours) in the prophylaxis of emesis in patients receiving highly emetogenic chemotherapy, at an acquisition cost 4- or 5-fold higher than that of the metoclopramide regimen. Furthermore, the combination of dexamethasone plus ondansetron has been shown to be more effective than ondansetron monotherapy in controlling emesis. In patients receiving high-dose ( greater than 50 mg/m2) cisplatin-based chemotherapy, antiemetic therapy with ondansetron (8mg intravenously as a single dose) plus dexamethasone (16mg total intravenous dose) was shown to be more cost-effective than the combination of high-dose metoclopramide (11 mg/kg total intravenous dose), dexamethasone (8mg intravenously as a single dose) plus lorazepam (1 to 1.5mg intravenously as a single dose). In a limited number of studies, quality-of-life scores, as assessed using the Rotterdam Symptom Checklist or the Functional Living Index--Emesis instrument, were significantly higher with ondansetron than with other antiemetic agents, including metoclopramide. Together, these results suggest that ondansetron, as an alternative to antiemetic regimens including high-dose metoclopramide, is appropriate cost-effective therapy for the prevention of acute nausea and vomiting in patients receiving highly emetogenic chemotherapy. Ondansetron is effective in controlling acute emesis associated with moderately emetogenic chemotherapy, and its use in this clinical setting may best be reserved for patients who have not responded well to previous antiemetic therapy with more traditional agents. However, poorly controlled emesis can lead to anticipatory nausea and vomiting in subsequent courses of chemotherapy, thus, consideration should also be given to the use of ondansetron in patients receiving moderately emetogenic chemotherapy, although further pharmacoeconomic investigations are required to clarify its use in this clinical setting.

Selegiline: an appraisal of the basis of its pharmacoeconomic and quality-of-life benefits in Parkinson's disease.

Selegiline (deprenyl) is a selective, irreversible cerebral monoamine oxidase type B inhibitor (MAO-B) that is used in the treatment of Parkinson's disease. It has a relatively mild adverse effect profile without risk of the tyramine ('cheese') reaction at normal therapeutic doses. In about half to two-thirds of patients with mild levodopa response fluctuations, selegiline improves overall disability and 'end-of-dose' fluctuations, with a levodopa-sparing effect. Selegiline thus may improve patient quality of life, although formal cost-utility analyses are required to establish the costs of these benefits. Cost-effectiveness studies may help characterise the relative pharmacoeconomic benefits of selegiline and the dopamine agonists, agents which can also be administered as adjuvant therapy at this stage of the disease. There is also evidence to suggest that selegiline may delay the need for levodopa therapy by up to 11 months in patients with early Parkinson's disease, although the relative contribution of neuroprotective and symptomatic effects of selegiline in these patients has yet to be clarified. From a societal perspective, a theoretical analysis indicates that the economic benefits of selegiline therapy are likely to be substantial. An agent which slowed progression of disability by around 10% would realise savings, through reduction in both direct and indirect costs, in the order of $US330 million per annum in the United States. Available data suggest that selegiline slows progression of symptoms well in excess of 10%. Further, if a simple and inexpensive method is developed to identify preclinical Parkinson's disease before nigrostriatal damage is advanced, selegiline may be useful in a broader patient population with possible financial benefits to society through reduction of the considerable indirect costs of Parkinson's disease.

Recombinant granulocyte colony-stimulating factor (rG-CSF): pharmacoeconomic considerations in chemotherapy-induced neutropenia.

Recombinant granulocyte colony-stimulating factor (rG-CSF) therapy is associated with a dose-proportional reduction in the frequency, duration and severity of neutropenia associated with cytotoxic chemotherapy. This is associated with a decrease in the incidence of infection, with subsequent reductions in the number of hospitalisations, days of hospitalisation and antibiotic requirements. These effects produce marked reductions in costs, and could contribute substantially towards offsetting the costs of rG-CSF, although the magnitude of the savings will vary between institutions and with the chemotherapy regimen used. Other benefits include a reduction in the frequency and severity of mucositis, and an improved patient quality of life. However, further research is required to evaluate other potentially important considerations including the targeting of specific patient populations (e.g. those receiving regimens with a curative intent), and additional improvements in patient quality of life and, perhaps, mortality. Thus, although specific pharmacoeconomic analyses are limited, preliminary evidence indicates that rG-CSF, administered prior to the onset of neutropenia in patients receiving cytotoxic chemotherapy, can provide cost reductions both from an institutional and a payor perspective, with even greater potential savings from a societal viewpoint.

Simvastatin: a pharmacoeconomic evaluation of its cost-effectiveness in hypercholesterolaemia and prevention of coronary heart disease.

Epidemiological and intervention study results support reduction of coronary heart disease (CHD) risk, and hence direct and indirect costs, by lowering plasma lipids. Cost-effectiveness of a lipid-lowering strategy thus depends significantly on the extent of plasma lipid decrease achieved. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor simvastatin is a well tolerated and highly effective antihyperlipidaemic agent. Despite a current lack of direct evidence that simvastatin reduces CHD incidence, the cost-effectiveness of the drug {in terms of years of life saved (YOLS)} has been studied, based on findings of epidemiological trials. Simvastatin 20 mg/day is more cost-effective than cholestyramine 4g 3 times daily, particularly in men and in those with a higher pretreatment cholesterol level ( greater than 8 mmol/L) and other risk factors. Cost-effectiveness is also enhanced if treatment is started at a younger age (35 to 45 years) and maintained for a defined period rather than lifelong. Thus, while additional direct comparative studies are needed to confirm this finding, present evidence suggests simvastatin is a cost-effective intervention in appropriately selected patients.

Celiprolol. An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in cardiovascular disease.

Celiprolol is a hydrophilic, beta 1-selective adrenoceptor antagonist with mild selective beta 2-agonist as well as weak vasodilator properties. Celiprolol 200 to 400mg once daily by mouth is similar in antihypertensive efficacy to usual doses of propranolol, atenolol, metoprolol and pindolol in patients with mild to moderate systemic hypertension. Similar doses of celiprolol are as efficacious as propranolol and atenolol in improving exercise tolerance and reducing the frequency of anginal attacks in patients with angina pectoris. Further clinical experience suggests that celiprolol does not produce bronchoconstriction and may have mild bronchodilating activity in asthmatic patients; it may also enhance the effects of bronchodilator drugs. Celiprolol has a slightly beneficial effect on serum lipid profiles, and does not appear to exert adverse effects on carbohydrate metabolism. If the apparent pharmacodynamic advantages of celiprolol translate into clinical benefits and are confirmed in well designed long term clinical trials, then celiprolol should represent a definite advance in beta-blocker therapy.

Ondansetron. Therapeutic use as an antiemetic.

Ondansetron (GR 38032F) is a highly selective 5-HT3 receptor antagonist, one of a new class of compounds which may have several therapeutic applications. Animal and clinical studies show that ondansetron reduces the 24-hour incidence and severity of nausea and vomiting induced by cytotoxic drugs, including cisplatin, and by single exposure, high dose radiation. Ondansetron is more effective than high dose metoclopramide in the 24 hours following chemotherapy, and preliminary clinical evidence suggests that it is equally effective in the following 4 days. It is also more effective than the 'moderate' doses of metoclopramide used to suppress emesis following radiotherapy. The antiemetic efficacy of ondansetron is enhanced by dexamethasone in cisplatin-treated patients. Importantly, extrapyramidal effects have not been reported with ondansetron. Further comparisons are required with standard combination antiemetic therapy to complement the data presently available. Thus, ondansetron is a promising new agent for prophylaxis against nausea and vomiting in chemotherapy and radiotherapy. It may be particularly useful in young and elderly patients who are more susceptible to extrapyramidal symptoms induced by high dose metoclopramide. With its improved tolerability and clinical response profiles, ondansetron represents an important advance in a difficult area of therapeutics.

Citalopram. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illness.

Citalopram is an antidepressant belonging to a new class of drugs which enhance serotoninergic neurotransmission through potent and selective inhibition of serotonin reuptake. Preliminary trials suggest that its short term therapeutic efficacy is significantly greater than that of placebo and mianserin, and comparable to that of amitriptyline, maprotiline and imipramine. It appears to be a weaker antidepressant agent than clomipramine, but better tolerated. Its elimination half-life of 33 hours permits once daily oral administration. Symptomatic improvement obtained with short term treatment has been maintained when therapy has been extended for up to 1 year; in the few patients studied for this extended period, the relapse rate was lower than with fluvoxamine, fluoxetine or imipramine. Compared to standard antidepressant agents, citalopram is well tolerated. It does not appear to be cardiotoxic, has not been associated with seizures in humans, and is relatively nonsedating. Unlike the tricyclic antidepressants, citalopram has minimal anticholinergic effects. Mild and transient nausea, with or without vomiting, is the most frequent adverse effect--occurring in 20% of patients--and increased perspiration, headache, dry mouth, tremor and insomnia are experienced by 15 to 18% of patients. Citalopram thus offers similar therapeutic efficacy and a more favourable tolerability profile than the tricyclic antidepressants. Preliminary data suggest that it may be particularly useful in patients who cannot tolerate the anticholinergic or cardiovascular side effects of tricyclic antidepressants and in those for whom sedation is not indicated.

Habituation to repeated painful and non-painful cutaneous stimuli: a quantitative psychophysical study.

Repeated stimuli elicit progressively smaller responses and elevated sensory and/or pain thresholds (habituation). The present experiments were designed to determine the rate of habituation of perceptual responses to supraliminal painful and non-painful cutaneous stimuli. Changes in the perceived intensity of electrical stimuli applied to the digital nerves of the index finger were determined by a matching procedure in which subjects set the current applied to the index finger of one hand to match the perceived intensity of a stimulus train (5 pulses at 20 Hz) applied to the other index finger. Twenty-five volunteers took part in 7 experiments in which both non-painful (2.5 times the sensory threshold Ts) and painful (1.2 times the pain threshold Tp) stimulus trains were presented. Subjects were required to match the stimuli at 30 s intervals over a period of 7.5 min. The percentage change in matching current (Y) was fitted by the function Y = -20.7*[1-exp(-0.56*t)] for both painful and non-painful stimuli repeated at 2 Hz. Responses recovered completely within 2 min of cessation of the stimulation. The degree of habituation increased or decreased with the rate of stimulus presentation. These results did not depend on changes in afferent fibre recruitment or fatigue because the afferent volley on the median nerve remained constant throughout the period of stimulation. Thus perceptual responses to the perceived intensity of supraliminal painful and non-painful stimuli delivered to the index finger habituate to the same extent, and the extent of the habituation is a function of the frequency of presentation of the stimulus.

Quaternary naloxone blocks morphine analgesia in spinal but not intact rats.

Quaternary derivatives of naloxone and other compounds are assumed not to enter the central nervous system following systemic administration. We report that i.p. naloxone methylbromide (5 mg/kg) completely reversed the antinociceptive effect of systemically administered morphine (6 mg/kg) in acutely spinalised rats, although it had no effect in the same animals prior to the transection. Naloxone hydrochloride was effective both before and after transection. Nuclear resonance spectra confirmed the purity of both compounds. These results suggest that acute spinal transection allows rapid entry of quaternary naloxone into the spinal cord. Quaternary compounds therefore may need to be used with caution in spinalised animals.

Behavioural modification of bulbospinal serotonergic inhibition and morphine analgesia.

Habituation to the stress of sham nociceptive testing enhances a rat's sensitivity to noxious thermal stimuli and reduces the antinociceptive effect of a subsequent acute dose of morphine. Since serotonin (5-hydroxytryptamine, 5-HT) mediates stress responses, experiments were designed to elucidate the role of 5-HT in these phenomena. Intrathecal methysergide or 5,7-dihydroxytryptamine (5,7-DHT) reduced baseline tail-flick latencies of novice rats to those of habituated animals. Morphine dose-response relationships were fitted to a 4 parameter sigmoidal function. Baseline latencies of novice animals were increased by 5-hydroxytryptophan (5-HTP) and reduced by parachlorophenylalanine (PCPA) in both reflex tests and in the hot-plate test, but latencies of habituated animals were unchanged by either treatment. In both reflex tests, the maximum effect due to morphine was increased by 5-HTP and reduced by PCPA in novice but not in habituated animals. We conclude that the serotonergic component of morphine's bulbospinal action represents the stress of the testing environment rather than an essential part of morphine's action.

Hypercapnia depresses nociception: endogenous opioids implicated.

Hypoventilation produces hypercapnia which can elevate pain thresholds. Hypercapnia is a potent stressor which releases catecholamines and activates the sympathetic nervous system. Some stressors produce analgesia by releasing endogenous opioids. To determine the roles of endogenous opioids and catecholamines in hypercapnic analgesia, we administered CO2 in the inspired gas mixture to conscious rats. CO2 in the range 5-10% elevated tail flick and leg flexion latencies 2- to 3-fold in both intact and spinalised animals. The effects on reflex latencies but not on paCO2 or pHa were blocked by naloxone (2 mg/kg), and were not present in morphine-tolerant animals. The effects were reduced by dexamethasone but were not changed either by adrenalectomy or by systemic guanethidine, propanolol or phentolamine. Hypercapnia delayed the onset of the late phase of behavioural responses to formalin injected into the plantar surface of the hindpaw. We conclude that moderate hypercapnia powerfully depresses flexor withdrawal responses to noxious stimuli, by a mechanism involving release of endogenous opioids but not systemic catecholamines. This effect may account in part for the elevation in pain threshold during hypoventilation.

Behavioural tolerance to morphine analgesia is supraspinally mediated: a quantitative analysis of dose-response relationships.

Repeated exposure of a rat to a nociceptive testing environment ('habituation') enhances its sensitivity to noxious thermal stimuli20 and reduces the antinociceptive effect of a subsequent acute dose of morphine ('behavioural tolerance'). The present study quantitatively characterises the effects of habituation upon morphine antinociception using hot-plate (50 and 55 degrees C) and reflex withdrawal tests (dipping the tail and hindpaws into water at 49 degrees C). Dose-response relationships were modeled with the empirical function; E = Eo + (EMAX*DN)/(ED50N + DN) where E is the time-integrated response, EMAX is the response attributable to morphine, Eo is the baseline response, D is the dose and N is a steepness parameter. Habituation reduced EMAX in both hot-plate tests and also reduced Eo on the 50 degrees C hot-plate. In both reflex tests, habituation reduced Eo to that of spinal animals and EMAX to a value intermediate between that of intact and spinal animals. Neither the ED50 nor the value of N was altered by habituation. Acute spinal novice and habituated animals had similar dose-response curves and parameters. Sham spinalisation had no significant effect on any of the parameters. It is concluded that habituation to the nociceptive testing environment substantially reduces the bulbospinal contribution to morphine analgesia but has no effect upon the spinal component.

Repeated exposure to sham testing procedures reduces reflex withdrawal and hot-plate latencies: attenuation of tonic descending inhibition?

Five days' repeated exposure of experimentally naive rats to the experimental environment and to sham nociceptive testing procedures ('habituation') reduced the latency for reflex withdrawal of the hindpaw from hot water (49 degrees C) by 43%, to that of spinalised habituated or novice animals. Hot-plate (50 degrees C) paw lick latencies were reduced equally (40%) by habituation or parachlorophenylalanine, and were increased 32% by D,L-5-hydroxytryptophan. Neither drug affected hot-plate latencies of habituated animals. Naloxone had no effect on flexor withdrawal or hot-plate latencies in either novice or habituated animals. These results suggest that habituation substantially attenuates tonic serotonergic inhibition of spinal nociceptive transmission.

Changes in perceived heaviness and motor commands produced by cutaneous reflexes in man.

1. This study examined the relationship between the perceived heaviness of a weight and reflexes acting on the motoneurones required for the contraction. The perceived heaviness of low (100 g) and high (500 g) reference weights lifted by the first dorsal interosseous muscle was estimated using a matching task. Weights were also lifted during stimulation of the digital nerves of the index finger at two times and four times sensory threshold (T). Averages of force and EMG were also made when isometric forces of 100 and 500 g were maintained. 2. Stimuli at 4T produced a significant increase in perceived heaviness in each subject for both reference weights. Averages of EMG made under isometric conditions showed a short-latency inhibition with a reflex reduction in force following single stimuli. This inhibition was also observed during weight lifting when trains of stimuli were given. 3. Stimuli at 2T produced less-marked changes in EMG, averaged force, and perceived heaviness for individual subjects. However, for the group of subjects, perceived heaviness declined significantly with 2T stimuli for the 500 g but not the 100 g weight. This decrease in perceived heaviness was associated with evidence of short-latency facilitation within the motoneurone pool. 4. Inhibition of the motoneurone pool was associated with an increase and facilitation with a decrease in perceived heaviness. These observations favour a role for a signal of centrally generated motor command in the sensation of heaviness and provide insight as to how this signal must change when reflex inputs change and when high-threshold motoneurones are recruited.