Pharmacological treatment for antipsychotic-related constipation.

BACKGROUND: Antipsychotic-related constipation is a common and serious adverse effect, especially for people taking clozapine. Clozapine has been shown to impede gastrointestinal motility, leading to constipation, and has been reported in up to 60% of patients receiving clozapine. In rare cases, complications can be fatal. Appropriate laxatives should be prescribed to treat constipation in people taking antipsychotics, but there is a lack of guidance on the comparative effectiveness and harms of different agents in this population. An understanding of the effectiveness and safety of treatment for antipsychotic-related constipation is important for clinicians and patients alike. OBJECTIVES: To evaluate the effectiveness and safety of pharmacologic treatment (versus placebo or compared against another treatment) for antipsychotic-related constipation (defined as constipated patients of any age, who are treated with antipsychotics, regardless of dose, in which constipation is considered to be an antipsychotic-related side effect). SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Trials Register (15 June 2015), which is based on regular searches of MEDLINE, Embase, CINAHL, BIOSIS, AMED, PubMed, PsycINFO, and registries of clinical trials, grey literature, and conference proceedings. There are no language, date, document type, or publication status limitations for inclusion of records in this register. We also handsearched bibliographies and contacted relevant authors for additional information. SELECTION CRITERIA: We included all published and unpublished randomised controlled trials (RCTs) investigating the efficacy of pharmacological treatments in patients with antipsychotic-related constipation. Pharmacological treatments included laxatives and other medicines that could reasonably be used to combat constipation in this population (e.g. anticholinergic agents, like bethanecol). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from all included studies and assessed trials for risk of bias. A third author reviewed 20% of trials. We analysed dichotomous data using relative risks (RR) and the 95% confidence intervals (CI). We assessed risk of bias for included studies and used GRADE to create a 'Summary of findings' table. We discussed any disagreement, documented decisions, and attempted to contact study authors when necessary. MAIN RESULTS: We identified two relevant Chinese studies (N = 480) that contributed data to this review. Both studies were over ten years old and poorly reported, lacking descriptions of contemporary CONSORT reporting prerequisites, such as sequence generation, allocation concealment, blinding, participant flow, how the sample size was determined, or how outcomes were measured. The studies also did not report trial registration, pre-specified protocols, consent processes, ethical review, or funding source. We were unsuccessful in making contact with the authors to clarify the missing details. We classified both studies as having an overall high risk of bias.One study compared glycerol suppository with the traditional Chinese medicine (TCM) approaches of tuina massage and acupuncture. Compared to tuina massage, glycerol laxative was less effective in relieving constipation at both two days after treatment (1 RCT; N = 120; RR 2.88, 95% CI 1.89 to 4.39; very low-quality evidence), and three days (1 RCT; N = 120; RR 4.80, CI 1.96 to 11.74, very low-quality evidence). Favourable results were also seen for acupuncture at two days (1 RCT; N = 120; RR 3.50; 95% CI 2.18 to 5.62; very low-quality evidence), and at three days (1 RCT; N = 120; RR 8.00, 95% CI 2.54 to 25.16; very low-quality evidence).The other study compared mannitol, an osmotic laxative, with rhubarb soda or phenolphthalein. Mannitol was more effective than rhubarb soda or phenolphthalein in trelieving constipation within 24 hours of treatment (1 RCT; N = 240; RR 0.07; 95% CI 0.02 to 0.27, very low-quality evidence).No data were reported for our other important outcomes: need for rescue medication, bowel obstruction (a complication of antipsychotic-related constipation), quality of life, adverse events, leaving the study early, and economic costs. AUTHORS' CONCLUSIONS: We had hoped to find clinically useful evidence appraising the relative merits of the interventions routinely used to manage antipsychotic-related constipation, a common and potentially serious adverse effect of the use of these drugs. The results were disappointing. There were no data comparing the common pharmacological interventions for constipation, such as lactulose, polyethylene glycol, stool softeners, lubricant laxatives, or of novel treatments such as linaclotide. Data available were very poor quality and the trials had a high risk of bias. Data from these biased studies suggested that mannitol, an osmotic laxative, was more effective than rhubarb soda and phenolphthalein in relieving constipation, and a two-week course of glycerol suppositories was less effective than the TCM approaches of tuina massage and acupuncture.Overall, there is insufficient trial-based evidence to assess the effectiveness and safety of pharmacological interventions for treating antipsychotic-related constipation, due to limited, poor quality data (few studies with high risk of bias and no meta-analyses). The methodological limitations in the included studies were obvious, and any conclusions based on their results should be made with caution. Methodologically rigorous RCTs evaluating interventions for treating antipsychotic-related constipation are needed.

Non-pharmacological interventions for cognitive impairment due to systemic cancer treatment.

BACKGROUND: It is estimated that up to 75% of cancer survivors may experience cognitive impairment as a result of cancer treatment and given the increasing size of the cancer survivor population, the number of affected people is set to rise considerably in coming years. There is a need, therefore, to identify effective, non-pharmacological interventions for maintaining cognitive function or ameliorating cognitive impairment among people with a previous cancer diagnosis. OBJECTIVES: To evaluate the cognitive effects, non-cognitive effects, duration and safety of non-pharmacological interventions among cancer patients targeted at maintaining cognitive function or ameliorating cognitive impairment as a result of cancer or receipt of systemic cancer treatment (i.e. chemotherapy or hormonal therapies in isolation or combination with other treatments). SEARCH METHODS: We searched the Cochrane Centre Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PUBMED, Cumulative Index of Nursing and Allied Health Literature (CINAHL) and PsycINFO databases. We also searched registries of ongoing trials and grey literature including theses, dissertations and conference proceedings. Searches were conducted for articles published from 1980 to 29 September 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) of non-pharmacological interventions to improve cognitive impairment or to maintain cognitive functioning among survivors of adult-onset cancers who have completed systemic cancer therapy (in isolation or combination with other treatments) were eligible. Studies among individuals continuing to receive hormonal therapy were included. We excluded interventions targeted at cancer survivors with central nervous system (CNS) tumours or metastases, non-melanoma skin cancer or those who had received cranial radiation or, were from nursing or care home settings. Language restrictions were not applied. DATA COLLECTION AND ANALYSIS: Author pairs independently screened, selected, extracted data and rated the risk of bias of studies. We were unable to conduct planned meta-analyses due to heterogeneity in the type of interventions and outcomes, with the exception of compensatory strategy training interventions for which we pooled data for mental and physical well-being outcomes. We report a narrative synthesis of intervention effectiveness for other outcomes. MAIN RESULTS: Five RCTs describing six interventions (comprising a total of 235 participants) met the eligibility criteria for the review. Two trials of computer-assisted cognitive training interventions (n = 100), two of compensatory strategy training interventions (n = 95), one of meditation (n = 47) and one of physical activity intervention (n = 19) were identified. Each study focused on breast cancer survivors. All five studies were rated as having a high risk of bias. Data for our primary outcome of interest, cognitive function were not amenable to being pooled statistically. Cognitive training demonstrated beneficial effects on objectively assessed cognitive function (including processing speed, executive functions, cognitive flexibility, language, delayed- and immediate- memory), subjectively reported cognitive function and mental well-being. Compensatory strategy training demonstrated improvements on objectively assessed delayed-, immediate- and verbal-memory, self-reported cognitive function and spiritual quality of life (QoL). The meta-analyses of two RCTs (95 participants) did not show a beneficial effect from compensatory strategy training on physical well-being immediately (standardised mean difference (SMD) 0.12, 95% confidence interval (CI) -0.59 to 0.83; I(2)= 67%) or two months post-intervention (SMD - 0.21, 95% CI -0.89 to 0.47; I(2) = 63%) or on mental well-being two months post-intervention (SMD -0.38, 95% CI -1.10 to 0.34; I(2) = 67%). Lower mental well-being immediately post-intervention appeared to be observed in patients who received compensatory strategy training compared to wait-list controls (SMD -0.57, 95% CI -0.98 to -0.16; I(2) = 0%). We assessed the assembled studies using GRADE for physical and mental health outcomes and this evidence was rated to be low quality and, therefore findings should be interpreted with caution. Evidence for physical activity and meditation interventions on cognitive outcomes is unclear. AUTHORS' CONCLUSIONS: Overall, the, albeit low-quality evidence may be interpreted to suggest that non-pharmacological interventions may have the potential to reduce the risk of, or ameliorate, cognitive impairment following systemic cancer treatment. Larger, multi-site studies including an appropriate, active attentional control group, as well as consideration of functional outcomes (e.g. activities of daily living) are required in order to come to firmer conclusions about the benefits or otherwise of this intervention approach. There is also a need to conduct research into cognitive impairment among cancer patient groups other than women with breast cancer.

How to connect the gap between clinical trials and clinical practice.

Clinical research methods have been rapidly developing, and the design of clinical trials including traditional Chinese medicine is advancing. To a certain extent, all of these ensure that the results of clinical research are objective and scientific, but whether these results and the resulting guidelines or consensus have much practical significance on clinical practice is still controversial. The authors engage in both clinical practice and clinical research; they strongly feel that it is necessary to discuss the relationship between clinical trials and clinical practice. This essay discusses this relationship in four parts.