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Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial - the SMART trial protocol.

ABSTRACT: Treatment of schizophrenia frequently includes prolonged benzodiazepine administration despite a lack of evidence of its use. It is often difficult to discontinue benzodiazepines because of the development of dependence. We aim to assess if melatonin can facilitate the withdrawal of prolonged benzodiazepine administration in patients with schizophrenia. Furthermore, we aim to investigate the association of benzodiazepine dose reduction with the following clinically important variables: sleep, psychophysiology, cognition, social function, and quality of life.Randomized, blinded, two-armed, parallel superiority trial. We plan to include 80 consenting outpatients diagnosed with schizophrenia or schizoaffective disorder, 18-55 years of age, treated with antipsychotic drug(s) and at least one benzodiazepine derivative for the last three months before inclusion.currently under treatment for alcohol or drug abuse, aggressive or violent behavior, known mental retardation, pervasive developmental disorder, dementia, epilepsy, terminal illness, severe co morbidity, inability to understand Danish, allergy to melatonin, lactose, starch, gelatin, or talc, hepatic impairment, pregnancy or nursing, or lack of informed consent. After being randomized to prolonged-release melatonin (Circadin®) 2 mg daily or matching placebo, participants are required to slowly taper off their benzodiazepine dose. The primary outcome measure is benzodiazepine dose at 6 months follow-up. Secondary outcome measures include sleep, psychophysiological, and neurocognitive measures. Data are collected at baseline and at 6 months follow-up regarding medical treatment, cognition, psychophysiology, sleep, laboratory tests, adverse events, psychopathology, social function, and quality of life. Data on medical treatment, cognition, psychophysiology, adverse events, social function, and quality of life are also collected at 2 and 4 months follow-up.The results from this trial will examine whether melatonin has a role in withdrawing long-term benzodiazepine administration in schizophrenia patients. This group of patients is difficult to treat and therefore often subject to polypharmacy which may play a role in the reduced life expectancy of patients compared to the background population. The results will also provide new information on the association of chronic benzodiazepine treatment with sleep, psychophysiology, cognition, social function, and quality of life. Knowledge of these important clinical aspects is lacking in this group of patients.ClinicalTrials NCT01431092.

SUBMITTER: Baandrup L

PROVIDER: S-EPMC3213077 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial - the SMART trial protocol.

Baandrup Lone L Fagerlund Birgitte B Jennum Poul P Lublin Henrik H Hansen Jane L JL Winkel Per P Gluud Christian C Oranje Bob B Glenthoj Birte Y BY

BMC psychiatry 20111005

<h4>Background</h4>Treatment of schizophrenia frequently includes prolonged benzodiazepine administration despite a lack of evidence of its use. It is often difficult to discontinue benzodiazepines because of the development of dependence. We aim to assess if melatonin can facilitate the withdrawal of prolonged benzodiazepine administration in patients with schizophrenia. Furthermore, we aim to investigate the association of benzodiazepine dose reduction with the following clinically important v ...[more]

PMID: 21975110

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Project description:INTRODUCTION:Melatonin, secreted by the pineal gland during the night phase, is a regulator of the biological clock and sleep tendency. Totally blind subjects frequently report severe, periodic sleep problems, with 50%-75% of cases displaying non-24-hour sleep-wake disorder (N24HSWD) due to inability to synchronize with the environmental day-night cycle. Melatonin immediate-release preparations are reportedly effective in N24HSWD. Here, we studied the efficacy and safety of prolonged-release melatonin (PRM), a registered drug for insomnia, for sleep disorders in totally blind subjects living in normal social environments. The primary endpoint was demonstration of clinically meaningful effects on sleep duration (upper confidence interval [CI] limit >20 minutes whether significant or not) to allow early decision-making on further drug development in this indication. TRIAL REGISTRATION:ClinicalTrials.gov registry - NCT00972075. METHODS:In a randomized, double-blind, placebo-controlled proof-of-principle study, 13 totally blind subjects had 2 weeks' placebo run-in, 6 weeks' randomized (1:1) PRM (Circadin(®)) or placebo nightly, and 2 weeks' placebo run-out. Outcome measures included daily voice recorded sleep diary, Clinical Global Impression of Change (CGIC), WHO-Five Well-being Index (WHO-5), and safety. RESULTS:Mean nightly sleep duration improved by 43 minutes in the PRM and 16 minutes in the placebo group (mean difference: 27 minutes, 95% CI: -14.4 to 69 minutes; P=0.18; effect size: 0.82) meeting the primary endpoint. Mean sleep latency decreased by 29 minutes with PRM over placebo (P=0.13; effect size: 0.92) and nap duration decreased in the PRM but not placebo group. The variability in sleep onset/offset and latency tended to decrease during PRM but not placebo treatment. The potentially beneficial effects of PRM persisted during the 2 weeks of discontinuation period, consistent with clock stabilizing effects. PRM was well-tolerated, adverse events were of mild or moderate severity and similar between PRM and placebo. CONCLUSION:Nightly use of PRM may potentially improve patient-reported sleep difficulties in totally blind individuals trying to adhere to normal social lifestyle. A larger study powered to demonstrate a statistically significant effect is warranted.

Project description:Patients with severe mental illness often suffer from disruptions in circadian rest-activity cycles, which might partly be attributed to ongoing psychopharmacological medication. Benzodiazepines are frequently prescribed for prolonged periods despite recommendations of only short-term usage. Melatonin, a naturally occurring nocturnal hormone, has the potential to stabilize disrupted circadian rhythmicity. Our aim was to investigate how prolonged-release melatonin affects rest-activity patterns in medicated patients with severe mental illness and if benzodiazepine dose reduction is associated with changes in circadian rhythm parameters.Data were derived from a randomized, double-blinded clinical trial with 24 weeks follow-up. Participants were randomized to add-on treatment with prolonged-release melatonin (2 mg) or matching placebo, and usual benzodiazepine dosage was gradually tapered. Here we report the results of 72 h of actigraphic assessment of activity-rest cycles performed pre and post tapering. Changes in rest-activity rhythm parameters between the melatonin and placebo group were analyzed using the univariate general linear model. Change in activity counts per 6 h, from baseline to follow-up, in the whole sample was analyzed using paired samples t-test.A subsample of 48 patients participated in the actigraphic assessment: 20 in the melatonin group and 28 in the placebo group. Rest-activity cycles varied from regular to highly disrupted. Melatonin significantly increased the interdaily stability and at a trend level decreased the intradaily variability compared with placebo. Benzodiazepine dose reduction was not associated with these circadian rhythm parameters. Activity counts were generally higher after benzodiazepine dose reduction compared with pre tapering, but differences did not reach statistical significance.Our data suggest melatonin as an aid during benzodiazepine withdrawal for patients distressed by disrupted circadian rest-activity cycles. Benzodiazepine tapering might result in diminished sedentary behavior but further research is needed.ClinicalTrials NCT01431092 , clinicaltrials.gov. Registered 31 August 2011.

Project description:Melatonin is extensively used in the USA in a non-regulated manner for sleep disorders. Prolonged release melatonin (PRM) is licensed in Europe and other countries for the short term treatment of primary insomnia in patients aged 55 years and over. However, a clear definition of the target patient population and well-controlled studies of long-term efficacy and safety are lacking. It is known that melatonin production declines with age. Some young insomnia patients also may have low melatonin levels. The study investigated whether older age or low melatonin excretion is a better predictor of response to PRM, whether the efficacy observed in short-term studies is sustained during continued treatment and the long term safety of such treatment.Adult outpatients (791, aged 18-80 years) with primary insomnia, were treated with placebo (2 weeks) and then randomized, double-blind to 3 weeks with PRM or placebo nightly. PRM patients continued whereas placebo completers were re-randomized 1:1 to PRM or placebo for 26 weeks with 2 weeks of single-blind placebo run-out. Main outcome measures were sleep latency derived from a sleep diary, Pittsburgh Sleep Quality Index (PSQI), Quality of Life (World Health Organzaton-5) Clinical Global Impression of Improvement (CGI-I) and adverse effects and vital signs recorded at each visit.On the primary efficacy variable, sleep latency, the effects of PRM (3 weeks) in patients with low endogenous melatonin (6-sulphatoxymelatonin [6-SMT] <or=8 microg/night) regardless of age did not differ from the placebo, whereas PRM significantly reduced sleep latency compared to the placebo in elderly patients regardless of melatonin levels (-19.1 versus -1.7 min; P = 0.002). The effects on sleep latency and additional sleep and daytime parameters that improved with PRM were maintained or enhanced over the 6-month period with no signs of tolerance. Most adverse events were mild in severity with no clinically relevant differences between PRM and placebo for any safety outcome.The results demonstrate short- and long-term efficacy and safety of PRM in elderly insomnia patients. Low melatonin production regardless of age is not useful in predicting responses to melatonin therapy in insomnia. The age cut-off for response warrants further investigation.

Project description:BackgroundSchizophrenia is a highly prevalent and chronic disorder that comprises a wide range of symptomatology. Asenapine is a recently developed atypical antipsychotic that is approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia.ObjectivesTo determine the clinical effects of asenapine for adults with schizophrenia or other schizophrenia-like disorders by comparing it with placebo.Search methodsWe searched the Cochrane Schizophrenia Group's Trials Register (July 04, 2014) which is based on regular searches of MEDLINE, EMBASE, CINAHL, BIOSIS, AMED, PubMed, PsycINFO, and registries of clinical trials. There are no language, date, document type, or publication status limitation for inclusion of records into the register. We inspected references of all included studies for further relevant studies.Selection criteriaOur review includes randomised controlled trials (RCTs) comparing asenapine with placebo in adults (however defined) with schizophrenia or related disorders, including schizophreniform disorder, schizoaffective disorder and delusional disorder, again, by any means of diagnosis.Data collection and analysisWe inspected citations from the searches and identified relevant abstracts, and extracted data from all included studies. For binary data we calculated risk ratio (RR) with 95% confidence intervals (CI), and for continuous data we calculated mean differences (MD). We used the GRADE approach to produce a 'Summary of findings' table which included our outcomes of interest, where possible. We used a fixed-effect model for our analyses.Main resultsWe obtained and scrutinised 41 potentially relevant records, and from these we could include only six trials (n = 1835). Five of the six trials had high risk of attrition bias and all trials were sponsored by pharmaceutical companies. Results showed a clinically important change in global state (1 RCT, n = 336, RR 0.81, 95% CI 0.68 to 0.97, low-quality evidence) and mental state (1 RCT, n = 336, RR 0.72, 95% CI 0.59 to 0.86, very low-quality evidence) at short-term amongst people receiving asenapine. People receiving asenapine demonstrated significant reductions in negative symptoms (1 RCT, n = 336, MD -1.10, 95% CI -2.29 to 0.09, very low-quality evidence) at short-term. Individuals receiving asenapine demonstrated significantly fewer incidents of serious adverse effects (1 RCT, n = 386, RR 0.29, 95% CI 0.14 to 0.63, very low-quality evidence) at medium-term. There was no clear difference in people discontinuing the study for any reason between asenapine and placebo at short-term (5 RCTs, n = 1046, RR 0.91, 95% CI 0.80 to 1.04, very low-quality evidence). No trial reported data for extrapyramidal symptoms or costs.Authors' conclusionsThere is some, albeit preliminary, evidence that asenapine provides an improvement in positive, negative, and depressive symptoms, whilst minimising the risk of adverse effects. However due to the low-quality and limited quantity of evidence, it remains difficult to recommend the use of asenapine for people with schizophrenia. We identify a need for large-scale, longer-term, better-designed and conducted randomised controlled trials investigating the clinical effects and safety of asenapine.

Project description:BackgroundBifeprunox is a novel antipsychotic drug designed to treat schizophrenia. However, research into the drug was ceased in 2009 due to rejection of licence to go to market by the US Food and Drug Administration (FDA), who could not approve the drug for acute or long-term symptoms of schizophrenia because more research was required to demonstrate convincing effects "beyond those already achieved" with currently licenced drugs. There were also concerns expressed over one death of a person whilst on the drug.ObjectivesTo investigate the clinical and adverse effects of bifeprunox for people with schizophrenia.Search methodsWe searched the Cochrane Schizophrenia Group's Trials Register on 23 October 2015, which is based on regular searches of MEDLINE, EMBASE, CINAHL, BIOSIS, AMED, PubMed, PsycINFO, and clinical trials registries. There are no language, date, document type, or publication status limitations for inclusion of records in the register.Selection criteriaAll randomised clinical trials focusing on bifeprunox versus placebo for schizophrenia.Data collection and analysisWe extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a random-effects model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE.Main resultsWe included four randomised controlled trials (RCTs). We found evidence of missing data and poor reporting. When bifeprunox 20 mg was compared with placebo for schizophrenia, the drug resulted in a reduction of the Positive and Negative Syndrome Scale (PANSS) positive subscale score regarding positive symptoms (n = 549, 2 RCTs, MD -1.89, 95% CI -2.85 to -0.92, low-quality evidence) and the PANSS negative subscale regarding negative symptoms (n = 549, 2 RCTs, MD -1.53, 95% CI -2.37 to -0.69, low-quality evidence). There was a clear improvement regarding deterioration in the bifeprunox 20 mg group (n = 231, 1 RCT, RR 0.71 95% CI, 0.54 to 0.93, very low-quality evidence). The total number of participants with equal to or greater than 7% weight increase was similar between bifeprunox and placebo (n = 483, 1 RCT, RR 1.02 95% CI 0.31 to 3.33 moderate-quality evidence). There were no useable data for quality of life, economic outcomes, and service use.Authors' conclusionsOur results showed some positive effects and a favourable adverse effect profile for bifeprunox, although there were few data overall and none were of high quality. It would seem that these data alone would not have been enough for the FDA to decide to halt progress of the drug to market. We can only assume that we are missing important data. Both the FDA and the relevant pharmaceutical companies have not made all relevant data accessible. As some of these trials also involved an additional haloperidol, olanzapine, quetiapine, or risperidone arm, these data are not only relevant to evaluation of bifeprunox. In not making all data accessible, it is hard to see how the FDA and the drug companies have fulfilled their full obligations to people with schizophrenia or their clinicians.

Project description:BackgroundRisperidone is the first new-generation antipsychotic drug made available in the market in its generic form.ObjectivesTo determine the clinical effects, safety and cost-effectiveness of risperidone compared with placebo for treating schizophrenia.Search methodsOn 19th October 2015, we searched the Cochrane Schizophrenia Group Trials Register, which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. We checked the references of all included studies and contacted industry and authors of included studies for relevant studies and data.Selection criteriaRandomised clinical trials (RCTs) comparing oral risperidone with placebo treatments for people with schizophrenia and/or schizophrenia-like psychoses.Data collection and analysisTwo review authors independently screened studies, assessed the risk of bias of included studies and extracted data. For dichotomous data, we calculated the risk ratio (RR), and the 95% confidence interval (CI) on an intention-to-treat basis. For continuous data, we calculated mean differences (MD) and the 95% CI. We created a 'Summary of findings table' using GRADE (Grading of Recommendations Assessment, Development and Evaluation).Main resultsThe review includes 15 studies (N = 2428). Risk of selection bias is unclear in most of the studies, especially concerning allocation concealment. Other areas of risk such as missing data and selective reporting also caused some concern, although not affected on the direction of effect of our primary outcome, as demonstrated by sensitivity analysis. Many of the included trials have industry sponsorship of involvement. Nonetheless, generally people in the risperidone group are more likely to achieve a significant clinical improvement in mental state (6 RCTs, N = 864, RR 0.64, CI 0.52 to 0.78, very low-quality evidence). The effect withstood, even when three studies with >50% attrition rate were removed from the analysis (3 RCTs, N = 589, RR 0.77, CI 0.67 to 0.88). Participants receiving placebo were less likely to have a clinically significant improvement on Clinical Global Impression scale (CGI) than those receiving risperidone (4 RCTs, N = 594, RR 0.69, CI 0.57 to 0.83, very low-quality evidence). Overall, the risperidone group was 31% less likely to leave early compared to placebo group (12 RCTs, N = 2261, RR 0.69, 95% CI 0.62 to 0.78, low-quality evidence), but Incidence of significant extrapyramidal side effect was more likely to occur in the risperidone group (7 RCTs, N = 1511, RR 1.56, 95% CI 1.13 to 2.15, very low-quality evidence).When risperidone and placebo were augmented with clozapine, there is no significant differences between groups for clinical response as defined by a less than 20% reduction in PANSS/BPRS scores (2 RCTs, N = 98, RR 1.15, 95% CI 0.93 to 1.42, low-quality evidence) and attrition (leaving the study early for any reason) (3 RCTs, N = 167, RR 1.13, 95% CI 0.53 to 2.42, low quality evidence). One study measured clinically significant responses using the CGI, no effect was evident (1 RCT, N = 68, RR 1.12 95% CI 0.87 to 1.44, low quality evidence). No data were available for extrapyramidal adverse effects.Authors' conclusionsBased on low quality evidence, risperidone appears to be benefitial in improving mental state compared with placebo, but it also causes more adverse events. Eight out of the 15 included trials were funded by pharmaceutical companies. The currently available evidence isvery low to low quality.

Dataset Information

Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial - the SMART trial protocol.

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Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial - the SMART trial protocol.

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