Pharmacotherapy for sleep disturbances in post-traumatic stress disorder (PTSD): A network meta-analysis.

BACKGROUND: Sleep disturbances are an important symptom dimension of post-traumatic-stress-disorder (PTSD). There is no meta-analytic evidence examining the effects of all types of pharmacotherapy on sleep outcomes among patients with PTSD. METHODS: Medline/Embase/PsychInfo/CENTRAL/clinicaltrials.gov/ICTRP, reference lists of published reviews and all included studies were searched for Randomised Controlled Trials (RCTs) examining any pharmacotherapy vs. placebo or any other drug among patients with PTSD. PRIMARY OUTCOMES: total sleep time, nightmares, sleep quality. SECONDARY OUTCOMES: sleep onset latency, number of nocturnal awakenings, time spent awake following sleep onset, dropouts due to sleep-related adverse-effects, insomnia/somnolence/vivid-dreams as adverse-effects. Pairwise and network meta-analyses were performed. RESULTS: 99 RCTs with 10,481 participants were included. Prazosin may be the most effective treatment for insomnia (SMD = -0.88, 95%CI = [-1.22;-0.54], nightmares (SMD = -0.44, 95%CI = [-0.84;-0.04]) and poor sleep quality (SMD = -0.55, 95%CI = [-1.01;-0.10]). Evidence is scarce and indicates lack of efficacy for SSRIs, Mirtazapine, z-drugs and benzodiazepines, which are widely used in daily practice. Risperidone and Quetiapine carry a high risk of causing somnolence without having a clear therapeutic benefit. Hydroxyzine, Trazodone, Nabilone, Paroxetine and MDMA-assisted psychotherapy may be promising options, but more research is needed. CONCLUSIONS: Underpowered individual comparisons and very-low to moderate confidence in effect estimates hinder the generalisability of the results. More RCTs, specifically reporting on sleep-related outcomes, are urgently needed.

Antidepressants compared to placebo for people with binge eating disorder: A systematic review and meta-analysis.

Binge eating disorder (BED) is the most prevalent eating disorder. Treatment options include pharmacotherapy as well as psychotherapy, with the latter recommended as a first-line option. However, the use of psychotherapeutic interventions poses several challenges. Antidepressants are easily accessible, but they lack robust evidence-base. This systematic review aims to comprehensively examine the efficacy and safety of antidepressants for the treatment of BED. Five databases were searched for randomized controlled trials (RCTs) comparing antidepressants vs. placebo in BED until 23/11/2023. Pairwise meta-analytic evaluations were performed. The primary outcomes were remission and binge eating frequency. Secondary outcomes were response to treatment, eating psychopathology, depression, anxiety, body weight, Body Mass Index (BMI), all-cause discontinuation, discontinuation due to adverse effects and total adverse events. Sixteen RCTs with a total of 984 participants were meta-analysed. Antidepressants were more effective than placebo in achieving remission (RR: 1.39, 95 % CI: 1.04 to 1.86) and in reducing binge eating episodes (SMD: -0.29, 95 % CI: -0.51 to -0.06). Similarly, in the secondary outcomes of response and depression, antidepressants demonstrated superiority over placebo. Antidepressants appear to be effective in reducing symptoms of BED. Small samples and effect sizes hinder the generalizability and clinical utility of these results. There is a lack of follow-up findings regarding the maintenance of effects. There is a pressing need for more RCTs examining antidepressants and other types of pharmacotherapy. Future research should include larger number of participants and increase the duration of follow-up.

Shortening the Alzheimer's disease assessment scale cognitive subscale.

BACKGROUND: A short yet reliable cognitive measure is needed that separates treatment and placebo for treatment trials for Alzheimer's disease. Hence, we aimed to shorten the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) and test its use as an efficacy measure. METHODS: Secondary data analysis of participant-level data from five pivotal clinical trials of donepezil compared with placebo for Alzheimer's disease (N = 2,198). Across all five trials, cognition was appraised using the original 11-item ADAS-Cog. Statistical analysis consisted of sample characterization, item response theory (IRT) to identify an ADAS-Cog short version, and mixed models for repeated-measures analysis to examine the effect sizes of ADAS-Cog change on the original and short versions in the placebo versus donepezil groups. RESULTS: Based on IRT, a short ADAS-Cog was developed with seven items and two response options. The original and short ADAS-Cog correlated at baseline and at weeks 12 and 24 at 0.7. Effect sizes based on mixed modeling showed that the short and original ADAS-Cog separated placebo and donepezil comparably (ADAS-Cog original ES = 0.33, 95% CI = 0.29, 0.40, ADAS-Cog short ES = 0.25, 95% CI =0.23, 0.34). CONCLUSIONS: IRT identified a short ADAS-cog version that separated donepezil and placebo, suggesting its clinical potential for assessment and treatment monitoring.

Is cognitive behavioral therapy more effective than pharmacotherapy for binge spectrum disorders? A systematic review and meta-analysis.

OBJECTIVES: Binge spectrum disorders are prevalent worldwide. Psychiatric and medical comorbidities are common, and societal costs are significant. Evidence-based treatment remains underutilized. Cognitive behavioral therapy is the recommended first-line treatment, but pharmacotherapy may be easier to access. INTERVENTIONS: Meta-analytic evidence directly comparing cognitive behavioral therapy with pharmacotherapy is lacking. We aimed to compare the effects of cognitive behavioral therapy interventions with any pharmacological treatment for binge spectrum disorders. We searched PubMed, Embase, CENTRAL, ClinicalTrials.gov and reference lists for randomized controlled trials comparing cognitive behavioral therapy with any pharmacotherapy for bulimia nervosa/binge eating disorder and performed pairwise meta-analytic evaluations. PRIMARY OUTCOMES: Primary outcomes are remission and frequency of binges. Secondary outcomes are frequency of purges, response, eating disorder psychopathology, weight/body mass index, depression, anxiety, quality of life and dropouts. RESULTS: Eleven randomized controlled trials comparing cognitive behavioral therapy with fluoxetine/imipramine/desipramine/methylphenidate/sibutramine were identified (N = 531). Cognitive behavioral therapy was superior to antidepressants in terms of remission, frequency of binges and eating disorder psychopathology. There were no statistically significant differences for any of the individual cognitive behavioral therapy vs drug comparisons in terms of response/depression/anxiety/weight/quality of life/dropouts. Cognitive behavioral therapy was not superior to sibutramine/methylphenidate for the primary outcomes. CONCLUSIONS: Data are scarce, comparisons underpowered and, considering the inherent methodological limitations of psychotherapy trials, questions arise regarding the presumed superiority of cognitive behavioral therapy. Further research is needed.

Sleep disorders and Alzheimer's disease pathophysiology: The role of the Glymphatic System. A scoping review.

BACKGROUND: Alzheimer's disease (AD) is highly intertwined with sleep disturbances throughout its whole natural history. Sleep consists of a major compound of the functionality of the glymphatic system, as the synchronized slow-wave activity during NREM facilitates cerebrospinal and interstitial long-distance mixing. OBJECTIVE: The present study undertakes a scoping review of research on the involvement of the glymphatic system in AD-related sleep disturbances. DESIGN: we searched Medline, Embase, PsychInfo and HEAL-link databases, without limitations on date and language, along with reference lists of relevant reviews and all included studies. We included in vivo, in vitro and post-mortem studies examining glymphatic implications of sleep disturbances in human populations with AD spectrum pathology. A thematic synthesis of evidence based on the extracted content was applied and presented in a narrative way. RESULTS: In total, 70 original research articles were included and were grouped as following: a) Protein aggregation and toxicity, after sleep deprivation, along with its effects on sleep architecture, b) Glymphatic Sequalae in SDB, yielding potential glymphatic markers c) Circadian Dysregulation, d) Possible Interventions. CONCLUSIONS: this review sought to provide insight into the role of sleep disturbances in AD pathogenesis, in the context of the glymphatic disruption.

Effects of Antidepressants on Sleep in Post-traumatic Stress Disorder: An Overview of Reviews.

Antidepressants are a commonly used, easily accessible, and overall safe treatment option for post-traumatic stress disorder (PTSD). The present review aims to evaluate the efficacy and safety of antidepressants in treating sleep disturbances in patients with PTSD. PubMed and the Cochrane Library were searched (July 2022) for systematic reviews and meta-analyses on the treatment of PTSD. Moreover, PubMed and ClinicalTrials.gov were searched for individual trials investigating the antidepressant treatment of PTSD (up to September 2022), and reference lists of all possibly relevant identified studies were screened. Sleep-related outcomes, i.e., total sleep time, sleep quality, dreams/ nightmares, insomnia, and somnolence, were extracted independently by at least two reviewers. Metaanalytic evaluations were performed wherever possible. 39 randomised controlled trials (RCTs) were identified; data from pooled analyses, reviews, and observational studies were used for antidepressants with a weak evidence base or when their findings were deemed important. Overall, scarce data exist on the effects of antidepressants on sleep outcomes among patients with PTSD. Some evidence may support the use of amitriptyline, nefazodone, paroxetine, and sertraline for improving sleep in patients with PTSD. Τhere was a meta-analytical trend indicating improvement of nightmares with fluoxetine, less insomnia with amitriptyline and more with brofaromine, as well as more somnolence with paroxetine vs. placebo, respectively. However, data from more than 1 RCT with a considerable number of patients were only available for paroxetine. Evidence is insufficient to draw safe conclusions. More and better-designed RCTs, with consistent reporting of sleep-related outcomes, are needed.

Antimanic Efficacy, Tolerability, and Acceptability of Clonazepam: A Systematic Review and Meta-Analysis.

(1) Background: The use of benzodiazepines for the treatment of acute mania remains prevalent. This systematic review and meta-analysis provides an updated assessment of Clonazepam's antimanic efficacy, tolerability, and acceptability. (2) Methods: A systematic search of multiple databases and clinical trial registries was conducted, aiming to identify any controlled studies of Clonazepam vs. placebo or any other pharmacotherapy for the treatment of acute mania. Pairwise meta-analytic evaluations were performed. (3) Results: Six studies were included with a total number of 192 participants, all of which were randomized controlled trials. Clonazepam may be superior to a placebo in the acute phase of treatment and no different to Lithium and Haloperidol in terms of efficacy, both acutely and in the medium to long term. Clonazepam may be an acceptable and well-tolerated treatment for acute mania, especially when used as an augmentation strategy. Comparisons were underpowered, with minimal sample sizes and only one study per comparison in many cases, thus limiting the generalizability of our findings and hindering firm clinical conclusions. (4) Conclusions: Given the prevalence of benzodiazepine use in current practice, more and larger studies are urgently needed.

A systematic review and metanalysis of questionnaires used for auditory processing screening and evaluation.

The recognition of Auditory Processing Disorder (APD) as a distinct clinical condition that impacts hearing capacity and mental health has gained attention. Although pure tone audiometry is the gold standard for assessing hearing, it inadequately reflects everyday hearing abilities, especially in challenging acoustic environments. Deficits in speech perception in noise, a key aspect of APD, have been linked to an increased risk of dementia. The World Health Organization emphasizes the need for evaluating central auditory function in cases of mild hearing loss and normal audiometry results. Specific questionnaires play a crucial role in documenting and quantifying the difficulties faced by individuals with APD. Validated questionnaires such as the Children's Auditory Processing Performance Scale, the Fisher's Auditory Problems Checklist, and the Auditory Processing Domains Questionnaire are available for children, while questionnaires for adults include items related to auditory functions associated with APD. This systematic review and meta-analysis identified six questionnaires used for screening and evaluating APD with a total of 783 participants across 12 studies. The questionnaires exhibited differences in domains evaluated, scoring methods, and evaluation of listening in quiet and noise. Meta-analysis results demonstrated that individuals with APD consistently exhibited worse scores compared to healthy controls across all questionnaires. Additionally, comparisons with clinical control groups showed varying results. The study highlights (i) the importance of standardized questionnaires in identifying and assessing APD, aiding in its diagnosis and management, and (ii) the need to use sub-scores as well as overall scores of questionnaires to elaborate on specific hearing and listening situations. There is a need to develop more APD specific questionnaires for the adult population as well as for more focused research on APD diagnosed individuals to further establish the validity and reliability of these questionnaires.

Pharmacotherapy compared to placebo for people with Bulimia Nervosa: A systematic review and meta-analysis.

Bulimia Nervosa is a disorder with high rates of psychiatric and medical comorbidity and substantial societal costs. Cognitive Behavioural Therapy is considered the preferred treatment, but access can be problematic. Pharmacotherapy is more accessible but remains significantly underutilised. We aimed to assess the efficacy, tolerability, and safety of all available forms of pharmacotherapy for the treatment of bulimia nervosa. We conducted a comprehensive search of PubMed, EMBASE, CENTRAL, ClinicalTrials.gov, and reference lists of relevant articles up until April 2023. The primary outcomes were remission and binge frequency. 52 randomised controlled trials (RCTs) involving 3313 participants were included in the meta-analysis. Overall, no significant difference was observed between drugs and placebo in terms of remission; however, the available data were limited. Notably, drugs, particularly antidepressants, demonstrated a significant reduction in the frequency of binge episodes compared to placebo. Antidepressants were also found to be more effective than placebo in terms of treatment response and other clinically meaningful outcomes. An important limitation is that few RCTs were available for individual drugs. Our findings provide evidence supporting the increased utilisation of pharmacotherapy in clinical practice and underscore the need for further research involving larger populations and a broader range of outcomes.

A network meta-analysis of efficacy, acceptability, and tolerability of antipsychotics in treatment-resistant schizophrenia.

OBJECTIVE: Clozapine is considered as the standard treatment for this subgroup, but the evidence is not unequivocal. There are several potential alternatives being used because of the possible adverse effects of clozapine. We aimed to examine the efficacy and adverse events of different antipsychotics in treatment-resistant schizophrenia by performing a network meta-analysis. METHODS: We searched the Cochrane Schizophrenia Group register for randomized-controlled trials (up to March 06, 2022) and MEDLINE (up to January 20, 2023). We included blinded and open studies and participants with a broad definition of treatment resistance. The primary outcome was overall symptoms of schizophrenia; secondary outcomes were response to treatment, positive and negative symptoms of schizophrenia, discontinuation, side effects, quality of life, and functioning. The study was registered in Open Science Framework ( https://osf.io/9nf2y/ ). RESULTS: We included 60 studies involving 6838 participants in the network meta-analysis. In the primary outcome, clozapine and olanzapine were more efficacious than risperidone, haloperidol, fluphenazine, sertindole, chlorpromazine, and quetiapine (range of mean SMDs, - 0.11 to - 0.48). The difference between clozapine and olanzapine was trivial and uncertain (SMD - 0.05, 95% CI, - 0.21 to 0.11). The result of other efficacy outcomes as well as subgroup and sensitivity analyses were consistent with the primary analysis. Clozapine and olanzapine were associated with more weight gain, and clozapine was associated with more sedation events compared to many other antipsychotics. CONCLUSIONS: Clozapine remains the gold standard for patients with treatment-resistant schizophrenia. Olanzapine seems to be second-best and could be tried before switching to clozapine.

Linkage of Young Mania Rating Scale to Clinical Global Impression Scale to Enhance Utility in Clinical Practice and Research Trials.

INTRODUCTION: The Young Mania Rating Scale (YMRS) is the gold standard to assess manic symptoms of bipolar disorder, yet the clinical meaning of scores is unknown. To clinically understand and interpret YMRS scores, we examined linkages between the total and change scores of YMRS with the Clinical Global Impression (CGI) ratings. METHODS: Individual participant data (N=2,988) from eight randomized, double-blind, placebo-controlled trials were included. Data were collected at baseline and subsequent visits. Spearman's correlation coefficients ρ were computed, and equipercentile linking was implemented. RESULTS: A YMRS score of 6 points corresponded approximately to 'borderline mentally ill,' 12 points to 'mildly ill,' 20 points to 'moderately ill,' 30 points to 'markedly ill,' 40 points to 'severely ill,' and 52 points to 'among the most extremely ill' patients on the CGI-S. A reduction of CGI-S by one point as well as 'minimally improved' on the CGI-I corresponded approximately to an absolute decrease of 4 to 8 YMRS points or a 21% to 29% reduction of YMRS baseline score whereas a reduction of CGI-S by two points and 'much improved' on the CGI-I corresponded to an absolute decrease of 10 to 15 points or a 42% to 53% reduction of YMRS baseline score. DISCUSSION: The current study findings offer clinicians meaningful cutoff values to interpret YMRS scores. Moreover, these values contribute to the definition of treatment targets, response, remission, and entry criteria in mania trials.

Antipsychotic dose reduction compared to dose continuation for people with schizophrenia.

BACKGROUND: Antipsychotic drugs are the mainstay treatment for schizophrenia, yet they are associated with diverse and potentially dose-related side effects which can reduce quality of life. For this reason, the lowest possible doses of antipsychotics are generally recommended, but higher doses are often used in clinical practice. It is still unclear if and how antipsychotic doses could be reduced safely in order to minimise the adverse-effect burden without increasing the risk of relapse. OBJECTIVES: To assess the efficacy and safety of reducing antipsychotic dose compared to continuing the current dose for people with schizophrenia. SEARCH METHODS: We conducted a systematic search on 10 February 2021 at the Cochrane Schizophrenia Group's Study-Based Register of Trials, which is based on CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, PubMed, ClinicalTrials.gov, ISRCTN, and WHO ICTRP. We also inspected the reference lists of included studies and previous reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing any dose reduction against continuation in people with schizophrenia or related disorders who were stabilised on their current antipsychotic treatment.  DATA COLLECTION AND ANALYSIS: At least two review authors independently screened relevant records for inclusion, extracted data from eligible studies, and assessed the risk of bias using RoB 2. We contacted study authors for missing data and additional information. Our primary outcomes were clinically important change in quality of life,  rehospitalisations and dropouts due to adverse effects; key secondary outcomes were clinically important change in functioning, relapse, dropouts for any reason, and at least one adverse effect. We also examined scales measuring symptoms, quality of life, and functioning as well as a comprehensive list of specific adverse effects. We pooled outcomes at the endpoint preferably closest to one year. We evaluated the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 25 RCTs, of which 22 studies provided data with 2635 participants (average age 38.4 years old). The median study sample size was 60 participants (ranging from 18 to 466 participants) and length was 37 weeks (ranging from 12 weeks to 2 years). There were variations in the dose reduction strategies in terms of speed of reduction (i.e. gradual in about half of the studies (within 2 to 16 weeks) and abrupt in the other half), and in terms of degree of reduction (i.e. median planned reduction of 66% of the dose up to complete withdrawal in three studies). We assessed risk of bias across outcomes predominantly as some concerns or high risk.  No study reported data on the number of participants with a clinically important change in quality of life or functioning, and only eight studies reported continuous data on scales measuring quality of life or functioning. There was no difference between dose reduction and continuation on scales measuring quality of life (standardised mean difference (SMD) -0.01, 95% confidence interval (CI) -0.17 to 0.15, 6 RCTs, n = 719, I2 = 0%, moderate certainty evidence) and scales measuring functioning (SMD 0.03, 95% CI -0.10 to 0.17, 6 RCTs, n = 966, I2 = 0%, high certainty evidence). Dose reduction in comparison to continuation may increase the risk of rehospitalisation based on data from eight studies with estimable effect sizes; however, the 95% CI does not exclude the possibility of no difference (risk ratio (RR) 1.53, 95% CI 0.84 to 2.81, 8 RCTs, n = 1413, I2 = 59% (moderate heterogeneity), very low certainty evidence). Similarly, dose reduction increased the risk of relapse based on data from 20 studies (RR 2.16, 95% CI 1.52 to 3.06, 20 RCTs, n = 2481, I2 = 70% (substantial heterogeneity), low certainty evidence).   More participants in the dose reduction group in comparison to the continuation group left the study early due to adverse effects (RR 2.20, 95% CI 1.39 to 3.49, 6 RCTs with estimable effect sizes, n = 1079, I2 = 0%, moderate certainty evidence) and for any reason (RR 1.38, 95% CI 1.05 to 1.81, 12 RCTs, n = 1551, I2 = 48% (moderate heterogeneity), moderate certainty evidence). Lastly, there was no difference between the dose reduction and continuation groups in the number of participants with at least one adverse effect based on data from four studies with estimable effect sizes (RR 1.03, 95% CI 0.94 to 1.12, 5 RCTs, n = 998 (4 RCTs, n = 980 with estimable effect sizes), I2 = 0%, moderate certainty evidence).  AUTHORS' CONCLUSIONS: This review synthesised the latest evidence on the reduction of antipsychotic doses for stable individuals with schizophrenia. There was no difference between dose reduction and continuation groups in quality of life, functioning, and number of participants with at least one adverse effect. However, there was a higher risk for relapse and dropouts, and potentially for rehospitalisations, with dose reduction. Of note, the majority of the trials focused on relapse prevention rather potential beneficial outcomes on quality of life, functioning, and adverse effects, and in some studies there was rapid and substantial reduction of doses. Further well-designed RCTs are therefore needed to provide more definitive answers.

The response of subgroups of patients with schizophrenia to different antipsychotic drugs: a systematic review and meta-analysis.

BACKGROUND: As comparatively few trials in subgroups of patients with schizophrenia have been done, clinicians need to know whether they can rely on the results of randomised controlled trials (RCTs) in the general population of patients with schizophrenia. We aimed to compare the efficacy and side-effects of antipsychotic drugs in different subgroups. METHODS: In this systematic review and meta-analysis, we searched reference lists of previous systematic reviews and meta-analyses, the Cochrane Schizophrenia Group's Study-Based Register (from database inception to April 27, 2020), and PubMed (from April 1, 2020 to June 14, 2021). We excluded studies in patients with stable schizophrenia (ie, relapse prevention studies), studies with a high risk of bias, and studies from mainland China due to quality concerns concerning allocation and masking methods. We included single-blind RCTs or better that assessed one or more of 16 second-generation and 18 first-generation antipsychotics in the general population of patients with schizophrenia or in one or more of the subgroups: children and adolescents (age range as defined in the original studies), patients with a first episode, patients with predominant or prominent negative symptoms, patients with comorbid substance use, patients with treatment-resistant schizophrenia, or older patients (age range as defined in the original studies). Two authors independently screened the results of the search, retrieved full-text articles, and checked the inclusion criteria. Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline, all parameters were extracted in duplicate. The primary outcome was change in overall symptoms. We compared drug efficacy between subgroups, by sex, schizoaffective disorder versus schizophrenia, and study origin using random-effects, inverse variance meta-analyses and random-effects subgroup tests, and meta-regression. FINDINGS: We included 537 RCTs with 76 382 participants, 26 627 (34·9%) women, 49 755 (65·1%) men, mean age 37·3 years (range of means 7·9-80·2; ethnicity data not available). 412 RCTs included patients in the general population of patients with schizophrenia, 42 included patients with treatment-resistant schizophrenia, 25 included children and adolescents, 20 included patients with their first episode, 20 included patients with predominant or prominent negative symptoms, 13 included patients with comorbid substance use, and 11 included older patients. Of 507 random-effects subgroup tests done, 46 (9%) showed a significant difference (p<0·05) between subgroups, but there was no clear indication as to which drug should be used in which subgroup. INTERPRETATION: The effects of antipsychotics in various patient subgroups were usually similar to those in the general population of patients with schizophrenia, but comparably few studies contributed to the subgroups, in particular in terms of side-effects. If the evidence for treatment in a given subgroup is small, guideline makers and clinicians should consider using the results in the much better studied group of the general population of patients with schizophrenia. FUNDING: German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung; FKZ 01KG1508).

COVID-19 Vaccination and Mental Health Outcomes among Greek Adults in 2021: Preliminary Evidence.

Existing research on the association between COVID-19 vaccination and quantitatively measured mental health outcomes is scarce. We conducted a cross-sectional telephone survey on a random sample of 1039 adult Greek citizens in June 2021. Among the participants, 39.6% were vaccinated with two doses, 23.1% with one dose, 21.4% were planning to become vaccinated later, and 8.1% refused vaccination. Compared to those fully vaccinated, those against vaccination ("deniers") and those who planned to do so later on ("not vaccinated yet") had significantly higher scores across three stress, anxiety, and depression construct scales. Our findings suggest an association between COVID-19 vaccination status and mental health.

Antipsychotic polypharmacy reduction versus polypharmacy continuation for people with schizophrenia.

BACKGROUND: In clinical practice, different antipsychotics can be combined in the treatment of people with schizophrenia (polypharmacy). This strategy can aim at increasing efficacy, but might also increase the adverse effects due to drug-drug interactions. Reducing polypharmacy by withdrawing one or more antipsychotics may reduce this problem, but must be done carefully, in order to maintain efficacy. OBJECTIVES: To examine the effects and safety of reducing antipsychotic polypharmacy compared to maintaining people with schizophrenia on the same number of antipsychotics. SEARCH METHODS: On 10 February 2021, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials, which is based on CENTRAL, CINAHL, ClinicalTrials.Gov, Embase, ISRCTN, MEDLINE, PsycINFO, PubMed and WHO ICTRP. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared reduction in the number of antipsychotics to continuation of the current number of antipsychotics. We included adults with schizophrenia or related disorders who were receiving more than one antipsychotic and were stabilised on their current treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all the identified references for inclusion, and all the full papers. We contacted study authors if we needed any further information. Two review authors independently extracted the data, assessed the risk of bias using RoB 2 and the certainty of the evidence using the GRADE approach. The primary outcomes were: quality of life assessed as number of participants with clinically important change in quality of life; service use assessed as number of participants readmitted to hospital and adverse effects assessed with number of participants leaving the study early due to adverse effects. MAIN RESULTS: We included five RCTs with 319 participants. Study duration ranged from three months to one year. All studies compared polypharmacy continuation with two antipsychotics to polypharmacy reduction to one antipsychotic.  We assessed the risk of bias of results as being of some concern or at high risk of bias. A lower number of participants left the study early due to any reason in the polypharmacy continuation group (risk ratio (RR) 0.44, 95% confidence interval (CI) 0.29 to 0.68; I2 = 0%; 5 RCTs, n = 319; low-certainty evidence), and a lower number of participants left the study early due to inefficacy (RR 0.21, 95% CI 0.07 to 0.65; I2 = 0%; 3 RCTs, n = 201).  Polypharmacy continuation resulted in more severe negative symptoms (MD 3.30, 95% CI 1.51 to 5.09; 1 RCT, n = 35). There was no clear difference between polypharmacy reduction and polypharmacy continuation on readmission to hospital, leaving the study early due to adverse effects, functioning, global state, general mental state and positive symptoms, number of participants with at least one adverse effect, weight gain and other specific adverse effects, mortality and cognition. We assessed the certainty of the evidence as very low or low across measured outcomes. No studies reported quality of life, days in hospital, relapse, depressive symptoms, behaviour and satisfaction with care. Due to lack of data, it was not possible to perform some planned sensitivity analyses, including one controlling for increasing the dose of the remaining antipsychotic. As a result, we do not know if the observed results might be influenced by adjustment of dose of remaining antipsychotic compound. AUTHORS' CONCLUSIONS: This review summarises the latest evidence on polypharmacy continuation compared with polypharmacy reduction. Our results show that polypharmacy continuation might be associated with a lower number of participants leaving the study early, especially due to  inefficacy. However, the evidence is of low and very low certainty and the data analyses based on few study only, so that it is not possible to draw strong conclusions based on the results of the present review. Further high-quality RCTs are needed to investigate this important topic.

Early- and subsequent- response of cognitive functioning in Alzheimer's disease: Individual-participant data from five pivotal randomized clinical trials of donepezil.

The association between early improvement and subsequent change in cognition is unexamined in antidementia clinical trials. We aimed to examine the consequences of early-response to antidementia medication in Alzheimer's disease. Participant-level data were analyzed from five pivotal clinical trials of donepezil for Alzheimer's disease lasting up to 24 weeks (N = 1917). Early-response was based on Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) change scores under minus four from baseline to week six, otherwise classified non-response; then subgrouped by donepezil or placebo. The primary analysis tested the group differences in ADAS-Cog change from baseline for the interval after week six up to 24, based on a three-level mixed-effects model repeated measures (MMRM) model. Four models of increasing complexity were tested, and the most parsimonious model was examined in the primary analysis. The remaining models were tested in sensitivity analysis. In the analytic sample, 32.09% (N = 396/1234) of donepezil and 24.01% (N = 164/683) of placebo participants were classified as early responders, and 67.91% donepezil (N = 838/1234), 75.99% (N = 519/683) placebo participants were not. MMRM identified a statistically significant (P < 0.05) responder group effect. Marginal means (MM) demonstrated more improvement for the early responders (donepezil: MM = -4.13, 95% CI = -5.93, -2.32; placebo MM = 1.81, 95% CI = -4.12, 0.50), compared to non-early responders (donepezil MM = 0.05, 95% CI = -1.40, 1.51; placebo MM = 2.59, 95% CI = 0.99, 4.19). Results replicated in sensitivity analysis. Our results inform clinicians regarding the extent and consequences of early improvement in cognitive functioning and potentially contribute to treatment monitoring and the design of clinical trials for Alzheimer's disease.

Cognitive impairment networks in Alzheimer's disease: Analysis of three double-blind randomized, placebo-controlled, clinical trials of donepezil.

Psychometric network analysis is an alternative theoretically-driven analytic approach that has the potential to conceptualize cognitive impairment in Alzheimer's disease differently than was previously assumed and consequently detect unknown treatment effects. Based on individual participant data, extracted from three double-blind, randomized placebo-controlled clinical trials, psychometric networks were computed on observed Alzheimer's Disease Assessment Scale Cognitive Subscale scores at baseline (N=1,554) and on predicted change scores at 24 weeks of follow-up for participants who received donepezil (N=797) or placebo (N=484). A novel conceptualization of cognitive impairment in Alzheimer's disease was displayed through the baseline network, that had 90% (n=27) positive statistically significant (p<0.05) associations, and a most central aspect of ideational praxis. Following 24 weeks, treatment effects emerged via the differences between the change score networks. The donepezil network had more statistically significant (p<0.05) positive associations and a higher global strength (n=15; S=1.22; p=0.03), than the placebo network (n=8; S=0.57). This suggests that for those who were treated with donepezil compared with placebo, cognition is a more unified construct. The main aspects of change in cognitive impairment were comprehension of spoken language for the donepezil network and spoken language ability for the placebo network. Comprehension of spoken language apears to be most sensitive to psychopharmaceutical interventions and should therefore be closely monitored. Overall, our psychometric network analysis presents a new conceptualization of cognitive impairment in Alzheimer's disease, points to previously unknown treatment effects and highlights well-defined aspects of cognitive impairment  that may translate into future treatment targets.