Method. NeuRA Cholinesterase inhibitors August 2016

Transcription

1 Introduction A supplementary, or adjunctive, treatment is administered in conjunction with a patient s ongoing antipsychotic therapy. (ChEI), or anticholinesterase, have been proposed as an additional therapy to standard antipsychotic treatments, in an attempt to improve functional outcomes and treat symptoms that are not addressed by the antipsychotic medication alone. work by blocking the cholinesterase enzymes that break down acetylcholine neurotransmitters (ACh), increasing the neurotransmitter action. Their action is in contrast to anti-cholinergic medications, which have an opposite effect, and block the action of cholinergic neurotransmitters on their receptors. There are two key forms of cholinesterase enzymes, acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE). There are several different cholinesterase inhibitor drugs that target these enzymes, and which vary in their specificity for each of these enzymes ( single-action or dual-action ). Essentially, cholinesterase inhibitors work by blocking the cholinesterase enzyme from metabolising ACh, resulting in increased availability of ACh in neuron synapses and increasing ACh activity on cholinergic receptors (called nicotinic and muscarinic receptors). These receptors are known to be involved in cognition 1, and the use of cholinesterase inhibitors has previously shown some efficacy for improving cognition in Alzheimer s disease 2, 3. Aspects of cognition are known to be impaired in schizophrenia (See Cognition topics). It is important to consider that any effects of ChEI may be biased by the younger age of the schizophrenia population. have also been proposed as treatments for visual hallucinations 4, possibly due to depleted ACh levels in the cortex including regions involved in visual processing and interpretation. Trials of ChEI efficacy are limited by considerable heterogeneity of both sample population and neuropsychological assessment, as well as potentially confounding effects such as the smoking status of patients (as nicotine affects cholinergic receptors and may interfere with ChEI mechanism of action), as well as medication heterogeneity (such as the concomitant use of anti-cholinergic medications, which may cancel out any effects) 5. Specifically, most antipsychotics affect the ACh system; however this possible confound has not been formally investigated by the available evidence. Method We have included only systematic reviews (systematic literature search, detailed methodology with inclusion/exclusion criteria) published in full text, in English, from the year 2000 that report results separately for people with a diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder or first episode schizophrenia. Reviews were identified by searching the databases MEDLINE, EMBASE, CINAHL, Current Contents, PsycINFO and the Cochrane library. Hand searching reference lists of identified reviews was also conducted. When multiple copies of reviews were found, only the most recent version was included. Reviews with pooled data are prioritised for inclusion. Review reporting assessment was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, which describes a preferred way to present a meta-analysis 6. Reviews rated as having less than 50% of items checked have been excluded from the library. The PRISMA flow diagram is a suggested way of providing information about studies included and excluded with reasons for exclusion. Where no Page 1

2 flow diagram has been presented by individual reviews, but identified studies have been described in the text, reviews have been checked for this item. Note that early reviews may have been guided by less stringent reporting checklists than the PRISMA, and that some reviews may have been limited by journal guidelines. Evidence was graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group approach where high quality evidence such as that gained from randomised controlled trials (RCTs) may be downgraded to moderate or low if review and study quality is limited, if there is inconsistency in results, indirect comparisons, imprecise or sparse data and high probability of reporting bias. It may also be downgraded if risks associated with the intervention or other matter under review are high. Conversely, low quality evidence such as that gained from observational studies may be upgraded if effect sizes are large or if there is a dose dependent response. We have also taken into account sample size and whether results are consistent, precise and direct with low associated risks (see end of table for an explanation of these terms) 7. The resulting table represents an objective summary of the available evidence, although the conclusions are solely the opinion of staff of NeuRA (Neuroscience Research Australia). Moderate to high quality evidence from prepost comparisons of memory, attention and motor function showed some improvement following administration of AChEI (singleand dual-action); however, there was no significant benefit of adjunctive AChEI compared to placebo for improving motor function, language or executive function. Some evidence suggests a benefit of AChEI compared to placebo for improving verbal learning and memory, and attention. High quality evidence suggests single-action AChEI alone (donepezil) may confer some benefit for attention and short-term memory. Results We found seven systematic reviews that met our inclusion criteria 1-5, 8, 9. High quality evidence suggests a mediumsized effect of adjunctive donepezil or galantamine for improving overall and negative symptoms compared to placebo. Page 2

3 Choi K, Wykes T, Kurtz M Adjunctive pharmacotherapy for cognitive deficits in schizophrenia: metaanalytical investigation of efficacy The British Journal of Psychiatry 2013; 203: View review abstract online Comparison Adjunctive donepezil or galantamine plus antipsychotics (various) vs. antipsychotics plus placebo. High quality evidence (consistent, precise, direct) suggests a medium-sized benefit of adjunctive donepezil or galantamine for improving overall and negative symptoms, but no benefit for cognitive function other than a small effect for verbal learning and memory. Psychiatric symptoms Medium effect of improved overall symptoms in those taking adjunctive donepezil or galantamine, with negative symptoms showing most improvement; Negative symptoms: 5 RCTs (N unclear), d = 0.54, 95%CI 0.10 to 0.98, p = 0.016, Q W = 5.82, p = 0.21 Positive symptoms: 5 RCTs (N unclear), d = 0.01, 95%CI to 0.44, p = 0.961, Q W = 0.84, p = 0.93 Overall symptoms: 5 RCTs (N unclear), d = 0.46, 95%CI 0.04 to 0.88, p = 0.032, Q W = 3.40, p = 0.49 Cognition A trend for a small improvement in verbal learning and memory only; Overall function: 13 RCTs (N = 577), d = 0.05, 95%CI to 0.27 p = Q W = 4.63, p = 0.97 Attention/vigilance: 11 RCTs (N unclear), d = -0.12, 95%CI to 0.10, p = 0.284, Q W = 8.87, p = 0.54 Verbal learning and memory: 9 RCTs (N unclear), d = 0.23, 95%CI to 0.46, p = 0.062, Q W = 6.85, p = 0.55 Verbal working memory 9 RCTs (N unclear), d = -0.08, 95%CI to 0.16, p = 0.517, Q W = 12.02, p = 0.15 Spatial learning and memory: 5 RCTs (N unclear), d = 0.21, 95%CI to 0.57, p = 0.253, Q W = Page 3

4 10.45, p = 0.03 Spatial working memory 3 RCTs (N unclear), d = 0.16, 95%CI to 0.50, p = 0.371, Q W = 0.97, p = 0.62 Reasoning/problem-solving: 8 RCTs (N unclear), d = -0.11, 95%CI to 0.16, p = 0.418, Q W = 4.46, p = 0.73 Speed of processing: 8 RCTs (N unclear), d = 0.06, 95%CI to 0.31, p = 0.659, Q W = 10.22, p = 0.17 Consistent, apart from spatial learning and memory. Precise Chouinard S, Sepehry AA, Stip E Oral cholinesterase inhibitor add-on therapy for cognitive enhancement in schizophrenia: a quantitative systematic review, Part I Clinical Neuropharmacology 2007; 30(3): View review abstract online Comparison 1 Cognitive function before and after treatment with oral cholinesterase inhibitors plus standard antipsychotic treatment. Note pre-post assessment, no placebo group. High quality evidence (consistent, precise, direct) suggests a small benefit of adjunctive AChEI treatment for improving motor function and attention (particularly with single action AChEI). Cognitive functioning Page 4

5 12 studies (N = 445; 5 RCTs, 2 double-blind controlled, 1 crossover, 3 open-label, 1 open-trial) compared acetylcholinesterase inhibitors (AChEI) as adjuncts to standard antipsychotic therapy for 6-24 weeks, for improving performance in various cognitive domains. 1 RCT comprised 251 participants; the remaining studies had very small samples Small effect sizes suggest significant improvement in motor function and attention following AChEI, with no significant benefit for executive functioning or language; Attention: 10 studies, g = 0.261, 95%CI to 0.448, p = 0.006, Q = (p = 0.910) Motor: 4 studies, g = 0.239, 95%CI to 0.465, p = 0.038, Q = NS (after removal of outlier) Executive functioning: 7 studies, g = , 95%CI to 0.163, p = 0.704, Q = (p = 0.900) Language: 6 studies, g = 0.247, 95%CI to 0.583, p = 0.148, Q = (p = 0.196) Subgroup comparison across medication types for cognitive improvement. Single action AChEI (donepezil and galantamine) improved attention, but not language; Attention: g = 0.241, 95%CI to 0.452, p = Language: g = 0.054, 95%CI to 0.299, p = No benefits of dual action AChEI (rivastigmine); Attention: g = (CI not reported, authors report results are NS) Language: g = 0.391, 95%CI to 1.348, p = Risks Comparison 2 Possible side effects may include nausea, diarrhoea, dizziness, depression. Consistent Precise Cognitive functioning following oral cholinesterase inhibitors vs. placebo plus standard antipsychotic treatment. High quality evidence (consistent precise and direct) suggests a small benefit of placebo over adjunctive AChEI treatment for language. No differences for motor function, or executive function, although there may be some benefit for improving attention. Cognitive functioning Page 5

6 Small effect size favours placebo group for improving language, with no differences in executive functioning, motor or attention (for all studies combined); Language: 4 studies, g = , 95%CI to , p = 0.002, Q = (p = 0.763) Attention: 5 studies, g = 0.175, 95%CI to 0.475, p = 0.253, Q = (p = 0.307). Note; with the exclusion of one RCT which represented > 50% of total sample, the results became significant, favouring AChEI (g = 0.441, CI not reported, p = 0.038) Executive function: 4 studies, g = 0.073, 95%CI to 0.354, p = 0.737, Q = (p = 0.153) Motor: 3 studies, g = 0.428, 95%CI to 1.322, p = 0.347, Q = (p = 0.002) Risks Possible side effects may include nausea, diarrhoea, dizziness, depression. Consistent for all except motor functioning. Precise for all except executive function and motor functioning. Ferreri F, Agbokou C, Gauthier S Cognitive dysfunctions in schizophrenia: potential benefits of cholinesterase inhibitor adjunctive therapy Journal of Psychiatry & Neuroscience 2006; 31(6): View review abstract online Comparison Efficacy of adjunctive AChEI for improving cognitive functioning. Moderate to low quality evidence (direct, small samples, unable to assess consistency or precision) suggests no benefit of donepezil, rivastigmine or galantamine for general cognition, learning, memory, attention, vigilance, motor speed, executive function, or visuospatial skills. Efficacy of Donepezil 6 RCTs, 2 open-trials (N = 128) investigated donepezil in people with a schizophrenia spectrum disorder (2 studies with comorbid dementia) for cognitive improvement, treatment duration 4-24 weeks. Page 6

7 One RCT and one open label trial (total N = 23) found no positive effect of donepezil for a broad measure of cognition in elderly people with schizophrenia. Only one of four studies (3 RCT, total N = 77) found an improvement in verbal learning and memory following donepezil in non-geriatric schizophrenia. One open label study (N = 14) reported improvement in manual dexterity, but this was not replicated by one RCT (N = 36). Limited benefit of donepezil was reported for visual learning in one RCT (N = 12) but not in one open trial (N = 15). No improvements were reported for attention (3 studies, N = 84), vigilance (2 studies, N = 48), motor speed (4 studies, N = 99), executive function (4 studies, N = 99), verbal fluency (3 studies, N = 78), or visuospatial skills (2 studies, N = 48). All 8 studies reported that the addition of donepezil did not improve mental state or symptom severity (PANSS or BPRS). Efficacy of Rivastigmine 2 RCTs, 2 open-trials (N = 63) investigated rivastigmine in people with a schizophrenia spectrum disorder (1 study with comorbid dementia) for cognitive improvement, treatment duration weeks. One open label study (N = 13) reported improvement in symptom severity (PANSS), but this was not replicated by one RCT (N = 20), while 2 open-trials (N = 23) showed no improvement on BPRS. Significant improvement was reported in two open-trials (N = 23) for mental state and activity levels and satisfaction with life. One open-trial (N = 10) reported significant improvement in memory, as well as an additional trial (N = 20) reporting short term benefit for attention (not sustained in the long term). One RCT (N = 20) showed no significant benefit for visual tracking, reaction time, verbal learning, executive function, and visuospatial skills. Efficacy of Galantamine 1 RCT, 1 open-trial (N = 29) investigated galantamine in people with a schizophrenia spectrum disorder for cognitive improvement, treatment duration 4-8 weeks. One very small open-trial (N = 5) reported no benefit of galantamine for symptom severity (PANSS), while non-significant improvements were reported for attention, response inhibition, working memory, verbal learning, motor speed, executive function and verbal fluency. One RCT (N = 24) reported some benefit for verbal fluency and attention, but no significant effect on working memory, another measure of attention, verbal memory, manual dexterity or executive function. No measure of consistency reported appears inconsistent. Page 7

8 No measure of precision reported. Patel SS, Attard A, Jacobsen P, Shergill S Acetylcholinesterase Inhibitors (AChEI's) for the treatment of visual hallucinations in schizophrenia: a review of the literature BMC Psychiatry 2010; 10: 69 View review abstract online Comparison Efficacy of adjunctive AChEI for improving visual hallucinations. No studies were identified that directly examined AChEI for visual hallucinations in people with schizophrenia. Visual hallucinations No studies were identified that directly examined AChEI for improving visual hallucinations in schizophrenia. No measure of consistency is reported. No measure of precision is reported. Unable to assess Ribeiz SRI, Bassitt DP, Arrais JA, Steffens DC, Bottino CMC as adjunctive therapy in patients with schizophrenia and schizoaffective disorder: a review and meta-analysis of the literature CNS Drugs 2010; 24(4): View review abstract online Page 8

9 Comparison Efficacy of adjunctive AChEI (rivastigmine, donepezil or galantamine) vs. placebo for improving cognitive functioning and psychopathology. Moderate quality evidence (direct, mostly consistent and precise) suggests a medium-sized improvement in the trail making test (visual attention, executive functioning and task switching), and a small effect for improvement in memory. Cognitive and clinical functioning 13 RCT (N = 564, including 4 cross-over design) compared endpoint performance in various cognitive and clinical domains in AChEI and placebo (adjunct to standard antipsychotic therapy) for 8-24 weeks. Authors report that a medium effect size shows significant improvement in the trail making test (which is classified as a test of visual attention, executive functioning and task switching) and small effect for improvement in memory, but no difference in broader measures of executive functioning, language, total PANSS or negative PANSS. Positive symptoms were reported as being more intense in the group receiving adjunctive AChEI. Executive functioning: 6 RCTs, N = 199, g = 0.049, 95%CI to 0.355, p = 0.751, Q = 4.85 (p = 1.0) Trail making test: 4 RCTs, N = 93, g = , 95%CI to , p = 0.003, Q = 3.41 (p = 0.332) Language: 4 RCTs, N = 63, g = 0.237, 95%CI to 0.592, p = 0.190, Q = 4.78 (p = 0.573) Memory: 3 RCTs, N = 146, g = 0.280, 95%CI to , p = 0.014, Q = (p = 0.118) Extrapyramidal symptoms: 3 RCT, N = 158, g = , 95%CI to , p = 0.059, Q = (p = 0.001) Total PANSS: 6 RCTs, N = 119, g = , 95%CI to , p = 0.669, Q = 1.05 (p = 958) Positive PANSS: 7 RCTs, N = 364, g = 0.282, 95%CI to , p = 0.010, Q = 1.91 (p = 0.927) Negative PANSS: 8 RCTs, N = 377, g = , 95%CI to , p = 0.499, Q = (p = 0.003) Consistent for all except Extrapyramidal symptoms and Negative PANSS. Precise for all except Trail Making, Extrapyramidal symptoms. Page 9

10 Singh J, Kour K, Jayaram MB Acetylcholinesterase inhibitors for schizophrenia (Review) Cochrane Database of Systematic Reviews 2012; Issue 1. Art. No.: CD DOI: / CD pub2. View review abstract online Comparison 1 8 to 24 weeks of adjunctive acetylcholinesterase inhibitors (donepezil, rivastigmine or galantamine) plus antipsychotics (various) vs. placebo plus antipsychotics. Low quality evidence (small samples, unable to assess precision) is unable to determine the benefits of adjunctive donepezil, rivastigmine or galantamine. All outcomes Acetylcholinesterase inhibitors plus antipsychotics showed benefit in the medium term (12-24 weeks) over placebo plus antipsychotics for: Negative symptoms (PANSS): 2 RCTs, N = 31, MD -1.69, 95%CI to -0.57, p = , I 2 0% General Psychopathology (PANSS): 2 RCTs, N = 31, MD -3.86, 95%CI to -2.32, p = , I 2 0% Processing speed: 1 RCT, N = 73, MD 1.20, 95%CI 0.14 to 2.26, p = Visual memory: 2 RCTs, N = 48, MD 1.79, 95%CI 0.62 to 2.96, p = , I 2 0% Verbal memory and language: 3 RCTs, N = 42, MD %CI 0.67 to 6.26, p = 0.015, I 2 0% Executive functioning: 1 RCT, N = 24, MD %CI 0.70 to 33.50, p = 0.041, I 2 0% No differences were found for all short-term outcomes (< 12weeks), leaving the study early, functioning, depression, PANSS total, positive symptoms, or other cognitive domains. Risks Acetylcholinesterase inhibitor group reported less extrapyramidal effects. No differences were reported for respiratory, gastrointestinal, cardiovascular, biochemical, metabolic, or central nervous system adverse effects. Consistent Precise Page 10

11 Comparison 2 12 weeks of rivastigmine plus antipsychotics (various) vs. antipsychotics alone. Low quality evidence (one very small RCT, unable to assess precision) is unable to determine the benefits of adjunctive rivastigmine. All outcomes One small RCT (N = 24) reported no significant differences were reported for any outcome including leaving the study early for any reason, positive and negative symptoms, disorganisation, cognition, hostility, excitement, anxiety or depression. Not applicable (1 RCT). Unable to assess (not SMD). Stip E, Sepehry AA, Chouinard S Add-on therapy with acetylcholinesterase inhibitors for memory dysfunction in schizophrenia: a systematic quantitative review, part 2 Clinical Neuropharmacology 2007; 30(4): View review abstract online Comparison 1 Long-term memory (LTM) and short-term memory (STM) function before and after 6-24 weeks of treatment with acetylcholinesterase inhibitors plus antipsychotics. High quality evidence (consistent, mostly precise, direct) suggests a small, significant improvement in long-term memory, but not short-term memory following AChEI. Single-action AChEI (donepezil) may confer some benefit for short-term memory. Memory functioning 10 studies (N = 447; 5 RCT, 1 double-blind, 1 crossover, 2 open-label, 1 case report. A small significant improvement in LTM but not STM following AChEI administration. Subgroup Page 11

12 analysis shows significant improvement in STM following single-action donepezil only; LTM: 8 studies, N = 192, g = 0.362, 95%CI to 0.663, p = 0.019, Q = , p = STM: 9 studies, N = 191, g = 0.226, 95%CI to 0.454, p = 0.117, Q = , p = Subgroup comparison: Across medication types STM: Single action AChEI (donepezil): 4 studies, g = 0.246, 95%CI to 0.473, p = STM: Dual action AChEI (rivastigmine): 4 studies, g = 0.299, 95%CI to 0.780, p = LTM: Single action AChEI (donepezil): 5 studies, g = , 95%CI to 0.765, p = LTM: Dual action AChEI (rivastigmine): 2 studies, g = 0.383, 95%CI to 1.099, p = Subgroup comparison: Across antipsychotic types; STM: Second generation antipsychotics: 7 studies, g = 0.279, 95%CI to 0.555, p = STM: First generation antipsychotics: 2 studies, g = 0.055, 95%CI to 0.596, p = LTM: Second generation antipsychotics: 6 studies, g = 0.424, 95%CI to 0.818, p = LTM: First generation antipsychotics: 2 studies, g = 0.207, 95%CI to 0.749, p = Comparison 2 Consistent Precise Long-term memory (LTM) and short-term memory (STM) function following acetylcholinesterase inhibitors plus antipsychotics vs. placebo plus antipsychotics. High quality evidence (consistent, precise, direct) suggests no significant difference between AChEI and placebo for short- or long-term memory. Memory function No significant difference between groups for memory function; LTM: 3 studies, N not reported, g = , 95%CI to 0.011, p = 0.061, Q = 0.769, p = STM: 4 studies, N = 263, g = , 95%CI to 0.132, p = 0.208, Q = 4.214, p = Consistent Precise Page 12

13 Explanation of acronyms CI = Confidence Interval, d = Cohen s d and g = Hedges g = standardised mean differences (see below for interpretation of effect size) I² = the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance), N = number of participants, p = statistical probability of obtaining that result (p < 0.05 generally regarded as significant), PANSS = Positive and Negative Syndrome Scale, Q = Q statistic for the test of heterogeneity, Q w = test for within group differences (heterogeneity in study results within a group of studies measure of study consistency), Q B = test for between group differences (heterogeneity between groups of studies for an outcome of interest), SMD = standardised mean difference, vs = versus Page 13

14 Explanation of technical terms * Bias has the potential to affect reviews of both RCT and observational studies. Forms of bias include; reporting bias selective reporting of results; publication bias - trials that are not formally published tend to show less effect than published trials, further if there are statistically significant differences between groups in a trial, these trial results tend to get published before those of trials without significant differences; language bias only including English language reports; funding bias - source of funding for the primary research with selective reporting of results within primary studies; outcome variable selection bias; database bias - including reports from some databases and not others; citation bias - preferential citation of authors. Trials can also be subject to bias when evaluators are not blind to treatment condition and selection bias of participants if trial samples are small 10. Different effect measures are reported by different reviews. Prevalence refers to how many existing cases there are at a particular point in time. Incidence refers to how many new cases there are per population in a specified time period. Incidence is usually reported as the number of new cases per 100,000 people per year. Alternatively some studies present the number of new cases that have accumulated over several years against a person-years denominator. This denominator is the sum of individual units of time that the persons in the population are at risk of becoming a case. It takes into account the size of the underlying population sample and its age structure over the duration of observation. Reliability and validity refers to how accurate the instrument is. Sensitivity is the proportion of actual positives that are correctly identified (100% sensitivity = correct identification of all actual positives) and specificity is the proportion of negatives that are correctly identified (100% specificity = not identifying anyone as positive if they are truly not). Weighted mean difference scores refer to mean differences between treatment and comparison groups after treatment (or occasionally pre to post treatment) and in a randomised trial there is an assumption that both groups are comparable on this measure prior to treatment. Standardised mean differences are divided by the pooled standard deviation (or the standard deviation of one group when groups are homogenous) which allows results from different scales to be combined and compared. Each study s mean difference is then given a weighting depending on the size of the sample and the variability in the data. Less than 0.4 represents a small effect, around 0.5 a medium effect, and over 0.8 represents a large effect 10. Odds ratio (OR) or relative risk (RR) refers to the probability of a reduction (< 1) or an increase (> 1) in a particular outcome in a treatment group, or a group exposed to a risk factor, relative to the comparison group. For example, a RR of 0.75 translates to a reduction in risk of an outcome of 25% relative to those not receiving the treatment or not exposed to the risk factor. Conversely, a RR of 1.25 translates to an increased risk of 25% relative to those not receiving treatment or not having been exposed to a risk factor. A RR or OR of 1.00 means there is no difference between groups. A medium effect is considered if RR > 2 or < 0.5 and a large effect if RR > 5 or < lnor stands for logarithmic OR where a lnor of 0 shows no difference between groups. Hazard ratios Page 14

15 measure the effect of an explanatory variable on the hazard or risk of an event. Correlation coefficients (eg, r) indicate the strength of association or relationship between variables. They can provide an indirect indication of prediction, but do not confirm causality due to possible and often unforseen confounding variables. An r of 0.10 represents a weak association, 0.25 a medium association and 0.40 and over represents a strong association. Unstandardised (b) regression coefficients indicate the average change in the dependent variable associated with a 1 unit change in the independent variable, statistically controlling for the other independent variables. Standardised regression coefficients represent the change being in units of standard deviations to allow comparison across different scales. Inconsistency refers to differing estimates of effect across studies (i.e. heterogeneity or variability in results) that is not explained by subgroup analyses and therefore reduces confidence in the effect estimate. I² is the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance) - 0% to 40%: heterogeneity might not be important, 30% to 60%: may represent moderate heterogeneity, 50% to 90%: may represent considerable heterogeneity and over this is considerable heterogeneity. I² can be calculated from Q (chi-square) for the test of heterogeneity with the following formula 10 ; Imprecision refers to wide confidence intervals indicating a lack of confidence in the effect estimate. Based on GRADE recommendations, a result for continuous data (standardised mean differences, not weighted mean differences) is considered imprecise if the upper or lower confidence limit crosses an effect size of 0.5 in either direction, and for binary and correlation data, an effect size of GRADE also recommends downgrading the evidence when sample size is smaller than 300 (for binary data) and 400 (for continuous data), although for some topics, these criteria should be relaxed 12. Indirectness of comparison occurs when a comparison of intervention A versus B is not available but A was compared with C and B was compared with C, which allows indirect comparisons of the magnitude of effect of A versus B. Indirectness of population, comparator and/or outcome can also occur when the available evidence regarding a particular population, intervention, comparator, or outcome is not available and is therefore inferred from available evidence. These inferred treatment effect sizes are of lower quality than those gained from head-tohead comparisons of A and B. Page 15

16 References 1. Ribeiz SRI, Bassitt DP, Arrais JA, Avila R, Steffens DC, Bottino CMC. as adjunctive therapy in patients with schizophrenia and schizoaffective disorder: a review and metaanalysis of the literature. CNS Drugs. 2010; 24(4): Stip E, Sepehry AA, Chouinard S. Add-on therapy with acetylcholinesterase inhibitors for memory dysfunction in schizophrenia: a systematic quantitative review, part 2. Clinical Neuropharmacology. 2007; 30(4): Chouinard S, Sepehry AA, Stip E. Oral cholinesterase inhibitor add-on therapy for cognitive enhancement in schizophrenia: a quantitative systematic review, Part I. Clinical Neuropharmacology. 2007; 30(3): Patel SS, Attard A, Jacobsen P, Shergill S. Acetylcholinesterase Inhibitors (AChEI's) for the treatment of visual hallucinations in schizophrenia: a review of the literature. BMC Psychiatry. 2010; 10: Ferreri F, Agbokou C, Gauthier S. Cognitive dysfunctions in schizophrenia: potential benefits of cholinesterase inhibitor adjunctive therapy. Journal of Psychiatry & Neuroscience. 2006; 31(6): Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMAGroup. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. British Medical Journal. 2009; 151(4): GRADEWorkingGroup. Grading quality of evidence and strength of recommendations. British Medical Journal. 2004; 328: Singh J, Kour K, Jayaram MB. Acetylcholinesterase inhibitors for schizophrenia. Cochrane Database of Systematic Reviews. 2012; 1: CD Choi KH, Til W, Kurtz MM. Adjunctive pharmacotherapy for cognitive deficits in schizophrenia: Metaanalytical investigation of efficacy. British Journal of Psychiatry. 2013; 203(3): CochraneCollaboration. Cochrane Handbook for Systematic Reviews of Interventions. 2008: Accessed 24/06/ Rosenthal JA. Qualitative Descriptors of Strength of Association and Effect Size. Journal of Social Service Research. 1996; 21(4): GRADEpro. [Computer program]. Jan Brozek, Andrew Oxman, Holger Schünemann. Version 32 for Windows Page 16