TECHNICAL COMMENTARY Metiapine Introduction When multiple copies of reviews were found and/or when findings conflict, we present the First generation ‘typical’ antipsychotics are an most recent version and the most recent older class of antipsychotic than second conclusions. generation ‘atypical’ antipsychotics. They are used primarily to treat positive symptoms Evidence was graded using the Grading of including the experiences of perceptual Recommendations Assessment, Development abnormalities (hallucinations) and fixed, false, and Evaluation (GRADE) Working Group irrational beliefs (delusions). approach where high quality evidence such as that gained from RCTs may be downgraded to First generation antipsychotics may cause side moderate or low if review and study quality is effects which can differ depending on which limited, if there is inconsistency in results, antipsychotic is being administered and on indirect comparisons, imprecise or sparse data individual differences in reaction to the drug. and high probability of reporting bias. It may Reactions may include dyskinesias such as also be downgraded if risks associated with the repetitive, involuntary, and purposeless body or intervention or other matter under review are facial movements, Parkinsonism (cogwheel high. Conversely, low quality evidence such as muscle rigidity, pill-rolling tremor and reduced that gained from observational studies may be or slowed movements), akathisia (motor upgraded if effect sizes are large, there is a restlessness, especially in the legs, and dose dependent response or if results are resembling agitation) and dystonias such as reasonably consistent, precise and direct with muscle contractions causing unusual twisting of low associated risks2. The resulting table parts of the body, most often in the neck. These represents an objective summary of the effects are caused by the dopamine receptor evidence, although the conclusions are solely antagonist action of these drugs. the opinion of staff of NeuRA (Neuroscience This table summarises overall group Research Australia). effectiveness of metiapine from information gained from randomised controlled trials (RCTs). Individual treatment programs need to Results be tailored by trained clinicians as response - both in symptoms and adverse effects - can We found one review that met our inclusion 3 vary between individuals. criteria . Method Owing to the vast number of reviews on antipsychotics, we have included only information reported in the abstracts of Cochrane systematic reviews1. This is because the Cochrane internal review process ensures a high level of scientific rigor and meta-analyses are usually conducted, giving treatment effect sizes. Data from the abstracts were supplemented from the full text when clarification was required. We have included only Cochrane reviews that have been published from the year 2000 to date to ensure the latest available evidence is presented. NeuRA Metiapine October 2020 Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected] Page 1 To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia TECHNICAL COMMENTARY Metiapine Metiapine Compared to first generation antipsychotics Efficacy: Moderate to low quality evidence (small samples, consistent, imprecise, direct) suggests no differences between chlorpromazine and metiapine in clinical improvement. Adverse effects: Moderate to low quality evidence finds no differences between chlorpromazine and metiapine in rates of parkinsonism. Zare M, Bazrafshan A. Chlorpromazine versus metiapine for schizophrenia. Cochrane Database of Systematic Reviews 2017, 3: CD011655. No difference between chlorpromazine and metiapine in clinically important improvement; 2 RCTs, N = 120, RR = 1.11, 95%CI 0.84 to 1.47, I2 = 8%, p = 0.30 Risks No difference in rate of parkinsonism; 2 RCTs, n = 70, RR = 0.97, 95%CI 0.46 to 2.03, I2 = 53%, p = 0.14 Consistency in results‡ Consistent Precision in results§ Imprecise Directness of results║ Direct Explanation of acronyms CI = confidence interval, 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, RCT = randomised controlled trial, RR = relative risk NeuRA Metiapine October 2020 Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected] Page 2 To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia TECHNICAL COMMENTARY Metiapine Explanation of technical terms prediction, but do not confirm causality due to possible and often unforseen confounding † Different effect measures are reported by variables. An r of 0.10 represents a weak different reviews. association, 0.25 a medium association and 0.40 and over represents a strong Weighted mean difference scores refer to association. Unstandardised (b) regression mean differences between treatment and coefficients indicate the average change in comparison groups after treatment (or the dependent variable associated with a 1 occasionally pre to post treatment) and in a unit change in the independent variable, randomized trial there is an assumption that statistically controlling for the other both groups are comparable on this measure independent variables. Standardised prior to treatment. Standardised mean regression coefficients represent the change differences are divided by the pooled being in units of standard deviations to allow standard deviation (or the standard deviation comparison across different scales. 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 ‡ Inconsistency refers to differing estimates depending on the size of the sample and the of effect across studies (i.e. heterogeneity or variability in the data. 0.2 represents a small variability in results) that effect, 0.5 a medium effect, and 0.8 and over is not explained by subgroup analyses and represents a large effect1. therefore reduces confidence in the effect Odds ratio (OR) or relative risk (RR) refers to estimate. I² is the percentage of the variability the probability of a reduction (< 1) or an in effect estimates that is due to heterogeneity increase (> 1) in a particular outcome in a rather than sampling error (chance) - 0% to treatment group, or a group exposed to a risk 40%: heterogeneity might not be important, factor, relative to the comparison group. For 30% to 60%: may represent moderate example, a RR of 0.75 translates to a heterogeneity, 50% to 90%: may represent reduction in risk of an outcome of 25% considerable heterogeneity and over this is relative to those not receiving the treatment or considerable heterogeneity. I² can be not exposed to the risk factor. Conversely, a calculated from Q (chi-square) for the test of RR of 1.25 translates to an increased risk of heterogeneity with the following formula1; 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 < 0.24. lnOR stands for logarithmic OR where a lnOR of 0 shows no § Imprecision refers to wide confidence difference between groups. Hazard ratios intervals indicating a lack of confidence in the measure the effect of an explanatory variable effect estimate. Based on GRADE on the hazard or risk of an event. recommendations, a result for continuous data (standardised mean differences, not Correlation coefficients (eg, r) indicate the weighted mean differences) is considered strength of association or relationship imprecise if the upper or lower confidence between variables. They are an indication of limit crosses an effect size of 0.5 in either NeuRA Metiapine October 2020 Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected] Page 3 To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia TECHNICAL COMMENTARY Metiapine direction, and for binary and correlation data, an effect size of 0.25. 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 relaxed5. ║ 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-to- head comparisons of A and B. NeuRA Metiapine October 2020 Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected] Page 4 To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia TECHNICAL COMMENTARY Metiapine References 1. CochraneCollaboration (2008): Cochrane Handbook for Systematic Reviews of Interventions. Accessed 24/06/2011. 2. GRADEWorkingGroup (2004): Grading quality of evidence and strength of recommendations. British Medical Journal 328: 1490. 3. Zare M, Bazrafshan A (2017): Chlorpromazine versus metiapine for schizophrenia. Cochrane Database of Systematic Reviews 3: CD011655. 4. Rosenthal JA (1996): Qualitative Descriptors of Strength of Association and Effect Size. Journal of Social Service Research 21: 37-59. 5. GRADEpro (2008): [Computer program]. Jan Brozek, Andrew Oxman, Holger Schünemann. Version 32 for Windows NeuRA Metiapine October 2020 Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected] Page 5 To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia .