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TECHNICAL COMMENTARY

Clocapramine

Introduction limbic system relative to the nigrostriatal system, which is the site responsible for Second generation (sometimes inducing . In addition referred to as ‘atypical’ antipsychotics) are a to , and also newer class of medication than tend to selectively block receptors in first generation ‘typical’ antipsychotics. Second the mesolimbic system but target generation antipsychotics are effective for the receptors. positive symptoms of . It is sometimes claimed that they are more effective This table summarises overall group than first generation antipsychotics in treating effectiveness of clocapramine, however the negative symptoms of schizophrenia, individual treatment programs need to be although the evidence for this is weak. Negative tailored by trained clinicians as response - both symptoms include a lack of ordinary mental in symptoms and adverse effects - can vary activities such as emotional expression, social between individuals. engagement, thinking and motivation, whereas positive symptoms include the experiences of Method perceptual abnormalities () and Owing to the vast number of reviews on fixed, false, irrational beliefs (). antipsychotics, we have prioritised information Second generation antipsychotics may also reported in the abstracts of Cochrane cause less extra-pyramidal side effects. These systematic reviews1. This is because the include such as repetitive, Cochrane internal review process ensures a involuntary, and purposeless body or facial high level of scientific rigor and meta-analyses movements, Parkinsonism (cogwheel muscle are usually conducted, giving treatment effect rigidity, pill-rolling tremor and reduced or sizes. Data from the abstracts were slowed movements), akathisia (motor supplemented from the full text when restlessness, especially in the legs, and clarification was required. We have included resembling agitation) and dystonias such as only Cochrane reviews that have been muscle contractions causing unusual twisting of published from the year 2000 to date to ensure parts of the body, most often in the neck. These the latest available evidence is presented. effects are caused by the When multiple copies of reviews were found antagonist action of these drugs. One and/or when findings conflict, we present the explanation for differences in producing these most recent version and the most recent side effects is that high potency first generation conclusions. Where no Cochrane review exists, antipsychotics are usually selective dopamine other reviews with pooled data are included. receptor antagonists with a high affinity for the Evidence was graded using the Grading of dopamine receptor and they induce Recommendations Assessment, Development extrapyramidal effects by the blockade of these and Evaluation (GRADE) Working Group dopamine receptors. In contrast, second approach where high quality evidence such as generation antipsychotics generally have a that gained from RCTs may be downgraded to lower affinity for the dopamine receptor and moderate or low if review and study quality is also block serotonin receptors, both of which limited, if there is inconsistency in results, mechanisms may play a role in mitigating the indirect comparisons, imprecise or sparse data effects of dopamine blockade. Amisulpride is an and high probability of reporting bias. It may exception to other second generation also be downgraded if risks associated with the antipsychotics in that it is a pure dopamine intervention or other matter under review are , however it tends to block high. Conversely, low quality evidence such as dopamine receptors more selectively in the

NeuRA Clocapramine November 2019

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Clocapramine that gained from observational studies may be upgraded if effect sizes are large, there is a dose dependent response or if results are reasonably consistent, precise and direct with low associated risks2. The resulting table represents an objective summary of the evidence, although the conclusions are solely the opinion of staff of NeuRA (Neuroscience Research Australia).

Results We found one review that met our inclusion criteria3.

NeuRA Clocapramine November 2019

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Clocapramine

Clocapramine

Compared to first or second generation antipsychotics Efficacy: Moderate quality evidence (large sample, consistent, imprecise, indirect) suggests no differences between clocapramine and first or second generation antipsychotics for discontinuation or response, although in comparison with second generation antipsychotics only, clocapramine may be less effective. Adverse effects: Moderate quality evidence (imprecise) suggests less headaches and decreased appetite with clocapramine.

Kishi T, Matsunaga S, Matsuda Y, Iwata N. Iminodibenzyl class antipsychotics for schizophrenia: a systematic review and meta-analysis of , clocapramine, and . Neuropsychiatric Disease and Treatment 2014; 10: 2339-2351

Clocapramine was compared with first generation antipsychotics (, , , and sulpride), and second generation antipsychotics (mosapramine and ) combined. There were no differences between groups for; Response: 6 RCTs, N = 1,048, OR = 1.12, 95%CI 0.86 to 1.47, p = 0.39, I2 = 0% Discontinuation: 6 RCTs, N = 1,048, OR = 0.77, 95%CI 0.53 to 1.11, p = 0.16, I2 = 0% Subgroup analysis of antipsychotic class found no difference when clocapramine was compared to first generation antipsychotics, and a trend effect of inferior response with clocapramine compared to second generation antipsychotics (p = 0.06).

Risks There were no differences between clocapramine and other antipsychotics in rates of at least one : 6 RCTs, N = 1,048, OR = 1.20, 95%CI 0.83 to 1.72, p = 0.34, I2 = 52%, p = 0.05. There were less headaches with clocapramine: 6 RCTs, N = 1,048, OR = 0.47, 95%CI 0.25 to 0.85, p = 0.01, I2 = 0%. There was decreased appetite with clocapramine: 6 RCTs, N = 1,048, OR = 0.57, 95%CI 0.39 to 0.85, p = 0.005, I2 = 0%.

Consistency in results‡ Consistent

Precision in results§ Imprecise

Directness of results║ Indirect for overall analysis (antipsychotic classes combined).

NeuRA Clocapramine November 2019

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Clocapramine

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, OR = odds ratio, p = statistical probability of obtaining that result (p < 0.05 generally regarded as significant), RCT = randomised controlled trials

NeuRA Clocapramine November 2019

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Clocapramine

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, randomised 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 Clocapramine November 2019

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

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Clocapramine

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 Clocapramine November 2019

Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected] Page 6 To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia

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Clocapramine

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. Kishi T, Matsunaga S, Matsuda Y, Iwata N (2014): Iminodibenzyl class antipsychotics for schizophrenia: A systematic review and meta-analysis of carpipramine, clocapramine, and mosapramine. Neuropsychiatric Disease and Treatment 10: 2339-51. 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 Clocapramine November 2019

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