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Technical Commentary TECHNICAL COMMENTARY Carpipramine Introduction limbic system relative to the nigrostriatal system, which is the site responsible for Second generation antipsychotics (sometimes inducing extrapyramidal symptoms. In addition referred to as ‘atypical’ antipsychotics) are a to amisulpride, olanzapine and quetiapine also newer class of antipsychotic medication than tend to selectively block dopamine receptors in first generation ‘typical’ antipsychotics. Second the mesolimbic system but target serotonin generation antipsychotics are effective for the receptors. positive symptoms of schizophrenia. It is sometimes claimed that they are more effective This table summarises overall group than first generation antipsychotics in treating effectiveness of carpipramine, 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 (hallucinations) and Owing to the vast number of reviews on fixed, false, irrational beliefs (delusions). antipsychotics, we have included only Second generation antipsychotics may also information reported in the abstracts of cause less extra-pyramidal side effects. These Cochrane systematic reviews3. This is because include dyskinesias such as repetitive, the 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 dopamine receptor 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 receptor antagonist, however it tends to block high. Conversely, low quality evidence such as dopamine receptors more selectively in the NeuRA Carpipramine November 2019 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 Carpipramine 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 risks4. 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 criteria5. NeuRA Carpipramine November 2019 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 Carpipramine Carpipramine Compared to first generation antipsychotics Efficacy: Moderate quality evidence (medium-sized samples, consistent, imprecise, direct) suggests no differences between carpipramine and clofluperol, oxypertine, penfluridol, or pimozide for response or discontinuation rates. Adverse effects: Moderate quality evidence suggests no differences between carpipramine and clofluperol, oxypertine, penfluridol, or pimozide for any side effect. Kishi T, Matsunaga S, Matsuda Y, Iwata N. Iminodibenzyl class antipsychotics for schizophrenia: a systematic review and meta-analysis of carpipramine, clocapramine, and mosapramine. Neuropsychiatric Disease and Treatment 2014; 10: 2339-2351 This review compared carpipramine with clofluperol, oxypertine, penfluridol, or pimozide. There were no differences between groups for; Discontinuation for any reason: 4 RCTs, N = 290, OR = 1.07, 95%CI 0.49 to 2.35, p = 0.87, I2 = 0% Response: 4 RCTs, N = 290, OR = 1.35, 95%CI 0.67 to 2.74, p = 0.41, I2 = 14% Risks There were no differences in rates of at least one side effect: 4 RCTs, N = 290, OR = 1.09, 95%CI 0.67 to 1.74, p = 0.72, I2 = 0% 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, OR = odds ratio, p = statistical probability of obtaining that result (p < 0.05 generally regarded as significant), RCTs = randomised controlled trials NeuRA Carpipramine November 2019 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 Carpipramine 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 effect3. 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 formula3; 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 < 0.26. 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
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