Dos klorpromazin untuk pesakit skizofrenia
Abstract
Background
The World Health Organization (WHO) Model Lists of Essential Medicines lists chlorpromazine as one of its five medicines used in psychotic disorders.
Objectives
To determine chlorpromazine dose response and dose side‐effect relationships for schizophrenia and schizophrenia‐like psychoses.
Search methods
We searched the Cochrane Schizophrenia Group’s Study‐Based Register of Trials (December 2008; 2 October 2014; 19 December 2016).
Selection criteria
All relevant randomised controlled trials (RCTs) comparing low doses of chlorpromazine (≤ 400 mg/day), medium dose (401 mg/day to 800 mg/day) or higher doses (> 800 mg/day) for people with schizophrenia, and which reported clinical outcomes.
Data collection and analysis
We included studies meeting review criteria and providing useable data. Review authors extracted data independently. For dichotomous data, we calculated fixed‐effect risk ratios (RR) and their 95% confidence intervals (CIs). For continuous data, we calculated mean differences (MD) and their 95% CIs based on a fixed‐effect model. We assessed risk of bias for included studies and graded trial quality using GRADE (Grading of Recommendations Assessment, Development and Evaluation).
Main results
As a result of searches undertaken in 2014, we found one new study and in 2016 more data for already included studies. Five relevant studies with 1132 participants (585 are relevant to this review) are now included. All are hospital‐based trials and, despite over 60 years of chlorpromazine use, have durations of less than six months and all are at least at moderate risk of bias. We found only data on low‐dose (≤ 400 mg/day) versus medium‐dose chlorpromazine (401 mg/day to 800 mg/day) and low‐dose versus high‐dose chlorpromazine (> 800 mg/day).
When low‐dose chlorpromazine (≤ 400 mg/day) was compared to medium‐dose chlorpromazine (401 mg/day to 800 mg/day), there was no clear benefit of one dose over the other for both global and mental state outcomes (low‐quality and very low‐quality evidence). There was also no clear evidence for people in one dosage group being more likely to leave the study early, over the other dosage group (moderate‐quality evidence). Similar numbers of participants from each group experienced agitation and restlessness (very low‐quality evidence). However, significantly more people in the medium‐dose group (401 mg/day to 800 mg/day) experienced extrapyramidal symptoms in the short term (2 RCTS, n = 108, RR 0.47, 95% CI 0.30 to 0.74, moderate‐quality evidence). No data for death were available.
When low‐dose chlorpromazine (≤ 400 mg/day) was compared to high‐dose chlorpromazine (> 800 mg/day), data from one study with 416 patients were available. Clear evidence of a benefit of the high dose was found with regards to global state. The low‐dose group had significantly fewer people improving (RR 1.13, 95% CI 1.01 to 1.25, moderate‐quality evidence). There was also a marked difference between the number of people leaving the study from each group for any reason, with significantly more people leaving from the high‐dose group (RR 0.60, 95% CI 0.40 to 0.89, moderate‐quality evidence). More people in the low‐dose group had to leave the study due to deterioration in behaviour (RR 2.70, 95% CI 1.34 to 5.44, low‐quality evidence). There was clear evidence of a greater risk of people experiencing extrapyramidal symptoms in general in the high‐dose group (RR 0.43, 95% CI 0.32 to 0.59, moderate‐quality evidence). One death was reported in the high‐dose group yet no effect was shown between the two dosage groups (RR 0.33, 95% CI 0.01 to 8.14, moderate‐quality evidence). No data for mental state were available.
Authors' conclusions
The dosage of chlorpromazine has changed drastically over the past 50 years with lower doses now being the preferred of choice. However, this change was gradual and arose not due to trial‐based evidence, but due to clinical experience and consensus. Chlorpromazine is one of the most widely used antipsychotic drugs yet appropriate use of lower levels has come about after many years of trial and error with much higher doses. In the absence of high‐grade evaluative studies, clinicians have had no alternative but to learn from experience. However, such an approach can lack scientific rigor and does not allow for proper dissemination of information that would assist clinicians find the optimum treatment dosage for their patients. In the future, data for recently released medication should be available from high‐quality trials and studies to provide optimum treatment to patients in the shortest amount of time.
PICO
Plain language summary
Dos klorpromazin untuk pesakit skizofrenia
Soalan sulasan
Ulasan ini melihat dos klorpromazin yang terbaik untuk merawat pesakit skizofrenia.
Latar belakang
Skizofrenia adalah penyakit mental serius yang melibatkan kira‐kira 1% daripada populasi orang dewasa di seluruh dunia. Pesakit skizofrenia sering mendengar suara dan melihat sesuatu (halusinasi) dan mempunyai kepercayaan aneh yang bertentangan dengan komuniti setempat (delusi). Rawatan utama untuk simptom skizofrenia adalah ubat antipsikotik. Klorpromazin adalah salah satu ubat antipsikotik pertama yang didapati berkesan sebagai rawatan skizofrenia pada tahun 1950‐an. Ia masih kekal sebagai salah satu rawatan yang paling biasa digunakan dan tidak mahal sehingga hari ini. Walau bagaimanapun, ia juga mempunyai kesan‐kesan sampingan yang serius seperti kabur penglihatan, mulut kering, terketar‐ketas atau gegaran yang tidak terkawal, kemurungan, kekejangan otot dan kegelisahan.
Ciri‐ciri kajian
Pencarian terkini untuk kajian rawak terkawal yang berkaitan telah dijalankan pada Oktober 2014, dan sekali lagi, pada Disember 2016 dan satu kajian baru telah ditemui. Lima kajian terkini telah ditemui yang memenuhi kriteria untuk semakan. Semua kajian yang disertakan telah dijalankan secara rawak, dan menyelidik kesan pemberian klorpromazin pada dos yang berbeza kepada pesakit skizofrenia. Jumlah peserta adalah 585 orang.
Keputusan utama
Klorpromazin menunjukkan kesan yang berlainan pada dos yang berbeza. Berdasarkan bukti yang lemah, kesan terhadap kesihatan mental peserta pada dos rendah dan dos sederhana adalah agak sama. Walau bagaimanapun, terdapat lebih banyak kesan sampingan pada dos sederhana. Terdapat lebih banyak peningkatan dalam kesihatan mental peserta pada dos tinggi berbanding dengan dos rendah. Namun, kesan sampingan adalah lebih banyak dan menjejaskan pada dos tinggi. Sepanjang lima puluh tahun yang lepas, dos rendah lebih digemari untuk diberikan kepada pesakit. Perubahan ini berlaku secara beransur‐ansur dan berdasarkan pengalaman harian dan kesepakatan, bukannya berdasarkan bukti saintifik yang kukuh. Klorpromazin mempunyai kos yang rendah dan boleh didapati secara meluas. Walaupun terdapat banyak kesan sampingan, klorpromazin berkemungkinan kekal sebagai ubat penanda aras atau piawaian, dan sebagai salah satu rawatan untuk skizofrenia yang paling banyak digunakan di seluruh dunia.
Kualiti bukti
Kesemua kajian dalam ulasan dijalankan di hospital dan semua kecuali satu telah dijalankan sejak 20 tahun lepas. Terdapat bilangan kajian yang terhad dengan kualiti yang terhad dan ini dilaporkan dengan lemah dan berjangka masa pendek. Penyelidikan lanjutan dan kajian mengenai dos klorpromazin adalah wajar untuk dijalankan.
Ben Gray, Senior Peer Researcher, McPin Foundation. http://mcpin.org/
