Flupentixol versus fármacos antipsicóticos de primera generación de baja potencia para la esquizofrenia
Resumen
Antecedentes
Los fármacos antipsicóticos son los pilares del tratamiento de la esquizofrenia. Las guías terapéuticas establecen que no hay ninguna diferencia en cuanto a la eficacia entre los fármacos antipsicóticos; sin embargo, los fármacos antipsicóticos de baja potencia suelen ser percibidos por los médicos como menos eficaces que los compuestos de alta potencia y también parecen diferir en cuanto a los efectos secundarios.
Objetivos
Examinar los efectos en la respuesta clínica del flupentixol y los antipsicóticos de baja potencia para los pacientes con esquizofrenia.
Métodos de búsqueda
Se hicieron búsquedas en el registro de ensayos del Grupo Cochrane de Esquizofrenia (Cochrane Schizophrenia Group) (julio de 2010).
Criterios de selección
Ensayos controlados aleatorios que compararan flupentixol con fármacos antipsicóticos de primera generación de baja potencia para los pacientes con esquizofrenia o psicosis similar a la esquizofrenia.
Obtención y análisis de los datos
Los datos se extrajeron de forma independiente. Para los datos continuos, se calcularon las diferencias de medias (DM) sobre la base de un modelo de efectos aleatorios.
Resultados principales
La revisión actualmente incluye un ensayo aleatorio de China continental con 153 participantes que duró dos meses y comparó flupentixol con clorpromazina. No se informaron los métodos exactos de generación de la secuencia y la ocultación de la asignación, y la medicación se proporcionó de una manera abierta. No hubo datos sobre los resultados que se habían seleccionado a priori para una tabla de “Resumen de los hallazgos”.
No hubo diferencias significativas entre el flupentixol y la clorpromazina en el estado mental general de los participantes al final del estudio según lo medido con la puntuación total Brief Psychiatric Rating Scale (BPRS) (1 ensayo controlado aleatorio [ECA], n = 153; DM 2,20; intervalo de confianza [IC] del 95%: ‐1,25 a 5,65). La clorpromazina se asoció con significativamente menos mareos (1 ECA, n = 153; DM 0,12; IC del 95%: 0,01 a 0,23); distonía (1 ECA, n = 153; DM 0,29; IC del 95%: 0,13 a 0,45); marcha inestable (1 ECA, n = 153; DM 0,46; IC del 95%: 0,28 a 0,64); expresión facial reducida (1 ECA, n = 153; DM 0,27; IC del 95%: 0,09 a 0,45); agitación (1 ECA, n = 153; DM 0,69; IC del 95%: 0,45 a 0,93); rigidez (codo) (1 ECA, n = 153; DM 0,48; IC del 95%: 0,28 a 0,68); y temblores (1 ECA, n = 153; DM 0,56; IC del 95%: 0,34 a 0,78); La clorpromazina produjo más sequedad bucal que el flupentixol (1 ECA, n = 153; DM ‐0,14; IC del 95%: ‐0,25 a ‐0,03).
Conclusiones de los autores
La base de pruebas del flupentixol versus antipsicóticos de primera generación de baja potencia actualmente está restringida a una comparación aleatoria con clorpromazina. Los pocos datos informados no indican una diferencia en cuanto a la eficacia, aunque el flupentixol pareció producir más trastornos del movimiento y mareos, mientras que la clorpromazina se asoció con un efecto secundario anticolinérgico ‐ sequedad bucal. Se necesitan más ensayos para establecer conclusiones acerca de los efectos relativos del flupentixol y los antipsicóticos de baja potencia.
PICO
Resumen en términos sencillos
Flupentixol en comparación con antipsicóticos de primera generación de baja potencia
El flupentixol estuvo disponible por primera vez en el Reino Unido en 1965 y se ha utilizado para tratar la esquizofrenia durante casi cinco décadas. Está disponible en forma de comprimido y como una inyección de acción prolongada. Tras investigarlo en numerosos estudios, se encontró que el flupentixol era efectivo y bien tolerado por los pacientes con esquizofrenia. Los efectos secundarios principales son temblores, estremecimiento o incapacidad de permanecer quieto, sequedad bucal y aumento de peso. Aunque este fármaco ha estado disponible durante décadas, existen pocas revisiones sistemáticas sobre el flupentixol. Actualmente no se conocen los efectos de este fármaco para ayudar a los pacientes a enfrentar los síntomas de la esquizofrenia, los mismos no se han medido ni cuantificado. Esta revisión solo pudo incluir un ensayo pequeño y limitado, realizado hace 13 años.El número de estudios fue reducido, y su calidad fue baja; para los resultados principales de interés los autores no pudieron calificar la calidad de las pruebas, debido a que el estudio no informó los resultados de interés para la tabla de “Resumen de los hallazgos”. El flupentixol se comparó con clorpromazina. No hubo diferencias claras en cuanto a la eficacia, ni hubo información clara sobre: aumento en el uso de los servicios; satisfacción de los pacientes con el tratamiento; calidad de vida; o costos y relación entre costo y eficacia. El flupentixol está ampliamente disponible y es económico. Tal vez sea comprensible que siga siendo uno de los muchos fármacos utilizados para el tratamiento de pacientes con enfermedades mentales graves. Esto se debe a que el uso de flupentixol se basa más en la experiencia clínica y en la decisión de los psiquiatras que en los resultados de estudios de investigación de gran escala e información basada en pruebas. La efectividad y los beneficios del flupentixol en comparación con la clorpromazina se desconocen ampliamente y son incompletos. Ensayos aleatorios amplios podrían ser útiles para aumentar el conocimiento acerca de este fármaco.
Este resumen en términos sencillos ha sido redactado por Benjamin Gray, usuario experto de servicios, Rethink Mental Illness.
Authors' conclusions
Summary of findings
| FLUPENTHIXOL versus LOW‐POTENCY ANTIPSYCHOTICS for schizophrenia | ||||||
| Patient or population: patients with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | FLUPENTHIXOL versus LOW‐POTENCY ANTIPSYCHOTICS | |||||
| Response to treatment | See comment | Not estimable | 0 (0) | See comment | There were no data available for these important outcomes | |
| Acceptability to treatment ‐ leaving the study early due to any reason | ||||||
| Adverse effects ‐ at least one adverse effect | ||||||
| Adverse effects ‐ at least one movement disorder | ||||||
| Adverse effects ‐ sedation | ||||||
| Adverse effects ‐ death | ||||||
| Quality of life | ||||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
Background
Description of the condition
Schizophrenia is often a chronic and disabling psychiatric disorder. It afflicts approximately one per cent of the population world‐wide with little gender difference. Its typical manifestations are 'positive' symptoms such as fixed, false beliefs (delusions) and perceptions without cause (hallucinations), 'negative' symptoms such as apathy and lack of drive, disorganisation of behaviour and thought, and catatonic symptoms such as mannerisms and bizarre posturing (Carpenter 1994). The degree of suffering and disability is considerable, with 80% to 90% not working (Marvaha 2004) and up to 10% dying by suicide (Tsuang 1978).
Description of the intervention
Antipsychotic drugs are the core treatment for schizophrenia. They can be classified according to their biochemical structure (e.g. butyrophenones, phenothiazines, thioxanthenes, etc.), their risk of producing movement disorders ('atypical' versus 'typical' antipsychotics) and the doses necessary for an antipsychotic effect (high‐potency versus low‐potency antipsychotics). The classification into high‐potency and low‐potency medication means that for low‐potency antipsychotic drugs, higher doses are necessary to obtain the same dopamine receptor occupancy and efficacy than for high‐potency antipsychotic drugs (Seeman 1975). In this context, flupenthixol belongs to the high‐potency antipsychotic drug group. It is a conventional antipsychotic drug which is primarily indicated for schizophrenia.
Low‐potency antipsychotic drugs will be the comparator drugs in this review. Typical examples of low‐potency antipsychotic drugs are chlorpromazine, chlorprothixene, thioridazine or levomepromazine. It is an old psychiatric dogma that can be found in textbooks and guidelines that ‐ with the exception of clozapine ‐ there is no difference in efficacy between antipsychotic compounds (Gaebel 2006; Lehman 2004). Nevertheless, low‐potency antipsychotic drugs are often perceived as less efficacious than high‐potency compounds by clnicians, and high‐ and low‐potency antipsychotics also seem to differ in side effects. Low‐potency drugs seem to have a high incidence of sedation or hypotonia, whereas high‐potency drugs might produce most extrapyramidal side effects.
How the intervention might work
The theory is that schizophrenia is a chronic disorder caused by hyperdopaminergic states in the limbic system (Berger 2003). Flupenthixol is a thioxanthene and was formulated in the 1960s. It has been said to be beneficial against negative symptoms of schizophrenia and also has an indication for the short‐term symptomatic treatment of depression of mild to moderate severity.
Flupenthixol acts by equally strong antagonism of D1 and D2 dopamine receptors as well as serotonin receptors. The metabolism of flupenthixol is via three main routes ‐ sulphoxidation, side chain N‐dealkylation, and glucuronic acid conjugation. Excretion is mainly via the faeces, but there is also some excretion in the urine (Kirk 1980). Its bioavailability is between 40% and 50%, and it has an elimination half‐life period of about 20‐40 hours. Side effects are similar to other high‐potency antipsychotics. Extrapyramidal symptoms such as akathisia and tremor are thought to be frequent, but anticholinergic side effects are rarer.
Low‐potency medications have a lower affinity for dopamine receptors so that a higher dose is required to effectively treat symptoms of schizophrenia. They additionally also block other dopamine receptors, such as cholinergic or histaminergic receptors. This also explains the occurrence of side effects, such as sedation or hypotonia, which are less frequent with high‐potency drugs. The cutoff between high‐ and low‐potency drugs is not clear, but attempts have been made to express their relationship in terms of dose equivalence. The most frequently applied concept is based on chlorpromazine equivalents according to Davis 1974 or Haase 1983 and provides data about comparable doses of various antipsychotic drugs to achieve an effect similar to 100 mg chlorpromazine.
Why it is important to do this review
Systematic reviews on the comparative effects of high‐potency versus low‐potency conventional antipsychotic drugs are not available. Cochrane reviews on the effects of specific conventional antipsychotic drugs have been published, but they compared the effects of one antipsychotic drug versus any other antipsychotic drug (e.g. pimozide versus any other antipsychotic drug, Sultana 2007) and thus did not consider the important classification in high‐potency and low‐potency antipsychotics. Due to this lack of evidence, treatment guidelines make statements such as “all conventional antipsychotics if adequately dosed have comparable efficacy” (German national schizophrenia guideline (Gaebel 2006); also see guideline of the World Federations of Societies of Biological Psychiatry (Falkai 2005)).
These guidelines contrast with the clinical impression that low‐potency conventional antipsychotic drugs are less efficacious than high‐potency conventional antipsychotic drugs. The clinical consequences to follow these guidelines are considerable, because high‐potency and low‐potency antipsychotics differ clearly in side effects. High‐potency antipsychotics often lead to strong extrapyramidal symptoms; low‐potency antipsychotics, on the other hand, have strong sedating properties and often also produce hypotension.
Conventional antipsychotic drugs are still the mainstay of treatment in countries that cannot afford newer, expensive 'atypical' or 'second‐generation' antipsychotic drugs. But even in some industrialised countries such as Germany, conventional antipsychotic medications still account for 50% of the market share (Lohse 2005). Recent studies about these more expensive second‐generation antipsychotics have also called into question their superiority (Jones 2006; Leucht 2009; Lieberman 2005). Therefore, research on older conventional agents is essential and has been requested. The results of this review could also have an impact on our principal understanding of antipsychotic drugs and is one of a series of similar reviews (Table 1).
| Title | Reference |
| Haloperidol versus first‐generation antipsychotics for schizophrenia | |
| Perphenazine versus low‐potency first generation antipsychotic drugs for schizophrenia | |
| Fluphenazine versus low‐potency first generation antipsychotic drugs or schizophrenia | |
| Trifluoperazine versus low‐potency first generation antipsychotic drugs or schizophrenia | |
| Haloperidol versus low‐potency first‐generation antipsychotic drugs or schizophrenia |
Objectives
To review the effects of the high‐potency antipsychotic drug flupenthixol versus low‐potency antipsychotic drugs.
Methods
Criteria for considering studies for this review
Types of studies
We included only randomised studies with people suffering schizophrenia or related disorders in this review. We excluded quasi‐randomised trials, such as those where allocation is undertaken on surname. If trials implied that they were randomised without fully describing allocation, we also included these.
Types of participants
We included people with schizophrenia and schizophrenia‐like psychoses (schizophreniform and schizoaffective disorders), irrespective of the diagnostic system applied. There is no clear evidence that the schizophrenia‐like psychoses are caused by fundamentally different disease processes or require different treatment approaches (Carpenter 1994). We included studies that use diagnostic criteria other than ICD‐10 (International Classification of Diseases, tenth revision) or DSM‐IV (Diagnostic and Statistical Manual of Mental Disorders, fourth edition). These diagnostic criteria are not meticulously used in clinical routine either, so broader inclusion criteria will enhance generalisability and representativeness.
Types of interventions
1. Intervention: flupenthixol
Any dose of oral mode of administration (no depots, no short‐acting parenteral forms of administration).
2. Comparators: low‐potency antipsychotic drugs
The control interventions were low‐potency conventional antipsychotic drugs with any oral form of administration and any dose. We used the dose equivalence tables developed by Davis 1974 and/or Haase 1983 to define drugs as low‐potency with a chlorpromazine equivalence roughly equal or higher than chlorpromazine. The chlorpromazine equivalences of sulpiride are often estimated to be approximately 100. However, its properties are similar to those of amisulpride, which is an atypical antipsychotic and not within the scope of this review. Moreover, sulpiride does not cause a lot of sedation, which is another important characteristic of low‐potency antipsychotics. Therefore, we decided a priori to not consider sulpiride in this review.
Types of outcome measures
We analysed the outcomes for different lengths of follow‐up: up to three months, six months or more than six months.
Primary outcomes
1. Clinical response
Response to treatment as defined by the original studies
Secondary outcomes
1. Mental state: symptoms of schizophrenia
1.1 Overall symptoms ‐ average score/change in mental state
1.2 Positive symptoms ‐ average score/change in positive symptoms
1.3 Negative symptoms ‐ average score/change in negative symptoms
2. Global state
2.1 Average score/change in global state
3. Relapse ‐ as defined by each of the studies
4. Leaving the study early
4.1 Acceptability of treatment ‐ leaving the study due to any reason
4.2 Leaving the study early due to inefficacy of treatment
4.3 Leaving the study early due to side effects
5. Service use
5.1 Rehospitalisation
6. Death
6.1 Death (all causes)
6.2 Suicide
7. Adverse effects
7.1 At least one adverse effect
7.2 Extrapyramidal/movement disorders
7.3 Cardiac effects
7.4 Hypotension
7.5 Sedation
7.6 Weight gain
8. Quality of life
8.1 Important change
8.2 Average score/change
9. Participant's/carer`s satisfaction with care
9.1 Important change
9.2 Average score/change
10. Economic outcomes
11. 'Summary of findings' table
We used the GRADE approach to interpret findings (Schünemann 2008) and GRADE profiler (GRADE) to import data from RevMan 5 (Review Manager) to create a 'Summary of Findings' table. These tables provide outcome‐specific information concerning the overall quality of evidence from each included study in the comparison, the magnitude of effect of the interventions examined, and the sum of available data on all outcomes rated as important to patient‐care and decision making.
We anticipated including the following short‐ or medium‐term outcomes in a 'Summary of findings' table.
1. Response to treatment
2. Acceptability of treatment ‐ leaving the study early due to any reason
3. Adverse effects ‐ at least one adverse effect
4. Adverse effects ‐ movement disorders ‐ at least one movement disorder
5. Adverse effects ‐ sedation
6. Adverse effects ‐ other
7. Death
8. Quality of life
Search methods for identification of studies
We did not apply any language restriction within the limitations of the search tools.
Electronic searches
Cochrane Schizophrenia Group Trials Register (July 2010)
We searched the register using the phrase:
[(*flupenthixol* in intervention of STUDY) AND (*flupenthixol* in title, abstract and index terms of REFERENCE entered 01/05/10 >=)]
This register is compiled by systematic searches of major databases, hand searches and conference proceedings (see group module).
This register is compiled by regular methodical searches in numerous electronic databases (BIOSIS, CINAHL, Dissertation Abstracts, EMBASE, LILACS, MEDLINE, PSYNDEX, PsycINFO, RUSSMED, Sociofile), supplemented by the regular handsearching of relevant journals and numerous conference proceedings (for details see the description of the Cochrane Schizophrenia Group (Adams 2008).
Searching other resources
1. Reference searching
We inspected the references of all identified studies for additional trials.
2. Previous reviews
We searched previously published conventional reviews (Davis 1989; Klein 1969).
3. Personal contact
We contacted the first author of the one included study for any missing information and to enquire about the existence of further studies.
Data collection and analysis
Selection of studies
Two review authors (MT, MD) independently inspected all abstracts identified in the searches. Disagreement was resolved by discussion and where doubt still remained, we acquired the full article for further inspection. Once the full articles were obtained, at least two review authors independently decided whether the studies met the review criteria. If disagreement could not be resolved by discussion, we resolved it with a third review author (SL), or sought further information from the study authors.
Data extraction and management
1. Extraction
Originally we planned that two review authors (MT, MD) would independently extract data from all selected trials. If disagreement arose, we planned to resolve it by discussion with a third review author (SL). Where this was not possible, we intended to contact the study authors to resolve the dilemma. It turned out that the only included study was written in Chinese. The study was extracted by a Chinese native speaker (HC, see Acknowledgements) who was otherwise not involved in the review.
2. Management
We extracted data onto simple, standard forms.
3. Scale‐derived data
3.1 Valid measures
We included continuous data from rating scales only if: (a) the psychometric properties of the measuring instrument had been described in a peer‐reviewed journal (Marshall 2000); (b) the measuring instrument was not written or modified by one of the trialists.
3.2 Endpoint versus change data
Since there is no principal statistical reason why endpoint and change data should measure different effects (Higgins 2011), we decided primarily to use scale endpoint data. If endpoint data were not available, we used change data.
Assessment of risk of bias in included studies
It was originally planned that two review authors (MT, MD) would work independently by using criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to assess trial quality. This new set of criteria is based on evidence of associations between overestimate of effect and high risk of bias of the article such as sequence generation, allocation concealment, blinding, incomplete outcome data and selective reporting. As the only included study was in Chinese, HC (see Acknowledgements) took over this task.
We have noted the level of risk of bias the text of the review see (Risk of bias in included studies).
Measures of treatment effect
1. Dichotomous data
For binary outcomes, we planned to calculate a standard estimation of the random‐effects (Der‐Simonian 1986) risk ratio (RR) and its 95% confidence interval (CI). It has been shown that RR is more intuitive (Boissel 1999) than odds ratios and that odds ratios tend to be interpreted as RR by clinicians (Deeks 2000). This misinterpretation then leads to an overestimate of the impression of the effect. We intended where possible, to convert outcome measures to dichotomous data. This could be done by identifying cut‐off points on rating scales and dividing participants accordingly into 'clinically improved' or 'not clinically improved'. We generally assumed that if there has been a 50% reduction in a scale‐derived score such as the Brief Psychiatric Rating Scale (BPRS, Overall 1962) or the Positive and Negative Syndrome Scale (PANSS, Kay 1986), this can be considered as a clinically significant response (Leucht 2005a; Leucht 2005b). If data based on these thresholds were not available, we planned to use the primary cut‐off presented by the original authors.
2. Continuous data
2.1 Summary statistic
For continuous outcomes we estimated mean differences (MD) between groups.
2.2 Skewed data
Continuous data on clinical and social outcomes are often not normally distributed. To avoid the pitfall of applying parametric tests to non‐parametric data, we planned to apply the following standards to all data before inclusion: (a) data from studies of at least 200 participants would have been entered in the analysis irrespective of the following rules, because skewed data pose less of a problem in large studies; (b) endpoint data: when a scale starts from the finite number zero, we planned to subtract the lowest possible value from the mean, and divide this by the standard deviation. If this value was lower than 1, it would have strongly suggested a skew and the study would have been excluded. If this ratio was higher than 1 but below 2, it would have suggested skew was present. We would have entered the study and tested whether its inclusion or exclusion substantially changed the results. If the ratio had been larger than 2, the study would have been included, because skew is less likely (Higgins 2011); (c) change data: when continuous data are presented on a scale which includes a possibility of negative values (such as change data), it is difficult to tell whether data are skewed or not. We planned to enter the study, because change data tend to be less skewed and because excluding studies would also lead to bias, because not all the available information was used.
Unit of analysis issues
1. Cluster trials
Studies increasingly employ 'cluster randomisation' (such as randomisation by clinician or practice) but analysis and pooling of clustered data poses problems. Firstly, authors often fail to account for intraclass correlation in clustered studies, leading to a 'unit of analysis' error (Divine 1992) whereby P values are spuriously low, confidence intervals unduly narrow and statistical significance overestimated. This causes type I errors (Bland 1997; Gulliford 1999).
If results from trials had not adjusted for clustering, we would have attempted to adjust the results for clustering, by multiplying the standard errors of the effect estimates (risk ratio or mean difference, ignoring clustering) by the square root of the design effect. The design effect is calculated as DEff = 1 + (M ‐ 1) ICC, where M is the average cluster size and ICC is the intra‐cluster coefficient (Higgins 2011). If an ICC was not available from the trial, other sources would have been used to impute ICCs (Campbell 2000).
If clustering had been incorporated into the analysis of primary studies, we would have presented these data as if from a non‐cluster randomised study, but adjusted for the clustering effect. If a cluster study had been appropriately analysed taking into account ICC and relevant data documented in the report, synthesis with parallel group randomised trials would have been possible using the generic inverse variance technique, where the natural logarithm of the effect estimate (and standard errors) for all included trials for that outcome would be calculated and entered into RevMan along with the log of the effect estimate (and standard errors) from the cluster randomised trial(s). We would have used methods described in section 7.7.7.2 and 7.7.7.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to obtain standard errors.
2. Cross‐over trials
A major concern of cross‐over trials is the carry‐over effect. It occurs if an effect (e.g. pharmacological, physiological or psychological) of the treatment in the first phase is carried over to the second phase. As a consequence, on entry to the second phase the participants can differ systematically from their initial state despite a wash‐out phase. For the same reason cross‐over trials are not appropriate if the condition of interest is unstable (Elbourne 2002). As both effects are very likely in schizophrenia, we considered randomised cross‐over studies eligible but only data up to the point of first cross‐over.
Dealing with missing data
1. Overall loss of credibility
At some degree of loss of follow‐up, data must lose credibility (Xia 2007). The loss to follow‐up in randomised schizophrenia trials is often considerable, calling the validity of the results into question. Nevertheless, it is unclear which degree of attrition leads to a high degree of bias. We used the 'Risk of bias' tool described above to indicate potential bias if more than 25% of the participants left the study prematurely, if the reasons for attrition differed between the intervention and the control group, and if no appropriate imputation strategies were applied.
2. Dichotomous data
We intended to present data on a 'once‐randomised‐always‐analyse' basis, assuming an intention‐to‐treat (ITT) analysis. If the authors applied such a strategy, we planned to use their results. If the original authors presented only the results of the per‐protocol or completer population, we would have assumed that those participants lost to follow‐up would have had the same percentage of events as those who remained in the study.
3. Continuous data:
3.1 General
We used ITT when available. We anticipated that in some studies, in order to do an ITT analysis, we would employ the method of last observation carried forward (LOCF) within the study report. As with all methods of imputation to deal with missing data, LOCF introduces uncertainty about the reliability of the results (Leon 2006). Therefore, if LOCF data had been used in the analysis, we would have indicated this in the review.
3.2 Missing standard deviations
Where there are missing measures of variance for continuous data but an exact standard error and confidence interval are available for group means, and either the P value or T value are available for differences in mean, we can calculate standard deviation value according to methods described in Section 7.7.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If standard deviations had not been reported and we could have calculated them from available data, we would have asked authors to supply the data. In the absence of data from authors, we would have used the mean standard deviation from other studies.
Assessment of heterogeneity
1. Clinical heterogeneity
We planned to consider included studies without any comparison data to judge clinical heterogeneity. We planned to inspect included studies for clearly outlying situations or people which we had not predicted would arise and discuss them fully, if such situations or participants arose.
2. Methodological heterogeneity
We planned to consider all included studies initially, without seeing comparison data, to judge methodological heterogeneity. We would have inspected all studies for clearly outlying methods which we had not predicted would arise and discussed them if they were evident.
3. Statistical
3.1 Visual inspection
We planned to visually inspect graphs to identify trials with non‐overlapping confidence intervals within a forest plot to suggest the possibility of statistical heterogeneity.
3.2 Employing the I2statistic
We planned to investigate heterogeneity between studies by considering the I2 method alongside the Chi2 P value. The I2 provides an estimate of the percentage of inconsistency thought to be due to chance (Higgins 2011). The importance of the observed value of I2 depends on i. magnitude and direction of effects and ii. strength of evidence for heterogeneity (e.g. P value from Chi2 test, or a confidence interval for I2). We planned to interpret an I2 estimate greater than or equal to 50% accompanied by a statistically significant Chi2 statistic as evidence of substantial levels of heterogeneity (Section 9.5.2 ‐ Higgins 2011) and to explore reasons for heterogeneity. If we had found inconsistency and clear reasons for it, we would have presented data separately.
Assessment of reporting biases
We planned to enter data from all identified and selected trials for each outcome into a funnel plot (trial effect versus trial size) in an attempt to investigate the likelihood of overt publication bias. We would have tested for funnel plot asymmetry only for outcomes where there were 10 or more studies, and if the studies were not of similar sizes, as recommended in Section 10.4.3.1 of the Cochrane Handbook (Higgins 2011). If there were outcomes with more than 10 studies, we would have used the statistical test by Egger (Egger 1997) to formally assess funnel‐plot asymmetry, and supplement visual inspection of the forest plot to differentiate small‐study effects from other reasons for funnel plot asymmetry.
Data synthesis
We employed a random‐effects model for analyses (Der‐Simonian 1986). We understand that there is no closed argument for preference for use of fixed‐effect or random‐effects models. The random‐effects method incorporates an assumption that the different studies are estimating different, yet related, intervention effects. This does seem true to us and the random‐effects model takes into account differences between studies even if there is no statistically significant heterogeneity. Therefore, the random‐effects model is usually more conservative in terms of statistical significance, although as a disadvantage, it puts added weight onto smaller studies which can either inflate or deflate the effect size. We planned therefore, to examine the primary outcome based on a fixed‐effect model in a sensitivity analysis.
Subgroup analysis and investigation of heterogeneity
1. Subgroup analysis
We planned to apply subgroup analyses only to the primary outcome.
1.1 Comparison drug
In order to reduce clinical and methodological reasons for heterogeneity, we planned to subgroup trials that compared flupenthixol versus each single low‐potency antipsychotic separately.
1.2 Clinical state, stage or problem
We proposed to undertake this review and provide an overview of the effects of flupenthixol for people with schizophrenia in general. In addition, however, we intended to report data on subgroups of people in the same clinical state, stage and with similar problems if data were available.
2. Investigation of heterogeneity
If we had detected statistical heterogeneity and quantified it as significant, we would have noted whether significant heterogeneity was present within the subgroups. If unanticipated clinical or methodological heterogeneity was evident among the trials in the subgroups, or in the pooled results, we planned to state hypotheses regarding these for future reviews or versions of this review. We would not have undertaken further analyses relating to these hypotheses.
Sensitivity analysis
We planned to apply sensitivity analyses only to the primary outcome.
1. Risk of bias
We intended to analyse the effects of excluding trials that were judged to be at high risk of bias across one or more of the domains of randomisation (implied as randomised with no further details available) allocation concealment, blinding and outcome reporting for the meta‐analysis of the primary outcome. If the exclusion of trials at high risk of bias did not substantially alter the direction of effect or the precision of the effect estimates, then data from these trials would have been included in the analysis.
2. Assessment of dosage
We planned to include trials in a sensitivity analysis if doses between high‐potency and low‐potency antipsychotics were clearly discrepant by our judgement, based on the chlorpromazine equivalence tables by Andreasen 2010, Davis 1974 and Haase 1983. If there was no substantive difference when studies with discrepant doses were added, then we would have employed all data from these studies.
3. Fixed‐effect and random‐effects
We planned to synthesise data for the primary outcome using a fixed‐effect model to evaluate whether the greater weights assigned to larger trials with greater event rates altered the significance of the results, compared to the more evenly distributed weights in the random‐effects model.
Results
Description of studies
For substantive description of studies please see Characteristics of included studies and Characteristics of excluded studies tables.
Results of the search
The search in the Cochrane Schizophrenia Group register yielded 184 references from 115 studies. Four studies were closely inspected. One of the inspected studies was included (Liu 2000). Seven publications on three studies had to be excluded (see Figure 1).
Study flow diagram.
Included studies
Only one randomised controlled trial (RCT) from mainland China (Liu 2000) met the inclusion criteria.
1. Length of trial
The study had a duration up to two months.
2. Participants
Few details on the medical histories of the participants were provided. Participants were diagnosed according to DSM‐IV (APA 2000) and the Chinese Classification of Mental Disorders Version 2, revised (CCMD‐2‐R). There were 117 women and 36 men, all were over 18 years of age.
3. Setting
The study was conducted in hospital.
4. Study size
One hundred and fifty‐three participants were randomised.
5. Interventions
The study compared flupenthixol and chlorpromazine, both given as tablets and in flexible doses. The minimum flupenthixol dose was 10 mg/day. There was no information about the chlorpromazine dose.
6. Outcomes
Scales that provided usable data are described below.
6.1 Brief Psychiatric Rating Scale ‐ BPRS (Overall 1962)
The BPRS is a rating scale used to measure psychiatric symptoms such as depression or hallucinations rated between 1 to 7 and, depending on the version, between 18 to 24 symptoms are scored.
6.2 Simpson Angus Scale ‐ SAS (Simpson 1970)
This 10‐item scale, with a scoring system of zero to four for each item, measures drug‐induced parkinsonism, a short‐term drug‐induced movement disorder. A low score indicates low levels of parkinsonism. For the purpose of the single included study the single items were used to examine single movement disorders.
6.3 Treatment Emergent Symptom Rating Scale ‐ TESS (NIMH 1985)
This six‐item scale, developed by the National Institute of Mental Health, measures various medication side effects. The authors of the single included study used it to examine various side effects in a continuous fashion.
These three scales provided the only usable outcomes for this review.
Excluded studies
We excluded three studies. Of these, Crow 1986 applied intra‐muscular flupenthixol; Ishimaru 1971 compared flupenthixol with perphenazine, which is not a low‐potency antipsychotic drug and Johnstone 1978 compared α‐flupenthixol and β‐flupenthixol with placebo.
Risk of bias in included studies
For graphical representations of our judgements of risk of bias please refer to Figure 2 and Figure 3. Full details of judgements are seen in the 'Risk of bias' table of the Characteristics of included studies.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Allocation
The single included study was described as randomised but further information on sequence generation was not provided. The authors only say that participants were first matched for gender and age, and were then randomised, but there was no descriptions as to how the randomisation sequence was generated. We therefore classified it as 'unclear risk of bias' concerning sequence generation. Similarly, it was not explained how participants were allocated to treatment groups so that we classified the study as unclear in this regard.
Blinding
The study was rated as high risk of bias concerning both performance and detection bias, as the authors did not give any information on blinding and the study was thus assumed to be open.
Incomplete outcome data
The publication did not report whether there were participants who discontinued the study prematurely. We gave it a high risk of bias in this domain.
Selective reporting
The study protocol was not available to us, but there was no obvious selective reporting when the method and the results sections of the publication were compared.
Other potential sources of bias
We did not identify any other clear sources of bias.
Effects of interventions
1. Flupenthixol versus low‐potency antipsychotics
1.1 Mental state: General ‐ average total score (BPRS endpoint)
We found no significant difference between flupenthixol and chlorpromazine (1 RCT, n = 153, mean difference (MD) 2.20 95% confidence interval (CI) ‐1.25 to 5.65).
1.2 Adverse effects
1.2.1 Movement disorders
For change in dystonia there was a significant difference in favour of chlorpromazine (1 RCT, n = 153, MD 0.29 95% CI 0.13 to 0.45), as was the case for unsteady gait (1 RCT, n = 153, MD 0.46 95% CI 0.28 to 0.64), reduced facial expression (1 RCT, n = 153, MD 0.27 95% CI 0.09 to 0.45), restlessness (1 RCT, n = 153, MD 0.69 95% CI 0.45 to 0.93), rigidity (elbow) (1 RCT, n = 153, MD 0.48 95% CI 0.28 to 0.68; 1 RCT, n = 153, MD 0.29 rigidity (wrist) 95% CI 0.09 to 0.49), and tremor (1 RCT, n = 153, MD 0.56 95% CI 0.34 to 0.78).
1.2.2 Others
a. Anticholinergic
Dry mouth was less prevalent with flupenthixol (1 RCT, n = 153, MD ‐0.14 95% CI ‐0.25 to ‐0.03), but there was no difference between flupenthixol and chlorpromazine for hypersalivation (1 RCT, n = 153, MD 0.13 95% CI ‐0.03 to 0.29).
b. Cardiovascular
For the outcome of 'dizziness' there was a significant difference in favour of chlorpromazine (1 RCT, n = 153, MD 0.12 95% CI 0.01 to 0.23), but not for 'tachycardia' (1 RCT, n = 153, MD 0.04 95% CI ‐0.19 to 0.27).
c. Central nervous system
There was no significant difference between flupenthixol and chlorpromazine for the outcome of 'somnolence' (1 RCT, n = 153, MD 0.00 95% CI ‐0.04 to 0.04).
2. Missing outcomes
The study did not report on outcomes such as response to treatment, leaving the study early, other adverse effects than the ones listed above, death, quality of life, service use or economic outcomes.
3. Subgroup/sensitivity analyses
There was only one study. Therefore subgroup and sensitivity analyses could not be applied.
4. Publication bias
As there was only one included study a funnel plot analysis would not have been meaningful.
5. 'Summary of findings' table
We had a priori planned to examine with more scrutiny the outcomes response to treatment, acceptability of treatment (leaving the study early for any reason), at least one adverse effect, at least one movement disorder, sedation, death and quality of life in a 'Summary of findings' table and GRADEpro. However, none of them was reported by the only included study (Liu 2000) so that no judgement could be made in the summary of findings Table for the main comparison.
Discussion
Summary of main results
1. General
This review intended to compare flupenthixol with low‐potency conventional antipsychotics. Our search yielded 184 publications, most of which either compared flupenthixol decanoate with other antipsychotics, or oral flupenthixol with other high‐potency first‐generation antipsychotics or flupenthixol with second‐generation antipsychotics. Finally, only one study with 153 participants from mainland China with poorly reported methods could be included (Liu 2000). The trial compared flupenthixol with the prototypal low‐potency drug chlorpromazine. This study did not report on the primary outcome response to treatment, nor on other outcomes that we had a priori decided to be important enough for a 'Summary of findings' table. We feel that these issues speak for themselves in that much more randomised evidence is needed to understand the relative effects of flupenthixol compared with low‐potency antipsychotics.
2. Treatment effects
2.1 Efficacy
The only usable efficacy data from the single included study were on the overall mental state as measured by the BPRS total score. There was no significant difference between flupenthixol and chlorpromazine in the 153 randomised participants. However, the result is difficult to interpret, because it has not been reported whether participants had discontinued the study prematurely and why. Therefore, this result could have been based on the study completers rather than applying an intention‐to‐treat (ITT) approach.
2.2 Adverse effects
Flupenthixol produced more movement disorders such as dystonia, unsteady gait, reduced facial expression, restlessness, rigidity and tremor. Chlorpromazine produced more dry mouth. These findings are consistent with statements in guidelines and textbooks that high‐potency antipsychotics such as flupenthixol produce more extrapyramidal side effects than low‐potency antipsychotics, while chlorpromazine has strong anticholinergic properties, which can lead to dry mouth. The most important limitations are that these results are again based on only one randomised controlled trial (RCT) and are only valid for flupenthixol versus chlorpromazine and not versus other low‐potency antipsychotics. Moreover, they are all based on single items of the Simpson Angus Scale (Simpson 1970) and the Treatment Emergent Symptoms Scale (NIMH 1985), which have been analysed in a continuous manner. This form of presentation is more difficult to interpret than the number of participants with an adverse event.
2.3 Missing outcomes
In some way, the most important result is what has not been measured. The study did not report on how many participants left the study early, and not on the primary outcome response to treatment, which is an easier to interpret efficacy outcome than the mean of a rating scale (here the BPRS). There are no data on important adverse effects (e.g. death, hypotension, sedation and weight gain), quality of life, satisfaction with care or cost, which are particularly important for policy makers.
3. Publication bias
Only one study was included, which did not report on the primary outcome response to treatment, so the test for funnel plot asymmetry was not meaningful. However, flupenthixol is an old drug and so are low‐potency first‐generation antipsychotics. As the efforts to reduce publication bias are relatively recent, it is possible that some studies have not been published, as flupenthixol was introduced decades ago.
4. Subgroup/sensitivity analyses
Data on the primary outcome response to treatment were not available, so no subgroup/sensitivity analyses were conducted. This shows that we do not have information on different stages of the illness, and that we do not have comparisons of flupenthixol with other low‐potency first‐generation antipsychotics than chlorpromazine.
Overall completeness and applicability of evidence
1. Completeness
There was only one included study, which compared flupenthixol with chlorpromazine and was short‐term. We do not know anything about how flupenthixol compares with other low‐potency antipsychotics. The participants in the single included study were acutely ill people with schizophrenia, which is quite typical for schizophrenia trials. There is no information on other stages of the illness such as those with a first episode of schizophrenia, those with predominant negative symptoms, treatment‐resistant people and other characteristics. Finally, only a few outcomes were reported by the single included study (Liu 2000). The issues show that the evidence if far from being complete.
2. Applicability
The single included study comes from mainland China. Due to various differences between Asian and Western populations, there are limitations in terms of generalisability. Liu 2000 was conducted in hospital, the results are therefore not necessarily applicable to outpatients. The total number of participants was only 153. It has been shown that approximately 1000 participants need to be included in psychiatric meta‐analyses for the results to be robust (Trikalinos 2004). The results of one trial comparing flupenthixol with chlorpromazine do also not automatically generalise to comparisons of flupenthixol with other low‐potency antipsychotics. In summary, there are many limitations in the applicability of the findings to routine care.
Quality of the evidence
The evidence is based on one study with only 153 participants. The study was randomised, but it did not report any details about how the sequence was generated and whether or not allocation was concealed. Studies from mainland China often use alternate allocation by hospital admission numbers, which can introduce bias. It was an open trial without any attempt to blind participants, staff or raters. Finally, it was not described whether there were any dropouts and how these were handled by the statistical analysis. All outcomes that we had a priori considered to be important so that we wanted to address them in a 'Summary of findings' table were simply not available. Overall, the quality of evidence is very low.
Potential biases in the review process
The search is based on Cochrane Schizophrenia Trials Register, so it is possible that there are unpublished trials we are not aware of. As mentioned above, this might well be the case, because the literature of interest can be expected to be quite old, and the older the studies, the more difficult they are to retrieve.
Agreements and disagreements with other studies or reviews
We are not aware of other reviews on the efficacy of flupenthixol versus low‐potency antipsychotic drugs.
Study flow diagram.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 FLUPENTHIXOL versus LOW‐POTENCY ANTIPSYCHOTICS, Outcome 1 Mental state: General ‐ average total score (BPRS, endpoint, high = poor).
Comparison 1 FLUPENTHIXOL versus LOW‐POTENCY ANTIPSYCHOTICS, Outcome 2 Adverse effects: 1. Specific ‐ movement disorders (SAS change, high = worse).
Comparison 1 FLUPENTHIXOL versus LOW‐POTENCY ANTIPSYCHOTICS, Outcome 3 Adverse effects: 2. Specific ‐ other (TESS change, high = worse).
| Comparison | Excluded study tag | Current Cochrane review |
| Antipsychotic (various) withdrawal versus continuation for schizophrenia | ‐ | |
| Flupenthixol isomers for schizophrenia | ‐ | |
| Flupenthixol versus high‐potency antipsychotics for schizophrenia | Ishimaru 1971 (perphenazine) | |
| Flupenthixol versus placebo for schizophrenia |
| Methods | Allocation: randomised ‐ clearly described generation of sequence and concealment of allocation. |
| Participants | People with schizophrenia or schizophrenia‐like disorder. |
| Interventions | 1. Flupenthixol (oral). 2. Any low‐potency antipsychotic (oral). |
| Outcomes | Global state: CGI, response to treatment ‐ primary outcome. Service use: rehospitalisation. Mental state: important change. Leaving the study early: including specific causes. Adverse effects/events: death, at least one EPS, at least one adverse effect, sedation, weight gain, sexual side effects, cardiac problems and other. Quality of life: important change. Satisfaction with care: important change. Economic: employment, costs. |
| CGI ‐ Clinical Global Impression. | |
| FLUPENTHIXOL versus LOW‐POTENCY ANTIPSYCHOTICS for schizophrenia | ||||||
| Patient or population: patients with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | FLUPENTHIXOL versus LOW‐POTENCY ANTIPSYCHOTICS | |||||
| Response to treatment | See comment | Not estimable | 0 (0) | See comment | There were no data available for these important outcomes | |
| Acceptability to treatment ‐ leaving the study early due to any reason | ||||||
| Adverse effects ‐ at least one adverse effect | ||||||
| Adverse effects ‐ at least one movement disorder | ||||||
| Adverse effects ‐ sedation | ||||||
| Adverse effects ‐ death | ||||||
| Quality of life | ||||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Title | Reference |
| Haloperidol versus first‐generation antipsychotics for schizophrenia | |
| Perphenazine versus low‐potency first generation antipsychotic drugs for schizophrenia | |
| Fluphenazine versus low‐potency first generation antipsychotic drugs or schizophrenia | |
| Trifluoperazine versus low‐potency first generation antipsychotic drugs or schizophrenia | |
| Haloperidol versus low‐potency first‐generation antipsychotic drugs or schizophrenia |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mental state: General ‐ average total score (BPRS, endpoint, high = poor) Show forest plot | 1 | 153 | Mean Difference (IV, Random, 95% CI) | 2.20 [‐1.25, 5.65] |
| 2 Adverse effects: 1. Specific ‐ movement disorders (SAS change, high = worse) Show forest plot | 1 | 1071 | Mean Difference (IV, Random, 95% CI) | 0.42 [0.31, 0.53] |
| 2.1 dystonia | 1 | 153 | Mean Difference (IV, Random, 95% CI) | 0.29 [0.13, 0.45] |
| 2.2 facial expression reduced | 1 | 153 | Mean Difference (IV, Random, 95% CI) | 0.27 [0.09, 0.45] |
| 2.3 gait unsteady | 1 | 153 | Mean Difference (IV, Random, 95% CI) | 0.46 [0.28, 0.64] |
| 2.4 restlessness | 1 | 153 | Mean Difference (IV, Random, 95% CI) | 0.69 [0.45, 0.93] |
| 2.5 rigidity ‐ elbow | 1 | 153 | Mean Difference (IV, Random, 95% CI) | 0.48 [0.28, 0.68] |
| 2.6 rigidity ‐ wrist | 1 | 153 | Mean Difference (IV, Random, 95% CI) | 0.29 [0.09, 0.49] |
| 2.7 tremor | 1 | 153 | Mean Difference (IV, Random, 95% CI) | 0.56 [0.34, 0.78] |
| 3 Adverse effects: 2. Specific ‐ other (TESS change, high = worse) Show forest plot | 1 | 765 | Mean Difference (IV, Random, 95% CI) | 0.02 [‐0.07, 0.11] |
| 3.1 anticholinergic ‐ dry mouth | 1 | 153 | Mean Difference (IV, Random, 95% CI) | ‐0.14 [‐0.25, ‐0.03] |
| 3.2 anticholinergic ‐ increased salivation | 1 | 153 | Mean Difference (IV, Random, 95% CI) | 0.13 [‐0.03, 0.29] |
| 3.3 cardiovascular ‐ dizziness | 1 | 153 | Mean Difference (IV, Random, 95% CI) | 0.12 [0.01, 0.23] |
| 3.4 cardiovascular ‐ tachycardia | 1 | 153 | Mean Difference (IV, Random, 95% CI) | 0.04 [‐0.19, 0.27] |
| 3.5 central nervous system ‐ somnolence | 1 | 153 | Mean Difference (IV, Random, 95% CI) | 0.0 [‐0.04, 0.04] |
