Abstract
Introduction
The lifetime prevalence of schizophrenia is approximately 0.7% and incidence rates vary between 7.7 and 43.0 per 100,000; about 75% of people have relapses and continued disability, and one third fail to respond to standard treatment. Positive symptoms include auditory hallucinations, delusions, and thought disorder. Negative symptoms (demotivation, self-neglect, and reduced emotion) have not been consistently improved by any treatment.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for positive, negative, or cognitive symptoms of schizophrenia? What are the effects of drug treatments in people with schizophrenia who are resistant to standard antipsychotic drugs? What are the effects of interventions to improve adherence to antipsychotic medication in people with schizophrenia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 51 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: amisulpride, chlorpromazine, clozapine, depot haloperidol decanoate, haloperidol, olanzapine, pimozide, quetiapine, risperidone, sulpiride, ziprasidone, zotepine, aripiprazole, sertindole, paliperidone, flupentixol, depot flupentixol decanoate, zuclopenthixol, depot zuclopenthixol decanoate, behavioural therapy, clozapine, compliance therapy, first-generation antipsychotic drugs in treatment-resistant people, multiple-session family interventions, psychoeducational interventions, and second-generation antipsychotic drugs in treatment-resistant people.
Key Points
The lifetime prevalence of schizophrenia is approximately 0.7% and incidence rates vary between 7.7 and 43.0 per 100,000; about 75% of people have relapses and continued disability, and one third fail to respond to standard treatment.
Positive symptoms include auditory hallucinations, delusions, and thought disorder. Negative symptoms (anhedonia, asociality, flattening of affect, and demotivation) and cognitive dysfunction have not been consistently improved by any treatment.
Standard treatment of schizophrenia has been antipsychotic drugs, the first of which included chlorpromazine and haloperidol, but these so-called first-generation antipsychotics can all cause adverse effects such as extrapyramidal adverse effects, hyperprolactinaemia, and sedation. Attempts to address these adverse effects led to the development of second-generation antipsychotics.
The second-generation antipsychotics amisulpride, clozapine, olanzapine, and risperidone may be more effective at reducing positive symptoms compared with first-generation antipsychotic drugs, but may cause similar adverse effects, plus additional metabolic effects such as weight gain.
CAUTION: Clozapine has been associated with potentially fatal blood dyscrasias. Blood monitoring is essential, and it is recommended that its use be limited to people with treatment-resistant schizophrenia.
Pimozide, quetiapine, aripiprazole, sulpiride, ziprasidone, and zotepine seem to be as effective as standard antipsychotic drugs at improving positive symptoms. Again, these drugs cause similar adverse effects to first-generation antipsychotics and other second-generation antipsychotics.
CAUTION: Pimozide has been associated with sudden cardiac death at doses above 20 mg daily.
We found very little evidence regarding depot injections of haloperidol decanoate, flupentixol decanoate, or zuclopenthixol decanoate; thus, we don’t know if they are more effective than oral treatments at improving symptoms.
In people who are resistant to standard antipsychotic drugs, clozapine may improve symptoms compared with first-generation antipsychotic agents, but this benefit must be balanced against the likelihood of adverse effects.
We found limited evidence on other individual first- or second-generation antipsychotic drugs other than clozapine in people with treatment-resistant schizophrenia.
In people with treatment-resistant schizophrenia, we don't know how second-generation agents other than clozapine compare with each other or first-generation antipsychotic agents, or how clozapine compares with other second-generation antipsychotic agents, because of a lack of evidence.
We don't know whether behavioural interventions, compliance therapy, psychoeducational interventions, or family interventions improve adherence to antipsychotic medication compared with usual care because of a paucity of good-quality evidence.
It is clear that some included studies in this review have serious failings and that the evidence base for the efficacy of antipsychotic medication and other interventions is surprisingly weak. For example, although in many trials haloperidol has been used as the standard comparator, the clinical trial evidence for haloperidol is less impressive may be expected.
By their very nature, systematic reviews and RCTs provide average indices of probable efficacy in groups of selected individuals. Although some RCTs limit inclusion criteria to a single category of diagnosis, many studies include individuals with different diagnoses such as schizoaffective disorder. In all RCTs, even in those recruiting people with a single DSM or ICD-10 diagnosis, there is considerable clinical heterogeneity.
Genome-wide association studies of large samples with schizophrenia demonstrate that this clinical heterogeneity reflects, in turn, complex biological heterogeneity. For example, genome-wide association studies suggest that around 1000 genetic variants of low penetrance and other individually rare genetic variants of higher penetrance, along with epistasis and epigenetic mechanisms, are thought to be responsible, probably with the biological and psychological effects of environmental factors, for the resultant complex clinical phenotype. A more stratified approach to clinical trials would help to identify those subgroups that seem to be the best responders to a particular intervention.
To date, however, there is little to suggest that stratification on the basis of clinical characteristics successfully helps to predict which drugs work best for which people. There is a pressing need for the development of biomarkers with clinical utility for mental health problems. Such measures could help to stratify clinical populations or provide better markers of efficacy in clinical trials, and would complement the current use of clinical outcome scales. Clinicians are also well aware that many people treated with antipsychotic medication develop significant adverse effects such as extrapyramidal symptoms or weight gain. Again, our ability to identify which people will develop which adverse effects is poorly developed, and might be assisted by using biomarkers to stratify populations.
The results of this review tend to indicate that as far as antipsychotic medication goes, current drugs are of limited efficacy in some people, and that most drugs cause adverse effects in most people. Although this is a rather downbeat conclusion, it should not be too surprising, given clinical experience and our knowledge of the pharmacology of the available antipsychotic medication. All currently available antipsychotic medications have the same putative mechanism of action — namely, dopaminergic antagonism with varying degrees of antagonism at other receptor sites. More efficacious antipsychotic medication awaits a better understanding of the biological pathogenesis of these conditions so that rational treatments can be developed.
About this condition
Definition
Schizophrenia is a complex syndrome characterised by three major symptom domains: positive symptoms, such as auditory hallucinations, delusions, and thought disorder; negative symptoms, including anhedonia, social withdrawal, affective flattening, and demotivation; and cognitive dysfunction, particularly in the domains of attention, working memory, and executive function. Schizophrenia is typically a life-long condition characterised by acute symptom exacerbations and widely varying degrees of functional disability. Maintenance antipsychotic drug regimens for schizophrenia are intended to limit the frequency and severity of relapses, maximise the beneficial effects of treatment for persistent symptoms, and enhance adherence to recommended regimens. Antipsychotic medications are primarily effective for positive symptoms, and most people require psychosocial interventions to manage the disability that often results from negative symptoms and cognitive dysfunction. Adherence to prescribed antipsychotic regimens is typically low, and several psychosocial interventions have been developed to enhance adherence. About 20% of people with schizophrenia are resistant to standard antipsychotics, as defined by lack of clinically important improvement in symptoms after two to three regimens of treatment with standard antipsychotic drugs for at least 6 weeks; an additional 30% to 40% of people improve but are residually symptomatic despite antipsychotic treatment. Several pharmacological strategies have been advocated for this group of people. This review focuses on three key aspects of the management of schizophrenia: 1) What are the effects of drug treatments for positive, negative, or cognitive symptoms of schizophrenia? 2) What are the effects of interventions in people with schizophrenia who are resistant to standard antipsychotic drugs? and 3) What are the effects of interventions to improve adherence to antipsychotic medication in people with schizophrenia?
Incidence/ Prevalence
The lifetime prevalence of schizophrenia is approximately 0.7% and incidence rates vary between 7.7 and 43.0 per 100,000. The onset of symptoms typically occurs in early adult life (average age 25 years), and occurs earlier in men than in women.
Aetiology/ Risk factors
Risk factors for schizophrenia include a family history (including genetic factors), obstetric complications, developmental difficulties, central nervous system infections in childhood, cannabis use, and acute life events. The precise contributions of these factors, and ways in which they may interact, are unclear.
Prognosis
About three-quarters of people with schizophrenia suffer recurrent relapse and continued disability. Outcome may be worse in people with insidious onset and delayed initial treatment, social isolation, or a strong family history; people living in industrialised countries; men; and in people who misuse drugs. Drug treatment is more successful in treating positive symptoms, but up to one third of people derive little benefit, and negative symptoms are difficult to treat. About half of people with schizophrenia do not adhere to treatment in the short term, and in the long term adherence is even lower.
Aims of intervention
To improve symptoms, prevent relapse and to improve quality of life, with minimal adverse effects of treatment.
Outcomes
We have reported symptom severity (severity of positive and negative symptoms; global clinical improvement; global clinical impression [a composite measure of symptoms and everyday functioning]) for the first two questions, and adverse effects for all three questions. For the third question on interventions to improve treatment adherence, we have reported adherence to treatment. Some systematic reviews calculate effect sizes to meta-analyse primary studies that use different outcome measures. Effect size is a difficult measure to interpret clinically, so we have given lower priority to analyses that use this measure.
Methods
Clinical Evidence search and appraisal May 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to May 2010, Embase 1980 to May 2010, and The Cochrane Database of Systematic Reviews, May 2010 [online] (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded, and containing >20 individuals of whom >50% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible, although we realise that there are inherent difficulties with blinding in studies of antipsychotics. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). Changes at this update: this review replaces and updates sections of two previous Clinical Evidence reviews, namely, Schizophrenia (acute) and Schizophrenia (maintenance treatment). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Schizophrenia.
| Important outcomes | Adherence to treatment, Relapse, Symptom severity | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of drug treatments for positive, negative, or cognitive symptoms of schizophrenia? | |||||||||
| 4 (514) | Symptom severity | Amisulpride versus placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of people with schizotypal personality disorder in 1 RCT |
| 5 (781) | Symptom severity | Amisulpride versus olanzapine | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of baseline comparisons |
| at least 4 (at least 624) | Symptom severity | Amisulpride versus risperidone | 4 | –1 | –1 | –1 | 0 | Very low | Quality point deducted for incomplete reporting of data. Consistency point deducted for conflicting results. Directness point deducted for inclusion of a mixed population in 1 RCT |
| 1 (123) | Symptom severity | Amisulpride versus ziprasidone | 4 | –2 | 0 | 0 | 0 | Low | Quality point deducted for sparse data and incomplete reporting of results |
| at least 10 (at least 929) | Symptom severity | Amisulpride versus first-generation antipsychotics | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 13 (1131) | Symptom severity | Chlorpromazine versus placebo | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for incomplete reporting of results, inclusion of open-label trials, and inclusion of RCTs with inadequate blinding and randomisation |
| 1 (164) | Symptom severity | Chlorpromazine versus clozapine | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results |
| at least 5 (at least 241) | Symptom severity | Chlorpromazine versus haloperidol | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and inclusion of trials with inadequate randomisation and blinding |
| 1 (60) | Symptom severity | Chlorpromazine versus risperidone | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and unclear blinding |
| 2 (317) | Symptom severity | Clozapine versus haloperidol | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results |
| at least 2 (at least 142) | Symptom severity | Clozapine versus quetiapine | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| at least 4 (at least 503) | Symptom severity | Clozapine versus olanzapine | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data, and inclusion of trials with a high risk of bias |
| 5 (491) | Symptom severity | Clozapine versus risperidone | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for low-dose clozapine compared with high-dose risperidone noted by the authors of the review |
| 1 (146) | Symptom severity | Clozapine versus ziprasidone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (57) | Symptom severity | Clozapine versus zotepine | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| unclear (at least 351) | Symptom severity | Clozapine versus newer atypical antipsychotics (risperidone, zotepine, olanzapine, remoxipride, pooled) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 17 at most (1603 at most) | Symptom severity | Clozapine versus typical/first-generation antipsychotics | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (22) | Symptom severity | Depot haloperidol decanoate versus standard antipsychotic drugs | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for the study being underpowered to detect clinically important differences |
| 1 (32) | Symptom severity | Depot haloperidol decanoate versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| at least 2 (at least 72) | Symptom severity | Haloperidol versus placebo | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results |
| 5 (1475) | Symptom severity | Haloperidol versus risperidone | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point for conflicting results |
| 5 (684) | Symptom severity | Haloperidol versus olanzapine | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of data. Consistency point deducted for conflicting results |
| 5 (1480) | Symptom severity | Haloperidol versus sertindole | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results |
| 3 (299) | Symptom severity | Olanzapine versus placebo | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results |
| 2 (794) | Symptom severity | Olanzapine versus aripiprazole | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| at least 3 (at least 715) | Symptom severity | Olanzapine versus paliperidone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| at least 3 (at least 483) | Symptom severity | Olanzapine versus quetiapine | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| at least 5 (at least 810) | Symptom severity | Olanzapine versus risperidone | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results |
| at least 2 (at least 790) | Symptom severity | Olanzapine versus ziprasidone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 24 (4189) | Symptom severity | Olanzapine versus first-generation antipsychotics | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 6 (206) | Symptom severity | Pimozide versus standard antipsychotic drugs | 4 | 0 | 0 | 0 | 0 | High | |
| 2 (812) | Symptom severity | Quetiapine versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (314) | Symptom severity | Quetiapine versus paliperidone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| at least 7 (at least 1264) | Symptom severity | Quetiapine versus risperidone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 3 (908) | Symptom severity | Quetiapine versus ziprasidone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 10 (1926) | Symptom severity | Quetiapine versus first-generation antipsychotics | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 5 (659) | Symptom severity | Risperidone versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (172) | Symptom severity | Risperidone versus sertindole | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 2 (372) | Symptom severity | Risperidone versus aripiprazole | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| at least 2 (at least 500) | Symptom severity | Risperidone versus ziprasidone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (40) | Symptom severity | Risperidone versus zotepine | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (107) | Symptom severity | Risperidone versus flupentixol | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| at least 30 (at least 3455) | Symptom severity | Risperidone versus first-generation antipsychotic drugs | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 7 (514) | Symptom severity | Sulpiride versus first-generation antipsychotic drugs | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (247) | Symptom severity | Ziprasidone versus aripiprazole | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and being underpowered to detect clinically important differences |
| at least 4 (at least 728) | Symptom severity | Ziprasidone versus first-generation antipsychotic drugs | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| at least 15 (at least 1125) | Symptom severity | Zotepine versus first-generation antipsychotic drugs | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 3 (984) | Symptom severity | Aripiprazole versus placebo | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results |
| at least 5 (at least 2409) | Symptom severity | Aripiprazole versus first-generation antipsychotic drugs | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 7 (1305) | Symptom severity | Paliperidone versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of data |
| What are the effects of drug treatments in people with schizophrenia who are resistant to standard antipsychotic drugs? | |||||||||
| 6 (1018) | Symptom severity | Clozapine versus first-generation antipsychotic drugs | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for inclusion of partial responders and for unclear comparator |
| 5 (819) | Relapse | Clozapine versus first-generation antipsychotic drugs | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for inclusion of partial responders and for unclear comparator |
| at least 4 (at least 315) | Symptom severity | Clozapine versus olanzapine, risperidone, and zotepine | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of non-treatment-resistant people |
| 4 (395) | Symptom severity | Clozapine versus olanzapine | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (146) | Symptom severity | Clozapine versus ziprasidone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (84) | Symptom severity | Olanzapine versus chlorpromazine | 4 | –1 | 0 | –2 | 0 | Very low | Quality point deducted for sparse data. Directness points deducted for inclusion of partial responders and for unclear duration of treatment-resistant illness |
| 1 (306) | Symptom severity | Ziprasidone versus chlorpromazine | 4 | –1 | –1 | –1 | 0 | Very low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for unclear washout period |
| 1 (300) | Symptom severity | Aripiprazole versus perphenazine | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting. Directness point deducted for no statistical analysis between groups for all outcomes |
| 1 (26) | Symptom severity | Risperidone versus fluphenazine | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for baseline comparisons |
| 1 (25) | Symptom severity | Quetiapine versus fluphenazine | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for the use of baseline comparisons |
| 1 (25) | Symptom severity | Second-generation antipsychotic agents (other than clozapine) versus risperidone | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for the use of baseline comparisons |
| What are the effects of interventions to improve adherence to antipsychotic medication in people with schizophrenia? | |||||||||
| 2 (99) | Adherence to treatment | Behavioural therapy versus usual care | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for uncertain validity of outcome assessment (pill count) |
| 1 (63) | Adherence to treatment | Behavioural therapy versus compliance therapy | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 4 (328) | Adherence to treatment | Psychoeducational interventions versus usual care | 4 | –1 | –1 | –1 | 0 | Very low | Quality point deducted for incomplete reporting of data. Consistency point deducted for conflicting results. Directness point deducted for unclear measure of outcome |
| 2 (75) | Adherence to treatment | Psychoeducational interventions versus behavioural therapy | 4 | –2 | –1 | –2 | 0 | Very low | Quality points deducted for sparse data and poor follow-up. Consistency point deducted for conflicting results. Directness points deducted for use of co-intervention (pill box) and uncertain validity of outcome assessment (pill count) |
| 1 (63) | Adherence to treatment | Compliance therapy versus usual care | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 2 (465) | Adherence to treatment | Compliance therapy versus non-specific therapy or health education | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for unclear comparator |
| 7 (at least 369) | Adherence to treatment | Family interventions compared with usual care, single-session family intervention, or psychoeducational intervention | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for incomplete reporting of results and inclusion of quasi-randomised RCTs. Directness point deducted for inclusion of people with schizophrenia-related disorders |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Clinical Global Impression Scale
A one-item, observer-rated scale for measuring the severity of a condition. It has been investigated for validity and reliability. The scale is scored from 0 (not ill at all) to 7 (severely ill).
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Negative symptoms
This generally refers to qualities that are abnormal by their absence (e.g., loss of drive, motivation, affective expression, and self-care).
- Positive symptoms
This refers to symptoms that characterise the onset or relapse of schizophrenia, usually hallucinations and delusions, but sometimes including thought disorder.
- Psychoeducational intervention
Intervention programmes aimed at the education of a person with psychiatric disorder in subject areas that serve the goals of treatment and rehabilitation. The terms “patient education”, “patient teaching”, and “patient instruction” have also been used for this process.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Sarah JE Barry, Robertson Centre for Biostatistics, Institute for Health and Wellbeing, University of Glasgow, Glasgow, UK.
Tracey M Gaughan, Pharmacy and Prescribing Support Unit, NHS Greater Glasgow and Clyde, Glasgow, UK.
Robert Hunter, NHS Greater Glasgow and Clyde, Professor, Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK.
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