Training to recognise the early signs of recurrence in schizophrenia
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To compare the effectiveness of EWS intervention plus TAU for those with schizophrenia with two types of TAU. Firstly TAU that includes another psychological therapy, and secondly TAU that does not include a psychological therapy as part of its care plan.
Another objective was, if possible, to compare the effectiveness of intermittent medication used on recognition of EWS in people not taking maintenance neuroleptic medication with TAU involving maintenance neuroleptic medication.
Other areas of interest were EWS as primary focus of the intervention or as part of another intervention; EWS intervention delivered to patient only or patient and carer or health professional; EWS intervention delivered to carer only versus carer and patient; EWS intervention delivered individually versus group intervention.
Background
The lifetime prevalence of schizophrenia is just less than one percent with onset usually occurring during adolescence or early adulthood. Diagnosis is predictive of increased risk of suicide, impaired occupational and social functioning, and a heightened risk of physical illness. Most people with schizophrenia experience a cyclical pattern of illness with periods of acute psychotic episodes followed by stable periods of full or partial remission, although these are often accompanied by the presence of residual symptoms (APA 1997).
The use of secondary prevention strategies, in which patients are encouraged to recognise signs of impending exacerbations of illness, are common in the treatment of several chronic physical illnesses such as diabetes and heart disease and may be equally beneficial to those suffering from severe mental illness (Bustillo 1995).
Both retrospective (Bechdolf 1998, Herz 1980) and prospective (Birchwood 1989, Marder 1991) observational studies indicate that relatively small changes in signs and symptoms of schizophrenia can reliably predict acute episodes of psychosis two to ten weeks later. The symptoms (observed and reported by the patient) and signs (mostly behaviours observed and reported by carers or mental health professionals) are idiosyncratic to the patient, but consistently predict recurrence of psychosis in those who have a relapsing and remitting course of schizophrenia (Birchwood 1989, Bustillo 1995, Herz 2000, Marder 1991).
Early warning interventions are based on the hypothesis that learning to detect and manage early warning signs (EWS) of impending relapse might prevent the onset of acute episodes (Lam 1997). The term prodromes has been used to delineate EWS, but this term will be avoided here because prodrome is now commonly used to delineate a period immediately before the first onset of psychotic symptoms in schizophrenia (Bustillo 1995).
Originally the recognition of EWS was combined with intermittent medication strategies. It was hoped that this would help prevent the long‐term side‐effects of medication such as tardive dyskinesis, by reducing overall exposure to neuroleptic medication (Herz 1980, Jolley 1989). However, early randomised controlled trials suggested that over a two year period, those randomised to EWS and intermittent antipsychotic medication strategy experienced more acute episodes of schizophrenia than those randomised to a continuous use of maintenance antipsychotic medication only (Gaebel 1993, Jolley 1990).
More recently, however, added clinical benefit has been demonstrated in patients on maintenance antipsychotics when EWS interventions are combined with short‐term additional treatment such as diazepam (Carpenter 1999), additional oral antipsychotic (Marder 1994), cognitive therapy (Gumley 2003) and multifaceted psycho‐educational and family interventions (Herz 2000). If such interventions were effective in reducing recurrences they would offer significant benefits to sufferers and their caregivers. Recent practice guidelines for schizophrenia (APA 1997) recommend working with patients and their families to address EWS of recurrence.
Monitoring for EWS in schizophrenia has often been included as a component of psychological interventions, for example, in combination with other cognitive strategies or as one aspect of family intervention. There is a need to identify which components of therapy have a positive influence on outcomes (Haddock 1998). Two narrative reviews have specifically evaluated studies in schizophrenia seeking to reduce relapse through interventions based on EWS (Birchwood 2001, Herz 1995) and conclusions to date have been promising. These reviews did not systematically search for studies, however, and did not attempt meta‐analysis so conclusions are open to bias. Furthermore, they did not consider the full range of possible outcomes in schizophrenia such as the individual's wellbeing and functioning and resulting difficulties incurred by friends and relatives.
It is also possible that EWS interventions in schizophrenia might be associated with adverse outcomes, for example increased depression due to increased self‐focus required by symptom monitoring. For people with a diagnosis of schizophrenia, those identified as less aware of their symptoms were less likely to report being depressed (Dixon 1998). Symptom awareness has also been linked to recurrent suicidal thoughts (Amador 1996). Another effect might be increased medication due to the possible effect of increased symptom reporting (Gaebel 1993).
Finally, the effectiveness of EWS interventions in schizophrenia might vary according to features of the intervention such as duration, participation of caregivers, group versus individually tailored intervention, severity of illness and the presence or absence of an acute episode of schizophrenia at the time of the intervention or the existence of co‐morbid conditions. Demographic factors such as age and gender should also be taken into account. There is evidence that first episode patients with schizophrenia can benefit from EWS interventions coupled with intermittent medication, but multi‐episode cases of schizophrenia must have maintenance medication (Gaebel 2002).
Objectives
To compare the effectiveness of EWS intervention plus TAU for those with schizophrenia with two types of TAU. Firstly TAU that includes another psychological therapy, and secondly TAU that does not include a psychological therapy as part of its care plan.
Another objective was, if possible, to compare the effectiveness of intermittent medication used on recognition of EWS in people not taking maintenance neuroleptic medication with TAU involving maintenance neuroleptic medication.
Other areas of interest were EWS as primary focus of the intervention or as part of another intervention; EWS intervention delivered to patient only or patient and carer or health professional; EWS intervention delivered to carer only versus carer and patient; EWS intervention delivered individually versus group intervention.
Methods
Criteria for considering studies for this review
Types of studies
We included all relevant randomised controlled trials. We included trials that were described as double‐blind, but that did not mention whether the study was randomised, in a sensitivity analysis. If there was no substantive difference within primary outcomes (see 'Types of outcome measures') when these studies were added, then we included them in the final analysis. If there was a substantive difference, we used only clearly randomised trials and described the results of the sensitivity analysis in the text. We excluded quasi‐randomised studies, such as those allocating by using alternate days of the week.
Types of participants
Adults with a diagnosis of schizophrenia and non‐affective serious or chronic mental illness, irrespective of mode of diagnosis.
Types of interventions
1. EWS intervention plus TAU
2. TAU not involving a psychological therapy
3. TAU plus another psychological therapy
4. EWS intervention with intermittent medication
5. TAU with maintenance medication.
An EWS intervention can be described as any intervention designed to train people with a diagnosis of schizophrenia and/or their carers to recognise the early warning signs of recurrence of episodes. Each person must receive at least one hour of face‐to‐face training in recognising and managing EWS.
Recognition of EWS requires detailed history taking, with or without additional techniques such as diary keeping, completion of questionnaires and card sorting techniques, and a plan of action based on the EWS. The interventions may be individually based or group‐based and can involve family members or carers. They can be carried out in any treatment setting.
In the absence of an explicit description of EWS, studies in which the intervention is described as cognitive, family, psychosocial, psychoeducational, self‐monitoring, interpersonal, relapse prevention, self‐help or targeted/intermittent medication will be considered as potentially including EWS training.
Types of outcome measures
1. Death: suicide or natural causes
2. Service utilisation outcomes
2.1 hospital admission
2.2 days in hospital
2.3 change in hospital status
3. Clinical response
3.1 relapse
3.2 time to relapse
3.3 clincially significant response in global state ‐ as defined by each of the studies
3.4 average score/change in global state
3.5 clinically significant response in mental state ‐ as defined by each of the studies
3.6 average score/change in mental state
3.7 clinically significant response in positive symptoms ‐ as defined by each of the studies
3.8 average score/change in positive symptoms
3.9 clinically significant response on negative symptoms ‐ as defined by each of the studies
3.10 average score/change in negative symptoms
3.11 use of/need for medication, specification of type if necessary
4. Satisfaction of care
4.1 Leaving the study early
4.2 Perceived control over illness
5. Behaviour
5.1 clinically significant response in behaviour ‐ as defined by each of the studies
5.2 average score/change in behaviour
5.3 occurrence of offensive behaviour
6. Social functioning
6.1 clinically significant response in social functioning ‐ as defined by each of the studies
6.2 average score/change in social functioning
7. Quality of life/satisfaction
7.1 significant change in quality of life/satisfaction ‐ as defined by each of the studies
7.2 average score/change in quality of life/satisfaction
7.3 employment status
8. Economic outcomes
Search methods for identification of studies
Electronic searches
We carried out electronic searches using the Cochrane Schizophrenia Group Register (2003), MEDLINE (1966‐2003), EMBASE (1980‐2003), PSYCH INFO (1974‐2003), CINAHL (1982‐2003), and The Cochrane Library (2003). We inspected all reference lists of selected studies and relevant reviews for additional relevant titles.
Electronic search terms used:
Those recommended by the Cochrane Schizophrenia group for schizophrenia and related psychosis
and
Intervention= "Clinical Status" or "Cognitive Therapy" or "Cognitive Behavioral Therapy" or "Consumer Advocacy" or "Consumer Led Care" or "Early Intervention" or "Family Therapy" or "Family Focused Psycho education Therapy" or "Group Therapy" or "Inpatient Family Intervention" or "MaritaI Therapy" or "Monitoring" or "Self‐Directed Health and Social Care Use" or "Psychoeducation" or "Psychotherapy" or "Self‐Evaluation" or "Self‐Evaluation" or "Skills Training" or "Spouses" or "Early Warning" or "Early Signs" or "Intermittent Medication" or "Targeted Medication".
Searching other resources
1. Hand searches
We did not undertake any hand searches.
2. NHS National Research Register (NRR)
We inspected this for information regarding ongoing research trials and, if possible we contacted the corresponding author regarding unpublished data.
Data collection and analysis
1. Selection of trials
The reviewers (MF, RM, JMC) independently inspected the citations identified from the search. Potentially relevant abstracts were identified and full papers ordered and reassessed for inclusion and methodological quality. Any disagreement was discussed and reported.
2. Assessment of quality
We allocated trials to three quality categories, as described in the Cochrane Reviewers' Handbook (Clarke 2002) by each reviewer. When disputes arose as to which category a trial was allocated, we attempted to resolve them by discussion. When this was not possible and further information was necessary to clarify into which category to allocate the trial, we did not enter data but allocated the trial to the list of those awaiting assessment. We included only trials in Category A or B in the review.
3. Data management
3.1 Data extraction
This was performed independently by two reviewers (MF and CB) and, where further clarification was needed we contacted authors of trials for missing data.
3.2 Intention to treat analysis
We excluded data from studies in which more than 50% of participants in any group were lost to follow up (this does not include the outcome of 'leaving the study early'). In studies with less than 50% dropout rate, people leaving early were considered to have had the negative outcome, except for the event of death. We analysed the impact of including studies with high attrition rates (25%‐50%) in a sensitivity analysis. If inclusion of data from this latter group did result in a substantive change in the estimate of effect we did not add their data to trials with less attrition but presented them separately.
4. Data analysis
4.1 Binary data
For binary outcomes we calculated a standard estimation of the random effects risk ratio (RR) and its 95% confidence interval (CI). We also calculated the weighted number needed to treat statistic (NNT), and its 95% confidence interval (CI). If heterogeneity was found (see section 5) we used a random effects model.
4.2 Continuous data
4.2.1 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 applied the following standards to all data before inclusion: (a) standard deviations and means were reported in the paper or were obtainable from the authors; (b) when a scale starts from a finite number (such as zero), the standard deviation, when multiplied by two, was less than the mean (as otherwise the mean was unlikely to be an appropriate measure of the centre of the distribution (Altman 1996). Endpoint scores on scales often have a finite start and end point and this rule can be applied to them.
4.2.2 Summary statistic: for continuous outcomes a weighted mean difference (WMD) between groups was estimated. Again, if heterogeneity was found (see section 5) we used a random effects model.
4.2.3 Valid scales: we included continuous data from rating scales only if the measuring instrument had been described in a peer‐reviewed journal and the instrument was either a self report or completed by an independent rater or relative (not the therapist). Unpublished instruments are more likely to report statistically significant findings than those that have been peer‐reviewed and published (Marshall 2000).
4.2.4 Endpoint versus change data: where possible we presented endpoint data. If both endpoint and change data were available for the same outcomes we reported only the former.
4.2.5 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 intra class 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).
Where clustering was not accounted for in primary studies, we presented the data in a table, with a (*) symbol to indicate the presence of a probable unit of analysis error. In subsequent versions of this review we will seek to contact first authors of studies to obtain intra class correlation co‐efficients of their clustered data and to adjust for this by using accepted methods (Gulliford 1999). Where clustering has been incorporated into the analysis of primary studies, we will also present these data as if from a non‐cluster randomised study, but adjusted for the clustering effect.
We have received statistical advice that the binary data as presented in a report should be divided by a 'design effect'. This is calculated using the mean number of participants per cluster (m) and the intra‐class correlation co‐efficient (ICC) Design effect = 1+(m‐1)*ICC (Donner 2002). If the ICC was not reported it was assumed to be 0.1 (Ukoumunne 1999).
If cluster studies had been appropriately analysed taking into account intra‐class correlation co‐efficients and relevant data documented in the report, synthesis with other studies would have been possible using the generic inverse variance technique. Where clustering has been incorporated into the analysis of primary studies, then we will also present these data in a table.
5. Test for heterogeneity
We used a chi squared test, as well as visual inspection of graphs, to investigate the possibility of heterogeneity. A significance level less than 0.10 was interpreted as evidence of heterogeneity. If heterogeneity was found we reanalysed data using a random effects model to see if this resulted in the data becoming homogeneous. If it did, we data were presented and reasons for the differing results discussed. If heterogeneity remained, studies clearly responsible for statistical or clinical heterogeneity were not added to the main body of homogeneous trials, but summated and presented separately and reasons for heterogeneity investigated.
6. Addressing publication bias
We entered data from all included studies into a funnel graph (trial effect against trial size) in an attempt to investigate the likelihood of overt publication bias (Egger 1997)
7.Sensitivity analyses
We examined the effect of including studies with high attrition rates in a sensitivity analysis.
8. General
Where possible we entered data in such a way that the area to the left of the line of no effect indicated a favourable outcome for the EWS treatment groups.
