This section presents the full report of the methods and results of a systematic review that was conducted to inform the development of Primrose intervention and training programme.
Summary
Background
People with SMI are at increased risk of developing CVD and die at a younger age than the general population. This study evaluated and synthesised evidence from published systematic reviews and individual RCTs on the effectiveness of pharmacological and behavioural interventions for reducing modifiable CVD risk factors in people with SMI.
Methods
We searched The Cochrane Library for existing systematic reviews. We then searched the Cochrane Schizophrenia and Cochrane Depression, Anxiety and Neurosis Group Trial Registers between 1966 and 2014 for additional RCTs not included in the identified reviews. We searched for interventions to manage levels of cholesterol, diabetes mellitus, hypertension, weight, smoking and alcohol consumption.
Findings
Fifteen systematic reviews and 28 additional RCTs were included in the review, from 11,028 references. The synthesised data demonstrated good evidence of effective pharmacological and behavioural interventions for weight management and some evidence that combined pharmacological and behavioural interventions might be more effective than either alone. There was good evidence that pharmacological interventions were effective for smoking cessation, or reducing smoking, and some evidence for behavioural or combined interventions. Three studies reported effective interventions to reduce alcohol misuse. No studies were found on effective interventions targeting levels of cholesterol, diabetes mellitus or hypertension in SMI.
Conclusion
There is evidence that CVD risk attributable to weight and smoking can be managed effectively in SMI, using pharmacological and behavioural approaches. Future research should determine the effectiveness of interventions to manage cholesterol levels, diabetes mellitus, hypertension and alcohol misuse in this population.
Introduction
People with SMI die at a significantly younger age than the general population.124 The majority of these premature deaths (66%) are due to potentially preventable or treatable CVD.3,5
Increased mortality risk for CVD is seen in people with SMI compared with the general population. Those aged 50–75 years have a twofold increased risk of death from CVD, rising to threefold for those < 50 years old.3 There is evidence that CVD risk screening for people with SMI does not meet international or national guidelines.23,111
Increased risk for CVD is attributable to metabolic and anthropomorphic effects of antipsychotic medication as well as lifestyle factors including poor diet, low levels of physical activity, smoking and, in some cases, higher than recommended levels of alcohol consumption.
The challenge is to design and deliver effective interventions to prevent CVD in this group and this requires synthesis of evidence about modifying the different risk factors that contribute to CVD in SMI. Our overarching aim was to identify the best international evidence regarding effective CVD risk management for people with SMI to allow clinicians, policy-makers and researchers to meet the challenge of implementing and appraising CVD risk reduction strategies.
In primary care, multiple risk factors for CVD are often addressed in one consultation but existing reviews of pharmacological or behavioural interventions to reduce CVD risk in people with SMI tend to be limited to one or two contributing risk factors/behaviours (e.g. smoking52,95 diet and physical activity96–99 or alcohol use).100 Furthermore much existing research has largely been generated in secondary care rather than primary care where, in the UK, evidence-based guidelines suggest CVD risk in SMI should be managed.17 One review has synthesised evidence across CVD risk factors up to 2010.53 We aimed to update and improve on this review by including (1) more recently published studies, (2) existing systematic reviews and meta-analyses in addition to individual studies and (3) including only the highest-quality studies using a randomised experimental design. This review informed the development of a primary care-based intervention to reduce CVD risk.106
Methods
We searched for published systematic reviews and additional RCTs that were not included in existing systematic reviews.
Inclusion/exclusion criteria
Studies were included if they met the following criteria: (1) they used a randomised controlled design, (2) ≥ 50% of participants were adults with a diagnosis of schizophrenia, bipolar disorder or other non-organic psychotic disorders including schizoaffective disorder, (3) they evaluated interventions aimed at managing levels of cholesterol, diabetes mellitus, hypertension, weight, smoking and/or alcohol consumption, (4) title and abstract were written in English (papers were only excluded on the basis of being written in a non-English language where translation of the full text was not possible) and (5) were published between 1966 and 2014.
Search strategy
We conducted the search strategy in five stages in the following order: (1) we searched the Cochrane group publications lists and Cochrane Library database for systematic reviews, (2) an information specialist from the Cochrane Schizophrenia Group searched the Cochrane Schizophrenia Group Trials Register for RCTs with schizophrenia and psychosis populations, (3) we searched The Cochrane Library database for additional RCTs using an adapted search strategy to include populations with bipolar disorder provided by the Cochrane Depression, Anxiety and Neurosis Group, (4) an expert reference group searched for non-peer-reviewed literature, (5) experts in the field were asked to identify any relevant publications not captured by the electronic search strategies and (6) principal investigators identified on trials registers were contacted for relevant publications.
The following search terms were used:
Schizophrenia* OR severe mental illness* OR bipolar or mania* OR manic* OR hypomani* OR psychos* OR psychotic OR postpsychotic OR “post psychotic” OR “rapid cycling” OR schizoaffective OR bipolar OR mania* OR manic* OR hypomani*
AND
*physical* OR *cardio* OR *metabolic* OR *weight* OR *Tobacc* OR *Smok* OR *medical* OR *alcohol* OR *nutrition* OR *diet* OR *health* OR *diabete* OR *blood pressure* OR *hypertension* OR *cholesterol*OR *statin*
Screening
Titles and abstracts of reports of RCTs identified in the electronic searches were screened by four researchers (LA, AB, MH and VT; see Acknowledgements). References not meeting the inclusion criteria and duplicates (including individual RCTs in included systematic reviews) were removed. To assess reliability of screening, reviewers independently screened 10% of each other’s allotted references resulting in < 5% level of disagreement. Disagreements were resolved by discussion.
Full-text reports were obtained and screened by the same researchers using the criteria described above. Data were extracted from reports meeting the inclusion criteria.
Data extraction
Data within the RCTs were extracted using a modified template from Methods for the Development of NICE Public Health Guidance125 to record methodological (publication, design, etc.) and substantive characteristics (participant, setting, etc.) of included studies.
Quality assessment
The quality of evidence in included reports was assessed using The Cochrane Collaboration’s tool for assessing risk of bias.126
Data synthesis
Reference lists of published systematic reviews were cross-checked and reviews including the greatest number of relevant references were summarised. Papers from less comprehensive reviews were also included if they were not covered by the more comprehensive reviews. A meta-analysis of findings from individual RCTs was not possible owing to the heterogeneity of reporting, so a narrative synthesis of findings was created. Findings from RCTs with fewer than 10 participants, which may not be sufficiently powered to detect change, are summarised separately.
We performed a narrative synthesis of the evidence, first by selecting the most comprehensive systematic review and summarising this and all the additional trial results.
Findings
Fifteen systematic reviews and 28 additional individual RCTs of interventions met the inclusion criteria [ and for Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of individual RCTs].
Systematic reviews and RCTs identified by the search strategy
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart of additional individual RCTs. CCDAN, Cochrane Depression, Anxiety and Neurosis Group; CSzG, Cochrane Schizophrenia Group.
No trials or reviews of interventions directly targeting levels of cholesterol, diabetes mellitus or hypertension in SMI were identified. Systematic reviews and individual RCTs meeting the inclusion criteria were therefore grouped into three categories of interventions: (1) weight, (2) smoking and (3) alcohol consumption.
In this section, we summarise the main findings of the systematic reviews, grouping the interventions according to their main target CVD risk factor and whether they were behavioural, pharmacological or both.
Risk of bias
Risk of bias was assessed in individual RCTs identified through the electronic searches (n = 28) and in an additional five RCTs that were taken from systematic reviews that were discarded from this review because the remaining studies had all been included in one of the 15 more comprehensive reviews, making a total of 33 assessments.
Three RCTs were rated as being at a high risk of bias. Of these, two were open-label studies of pharmacological interventions54,55 and one had high attrition, which differed across treatment groups.56
Seven RCTs were rated as being at a low risk of bias.57–63
The remaining 23 RCTs were rated as being at an unclear risk of bias. Although all studies reported using randomisation, 20 of the 23 RCTs did not adequately describe methods of allocation concealment and 17 out of 23 did not describe how participants were randomised.
Interpretation
Summary of main findings
We performed a comprehensive review of international evidence regarding interventions to reduce cardiovascular risk in people with SMI. We included existing systematic reviews as well as more recent RCTs. We found evidence for effective pharmacological and behavioural interventions to decrease weight and smoking, but limited evidence on effective interventions to manage alcohol misuse. We did not find RCT evidence regarding interventions directly targeting cholesterol levels, hypertension, diabetes mellitus or CVD multiple risk factors.
Regarding pharmacological interventions for managing weight, metformin appeared to be most effective over an average 13-week period, with a modest weight loss of nearly 3 kg on average.98 Evidence from the 10 more recent individual trials focused mainly on topiramate, which was also shown to be similarly effective in managing weight,57,67,70 although adverse effects may limit its tolerability.17 Incidentally, it also prevented an increase in the level of cholesterol.70
For behavioural interventions for managing weight, those aimed at individuals (rather than groups), with both dietary and physical activity components were most effective in reducing BMI.96 No trials were identified that assessed the effectiveness of physical activity alone. The most effective interventions to reduce BMI were those combining dietary, physical activity and behavioural support.63,83,85 although adverse effects may limit its tolerability.17 There was some evidence of effectiveness of behavioural interventions on metabolic outcomes with one of three RCTs reporting a significant effect on plasma glucose levels.62
The one trial of a combined pharmacological and behavioural (diet and physical activity) intervention was significantly more effective in reducing BMI, weight and fasting glucose than the pharmacological or behavioural components of the intervention alone.63
Smoking
A meta-analysis demonstrated significant effects of bupropion on smoking abstinence and reduction.95 One trial of NRT reported significant effects on abstinence, number of cigarettes smoked and CO levels.90
One trial of a standardised smoking cessation programme included in a published review was significantly more effective than a SMI-tailored intervention in promoting abstinence.95 Limited conclusions can be drawn from the two RCTs of behavioural interventions identified in this review as their findings conflict: one reported significant effects on reducing smoking; the other reported no significant effect on abstinence.95
One RCT comparing contingency management and bupropion alone or in combination reported a significant effect of contingency management on CO levels but no additional effects of bupropion.95
Most of the trials of smoking cessation or reduction interventions included in the review and RCTs identified by this review were conducted in secondary care. It may be that delivering these interventions to patients in primary care who are likely to be more stable may result in a better response.
Alcohol
There was less evidence regarding alcohol in SMI. Two trials of acamprosate reported no significant effects on frequency of alcohol use.54,93 Two RCTs compared naltrexone plus behavioural support with behavioural support alone; one reported a significant effect in reducing quantity and frequency of use,91 while the other reported no effect. One RCT reported no differentiation in the effectiveness of naltrexone over disulfiram.55
A published review of 32 interventions reported that only one intervention based on motivational interviewing was effective in promoting abstinence but was rated as very low quality of evidence.94
Clinical implications
CVD risk could be reduced in people with SMI by delivering combined pharmacological and behavioural interventions for both smoking and weight reduction. The exact content of interventions could be tailored to the preference of the individual as a variety of elements have been shown to be effective, mostly for individuals but also in groups.
There is little specific evidence regarding the effectiveness of interventions to reduce other CVD risk factors commonly found in SMI, including dyslipidaemia, diabetes mellitus and hypertension; however, there is evidence from the general population on what interventions might work to reduce and manage CVD risk. Algorithms are also available to guide treatment recommendations for reducing CVD risk in the general population in both Australia and the UK.38
Our research findings are in line with recent international guidelines in both England17 and Scotland127 regarding the management of physical health in people with psychosis or bipolar disorder. The lack of evidence regarding managing lipids, diabetes mellitus and hypertension in SMI requires attention. We need to know whether this disadvantaged group of people are accessing and receiving the best interventions to prevent CVD, and then whether interventions, such as statins and antihypertensive drugs, are decreasing excessive rates of CVD. This will require international research to determine whether or not these effective interventions are actually being offered and accepted by people with SMI and ultimately to assess whether or not the stubborn mortality gaps for people with SMI can be diminished in years to come.
Review limitations
It is not straightforward to synthesise all the evidence regarding CVD risk management in SMI. The individual studies frequently have their own design problems and limitations, and evidence is extremely heterogeneous in terms of interventions, settings, target groups and outcome measures. Factors limiting interpretation of findings included small sample sizes, varying or undefined inclusion criteria, setting, short length of follow-up and completeness of intervention description.
Nine of the 23 RCTs not included in the systematic reviews of pharmacological or behavioural interventions to manage weight were tested on SMI patients with a minimum BMI or minimum weight gain since commencing antipsychotic medication (e.g. BMI of > 25 kg/m2 was one of the inclusion criteria).56–58,65–68,79,83 This limits the generalisability of findings to all SMI patients and highlights a reactive rather than proactive approach to weight management in SMI.
Most of the trials identified by this review were conducted in secondary care limiting their generalisability to other settings, such as primary care.
A further limitation is the length of time between intervention end and collection of follow-up data. As is the nature of pharmacological interventions, follow-up data were collected at the end of the intervention which was, on average, 13 weeks after baseline assessment (aside from one that collected data 4 weeks after intervention end). Of the behavioural and combined pharmacological and behavioural interventions the average length of time between intervention end and collection of follow-up data was 19 weeks. This is a relatively short amount of time in the lifespan of people with SMI, so conclusions regarding longer term effectiveness cannot be made.
There was a lack of detail used to describe behavioural interventions. This problem has been acknowledged in the wider literature on interventions to change behaviour.128 Although guidance exists to promote detailed reporting to allow replication;129 for some interventions, replication would not be possible based on the descriptions in published reports we have reviewed.
