Background
Cannabis is the most commonly used illicit substance amongst people with psychosis [
1]. In longitudinal studies, cannabis use in first episode psychosis is associated with substantially higher acute psychiatric admission rates [
2]: an Australian study reported a 51% admission rate over 15 months follow-up amongst substance users (mostly cannabis) compared with 17% amongst non-users [
3], accompanied by a threefold difference in inpatient admission rates. Similarly, a Dutch study reported a 42% admission rate amongst persistent cannabis users compared with 17% amongst those who never used or stopped round the time of first onset [
4]. A dose-response relationship between severity of cannabis misuse and time to admission was also reported in this study. Problematic cannabis use in psychosis is also associated with marked delays in remission [
5], and lower engagement in work or education, as well as poorer outcomes in other clinical and social domains [
3,
6,
7]. Despite the clear need for effective treatments in this group, so far none have been identified. A Cochrane review [
8] of psychosocial interventions for substance misuse in severe mental illness identified 32 randomised controlled trials but found little evidence that any type of therapy was more effective than treatment as usual, including Cognitive Behavioural Therapy and Motivational Interviewing.
Contingency management (CM) is an operant conditioning-based intervention for substance misuse that typically uses financial rewards to reinforce target behaviours, such as abstinence from substance use or treatment adherence. CM has an increasingly substantial evidence base in a variety of contexts, including cannabis misuse [
9‐
11], smoking cessation [
12], heavy drinking [
13], and other illicit drug misuse [
14,
15]. The National Institute for Health and Care Excellence (NICE) advocates its adoption in England in the management of substance use [
16]. In a review conducted by NICE as part of its guidance of psychosocial interventions for substance misuse, 14 trials of CM were identified, all from the USA, of which three involved cannabis use. A consistent finding of a benefit for CM was reported, with most studies using abstinence at 12 weeks as their outcome measure. In the context of severe mental illness, a number of trials have found CM to be effective in reducing use in patients with severe mental illness for alcohol [
17], stimulant use [
18], and cigarette smoking [
19]. This includes one fairly recent trial of a 12-week CM intervention for stimulant misuse that found the treatment to be clinical and cost-effective [
20].
However, to date there is little research on CM for cannabis use in severe mental illness, with only one randomised controlled trial [
21] reported. The trial found that CM, combined with an enhanced treatment as usual psychosocial intervention (Supportive Treatment for Addiction Recovery), resulted in more drug-free urines, reduced hospitalisation, and better quality of life than treatment as usual alone. However, only a small proportion of participants abused cannabis (7%), with 93% abusing cocaine or heroin. Beyond this, there have also been three small feasibility studies [
22‐
24], which taken together also provide some evidence that CM may be feasible, acceptable, and efficacious in this cohort. Furthermore, with the exception of a small number of recent evaluative studies in Europe [
25], the evidence base for CM is drawn almost entirely from the USA. There is relatively little experience of using CM in the UK, with only a few studies reported in any clinical group. Some recent examples include the CONMAN trial, which provided an evidence base for CM in uptake of hepatitis B vaccines amongst opiate users [
26], and FIAT, which found incentives to be effective for reinforcing adherence to antipsychotic medication [
27].
The present study investigated the clinical and cost-effectiveness of CM for reducing cannabis use and thus time to acute psychiatric admission amongst Early Intervention in Psychosis (EIP) service users. The objectives were (1) to conduct a pilot study of a CM intervention for cannabis use in early psychosis, (2) if the pilot was successful, to proceed with a full multi-centre pragmatic randomised controlled trial, (3) to test whether the intervention results in an increase in the time to acute psychiatric admission (the primary outcome), (4) to test whether the intervention results in a decrease in cannabis use, reduced positive psychotic symptoms, and in an increase in participation in work or education (secondary outcomes), (5) to assess the cost-effectiveness of the intervention from an NHS perspective.
Discussion
The results of this trial indicate that CM confers no clinical advantage over TAU for patients with psychosis who use cannabis. Neither was any effect seen in our secondary outcomes, including cannabis use, engagement in work or education, and positive psychotic symptoms. However, a post hoc analysis found that compliance with psychoeducation in the CM arm resulted in a statistically significant improvement in time to acute psychiatric admission, while the same was not true for the control group. This suggests that CM had a clinical benefit amongst those who also engaged with psychoeducation.
The economic analyses show that the costs associated with CM were less than for the TAU, although the difference was not statistically significant and this analysis was carried out after imputation for a large proportion of cases, while we had primary outcome data for most who entered the trial. QALY differences based on the EQ-5D-3L were relatively large compared to other studies, but less so with the SF-6D. The lower costs and greater number of QALYs mean that CM is more cost-effective than TAU even though the differences for both costs and QALYs were not statistically significant. While interpretation of this is complex as there was little difference between CM groups in the intention-to-treat analyses, one possible explanation is that time to acute psychiatric admission was better amongst those who complied with psychoeducation in the CM group, but not the control group. The admission rate was lower than anticipated in the trial as a whole. Only around a third in each group required admission to acute care, while it was expected [
3,
4] for the purposes of our sample size calculation and based on previous literature that half would experience an acute psychiatric admission. This suggests that a comparatively stable group of patients was recruited to trial and/or that the psychoeducation and/or the extra attention of being in a research study had a beneficial impact. Although the majority still had cannabis-positive urine, the number of reported cannabis-using days in the previous 6 months fell from over 100 to 26 in each group by 18-month follow-up, indicating that cannabis use declined in both groups over this period. This could be due to the psychoeducation intervention, the normal progression of use in this group, regression to the mean, or a combination of these factors. Low levels of self-reported illicit substance and alcohol use at follow-up indicate that people were not substituting them for cannabis.
Overall, the results of the trial are mixed, and stand in contrast to the frequently positive benefits reported for CM interventions [
15,
16], including for substance misuse in psychosis [
17‐
19,
21]. Reasons for this are unclear; however, some possible explanations include the following: Firstly, offering more frequent CM sessions or offering a higher reward might have been more clinically effective. The CM schedule was adapted from two trials by Budney et al. [
10,
11], which both found a positive effect in cannabis misuse. However, the reward sessions in one of those trials occurred once per week, while in the other they occurred twice per week. Bellack et al. [
21], which is the only other trial of CM to include cannabis in severe mental illness, also used a twice weekly reward schedule. CIRCLE was intended to be a pragmatic trial of a CM intervention in an EIP context, and based on feedback from EIP clinicians, it was thought that delivering sessions more frequently than once per week would not be feasible, while the reward value was intended to be substantial enough to incentivise abstinence without being viewed as too lavish and thus ethically problematic, and was supported by clinicians, service users involved in the patient and public involvement consultation, and experts in the field. It was also approximately in line with other trials in this field (e.g. [
10,
21]). However, it was lower than that offered in some feasibility studies that found a positive effect (e.g. [
22,
23]). Further discussions with stakeholders and experts in the field might elucidate this issue.
Secondly, cannabis dependence was high in this sample (around three quarters of participants at baseline), and those with dependence may find it harder to change their behaviour compared to those with less-severe problematic cannabis use. However, in the two trials by Budney et al. [
10,
11] and Bellack et al. [
21], all participants were dependent, and so it is unlikely that the CM intervention failed to provide a benefit because of high rates of dependence. An alternative explanation is that participants may have been using more highly potent forms of the cannabis and consequently may have found it more difficult to abstain than those using less-potent forms. There is good evidence that this cohort typically uses more potent forms of cannabis than non-psychiatric groups [
40] and that high potency cannabis use is relatively prevalent in London, where much of our sample was recruited [
41]. It is therefore plausible that use of highly potent types of cannabis may have been relatively widespread in our sample. However, we did not systematically record the type of cannabis participants were using, making further exploration of this possibility difficult.
Thirdly, while engagement was good with people attending a median of 4 psychoeducation sessions in the control group and 6 in the CM group, a substantial proportion of people (around one third of people in the control group and one fifth in the CM group) declined to take part in either the CM and/or the PE or did not attend any sessions. This suggests there may have been a substantial minority who were not particularly motivated to quit cannabis, but perhaps participated due to the enthusiastic approach to recruitment by staff and researchers and/or the small payment received to acknowledge baseline interview assessment participation. Recruitment was slower than anticipated, partly because fewer service users than expected wanted to enter treatment for cannabis use. The post hoc analysis results suggested that people who were motivated to adhere to the psychoeducation had better outcomes. It may be that a more engaged cohort would have benefited more from the CM.
Fourthly, patients in this cohort are often multiply disadvantaged [
2,
5,
42], which is likely to make behavioural change much more challenging. This includes being less likely to be in work or education, having poorer social networks, and thereby being more socially isolated but also the nature of psychotic illness itself, which can include greater disorganisation, poorer social skills, and lower motivation [
43,
44]. It may be that interventions are needed in this cohort that have a broader focus than just reducing cannabis use. It may be that a better approach would support patients in becoming less socially isolated or spending less time with cannabis-using peers, as well as helping them back into work or engaging in other meaningful activities.
Finally, the trial focused only on cannabis, but baseline data indicated considerable history of alcohol and substance use disorders. It may be that the CM would have been more effective if it had addressed these additional substances as well.
There were several limitations to the study. Firstly, CIRCLE was a pragmatic trial of a CM intervention delivered in EIP services in the UK. The CM and psychoeducation treatments were designed to be feasible for EIP clinicians to deliver in routine practice, which required limiting the additional workload to clinicians. As such, during the intervention period, urinalysis samples were only collected from the CM group and not controls. This makes it more challenging to analyse whether the CM group participants reduced their use more than the controls during the intervention period. However, self-reported days of cannabis use at treatment end did not differ between groups, suggesting no impact from the CM. However, CIRCLE should be viewed as a trial of a pragmatic CM intervention rather as a definitive trial of whether CM reduces cannabis use in psychosis. Studies that more rigorously assess drug use in both treatment groups are needed to investigate whether CM could be effective at reducing use in psychosis.
Secondly, the inclusion of an active control makes it more difficult to interpret results. The fall in cannabis use across the trial population suggests there may have been benefit from the enhanced TAU. While it was intended to be a standardised form of treatment as usual, it became apparent that it was a much better developed and more ambitious psychoeducation than was otherwise available in many of the participating EIP teams.
Thirdly, originally, the CM (and psychoeducation) was originally intended to be delivered by care coordinators (the nurses, occupational therapist or social workers with primary responsibility for keeping in touch with patients and organising their care). However, few care coordinators were prepared to deliver the interventions, largely due to concerns regarding time pressures and potential disruption to therapeutic relationships. Instead, other clinical staff, such as support workers or assistant psychologists, were trained to deliver it. Greater integration into routine care may have improved its effectiveness. However, data on delivery of the CM intervention suggested that those delivering it did adhere well to the intended protocols, and it may be that care coordinators would have been less successful in this.
Fourthly, while the follow-up rate for the primary outcome was very high, attrition was greater than anticipated on the interview measures, potentially introducing response bias.
Fifthly, while a standard threshold was used for the urinalysis at assessment interview (50 ng/ml), a lower threshold would have given a slightly more accurate measure of abstinence rates. A lower threshold may have identified a small difference between groups. However, as there was no difference in either the proportion of cannabis-free urine using a threshold of 50 ng/ml or self-reported days of use at either follow-up, it seems unlikely that a clinically significant difference would be identified.
Sixthly, while we approached all EIP patients who were identified to trial researchers as potentially eligible by their clinicians and who agreed to be contacted by a trial researcher, it may be that gate-keeping by EIP clinicians or self-selection by patients could have introduced bias. However, this was a pragmatic RCT and it is likely that the trial sample is a good reflection of the range of characteristics of the EIP service users who would enter treatment if the intervention was offered through EIP or specialist drug treatment services. Similar issues seem likely if the intervention was introduced as part of routine care.
Seventhly, we did not systematically record the type of cannabis participants were using. It may be that those using more potent types of cannabis would respond differently to the intervention compared to those using milder forms, either by finding it harder to change behaviour, or potentially by showing greater benefit from the CM treatment in terms of acute psychiatric service use.
Eighthly, although not a limitation in the analyses, the finding that CM has over 80% likelihood of being cost-effective needs to be treated with caution. In the sample that were followed up at both time points, the costs were lower and QALY outcomes better for the CM group compared to controls, and this led to a favourable cost-effectiveness ratio for CM which applied to most bootstrapped resamples. The cost and QALY differences were though limited and not statistically significant.
Finally, using acute psychiatric admission as the outcome is a pragmatic choice because it is routinely available data that are relatively accessible via patient records. But it is limited in that some acute psychiatric episodes are likely to be contained without acute service use, for example, it may be handled by the EIP team instead, and also that thresholds for admission to acute care may vary considerably, for example by clinician and by area.
Acknowledgements
CIRCLE was funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme (09/144/50). The views expressed in this publication are those of the authors and not necessarily those of the NIHR, HTA programme, NHS, or the Department of Health. We would like to thank all the participants who took part in the trial, as well as all the Early Intervention in Psychosis (EIP) clinical staff who assisted with recruitment or delivered the interventions. We are also grateful to the members of the Trial Steering Committee (Professor Thomas Barnes, Dr. Jonathan Haynes, Dr. Sara Brookes, Maurice Arbuthnott, Katherine Barrett, Nick Barber, and Beverley Chipp) and the Data Monitoring and Ethics Committee (Professor David Kingdon, Dr. Chris Metcalfe, Dr. Rob McPherson, and Dr. David Li) for providing oversight throughout, and the principal investigators (Dr. Charlot Johnston-Webber, Mr. Simon Clark, Dr. Nikola Rahaman, Dr. Manoj Sukumaran, Dr. Peter Carter, Dr. Rick Fraser, Dr. Nilamadhab Kar, Dr. Sajad Yousuf, Dr. Jonathan West, Mr. Nicholas Chamberlain-Kent, Dr. Abu Abraham, Prof. Hana Soliman, Dr. John Joseph Scanlon, Dr. Nandini Chakraborty, Dr. Sazgar Hamad, Dr. Eileen O’Regan, Dr. Chris Harrop, Dr. Sanjoo Chengappa, Prof. Belinda Lennox, Dr. Jesus Perez) for supporting the trial. Finally, we would like to thank Dr. Barnaby Major, Kelly Wilson, Leila Hughes, Melanie Whyman, Simon Spencer, Alyssa Milton, Danielle Lamb, Kate Fullarton, Johanna Frerichs, Kirsty Shepherd, Danelle Pettman, Ruth Mintah, Sherene Olusesi, Tayla McCloud, and the clinical studies officers who contributed to the trial for all their efforts.