| Summary: | Background Antipsychotic medication is beneficial for people with psychosis or schizophrenia in the short term, but the balance of risks and benefits in the long term is less clear. Many patients remain functionally impaired, experience significant and distressing side effects and physical health problems. Evidence in people with first episode psychosis suggests that social functioning may be improved for some patients following a gradual reduction or discontinuation of antipsychotics, but there is no evidence in people with recurrent conditions. Objectives To assess patients’ attitudes to long-term use of antipsychotic medication (work package 1a). To develop a gradual strategy of antipsychotic reduction and discontinuation and to design a trial to assess its benefits and harms (work packages 1a and 1b). To evaluate the antipsychotic reduction strategy in a randomised pilot trial (work package 2). To conduct a full randomised trial (work package 3a) of the antipsychotic reduction strategy in patients with multie pisode psychosis. To explore the experiences of people enrolled in the antipsychotic reduction strategy (work package 3b). Methods Design Objective 1: A mixed-methods survey of attitudes to long-term treatment and (work package 1a). Objective 2: Survey of attitudes to participation in a randomised trial, expert consultation, lived experience consultation, literature review, including a systematic review of definitions of relapse in previous trials of antipsychotics, focus groups (work packages 1a and 1b). Objectives 3 and 4: Multicentre, pragmatic, open, parallel group randomised controlled trial (with blinded assessors) (work packages 2 and 3a). Objective 5: qualitative study using semistructured interviews (work package 3b). Participants Patients with schizophrenia or recurrent, non-affective psychotic episodes, taking antipsychotics. Setting English community mental health services. Interventions A gradual strategy of antipsychotic reduction, with discontinuation where possible (evaluated in work packages 2 and 3, developed during work package 1). Main outcome measures In work package 1a: Patients’ views of antipsychotic medication and participation in a randomised trial of antipsychotic reduction. In work package 2: Recruitment rates and adherence to trial procedures. In work package 3a: Primary outcome was the Social Functioning Scale. The principal secondary outcome was severe relapse (admission to mental health inpatient care). Other outcomes included any relapse, symptoms, and a full economic analysis was performed. Results Work package 1a – 269 participants were interviewed. Only 33% were content with taking antipsychotic medication for long term, and 31% and 45% wished to try and stop or reduce it, respectively, with clinical support. Seventy-nine per cent indicated that they would or might be interested in taking part in a future trial. Work package 1b – Trial recruitment strategy and intervention protocol, procedures and adherence protocols were developed, along with definitions and procedures for determining relapse. The systematic review failed to identify a previous definition of relapse that was reliable, clinically relevant and feasibly to apply. Work package 2 – Recruitment was 65% of the projected target and the trial was approved to continue to a full trial. Work package 3a – 253 participants were randomised, 126 to supported reduction, 127 to maintenance antipsychotic treatment. At 24 months, there was no statistically significant difference between groups in change on the Social Functioning Scale (b: 0.19, 95% confidence interval −1.94 to 2.33, p = 0.859). The rate of severe relapse was significantly higher in the intervention group (25%) compared to the maintenance group (13%) (odds ratio, b: 2.39, 95% confidence interval 1.25 to 4.56). The risk of any relapse was also higher, but there was no difference in other outcomes. There were 93 serious adverse events in 49 individuals in the reduction arm (mostly admissions to hospital for a mental health relapse) and there were 64 in 29 individuals in the maintenance arm. In the economic analysis, at 24 months, there was no significant difference between the two arms in costs (£5619; 95% confidence interval −£386 to £11,625) or quality-adjusted life-years (−0.035, 95% confidence interval −0.125 to 0.054). There were significantly fewer years of full capability in the supported reduction arm (−0.103, 95% confidence interval −0.191 to −0.015). Work package 3b – 26 patients were interviewed. Analysis indicated that patients experienced improvements in adverse effects, social functioning and sense of self. However, some experienced increased symptoms, challenging emotional intensity and relapse. For some patients, supported medication reduction provided an opportunity for learning and empowerment. Work package 3c – 15 clinicians provided feedback on their experiences. They felt that antipsychotic reduction had been beneficial for some but had led to negative outcomes for other patients. Some reported that the trial enabled more collaborative relationships with patients. Limitations Recruitment was challenging, and some participants did not adhere to their randomised treatment programme. The number recruited was a small proportion of the number screened, which means the sample may differ from the general population of people considered likely to be suitable to take part in a trial of this sort. The COVID pandemic affected the social functioning measure. Conclusions Quantitative analysis showed that antipsychotic reduction and discontinuation over a period of months does not improve social functioning at 24 months, and increases the risk of severe relapse. There is a low probability that supported reduction is cost-effective compared to maintenance. In qualitative findings, patients and clinicians noted positive and negative effects of antipsychotic reduction. Future work Future work should include long-term follow-up of the trial cohort and investigation of more gradual reduction strategies. Trial registration The trial is registered as ISRCTN90298520 on 7 February 2017 and at ClinicalTrials.gov on 18 June 2018. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-0514-20004) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 5. See the NIHR Funding and Awards website for further award information.
Plain language summary Schizophrenia and other psychotic conditions are common and can cause considerable suffering. The widely established treatment is long-term antipsychotic medication, but this can cause harmful and unpleasant side effects. In this programme, we designed a ‘clinical trial’ to test the benefits and harms of helping people to gradually reduce and stop their antipsychotic medication. In the trial, people were randomly assigned to have their antipsychotic medication dose reduced or to continue on their current dose. We followed up people and assessed their ability to live their daily lives (social functioning) and other outcomes. In the first part of the research, we interviewed 269 patients and found that almost a third (31%) would welcome an opportunity to try to stop their antipsychotic medication with support from their psychiatrist. Just under half (45%) would like to reduce it. We enrolled 253 participants in the clinical trial and followed up 190 people 2 years later. At 2 years, there were no differences in social functioning between people who were assigned to antipsychotic reduction and those assigned to continue their antipsychotic treatment. People assigned to antipsychotic reduction were approximately twice as likely to have a severe relapse of their condition. At 2 years, there were no differences in the levels of symptoms or side effects. Antipsychotic reduction was more costly and did not lead to financial savings. In-depth interviews showed that people experienced some beneficial effects from reducing antipsychotics, including reduced side effects and increased empowerment, and some negative effects, including intense emotions, worsening of symptoms and relapse. Psychiatrists felt that antipsychotic reduction had been beneficial for some patients but had led to negative outcomes for others. Psychiatrists felt that the reduction process had enabled them to develop a more equal partnership with some patients.
Scientific summary Background Antipsychotic medication suppresses acute symptoms and prevents relapse in the short term, but the balance of risks and benefits in the long term is less clear. Many patients remain functionally impaired, experience significant and distressing side effects and physical health problems, leading to dissatisfaction with treatment and non-adherence. Evidence in people with first episode psychosis suggests that social functioning may be improved for some patients following a gradual and supported reduction and discontinuation, but there is no evidence in people with recurrent psychotic conditions. Work package 1a Objective To explore patients’ attitudes to long-term use of antipsychotic medication and to reduction and discontinuation of antipsychotics. Methods Design A mixed-methods survey of attitudes to long-term treatment and willingness to participate in a randomised controlled trial (RCT) of an antipsychotic reduction programme. Participants Patients with schizophrenia or recurrent, non-affective psychosis, taking antipsychotics, aged ≥ 18 years with sufficient English to complete assessments, who have capacity to consent and are not legally compelled to take medication recruited from community mental health services in four London-based mental health trusts and general practices. Setting Community mental health services in four mental health Trusts in London and London-based general practices. Interventions A survey of attitudes to antipsychotics and antipsychotic reduction and discontinuation. Main outcomes Views about use of long-term antipsychotic medication, reduction and discontinuation of antipsychotic medication. Views about participation in a randomised trial of a clinically supported antipsychotic reduction strategy. Results A total of 269 participants with psychosis were interviewed. Of these, 31% wished to try and stop their antipsychotic with professional support, and 45% tried to reduce it. Only 33% were content with taking antipsychotic medication for long term. People who wanted to discontinue had more negative attitudes towards the medication but were otherwise similar to other participants. Wanting to stop or reduce medication was motivated mainly by adverse effects and health concerns. Professional support was identified as potentially helpful to achieve reduction. Seventy-nine per cent indicated that they would or might be interested in taking part in a future trial. Altruistic reasons were most commonly given for wanting to take part and concern about randomisation for not wanting to. Limitations The survey sample was influenced by clinician’s decisions to put people forward and patients’ interest and consent. The majority of participants had used antipsychotics for many years, so the sample does not necessarily reflect the views of shorter-term users. Conclusions A substantial proportion of people using long-term antipsychotics would like support to try to reduce their dose or discontinue treatment, mainly due to adverse effects. The survey was a useful recruitment strategy for the main trial even though fewer people eventually enrolled in the trial than had indicated they would be interested. Work package 1b Objectives To explore how antipsychotics should be reduced in clinical practise and how a trial could be designed to evaluate such a process. Methods Methods consisted of: expert consultation with national and international experts, lived experience consultation with the programme’s Lived Experience Advisory Committee members, literature review and focus groups with staff members from two London-based mental health trusts. These were conducted to inform trial design, recruitment and outcomes. A systematic review of relapse definitions in antipsychotic discontinuation trials was conducted. Results The systematic review failed to identify a previous definition of relapse that was reliable, clinically relevant and feasibly to apply. The trial recruitment strategy, the intervention protocol, procedures and monitoring protocols were developed. Eligibility criteria were determined and definitions and procedures for determining relapse were developed, including terms of reference for an end-point committee to assess non-severe relapses. Conclusions Procedures to conduct a randomised trial comparing gradual antipsychotic reduction and discontinuation with maintenance treatment were developed. Work package 2 Objective To ascertain whether a trial of a supported antipsychotic reduction programme is feasible. Methods Design Pilot trial of a multicentre, pragmatic, open, parallel group RCT of antipsychotic reduction in people with schizophrenia and recurrent psychotic conditions. Participants Patients with schizophrenia or recurrent, non-affective psychosis, aged ≥ 18 years, taking antipsychotics, with sufficient English to complete assessments, who have capacity to consent and are not legally compelled to take medication recruited from community mental health services in two London-based mental health trusts. Setting Two London-based mental health trusts. Intervention Evaluation of a strategy of gradual antipsychotic reduction and discontinuation overseen by a clinician. Outcomes Recruitment rate and feasibility of monitoring. Results The recruitment during the 4 months of the pilot trial was 65% of the projected target. Intervention monitoring was judged to be feasible. Conclusions The trial was approved to continue to a full trial. Work package 3a Some text in this section has been reproduced with permission from Moncrieff J, Crellin N, Stansfeld J, Cooper R, Marston L, Freemantle N, et al. Randomised controlled trial of antipsychotic dose reduction and discontinuation versus maintenance treatment in people with schizophrenia and other recurrent psychotic disorders in England (the RADAR trial). Lancet Psychiatry 2023;10:848–59. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text. Objectives To evaluate the benefits and harms of an antipsychotic reduction programme compared to maintenance treatment in patients with multiepisode psychosis. Methods Design A full RCT of antipsychotic reduction in people with schizophrenia and recurrent psychotic conditions. Participants Patients with schizophrenia or recurrent, non-affective psychosis, taking antipsychotics, with sufficient English to complete assessments, who have capacity to consent and are not legally compelled to take medication recruited from community mental health services in 19 mental health trusts in England. Setting Community mental health services in 19 mental health trusts in England. Interventions A strategy of gradual antipsychotic reduction and discontinuation overseen by a clinician. Outcomes The primary outcome was social functioning at 24-month follow-up, measured using the Social Functioning Scale (SFS). The principal secondary outcome was severe relapse, which was defined as hospital admission for psychiatric inpatient treatment. An expert end-point committee was convened to assess the presence or absence of relapse more broadly, which was based on blinded information from clinical case-notes, using predefined criteria and guidance. Other secondary outcomes were mental state, measured by the Positive and Negative Syndrome Scale, quality of life, measured by the Manchester Short Assessment of quality of life, and the Objective Social Outcomes Index (SIX), which is derived from it. Adverse effects of antipsychotics were measured using a modified version of the Glasgow Antipsychotic Side-Effect Scale, body weight and sexual dysfunction using the Arizona Sexual Experiences Scale. Other assessments included the Questionnaire about the Process of Recovery, the Client Satisfaction Questionnaire and the Medication Adherence Report Scale. Neuropsychological function was measured using a brief battery of tests designed for this trial. Health economics outcome measures included the EuroQol-5 Dimensions, five-level version and the ICEpop CAPability measure for Adults. Results A total of 253 participants were randomised: 126 were assigned to antipsychotic dose reduction and 127 to maintenance. One hundred and ninety participants were interviewed at a 24-month follow-up. The difference between the groups on the primary outcome, the SFS, was small and not statistically significant (0.19, −1.9 to 2.3: Table a). Sensitivity analyses, including the degree of COVID-19 lockdown and predictors of missingness, did not change this. The time to severe relapse was shorter in the reduction group compared with the maintenance group [hazard ratio 2.2, 95% confidence interval (CI) 1.2 to 4.0, p = 0.007]. At 24 months, 32 participants (25.4%) in the reduction group had had at least 1 severe relapse compared with 17 (13.4%) of the maintenance group (odds ratio 2.2, 95% CI 1.2 to 4.2). Rates of non-severe and overall relapse were also higher in the reduction group. There was no difference in median bed-days between groups. TABLE aBaseline demographic and clinical characteristics of randomised trial participants Characteristic Antipsychotic dose reduction/discontinuation, maximum, N = 126 Antipsychotic maintenance treatment, maximum, N = 127 N n (%) or mean (SD) or median (IQR) N n (%) or mean (SD) or median (IQR) Male 126 85 (67.4%) 127 83 (65.3%) Female 126 40 (31.7%) 127 42 (33.1%) Transgender 126 1 (0.79%) 127 2 (1.6%) Age 126 Mean 46.6 (SD 12.2) 127 Mean 46.0 (SD 11.5) Marital status Single, separated, divorced, widowed 126 106 (84.1%) 127 110 (86.6%) Married, cohabiting, civil partnership 126 20 (15.9%) 127 17 (13.4%) Ethnicity White 126 89 (70.6%) 125 82 (65.6%) Black 126 25 (19.8%) 125 27 (21.6%) Asian 126 8 (6.3%) 125 8 (6.4%) Other 126 4 (3.2%) 125 8 (6.4%) First language English 126 107 (84.9%) 127 114 (89.8%) Highest educational achievement Primary and secondary education to age 16 years 125 49 (39.2%) 126 36 (28.6%) Primary and secondary education to age 18 years 125 22 (17.6%) 126 27 (21.4%) Tertiary or further education 125 40 (32.0%) 126 56 (44.4%) Other general education 125 14 (11.2%) 126 7 (5.6%) Years of completed education 121 Mean 14 (SD 3.3) 125 Mean 14 (SD 3.9) Employment Employed, voluntary or in education 126 38 (30.2%) 125 36 (28.8%) Not working or in education 126 88 (69.8%) 125 89 (71.2%) Length of time in contact with mental health services 0–3 years 126 11 (8.7%) 127 6 (4.7%) 4–10 years 126 34 (27.0%) 127 28 (22.0%) 11–15 years 126 20 (15.9%) 127 23 (18.1%) 16–20 years 126 20 (15.9%) 127 22 (17.3%) > 20 years 126 41 (32.5%) 127 48 (37.8%) Age when first referred to mental health services < 20 years 126 26 (20.6%) 127 27 (21.3%) 20–30 years 126 57 (45.2%) 127 67 (52.7%) 31–40 years 126 25 (19.8%) 127 22 (17.3%) ≥ 41 years 126 18 (14.3%) 127 11 (8.7%) Number of previous mental health admissions Median 3 (IQR 1–5) Median 3 (IQR 1–5) Recreational drugs used in the last month 126 11 (8.7%) 126 14 (11.1%) Alcohol use over the past month Once a month or less 126 80 (63.5%) 126 82 (65.1%) Two to four times a month 126 24 (19.0%) 126 20 (15.9%) Two or more times a week 126 22 (17.5%) 126 19 (19.0%) Antipsychotic medication dose in chlorpromazine equivalents 126 Median 300 (IQR 200–450) 127 Median 300 (IQR 200–400) Outcome measures at baseline SFS overall 123 Mean 107.7 (SD 8.6) 120 Mean 108.2 (SD 10.2) PANSS positive symptom subscale 124 Median 10 (IQR 8–14) 127 Median 11 (8–16) PANSS negative symptom subscale 124 Median 11 (IQR 9–15) 124 Median 11 (8–15) PANSS total 122 Median 48 (IQR 41–59) 123 Median 48 (IQR 40–61) MANSA 126 Mean 4.7 (SD 0.82) 127 Mean 4.6 (SD 0.83) SIX 125 Mean 3.4 (SD 1.3) 127 Mean 3.4 (SD 1.3) Modified GASS 105 Mean 27.6 (SD 15.2) 104 Mean 29.0 (SD 17.1) Body weight in kg 114 Mean 90.9 (SD 20.2) 116 Mean 89.7 (SD 19.1) CSQ-8 125 Median 20 (IQR 20–21) 122 Median 20 (IQR 19–21) MARS-5 124 Median 24 (IQR 22–25) 124 Median 25 (IQR 23–25) QPR-15 123 Mean 55.7 (SD 9.9) 122 Mean 56.6 (SD 10.0) ASEX 42 Mean 16.3 (SD 6.1) 39 Mean 15.5 (SD 5.0) Cognitive tests Digit span 124 Mean 14.8 (SD 4.5) 126 Mean 14.7 (SD 4.7) Digit symbol substitution 117 Mean 47.2 (SD 17.4) 121 Mean 47.3 (SD 18.2) Rey Auditory Verbal Learning 121 Mean 35.7 (SD 12.0) 120 Mean 36.1 (SD 12.4) Trail making 121 Median 45 (IQR 35–62) 121 Median 50 (IQR 36–64) Verbal fluency 124 Mean 16.5 (SD 4.9) 126 Mean 16.6 (SD 5.2) ASEX, Arizona Sexual Experience Scale; CSQ, Client Satisfaction Questionnaire; GASS, Glasgow Antipsychotic Side-Effect Scale; IQR, interquartile range; MANSA, Manchester Short Assessment of quality of life; MARS, Medication Adherence Report Scale; PANSS, Positive and Negative Syndrome Scale; QPR, Questionnaire about the Process of Recovery; SD, standard deviation. Other secondary outcomes showed no difference between the groups at 24 months, including measures of symptoms, quality of life, adverse effects scales, body weight and employment. The median dose reduction at any point during the trial was 67% in the reduction arm and 0% in the maintenance arm. At 24 months, it was 33% versus 0%. Thirty-four people (27.0%) randomised to reduction stopped their antipsychotic medication completely at some time during the 24-month follow-up period, and 13 (10.2%) of those randomised to maintenance treatment did so. Eighty-eight (69.8%) participants in the reduction group reduced their antipsychotic dose by 50% or more when compared with 21 (16.5%) of the maintenance participants. Serious adverse events were more common in the reduction group, largely due to a higher number of hospitalisations for relapse. There were no significant differences between arms in total costs for any perspectives. There were no significant difference in quality-adjusted life-years (−0.035, 95% CI −0.123 to 0.052), whereas years of full capability were significantly lower in the reduction arm compared to the maintenance arm (baseline-adjusted difference: −0.103, 95% CI −0.192 to −0.014). The reduction strategy was dominated by maintenance and was not likely to be cost-effective for all perspectives taken and outcomes employed. Limitations Recruitment was challenging, and some participants did not adhere to their randomised treatment programme. The COVID pandemic affected the social functioning measure. Conclusions The current trial provides data on the pros and cons of a gradual strategy of antipsychotic reduction and discontinuation in people with recurrent psychotic disorders. The findings demonstrate that a strategy of reducing and stopping antipsychotic medication over several months increases the risk of relapse compared with maintenance treatment but does not measurably improve social functioning or affect other clinical and social outcomes after 2 years. Further follow-up data will provide information about longer-term outcomes. Trial registration The trial is registered as ISRCTN90298520 on 7 February 2017 and at ClinicalTrials.gov on 18 June 2018. Work package 3b Some text in this section has been reproduced with permission from Morant N, Long M, Jayacodi S, Cooper R, Akther-Robertson J, Stansfeld J, et al. Experiences of reduction and discontinuation of antipsychotics: a qualitative investigation within the ‘RADAR’ trial. eClinicalMedicine 2023;64:102135. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text. Objectives To explore the experiences of people enrolled in an antipsychotic reduction programme in a clinical trial. Methods Design Qualitative study using semistructured interviews. Participants Participants in the full trial in work package 3a who were randomised to the antipsychotic reduction arm. Setting Community mental health services involved in the randomised trial. Outcomes Qualitative data on patients’ experiences of antipsychotic reduction within the randomised trial. Results Twenty-six participants from the antipsychotic reduction arm of the trial were interviewed. Most reported reduced adverse effects of antipsychotics with dose reductions, primarily in mental clouding, emotional blunting and sedation, and some positive impacts on social functioning and sense of self. Over half experienced deteriorations in mental health, including psychotic symptoms and intolerable levels of emotional intensity. Nine had a psychotic relapse. The trial context in which medication reduction was explicitly part of clinical care provided various learning opportunities. Some participants were highly engaged with reduction processes, and despite difficulties, including relapses, they developed novel perspectives on medication, dose optimisation and how to manage their mental health. Others were more ambivalent about reduction or experienced less overall impact. Experiences of antipsychotic reductions over 2 years were dynamic and diverse, shaped by variations in dose reduction profiles, reduction effects, personal motivation and engagement levels, and relationships with prescribers. Relapse risks and challenges were apparent, but some people experienced medication reduction done with clinical guidance as empowering. Limitations The sample may have excluded people with more negative experiences. Conclusions Participants described both positive and negative effects of reducing antipsychotics. Some gained a deeper understanding of their condition and felt empowered to take a more active role in managing their medication. Work package 3c Objectives To explore clinician’s experiences of being involved in a trial of supported antipsychotic reduction. Methods Design Qualitative study using semistructured interviews. Outcomes Clinician’s experiences of taking part in a randomised trial of antipsychotic reduction. Results Fifteen psychiatrists were interviewed. They described the positive and negative effects of antipsychotic reduction. Some felt that the trial had enabled them to establish more collaborative relationships with patients. Limitations The sample may have excluded clinicians with more negative experiences. Conclusions Clinicians have mixed views about antipsychotic reduction. Trial registration The trial is registered as ISRCTN90298520 on 7 February 2017 and at ClinicalTrials.gov on 18 June 2018. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-0514-20004) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 5. See the NIHR Funding and Awards website for further award information.
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