NIHR Signal Uncertain benefit of adding amisulpiride to clozapine for treatment-resistant schizophrenia

Published on 14 November 2017

For adults with schizophrenia who continue to have symptoms despite treatment with the antipsychotic drug clozapine, adding amisulpride (another antipsychotic) was not shown to improve their chance of responding. It is not yet clear whether a larger trial would show an effect, as too few people were recruited to the NIHR-funded trial to be sure. Participants were more likely to experience side effects and the trial does provide some important information for future studies in this difficult treatment area.

The current NICE guidance recommends adding a second antipsychotic to clozapine for patients in these circumstances but does not specify any particular drug. Amisulpride is often used in practice, but to date, there had not been much evidence on which to base this decision.

Only 68 people with this severe form of schizophrenia were recruited instead of the expected 230, so the ability to detect any clinically significant differences between the groups is reduced.

Uncertain benefit of adding amisulpiride to clozapine for treatment-resistant schizophrenia

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Why was this study needed?

About 220,000 people in England and Wales have a diagnosis of schizophrenia. In 2007, approximately 30% of the total expenditure on adult mental health and social care services was for people with schizophrenia. But around a third of people with the illness do not respond well to standard treatment with antipsychotic medication. 

Clozapine is the only antipsychotic drug which has been shown to be effective for such treatment-resistant illness, but still about two-thirds of patients do not have their illness controlled. In these cases, clinicians often prescribe a second antipsychotic to take with clozapine.

There is little evidence that this approach is effective and no guidance about which additional drugs should be used. Amisulpride is a drug commonly used in combination with clozapine, but only one small trial had previously been conducted. This research aimed to investigate its benefits, risks and costs.

What did this study do?

The AMICUS trial was an NIHR funded 12-week randomised controlled trial of 68 adults with schizophrenia who continued to have symptoms despite treatment with clozapine. Nine were currently inpatients.

They were recruited from 22 adult psychiatric services in England. All participants continued to take clozapine. Half were assigned amisulpride in addition to clozapine, and half were assigned a placebo. Only 52 completed their assessment at the 12-week follow-up.

Participants started with 400mg of amisulpride, or two identical-looking placebo tablets, for the first four weeks. The dose could be adjusted up to 800mg of amisulpride, or four placebo tablets, for the remaining eight weeks.

The severity of symptoms was measured at the start and end of the trial to assess improvement. Side effects were monitored.

The study was well-designed and aimed to recruit 230 people. However, it proved hard to recruit enough participants to detect significant differences between the groups. We cannot be certain whether the combination was effective or ineffective, although larger trials might show a difference.

What did it find?

  • The primary outcome measure was the proportion of participants with a 20% reduction in total PANSS (Positive and Negative Syndrome Scale) score. PANSS is a 30-item scale, with a score of 1-7 for each item. The percentage of participants who showed a 20% reduction in PANSS score over the 12 weeks was similar in both groups: 44% of the amisulpride group versus 40% the placebo group. Odds Ratio 1.17, 95% confidence interval (CI) 0.40 to 3.42. This finding is not statistically significant.
  • Those in the amisulpride group had a greater number of side effects than the placebo group (47 events in the amisulpride group, versus 18 events in the placebo group). At least one event was experienced by 60% of the amisulpride group compared with 30% in the placebo group. Most of these were mild and resolved; serious adverse events were rare.

What does current guidance say on this issue?

The 2009 NICE guideline on the prevention and management of psychosis and schizophrenia in adults recommends that a second antipsychotic should be prescribed to augment treatment with clozapine for people whose illness has not responded adequately to clozapine on its own. It does not name a specific drug to use, just recommends that healthcare professionals should choose one that does not worsen the common side effects of clozapine.

What are the implications?

Augmenting clozapine with amisulpride is already a strategy commonly used by clinicians in the NHS, without there being a robust evidence base on the risks and benefits.

The main problem was difficulty in recruiting. This was despite increasing the number of participating services from four to 22 and paying £20 to each person per assessment to cover travel expenses and inconvenience. Reasons included clinicians feeling it was unethical to give a placebo and the strict inclusion criteria.

The extent and nature of the side effects suggest, for example, that the safety and tolerability of two antipsychotics in both clinical and research settings should be monitored closely. There are some cost data collected that could allow for cost-effectiveness analysis if efficacy could be proven. 

The trial only included people who had a poor response to clozapine. Therefore, the results would not apply to the many people who have amisulpride because of a partial response to clozapine.

Citation and Funding

Barnes TR, Leeson VC, Paton C, et al. Amisulpride augmentation in clozapine-unresponsive schizophrenia (AMICUS): a double-blind, placebo-controlled, randomised trial of clinical effectiveness and cost-effectiveness. Health Technol Assess. 2017;21(49):1-56.

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (project number 08/116/12).

Bibliography

NHS Choices. Schizophrenia. London: Department of Health; updated 2016.

NICE. Psychosis and schizophrenia in adults: prevention and management. CG178. London: National Institute for Health and Care Excellence; 2009 (updated 2014).

Why was this study needed?

About 220,000 people in England and Wales have a diagnosis of schizophrenia. In 2007, approximately 30% of the total expenditure on adult mental health and social care services was for people with schizophrenia. But around a third of people with the illness do not respond well to standard treatment with antipsychotic medication. 

Clozapine is the only antipsychotic drug which has been shown to be effective for such treatment-resistant illness, but still about two-thirds of patients do not have their illness controlled. In these cases, clinicians often prescribe a second antipsychotic to take with clozapine.

There is little evidence that this approach is effective and no guidance about which additional drugs should be used. Amisulpride is a drug commonly used in combination with clozapine, but only one small trial had previously been conducted. This research aimed to investigate its benefits, risks and costs.

What did this study do?

The AMICUS trial was an NIHR funded 12-week randomised controlled trial of 68 adults with schizophrenia who continued to have symptoms despite treatment with clozapine. Nine were currently inpatients.

They were recruited from 22 adult psychiatric services in England. All participants continued to take clozapine. Half were assigned amisulpride in addition to clozapine, and half were assigned a placebo. Only 52 completed their assessment at the 12-week follow-up.

Participants started with 400mg of amisulpride, or two identical-looking placebo tablets, for the first four weeks. The dose could be adjusted up to 800mg of amisulpride, or four placebo tablets, for the remaining eight weeks.

The severity of symptoms was measured at the start and end of the trial to assess improvement. Side effects were monitored.

The study was well-designed and aimed to recruit 230 people. However, it proved hard to recruit enough participants to detect significant differences between the groups. We cannot be certain whether the combination was effective or ineffective, although larger trials might show a difference.

What did it find?

  • The primary outcome measure was the proportion of participants with a 20% reduction in total PANSS (Positive and Negative Syndrome Scale) score. PANSS is a 30-item scale, with a score of 1-7 for each item. The percentage of participants who showed a 20% reduction in PANSS score over the 12 weeks was similar in both groups: 44% of the amisulpride group versus 40% the placebo group. Odds Ratio 1.17, 95% confidence interval (CI) 0.40 to 3.42. This finding is not statistically significant.
  • Those in the amisulpride group had a greater number of side effects than the placebo group (47 events in the amisulpride group, versus 18 events in the placebo group). At least one event was experienced by 60% of the amisulpride group compared with 30% in the placebo group. Most of these were mild and resolved; serious adverse events were rare.

What does current guidance say on this issue?

The 2009 NICE guideline on the prevention and management of psychosis and schizophrenia in adults recommends that a second antipsychotic should be prescribed to augment treatment with clozapine for people whose illness has not responded adequately to clozapine on its own. It does not name a specific drug to use, just recommends that healthcare professionals should choose one that does not worsen the common side effects of clozapine.

What are the implications?

Augmenting clozapine with amisulpride is already a strategy commonly used by clinicians in the NHS, without there being a robust evidence base on the risks and benefits.

The main problem was difficulty in recruiting. This was despite increasing the number of participating services from four to 22 and paying £20 to each person per assessment to cover travel expenses and inconvenience. Reasons included clinicians feeling it was unethical to give a placebo and the strict inclusion criteria.

The extent and nature of the side effects suggest, for example, that the safety and tolerability of two antipsychotics in both clinical and research settings should be monitored closely. There are some cost data collected that could allow for cost-effectiveness analysis if efficacy could be proven. 

The trial only included people who had a poor response to clozapine. Therefore, the results would not apply to the many people who have amisulpride because of a partial response to clozapine.

Citation and Funding

Barnes TR, Leeson VC, Paton C, et al. Amisulpride augmentation in clozapine-unresponsive schizophrenia (AMICUS): a double-blind, placebo-controlled, randomised trial of clinical effectiveness and cost-effectiveness. Health Technol Assess. 2017;21(49):1-56.

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (project number 08/116/12).

Bibliography

NHS Choices. Schizophrenia. London: Department of Health; updated 2016.

NICE. Psychosis and schizophrenia in adults: prevention and management. CG178. London: National Institute for Health and Care Excellence; 2009 (updated 2014).

Amisulpride augmentation in clozapine-unresponsive schizophrenia (AMICUS): a double-blind, placebo-controlled, randomised trial of clinical effectiveness and cost-effectiveness

Published on 4 September 2017

Barnes T R, Leeson V C, Paton C, Marston L, Davies L, Whittaker W, Osborn D, Kumar R, Keown P, Zafar R, Iqbal K, Singh V, Fridrich P, Fitzgerald Z, Bagalkote H, Haddad P M, Husni M & Amos T.

Health Technology Assessment Volume 21 Issue 49 , 2017

Background When treatment-refractory schizophrenia shows an insufficient response to a trial of clozapine, clinicians commonly add a second antipsychotic, despite the lack of robust evidence to justify this practice. Objectives The main objectives of the study were to establish the clinical effectiveness and cost-effectiveness of augmentation of clozapine medication with a second antipsychotic, amisulpride, for the management of treatment-resistant schizophrenia. Design The study was a multicentre, double-blind, individually randomised, placebo-controlled trial with follow-up at 12 weeks. Settings The study was set in NHS multidisciplinary teams in adult psychiatry. Participants Eligible participants were people aged 18–65 years with treatment-resistant schizophrenia unresponsive, at a criterion level of persistent symptom severity and impaired social function, to an adequate trial of clozapine monotherapy. Interventions Interventions comprised clozapine augmentation over 12 weeks with amisulpride or placebo. Participants received 400 mg of amisulpride or two matching placebo capsules for the first 4 weeks, after which there was a clinical option to titrate the dosage of amisulpride up to 800 mg or four matching placebo capsules for the remaining 8 weeks. Main outcome measures The primary outcome measure was the proportion of ‘responders’, using a criterion response threshold of a 20% reduction in total score on the Positive and Negative Syndrome Scale. Results A total of 68 participants were randomised. Compared with the participants assigned to placebo, those receiving amisulpride had a greater chance of being a responder by the 12-week follow-up (odds ratio 1.17, 95% confidence interval 0.40 to 3.42) and a greater improvement in negative symptoms, although neither finding had been present at 6-week follow-up and neither was statistically significant. Amisulpride was associated with a greater side effect burden, including cardiac side effects. Economic analyses indicated that amisulpride augmentation has the potential to be cost-effective in the short term [net saving of between £329 and £2011; no difference in quality-adjusted life-years (QALYs)] and possibly in the longer term. Limitations The trial under-recruited and, therefore, the power of statistical analysis to detect significant differences between the active and placebo groups was limited. The economic analyses indicated high uncertainty because of the short duration and relatively small number of participants. Conclusions The risk–benefit of amisulpride augmentation of clozapine for schizophrenia that has shown an insufficient response to a trial of clozapine monotherapy is worthy of further investigation in larger studies. The size and extent of the side effect burden identified for the amisulpride–clozapine combination may partly reflect the comprehensive assessment of side effects in this study. The design of future trials of such a treatment strategy should take into account that a clinical response may be not be evident within the 4- to 6-week follow-up period usually considered adequate in studies of antipsychotic treatment of acute psychotic episodes. Economic evaluation indicated the need for larger, longer-term studies to address uncertainty about the extent of savings because of amisulpride and impact on QALYs. The extent and nature of the side effect burden identified for the amisulpride–clozapine combination has implications for the nature and frequency of safety and tolerability monitoring of clozapine augmentation with a second antipsychotic in both clinical and research settings. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 49. See the NIHR Journals Library website for further project information.

Expert commentary

Sadly, refractory or ‘treatment resistant’ psychosis is all too common a phenomenon. Clozapine is our gold-standard ‘go-to’ medication in such instances, but it only works well in about half those trialled on it. Most guidelines discourage using more than one antipsychotic but it is common in clinical practice, where doctors are faced with the harsh reality of treatment limitations and illness burden on sufferers and their families.

It is crucial to have better evidence on the utility, or otherwise, of such real-world combinations to enhance care and people’s well-being: psychosis already robs many of up to twenty years of life.

Dr Derek Tracy, Consultant Psychiatrist and Clinical Director, Oxleas NHS Foundation Trust; Senior Lecturer, King's College London