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This is a plain English summary of an original research article. The views expressed are those of the author(s) and reviewer(s) at the time of publication.

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.


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).



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).

Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre


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