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Sequential amisulpride, clozapine may lead to remission in early schizophrenia

Study data showed that switching antipsychotic medications did not improve clinical outcomes in patients with first-episode schizophrenia who had not achieved remission.

Instead, the findings published in The Lancet Psychiatry indicated that achieving remission in the early stages of schizophrenia was possible for most patients using a treatment system comprising the sequential use of amisulpride and clozapine.

“In clinical practice, when a patient has not responded to the initial treatment, they are often switched from one antipsychotic medication to another; however, there is surprisingly little evidence that this treatment switch improves clinical outcomes,” René S. Kahn, MD, from the department of psychiatry, Icahn School of Medicine at Mount Sinai, and colleagues wrote. “One of the most relevant questions in the treatment of the early phase of schizophrenia — and essential to any treatment algorithm — is whether switching to another antipsychotic improves outcome when a patient has not responded to the initial treatment is clinically useful.”

Researchers conducted a three-phase study at centers across 14 European countries and Israel to determine whether switching antipsychotics improved outcomes in first-episode schizophrenia.

In phase 1, patients aged 18 to 40 years with a schizophrenia-related disorder received treatment for 4 weeks with up to 800 mg per day oral amisulpride using an open-label design. In the second, 6-week double-blind phase, those who did not achieve symptomatic remission at 4 weeks were randomly allocated to continue receiving amisulpride or switch to 20 mg or more per day of olanzapine. Patients who were not in remission at 10 weeks received clozapine ( 900 mg/day) for another 12 weeks in the open-label third phase.

In the intention-to-treat analysis, 371 patients completed amisulpride treatment and 250 reached remission after phase 1. Of the 93 patients who did not reach remission and continued to the 6-week, double-blind second phase, an almost equal proportion achieved remission whether they continued treatment with amisulpride (45%) or switched to olanzapine (44%). Furthermore, the clinical outcome was similar in the two groups when this was defined in terms of symptomatic improvement, the authors reported.

After 10 weeks of treatment, 28 patients who were not in remission started on clozapine. In total, 18 patients completed the 12-week treatment and five achieved remission. In phase 2, the number of serious adverse events did not differ between the treatment arms. There were two suicide attempts reported over the course of the trial.

“Through the use of an algorithm of treatment with a single antipsychotic for up to 10 weeks and subsequent use of clozapine in individuals who were not in remission, remission can be achieved within 22 weeks for more than three-quarters of first-episode patients who complete treatment and for almost two-thirds of patients who initiate treatment,” the authors wrote. “Although these results need to be replicated and broadened (by use of different antipsychotics), they suggest that achievement of remission in the early stages of schizophrenia is possible in most patients using a simple treatment algorithm of sequential use of amisulpride and clozapine.”

Further research is needed given the risks relating to clozapine use before a trial of clozapine should be recommended, Robert B. Zipursky, MD, from the department of psychiatry, University of Toronto, wrote in a related editorial.

“In clinical practice, it would be valuable to know whether treatment with a long-acting injectable antipsychotic should be offered to patients with first-episode schizophrenia before recommending clozapine, given the evidence that poor treatment response might result from non-adherence,” Zipursky wrote. – by Savannah Demko

Disclosures: Kahn reports personal fees from Alkermes, Gedeon Richter, Minerva Neuroscience and Otsuka/Lundbeck. Please see the study for all other authors’ relevant financial disclosures. Zipursky reports an educational grant and speaking fees from Janssen.