Algorithm aims to tackle clozapine resistance

SAN DIEGO – The atypical antipsychotic drug clozapine is the standard of care for patients with treatment-resistant schizophrenia, but about half do not see an adequate response.

At the annual meeting of the American Psychiatric Association, Randall F. White, MD, presented an algorithm for clozapine-resistant patients intended to simplify and clarify a path forward. He also presented outcome data from a cohort of patients managed using this approach.

The algorithm recommends electroconvulsive therapy if there is inadequate response to clozapine alone or with fluvoxamine, which sometimes is used to boost clozapine serum level, especially in patients who are heavy smokers. If ECT fails to reduce symptoms or the patient refuses it, topiramate, aripiprazole, or sulpiride may be added to clozapine treatment, said Dr. White of the University of British Columbia, Vancouver.

And finally, if psychosis persists, certain patients should be offered cognitive-behavioral therapy with a psychologist trained in helping people with psychosis, Dr. White and his colleagues advise.

Dr. White said in an interview that the idea for a systematic approach to clozapine resistance came from clinical experience of the British Columbia Psychosis Program, which specializes in patients with severe schizophrenia and treatment resistance.

“About half of our patients come to us already on clozapine and aren’t getting better, so we needed to figure out a coherent approach to help them,” he said, noting that there is no current standard of care and that many “come to us already on four or five medications, and it can seem a bit random.”

When these patients are admitted, “we try to simplify their treatment and figure out what’s going on, and then offer ECT if appropriate,” he said.

Dr. White presented data from a cohort of patients assessed at the program between 2012 and 2017, of which 114 were taking clozapine at admission and had a diagnosis of schizophrenia or schizoaffective disorder.

To be considered clozapine-resistant, patients had to be taking 500 mg or more for at least 60 days, yet have persistent positive symptoms and moderate to severe impairment. Dr. White and his colleagues identified 20 patients with clozapine resistance. Of these, eight were offered ECT, and three accepted. At the time of discharge, 16 patients remained on clozapine with or without fluvoxamine. Four patients were treated with the recommended adjunctive agents aripiprazole or sulpiride and five with other agents.

Dr. White said the three agents recommended in the algorithm were determined by literature reviews, including meta-analyses of randomized trials. Several commonly used adjunctive agents to clozapine, including risperidone, were ruled out, for lack of evidence in this patient group.

Sulpiride, one of the drugs recommended in the algorithm, is not marketed in North America, and in Canada is accessible only by special arrangement. The evidence for aripiprazole, meanwhile, “is not stupendous,” Dr. White said, “but there’s a signal.”

The topiramate recommendation is based on results from a 2016 meta-analysis of randomized controlled trials. “Topiramate has a possible advantage of ameliorating metabolic problems,” Dr. White said, and the meta-analysis showed a significant effect size in improving positive and negative symptoms. However, he noted, on rare occasions, it has been seen to exacerbate psychosis.

Dr. White said few of the treatment-resistant patients seen in his program have had a course of ECT despite evidence of benefit. “Instead of ECT, they usually are put on multiple medications,” he said. “Admittedly, getting some of these patients to accept ECT isn’t easy.”

Because the program is designed to keep patients for 6 or more months as needed, “we have the luxury of time,” Dr. White said, to allow for the discontinuation of extraneous medicines and for an ECT trial if indicated.

“I know that in other hospitals, and other health care settings, they don’t have that – they have to figure out what to do quickly. And ECT is not the quickest treatment.”

Offering cognitive-behavioral therapy to people with psychosis is possible, he stressed, and supported by evidence from at least one study. “In this population, it’s challenging,” he acknowledged. “I don’t think I’d do it concurrently with ECT but as an alternative to or after ECT.”

Dr. White disclosed no conflicts of interest related to his research.

SAN DIEGO – The atypical antipsychotic drug clozapine is the standard of care for patients with treatment-resistant schizophrenia, but about half do not see an adequate response.

At the annual meeting of the American Psychiatric Association, Randall F. White, MD, presented an algorithm for clozapine-resistant patients intended to simplify and clarify a path forward. He also presented outcome data from a cohort of patients managed using this approach.

The algorithm recommends electroconvulsive therapy if there is inadequate response to clozapine alone or with fluvoxamine, which sometimes is used to boost clozapine serum level, especially in patients who are heavy smokers. If ECT fails to reduce symptoms or the patient refuses it, topiramate, aripiprazole, or sulpiride may be added to clozapine treatment, said Dr. White of the University of British Columbia, Vancouver.

And finally, if psychosis persists, certain patients should be offered cognitive-behavioral therapy with a psychologist trained in helping people with psychosis, Dr. White and his colleagues advise.

Dr. White said in an interview that the idea for a systematic approach to clozapine resistance came from clinical experience of the British Columbia Psychosis Program, which specializes in patients with severe schizophrenia and treatment resistance.

“About half of our patients come to us already on clozapine and aren’t getting better, so we needed to figure out a coherent approach to help them,” he said, noting that there is no current standard of care and that many “come to us already on four or five medications, and it can seem a bit random.”

When these patients are admitted, “we try to simplify their treatment and figure out what’s going on, and then offer ECT if appropriate,” he said.

Dr. White presented data from a cohort of patients assessed at the program between 2012 and 2017, of which 114 were taking clozapine at admission and had a diagnosis of schizophrenia or schizoaffective disorder.

To be considered clozapine-resistant, patients had to be taking 500 mg or more for at least 60 days, yet have persistent positive symptoms and moderate to severe impairment. Dr. White and his colleagues identified 20 patients with clozapine resistance. Of these, eight were offered ECT, and three accepted. At the time of discharge, 16 patients remained on clozapine with or without fluvoxamine. Four patients were treated with the recommended adjunctive agents aripiprazole or sulpiride and five with other agents.

Dr. White said the three agents recommended in the algorithm were determined by literature reviews, including meta-analyses of randomized trials. Several commonly used adjunctive agents to clozapine, including risperidone, were ruled out, for lack of evidence in this patient group.

Sulpiride, one of the drugs recommended in the algorithm, is not marketed in North America, and in Canada is accessible only by special arrangement. The evidence for aripiprazole, meanwhile, “is not stupendous,” Dr. White said, “but there’s a signal.”

The topiramate recommendation is based on results from a 2016 meta-analysis of randomized controlled trials. “Topiramate has a possible advantage of ameliorating metabolic problems,” Dr. White said, and the meta-analysis showed a significant effect size in improving positive and negative symptoms. However, he noted, on rare occasions, it has been seen to exacerbate psychosis.

Dr. White said few of the treatment-resistant patients seen in his program have had a course of ECT despite evidence of benefit. “Instead of ECT, they usually are put on multiple medications,” he said. “Admittedly, getting some of these patients to accept ECT isn’t easy.”

Because the program is designed to keep patients for 6 or more months as needed, “we have the luxury of time,” Dr. White said, to allow for the discontinuation of extraneous medicines and for an ECT trial if indicated.

“I know that in other hospitals, and other health care settings, they don’t have that – they have to figure out what to do quickly. And ECT is not the quickest treatment.”

Offering cognitive-behavioral therapy to people with psychosis is possible, he stressed, and supported by evidence from at least one study. “In this population, it’s challenging,” he acknowledged. “I don’t think I’d do it concurrently with ECT but as an alternative to or after ECT.”

Dr. White disclosed no conflicts of interest related to his research.

SAN DIEGO – The atypical antipsychotic drug clozapine is the standard of care for patients with treatment-resistant schizophrenia, but about half do not see an adequate response.

At the annual meeting of the American Psychiatric Association, Randall F. White, MD, presented an algorithm for clozapine-resistant patients intended to simplify and clarify a path forward. He also presented outcome data from a cohort of patients managed using this approach.

The algorithm recommends electroconvulsive therapy if there is inadequate response to clozapine alone or with fluvoxamine, which sometimes is used to boost clozapine serum level, especially in patients who are heavy smokers. If ECT fails to reduce symptoms or the patient refuses it, topiramate, aripiprazole, or sulpiride may be added to clozapine treatment, said Dr. White of the University of British Columbia, Vancouver.

And finally, if psychosis persists, certain patients should be offered cognitive-behavioral therapy with a psychologist trained in helping people with psychosis, Dr. White and his colleagues advise.

Dr. White said in an interview that the idea for a systematic approach to clozapine resistance came from clinical experience of the British Columbia Psychosis Program, which specializes in patients with severe schizophrenia and treatment resistance.

“About half of our patients come to us already on clozapine and aren’t getting better, so we needed to figure out a coherent approach to help them,” he said, noting that there is no current standard of care and that many “come to us already on four or five medications, and it can seem a bit random.”

When these patients are admitted, “we try to simplify their treatment and figure out what’s going on, and then offer ECT if appropriate,” he said.

Dr. White presented data from a cohort of patients assessed at the program between 2012 and 2017, of which 114 were taking clozapine at admission and had a diagnosis of schizophrenia or schizoaffective disorder.

To be considered clozapine-resistant, patients had to be taking 500 mg or more for at least 60 days, yet have persistent positive symptoms and moderate to severe impairment. Dr. White and his colleagues identified 20 patients with clozapine resistance. Of these, eight were offered ECT, and three accepted. At the time of discharge, 16 patients remained on clozapine with or without fluvoxamine. Four patients were treated with the recommended adjunctive agents aripiprazole or sulpiride and five with other agents.

Dr. White said the three agents recommended in the algorithm were determined by literature reviews, including meta-analyses of randomized trials. Several commonly used adjunctive agents to clozapine, including risperidone, were ruled out, for lack of evidence in this patient group.

Sulpiride, one of the drugs recommended in the algorithm, is not marketed in North America, and in Canada is accessible only by special arrangement. The evidence for aripiprazole, meanwhile, “is not stupendous,” Dr. White said, “but there’s a signal.”

The topiramate recommendation is based on results from a 2016 meta-analysis of randomized controlled trials. “Topiramate has a possible advantage of ameliorating metabolic problems,” Dr. White said, and the meta-analysis showed a significant effect size in improving positive and negative symptoms. However, he noted, on rare occasions, it has been seen to exacerbate psychosis.

Dr. White said few of the treatment-resistant patients seen in his program have had a course of ECT despite evidence of benefit. “Instead of ECT, they usually are put on multiple medications,” he said. “Admittedly, getting some of these patients to accept ECT isn’t easy.”

Because the program is designed to keep patients for 6 or more months as needed, “we have the luxury of time,” Dr. White said, to allow for the discontinuation of extraneous medicines and for an ECT trial if indicated.

“I know that in other hospitals, and other health care settings, they don’t have that – they have to figure out what to do quickly. And ECT is not the quickest treatment.”

Offering cognitive-behavioral therapy to people with psychosis is possible, he stressed, and supported by evidence from at least one study. “In this population, it’s challenging,” he acknowledged. “I don’t think I’d do it concurrently with ECT but as an alternative to or after ECT.”

Dr. White disclosed no conflicts of interest related to his research.