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High antipsychotic switch rates suggest ‘suboptimal’ prescribing for first-episode psychosis
In a large-scale, real-world analysis of U.K. prescribing patterns, researchers found more than two-thirds of patients who received antipsychotics for FEP switched medication, and almost half switched drugs three times.
Although this is “one of the largest real-world studies examining antipsychotic treatment strategies,” it reflects findings from previous, smaller studies showing “antipsychotic switching in first episode psychosis is high,” said study investigator Aimee Brinn, Institute of Psychiatry, Psychology & Neuroscience at King’s College London.
This may reflect reports of poor efficacy and suggests that first-line prescribing is “suboptimal,” Ms. Brinn noted. In addition, olanzapine remains the most popular antipsychotic for prescribing despite recent guidelines indicating it is “not ideal ... due to its dangerous metabolic side effects,” she added.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
Real-world data
The response to, and tolerability of, antipsychotics differs between patients with FEP; and prescribing patterns “reflect clinician and patient-led decisionmaking,” Ms. Brinn told meeting attendees.
Since randomized controlled trials “do not necessarily reflect prescribing practice in real-world clinical settings,” the researchers gathered data from a large mental health care electronic health record dataset.
The investigators examined records from the South London and Maudsley NHS Foundation Trust (SLaM), which has a catchment area of 1.2 million individuals across four boroughs of London. The group sees approximately 37,500 active patients per week.
The team used the Clinical Interactive Record Search tool to extract data on 2,309 adults with FEP who received care from a SLaM early intervention in psychosis service between April 1, 2008, and March 31, 2019.
They found that 12 different antipsychotics were prescribed as first-line treatment. The most common were olanzapine (43.9%), risperidone (24.7%), and aripiprazole (19.9%).
Results showed that over 81,969.5 person-years of follow-up, at a minimum of 24 months per patient, 68.8% had an antipsychotic switch. The most common first treatment switch, in 17.9% of patients, was from olanzapine to aripiprazole.
Of patients who switched to aripiprazole, 48.4% stayed on the drug, 26% switched back to olanzapine, and 25.6% received other treatment. Overall, 44.7% of patients switched medication at least three times.
Among patients with FEP who did not switch, 42.2% were prescribed olanzapine, 26.2% risperidone, 23.3% aripiprazole, 5.6% quetiapine, and 2.7% amisulpride.
During the post-presentation discussion, Ms. Brinn was asked whether the high rate of first-line olanzapine prescribing could be because patients started treatment as inpatients and were then switched once they were moved to community care.
“We found that a lot of patients would be prescribed olanzapine for around 7 days at the start of their prescription and then switch,” Ms. Brinn said, adding it is “likely” they started as inpatients. The investigators are currently examining the differences between inpatient and outpatient prescriptions to verify whether this is indeed the case, she added.
‘Pulling out the big guns too fast?’
Commenting on the findings, Thomas W. Sedlak, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, said the study raises a “number of questions.”
Both olanzapine and risperidone “tend to have higher treatment effect improvements than aripiprazole, so it’s curious that a switch to aripiprazole was common,” said Dr. Sedlak, who was not involved with the research.
“Are we pulling out the ‘big guns’ too fast, or inappropriately, especially as olanzapine and risperidone carry greater risk of weight gain?” he asked. In addition, “now that olanzapine is available with samidorphan to mitigate weight gain, will that shape future patterns, if it can be paid for?”
Dr. Sedlak noted it was unclear why olanzapine was chosen so often as first-line treatment in the study and agreed it is “possible that hospitalized patients had been prescribed a ‘stronger’ medication like olanzapine compared to never-hospitalized patients.”
He also underlined that it is “not clear if patients in this FEP program are representative of all FEP patients.”
“For instance, if the program is well known to inpatient hospital social workers, then the program might be disproportionately filled with patients who have had more severe symptoms,” Dr. Sedlak said.
The study was supported by Janssen-Cilag. The investigators and Dr. Sedlak have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a large-scale, real-world analysis of U.K. prescribing patterns, researchers found more than two-thirds of patients who received antipsychotics for FEP switched medication, and almost half switched drugs three times.
Although this is “one of the largest real-world studies examining antipsychotic treatment strategies,” it reflects findings from previous, smaller studies showing “antipsychotic switching in first episode psychosis is high,” said study investigator Aimee Brinn, Institute of Psychiatry, Psychology & Neuroscience at King’s College London.
This may reflect reports of poor efficacy and suggests that first-line prescribing is “suboptimal,” Ms. Brinn noted. In addition, olanzapine remains the most popular antipsychotic for prescribing despite recent guidelines indicating it is “not ideal ... due to its dangerous metabolic side effects,” she added.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
Real-world data
The response to, and tolerability of, antipsychotics differs between patients with FEP; and prescribing patterns “reflect clinician and patient-led decisionmaking,” Ms. Brinn told meeting attendees.
Since randomized controlled trials “do not necessarily reflect prescribing practice in real-world clinical settings,” the researchers gathered data from a large mental health care electronic health record dataset.
The investigators examined records from the South London and Maudsley NHS Foundation Trust (SLaM), which has a catchment area of 1.2 million individuals across four boroughs of London. The group sees approximately 37,500 active patients per week.
The team used the Clinical Interactive Record Search tool to extract data on 2,309 adults with FEP who received care from a SLaM early intervention in psychosis service between April 1, 2008, and March 31, 2019.
They found that 12 different antipsychotics were prescribed as first-line treatment. The most common were olanzapine (43.9%), risperidone (24.7%), and aripiprazole (19.9%).
Results showed that over 81,969.5 person-years of follow-up, at a minimum of 24 months per patient, 68.8% had an antipsychotic switch. The most common first treatment switch, in 17.9% of patients, was from olanzapine to aripiprazole.
Of patients who switched to aripiprazole, 48.4% stayed on the drug, 26% switched back to olanzapine, and 25.6% received other treatment. Overall, 44.7% of patients switched medication at least three times.
Among patients with FEP who did not switch, 42.2% were prescribed olanzapine, 26.2% risperidone, 23.3% aripiprazole, 5.6% quetiapine, and 2.7% amisulpride.
During the post-presentation discussion, Ms. Brinn was asked whether the high rate of first-line olanzapine prescribing could be because patients started treatment as inpatients and were then switched once they were moved to community care.
“We found that a lot of patients would be prescribed olanzapine for around 7 days at the start of their prescription and then switch,” Ms. Brinn said, adding it is “likely” they started as inpatients. The investigators are currently examining the differences between inpatient and outpatient prescriptions to verify whether this is indeed the case, she added.
‘Pulling out the big guns too fast?’
Commenting on the findings, Thomas W. Sedlak, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, said the study raises a “number of questions.”
Both olanzapine and risperidone “tend to have higher treatment effect improvements than aripiprazole, so it’s curious that a switch to aripiprazole was common,” said Dr. Sedlak, who was not involved with the research.
“Are we pulling out the ‘big guns’ too fast, or inappropriately, especially as olanzapine and risperidone carry greater risk of weight gain?” he asked. In addition, “now that olanzapine is available with samidorphan to mitigate weight gain, will that shape future patterns, if it can be paid for?”
Dr. Sedlak noted it was unclear why olanzapine was chosen so often as first-line treatment in the study and agreed it is “possible that hospitalized patients had been prescribed a ‘stronger’ medication like olanzapine compared to never-hospitalized patients.”
He also underlined that it is “not clear if patients in this FEP program are representative of all FEP patients.”
“For instance, if the program is well known to inpatient hospital social workers, then the program might be disproportionately filled with patients who have had more severe symptoms,” Dr. Sedlak said.
The study was supported by Janssen-Cilag. The investigators and Dr. Sedlak have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a large-scale, real-world analysis of U.K. prescribing patterns, researchers found more than two-thirds of patients who received antipsychotics for FEP switched medication, and almost half switched drugs three times.
Although this is “one of the largest real-world studies examining antipsychotic treatment strategies,” it reflects findings from previous, smaller studies showing “antipsychotic switching in first episode psychosis is high,” said study investigator Aimee Brinn, Institute of Psychiatry, Psychology & Neuroscience at King’s College London.
This may reflect reports of poor efficacy and suggests that first-line prescribing is “suboptimal,” Ms. Brinn noted. In addition, olanzapine remains the most popular antipsychotic for prescribing despite recent guidelines indicating it is “not ideal ... due to its dangerous metabolic side effects,” she added.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
Real-world data
The response to, and tolerability of, antipsychotics differs between patients with FEP; and prescribing patterns “reflect clinician and patient-led decisionmaking,” Ms. Brinn told meeting attendees.
Since randomized controlled trials “do not necessarily reflect prescribing practice in real-world clinical settings,” the researchers gathered data from a large mental health care electronic health record dataset.
The investigators examined records from the South London and Maudsley NHS Foundation Trust (SLaM), which has a catchment area of 1.2 million individuals across four boroughs of London. The group sees approximately 37,500 active patients per week.
The team used the Clinical Interactive Record Search tool to extract data on 2,309 adults with FEP who received care from a SLaM early intervention in psychosis service between April 1, 2008, and March 31, 2019.
They found that 12 different antipsychotics were prescribed as first-line treatment. The most common were olanzapine (43.9%), risperidone (24.7%), and aripiprazole (19.9%).
Results showed that over 81,969.5 person-years of follow-up, at a minimum of 24 months per patient, 68.8% had an antipsychotic switch. The most common first treatment switch, in 17.9% of patients, was from olanzapine to aripiprazole.
Of patients who switched to aripiprazole, 48.4% stayed on the drug, 26% switched back to olanzapine, and 25.6% received other treatment. Overall, 44.7% of patients switched medication at least three times.
Among patients with FEP who did not switch, 42.2% were prescribed olanzapine, 26.2% risperidone, 23.3% aripiprazole, 5.6% quetiapine, and 2.7% amisulpride.
During the post-presentation discussion, Ms. Brinn was asked whether the high rate of first-line olanzapine prescribing could be because patients started treatment as inpatients and were then switched once they were moved to community care.
“We found that a lot of patients would be prescribed olanzapine for around 7 days at the start of their prescription and then switch,” Ms. Brinn said, adding it is “likely” they started as inpatients. The investigators are currently examining the differences between inpatient and outpatient prescriptions to verify whether this is indeed the case, she added.
‘Pulling out the big guns too fast?’
Commenting on the findings, Thomas W. Sedlak, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, said the study raises a “number of questions.”
Both olanzapine and risperidone “tend to have higher treatment effect improvements than aripiprazole, so it’s curious that a switch to aripiprazole was common,” said Dr. Sedlak, who was not involved with the research.
“Are we pulling out the ‘big guns’ too fast, or inappropriately, especially as olanzapine and risperidone carry greater risk of weight gain?” he asked. In addition, “now that olanzapine is available with samidorphan to mitigate weight gain, will that shape future patterns, if it can be paid for?”
Dr. Sedlak noted it was unclear why olanzapine was chosen so often as first-line treatment in the study and agreed it is “possible that hospitalized patients had been prescribed a ‘stronger’ medication like olanzapine compared to never-hospitalized patients.”
He also underlined that it is “not clear if patients in this FEP program are representative of all FEP patients.”
“For instance, if the program is well known to inpatient hospital social workers, then the program might be disproportionately filled with patients who have had more severe symptoms,” Dr. Sedlak said.
The study was supported by Janssen-Cilag. The investigators and Dr. Sedlak have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM SIRS 2022
New combination med for severe mental illness tied to less weight gain
, new research suggests. However, at least one expert says the weight difference between the two drugs is of “questionable clinical benefit.”
Last year, the Food and Drug Administration approved the drug for the treatment of adults with schizophrenia or bipolar I disorder, as a maintenance monotherapy or as either monotherapy or an adjunct to lithium or valproate for acute manic or mixed episodes.
In the ENLIGHTEN-Early trial, researchers examined weight-gain profiles of more than 400 patients with early schizophrenia, schizophreniform disorder, or bipolar I disorder.
Results showed those given combination treatment gained just over half the amount of weight as those given monotherapy. They were also 36% less likely to gain at least 10% of their body weight during the 12-week treatment period.
They indicate that the weight-mitigating effects shown with olanzapine plus samidorphan are “consistent, regardless of the stage of illness,” Dr. Kahn added.
He presented the findings at the annual congress of the Schizophrenia International Research Society.
Potential benefit
“Early intervention with antipsychotic treatment is critical in shaping the course of treatment and the disease trajectory,” coinvestigator Christine Graham, PhD, with Alkermes, which manufactures the drug, told this news organization.
Olanzapine is a “highly effective antipsychotic, but it’s really avoided a lot in this population,” Dr. Graham said. Therefore, patients “could really stand to benefit” from a combination that delivers the same amount of antipsychotic effect, but “reduces the propensity” for clinically significant weight gain, she added.
Dr. Kahn noted in his meeting presentation that antipsychotics are the “cornerstone” of the treatment of serious mental illness, but that “many are associated with concerning weight gain and cardiometabolic effects.”
While olanzapine is an effective medication, it has “one of the highest weight gain” profiles of the available antipsychotics and patients early on in their illness are “especially vulnerable,” Dr. Kahn said.
Previous studies have shown the combination of olanzapine plus samidorphan is similarly effective as olanzapine, but is associated with less weight gain.
To determine its impact in recent-onset illness, the current researchers screened patients with schizophrenia, schizophreniform disorder, or bipolar I disorder. The patients were aged 16-39 years and had an initial onset of active phase symptoms less than 4 years previously. They had less than 24 weeks’ cumulative lifetime exposure to antipsychotics.
Participants were randomly assigned to receive olanzapine plus samidorphan or olanzapine alone for 12 weeks, and then followed up for safety assessment for a further 4 weeks.
A total of 426 patients were recruited and 76.5% completed the study. The mean age was 25.8 years, 66.2% were men, 66.4% were White, and 28.2% were Black.
The mean body mass index at baseline was 23.69 kg/m2. The most common diagnosis among the participants was schizophrenia (62.9%) followed by bipolar I disorder (21.6%).
Less weight gain
Results of the 12-week study showed a significant difference in percent change in body weight from baseline between the two treatment groups, with a gain of 4.91% for the olanzapine plus samidorphan group vs. 6.77% for the olanzapine-alone group (between-group difference, 1.87%; P = .012).
Dr. Kahn noted this equates to an average weight gain of 2.8 kg (6.2 pounds) with olanzapine plus samidorphan and a gain of about 5 kg (11pounds) with olanzapine.
“It’s not a huge difference, but it’s certainly a significant one,” he said. “I also think it’s clinically important and significant.”
The reduction in weight gain compared with olanzapine was even maintained in patients assigned to olanzapine plus samidorphan who dropped out and did not complete the study, Dr. Kahn reported. “No one really had a weight gain,” he said.
In contrast, patients in the olanzapine groups who dropped out of the study had weight gain larger than their counterparts who stayed in it.
Further analysis showed the proportion of patients who gained 10% or more of their body weight by week 12 was 21.9% for those receiving olanzapine plus samidorphan vs. 30.4% for those receiving just olanzapine (odds ratio, 0.64; P = .075).
As expected, the improvement in Clinical Global Impression–Severity scale scores was almost identical between the olanzapine + samidorphan and olanzapine-only groups.
For safety, Dr. Kahn said the adverse event rates were “very, very similar” between the two treatment arms, which was a pattern that was repeated for serious AEs. This led him to note that “nothing out of the ordinary” was observed.
Clinical impact 'questionable'
Commenting on the study, Laura LaChance, MD, a psychiatrist at St. Mary’s Hospital Centre, McGill University, Montreal, said the actual amount of weight loss shown in the study “is of questionable clinical significance.”
On the other hand, Dr. LaChance said she has achieved “better results with metformin, which has a great safety profile and is cheap and widely available.
“Cost is always a concern in patients with psychotic disorders,” she concluded.
The study was funded by Alkermes. Dr. Kahn reported having relationships with Alkermes, Angelini, Janssen, Sunovion, Otsuka, Merck, Minerva Neuroscience, Roche, and Teva. Dr. Graham is an employee of Alkermes.
A version of this article first appeared on Medscape.com.
, new research suggests. However, at least one expert says the weight difference between the two drugs is of “questionable clinical benefit.”
Last year, the Food and Drug Administration approved the drug for the treatment of adults with schizophrenia or bipolar I disorder, as a maintenance monotherapy or as either monotherapy or an adjunct to lithium or valproate for acute manic or mixed episodes.
In the ENLIGHTEN-Early trial, researchers examined weight-gain profiles of more than 400 patients with early schizophrenia, schizophreniform disorder, or bipolar I disorder.
Results showed those given combination treatment gained just over half the amount of weight as those given monotherapy. They were also 36% less likely to gain at least 10% of their body weight during the 12-week treatment period.
They indicate that the weight-mitigating effects shown with olanzapine plus samidorphan are “consistent, regardless of the stage of illness,” Dr. Kahn added.
He presented the findings at the annual congress of the Schizophrenia International Research Society.
Potential benefit
“Early intervention with antipsychotic treatment is critical in shaping the course of treatment and the disease trajectory,” coinvestigator Christine Graham, PhD, with Alkermes, which manufactures the drug, told this news organization.
Olanzapine is a “highly effective antipsychotic, but it’s really avoided a lot in this population,” Dr. Graham said. Therefore, patients “could really stand to benefit” from a combination that delivers the same amount of antipsychotic effect, but “reduces the propensity” for clinically significant weight gain, she added.
Dr. Kahn noted in his meeting presentation that antipsychotics are the “cornerstone” of the treatment of serious mental illness, but that “many are associated with concerning weight gain and cardiometabolic effects.”
While olanzapine is an effective medication, it has “one of the highest weight gain” profiles of the available antipsychotics and patients early on in their illness are “especially vulnerable,” Dr. Kahn said.
Previous studies have shown the combination of olanzapine plus samidorphan is similarly effective as olanzapine, but is associated with less weight gain.
To determine its impact in recent-onset illness, the current researchers screened patients with schizophrenia, schizophreniform disorder, or bipolar I disorder. The patients were aged 16-39 years and had an initial onset of active phase symptoms less than 4 years previously. They had less than 24 weeks’ cumulative lifetime exposure to antipsychotics.
Participants were randomly assigned to receive olanzapine plus samidorphan or olanzapine alone for 12 weeks, and then followed up for safety assessment for a further 4 weeks.
A total of 426 patients were recruited and 76.5% completed the study. The mean age was 25.8 years, 66.2% were men, 66.4% were White, and 28.2% were Black.
The mean body mass index at baseline was 23.69 kg/m2. The most common diagnosis among the participants was schizophrenia (62.9%) followed by bipolar I disorder (21.6%).
Less weight gain
Results of the 12-week study showed a significant difference in percent change in body weight from baseline between the two treatment groups, with a gain of 4.91% for the olanzapine plus samidorphan group vs. 6.77% for the olanzapine-alone group (between-group difference, 1.87%; P = .012).
Dr. Kahn noted this equates to an average weight gain of 2.8 kg (6.2 pounds) with olanzapine plus samidorphan and a gain of about 5 kg (11pounds) with olanzapine.
“It’s not a huge difference, but it’s certainly a significant one,” he said. “I also think it’s clinically important and significant.”
The reduction in weight gain compared with olanzapine was even maintained in patients assigned to olanzapine plus samidorphan who dropped out and did not complete the study, Dr. Kahn reported. “No one really had a weight gain,” he said.
In contrast, patients in the olanzapine groups who dropped out of the study had weight gain larger than their counterparts who stayed in it.
Further analysis showed the proportion of patients who gained 10% or more of their body weight by week 12 was 21.9% for those receiving olanzapine plus samidorphan vs. 30.4% for those receiving just olanzapine (odds ratio, 0.64; P = .075).
As expected, the improvement in Clinical Global Impression–Severity scale scores was almost identical between the olanzapine + samidorphan and olanzapine-only groups.
For safety, Dr. Kahn said the adverse event rates were “very, very similar” between the two treatment arms, which was a pattern that was repeated for serious AEs. This led him to note that “nothing out of the ordinary” was observed.
Clinical impact 'questionable'
Commenting on the study, Laura LaChance, MD, a psychiatrist at St. Mary’s Hospital Centre, McGill University, Montreal, said the actual amount of weight loss shown in the study “is of questionable clinical significance.”
On the other hand, Dr. LaChance said she has achieved “better results with metformin, which has a great safety profile and is cheap and widely available.
“Cost is always a concern in patients with psychotic disorders,” she concluded.
The study was funded by Alkermes. Dr. Kahn reported having relationships with Alkermes, Angelini, Janssen, Sunovion, Otsuka, Merck, Minerva Neuroscience, Roche, and Teva. Dr. Graham is an employee of Alkermes.
A version of this article first appeared on Medscape.com.
, new research suggests. However, at least one expert says the weight difference between the two drugs is of “questionable clinical benefit.”
Last year, the Food and Drug Administration approved the drug for the treatment of adults with schizophrenia or bipolar I disorder, as a maintenance monotherapy or as either monotherapy or an adjunct to lithium or valproate for acute manic or mixed episodes.
In the ENLIGHTEN-Early trial, researchers examined weight-gain profiles of more than 400 patients with early schizophrenia, schizophreniform disorder, or bipolar I disorder.
Results showed those given combination treatment gained just over half the amount of weight as those given monotherapy. They were also 36% less likely to gain at least 10% of their body weight during the 12-week treatment period.
They indicate that the weight-mitigating effects shown with olanzapine plus samidorphan are “consistent, regardless of the stage of illness,” Dr. Kahn added.
He presented the findings at the annual congress of the Schizophrenia International Research Society.
Potential benefit
“Early intervention with antipsychotic treatment is critical in shaping the course of treatment and the disease trajectory,” coinvestigator Christine Graham, PhD, with Alkermes, which manufactures the drug, told this news organization.
Olanzapine is a “highly effective antipsychotic, but it’s really avoided a lot in this population,” Dr. Graham said. Therefore, patients “could really stand to benefit” from a combination that delivers the same amount of antipsychotic effect, but “reduces the propensity” for clinically significant weight gain, she added.
Dr. Kahn noted in his meeting presentation that antipsychotics are the “cornerstone” of the treatment of serious mental illness, but that “many are associated with concerning weight gain and cardiometabolic effects.”
While olanzapine is an effective medication, it has “one of the highest weight gain” profiles of the available antipsychotics and patients early on in their illness are “especially vulnerable,” Dr. Kahn said.
Previous studies have shown the combination of olanzapine plus samidorphan is similarly effective as olanzapine, but is associated with less weight gain.
To determine its impact in recent-onset illness, the current researchers screened patients with schizophrenia, schizophreniform disorder, or bipolar I disorder. The patients were aged 16-39 years and had an initial onset of active phase symptoms less than 4 years previously. They had less than 24 weeks’ cumulative lifetime exposure to antipsychotics.
Participants were randomly assigned to receive olanzapine plus samidorphan or olanzapine alone for 12 weeks, and then followed up for safety assessment for a further 4 weeks.
A total of 426 patients were recruited and 76.5% completed the study. The mean age was 25.8 years, 66.2% were men, 66.4% were White, and 28.2% were Black.
The mean body mass index at baseline was 23.69 kg/m2. The most common diagnosis among the participants was schizophrenia (62.9%) followed by bipolar I disorder (21.6%).
Less weight gain
Results of the 12-week study showed a significant difference in percent change in body weight from baseline between the two treatment groups, with a gain of 4.91% for the olanzapine plus samidorphan group vs. 6.77% for the olanzapine-alone group (between-group difference, 1.87%; P = .012).
Dr. Kahn noted this equates to an average weight gain of 2.8 kg (6.2 pounds) with olanzapine plus samidorphan and a gain of about 5 kg (11pounds) with olanzapine.
“It’s not a huge difference, but it’s certainly a significant one,” he said. “I also think it’s clinically important and significant.”
The reduction in weight gain compared with olanzapine was even maintained in patients assigned to olanzapine plus samidorphan who dropped out and did not complete the study, Dr. Kahn reported. “No one really had a weight gain,” he said.
In contrast, patients in the olanzapine groups who dropped out of the study had weight gain larger than their counterparts who stayed in it.
Further analysis showed the proportion of patients who gained 10% or more of their body weight by week 12 was 21.9% for those receiving olanzapine plus samidorphan vs. 30.4% for those receiving just olanzapine (odds ratio, 0.64; P = .075).
As expected, the improvement in Clinical Global Impression–Severity scale scores was almost identical between the olanzapine + samidorphan and olanzapine-only groups.
For safety, Dr. Kahn said the adverse event rates were “very, very similar” between the two treatment arms, which was a pattern that was repeated for serious AEs. This led him to note that “nothing out of the ordinary” was observed.
Clinical impact 'questionable'
Commenting on the study, Laura LaChance, MD, a psychiatrist at St. Mary’s Hospital Centre, McGill University, Montreal, said the actual amount of weight loss shown in the study “is of questionable clinical significance.”
On the other hand, Dr. LaChance said she has achieved “better results with metformin, which has a great safety profile and is cheap and widely available.
“Cost is always a concern in patients with psychotic disorders,” she concluded.
The study was funded by Alkermes. Dr. Kahn reported having relationships with Alkermes, Angelini, Janssen, Sunovion, Otsuka, Merck, Minerva Neuroscience, Roche, and Teva. Dr. Graham is an employee of Alkermes.
A version of this article first appeared on Medscape.com.
FROM SIRS 2022
‘Fragmented’ speech patterns may predict psychosis relapse
In the first study, an algorithm was created to analyze speech patterns and semantic content to create novel “speech networks.” Compared with their healthy peers, patients with FEP had smaller and more fragmented networks. At-risk individuals had fragmented values that were in between those of the FEP and healthy control groups.
“This suggests that semantic speech networks can enable deeper phenotyping of formal thought disorder and psychosis,” said lead author Caroline Nettekoven, PhD, department of psychiatry, University of Cambridge, England.
In the second study, Janna N. de Boer, MD, University of Groningen, the Netherlands, and colleagues examined patients with FEP who did and did not experience relapse after 24 months of follow-up.
An algorithm based on natural language processing (NLP) of speech recordings predicted the relapses with an accuracy of more than 80%.
NLP “is a powerful tool with high potential for clinical application and diagnosis and differentiation, given its ease in acquirement, low cost, and naturally low patient burden,” said de Boer.
The findings for both studies were presented at the annual congress of the Schizophrenia International Research Society.
Fragmented networks
Dr. Nettekoven noted that previous research has shown “mapping the speech of a psychosis patient as a network and analyzing the network using graph theory is useful for understanding formal thought disorder.”
However, these tools ignore the semantic content of speech, which is a “key feature” that is altered in psychotic language, she added.
The researchers therefore proposed a “novel type of network to map the content of speech.”
For example, if someone said, “I see a man,” a semantic speech network developed from this sentence would have the first and last words connected by “the edge” to the word “see,” Dr. Nettekoven explained.
To explore further, the investigators developed an algorithm known as “netts” that automatically creates semantic speech networks from transcribed speech.
They first applied the algorithm to transcribed speech from a general population sample of 436 individuals and then to a clinical sample (n = 53) comprising patients with FEP, those at clinical high risk for psychosis, and a healthy control group.
Comparing the general population sample with randomly generated semantic speech networks, the investigators found that networks from the general population had fewer but larger connected components, which “reflects the nonrandom nature of speech,” said Dr. Nettekoven.
In the clinical sample, networks from the FEP group had a significantly higher number of connected components compared with the healthy control group (P = .05) and a significantly smaller median connected-component size (P < .01).
“So patients’ mental speech networks are more fragmented than those from controls,” said Dr. Nettekoven. She added that the networks from clinically high-risk individuals “showed fragmentation values in between [those of] patients and controls.”
A further clustering analysis suggested the semantic speech networks “capture a novel signal that is not already described” by other NLP measures, Dr. Nettekoven said. In addition, the network features were related to negative symptom scores and scores on the Thought and Language Index.
However, Dr. Nettekoven noted that these relationships “did not survive correcting for multiple comparisons.”
Relapse predictor
During her presentation of the second study, Dr. de Boer said that “predicting relapse remains challenging” in FEP.
However, she noted that recent developments in NLP have proved to be effective in a “range of applications,” including early symptom recognition and differential diagnosis in psychosis.
To determine whether NLP could help predict relapse, the study included 104 patients aged 16-55 years with FEP whose conditions had been in remission for 3-6 months. Speech recordings were made at baseline and after 3 and 6 months and were analyzed via OpenSMILE software.
After a follow-up of 24 months, 24 of the patients remaining in the study had not experienced relapse, while 21 patients had experienced relapse. There were no significant age, education, or gender differences between those who did and those who did not experience relapse.
On the basis of speech analysis, the investigators identified a machine learning classifier, which showed an accuracy of 80.8% in predicting relapse 3 months in advance of the occurrence.
‘Valid and informative’
Commenting on the studies, Eric J. Tan, PhD, Centre for Mental Health, Swinburne University of Technology, Melbourne, said they are “but two of a variety of ways in which speech can be analyzed and are both equally valid and informative.”
The key takeaway “is that both studies are examples of the ways in which speech can be used clinically, such as for predicting relapse and for the potential proxy measure for the assessment of symptom severity,” said Dr. Tan, who was not involved with the research.
The studies also show that “speech is sensitive to different stages of the disorder, as well as its individual symptoms,” he added.
However, Dr. Tan noted that although “speech may be more of a sign of an underlying pathology or dysfunction, given that it waxes and wanes with illness severity, more analyses are needed before drawing definitive conclusions.” This is especially needed “given the relative infancy of quantitative speech analysis,” he said.
“It would also be useful to conduct these analyses across a variety of different languages to look for commonalities and differences that will help shed light on the variables most closely linked to the disorder,” Dr. Tan concluded.
The investigators have reported no relevant financial relationships. Dr. Tan has received an Early Career Research Fellowship from the National Health and Medical Research Council of Australia.
A version of this article first appeared on Medscape.com.
In the first study, an algorithm was created to analyze speech patterns and semantic content to create novel “speech networks.” Compared with their healthy peers, patients with FEP had smaller and more fragmented networks. At-risk individuals had fragmented values that were in between those of the FEP and healthy control groups.
“This suggests that semantic speech networks can enable deeper phenotyping of formal thought disorder and psychosis,” said lead author Caroline Nettekoven, PhD, department of psychiatry, University of Cambridge, England.
In the second study, Janna N. de Boer, MD, University of Groningen, the Netherlands, and colleagues examined patients with FEP who did and did not experience relapse after 24 months of follow-up.
An algorithm based on natural language processing (NLP) of speech recordings predicted the relapses with an accuracy of more than 80%.
NLP “is a powerful tool with high potential for clinical application and diagnosis and differentiation, given its ease in acquirement, low cost, and naturally low patient burden,” said de Boer.
The findings for both studies were presented at the annual congress of the Schizophrenia International Research Society.
Fragmented networks
Dr. Nettekoven noted that previous research has shown “mapping the speech of a psychosis patient as a network and analyzing the network using graph theory is useful for understanding formal thought disorder.”
However, these tools ignore the semantic content of speech, which is a “key feature” that is altered in psychotic language, she added.
The researchers therefore proposed a “novel type of network to map the content of speech.”
For example, if someone said, “I see a man,” a semantic speech network developed from this sentence would have the first and last words connected by “the edge” to the word “see,” Dr. Nettekoven explained.
To explore further, the investigators developed an algorithm known as “netts” that automatically creates semantic speech networks from transcribed speech.
They first applied the algorithm to transcribed speech from a general population sample of 436 individuals and then to a clinical sample (n = 53) comprising patients with FEP, those at clinical high risk for psychosis, and a healthy control group.
Comparing the general population sample with randomly generated semantic speech networks, the investigators found that networks from the general population had fewer but larger connected components, which “reflects the nonrandom nature of speech,” said Dr. Nettekoven.
In the clinical sample, networks from the FEP group had a significantly higher number of connected components compared with the healthy control group (P = .05) and a significantly smaller median connected-component size (P < .01).
“So patients’ mental speech networks are more fragmented than those from controls,” said Dr. Nettekoven. She added that the networks from clinically high-risk individuals “showed fragmentation values in between [those of] patients and controls.”
A further clustering analysis suggested the semantic speech networks “capture a novel signal that is not already described” by other NLP measures, Dr. Nettekoven said. In addition, the network features were related to negative symptom scores and scores on the Thought and Language Index.
However, Dr. Nettekoven noted that these relationships “did not survive correcting for multiple comparisons.”
Relapse predictor
During her presentation of the second study, Dr. de Boer said that “predicting relapse remains challenging” in FEP.
However, she noted that recent developments in NLP have proved to be effective in a “range of applications,” including early symptom recognition and differential diagnosis in psychosis.
To determine whether NLP could help predict relapse, the study included 104 patients aged 16-55 years with FEP whose conditions had been in remission for 3-6 months. Speech recordings were made at baseline and after 3 and 6 months and were analyzed via OpenSMILE software.
After a follow-up of 24 months, 24 of the patients remaining in the study had not experienced relapse, while 21 patients had experienced relapse. There were no significant age, education, or gender differences between those who did and those who did not experience relapse.
On the basis of speech analysis, the investigators identified a machine learning classifier, which showed an accuracy of 80.8% in predicting relapse 3 months in advance of the occurrence.
‘Valid and informative’
Commenting on the studies, Eric J. Tan, PhD, Centre for Mental Health, Swinburne University of Technology, Melbourne, said they are “but two of a variety of ways in which speech can be analyzed and are both equally valid and informative.”
The key takeaway “is that both studies are examples of the ways in which speech can be used clinically, such as for predicting relapse and for the potential proxy measure for the assessment of symptom severity,” said Dr. Tan, who was not involved with the research.
The studies also show that “speech is sensitive to different stages of the disorder, as well as its individual symptoms,” he added.
However, Dr. Tan noted that although “speech may be more of a sign of an underlying pathology or dysfunction, given that it waxes and wanes with illness severity, more analyses are needed before drawing definitive conclusions.” This is especially needed “given the relative infancy of quantitative speech analysis,” he said.
“It would also be useful to conduct these analyses across a variety of different languages to look for commonalities and differences that will help shed light on the variables most closely linked to the disorder,” Dr. Tan concluded.
The investigators have reported no relevant financial relationships. Dr. Tan has received an Early Career Research Fellowship from the National Health and Medical Research Council of Australia.
A version of this article first appeared on Medscape.com.
In the first study, an algorithm was created to analyze speech patterns and semantic content to create novel “speech networks.” Compared with their healthy peers, patients with FEP had smaller and more fragmented networks. At-risk individuals had fragmented values that were in between those of the FEP and healthy control groups.
“This suggests that semantic speech networks can enable deeper phenotyping of formal thought disorder and psychosis,” said lead author Caroline Nettekoven, PhD, department of psychiatry, University of Cambridge, England.
In the second study, Janna N. de Boer, MD, University of Groningen, the Netherlands, and colleagues examined patients with FEP who did and did not experience relapse after 24 months of follow-up.
An algorithm based on natural language processing (NLP) of speech recordings predicted the relapses with an accuracy of more than 80%.
NLP “is a powerful tool with high potential for clinical application and diagnosis and differentiation, given its ease in acquirement, low cost, and naturally low patient burden,” said de Boer.
The findings for both studies were presented at the annual congress of the Schizophrenia International Research Society.
Fragmented networks
Dr. Nettekoven noted that previous research has shown “mapping the speech of a psychosis patient as a network and analyzing the network using graph theory is useful for understanding formal thought disorder.”
However, these tools ignore the semantic content of speech, which is a “key feature” that is altered in psychotic language, she added.
The researchers therefore proposed a “novel type of network to map the content of speech.”
For example, if someone said, “I see a man,” a semantic speech network developed from this sentence would have the first and last words connected by “the edge” to the word “see,” Dr. Nettekoven explained.
To explore further, the investigators developed an algorithm known as “netts” that automatically creates semantic speech networks from transcribed speech.
They first applied the algorithm to transcribed speech from a general population sample of 436 individuals and then to a clinical sample (n = 53) comprising patients with FEP, those at clinical high risk for psychosis, and a healthy control group.
Comparing the general population sample with randomly generated semantic speech networks, the investigators found that networks from the general population had fewer but larger connected components, which “reflects the nonrandom nature of speech,” said Dr. Nettekoven.
In the clinical sample, networks from the FEP group had a significantly higher number of connected components compared with the healthy control group (P = .05) and a significantly smaller median connected-component size (P < .01).
“So patients’ mental speech networks are more fragmented than those from controls,” said Dr. Nettekoven. She added that the networks from clinically high-risk individuals “showed fragmentation values in between [those of] patients and controls.”
A further clustering analysis suggested the semantic speech networks “capture a novel signal that is not already described” by other NLP measures, Dr. Nettekoven said. In addition, the network features were related to negative symptom scores and scores on the Thought and Language Index.
However, Dr. Nettekoven noted that these relationships “did not survive correcting for multiple comparisons.”
Relapse predictor
During her presentation of the second study, Dr. de Boer said that “predicting relapse remains challenging” in FEP.
However, she noted that recent developments in NLP have proved to be effective in a “range of applications,” including early symptom recognition and differential diagnosis in psychosis.
To determine whether NLP could help predict relapse, the study included 104 patients aged 16-55 years with FEP whose conditions had been in remission for 3-6 months. Speech recordings were made at baseline and after 3 and 6 months and were analyzed via OpenSMILE software.
After a follow-up of 24 months, 24 of the patients remaining in the study had not experienced relapse, while 21 patients had experienced relapse. There were no significant age, education, or gender differences between those who did and those who did not experience relapse.
On the basis of speech analysis, the investigators identified a machine learning classifier, which showed an accuracy of 80.8% in predicting relapse 3 months in advance of the occurrence.
‘Valid and informative’
Commenting on the studies, Eric J. Tan, PhD, Centre for Mental Health, Swinburne University of Technology, Melbourne, said they are “but two of a variety of ways in which speech can be analyzed and are both equally valid and informative.”
The key takeaway “is that both studies are examples of the ways in which speech can be used clinically, such as for predicting relapse and for the potential proxy measure for the assessment of symptom severity,” said Dr. Tan, who was not involved with the research.
The studies also show that “speech is sensitive to different stages of the disorder, as well as its individual symptoms,” he added.
However, Dr. Tan noted that although “speech may be more of a sign of an underlying pathology or dysfunction, given that it waxes and wanes with illness severity, more analyses are needed before drawing definitive conclusions.” This is especially needed “given the relative infancy of quantitative speech analysis,” he said.
“It would also be useful to conduct these analyses across a variety of different languages to look for commonalities and differences that will help shed light on the variables most closely linked to the disorder,” Dr. Tan concluded.
The investigators have reported no relevant financial relationships. Dr. Tan has received an Early Career Research Fellowship from the National Health and Medical Research Council of Australia.
A version of this article first appeared on Medscape.com.
FROM SIRS 2022
Novel long-acting injection cuts schizophrenia relapse
A long-acting subcutaneous antipsychotic (LASCA) suspension that combines risperidone with a novel copolymer substantially reduces risk for relapse and prolongs time to impending relapse for patients with schizophrenia, new research suggests.
In the phase 3 Risperidone Subcutaneous Extended-Release (RISE) trial, which included more than 500 patients with schizophrenia, those who received the novel combination treatment, known as TV-46000, had relapse reduced by 80% with monthly administration and by 63.5% with the bimonthly dose.
“Long-acting injectable medications are grossly underutilized,” study investigator John M. Kane, MD, Hofstra University, Hempstead, N.Y., told this news organization.
The attributes of TV-46000, which include its subcutaneous delivery rather than intramuscular injections, its being active within 24 hours of first treatment, and its being administered monthly or bimonthly, “might be advantageous for some patients,” Dr. Kane noted.
Because it is also effective in reducing risk for relapse, TV-46000 is “another alternative when people are looking at the possibility of using a long-acting injectable formulation,” he added.
The findings were presented at the annual congress of the Schizophrenia International Research Society.
Time to relapse
To examine the efficacy and safety of monthly and bimonthly doses of the drug, the researchers recruited patients aged 13-65 years who were diagnosed with schizophrenia more than a year previously and who had experienced at least one relapse in the previous 24 months.
After a screening period of up to 4 weeks, participants entered a 12-week pretreatment phase, during which their condition was stabilized on oral risperidone. During this period, the patients’ conditions had to remain stable for at least 4 consecutive weeks.
Patients were then randomly assigned in a 1:1:1 ratio to receive TV-46000 monthly, TV-46000 every 2 months, or matching placebo. All doses were given as subcutaneous injections.
Treatment was continued until participants experienced a relapse event, met at least one criteria for study withdrawal, or the study recorded a total of 90 or more relapse events.
Of 1,267 patients screened, 863 were enrolled in the study, and 544 underwent randomization. The median age of the patients who underwent randomization was 52 years; 61% were male; and the majority (59%) were Black.
In addition, the average length of time with the disease was 20.8 years, and the average time since the most recent relapse was 10.2 months.
The primary endpoint was time to impending relapse, the criteria for which included the following:
- Increases in Positive and Negative Syndrome Scale (PANSS) scores from randomization.
- Hospitalization because of worsening psychotic symptoms.
- Violent behavior resulting in clinically significant injury or damage.
Well tolerated?
In the intent-to-treat population, which comprised all adults who underwent randomization, monthly TV-46000 was associated with a fivefold prolongation of time to impending relapse in comparison with placebo; TV-46000 given every 2 months prolonged the time 2.7-fold.
This translated into a significant benefit vs. placebo for both TV-46000 monthly (hazard ratio for impending relapse, 0.2) and TV-46000 every 2 months (HR, 0.375; P < .0001 for both comparisons).
At the trial’s endpoint, impending relapse rates were 29% in the placebo group vs. 7% in the TV-46000 monthly group and 13% in the group that received TV-46000 every 2 months (P < .0001 for both).
While more patients in the two active-treatment groups met the strict criteria for remission, which included no relapse during the study and PANSS scores of 3 or less for at least 6 months prior to the study endpoint, the differences were not significant.
Treatment-related adverse events (AEs) were experienced by 39%-42% of the TV-46000 groups and by 26% of the placebo group. Serious AEs were experienced by 4%-6% of the TV-46000 groups and by 8% of the placebo group.
The investigators note that TV-46000 was “well tolerated” and that there were no new safety signals in comparison with what is already known about risperidone and “other long-acting risperidone formulations.”
Expanding on the reasons why long-acting antipsychotics are underprescribed, Dr. Kane said that “doctors often overestimate how adherent their patients are.”
He added that doctors may worry they are “insulting” their patient by suggesting they receive injections in order to increase adherence and that doctors are “not very good” at having these types of conversation with their patients.
“We did a study where we trained the clinical staff on how to have those conversations, and the result was the uptake [in patients switching to long-acting antipsychotics] was very high,” Dr. Kane said.
The personnel who received training included all of the medical team, therapists, who spend “much more time” with the patient than does the prescriber, and also social workers, case managers, and rehabilitation counselors, who are typically “not very familiar” with the idea of long-acting medications, he added.
‘Highly desirable’ option
Commenting on the study, Stephen R. Saklad, PharmD, director of the psychiatric pharmacy program, University of Texas Health Science Center at San Antonio, said that to call TV-46000 a LASCA rather than a depot injection is merely a “change in nomenclature.”
However, compared with a once-monthly subcutaneous injection of risperidone (Perseris), which was approved by the U.S. Food and Drug Administration in 2018 for the treatment of schizophrenia, the new drug has fewer injection site reactions, said Dr. Saklad, who was not involved with the current research.
That benefit plus having efficacy similar to that of oral risperidone and having the “more patient- and clinician-desirable administration location” of the upper arm as well as the abdomen means the option to switch a risperidone-stabilized patient directly to TV-46000 monthly or bimonthly is “highly desirable,” he added.
Dr. Saklad also noted the reduction in the likelihood of impending relapse with TV-46000 over placebo is a relatively large effect size “and shows the value toward improving the care of these patients.”
In addition, he agreed with Dr. Kane that the uptake of long-acting antipsychotics is “deplorably low.”
“This is due to a number of factors that include patient reluctance to get a ‘shot’ or ‘jab,’ clinician inexperience with LAIs during training, and the incorrect presentation of LAIs as a punishment paradigm for ‘bad’ patients,” Dr. Saklad said.
He added that “everyone tires of taking their medication or just forgets to take a dose,” and most patients with other disorders will resume their medication the next day.
However, patients with schizophrenia have a “specific cognitive difficulty” in making the connection between stopping their medication and a later relapse. If they miss a dose, they will “incorrectly conclude that they are now ‘well’ and don’t need the medication any longer,” he said.
Dr. Saklad stressed that for a patient with schizophrenia a relapse can mean substantial loss of function and of assets such as housing or support networks, and many “will complete suicide.”
The study was supported by Teva Branded Pharmaceutical Products R&D. Dr. Kane reported relationships with Alkermes, Allergan, Dainioppon Sumitomo, H. Lundbeck, Indivior, Intracellular Therapies, Janssen, Janssen Pharmaceuticals, Johnson & Johnson, LB Pharmaceuticals, Merck, Neurocine, North Shore Therapeutics, Novartis Pharmaceutical, Otsuka, Reviva, Roche, Saladex, Sunovion, Takeda, Teva, Otsuka, Lundbeck, Sunovion, UptoDate, and Vanguard Research Group.
A version of this article first appeared on Medscape.com.
A long-acting subcutaneous antipsychotic (LASCA) suspension that combines risperidone with a novel copolymer substantially reduces risk for relapse and prolongs time to impending relapse for patients with schizophrenia, new research suggests.
In the phase 3 Risperidone Subcutaneous Extended-Release (RISE) trial, which included more than 500 patients with schizophrenia, those who received the novel combination treatment, known as TV-46000, had relapse reduced by 80% with monthly administration and by 63.5% with the bimonthly dose.
“Long-acting injectable medications are grossly underutilized,” study investigator John M. Kane, MD, Hofstra University, Hempstead, N.Y., told this news organization.
The attributes of TV-46000, which include its subcutaneous delivery rather than intramuscular injections, its being active within 24 hours of first treatment, and its being administered monthly or bimonthly, “might be advantageous for some patients,” Dr. Kane noted.
Because it is also effective in reducing risk for relapse, TV-46000 is “another alternative when people are looking at the possibility of using a long-acting injectable formulation,” he added.
The findings were presented at the annual congress of the Schizophrenia International Research Society.
Time to relapse
To examine the efficacy and safety of monthly and bimonthly doses of the drug, the researchers recruited patients aged 13-65 years who were diagnosed with schizophrenia more than a year previously and who had experienced at least one relapse in the previous 24 months.
After a screening period of up to 4 weeks, participants entered a 12-week pretreatment phase, during which their condition was stabilized on oral risperidone. During this period, the patients’ conditions had to remain stable for at least 4 consecutive weeks.
Patients were then randomly assigned in a 1:1:1 ratio to receive TV-46000 monthly, TV-46000 every 2 months, or matching placebo. All doses were given as subcutaneous injections.
Treatment was continued until participants experienced a relapse event, met at least one criteria for study withdrawal, or the study recorded a total of 90 or more relapse events.
Of 1,267 patients screened, 863 were enrolled in the study, and 544 underwent randomization. The median age of the patients who underwent randomization was 52 years; 61% were male; and the majority (59%) were Black.
In addition, the average length of time with the disease was 20.8 years, and the average time since the most recent relapse was 10.2 months.
The primary endpoint was time to impending relapse, the criteria for which included the following:
- Increases in Positive and Negative Syndrome Scale (PANSS) scores from randomization.
- Hospitalization because of worsening psychotic symptoms.
- Violent behavior resulting in clinically significant injury or damage.
Well tolerated?
In the intent-to-treat population, which comprised all adults who underwent randomization, monthly TV-46000 was associated with a fivefold prolongation of time to impending relapse in comparison with placebo; TV-46000 given every 2 months prolonged the time 2.7-fold.
This translated into a significant benefit vs. placebo for both TV-46000 monthly (hazard ratio for impending relapse, 0.2) and TV-46000 every 2 months (HR, 0.375; P < .0001 for both comparisons).
At the trial’s endpoint, impending relapse rates were 29% in the placebo group vs. 7% in the TV-46000 monthly group and 13% in the group that received TV-46000 every 2 months (P < .0001 for both).
While more patients in the two active-treatment groups met the strict criteria for remission, which included no relapse during the study and PANSS scores of 3 or less for at least 6 months prior to the study endpoint, the differences were not significant.
Treatment-related adverse events (AEs) were experienced by 39%-42% of the TV-46000 groups and by 26% of the placebo group. Serious AEs were experienced by 4%-6% of the TV-46000 groups and by 8% of the placebo group.
The investigators note that TV-46000 was “well tolerated” and that there were no new safety signals in comparison with what is already known about risperidone and “other long-acting risperidone formulations.”
Expanding on the reasons why long-acting antipsychotics are underprescribed, Dr. Kane said that “doctors often overestimate how adherent their patients are.”
He added that doctors may worry they are “insulting” their patient by suggesting they receive injections in order to increase adherence and that doctors are “not very good” at having these types of conversation with their patients.
“We did a study where we trained the clinical staff on how to have those conversations, and the result was the uptake [in patients switching to long-acting antipsychotics] was very high,” Dr. Kane said.
The personnel who received training included all of the medical team, therapists, who spend “much more time” with the patient than does the prescriber, and also social workers, case managers, and rehabilitation counselors, who are typically “not very familiar” with the idea of long-acting medications, he added.
‘Highly desirable’ option
Commenting on the study, Stephen R. Saklad, PharmD, director of the psychiatric pharmacy program, University of Texas Health Science Center at San Antonio, said that to call TV-46000 a LASCA rather than a depot injection is merely a “change in nomenclature.”
However, compared with a once-monthly subcutaneous injection of risperidone (Perseris), which was approved by the U.S. Food and Drug Administration in 2018 for the treatment of schizophrenia, the new drug has fewer injection site reactions, said Dr. Saklad, who was not involved with the current research.
That benefit plus having efficacy similar to that of oral risperidone and having the “more patient- and clinician-desirable administration location” of the upper arm as well as the abdomen means the option to switch a risperidone-stabilized patient directly to TV-46000 monthly or bimonthly is “highly desirable,” he added.
Dr. Saklad also noted the reduction in the likelihood of impending relapse with TV-46000 over placebo is a relatively large effect size “and shows the value toward improving the care of these patients.”
In addition, he agreed with Dr. Kane that the uptake of long-acting antipsychotics is “deplorably low.”
“This is due to a number of factors that include patient reluctance to get a ‘shot’ or ‘jab,’ clinician inexperience with LAIs during training, and the incorrect presentation of LAIs as a punishment paradigm for ‘bad’ patients,” Dr. Saklad said.
He added that “everyone tires of taking their medication or just forgets to take a dose,” and most patients with other disorders will resume their medication the next day.
However, patients with schizophrenia have a “specific cognitive difficulty” in making the connection between stopping their medication and a later relapse. If they miss a dose, they will “incorrectly conclude that they are now ‘well’ and don’t need the medication any longer,” he said.
Dr. Saklad stressed that for a patient with schizophrenia a relapse can mean substantial loss of function and of assets such as housing or support networks, and many “will complete suicide.”
The study was supported by Teva Branded Pharmaceutical Products R&D. Dr. Kane reported relationships with Alkermes, Allergan, Dainioppon Sumitomo, H. Lundbeck, Indivior, Intracellular Therapies, Janssen, Janssen Pharmaceuticals, Johnson & Johnson, LB Pharmaceuticals, Merck, Neurocine, North Shore Therapeutics, Novartis Pharmaceutical, Otsuka, Reviva, Roche, Saladex, Sunovion, Takeda, Teva, Otsuka, Lundbeck, Sunovion, UptoDate, and Vanguard Research Group.
A version of this article first appeared on Medscape.com.
A long-acting subcutaneous antipsychotic (LASCA) suspension that combines risperidone with a novel copolymer substantially reduces risk for relapse and prolongs time to impending relapse for patients with schizophrenia, new research suggests.
In the phase 3 Risperidone Subcutaneous Extended-Release (RISE) trial, which included more than 500 patients with schizophrenia, those who received the novel combination treatment, known as TV-46000, had relapse reduced by 80% with monthly administration and by 63.5% with the bimonthly dose.
“Long-acting injectable medications are grossly underutilized,” study investigator John M. Kane, MD, Hofstra University, Hempstead, N.Y., told this news organization.
The attributes of TV-46000, which include its subcutaneous delivery rather than intramuscular injections, its being active within 24 hours of first treatment, and its being administered monthly or bimonthly, “might be advantageous for some patients,” Dr. Kane noted.
Because it is also effective in reducing risk for relapse, TV-46000 is “another alternative when people are looking at the possibility of using a long-acting injectable formulation,” he added.
The findings were presented at the annual congress of the Schizophrenia International Research Society.
Time to relapse
To examine the efficacy and safety of monthly and bimonthly doses of the drug, the researchers recruited patients aged 13-65 years who were diagnosed with schizophrenia more than a year previously and who had experienced at least one relapse in the previous 24 months.
After a screening period of up to 4 weeks, participants entered a 12-week pretreatment phase, during which their condition was stabilized on oral risperidone. During this period, the patients’ conditions had to remain stable for at least 4 consecutive weeks.
Patients were then randomly assigned in a 1:1:1 ratio to receive TV-46000 monthly, TV-46000 every 2 months, or matching placebo. All doses were given as subcutaneous injections.
Treatment was continued until participants experienced a relapse event, met at least one criteria for study withdrawal, or the study recorded a total of 90 or more relapse events.
Of 1,267 patients screened, 863 were enrolled in the study, and 544 underwent randomization. The median age of the patients who underwent randomization was 52 years; 61% were male; and the majority (59%) were Black.
In addition, the average length of time with the disease was 20.8 years, and the average time since the most recent relapse was 10.2 months.
The primary endpoint was time to impending relapse, the criteria for which included the following:
- Increases in Positive and Negative Syndrome Scale (PANSS) scores from randomization.
- Hospitalization because of worsening psychotic symptoms.
- Violent behavior resulting in clinically significant injury or damage.
Well tolerated?
In the intent-to-treat population, which comprised all adults who underwent randomization, monthly TV-46000 was associated with a fivefold prolongation of time to impending relapse in comparison with placebo; TV-46000 given every 2 months prolonged the time 2.7-fold.
This translated into a significant benefit vs. placebo for both TV-46000 monthly (hazard ratio for impending relapse, 0.2) and TV-46000 every 2 months (HR, 0.375; P < .0001 for both comparisons).
At the trial’s endpoint, impending relapse rates were 29% in the placebo group vs. 7% in the TV-46000 monthly group and 13% in the group that received TV-46000 every 2 months (P < .0001 for both).
While more patients in the two active-treatment groups met the strict criteria for remission, which included no relapse during the study and PANSS scores of 3 or less for at least 6 months prior to the study endpoint, the differences were not significant.
Treatment-related adverse events (AEs) were experienced by 39%-42% of the TV-46000 groups and by 26% of the placebo group. Serious AEs were experienced by 4%-6% of the TV-46000 groups and by 8% of the placebo group.
The investigators note that TV-46000 was “well tolerated” and that there were no new safety signals in comparison with what is already known about risperidone and “other long-acting risperidone formulations.”
Expanding on the reasons why long-acting antipsychotics are underprescribed, Dr. Kane said that “doctors often overestimate how adherent their patients are.”
He added that doctors may worry they are “insulting” their patient by suggesting they receive injections in order to increase adherence and that doctors are “not very good” at having these types of conversation with their patients.
“We did a study where we trained the clinical staff on how to have those conversations, and the result was the uptake [in patients switching to long-acting antipsychotics] was very high,” Dr. Kane said.
The personnel who received training included all of the medical team, therapists, who spend “much more time” with the patient than does the prescriber, and also social workers, case managers, and rehabilitation counselors, who are typically “not very familiar” with the idea of long-acting medications, he added.
‘Highly desirable’ option
Commenting on the study, Stephen R. Saklad, PharmD, director of the psychiatric pharmacy program, University of Texas Health Science Center at San Antonio, said that to call TV-46000 a LASCA rather than a depot injection is merely a “change in nomenclature.”
However, compared with a once-monthly subcutaneous injection of risperidone (Perseris), which was approved by the U.S. Food and Drug Administration in 2018 for the treatment of schizophrenia, the new drug has fewer injection site reactions, said Dr. Saklad, who was not involved with the current research.
That benefit plus having efficacy similar to that of oral risperidone and having the “more patient- and clinician-desirable administration location” of the upper arm as well as the abdomen means the option to switch a risperidone-stabilized patient directly to TV-46000 monthly or bimonthly is “highly desirable,” he added.
Dr. Saklad also noted the reduction in the likelihood of impending relapse with TV-46000 over placebo is a relatively large effect size “and shows the value toward improving the care of these patients.”
In addition, he agreed with Dr. Kane that the uptake of long-acting antipsychotics is “deplorably low.”
“This is due to a number of factors that include patient reluctance to get a ‘shot’ or ‘jab,’ clinician inexperience with LAIs during training, and the incorrect presentation of LAIs as a punishment paradigm for ‘bad’ patients,” Dr. Saklad said.
He added that “everyone tires of taking their medication or just forgets to take a dose,” and most patients with other disorders will resume their medication the next day.
However, patients with schizophrenia have a “specific cognitive difficulty” in making the connection between stopping their medication and a later relapse. If they miss a dose, they will “incorrectly conclude that they are now ‘well’ and don’t need the medication any longer,” he said.
Dr. Saklad stressed that for a patient with schizophrenia a relapse can mean substantial loss of function and of assets such as housing or support networks, and many “will complete suicide.”
The study was supported by Teva Branded Pharmaceutical Products R&D. Dr. Kane reported relationships with Alkermes, Allergan, Dainioppon Sumitomo, H. Lundbeck, Indivior, Intracellular Therapies, Janssen, Janssen Pharmaceuticals, Johnson & Johnson, LB Pharmaceuticals, Merck, Neurocine, North Shore Therapeutics, Novartis Pharmaceutical, Otsuka, Reviva, Roche, Saladex, Sunovion, Takeda, Teva, Otsuka, Lundbeck, Sunovion, UptoDate, and Vanguard Research Group.
A version of this article first appeared on Medscape.com.
FROM SIRS 2022
A new target in schizophrenia treatment: Brain gamma oscillations
In a randomized, double-blind study that included two dozen men with schizophrenia, AUT00206, compared with placebo, increased the power of gamma oscillations, which were in turn associated with positive symptom scores.
The investigators note that targeting a potassium channel linked to brain gamma oscillations may offer a novel way to treat schizophrenia.
In addition, lead author Charles Large, PhD, chief executive officer, Autifony Therapeutics, Stevenage, United Kingdom, told this news organization that it may be “important” to study patients relatively early in their disease course. Participants in the current study were diagnosed less than 5 years previously.
Many previous trials in this area have failed, “and some of the questions were maybe the patients were sort of beyond the point in which you can actually make a difference,” Dr. Large said.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
‘Opportunity to intervene’
Dr. Large noted that patients with chronic, long-term symptoms of schizophrenia have been treated with antipsychotics for decades, “and the pathology of that stage is then different.”
For the current study, the investigators hypothesized that the brain may be more “plastic” earlier on in the disease course, and so “maybe there’s an opportunity to intervene and make a change,” said Dr. Large.
In addition, patients with schizophrenia have abnormalities in both their resting state and induced and evolved gamma oscillations, which can include increased resting state power – and reduced power and “phase locking” to cyclical stimuli – the researchers note.
Previous studies have suggested such abnormalities are associated with dysfunction in parvalbumin-expressing interneurons (PVINs) found in cortical and subcortical circuits.
Moreover, Kv3.1 potassium channels expressed on PVINs are integral to establishing and maintaining fast-firing activity and to network synchronization across the brain. They may, therefore, offer a “potential therapeutic approach” for countering PVIN dysfunction, the investigators write.
To examine the impact of AUT00206, a novel Kv3.1/Kv3.2 positive neuromodulator, on resting state and induced gamma oscillations, they conducted a randomized, double-blind study in 24 men with schizophrenia who were aged 18-50 years.
Participants had been diagnosed less than 5 years previously and were stable on a maximum of two antipsychotic medications. They were randomly assigned 2:1 to a loading 2,000-mg dose of AUT00206 on day 1 and then 800 mg twice daily for 27 days or to placebo.
At baseline/day 1, and on a further 3 days over the treatment period, the men underwent resting-state electroencephalography, 40-Hz auditory steady-state response stimulation, and deviant and standard stimulation in an auditory oddball paradigm to assess resting state, induced, and evoked oscillations, respectively.
Positive associations
Results showed that early auditory gamma responses were increased at day 28 in patients who received AUT00206 but not in those who received placebo. The active drug was also associated with increases in the power of gamma oscillations from Day 5 in response to stimuli but not in phase locking.
There was also a significant positive association between frontal resting gamma power and baseline Positive and Negative Syndrome Scale (PANSS) positive symptom severity scores (r = 0.675; P < .001).
Moreover, changes in PANSS positive scores were significantly correlated with a decrease in frontal resting gamma power in patients treated with AUT00206 (r = 0.532; P = .05).
While a similar correlation was not found with placebo, the investigators note this “may be in part due to the low number” of individuals in the group.
They add that a larger study is now needed to confirm their findings and to “explore efficacy versus clinical symptoms.”
However, Dr. Large noted that participants in their next study will have fragile X syndrome.
He added the reason for this is “not because we’ve given up on schizophrenia – we feel that schizophrenia is a massive opportunity.”
Patients with schizophrenia are heterogeneous, both in terms of their clinical course and prior treatment. So it is “impossible” for a company of their size to take all of that into account in a single study, Dr. Large said.
In contrast, fragile X is “genetically homogenous,” and so it is possible to focus on the deficit and then translate the findings out into a “broader population.”
Preliminary but worth pursuing?
Commenting on the study, James M. McNally, PhD, assistant professor of psychiatry, Harvard Medical School, Boston, said the findings are “quite preliminary” and that the investigators provided “limited information as to how their findings were derived.”
Nevertheless, it is “nice to see that they observed a significant correlation between resting gamma and positive symptom severity at baseline [and] that the observed change in gamma correlates with change in PANSS scores,” said Dr. McNally, who was not involved with the research.
He added that the “idea of targeting Kv3.1 function to restore PV neuron/gamma activity is very interesting and worth pursuing.”
The study was funded by Autifony Therapeutics, of which Dr. Large is an employee.
A version of this article first appeared on Medscape.com.
In a randomized, double-blind study that included two dozen men with schizophrenia, AUT00206, compared with placebo, increased the power of gamma oscillations, which were in turn associated with positive symptom scores.
The investigators note that targeting a potassium channel linked to brain gamma oscillations may offer a novel way to treat schizophrenia.
In addition, lead author Charles Large, PhD, chief executive officer, Autifony Therapeutics, Stevenage, United Kingdom, told this news organization that it may be “important” to study patients relatively early in their disease course. Participants in the current study were diagnosed less than 5 years previously.
Many previous trials in this area have failed, “and some of the questions were maybe the patients were sort of beyond the point in which you can actually make a difference,” Dr. Large said.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
‘Opportunity to intervene’
Dr. Large noted that patients with chronic, long-term symptoms of schizophrenia have been treated with antipsychotics for decades, “and the pathology of that stage is then different.”
For the current study, the investigators hypothesized that the brain may be more “plastic” earlier on in the disease course, and so “maybe there’s an opportunity to intervene and make a change,” said Dr. Large.
In addition, patients with schizophrenia have abnormalities in both their resting state and induced and evolved gamma oscillations, which can include increased resting state power – and reduced power and “phase locking” to cyclical stimuli – the researchers note.
Previous studies have suggested such abnormalities are associated with dysfunction in parvalbumin-expressing interneurons (PVINs) found in cortical and subcortical circuits.
Moreover, Kv3.1 potassium channels expressed on PVINs are integral to establishing and maintaining fast-firing activity and to network synchronization across the brain. They may, therefore, offer a “potential therapeutic approach” for countering PVIN dysfunction, the investigators write.
To examine the impact of AUT00206, a novel Kv3.1/Kv3.2 positive neuromodulator, on resting state and induced gamma oscillations, they conducted a randomized, double-blind study in 24 men with schizophrenia who were aged 18-50 years.
Participants had been diagnosed less than 5 years previously and were stable on a maximum of two antipsychotic medications. They were randomly assigned 2:1 to a loading 2,000-mg dose of AUT00206 on day 1 and then 800 mg twice daily for 27 days or to placebo.
At baseline/day 1, and on a further 3 days over the treatment period, the men underwent resting-state electroencephalography, 40-Hz auditory steady-state response stimulation, and deviant and standard stimulation in an auditory oddball paradigm to assess resting state, induced, and evoked oscillations, respectively.
Positive associations
Results showed that early auditory gamma responses were increased at day 28 in patients who received AUT00206 but not in those who received placebo. The active drug was also associated with increases in the power of gamma oscillations from Day 5 in response to stimuli but not in phase locking.
There was also a significant positive association between frontal resting gamma power and baseline Positive and Negative Syndrome Scale (PANSS) positive symptom severity scores (r = 0.675; P < .001).
Moreover, changes in PANSS positive scores were significantly correlated with a decrease in frontal resting gamma power in patients treated with AUT00206 (r = 0.532; P = .05).
While a similar correlation was not found with placebo, the investigators note this “may be in part due to the low number” of individuals in the group.
They add that a larger study is now needed to confirm their findings and to “explore efficacy versus clinical symptoms.”
However, Dr. Large noted that participants in their next study will have fragile X syndrome.
He added the reason for this is “not because we’ve given up on schizophrenia – we feel that schizophrenia is a massive opportunity.”
Patients with schizophrenia are heterogeneous, both in terms of their clinical course and prior treatment. So it is “impossible” for a company of their size to take all of that into account in a single study, Dr. Large said.
In contrast, fragile X is “genetically homogenous,” and so it is possible to focus on the deficit and then translate the findings out into a “broader population.”
Preliminary but worth pursuing?
Commenting on the study, James M. McNally, PhD, assistant professor of psychiatry, Harvard Medical School, Boston, said the findings are “quite preliminary” and that the investigators provided “limited information as to how their findings were derived.”
Nevertheless, it is “nice to see that they observed a significant correlation between resting gamma and positive symptom severity at baseline [and] that the observed change in gamma correlates with change in PANSS scores,” said Dr. McNally, who was not involved with the research.
He added that the “idea of targeting Kv3.1 function to restore PV neuron/gamma activity is very interesting and worth pursuing.”
The study was funded by Autifony Therapeutics, of which Dr. Large is an employee.
A version of this article first appeared on Medscape.com.
In a randomized, double-blind study that included two dozen men with schizophrenia, AUT00206, compared with placebo, increased the power of gamma oscillations, which were in turn associated with positive symptom scores.
The investigators note that targeting a potassium channel linked to brain gamma oscillations may offer a novel way to treat schizophrenia.
In addition, lead author Charles Large, PhD, chief executive officer, Autifony Therapeutics, Stevenage, United Kingdom, told this news organization that it may be “important” to study patients relatively early in their disease course. Participants in the current study were diagnosed less than 5 years previously.
Many previous trials in this area have failed, “and some of the questions were maybe the patients were sort of beyond the point in which you can actually make a difference,” Dr. Large said.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
‘Opportunity to intervene’
Dr. Large noted that patients with chronic, long-term symptoms of schizophrenia have been treated with antipsychotics for decades, “and the pathology of that stage is then different.”
For the current study, the investigators hypothesized that the brain may be more “plastic” earlier on in the disease course, and so “maybe there’s an opportunity to intervene and make a change,” said Dr. Large.
In addition, patients with schizophrenia have abnormalities in both their resting state and induced and evolved gamma oscillations, which can include increased resting state power – and reduced power and “phase locking” to cyclical stimuli – the researchers note.
Previous studies have suggested such abnormalities are associated with dysfunction in parvalbumin-expressing interneurons (PVINs) found in cortical and subcortical circuits.
Moreover, Kv3.1 potassium channels expressed on PVINs are integral to establishing and maintaining fast-firing activity and to network synchronization across the brain. They may, therefore, offer a “potential therapeutic approach” for countering PVIN dysfunction, the investigators write.
To examine the impact of AUT00206, a novel Kv3.1/Kv3.2 positive neuromodulator, on resting state and induced gamma oscillations, they conducted a randomized, double-blind study in 24 men with schizophrenia who were aged 18-50 years.
Participants had been diagnosed less than 5 years previously and were stable on a maximum of two antipsychotic medications. They were randomly assigned 2:1 to a loading 2,000-mg dose of AUT00206 on day 1 and then 800 mg twice daily for 27 days or to placebo.
At baseline/day 1, and on a further 3 days over the treatment period, the men underwent resting-state electroencephalography, 40-Hz auditory steady-state response stimulation, and deviant and standard stimulation in an auditory oddball paradigm to assess resting state, induced, and evoked oscillations, respectively.
Positive associations
Results showed that early auditory gamma responses were increased at day 28 in patients who received AUT00206 but not in those who received placebo. The active drug was also associated with increases in the power of gamma oscillations from Day 5 in response to stimuli but not in phase locking.
There was also a significant positive association between frontal resting gamma power and baseline Positive and Negative Syndrome Scale (PANSS) positive symptom severity scores (r = 0.675; P < .001).
Moreover, changes in PANSS positive scores were significantly correlated with a decrease in frontal resting gamma power in patients treated with AUT00206 (r = 0.532; P = .05).
While a similar correlation was not found with placebo, the investigators note this “may be in part due to the low number” of individuals in the group.
They add that a larger study is now needed to confirm their findings and to “explore efficacy versus clinical symptoms.”
However, Dr. Large noted that participants in their next study will have fragile X syndrome.
He added the reason for this is “not because we’ve given up on schizophrenia – we feel that schizophrenia is a massive opportunity.”
Patients with schizophrenia are heterogeneous, both in terms of their clinical course and prior treatment. So it is “impossible” for a company of their size to take all of that into account in a single study, Dr. Large said.
In contrast, fragile X is “genetically homogenous,” and so it is possible to focus on the deficit and then translate the findings out into a “broader population.”
Preliminary but worth pursuing?
Commenting on the study, James M. McNally, PhD, assistant professor of psychiatry, Harvard Medical School, Boston, said the findings are “quite preliminary” and that the investigators provided “limited information as to how their findings were derived.”
Nevertheless, it is “nice to see that they observed a significant correlation between resting gamma and positive symptom severity at baseline [and] that the observed change in gamma correlates with change in PANSS scores,” said Dr. McNally, who was not involved with the research.
He added that the “idea of targeting Kv3.1 function to restore PV neuron/gamma activity is very interesting and worth pursuing.”
The study was funded by Autifony Therapeutics, of which Dr. Large is an employee.
A version of this article first appeared on Medscape.com.
FROM SIRS 2022