Bruce Jancin

Two oral agents with novel mechanisms of action in schizophrenia generated considerable audience interest after acing large phase 2 clinical trials presented at the virtual congress of the European College of Neuropsychopharmacology.

The two successful drugs moving on to definitive phase 3 studies after their performance at ECNP 2020 are KarXT, a proprietary combination of xanomeline and trospium chloride, and an inhibitor of glycine transporter 1 (Gly-T1) known for now as BI 425809.

Pimavanserin, an oral selective serotonin inverse agonist with a high affinity for 5-HT2A receptors and low affinity for 5-HT2C receptors, has taken a more convoluted path through the developmental pipeline for schizophrenia. It recently failed to outperform placebo as adjunctive treatment for schizophrenia on the primary endpoint of improvement in Positive And Negative Syndrome Scale (PANSS) total score in the 6-week, phase 3 ENHANCE (Efficacy and Safety of Adjunctive Pimavanserin for the Treatment of Schizophrenia) study. The drug did, however, show significant benefit on secondary endpoints involving negative symptoms.

And in the 400-patient, 26-week, placebo-controlled, phase 2 ADVANCE trial, adjunctive pimavanserin was positive for the primary endpoint of improvement in the Negative Symptom Assessment-16 (NSA-16) score. A phase 3 program evaluating the drug specifically for negative symptoms is underway.

Another novel therapy, an investigational selective estrogen receptor beta agonist, proved reassuringly safe but completely ineffective in men with schizophrenia in a study presented at ECNP 2020.

“The results, unfortunately, were disappointing. We saw no signal on cognition, no change on brain imaging with fMRI, and no improvement in negative symptoms or PANSS total score,” reported Alan Breier, MD, professor and vice chair of the department of psychiatry at Indiana University in Indianapolis.

KarXT

KarXT combines xanomeline, a selective M1/M4 muscarinic receptor agonist exclusively licensed from Lilly to Karuna Therapeutics, with trospium chloride, a muscarinic antagonist approved for more than a decade in the United States and Europe for treatment of overactive bladder. Xanomeline was synthesized in the 1990s. It showed promising evidence of antipsychotic efficacy in schizophrenia and Alzheimer’s disease in yearlong clinical trials totaling more than 800 patients, but interest in further developing the drug cooled because of limiting GI and other cholinergic adverse events. KarXT, Karuna’s lead product candidate, is designed to maintain the efficacy of xanomeline while trospium, which doesn’t cross the blood-brain barrier, cancels out its side effects, explained Stephen Brannan, MD, a psychiatrist and chief medical officer at the company.

He presented the results of the phase 2 study, a multicenter, randomized, double-blind, placebo-controlled, 5-week trial conducted with 182 schizophrenia inpatients experiencing an acute psychotic exacerbation. All other antipsychotics were washed out before randomization to KarXT at 50 mg xanomeline/20 mg trospium twice daily, titrated to 100/20 twice daily on days 3-7 and 100/20 b.i.d. thereafter, with an optional increase to 125/30 twice daily.

The primary study endpoint was change from baseline to week 5 in PANSS total score. The results were positive at the P < .0001 level, with a mean 17.4-point reduction in the KarXT group, compared with a 5.9-point improvement in placebo-treated controls. The between-group difference was significant by the first assessment at week 2.

Four of five prespecified secondary endpoints were also positive in rapid and sustained fashion: improvement in the PANSS positive subscore, PANSS negative subscore, Marder PANSS negative subscore, and Clinical Global Impressions-Severity. The fifth secondary endpoint – the proportion of patients with a Clinical Global Impressions rating of 1 or 2, meaning normal or only mildly mentally ill – wasn’t significantly different with KarXT, compared with placebo, but Dr. Brannan shrugged that off.

“In hindsight, it was probably a little overly optimistic to think that after 5 weeks [patients with schizophrenia] would be either well or almost well,” he quipped.

An exploratory analysis of participants’ before-and-after scores on a battery of six cognitive tests showed an encouraging trend: Patients on KarXT performed numerically better than did controls on five of the six tests, albeit not significantly so. Moreover, in a further analysis stratified by baseline impairment, patients in the most impaired tertile showed a larger, statistically significant benefit in response to KarXT.

“We’re interested enough that we plan to continue to look at this in our upcoming larger and longer-term trials,” Dr. Brannan said.

As for safety and tolerability, he continued: “We were pleasantly surprised. We certainly see more side effects with KarXT than with placebo, but not by that much, and they’re much, much better than with xanomeline alone.”

The side effects, mostly cholinergic and anticholinergic, occurred 2-4 times more frequently than in controls. Notably, the rates of nausea, vomiting, and dry mouth – three of the five most common treatment-related adverse events in patients on KarXT – decreased over time to levels similar to placebo by week 5. In contrast, rates of constipation and dyspepsia remained stable over time. All side effects were mild to moderate, and none led to study discontinuation.

A key point was that the KarXT-related side effects were not the same ones that are commonly problematic and limiting with current antipsychotics. There was no weight gain or other metabolic changes, sleepiness or sedation, or extrapyramidal symptoms.

“These results show KarXT has the potential to offer patients a novel mechanism-of-action antipsychotic with a different efficacy and/or tolerability profile than current antipsychotic medications,” Dr. Brannan said.

BI 425809

BI 425809 is a once-daily oral inhibitor of glycine transporter 1 (Gly-T1) specifically designed to alleviate cognitive impairment in people with schizophrenia. Underactivity by the NMDA (N-methyl-D-aspartic acid) receptor has been implicated in this cognitive dysfunction. Glycine is an NMDA cotransmitter. By blocking glutamatergic presynaptic and astrocyte reuptake of glycine, BI 425809 results in increased glycine levels in the synaptic cleft, facilitating neurotransmission, explained W. Wolfgang Fleischhacker, MD, president of the Medical University of Innsbruck (Austria), where he is also professor of psychiatry.

He presented the results of a phase 2, randomized, double-blind, 11-country study in which 509 adults with stable schizophrenia on no more than two antipsychotics were placed on add-on BI 425809 at 2, 5, 10, or 25 mg once daily or placebo for 12 weeks.

The primary endpoint was change from baseline to 12 weeks in the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB) score. The results were strongly positive, with patients on the two top doses of BI 425809 – 10 and 25 mg/day – showing roughly a 2-point greater improvement in MCCB overall composite T-score compared with controls. Dr. Fleischhacker drew attention to the high study completion rates in the various study arms, ranging from a low of 91% to 97.6% in the 25 mg/day group.

“That’s a very nice but also an unusual finding for a trial of this length,” he observed.

The high study completion rate was a reflection of the drug’s high-level tolerability. Indeed, the rate of adverse events leading to treatment discontinuation was 0% with BI 425809 at 10 mg/day, 2.4% at 25 mg/day, and identical at 2.4% with placebo. No increase was found in psychiatric adverse events such as suicidal ideation or behavior.

“This is a first very promising result,” Dr. Fleischhacker concluded. “Basically, this is the first study that has really shown in a convincing fashion an effect of any novel compound on cognitive impairment in people suffering from schizophrenia.”

A separate ongoing phase 2 study is evaluating BI 425809 in combination with adjunctive computerized cognitive training in an effort to increase cognitive stimulation. The company is awaiting those study results before designing its phase 3 program.
 

Pimavanserin

It has been a busy year for pimavanserin, with both successes and disappointments in clinical trials addressing a range of psychotic disorders, according to Dragana Bugarski-Kirola, MD, MBA, MSc, vice president for clinical development at Acadia Pharmaceuticals in San Diego.

At present, pimavanserin is Food and Drug Administration–approved as Nuplazid only for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But in July 2020, on the strength of the positive results of the pivotal phase 3 HARMONY trial, Acadia filed an application with the FDA for marketing approval of the drug for treatment of dementia-related psychosis. In HARMONY, patients on placebo proved to be 2.8-fold more likely to experience a relapse of delusions or hallucinations than with pimavanserin.

A big recent disappointment was that pimavanserin failed to meet its primary endpoint in the phase 3 CLARITY I and CLARITY II trials as adjunctive therapy for major depressive disorder inadequately responsive to a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor. The change in Hamilton Depression Rating Scale–17 scores in patients on the atypical antipsychotic wasn’t significantly better than with placebo. However, pimavanserin did outperform placebo on the secondary endpoint of Clinical Global Impression–Severity. Additional clinical trials of the drug for treatment of major depression are planned, Dr. Bugarski-Kirola said.
 

LY500307

Although schizophrenia is equally common in men and women, the disease has a later onset and more benign course in women. This suggests a possible protective effect of estrogen, and indeed, extensive literature supports the use of exogenous estrogen in schizophrenia, where it reduces relapses and improves cognitive impairment and negative symptoms.

“We have no other agents that do that,” noted Dr. Breier, also chief of the psychotic disorders program and director of the Prevention and Recovery Center at Indiana University.

What he considers the best-executed clinical trial of estradiol in schizophrenia, an 8-week, double-blind, randomized study of a 200-mcg estradiol patch or placebo in 200 women aged 19-46 on antipsychotics, was published last year (JAMA Psychiatry. 2019 Jul 31;76[10]:1-9).

The results were impressive. However, estrogen may not be a viable treatment for men and premenopausal women because of its side effects, including feminization, and increased thrombotic and malignancy risks.

This was the impetus for the placebo-controlled randomized trial of LY500307, a highly selective estrogen receptor beta agonist originally developed by Eli Lilly as a potential treatment for benign prostatic hypertrophy, for which it proved ineffective. In animal models, estrogen receptor beta is responsible for a range of effects, including enhanced cognition, social behavior, and an anxiolytic action, whereas the alpha receptor affects the sex organs, skeletal and metabolic homeostasis, and is responsible for estrogen’s problematic side effects.

All three doses studied in the phase 2 randomized trial, which included 94 men with schizophrenia, proved safe, well-tolerated – and ineffective.

“I think one potential conclusion one could consider from these data is that estrogen receptor alpha engagement may be necessary for the estrogenic therapeutics in schizophrenia,” Dr. Breier said.

He reported having no financial conflicts regarding the trial, funded by Indiana University. Outside the scope of the study, he serves as a consultant to Karuna Therapeutics, BioXcel, and Perception Neuroscience.

Dr. Fleischhacker serves as a consultant to Boehringer Ingelheim, which sponsored the phase 2 study of BI 425809, as well as to Angelini, Richter, and Recordati.
 

bjancin@mdedge.com

SOURCE: ECNP 2020, Session S.12.

Two oral agents with novel mechanisms of action in schizophrenia generated considerable audience interest after acing large phase 2 clinical trials presented at the virtual congress of the European College of Neuropsychopharmacology.

The two successful drugs moving on to definitive phase 3 studies after their performance at ECNP 2020 are KarXT, a proprietary combination of xanomeline and trospium chloride, and an inhibitor of glycine transporter 1 (Gly-T1) known for now as BI 425809.

Pimavanserin, an oral selective serotonin inverse agonist with a high affinity for 5-HT2A receptors and low affinity for 5-HT2C receptors, has taken a more convoluted path through the developmental pipeline for schizophrenia. It recently failed to outperform placebo as adjunctive treatment for schizophrenia on the primary endpoint of improvement in Positive And Negative Syndrome Scale (PANSS) total score in the 6-week, phase 3 ENHANCE (Efficacy and Safety of Adjunctive Pimavanserin for the Treatment of Schizophrenia) study. The drug did, however, show significant benefit on secondary endpoints involving negative symptoms.

And in the 400-patient, 26-week, placebo-controlled, phase 2 ADVANCE trial, adjunctive pimavanserin was positive for the primary endpoint of improvement in the Negative Symptom Assessment-16 (NSA-16) score. A phase 3 program evaluating the drug specifically for negative symptoms is underway.

Another novel therapy, an investigational selective estrogen receptor beta agonist, proved reassuringly safe but completely ineffective in men with schizophrenia in a study presented at ECNP 2020.

“The results, unfortunately, were disappointing. We saw no signal on cognition, no change on brain imaging with fMRI, and no improvement in negative symptoms or PANSS total score,” reported Alan Breier, MD, professor and vice chair of the department of psychiatry at Indiana University in Indianapolis.

KarXT

KarXT combines xanomeline, a selective M1/M4 muscarinic receptor agonist exclusively licensed from Lilly to Karuna Therapeutics, with trospium chloride, a muscarinic antagonist approved for more than a decade in the United States and Europe for treatment of overactive bladder. Xanomeline was synthesized in the 1990s. It showed promising evidence of antipsychotic efficacy in schizophrenia and Alzheimer’s disease in yearlong clinical trials totaling more than 800 patients, but interest in further developing the drug cooled because of limiting GI and other cholinergic adverse events. KarXT, Karuna’s lead product candidate, is designed to maintain the efficacy of xanomeline while trospium, which doesn’t cross the blood-brain barrier, cancels out its side effects, explained Stephen Brannan, MD, a psychiatrist and chief medical officer at the company.

He presented the results of the phase 2 study, a multicenter, randomized, double-blind, placebo-controlled, 5-week trial conducted with 182 schizophrenia inpatients experiencing an acute psychotic exacerbation. All other antipsychotics were washed out before randomization to KarXT at 50 mg xanomeline/20 mg trospium twice daily, titrated to 100/20 twice daily on days 3-7 and 100/20 b.i.d. thereafter, with an optional increase to 125/30 twice daily.

The primary study endpoint was change from baseline to week 5 in PANSS total score. The results were positive at the P < .0001 level, with a mean 17.4-point reduction in the KarXT group, compared with a 5.9-point improvement in placebo-treated controls. The between-group difference was significant by the first assessment at week 2.

Four of five prespecified secondary endpoints were also positive in rapid and sustained fashion: improvement in the PANSS positive subscore, PANSS negative subscore, Marder PANSS negative subscore, and Clinical Global Impressions-Severity. The fifth secondary endpoint – the proportion of patients with a Clinical Global Impressions rating of 1 or 2, meaning normal or only mildly mentally ill – wasn’t significantly different with KarXT, compared with placebo, but Dr. Brannan shrugged that off.

“In hindsight, it was probably a little overly optimistic to think that after 5 weeks [patients with schizophrenia] would be either well or almost well,” he quipped.

An exploratory analysis of participants’ before-and-after scores on a battery of six cognitive tests showed an encouraging trend: Patients on KarXT performed numerically better than did controls on five of the six tests, albeit not significantly so. Moreover, in a further analysis stratified by baseline impairment, patients in the most impaired tertile showed a larger, statistically significant benefit in response to KarXT.

“We’re interested enough that we plan to continue to look at this in our upcoming larger and longer-term trials,” Dr. Brannan said.

As for safety and tolerability, he continued: “We were pleasantly surprised. We certainly see more side effects with KarXT than with placebo, but not by that much, and they’re much, much better than with xanomeline alone.”

The side effects, mostly cholinergic and anticholinergic, occurred 2-4 times more frequently than in controls. Notably, the rates of nausea, vomiting, and dry mouth – three of the five most common treatment-related adverse events in patients on KarXT – decreased over time to levels similar to placebo by week 5. In contrast, rates of constipation and dyspepsia remained stable over time. All side effects were mild to moderate, and none led to study discontinuation.

A key point was that the KarXT-related side effects were not the same ones that are commonly problematic and limiting with current antipsychotics. There was no weight gain or other metabolic changes, sleepiness or sedation, or extrapyramidal symptoms.

“These results show KarXT has the potential to offer patients a novel mechanism-of-action antipsychotic with a different efficacy and/or tolerability profile than current antipsychotic medications,” Dr. Brannan said.

BI 425809

BI 425809 is a once-daily oral inhibitor of glycine transporter 1 (Gly-T1) specifically designed to alleviate cognitive impairment in people with schizophrenia. Underactivity by the NMDA (N-methyl-D-aspartic acid) receptor has been implicated in this cognitive dysfunction. Glycine is an NMDA cotransmitter. By blocking glutamatergic presynaptic and astrocyte reuptake of glycine, BI 425809 results in increased glycine levels in the synaptic cleft, facilitating neurotransmission, explained W. Wolfgang Fleischhacker, MD, president of the Medical University of Innsbruck (Austria), where he is also professor of psychiatry.

He presented the results of a phase 2, randomized, double-blind, 11-country study in which 509 adults with stable schizophrenia on no more than two antipsychotics were placed on add-on BI 425809 at 2, 5, 10, or 25 mg once daily or placebo for 12 weeks.

The primary endpoint was change from baseline to 12 weeks in the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB) score. The results were strongly positive, with patients on the two top doses of BI 425809 – 10 and 25 mg/day – showing roughly a 2-point greater improvement in MCCB overall composite T-score compared with controls. Dr. Fleischhacker drew attention to the high study completion rates in the various study arms, ranging from a low of 91% to 97.6% in the 25 mg/day group.

“That’s a very nice but also an unusual finding for a trial of this length,” he observed.

The high study completion rate was a reflection of the drug’s high-level tolerability. Indeed, the rate of adverse events leading to treatment discontinuation was 0% with BI 425809 at 10 mg/day, 2.4% at 25 mg/day, and identical at 2.4% with placebo. No increase was found in psychiatric adverse events such as suicidal ideation or behavior.

“This is a first very promising result,” Dr. Fleischhacker concluded. “Basically, this is the first study that has really shown in a convincing fashion an effect of any novel compound on cognitive impairment in people suffering from schizophrenia.”

A separate ongoing phase 2 study is evaluating BI 425809 in combination with adjunctive computerized cognitive training in an effort to increase cognitive stimulation. The company is awaiting those study results before designing its phase 3 program.
 

Pimavanserin

It has been a busy year for pimavanserin, with both successes and disappointments in clinical trials addressing a range of psychotic disorders, according to Dragana Bugarski-Kirola, MD, MBA, MSc, vice president for clinical development at Acadia Pharmaceuticals in San Diego.

At present, pimavanserin is Food and Drug Administration–approved as Nuplazid only for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But in July 2020, on the strength of the positive results of the pivotal phase 3 HARMONY trial, Acadia filed an application with the FDA for marketing approval of the drug for treatment of dementia-related psychosis. In HARMONY, patients on placebo proved to be 2.8-fold more likely to experience a relapse of delusions or hallucinations than with pimavanserin.

A big recent disappointment was that pimavanserin failed to meet its primary endpoint in the phase 3 CLARITY I and CLARITY II trials as adjunctive therapy for major depressive disorder inadequately responsive to a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor. The change in Hamilton Depression Rating Scale–17 scores in patients on the atypical antipsychotic wasn’t significantly better than with placebo. However, pimavanserin did outperform placebo on the secondary endpoint of Clinical Global Impression–Severity. Additional clinical trials of the drug for treatment of major depression are planned, Dr. Bugarski-Kirola said.
 

LY500307

Although schizophrenia is equally common in men and women, the disease has a later onset and more benign course in women. This suggests a possible protective effect of estrogen, and indeed, extensive literature supports the use of exogenous estrogen in schizophrenia, where it reduces relapses and improves cognitive impairment and negative symptoms.

“We have no other agents that do that,” noted Dr. Breier, also chief of the psychotic disorders program and director of the Prevention and Recovery Center at Indiana University.

What he considers the best-executed clinical trial of estradiol in schizophrenia, an 8-week, double-blind, randomized study of a 200-mcg estradiol patch or placebo in 200 women aged 19-46 on antipsychotics, was published last year (JAMA Psychiatry. 2019 Jul 31;76[10]:1-9).

The results were impressive. However, estrogen may not be a viable treatment for men and premenopausal women because of its side effects, including feminization, and increased thrombotic and malignancy risks.

This was the impetus for the placebo-controlled randomized trial of LY500307, a highly selective estrogen receptor beta agonist originally developed by Eli Lilly as a potential treatment for benign prostatic hypertrophy, for which it proved ineffective. In animal models, estrogen receptor beta is responsible for a range of effects, including enhanced cognition, social behavior, and an anxiolytic action, whereas the alpha receptor affects the sex organs, skeletal and metabolic homeostasis, and is responsible for estrogen’s problematic side effects.

All three doses studied in the phase 2 randomized trial, which included 94 men with schizophrenia, proved safe, well-tolerated – and ineffective.

“I think one potential conclusion one could consider from these data is that estrogen receptor alpha engagement may be necessary for the estrogenic therapeutics in schizophrenia,” Dr. Breier said.

He reported having no financial conflicts regarding the trial, funded by Indiana University. Outside the scope of the study, he serves as a consultant to Karuna Therapeutics, BioXcel, and Perception Neuroscience.

Dr. Fleischhacker serves as a consultant to Boehringer Ingelheim, which sponsored the phase 2 study of BI 425809, as well as to Angelini, Richter, and Recordati.
 

bjancin@mdedge.com

SOURCE: ECNP 2020, Session S.12.

Two oral agents with novel mechanisms of action in schizophrenia generated considerable audience interest after acing large phase 2 clinical trials presented at the virtual congress of the European College of Neuropsychopharmacology.

The two successful drugs moving on to definitive phase 3 studies after their performance at ECNP 2020 are KarXT, a proprietary combination of xanomeline and trospium chloride, and an inhibitor of glycine transporter 1 (Gly-T1) known for now as BI 425809.

Pimavanserin, an oral selective serotonin inverse agonist with a high affinity for 5-HT2A receptors and low affinity for 5-HT2C receptors, has taken a more convoluted path through the developmental pipeline for schizophrenia. It recently failed to outperform placebo as adjunctive treatment for schizophrenia on the primary endpoint of improvement in Positive And Negative Syndrome Scale (PANSS) total score in the 6-week, phase 3 ENHANCE (Efficacy and Safety of Adjunctive Pimavanserin for the Treatment of Schizophrenia) study. The drug did, however, show significant benefit on secondary endpoints involving negative symptoms.

And in the 400-patient, 26-week, placebo-controlled, phase 2 ADVANCE trial, adjunctive pimavanserin was positive for the primary endpoint of improvement in the Negative Symptom Assessment-16 (NSA-16) score. A phase 3 program evaluating the drug specifically for negative symptoms is underway.

Another novel therapy, an investigational selective estrogen receptor beta agonist, proved reassuringly safe but completely ineffective in men with schizophrenia in a study presented at ECNP 2020.

“The results, unfortunately, were disappointing. We saw no signal on cognition, no change on brain imaging with fMRI, and no improvement in negative symptoms or PANSS total score,” reported Alan Breier, MD, professor and vice chair of the department of psychiatry at Indiana University in Indianapolis.

KarXT

KarXT combines xanomeline, a selective M1/M4 muscarinic receptor agonist exclusively licensed from Lilly to Karuna Therapeutics, with trospium chloride, a muscarinic antagonist approved for more than a decade in the United States and Europe for treatment of overactive bladder. Xanomeline was synthesized in the 1990s. It showed promising evidence of antipsychotic efficacy in schizophrenia and Alzheimer’s disease in yearlong clinical trials totaling more than 800 patients, but interest in further developing the drug cooled because of limiting GI and other cholinergic adverse events. KarXT, Karuna’s lead product candidate, is designed to maintain the efficacy of xanomeline while trospium, which doesn’t cross the blood-brain barrier, cancels out its side effects, explained Stephen Brannan, MD, a psychiatrist and chief medical officer at the company.

He presented the results of the phase 2 study, a multicenter, randomized, double-blind, placebo-controlled, 5-week trial conducted with 182 schizophrenia inpatients experiencing an acute psychotic exacerbation. All other antipsychotics were washed out before randomization to KarXT at 50 mg xanomeline/20 mg trospium twice daily, titrated to 100/20 twice daily on days 3-7 and 100/20 b.i.d. thereafter, with an optional increase to 125/30 twice daily.

The primary study endpoint was change from baseline to week 5 in PANSS total score. The results were positive at the P < .0001 level, with a mean 17.4-point reduction in the KarXT group, compared with a 5.9-point improvement in placebo-treated controls. The between-group difference was significant by the first assessment at week 2.

Four of five prespecified secondary endpoints were also positive in rapid and sustained fashion: improvement in the PANSS positive subscore, PANSS negative subscore, Marder PANSS negative subscore, and Clinical Global Impressions-Severity. The fifth secondary endpoint – the proportion of patients with a Clinical Global Impressions rating of 1 or 2, meaning normal or only mildly mentally ill – wasn’t significantly different with KarXT, compared with placebo, but Dr. Brannan shrugged that off.

“In hindsight, it was probably a little overly optimistic to think that after 5 weeks [patients with schizophrenia] would be either well or almost well,” he quipped.

An exploratory analysis of participants’ before-and-after scores on a battery of six cognitive tests showed an encouraging trend: Patients on KarXT performed numerically better than did controls on five of the six tests, albeit not significantly so. Moreover, in a further analysis stratified by baseline impairment, patients in the most impaired tertile showed a larger, statistically significant benefit in response to KarXT.

“We’re interested enough that we plan to continue to look at this in our upcoming larger and longer-term trials,” Dr. Brannan said.

As for safety and tolerability, he continued: “We were pleasantly surprised. We certainly see more side effects with KarXT than with placebo, but not by that much, and they’re much, much better than with xanomeline alone.”

The side effects, mostly cholinergic and anticholinergic, occurred 2-4 times more frequently than in controls. Notably, the rates of nausea, vomiting, and dry mouth – three of the five most common treatment-related adverse events in patients on KarXT – decreased over time to levels similar to placebo by week 5. In contrast, rates of constipation and dyspepsia remained stable over time. All side effects were mild to moderate, and none led to study discontinuation.

A key point was that the KarXT-related side effects were not the same ones that are commonly problematic and limiting with current antipsychotics. There was no weight gain or other metabolic changes, sleepiness or sedation, or extrapyramidal symptoms.

“These results show KarXT has the potential to offer patients a novel mechanism-of-action antipsychotic with a different efficacy and/or tolerability profile than current antipsychotic medications,” Dr. Brannan said.

BI 425809

BI 425809 is a once-daily oral inhibitor of glycine transporter 1 (Gly-T1) specifically designed to alleviate cognitive impairment in people with schizophrenia. Underactivity by the NMDA (N-methyl-D-aspartic acid) receptor has been implicated in this cognitive dysfunction. Glycine is an NMDA cotransmitter. By blocking glutamatergic presynaptic and astrocyte reuptake of glycine, BI 425809 results in increased glycine levels in the synaptic cleft, facilitating neurotransmission, explained W. Wolfgang Fleischhacker, MD, president of the Medical University of Innsbruck (Austria), where he is also professor of psychiatry.

He presented the results of a phase 2, randomized, double-blind, 11-country study in which 509 adults with stable schizophrenia on no more than two antipsychotics were placed on add-on BI 425809 at 2, 5, 10, or 25 mg once daily or placebo for 12 weeks.

The primary endpoint was change from baseline to 12 weeks in the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB) score. The results were strongly positive, with patients on the two top doses of BI 425809 – 10 and 25 mg/day – showing roughly a 2-point greater improvement in MCCB overall composite T-score compared with controls. Dr. Fleischhacker drew attention to the high study completion rates in the various study arms, ranging from a low of 91% to 97.6% in the 25 mg/day group.

“That’s a very nice but also an unusual finding for a trial of this length,” he observed.

The high study completion rate was a reflection of the drug’s high-level tolerability. Indeed, the rate of adverse events leading to treatment discontinuation was 0% with BI 425809 at 10 mg/day, 2.4% at 25 mg/day, and identical at 2.4% with placebo. No increase was found in psychiatric adverse events such as suicidal ideation or behavior.

“This is a first very promising result,” Dr. Fleischhacker concluded. “Basically, this is the first study that has really shown in a convincing fashion an effect of any novel compound on cognitive impairment in people suffering from schizophrenia.”

A separate ongoing phase 2 study is evaluating BI 425809 in combination with adjunctive computerized cognitive training in an effort to increase cognitive stimulation. The company is awaiting those study results before designing its phase 3 program.
 

Pimavanserin

It has been a busy year for pimavanserin, with both successes and disappointments in clinical trials addressing a range of psychotic disorders, according to Dragana Bugarski-Kirola, MD, MBA, MSc, vice president for clinical development at Acadia Pharmaceuticals in San Diego.

At present, pimavanserin is Food and Drug Administration–approved as Nuplazid only for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But in July 2020, on the strength of the positive results of the pivotal phase 3 HARMONY trial, Acadia filed an application with the FDA for marketing approval of the drug for treatment of dementia-related psychosis. In HARMONY, patients on placebo proved to be 2.8-fold more likely to experience a relapse of delusions or hallucinations than with pimavanserin.

A big recent disappointment was that pimavanserin failed to meet its primary endpoint in the phase 3 CLARITY I and CLARITY II trials as adjunctive therapy for major depressive disorder inadequately responsive to a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor. The change in Hamilton Depression Rating Scale–17 scores in patients on the atypical antipsychotic wasn’t significantly better than with placebo. However, pimavanserin did outperform placebo on the secondary endpoint of Clinical Global Impression–Severity. Additional clinical trials of the drug for treatment of major depression are planned, Dr. Bugarski-Kirola said.
 

LY500307

Although schizophrenia is equally common in men and women, the disease has a later onset and more benign course in women. This suggests a possible protective effect of estrogen, and indeed, extensive literature supports the use of exogenous estrogen in schizophrenia, where it reduces relapses and improves cognitive impairment and negative symptoms.

“We have no other agents that do that,” noted Dr. Breier, also chief of the psychotic disorders program and director of the Prevention and Recovery Center at Indiana University.

What he considers the best-executed clinical trial of estradiol in schizophrenia, an 8-week, double-blind, randomized study of a 200-mcg estradiol patch or placebo in 200 women aged 19-46 on antipsychotics, was published last year (JAMA Psychiatry. 2019 Jul 31;76[10]:1-9).

The results were impressive. However, estrogen may not be a viable treatment for men and premenopausal women because of its side effects, including feminization, and increased thrombotic and malignancy risks.

This was the impetus for the placebo-controlled randomized trial of LY500307, a highly selective estrogen receptor beta agonist originally developed by Eli Lilly as a potential treatment for benign prostatic hypertrophy, for which it proved ineffective. In animal models, estrogen receptor beta is responsible for a range of effects, including enhanced cognition, social behavior, and an anxiolytic action, whereas the alpha receptor affects the sex organs, skeletal and metabolic homeostasis, and is responsible for estrogen’s problematic side effects.

All three doses studied in the phase 2 randomized trial, which included 94 men with schizophrenia, proved safe, well-tolerated – and ineffective.

“I think one potential conclusion one could consider from these data is that estrogen receptor alpha engagement may be necessary for the estrogenic therapeutics in schizophrenia,” Dr. Breier said.

He reported having no financial conflicts regarding the trial, funded by Indiana University. Outside the scope of the study, he serves as a consultant to Karuna Therapeutics, BioXcel, and Perception Neuroscience.

Dr. Fleischhacker serves as a consultant to Boehringer Ingelheim, which sponsored the phase 2 study of BI 425809, as well as to Angelini, Richter, and Recordati.
 

bjancin@mdedge.com

SOURCE: ECNP 2020, Session S.12.

The disinhibited binge eating style often seen in individuals with high ADHD symptoms is attributable to a heightened neural reward response to food rather than to the impulsivity that’s a core feature of ADHD, Elizabeth Martin, MSc, reported at the virtual congress of the European College of Neuropsychopharmacology.

She presented a functional MRI brain-imaging study designed to help pin down the mechanism involved in the disordered eating patterns that often accompany ADHD.

“Determining the underlying mechanism between binge eating and ADHD may be helpful in developing novel therapies for both ADHD and binge eating disorder. Our research suggests that further investigation of the role of altered reward processing in ADHD may be an avenue for this,” said Ms. Martin, a doctoral researcher in the department of psychology at the University of Birmingham (England).

She and her coinvestigators recruited 31 university student volunteers with high ADHD symptoms as evidenced by their mean score of 29.3 on the 0-54 Conners’ Adult ADHD Rating Scale, and 27 others with low ADHD symptoms and a mean Conners’ score of 6.8. The two groups didn’t differ in age or BMI. However, not surprisingly, the high-ADHD group exhibited greater impulsivity, with a mean score of 72 on the Barratt Impulsiveness Scale, versus 56.5 in the low ADHD group.

A battery of eating disorder scales was applied to assess participants in terms of binge/disinhibited or restrictive eating patterns. The high- and low–ADHD symptom groups didn’t differ in terms of prevalence of a restrictive eating style, which was low, but the high-ADHD participants scored on average roughly 50% higher on the binge/disinhibited eating style measure, compared with the low-ADHD group.

Each study participant underwent a 1-hour BOLD (blood oxygen level dependent) functional MRI scan while performing two sets of tasks. One task entailed quickly looking at 120 photos of food items and an equal number of nonfood items and rating how appealing the pictures were. The other challenge was what psychologists call a go/no-go task, a computerized cognitive test used to assess inhibitory control based upon reaction times and error rates.

On the go/no-go task, there were no between-group differences in rates of errors of omission or commission or reaction time. Moreover, the MRI results indicated there were no between-group differences in neural circuitry activation during this task. The investigators therefore concluded that the tendency toward binge eating in the high–ADHD symptoms group was not tied to greater impulsivity as reflected in less effective inhibitory processes.

The food picture rating task told a different story. The MRIs demonstrated increased responses to food versus nonfood images in the high-ADHD subjects, compared with the low-ADHD subjects in reward-related brain areas, including the ventromedial prefrontal cortex, caudate nucleus, and ventral tegmental area.

“This is the first evidence that ADHD symptoms in young adults are associated with enhanced neural activation in key reward-related brain areas in response to viewing food pictures,” according to Ms. Martin. “This suggests that enhanced responsiveness to food cues may be a mediating mechanism underlying overeating in ADHD.”

Of note, only one drug – lisdexamfetamine dimesylate (Vyvanse) is Food and Drug Administration-approved for the treatment of both ADHD and binge-eating disorder.

“Until now it’s been unclear how lisdexamfetamine dimesylate reduces binge eating, but our results suggest that one mechanism worthy of further investigation is the potential effect of the drug on food reward processes,” Ms. Martin said.

She reported having no financial conflicts regarding the study, which was supported by university funding.

bjancin@mdedge.com

SOURCE: Martin E. ECNP 2020. Abstr. P.041.

The disinhibited binge eating style often seen in individuals with high ADHD symptoms is attributable to a heightened neural reward response to food rather than to the impulsivity that’s a core feature of ADHD, Elizabeth Martin, MSc, reported at the virtual congress of the European College of Neuropsychopharmacology.

She presented a functional MRI brain-imaging study designed to help pin down the mechanism involved in the disordered eating patterns that often accompany ADHD.

“Determining the underlying mechanism between binge eating and ADHD may be helpful in developing novel therapies for both ADHD and binge eating disorder. Our research suggests that further investigation of the role of altered reward processing in ADHD may be an avenue for this,” said Ms. Martin, a doctoral researcher in the department of psychology at the University of Birmingham (England).

She and her coinvestigators recruited 31 university student volunteers with high ADHD symptoms as evidenced by their mean score of 29.3 on the 0-54 Conners’ Adult ADHD Rating Scale, and 27 others with low ADHD symptoms and a mean Conners’ score of 6.8. The two groups didn’t differ in age or BMI. However, not surprisingly, the high-ADHD group exhibited greater impulsivity, with a mean score of 72 on the Barratt Impulsiveness Scale, versus 56.5 in the low ADHD group.

A battery of eating disorder scales was applied to assess participants in terms of binge/disinhibited or restrictive eating patterns. The high- and low–ADHD symptom groups didn’t differ in terms of prevalence of a restrictive eating style, which was low, but the high-ADHD participants scored on average roughly 50% higher on the binge/disinhibited eating style measure, compared with the low-ADHD group.

Each study participant underwent a 1-hour BOLD (blood oxygen level dependent) functional MRI scan while performing two sets of tasks. One task entailed quickly looking at 120 photos of food items and an equal number of nonfood items and rating how appealing the pictures were. The other challenge was what psychologists call a go/no-go task, a computerized cognitive test used to assess inhibitory control based upon reaction times and error rates.

On the go/no-go task, there were no between-group differences in rates of errors of omission or commission or reaction time. Moreover, the MRI results indicated there were no between-group differences in neural circuitry activation during this task. The investigators therefore concluded that the tendency toward binge eating in the high–ADHD symptoms group was not tied to greater impulsivity as reflected in less effective inhibitory processes.

The food picture rating task told a different story. The MRIs demonstrated increased responses to food versus nonfood images in the high-ADHD subjects, compared with the low-ADHD subjects in reward-related brain areas, including the ventromedial prefrontal cortex, caudate nucleus, and ventral tegmental area.

“This is the first evidence that ADHD symptoms in young adults are associated with enhanced neural activation in key reward-related brain areas in response to viewing food pictures,” according to Ms. Martin. “This suggests that enhanced responsiveness to food cues may be a mediating mechanism underlying overeating in ADHD.”

Of note, only one drug – lisdexamfetamine dimesylate (Vyvanse) is Food and Drug Administration-approved for the treatment of both ADHD and binge-eating disorder.

“Until now it’s been unclear how lisdexamfetamine dimesylate reduces binge eating, but our results suggest that one mechanism worthy of further investigation is the potential effect of the drug on food reward processes,” Ms. Martin said.

She reported having no financial conflicts regarding the study, which was supported by university funding.

bjancin@mdedge.com

SOURCE: Martin E. ECNP 2020. Abstr. P.041.

The disinhibited binge eating style often seen in individuals with high ADHD symptoms is attributable to a heightened neural reward response to food rather than to the impulsivity that’s a core feature of ADHD, Elizabeth Martin, MSc, reported at the virtual congress of the European College of Neuropsychopharmacology.

She presented a functional MRI brain-imaging study designed to help pin down the mechanism involved in the disordered eating patterns that often accompany ADHD.

“Determining the underlying mechanism between binge eating and ADHD may be helpful in developing novel therapies for both ADHD and binge eating disorder. Our research suggests that further investigation of the role of altered reward processing in ADHD may be an avenue for this,” said Ms. Martin, a doctoral researcher in the department of psychology at the University of Birmingham (England).

She and her coinvestigators recruited 31 university student volunteers with high ADHD symptoms as evidenced by their mean score of 29.3 on the 0-54 Conners’ Adult ADHD Rating Scale, and 27 others with low ADHD symptoms and a mean Conners’ score of 6.8. The two groups didn’t differ in age or BMI. However, not surprisingly, the high-ADHD group exhibited greater impulsivity, with a mean score of 72 on the Barratt Impulsiveness Scale, versus 56.5 in the low ADHD group.

A battery of eating disorder scales was applied to assess participants in terms of binge/disinhibited or restrictive eating patterns. The high- and low–ADHD symptom groups didn’t differ in terms of prevalence of a restrictive eating style, which was low, but the high-ADHD participants scored on average roughly 50% higher on the binge/disinhibited eating style measure, compared with the low-ADHD group.

Each study participant underwent a 1-hour BOLD (blood oxygen level dependent) functional MRI scan while performing two sets of tasks. One task entailed quickly looking at 120 photos of food items and an equal number of nonfood items and rating how appealing the pictures were. The other challenge was what psychologists call a go/no-go task, a computerized cognitive test used to assess inhibitory control based upon reaction times and error rates.

On the go/no-go task, there were no between-group differences in rates of errors of omission or commission or reaction time. Moreover, the MRI results indicated there were no between-group differences in neural circuitry activation during this task. The investigators therefore concluded that the tendency toward binge eating in the high–ADHD symptoms group was not tied to greater impulsivity as reflected in less effective inhibitory processes.

The food picture rating task told a different story. The MRIs demonstrated increased responses to food versus nonfood images in the high-ADHD subjects, compared with the low-ADHD subjects in reward-related brain areas, including the ventromedial prefrontal cortex, caudate nucleus, and ventral tegmental area.

“This is the first evidence that ADHD symptoms in young adults are associated with enhanced neural activation in key reward-related brain areas in response to viewing food pictures,” according to Ms. Martin. “This suggests that enhanced responsiveness to food cues may be a mediating mechanism underlying overeating in ADHD.”

Of note, only one drug – lisdexamfetamine dimesylate (Vyvanse) is Food and Drug Administration-approved for the treatment of both ADHD and binge-eating disorder.

“Until now it’s been unclear how lisdexamfetamine dimesylate reduces binge eating, but our results suggest that one mechanism worthy of further investigation is the potential effect of the drug on food reward processes,” Ms. Martin said.

She reported having no financial conflicts regarding the study, which was supported by university funding.

bjancin@mdedge.com

SOURCE: Martin E. ECNP 2020. Abstr. P.041.

Suicidality appears to have increased sharply in Israel during the initial nationwide lockdown implemented in response to the COVID-19 pandemic, Gil Zalsman, MD, MHA, reported at the virtual congress of the European College of Neuropsychopharmacology.

He presented highlights from a soon-to-be-published analysis of the content of online chat sessions fielded by a national crisis hotline (Sahar.org.il) during the first 6 months of 2020, compared with January through June 2019, in the pre-COVID-19 era.

It’s far too early to say whether actual deaths tied to suicide rose significantly during the spring lockdown, since medical examiners often take a long time before ruling suicide as cause of death. But this much is clear: The number of suicide-related chat sessions recorded at the volunteer-staffed national hotline during April 2020 was two-and-a-half times greater than in April 2019, and threefold greater in May 2020 than a year earlier, according to Dr. Zalsman, professor of psychiatry at Tel Aviv University and director of the Geha Mental Health Center in Petach Tikva, Israel, where he also directs an adolescent day unit.

The proportion of chats handled at the crisis hotline, many of them concerned with the standard topics – relationships, stress, fears, anxiety, and other non–suicide-related issues – was 48% greater in the first half of 2020, compared with a year earlier. Indeed, the pandemic is putting an enormous strain on crisis hotlines the world over.

“Everybody who is working hotlines knows that they’re falling apart. There are too many calls, too many chats. They need to multiply their volunteers,” Dr. Zalsman said.

The number of suicide-related online chats jumped the week of March 12, when schools closed across Israel and a partial lockdown began. The peak in suicide-related chats occurred beginning the week of April 17, when the forced total lockdown was declared.

“Everything was closed. You couldn’t go out or the police would arrest you,” Dr. Zalsman recalled.

The suicide-related chat count started to drop off in mid-May, when schools reopened, and continued to decline through the end of June.

Only a small percentage of suicide-related chats were deemed by crisis hotline volunteers and their supervisors to be truly life-threatening situations necessitating a call to the police. But the number of such exchanges was significantly greater in April and May 2020 than in January and February, or in April and May 2019.

Use of the crisis hotline is ordinarily skewed toward tech-savvy young people, or as Dr. Zalsman called them, “kids who live inside their computers.” He note that the psychological impact of the pandemic on children and adolescents is largely unexplored research territory to date.

“For some young kids, the fear that they will contaminate their parents or grandparents is horrifying. You can kill your grandfather by coughing,” Dr. Zalsman said.
 

Older people also seek help

A finding that he and his coinvestigators didn’t anticipate was the significantly increased use of the service by individuals aged 65 and older during the pandemic. This underscores the increased vulnerability of older people, which stems in part from their heightened risk for severe infection and consequent need for prolonged physical isolation, he said.

The conventional thinking among suicidologists is that during times of crisis – wars, natural disasters – suicidality plunges, then rises quickly afterward.

“People withhold themselves. When there’s a big danger from outside they ignore the danger from inside. And once the danger from outside is gone, they’re left with emptiness, unemployment, economic crisis, and they start” taking their own lives, Dr. Zalsman explained. He expects suicidality to increase after the pandemic, or as the Israeli crisis hotline data suggest, perhaps even during it, for multiple reasons. Patients with preexisting psychiatric disorders are often going untreated. The prolonged physical isolation causes emotional difficulties for some people, especially when accompanied by social isolation and loneliness. There is grief over the loss of friends and relatives because of COVID-19. And there is an expectation of looming economic hardship, with mounting unemployment and bankruptcies.

Dr. Zalsman reported having no financial conflicts regarding his study, conducted free of commercial support.

bjancin@mdedge.com

SOURCE: Zalsman G. ECNP 2020, Session TP.06.

Suicidality appears to have increased sharply in Israel during the initial nationwide lockdown implemented in response to the COVID-19 pandemic, Gil Zalsman, MD, MHA, reported at the virtual congress of the European College of Neuropsychopharmacology.

He presented highlights from a soon-to-be-published analysis of the content of online chat sessions fielded by a national crisis hotline (Sahar.org.il) during the first 6 months of 2020, compared with January through June 2019, in the pre-COVID-19 era.

It’s far too early to say whether actual deaths tied to suicide rose significantly during the spring lockdown, since medical examiners often take a long time before ruling suicide as cause of death. But this much is clear: The number of suicide-related chat sessions recorded at the volunteer-staffed national hotline during April 2020 was two-and-a-half times greater than in April 2019, and threefold greater in May 2020 than a year earlier, according to Dr. Zalsman, professor of psychiatry at Tel Aviv University and director of the Geha Mental Health Center in Petach Tikva, Israel, where he also directs an adolescent day unit.

The proportion of chats handled at the crisis hotline, many of them concerned with the standard topics – relationships, stress, fears, anxiety, and other non–suicide-related issues – was 48% greater in the first half of 2020, compared with a year earlier. Indeed, the pandemic is putting an enormous strain on crisis hotlines the world over.

“Everybody who is working hotlines knows that they’re falling apart. There are too many calls, too many chats. They need to multiply their volunteers,” Dr. Zalsman said.

The number of suicide-related online chats jumped the week of March 12, when schools closed across Israel and a partial lockdown began. The peak in suicide-related chats occurred beginning the week of April 17, when the forced total lockdown was declared.

“Everything was closed. You couldn’t go out or the police would arrest you,” Dr. Zalsman recalled.

The suicide-related chat count started to drop off in mid-May, when schools reopened, and continued to decline through the end of June.

Only a small percentage of suicide-related chats were deemed by crisis hotline volunteers and their supervisors to be truly life-threatening situations necessitating a call to the police. But the number of such exchanges was significantly greater in April and May 2020 than in January and February, or in April and May 2019.

Use of the crisis hotline is ordinarily skewed toward tech-savvy young people, or as Dr. Zalsman called them, “kids who live inside their computers.” He note that the psychological impact of the pandemic on children and adolescents is largely unexplored research territory to date.

“For some young kids, the fear that they will contaminate their parents or grandparents is horrifying. You can kill your grandfather by coughing,” Dr. Zalsman said.
 

Older people also seek help

A finding that he and his coinvestigators didn’t anticipate was the significantly increased use of the service by individuals aged 65 and older during the pandemic. This underscores the increased vulnerability of older people, which stems in part from their heightened risk for severe infection and consequent need for prolonged physical isolation, he said.

The conventional thinking among suicidologists is that during times of crisis – wars, natural disasters – suicidality plunges, then rises quickly afterward.

“People withhold themselves. When there’s a big danger from outside they ignore the danger from inside. And once the danger from outside is gone, they’re left with emptiness, unemployment, economic crisis, and they start” taking their own lives, Dr. Zalsman explained. He expects suicidality to increase after the pandemic, or as the Israeli crisis hotline data suggest, perhaps even during it, for multiple reasons. Patients with preexisting psychiatric disorders are often going untreated. The prolonged physical isolation causes emotional difficulties for some people, especially when accompanied by social isolation and loneliness. There is grief over the loss of friends and relatives because of COVID-19. And there is an expectation of looming economic hardship, with mounting unemployment and bankruptcies.

Dr. Zalsman reported having no financial conflicts regarding his study, conducted free of commercial support.

bjancin@mdedge.com

SOURCE: Zalsman G. ECNP 2020, Session TP.06.

Suicidality appears to have increased sharply in Israel during the initial nationwide lockdown implemented in response to the COVID-19 pandemic, Gil Zalsman, MD, MHA, reported at the virtual congress of the European College of Neuropsychopharmacology.

He presented highlights from a soon-to-be-published analysis of the content of online chat sessions fielded by a national crisis hotline (Sahar.org.il) during the first 6 months of 2020, compared with January through June 2019, in the pre-COVID-19 era.

It’s far too early to say whether actual deaths tied to suicide rose significantly during the spring lockdown, since medical examiners often take a long time before ruling suicide as cause of death. But this much is clear: The number of suicide-related chat sessions recorded at the volunteer-staffed national hotline during April 2020 was two-and-a-half times greater than in April 2019, and threefold greater in May 2020 than a year earlier, according to Dr. Zalsman, professor of psychiatry at Tel Aviv University and director of the Geha Mental Health Center in Petach Tikva, Israel, where he also directs an adolescent day unit.

The proportion of chats handled at the crisis hotline, many of them concerned with the standard topics – relationships, stress, fears, anxiety, and other non–suicide-related issues – was 48% greater in the first half of 2020, compared with a year earlier. Indeed, the pandemic is putting an enormous strain on crisis hotlines the world over.

“Everybody who is working hotlines knows that they’re falling apart. There are too many calls, too many chats. They need to multiply their volunteers,” Dr. Zalsman said.

The number of suicide-related online chats jumped the week of March 12, when schools closed across Israel and a partial lockdown began. The peak in suicide-related chats occurred beginning the week of April 17, when the forced total lockdown was declared.

“Everything was closed. You couldn’t go out or the police would arrest you,” Dr. Zalsman recalled.

The suicide-related chat count started to drop off in mid-May, when schools reopened, and continued to decline through the end of June.

Only a small percentage of suicide-related chats were deemed by crisis hotline volunteers and their supervisors to be truly life-threatening situations necessitating a call to the police. But the number of such exchanges was significantly greater in April and May 2020 than in January and February, or in April and May 2019.

Use of the crisis hotline is ordinarily skewed toward tech-savvy young people, or as Dr. Zalsman called them, “kids who live inside their computers.” He note that the psychological impact of the pandemic on children and adolescents is largely unexplored research territory to date.

“For some young kids, the fear that they will contaminate their parents or grandparents is horrifying. You can kill your grandfather by coughing,” Dr. Zalsman said.
 

Older people also seek help

A finding that he and his coinvestigators didn’t anticipate was the significantly increased use of the service by individuals aged 65 and older during the pandemic. This underscores the increased vulnerability of older people, which stems in part from their heightened risk for severe infection and consequent need for prolonged physical isolation, he said.

The conventional thinking among suicidologists is that during times of crisis – wars, natural disasters – suicidality plunges, then rises quickly afterward.

“People withhold themselves. When there’s a big danger from outside they ignore the danger from inside. And once the danger from outside is gone, they’re left with emptiness, unemployment, economic crisis, and they start” taking their own lives, Dr. Zalsman explained. He expects suicidality to increase after the pandemic, or as the Israeli crisis hotline data suggest, perhaps even during it, for multiple reasons. Patients with preexisting psychiatric disorders are often going untreated. The prolonged physical isolation causes emotional difficulties for some people, especially when accompanied by social isolation and loneliness. There is grief over the loss of friends and relatives because of COVID-19. And there is an expectation of looming economic hardship, with mounting unemployment and bankruptcies.

Dr. Zalsman reported having no financial conflicts regarding his study, conducted free of commercial support.

bjancin@mdedge.com

SOURCE: Zalsman G. ECNP 2020, Session TP.06.

Current American and European guidelines recommending long-term beta-blocker therapy following an acute MI appear to be obsolete in the modern reperfusion era, suggests an analysis of Danish registry data.

Those guidelines are based on old randomized trials of beta-blocker therapy conducted prior to introduction of routine percutaneous coronary intervention and modern multidrug optimal medical therapy for acute MI. There have been no prospective controlled studies in the reperfusion era. And a new Danish national observational study strongly suggests it’s time to reexamine the beta-blocker recommendation, Anders Holt, MD, said at the virtual annual congress of the European Society of Cardiology.

“Stable, optimally treated MI patients do not seem to benefit from beta-blocker treatment exceeding 3 months post hospitalization – bearing in mind this doesn’t apply to patients with other indications for beta-blockers, like heart failure or atrial fibrillation,” said Dr. Holt of Copenhagen University Hospital.

His analysis of Danish national registry data on more than 30,000 patients hospitalized for acute MI during 2003-2018 earned him the annual ESC Young Investigator Award in Population Science.

Frontline Medical News

“This was a crisp and clear presentation of a very creative use of observational epidemiology to try to understand the length of therapy that may or may not be appropriate,” commented award session cochair Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston.

Dr. Holt reported on 30,177 patients optimally treated for a first MI in Danish hospitals during 2003-2018, none of whom had a prior indication or contraindication for beta-blocker therapy. “Optimally treated” meant they underwent percutaneous coronary revascularization and were discharged on a statin and aspirin. As a study requirement, all had to be stable 90 days post hospitalization, at which point 24,770 of the patients were on long-term beta-blocker therapy, and 5,407 (18%) were not. The two groups were comparable in terms of age, sex, comorbidities, and baseline medications. All patients were followed through the registries for a maximum of 3 years, the duration of beta-blocker therapy post MI recommended in American Heart Association/American College of Cardiology guidelines. (The Danish Society of Cardiology recommends 2 years.)

At 3 years post MI, there was no between-group difference in a composite outcome comprising cardiovascular death, recurrent MI, heart failure, stroke, angina, or a cardiac procedure, with a rate of 22.9% in the beta-blocker group and 21.6% in patients not on long-term beta-blocker therapy. The rate of recurrent MI was identical at 6.7% in both groups. Cardiovascular death occurred during 3 years of follow-up in 1.4% of patients on beta-blocker therapy and 1.7% who weren’t, a nonsignificant difference.

“We saw no evidence of any cardioprotective effect, but no increased risk of adverse events resulting in hospitalization, either,” Dr. Holt observed. “I would like to acknowledge that no evidence of effect does not necessarily equal evidence of no effect, but even if there was an effect we can with fair certainty say that it’s probably quite minimal.”

He noted that the Danish registry data indicates that each year since 2012 has shown a growing trend for Danish patients to dispense with long-term beta-blocker therapy after an acute MI.

“This might indicate we are nudging toward a change in practice, where more physicians are thinking that long-term beta-blocker therapy might not be indicated for all MI patients in the reperfusion era,” according to Dr. Holt.

Asked by the four-judge award panel about the possibility of unmeasured confounding in this observational study, Dr Holt responded: “I would be very cautious about asking patients to stop beta-blocker therapy after 3 months just based on this observational data. We can’t speak to causality in an observational study.” But he added that “well-designed observational studies provide valuable data regarding this topic and should not be ignored. They should possibly influence the guidelines and the designs for upcoming randomized trials.”

He conducted several supplementary analyses designed to address the possibility of unevenly distributed unmeasured confounding in the registry study. These analyses proved reassuring. A positive exposure control analysis compared 3-year outcomes in patients who remained on long-term statin therapy and those who didn’t. As expected, outcomes were significantly better in those who did: a 3-year composite outcome rate of 22.1%, compared with 32.1% in patients not on a statin; a cardiovascular death rate of 1.3% with and 2.1% without statin therapy; a recurrent MI rate of 6.6%, compared with 10.1% without a statin; and a 2.8% all-cause mortality with and 5.4% without statin therapy.

In contrast, all-cause mortality was unaffected by whether or not patients were on long-term beta-blocker therapy. And in a negative exposure outcome analysis, no association was found between beta-blocker therapy and the risk of hospitalization for pneumonia, as to be expected if the beta-blocker and no-beta-blocker groups were comparable in key respects.

Dr. Holt reported having no financial conflicts regarding his study.

bjancin@mdedge.com

Current American and European guidelines recommending long-term beta-blocker therapy following an acute MI appear to be obsolete in the modern reperfusion era, suggests an analysis of Danish registry data.

Those guidelines are based on old randomized trials of beta-blocker therapy conducted prior to introduction of routine percutaneous coronary intervention and modern multidrug optimal medical therapy for acute MI. There have been no prospective controlled studies in the reperfusion era. And a new Danish national observational study strongly suggests it’s time to reexamine the beta-blocker recommendation, Anders Holt, MD, said at the virtual annual congress of the European Society of Cardiology.

“Stable, optimally treated MI patients do not seem to benefit from beta-blocker treatment exceeding 3 months post hospitalization – bearing in mind this doesn’t apply to patients with other indications for beta-blockers, like heart failure or atrial fibrillation,” said Dr. Holt of Copenhagen University Hospital.

His analysis of Danish national registry data on more than 30,000 patients hospitalized for acute MI during 2003-2018 earned him the annual ESC Young Investigator Award in Population Science.

Frontline Medical News

“This was a crisp and clear presentation of a very creative use of observational epidemiology to try to understand the length of therapy that may or may not be appropriate,” commented award session cochair Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston.

Dr. Holt reported on 30,177 patients optimally treated for a first MI in Danish hospitals during 2003-2018, none of whom had a prior indication or contraindication for beta-blocker therapy. “Optimally treated” meant they underwent percutaneous coronary revascularization and were discharged on a statin and aspirin. As a study requirement, all had to be stable 90 days post hospitalization, at which point 24,770 of the patients were on long-term beta-blocker therapy, and 5,407 (18%) were not. The two groups were comparable in terms of age, sex, comorbidities, and baseline medications. All patients were followed through the registries for a maximum of 3 years, the duration of beta-blocker therapy post MI recommended in American Heart Association/American College of Cardiology guidelines. (The Danish Society of Cardiology recommends 2 years.)

At 3 years post MI, there was no between-group difference in a composite outcome comprising cardiovascular death, recurrent MI, heart failure, stroke, angina, or a cardiac procedure, with a rate of 22.9% in the beta-blocker group and 21.6% in patients not on long-term beta-blocker therapy. The rate of recurrent MI was identical at 6.7% in both groups. Cardiovascular death occurred during 3 years of follow-up in 1.4% of patients on beta-blocker therapy and 1.7% who weren’t, a nonsignificant difference.

“We saw no evidence of any cardioprotective effect, but no increased risk of adverse events resulting in hospitalization, either,” Dr. Holt observed. “I would like to acknowledge that no evidence of effect does not necessarily equal evidence of no effect, but even if there was an effect we can with fair certainty say that it’s probably quite minimal.”

He noted that the Danish registry data indicates that each year since 2012 has shown a growing trend for Danish patients to dispense with long-term beta-blocker therapy after an acute MI.

“This might indicate we are nudging toward a change in practice, where more physicians are thinking that long-term beta-blocker therapy might not be indicated for all MI patients in the reperfusion era,” according to Dr. Holt.

Asked by the four-judge award panel about the possibility of unmeasured confounding in this observational study, Dr Holt responded: “I would be very cautious about asking patients to stop beta-blocker therapy after 3 months just based on this observational data. We can’t speak to causality in an observational study.” But he added that “well-designed observational studies provide valuable data regarding this topic and should not be ignored. They should possibly influence the guidelines and the designs for upcoming randomized trials.”

He conducted several supplementary analyses designed to address the possibility of unevenly distributed unmeasured confounding in the registry study. These analyses proved reassuring. A positive exposure control analysis compared 3-year outcomes in patients who remained on long-term statin therapy and those who didn’t. As expected, outcomes were significantly better in those who did: a 3-year composite outcome rate of 22.1%, compared with 32.1% in patients not on a statin; a cardiovascular death rate of 1.3% with and 2.1% without statin therapy; a recurrent MI rate of 6.6%, compared with 10.1% without a statin; and a 2.8% all-cause mortality with and 5.4% without statin therapy.

In contrast, all-cause mortality was unaffected by whether or not patients were on long-term beta-blocker therapy. And in a negative exposure outcome analysis, no association was found between beta-blocker therapy and the risk of hospitalization for pneumonia, as to be expected if the beta-blocker and no-beta-blocker groups were comparable in key respects.

Dr. Holt reported having no financial conflicts regarding his study.

bjancin@mdedge.com

Current American and European guidelines recommending long-term beta-blocker therapy following an acute MI appear to be obsolete in the modern reperfusion era, suggests an analysis of Danish registry data.

Those guidelines are based on old randomized trials of beta-blocker therapy conducted prior to introduction of routine percutaneous coronary intervention and modern multidrug optimal medical therapy for acute MI. There have been no prospective controlled studies in the reperfusion era. And a new Danish national observational study strongly suggests it’s time to reexamine the beta-blocker recommendation, Anders Holt, MD, said at the virtual annual congress of the European Society of Cardiology.

“Stable, optimally treated MI patients do not seem to benefit from beta-blocker treatment exceeding 3 months post hospitalization – bearing in mind this doesn’t apply to patients with other indications for beta-blockers, like heart failure or atrial fibrillation,” said Dr. Holt of Copenhagen University Hospital.

His analysis of Danish national registry data on more than 30,000 patients hospitalized for acute MI during 2003-2018 earned him the annual ESC Young Investigator Award in Population Science.

Frontline Medical News

“This was a crisp and clear presentation of a very creative use of observational epidemiology to try to understand the length of therapy that may or may not be appropriate,” commented award session cochair Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston.

Dr. Holt reported on 30,177 patients optimally treated for a first MI in Danish hospitals during 2003-2018, none of whom had a prior indication or contraindication for beta-blocker therapy. “Optimally treated” meant they underwent percutaneous coronary revascularization and were discharged on a statin and aspirin. As a study requirement, all had to be stable 90 days post hospitalization, at which point 24,770 of the patients were on long-term beta-blocker therapy, and 5,407 (18%) were not. The two groups were comparable in terms of age, sex, comorbidities, and baseline medications. All patients were followed through the registries for a maximum of 3 years, the duration of beta-blocker therapy post MI recommended in American Heart Association/American College of Cardiology guidelines. (The Danish Society of Cardiology recommends 2 years.)

At 3 years post MI, there was no between-group difference in a composite outcome comprising cardiovascular death, recurrent MI, heart failure, stroke, angina, or a cardiac procedure, with a rate of 22.9% in the beta-blocker group and 21.6% in patients not on long-term beta-blocker therapy. The rate of recurrent MI was identical at 6.7% in both groups. Cardiovascular death occurred during 3 years of follow-up in 1.4% of patients on beta-blocker therapy and 1.7% who weren’t, a nonsignificant difference.

“We saw no evidence of any cardioprotective effect, but no increased risk of adverse events resulting in hospitalization, either,” Dr. Holt observed. “I would like to acknowledge that no evidence of effect does not necessarily equal evidence of no effect, but even if there was an effect we can with fair certainty say that it’s probably quite minimal.”

He noted that the Danish registry data indicates that each year since 2012 has shown a growing trend for Danish patients to dispense with long-term beta-blocker therapy after an acute MI.

“This might indicate we are nudging toward a change in practice, where more physicians are thinking that long-term beta-blocker therapy might not be indicated for all MI patients in the reperfusion era,” according to Dr. Holt.

Asked by the four-judge award panel about the possibility of unmeasured confounding in this observational study, Dr Holt responded: “I would be very cautious about asking patients to stop beta-blocker therapy after 3 months just based on this observational data. We can’t speak to causality in an observational study.” But he added that “well-designed observational studies provide valuable data regarding this topic and should not be ignored. They should possibly influence the guidelines and the designs for upcoming randomized trials.”

He conducted several supplementary analyses designed to address the possibility of unevenly distributed unmeasured confounding in the registry study. These analyses proved reassuring. A positive exposure control analysis compared 3-year outcomes in patients who remained on long-term statin therapy and those who didn’t. As expected, outcomes were significantly better in those who did: a 3-year composite outcome rate of 22.1%, compared with 32.1% in patients not on a statin; a cardiovascular death rate of 1.3% with and 2.1% without statin therapy; a recurrent MI rate of 6.6%, compared with 10.1% without a statin; and a 2.8% all-cause mortality with and 5.4% without statin therapy.

In contrast, all-cause mortality was unaffected by whether or not patients were on long-term beta-blocker therapy. And in a negative exposure outcome analysis, no association was found between beta-blocker therapy and the risk of hospitalization for pneumonia, as to be expected if the beta-blocker and no-beta-blocker groups were comparable in key respects.

Dr. Holt reported having no financial conflicts regarding his study.

bjancin@mdedge.com

Maybe the hipsters patronizing trendy oxygen bars seeking elevation of mood back in the prepandemic era were actually onto something – because Israeli investigators have now shown in a pilot double-blind, placebo-controlled, randomized trial that breathing enriched oxygen on a nightly basis resulted in clinically meaningful symptomatic improvement in mild to moderate major depression.

Courtesy Dr. R. Haim Belmaker

“We saw a highly significant effect of normobaric hyperoxia therapy in lowering Hamilton Rating Scale for Depression scores,” R. Haim Belmaker, MD, reported at the virtual congress of the European College of Neuropsychopharmacology.

In addition, the patients on enriched oxygen also showed statistically significant and clinically meaningful improvements relative to sham-treated controls on the secondary endpoints of Clinical Global Impressions Scale, the World Health Organization–Five Well-Being Index, the Sheehan Disability Scale, and the Sense of Coherence Scale, added Dr. Belmaker, professor emeritus of psychiatry at the Ben Gurion University of the Negev in Beersheva, Israel.

Numerous PET imaging studies have documented diminished brain mitochondrial function in patients with depression or schizophrenia. And mitochondria need oxygen to do their work. Yet, the idea of administering enriched oxygen in an effort to boost mitochondrial energy metabolism has long been viewed with skepticism – even though it’s a simple and well-tolerated intervention – because of the fact that 90%-95% of the oxygen supply is carried bound to hemoglobin, and oxygen enrichment doesn’t further increase hemoglobin saturation in individuals with normal lung function. However, recently it has been shown that inspired enriched oxygen roughly doubles arterial oxygen tension, and while this doesn’t translate into anything close to a doubled oxygen supply to tissues, it may result in increased oxygen diffusion into brain tissue, the psychiatrist explained.

Normobaric hyperoxia therapy is not to be confused with hyperbaric oxygen therapy, which requires a special chamber to handle markedly increased atmospheric pressures and has some inherent dangers. Mobile bedside oxygen generator units for oxygen enrichment are commercially available over the counter. Those used in the Israeli study were about the size of a vacuum cleaner and weighed a little more than 40 lb. Much smaller, more convenient units are available as well, but are costlier.

Dr. Belmaker reported on 51 adults with mild or moderate symptoms of major depressive disorder and a mean 11-year disease history who were randomized double blind to breathe either 35% oxygen or normal air – that is, 21% oxygen – at 1 atm pressure delivered from an investigator-supplied oxygen generator through standard plastic nasal prongs at a flow rate of 5 L/min for 7 hours nightly for 1 month.

“Controls heard the same flow and felt the same feeling on the face but were receiving 21% oxygen,” he noted.

Oxygen generator units are capable of enriching air to more than 90% oxygen; however, the investigators wanted to be cautious in a pilot study of an untested therapy, and they found evidence from both animal and human studies that 40% oxygen is reassuringly safe. Most participants were on stable doses of antidepressant medications. Study exclusion criteria included obesity, acute or chronic respiratory disease, psychosis, and suicidality.

The primary study endpoint was the change in Hamilton Rating Scale for Depression score at 1 month. From a mean baseline of 14.6, the score in the normobaric hyperoxia group dropped by more than 4 points while remaining unchanged in controls. In a subscale analysis, it was apparent that most of the improvement occurred in the anxiety and cognitive disturbance subscale domains, according to Dr. Belmaker.

Of note, all patients rated by blinded investigators as much improved or very much improved on the Clinical Global Impression scale came from the enriched oxygen group.

No treatment-related adverse events occurred in the study.

“We don’t know the mechanism of the benefit of oxygen on the brain. It’s complex. In stroke and acute MI we used to think oxygen was beneficial, but scientists now feel that it’s not,” the psychiatrist said. “This early data deserve replication with higher concentrations of oxygen, different time periods of application, and in different patient groups.”

He emphasized that, since individuals with physical illnesses – including sleep apnea and chronic obstructive pulmonary disease – were excluded from the study, it’s not possible to say whether normobaric hyperoxia therapy would have an antidepressant effect in such patients.

“I would be especially careful with the normobaric oxygen in any patients with any cardiovascular or hypertensive disease because the increased oxygen pressure can have the side effect of contracting cardiac capillaries as a reflex action. So I certainly cannot recommend applying this study in any patients with a physical disease at this point,” Dr. Belmaker emphasized.

He reported having no financial conflicts regarding the study, funded by a grant from the Brain and Behavior Research Foundation.

bjancin@mdedge.com

SOURCE: Belmaker RH. ECNP 2020, Session S.12.

Maybe the hipsters patronizing trendy oxygen bars seeking elevation of mood back in the prepandemic era were actually onto something – because Israeli investigators have now shown in a pilot double-blind, placebo-controlled, randomized trial that breathing enriched oxygen on a nightly basis resulted in clinically meaningful symptomatic improvement in mild to moderate major depression.

Courtesy Dr. R. Haim Belmaker

“We saw a highly significant effect of normobaric hyperoxia therapy in lowering Hamilton Rating Scale for Depression scores,” R. Haim Belmaker, MD, reported at the virtual congress of the European College of Neuropsychopharmacology.

In addition, the patients on enriched oxygen also showed statistically significant and clinically meaningful improvements relative to sham-treated controls on the secondary endpoints of Clinical Global Impressions Scale, the World Health Organization–Five Well-Being Index, the Sheehan Disability Scale, and the Sense of Coherence Scale, added Dr. Belmaker, professor emeritus of psychiatry at the Ben Gurion University of the Negev in Beersheva, Israel.

Numerous PET imaging studies have documented diminished brain mitochondrial function in patients with depression or schizophrenia. And mitochondria need oxygen to do their work. Yet, the idea of administering enriched oxygen in an effort to boost mitochondrial energy metabolism has long been viewed with skepticism – even though it’s a simple and well-tolerated intervention – because of the fact that 90%-95% of the oxygen supply is carried bound to hemoglobin, and oxygen enrichment doesn’t further increase hemoglobin saturation in individuals with normal lung function. However, recently it has been shown that inspired enriched oxygen roughly doubles arterial oxygen tension, and while this doesn’t translate into anything close to a doubled oxygen supply to tissues, it may result in increased oxygen diffusion into brain tissue, the psychiatrist explained.

Normobaric hyperoxia therapy is not to be confused with hyperbaric oxygen therapy, which requires a special chamber to handle markedly increased atmospheric pressures and has some inherent dangers. Mobile bedside oxygen generator units for oxygen enrichment are commercially available over the counter. Those used in the Israeli study were about the size of a vacuum cleaner and weighed a little more than 40 lb. Much smaller, more convenient units are available as well, but are costlier.

Dr. Belmaker reported on 51 adults with mild or moderate symptoms of major depressive disorder and a mean 11-year disease history who were randomized double blind to breathe either 35% oxygen or normal air – that is, 21% oxygen – at 1 atm pressure delivered from an investigator-supplied oxygen generator through standard plastic nasal prongs at a flow rate of 5 L/min for 7 hours nightly for 1 month.

“Controls heard the same flow and felt the same feeling on the face but were receiving 21% oxygen,” he noted.

Oxygen generator units are capable of enriching air to more than 90% oxygen; however, the investigators wanted to be cautious in a pilot study of an untested therapy, and they found evidence from both animal and human studies that 40% oxygen is reassuringly safe. Most participants were on stable doses of antidepressant medications. Study exclusion criteria included obesity, acute or chronic respiratory disease, psychosis, and suicidality.

The primary study endpoint was the change in Hamilton Rating Scale for Depression score at 1 month. From a mean baseline of 14.6, the score in the normobaric hyperoxia group dropped by more than 4 points while remaining unchanged in controls. In a subscale analysis, it was apparent that most of the improvement occurred in the anxiety and cognitive disturbance subscale domains, according to Dr. Belmaker.

Of note, all patients rated by blinded investigators as much improved or very much improved on the Clinical Global Impression scale came from the enriched oxygen group.

No treatment-related adverse events occurred in the study.

“We don’t know the mechanism of the benefit of oxygen on the brain. It’s complex. In stroke and acute MI we used to think oxygen was beneficial, but scientists now feel that it’s not,” the psychiatrist said. “This early data deserve replication with higher concentrations of oxygen, different time periods of application, and in different patient groups.”

He emphasized that, since individuals with physical illnesses – including sleep apnea and chronic obstructive pulmonary disease – were excluded from the study, it’s not possible to say whether normobaric hyperoxia therapy would have an antidepressant effect in such patients.

“I would be especially careful with the normobaric oxygen in any patients with any cardiovascular or hypertensive disease because the increased oxygen pressure can have the side effect of contracting cardiac capillaries as a reflex action. So I certainly cannot recommend applying this study in any patients with a physical disease at this point,” Dr. Belmaker emphasized.

He reported having no financial conflicts regarding the study, funded by a grant from the Brain and Behavior Research Foundation.

bjancin@mdedge.com

SOURCE: Belmaker RH. ECNP 2020, Session S.12.

Maybe the hipsters patronizing trendy oxygen bars seeking elevation of mood back in the prepandemic era were actually onto something – because Israeli investigators have now shown in a pilot double-blind, placebo-controlled, randomized trial that breathing enriched oxygen on a nightly basis resulted in clinically meaningful symptomatic improvement in mild to moderate major depression.

Courtesy Dr. R. Haim Belmaker

“We saw a highly significant effect of normobaric hyperoxia therapy in lowering Hamilton Rating Scale for Depression scores,” R. Haim Belmaker, MD, reported at the virtual congress of the European College of Neuropsychopharmacology.

In addition, the patients on enriched oxygen also showed statistically significant and clinically meaningful improvements relative to sham-treated controls on the secondary endpoints of Clinical Global Impressions Scale, the World Health Organization–Five Well-Being Index, the Sheehan Disability Scale, and the Sense of Coherence Scale, added Dr. Belmaker, professor emeritus of psychiatry at the Ben Gurion University of the Negev in Beersheva, Israel.

Numerous PET imaging studies have documented diminished brain mitochondrial function in patients with depression or schizophrenia. And mitochondria need oxygen to do their work. Yet, the idea of administering enriched oxygen in an effort to boost mitochondrial energy metabolism has long been viewed with skepticism – even though it’s a simple and well-tolerated intervention – because of the fact that 90%-95% of the oxygen supply is carried bound to hemoglobin, and oxygen enrichment doesn’t further increase hemoglobin saturation in individuals with normal lung function. However, recently it has been shown that inspired enriched oxygen roughly doubles arterial oxygen tension, and while this doesn’t translate into anything close to a doubled oxygen supply to tissues, it may result in increased oxygen diffusion into brain tissue, the psychiatrist explained.

Normobaric hyperoxia therapy is not to be confused with hyperbaric oxygen therapy, which requires a special chamber to handle markedly increased atmospheric pressures and has some inherent dangers. Mobile bedside oxygen generator units for oxygen enrichment are commercially available over the counter. Those used in the Israeli study were about the size of a vacuum cleaner and weighed a little more than 40 lb. Much smaller, more convenient units are available as well, but are costlier.

Dr. Belmaker reported on 51 adults with mild or moderate symptoms of major depressive disorder and a mean 11-year disease history who were randomized double blind to breathe either 35% oxygen or normal air – that is, 21% oxygen – at 1 atm pressure delivered from an investigator-supplied oxygen generator through standard plastic nasal prongs at a flow rate of 5 L/min for 7 hours nightly for 1 month.

“Controls heard the same flow and felt the same feeling on the face but were receiving 21% oxygen,” he noted.

Oxygen generator units are capable of enriching air to more than 90% oxygen; however, the investigators wanted to be cautious in a pilot study of an untested therapy, and they found evidence from both animal and human studies that 40% oxygen is reassuringly safe. Most participants were on stable doses of antidepressant medications. Study exclusion criteria included obesity, acute or chronic respiratory disease, psychosis, and suicidality.

The primary study endpoint was the change in Hamilton Rating Scale for Depression score at 1 month. From a mean baseline of 14.6, the score in the normobaric hyperoxia group dropped by more than 4 points while remaining unchanged in controls. In a subscale analysis, it was apparent that most of the improvement occurred in the anxiety and cognitive disturbance subscale domains, according to Dr. Belmaker.

Of note, all patients rated by blinded investigators as much improved or very much improved on the Clinical Global Impression scale came from the enriched oxygen group.

No treatment-related adverse events occurred in the study.

“We don’t know the mechanism of the benefit of oxygen on the brain. It’s complex. In stroke and acute MI we used to think oxygen was beneficial, but scientists now feel that it’s not,” the psychiatrist said. “This early data deserve replication with higher concentrations of oxygen, different time periods of application, and in different patient groups.”

He emphasized that, since individuals with physical illnesses – including sleep apnea and chronic obstructive pulmonary disease – were excluded from the study, it’s not possible to say whether normobaric hyperoxia therapy would have an antidepressant effect in such patients.

“I would be especially careful with the normobaric oxygen in any patients with any cardiovascular or hypertensive disease because the increased oxygen pressure can have the side effect of contracting cardiac capillaries as a reflex action. So I certainly cannot recommend applying this study in any patients with a physical disease at this point,” Dr. Belmaker emphasized.

He reported having no financial conflicts regarding the study, funded by a grant from the Brain and Behavior Research Foundation.

bjancin@mdedge.com

SOURCE: Belmaker RH. ECNP 2020, Session S.12.

New guidelines on sports cardiology from the European Society of Cardiology break fresh ground by green-lighting participation in vigorous competitive sports by selected patients with stable coronary artery disease, heart failure, or mild arrhythmias.

These liberalized guidelines, released at the virtual annual congress of the European Society of Cardiology, thus move well beyond the standard exercise advice to engage in about 150 minutes per week of moderate physical activity, typically defined as brisk walking or its equivalent.

The guidelines reflect a conviction that exercise is powerful medicine for patients with cardiovascular disease and also affords a means to help curb the epidemics of diabetes and obesity that drive cardiovascular risk, according to Antonio Pelliccia, MD, who cochaired the 24-member task force of European and American experts that developed the guidelines.

In a session highlighting the new sports cardiology guidelines, Mats Borjesson, MD, head of the Center for Health and Performance at Gothenburg (Sweden) University, summarized the section devoted to patients with stable coronary artery disease: “If you have established CAD and a low risk of adverse events during exercise, you are eligible for high-intensity exercise and competitive sports. But if you have persistent ischemia despite medical treatment, or symptoms, then you’re only eligible for leisure-time subthreshold activity.”

Dr. Pelliccia put this new recommendation into context.

“We are not talking anymore in this particular disease just about cardiac rehabilitation or leisure-time activity, but we are also opening the border and talking about competitive sports activity in selected patients where you have the evidence for low risk of exercise-induced adverse events. This is a major achievement now for what is the major disease in our adult population,” said Dr. Pelliccia, chief of cardiology at the Institute of Sports Medicine and Science at the Italian National Olympic Committee and professor of sports cardiology at La Sapienza University of Rome.

The recommendation for individualized consideration of all types of exercise, even including vigorous competitive sports, in low-risk patients with CAD gets a class IIa, level of evidence (LOE) C recommendation in the new guidelines. That’s a big step down from a ringing class Ia endorsement, but since sports cardiology is a relatively young field with little evidence that’s based on randomized trials, the guidelines are rife with many other class IIa, LOE C recommendations as well.

“The level of evidence is rather low, so these guidelines are very much the personal perspective of the expert panel,” explained Martin Halle, MD, professor and head of the department of prevention, rehabilitation, and sports cardiology at Technical University of Munich.

The high-risk features for exercise-induced cardiac adverse events in patients with longstanding stable CAD, as cited in the guidelines, include a critical coronary stenosis, defined as a more than 70% lesion in a major coronary artery or a greater than 50% stenosis in the left main, and/or a fractional flow reserve score of less than 0.8; a left ventricular ejection fraction of 50% or less with wall-motion abnormalities; inducible myocardial ischemia on maximal exercise testing; nonsustained ventricular tachycardia; polymorphic or very frequent ventricular premature beats at rest and during maximum stress; and a recent acute coronary syndrome (ACS). These features call for an exercise prescription tailored to remain below the patient’s angina and ischemia thresholds.

“It’s important for cardiologists out there to understand that we definitely need a maximal exercise test. In somebody who is running and has an ACS and then wants to start running again, 200 watts on an ergometer is too low. We have to push them up to the end, and then if everything is okay – left ventricular function is okay, no ischemia, no arrhythmias under exercise testing – then it’s fine,” Dr. Halle said.

Dr. Pelliccia added that close follow-up is needed, because this is an evolving disease.”
 

Exercise and heart failure

Massimo F. Piepoli, MD, PhD, noted that the guidelines give a class IIb, LOE C recommendation for consideration of high-intensity recreational endurance and power sports in patients with heart failure with either midrange or preserved ejection fraction, provided they are stable, asymptomatic, on optimal guideline-directed medical therapy, and without abnormalities on a maximal exercise stress test.

European Society of Cardiology

However, such intense physical activity is not recommended in patients with heart failure with reduced ejection fraction, regardless of their symptom status, added Dr. Piepoli of Guglielmo da Saliceto Hospital in Placenza, Italy.

“We’re talking here, I think for the first time, about possible competitive sports participation in individuals with heart failure, depending on their clinical condition. We are really opening the barriers to sports participation, even in these patients in whom we never thought of it before,” Dr. Pelliccia observed.

Valvular heart disease and exercise

Guidelines panelist Sabiha Gati, MRCP, PhD, said asymptomatic individuals with mild valvular abnormalities can participate in all recreational and competitive sports; that’s a class I, LOE C recommendation.

European Society of Cardiology

“Moderate regurgitant lesions are better tolerated than stenotic lesions, and those with preserved systolic function, good functional capacity, without any exercise-induced arrhythmias or ischemia or abnormal hemodynamic response are considered to be low risk and can participate in all sports,” added Dr. Gati, a cardiologist at Royal Brompton Hospital, London.

The two most common valvular abnormalities encountered in clinical practice are bicuspid aortic valve and mitral valve prolapse. Dr. Gati noted that, while mitral valve prolapse has a benign prognosis in the great majority of affected individuals, the presence of specific features indicative of increased risk for sudden cardiac death precludes participation in strenuous exercise. These include T-wave inversion in the inferior leads on a 12-lead ECG, long QT, bileaflet mitral valve prolapse, basal inferolateral wall fibrosis, severe mitral regurgitation, or a family history of sudden cardiac death.

Bicuspid aortic valve has a prevalence of 1%-2% in the general population. It can be associated with aortic stenosis, aortic regurgitation, and increased risk of ascending aortic aneurysm and dissection. Since it remains unclear whether intensive exercise accelerates aortic dilatation, a cautious approach to sports participation is recommended in patients with an ascending aorta above the normal limit of 40 mm, she said.

The 80-page ESC sports cardiology guidelines, published online simultaneously with their presentation, cover a broad range of additional topics, including exercise recommendations for the general public, for the elderly, as well as for patients with cardiomyopathies, adult congenital heart disease, arrhythmias, and channelopathies. Gaps in evidence are also highlighted.

bjancin@mdedge.com

SOURCE: Pelliccia A. ESC 2020 and Eur Heart J. 2020 Aug 29. doi: 10.1093/eurheartj/ehaa605.

New guidelines on sports cardiology from the European Society of Cardiology break fresh ground by green-lighting participation in vigorous competitive sports by selected patients with stable coronary artery disease, heart failure, or mild arrhythmias.

These liberalized guidelines, released at the virtual annual congress of the European Society of Cardiology, thus move well beyond the standard exercise advice to engage in about 150 minutes per week of moderate physical activity, typically defined as brisk walking or its equivalent.

The guidelines reflect a conviction that exercise is powerful medicine for patients with cardiovascular disease and also affords a means to help curb the epidemics of diabetes and obesity that drive cardiovascular risk, according to Antonio Pelliccia, MD, who cochaired the 24-member task force of European and American experts that developed the guidelines.

In a session highlighting the new sports cardiology guidelines, Mats Borjesson, MD, head of the Center for Health and Performance at Gothenburg (Sweden) University, summarized the section devoted to patients with stable coronary artery disease: “If you have established CAD and a low risk of adverse events during exercise, you are eligible for high-intensity exercise and competitive sports. But if you have persistent ischemia despite medical treatment, or symptoms, then you’re only eligible for leisure-time subthreshold activity.”

Dr. Pelliccia put this new recommendation into context.

“We are not talking anymore in this particular disease just about cardiac rehabilitation or leisure-time activity, but we are also opening the border and talking about competitive sports activity in selected patients where you have the evidence for low risk of exercise-induced adverse events. This is a major achievement now for what is the major disease in our adult population,” said Dr. Pelliccia, chief of cardiology at the Institute of Sports Medicine and Science at the Italian National Olympic Committee and professor of sports cardiology at La Sapienza University of Rome.

The recommendation for individualized consideration of all types of exercise, even including vigorous competitive sports, in low-risk patients with CAD gets a class IIa, level of evidence (LOE) C recommendation in the new guidelines. That’s a big step down from a ringing class Ia endorsement, but since sports cardiology is a relatively young field with little evidence that’s based on randomized trials, the guidelines are rife with many other class IIa, LOE C recommendations as well.

“The level of evidence is rather low, so these guidelines are very much the personal perspective of the expert panel,” explained Martin Halle, MD, professor and head of the department of prevention, rehabilitation, and sports cardiology at Technical University of Munich.

The high-risk features for exercise-induced cardiac adverse events in patients with longstanding stable CAD, as cited in the guidelines, include a critical coronary stenosis, defined as a more than 70% lesion in a major coronary artery or a greater than 50% stenosis in the left main, and/or a fractional flow reserve score of less than 0.8; a left ventricular ejection fraction of 50% or less with wall-motion abnormalities; inducible myocardial ischemia on maximal exercise testing; nonsustained ventricular tachycardia; polymorphic or very frequent ventricular premature beats at rest and during maximum stress; and a recent acute coronary syndrome (ACS). These features call for an exercise prescription tailored to remain below the patient’s angina and ischemia thresholds.

“It’s important for cardiologists out there to understand that we definitely need a maximal exercise test. In somebody who is running and has an ACS and then wants to start running again, 200 watts on an ergometer is too low. We have to push them up to the end, and then if everything is okay – left ventricular function is okay, no ischemia, no arrhythmias under exercise testing – then it’s fine,” Dr. Halle said.

Dr. Pelliccia added that close follow-up is needed, because this is an evolving disease.”
 

Exercise and heart failure

Massimo F. Piepoli, MD, PhD, noted that the guidelines give a class IIb, LOE C recommendation for consideration of high-intensity recreational endurance and power sports in patients with heart failure with either midrange or preserved ejection fraction, provided they are stable, asymptomatic, on optimal guideline-directed medical therapy, and without abnormalities on a maximal exercise stress test.

European Society of Cardiology

However, such intense physical activity is not recommended in patients with heart failure with reduced ejection fraction, regardless of their symptom status, added Dr. Piepoli of Guglielmo da Saliceto Hospital in Placenza, Italy.

“We’re talking here, I think for the first time, about possible competitive sports participation in individuals with heart failure, depending on their clinical condition. We are really opening the barriers to sports participation, even in these patients in whom we never thought of it before,” Dr. Pelliccia observed.

Valvular heart disease and exercise

Guidelines panelist Sabiha Gati, MRCP, PhD, said asymptomatic individuals with mild valvular abnormalities can participate in all recreational and competitive sports; that’s a class I, LOE C recommendation.

European Society of Cardiology

“Moderate regurgitant lesions are better tolerated than stenotic lesions, and those with preserved systolic function, good functional capacity, without any exercise-induced arrhythmias or ischemia or abnormal hemodynamic response are considered to be low risk and can participate in all sports,” added Dr. Gati, a cardiologist at Royal Brompton Hospital, London.

The two most common valvular abnormalities encountered in clinical practice are bicuspid aortic valve and mitral valve prolapse. Dr. Gati noted that, while mitral valve prolapse has a benign prognosis in the great majority of affected individuals, the presence of specific features indicative of increased risk for sudden cardiac death precludes participation in strenuous exercise. These include T-wave inversion in the inferior leads on a 12-lead ECG, long QT, bileaflet mitral valve prolapse, basal inferolateral wall fibrosis, severe mitral regurgitation, or a family history of sudden cardiac death.

Bicuspid aortic valve has a prevalence of 1%-2% in the general population. It can be associated with aortic stenosis, aortic regurgitation, and increased risk of ascending aortic aneurysm and dissection. Since it remains unclear whether intensive exercise accelerates aortic dilatation, a cautious approach to sports participation is recommended in patients with an ascending aorta above the normal limit of 40 mm, she said.

The 80-page ESC sports cardiology guidelines, published online simultaneously with their presentation, cover a broad range of additional topics, including exercise recommendations for the general public, for the elderly, as well as for patients with cardiomyopathies, adult congenital heart disease, arrhythmias, and channelopathies. Gaps in evidence are also highlighted.

bjancin@mdedge.com

SOURCE: Pelliccia A. ESC 2020 and Eur Heart J. 2020 Aug 29. doi: 10.1093/eurheartj/ehaa605.

New guidelines on sports cardiology from the European Society of Cardiology break fresh ground by green-lighting participation in vigorous competitive sports by selected patients with stable coronary artery disease, heart failure, or mild arrhythmias.

These liberalized guidelines, released at the virtual annual congress of the European Society of Cardiology, thus move well beyond the standard exercise advice to engage in about 150 minutes per week of moderate physical activity, typically defined as brisk walking or its equivalent.

The guidelines reflect a conviction that exercise is powerful medicine for patients with cardiovascular disease and also affords a means to help curb the epidemics of diabetes and obesity that drive cardiovascular risk, according to Antonio Pelliccia, MD, who cochaired the 24-member task force of European and American experts that developed the guidelines.

In a session highlighting the new sports cardiology guidelines, Mats Borjesson, MD, head of the Center for Health and Performance at Gothenburg (Sweden) University, summarized the section devoted to patients with stable coronary artery disease: “If you have established CAD and a low risk of adverse events during exercise, you are eligible for high-intensity exercise and competitive sports. But if you have persistent ischemia despite medical treatment, or symptoms, then you’re only eligible for leisure-time subthreshold activity.”

Dr. Pelliccia put this new recommendation into context.

“We are not talking anymore in this particular disease just about cardiac rehabilitation or leisure-time activity, but we are also opening the border and talking about competitive sports activity in selected patients where you have the evidence for low risk of exercise-induced adverse events. This is a major achievement now for what is the major disease in our adult population,” said Dr. Pelliccia, chief of cardiology at the Institute of Sports Medicine and Science at the Italian National Olympic Committee and professor of sports cardiology at La Sapienza University of Rome.

The recommendation for individualized consideration of all types of exercise, even including vigorous competitive sports, in low-risk patients with CAD gets a class IIa, level of evidence (LOE) C recommendation in the new guidelines. That’s a big step down from a ringing class Ia endorsement, but since sports cardiology is a relatively young field with little evidence that’s based on randomized trials, the guidelines are rife with many other class IIa, LOE C recommendations as well.

“The level of evidence is rather low, so these guidelines are very much the personal perspective of the expert panel,” explained Martin Halle, MD, professor and head of the department of prevention, rehabilitation, and sports cardiology at Technical University of Munich.

The high-risk features for exercise-induced cardiac adverse events in patients with longstanding stable CAD, as cited in the guidelines, include a critical coronary stenosis, defined as a more than 70% lesion in a major coronary artery or a greater than 50% stenosis in the left main, and/or a fractional flow reserve score of less than 0.8; a left ventricular ejection fraction of 50% or less with wall-motion abnormalities; inducible myocardial ischemia on maximal exercise testing; nonsustained ventricular tachycardia; polymorphic or very frequent ventricular premature beats at rest and during maximum stress; and a recent acute coronary syndrome (ACS). These features call for an exercise prescription tailored to remain below the patient’s angina and ischemia thresholds.

“It’s important for cardiologists out there to understand that we definitely need a maximal exercise test. In somebody who is running and has an ACS and then wants to start running again, 200 watts on an ergometer is too low. We have to push them up to the end, and then if everything is okay – left ventricular function is okay, no ischemia, no arrhythmias under exercise testing – then it’s fine,” Dr. Halle said.

Dr. Pelliccia added that close follow-up is needed, because this is an evolving disease.”
 

Exercise and heart failure

Massimo F. Piepoli, MD, PhD, noted that the guidelines give a class IIb, LOE C recommendation for consideration of high-intensity recreational endurance and power sports in patients with heart failure with either midrange or preserved ejection fraction, provided they are stable, asymptomatic, on optimal guideline-directed medical therapy, and without abnormalities on a maximal exercise stress test.

European Society of Cardiology

However, such intense physical activity is not recommended in patients with heart failure with reduced ejection fraction, regardless of their symptom status, added Dr. Piepoli of Guglielmo da Saliceto Hospital in Placenza, Italy.

“We’re talking here, I think for the first time, about possible competitive sports participation in individuals with heart failure, depending on their clinical condition. We are really opening the barriers to sports participation, even in these patients in whom we never thought of it before,” Dr. Pelliccia observed.

Valvular heart disease and exercise

Guidelines panelist Sabiha Gati, MRCP, PhD, said asymptomatic individuals with mild valvular abnormalities can participate in all recreational and competitive sports; that’s a class I, LOE C recommendation.

European Society of Cardiology

“Moderate regurgitant lesions are better tolerated than stenotic lesions, and those with preserved systolic function, good functional capacity, without any exercise-induced arrhythmias or ischemia or abnormal hemodynamic response are considered to be low risk and can participate in all sports,” added Dr. Gati, a cardiologist at Royal Brompton Hospital, London.

The two most common valvular abnormalities encountered in clinical practice are bicuspid aortic valve and mitral valve prolapse. Dr. Gati noted that, while mitral valve prolapse has a benign prognosis in the great majority of affected individuals, the presence of specific features indicative of increased risk for sudden cardiac death precludes participation in strenuous exercise. These include T-wave inversion in the inferior leads on a 12-lead ECG, long QT, bileaflet mitral valve prolapse, basal inferolateral wall fibrosis, severe mitral regurgitation, or a family history of sudden cardiac death.

Bicuspid aortic valve has a prevalence of 1%-2% in the general population. It can be associated with aortic stenosis, aortic regurgitation, and increased risk of ascending aortic aneurysm and dissection. Since it remains unclear whether intensive exercise accelerates aortic dilatation, a cautious approach to sports participation is recommended in patients with an ascending aorta above the normal limit of 40 mm, she said.

The 80-page ESC sports cardiology guidelines, published online simultaneously with their presentation, cover a broad range of additional topics, including exercise recommendations for the general public, for the elderly, as well as for patients with cardiomyopathies, adult congenital heart disease, arrhythmias, and channelopathies. Gaps in evidence are also highlighted.

bjancin@mdedge.com

SOURCE: Pelliccia A. ESC 2020 and Eur Heart J. 2020 Aug 29. doi: 10.1093/eurheartj/ehaa605.

The two top developments of the year in the field of neurostimulation involve the oldest form of the therapy: electroconvulsive therapy, Alexander Sartorius, MD, said at the virtual congress of the European College of Neuropsychopharmacology.

Bram Janssens/Thinkstock

One of these studies shot down the longstanding notion that ECT causes brain damage. The other, a Danish national registry study, demonstrated that ECT is associated with lower all-cause mortality than in patients with similarly severe depression who don’t undergo ECT.

“The take-home messages are that ECT does not lead to brain damage but rather to a profound gray matter increase. And secondly, ECT lowers all-cause mortality in patients with depression,” said Dr. Sartorius, a psychiatrist at the Central Institute of Mental Health in Mannheim, Germany.

The year has been less fruitful in terms of research involving deep brain stimulation using implantable electrodes, he continued.

“Basically, one can state that there is no breaking news in the field of deep brain stimulation. DBS remains a highly experimental form of therapy,” Dr. Sartorius said.
 

ECT-induced brain changes

Investigators participating in the international multicenter Global ECT-MRI Research Collaboration (GEMRIC) reported on the longitudinal effects of ECT on gray matter, white matter, and ventricular volumes in 328 patients who underwent imaging before and after ECT for a major depressive episode, as well as in 95 nondepressed controls.

The key finding was that ECT induced a widespread, nonspecific global increase in gray matter volume. Indeed, the volumetric increase was documented in 79 of 84 gray matter regions of interest. Subcortical gray matter volume increased by a mean of 1.47% in ECT-treated patients, and total cortical volume rose by 1.04%. Total white matter volume remained unchanged.

“The gray matter increase induced by ECT looks quite similar to the gray matter increase seen with physical activity,” Dr. Sartorius noted.

The size of the gray matter volume increase rose with the number of ECT sessions. However, gray matter enlargement in response to ECT showed no relationship with clinical response, indicating that this finding on brain imaging doesn’t have a promising future as a potential biomarker of treatment effectiveness (Biol Psychiatry. 2020 Mar 1;87[5]:451-61).

“The good news from this study is there is no gray matter decrease,” Dr. Sartorius said. “This study enhances the existing evidence falsifying the old idea or dogma that ECT induces brain damage. I would claim that the opposite is clearly the case.”
 

ECT and mortality

The same group of investigators at the University of Copenhagen who several years ago harnessed Danish national patient registries data to report that ECT was associated with an unadjusted 32% and adjusted 23% reduction in the risk of developing dementia in patients aged 70 years and older (Lancet Psychiatry. 2018 Apr;5[4]:348-56) have recently concluded that ECT was also associated with a 19% reduction in all-cause mortality, compared with that of patients hospitalized for major depression who didn’t receive ECT.

The national registries study included 5,004 patients who were treated with ECT and nearly 88,000 others who were hospitalized for major depression during 2005-2016 but didn’t receive ECT. During up to 11.3 years of follow-up, the risk of all-cause mortality was 8% lower with ECT than with no ECT in patients categorized as having mild depression, 17% lower with a history of ECT for moderate depression, 4% less with severe depression without psychotic features, and 30% less with ECT than no ECT for severe depression with psychotic features (J Psychopharmacol. 2020 Mar;34[3]:273-9).

ECT was associated with an adjusted 6.99-fold increased risk of suicide in patients with mild depression. At first look that’s unsettling, Dr. Sartorius said, but he pointed out that the size of the ECT-associated suicide risk lessened with increasing severity of depression, and in fact, there was no increased suicide risk with ECT in severely depressed patients with psychotic features. ECT was also associated with significantly higher rates of psychiatric rehospitalization, emergency department visits, and suicidal behavior in patients classified as having mild or moderate depression. Dr. Sartorius suspects these findings reflect diagnostic uncertainty surrounding the milder forms of depression, coupled with the reality that ECT is generally reserved for the most unstable, treatment-resistant patients.

Deep transcranial magnetic stimulation

A Taiwanese meta-analysis has helped clarify the role of deep transcranial magnetic stimulation (dTMS) for treatment-resistant depression. The meta-analysis included 198 patients with treatment-resistant depression who underwent dTMS and 219 who received sham treatment in a total of 15 studies, only three of which were randomized controlled trials.

Active treatment was associated with a 2.06-fold increased likelihood of remission of depressive symptoms; however, the effect was statistically significant only in the subgroup of patients on concurrent antidepressant medication. Moreover, the therapeutic benefit of dTMS was significantly greater in the nonrandomized studies, where the odds ratio for remission was 3.8-fold greater than with sham therapy. In contrast, the odds ratio for remission with dTMS dropped to 1.37 in the randomized trials (Prog Neuropsychopharmacol Biol Psychiatry. 2020 Apr 20;99:109850. doi: 10.1016/j.pnpbp.2019.109850). “dTMS has quite a bit of antidepressant potential in treatment-resistant depression, but as an augmentation strategy. More randomized trials are needed, with a particular focus on which classes of antidepressants might be most effective as concurrent therapy,” Dr. Sartorius concluded.

He reported having no financial conflicts regarding his presentation.

bjancin@mdedge.com

SOURCE: Sartorius A. ECNP 2020, Session TP.03.

The two top developments of the year in the field of neurostimulation involve the oldest form of the therapy: electroconvulsive therapy, Alexander Sartorius, MD, said at the virtual congress of the European College of Neuropsychopharmacology.

Bram Janssens/Thinkstock

One of these studies shot down the longstanding notion that ECT causes brain damage. The other, a Danish national registry study, demonstrated that ECT is associated with lower all-cause mortality than in patients with similarly severe depression who don’t undergo ECT.

“The take-home messages are that ECT does not lead to brain damage but rather to a profound gray matter increase. And secondly, ECT lowers all-cause mortality in patients with depression,” said Dr. Sartorius, a psychiatrist at the Central Institute of Mental Health in Mannheim, Germany.

The year has been less fruitful in terms of research involving deep brain stimulation using implantable electrodes, he continued.

“Basically, one can state that there is no breaking news in the field of deep brain stimulation. DBS remains a highly experimental form of therapy,” Dr. Sartorius said.
 

ECT-induced brain changes

Investigators participating in the international multicenter Global ECT-MRI Research Collaboration (GEMRIC) reported on the longitudinal effects of ECT on gray matter, white matter, and ventricular volumes in 328 patients who underwent imaging before and after ECT for a major depressive episode, as well as in 95 nondepressed controls.

The key finding was that ECT induced a widespread, nonspecific global increase in gray matter volume. Indeed, the volumetric increase was documented in 79 of 84 gray matter regions of interest. Subcortical gray matter volume increased by a mean of 1.47% in ECT-treated patients, and total cortical volume rose by 1.04%. Total white matter volume remained unchanged.

“The gray matter increase induced by ECT looks quite similar to the gray matter increase seen with physical activity,” Dr. Sartorius noted.

The size of the gray matter volume increase rose with the number of ECT sessions. However, gray matter enlargement in response to ECT showed no relationship with clinical response, indicating that this finding on brain imaging doesn’t have a promising future as a potential biomarker of treatment effectiveness (Biol Psychiatry. 2020 Mar 1;87[5]:451-61).

“The good news from this study is there is no gray matter decrease,” Dr. Sartorius said. “This study enhances the existing evidence falsifying the old idea or dogma that ECT induces brain damage. I would claim that the opposite is clearly the case.”
 

ECT and mortality

The same group of investigators at the University of Copenhagen who several years ago harnessed Danish national patient registries data to report that ECT was associated with an unadjusted 32% and adjusted 23% reduction in the risk of developing dementia in patients aged 70 years and older (Lancet Psychiatry. 2018 Apr;5[4]:348-56) have recently concluded that ECT was also associated with a 19% reduction in all-cause mortality, compared with that of patients hospitalized for major depression who didn’t receive ECT.

The national registries study included 5,004 patients who were treated with ECT and nearly 88,000 others who were hospitalized for major depression during 2005-2016 but didn’t receive ECT. During up to 11.3 years of follow-up, the risk of all-cause mortality was 8% lower with ECT than with no ECT in patients categorized as having mild depression, 17% lower with a history of ECT for moderate depression, 4% less with severe depression without psychotic features, and 30% less with ECT than no ECT for severe depression with psychotic features (J Psychopharmacol. 2020 Mar;34[3]:273-9).

ECT was associated with an adjusted 6.99-fold increased risk of suicide in patients with mild depression. At first look that’s unsettling, Dr. Sartorius said, but he pointed out that the size of the ECT-associated suicide risk lessened with increasing severity of depression, and in fact, there was no increased suicide risk with ECT in severely depressed patients with psychotic features. ECT was also associated with significantly higher rates of psychiatric rehospitalization, emergency department visits, and suicidal behavior in patients classified as having mild or moderate depression. Dr. Sartorius suspects these findings reflect diagnostic uncertainty surrounding the milder forms of depression, coupled with the reality that ECT is generally reserved for the most unstable, treatment-resistant patients.

Deep transcranial magnetic stimulation

A Taiwanese meta-analysis has helped clarify the role of deep transcranial magnetic stimulation (dTMS) for treatment-resistant depression. The meta-analysis included 198 patients with treatment-resistant depression who underwent dTMS and 219 who received sham treatment in a total of 15 studies, only three of which were randomized controlled trials.

Active treatment was associated with a 2.06-fold increased likelihood of remission of depressive symptoms; however, the effect was statistically significant only in the subgroup of patients on concurrent antidepressant medication. Moreover, the therapeutic benefit of dTMS was significantly greater in the nonrandomized studies, where the odds ratio for remission was 3.8-fold greater than with sham therapy. In contrast, the odds ratio for remission with dTMS dropped to 1.37 in the randomized trials (Prog Neuropsychopharmacol Biol Psychiatry. 2020 Apr 20;99:109850. doi: 10.1016/j.pnpbp.2019.109850). “dTMS has quite a bit of antidepressant potential in treatment-resistant depression, but as an augmentation strategy. More randomized trials are needed, with a particular focus on which classes of antidepressants might be most effective as concurrent therapy,” Dr. Sartorius concluded.

He reported having no financial conflicts regarding his presentation.

bjancin@mdedge.com

SOURCE: Sartorius A. ECNP 2020, Session TP.03.

The two top developments of the year in the field of neurostimulation involve the oldest form of the therapy: electroconvulsive therapy, Alexander Sartorius, MD, said at the virtual congress of the European College of Neuropsychopharmacology.

Bram Janssens/Thinkstock

One of these studies shot down the longstanding notion that ECT causes brain damage. The other, a Danish national registry study, demonstrated that ECT is associated with lower all-cause mortality than in patients with similarly severe depression who don’t undergo ECT.

“The take-home messages are that ECT does not lead to brain damage but rather to a profound gray matter increase. And secondly, ECT lowers all-cause mortality in patients with depression,” said Dr. Sartorius, a psychiatrist at the Central Institute of Mental Health in Mannheim, Germany.

The year has been less fruitful in terms of research involving deep brain stimulation using implantable electrodes, he continued.

“Basically, one can state that there is no breaking news in the field of deep brain stimulation. DBS remains a highly experimental form of therapy,” Dr. Sartorius said.
 

ECT-induced brain changes

Investigators participating in the international multicenter Global ECT-MRI Research Collaboration (GEMRIC) reported on the longitudinal effects of ECT on gray matter, white matter, and ventricular volumes in 328 patients who underwent imaging before and after ECT for a major depressive episode, as well as in 95 nondepressed controls.

The key finding was that ECT induced a widespread, nonspecific global increase in gray matter volume. Indeed, the volumetric increase was documented in 79 of 84 gray matter regions of interest. Subcortical gray matter volume increased by a mean of 1.47% in ECT-treated patients, and total cortical volume rose by 1.04%. Total white matter volume remained unchanged.

“The gray matter increase induced by ECT looks quite similar to the gray matter increase seen with physical activity,” Dr. Sartorius noted.

The size of the gray matter volume increase rose with the number of ECT sessions. However, gray matter enlargement in response to ECT showed no relationship with clinical response, indicating that this finding on brain imaging doesn’t have a promising future as a potential biomarker of treatment effectiveness (Biol Psychiatry. 2020 Mar 1;87[5]:451-61).

“The good news from this study is there is no gray matter decrease,” Dr. Sartorius said. “This study enhances the existing evidence falsifying the old idea or dogma that ECT induces brain damage. I would claim that the opposite is clearly the case.”
 

ECT and mortality

The same group of investigators at the University of Copenhagen who several years ago harnessed Danish national patient registries data to report that ECT was associated with an unadjusted 32% and adjusted 23% reduction in the risk of developing dementia in patients aged 70 years and older (Lancet Psychiatry. 2018 Apr;5[4]:348-56) have recently concluded that ECT was also associated with a 19% reduction in all-cause mortality, compared with that of patients hospitalized for major depression who didn’t receive ECT.

The national registries study included 5,004 patients who were treated with ECT and nearly 88,000 others who were hospitalized for major depression during 2005-2016 but didn’t receive ECT. During up to 11.3 years of follow-up, the risk of all-cause mortality was 8% lower with ECT than with no ECT in patients categorized as having mild depression, 17% lower with a history of ECT for moderate depression, 4% less with severe depression without psychotic features, and 30% less with ECT than no ECT for severe depression with psychotic features (J Psychopharmacol. 2020 Mar;34[3]:273-9).

ECT was associated with an adjusted 6.99-fold increased risk of suicide in patients with mild depression. At first look that’s unsettling, Dr. Sartorius said, but he pointed out that the size of the ECT-associated suicide risk lessened with increasing severity of depression, and in fact, there was no increased suicide risk with ECT in severely depressed patients with psychotic features. ECT was also associated with significantly higher rates of psychiatric rehospitalization, emergency department visits, and suicidal behavior in patients classified as having mild or moderate depression. Dr. Sartorius suspects these findings reflect diagnostic uncertainty surrounding the milder forms of depression, coupled with the reality that ECT is generally reserved for the most unstable, treatment-resistant patients.

Deep transcranial magnetic stimulation

A Taiwanese meta-analysis has helped clarify the role of deep transcranial magnetic stimulation (dTMS) for treatment-resistant depression. The meta-analysis included 198 patients with treatment-resistant depression who underwent dTMS and 219 who received sham treatment in a total of 15 studies, only three of which were randomized controlled trials.

Active treatment was associated with a 2.06-fold increased likelihood of remission of depressive symptoms; however, the effect was statistically significant only in the subgroup of patients on concurrent antidepressant medication. Moreover, the therapeutic benefit of dTMS was significantly greater in the nonrandomized studies, where the odds ratio for remission was 3.8-fold greater than with sham therapy. In contrast, the odds ratio for remission with dTMS dropped to 1.37 in the randomized trials (Prog Neuropsychopharmacol Biol Psychiatry. 2020 Apr 20;99:109850. doi: 10.1016/j.pnpbp.2019.109850). “dTMS has quite a bit of antidepressant potential in treatment-resistant depression, but as an augmentation strategy. More randomized trials are needed, with a particular focus on which classes of antidepressants might be most effective as concurrent therapy,” Dr. Sartorius concluded.

He reported having no financial conflicts regarding his presentation.

bjancin@mdedge.com

SOURCE: Sartorius A. ECNP 2020, Session TP.03.

Recent studies constitute a clarion call for clinicians to routinely screen adolescents with ADHD for nonsuicidal self-injury (NSSI) and its risk factors, Judit Balazs, MD, PhD, said at the virtual congress of the European College of Neuropsychopharmacology.

She was lead author of one of these studies, which drew a remarkable and disturbing conclusion: “We found – and it’s a very alarming result – that more than 70% of those people who had ADHD and [nonsuicidal self-injury] were girls. The girls with ADHD seem to be a high-risk population,” observed Dr. Balazs, professor and chair of the department of developmental psychology at Eotvos Lorand University, Budapest.

NSSI first became a specific diagnosis in the DSM-5. It is defined as deliberate, nonculturally sanctioned, nonsuicidal self-injury on at least five occasions within the past year and carried out with the aim of improving one’s emotional state as a result. The prevalence of NSSI among the general population of adolescents is high, with various investigators reporting rates of 15%-45%. Among adolescents with mental disorders, the reported prevalence climbs to 40%-80%. Intriguingly, however, the prevalence of NSSI among adults is just 4%, even though it’s now clear that many cases of pediatric-onset ADHD continue on well into adulthood, albeit often undiagnosed.

Whether NSSI and suicidal behavior are actually the same entity is currently a topic of intense research, according to Dr. Balazs, who is both a child and adolescent psychiatrist, as well as an adult psychiatrist.

She presented highlights of her cross-sectional study of 202 adolescent inpatients, 51% of them female, at the Vadaskert Child and Adolescent Psychiatry Hospital, a tertiary care center in Budapest. Using the structured diagnostic Mini International Neuropsychiatric Interview for Children and Adolescents (MINI Kid) and the self-rated Deliberate Self-Harm Inventory, Dr. Balazs and her coinvestigators determined that 52 of the adolescents, including 23 boys and 29 girls, met full diagnostic criteria for ADHD and another 77 demonstrated more than five subthreshold ADHD symptoms.

Strikingly, 35 of the 52 teens diagnosed with ADHD, or 67%, had current NSSI. Only 10 of these patients were boys. The other 25, or 71% of the total, were girls.

Psychiatric comorbidities proved to be the rule rather than the exception in the adolescent inpatients with ADHD plus NSSI. Among these inpatients, 94% had a history of suicidal behavior. In addition, 66% carried the diagnosis of oppositional defiant disorder, 63% generalized anxiety disorder, 60% had a psychotic disorder, and 51% had experienced a manic episode. Among them, 49% were diagnosed with social anxiety disorder, 46% with obsessive-compulsive disorder, 31% with panic disorder, 23% with conduct disorder, and an equal percentage with agoraphobia. Furthermore, 43% had a major depressive disorder and 34%, dysthymia. Alcohol abuse or dependence was present in 20%, and an equal percentage had psychoactive substance use disorder.

Dr. Balazs said she and her coinvestigators were surprised by the high prevalence of symptoms of comorbid psychotic disorder in conjunction with NSSI and ADHD. One possible explanation, she opined, is that as inpatients the study participants were at the more severe end of the disease spectrum, and some patients may have been admitted not solely because of the severity of their comorbidities. Another possibility is that, in some cases, what was labeled psychotic disorder may actually have been prodromal unipolar depression.

A key finding in Dr. Balazs’s study was that, according to a regression analysis, the relationship between ADHD and NSSI was mediated entirely by the symptoms of the ADHD comorbidities. Specifically, the significant risk factors for NSSI in patients with ADHD were affective disorders, suicidality, and psychotic disorders in both sexes, with the addition of comorbid alcohol abuse or dependence in girls only. There was no evidence of a direct causal relationship between ADHD, per se, and NSSI.
 

‘Findings warrant further investigation’

The study, which looks at the association between NSSI and adolescents is interesting, yet preliminary, said David Fassler, MD, in an interview.

“The authors conclude that girls with ADHD are at particularly high risk of NSSI,” said Dr. Fassler, clinical professor of psychiatry at the University of Vermont, Burlington. Dr. Fassler was not involved with the study.

“It is limited by sample size, acuity, and the incidence of comorbidities,” said Dr. Fassler, who had no conflicts of interest. “Nonetheless, the findings are intriguing and warrant further investigation with larger samples in diverse clinical settings.”

The study was supported by the Hungarian Scientific Research Fund. In addition, Dr. Balazs received funding from the Hungarian Academy of Sciences. The full details of the study have been published (BMC Psychiatry. 2018 Feb 6;18[1]:34).

bjancin@mdedge.com

SOURCE: Balazs J et al. ECNP 2020, Abstract EDU.02.

Recent studies constitute a clarion call for clinicians to routinely screen adolescents with ADHD for nonsuicidal self-injury (NSSI) and its risk factors, Judit Balazs, MD, PhD, said at the virtual congress of the European College of Neuropsychopharmacology.

She was lead author of one of these studies, which drew a remarkable and disturbing conclusion: “We found – and it’s a very alarming result – that more than 70% of those people who had ADHD and [nonsuicidal self-injury] were girls. The girls with ADHD seem to be a high-risk population,” observed Dr. Balazs, professor and chair of the department of developmental psychology at Eotvos Lorand University, Budapest.

NSSI first became a specific diagnosis in the DSM-5. It is defined as deliberate, nonculturally sanctioned, nonsuicidal self-injury on at least five occasions within the past year and carried out with the aim of improving one’s emotional state as a result. The prevalence of NSSI among the general population of adolescents is high, with various investigators reporting rates of 15%-45%. Among adolescents with mental disorders, the reported prevalence climbs to 40%-80%. Intriguingly, however, the prevalence of NSSI among adults is just 4%, even though it’s now clear that many cases of pediatric-onset ADHD continue on well into adulthood, albeit often undiagnosed.

Whether NSSI and suicidal behavior are actually the same entity is currently a topic of intense research, according to Dr. Balazs, who is both a child and adolescent psychiatrist, as well as an adult psychiatrist.

She presented highlights of her cross-sectional study of 202 adolescent inpatients, 51% of them female, at the Vadaskert Child and Adolescent Psychiatry Hospital, a tertiary care center in Budapest. Using the structured diagnostic Mini International Neuropsychiatric Interview for Children and Adolescents (MINI Kid) and the self-rated Deliberate Self-Harm Inventory, Dr. Balazs and her coinvestigators determined that 52 of the adolescents, including 23 boys and 29 girls, met full diagnostic criteria for ADHD and another 77 demonstrated more than five subthreshold ADHD symptoms.

Strikingly, 35 of the 52 teens diagnosed with ADHD, or 67%, had current NSSI. Only 10 of these patients were boys. The other 25, or 71% of the total, were girls.

Psychiatric comorbidities proved to be the rule rather than the exception in the adolescent inpatients with ADHD plus NSSI. Among these inpatients, 94% had a history of suicidal behavior. In addition, 66% carried the diagnosis of oppositional defiant disorder, 63% generalized anxiety disorder, 60% had a psychotic disorder, and 51% had experienced a manic episode. Among them, 49% were diagnosed with social anxiety disorder, 46% with obsessive-compulsive disorder, 31% with panic disorder, 23% with conduct disorder, and an equal percentage with agoraphobia. Furthermore, 43% had a major depressive disorder and 34%, dysthymia. Alcohol abuse or dependence was present in 20%, and an equal percentage had psychoactive substance use disorder.

Dr. Balazs said she and her coinvestigators were surprised by the high prevalence of symptoms of comorbid psychotic disorder in conjunction with NSSI and ADHD. One possible explanation, she opined, is that as inpatients the study participants were at the more severe end of the disease spectrum, and some patients may have been admitted not solely because of the severity of their comorbidities. Another possibility is that, in some cases, what was labeled psychotic disorder may actually have been prodromal unipolar depression.

A key finding in Dr. Balazs’s study was that, according to a regression analysis, the relationship between ADHD and NSSI was mediated entirely by the symptoms of the ADHD comorbidities. Specifically, the significant risk factors for NSSI in patients with ADHD were affective disorders, suicidality, and psychotic disorders in both sexes, with the addition of comorbid alcohol abuse or dependence in girls only. There was no evidence of a direct causal relationship between ADHD, per se, and NSSI.
 

‘Findings warrant further investigation’

The study, which looks at the association between NSSI and adolescents is interesting, yet preliminary, said David Fassler, MD, in an interview.

“The authors conclude that girls with ADHD are at particularly high risk of NSSI,” said Dr. Fassler, clinical professor of psychiatry at the University of Vermont, Burlington. Dr. Fassler was not involved with the study.

“It is limited by sample size, acuity, and the incidence of comorbidities,” said Dr. Fassler, who had no conflicts of interest. “Nonetheless, the findings are intriguing and warrant further investigation with larger samples in diverse clinical settings.”

The study was supported by the Hungarian Scientific Research Fund. In addition, Dr. Balazs received funding from the Hungarian Academy of Sciences. The full details of the study have been published (BMC Psychiatry. 2018 Feb 6;18[1]:34).

bjancin@mdedge.com

SOURCE: Balazs J et al. ECNP 2020, Abstract EDU.02.

Recent studies constitute a clarion call for clinicians to routinely screen adolescents with ADHD for nonsuicidal self-injury (NSSI) and its risk factors, Judit Balazs, MD, PhD, said at the virtual congress of the European College of Neuropsychopharmacology.

She was lead author of one of these studies, which drew a remarkable and disturbing conclusion: “We found – and it’s a very alarming result – that more than 70% of those people who had ADHD and [nonsuicidal self-injury] were girls. The girls with ADHD seem to be a high-risk population,” observed Dr. Balazs, professor and chair of the department of developmental psychology at Eotvos Lorand University, Budapest.

NSSI first became a specific diagnosis in the DSM-5. It is defined as deliberate, nonculturally sanctioned, nonsuicidal self-injury on at least five occasions within the past year and carried out with the aim of improving one’s emotional state as a result. The prevalence of NSSI among the general population of adolescents is high, with various investigators reporting rates of 15%-45%. Among adolescents with mental disorders, the reported prevalence climbs to 40%-80%. Intriguingly, however, the prevalence of NSSI among adults is just 4%, even though it’s now clear that many cases of pediatric-onset ADHD continue on well into adulthood, albeit often undiagnosed.

Whether NSSI and suicidal behavior are actually the same entity is currently a topic of intense research, according to Dr. Balazs, who is both a child and adolescent psychiatrist, as well as an adult psychiatrist.

She presented highlights of her cross-sectional study of 202 adolescent inpatients, 51% of them female, at the Vadaskert Child and Adolescent Psychiatry Hospital, a tertiary care center in Budapest. Using the structured diagnostic Mini International Neuropsychiatric Interview for Children and Adolescents (MINI Kid) and the self-rated Deliberate Self-Harm Inventory, Dr. Balazs and her coinvestigators determined that 52 of the adolescents, including 23 boys and 29 girls, met full diagnostic criteria for ADHD and another 77 demonstrated more than five subthreshold ADHD symptoms.

Strikingly, 35 of the 52 teens diagnosed with ADHD, or 67%, had current NSSI. Only 10 of these patients were boys. The other 25, or 71% of the total, were girls.

Psychiatric comorbidities proved to be the rule rather than the exception in the adolescent inpatients with ADHD plus NSSI. Among these inpatients, 94% had a history of suicidal behavior. In addition, 66% carried the diagnosis of oppositional defiant disorder, 63% generalized anxiety disorder, 60% had a psychotic disorder, and 51% had experienced a manic episode. Among them, 49% were diagnosed with social anxiety disorder, 46% with obsessive-compulsive disorder, 31% with panic disorder, 23% with conduct disorder, and an equal percentage with agoraphobia. Furthermore, 43% had a major depressive disorder and 34%, dysthymia. Alcohol abuse or dependence was present in 20%, and an equal percentage had psychoactive substance use disorder.

Dr. Balazs said she and her coinvestigators were surprised by the high prevalence of symptoms of comorbid psychotic disorder in conjunction with NSSI and ADHD. One possible explanation, she opined, is that as inpatients the study participants were at the more severe end of the disease spectrum, and some patients may have been admitted not solely because of the severity of their comorbidities. Another possibility is that, in some cases, what was labeled psychotic disorder may actually have been prodromal unipolar depression.

A key finding in Dr. Balazs’s study was that, according to a regression analysis, the relationship between ADHD and NSSI was mediated entirely by the symptoms of the ADHD comorbidities. Specifically, the significant risk factors for NSSI in patients with ADHD were affective disorders, suicidality, and psychotic disorders in both sexes, with the addition of comorbid alcohol abuse or dependence in girls only. There was no evidence of a direct causal relationship between ADHD, per se, and NSSI.
 

‘Findings warrant further investigation’

The study, which looks at the association between NSSI and adolescents is interesting, yet preliminary, said David Fassler, MD, in an interview.

“The authors conclude that girls with ADHD are at particularly high risk of NSSI,” said Dr. Fassler, clinical professor of psychiatry at the University of Vermont, Burlington. Dr. Fassler was not involved with the study.

“It is limited by sample size, acuity, and the incidence of comorbidities,” said Dr. Fassler, who had no conflicts of interest. “Nonetheless, the findings are intriguing and warrant further investigation with larger samples in diverse clinical settings.”

The study was supported by the Hungarian Scientific Research Fund. In addition, Dr. Balazs received funding from the Hungarian Academy of Sciences. The full details of the study have been published (BMC Psychiatry. 2018 Feb 6;18[1]:34).

bjancin@mdedge.com

SOURCE: Balazs J et al. ECNP 2020, Abstract EDU.02.

Individualized 10-year and lifetime risks of cancer can now for the first time be estimated in patients with established cardiovascular disease, Cilie C. van ’t Klooster, MD, reported at the virtual annual congress of the European Society of Cardiology.

©sripfoto/Thinkstock.com

She and her coinvestigators have developed an easy-to-use predictive model that generates individualized risk estimates for total cancer, lung cancer, and colorectal cancer. The tool relies on nine readily available clinical variables: age, sex, smoking, weight, height, alcohol use, diabetes, antiplatelet drug use, and C-reactive protein level. The cancer risk calculator factors in an individual’s competing risk of death because of cardiovascular disease (CVD).

The risk calculator was developed using data on 7,280 patients with established CVD enrolled in the ongoing long-term Dutch UCC-SMART (Utrecht Cardiovascular Cohort – Second Manifestations of Arterial Disease) study, then independently validated in 9,322 patients in the double-blind CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes) trial, explained Dr. van ’t Klooster of Utrecht (the Netherlands) University.

Several other prediction models estimate the risk of a specific type of cancer, most commonly breast cancer or lung cancer. But the new Utrecht prediction tool is the first one to estimate total cancer risk. It’s also the first to apply specifically to patients with known CVD, thus filling an unmet need, because patients with established CVD are known to be on average at 19% increased risk of total cancer and 56% greater risk for lung cancer, compared with the general population. This is thought to be caused mainly by shared risk factors, including smoking, obesity, and low-grade systemic inflammation.

As the Utrecht/CANTOS analysis shows, however, that 19% increased relative risk for cancer in patients with CVD doesn’t tell the whole story. While the median lifetime and 10-year risks of total cancer in CANTOS were 26% and 10%, respectively, the individual patient risks for total cancer estimated using the Dutch prediction model ranged from 1% to 52% for lifetime and from 1% to 31% for 10-year risk. The same was true for lung cancer risk: median 5% lifetime and 2% 10-year risks, with individual patient risks ranging from 0% to 37% and from 0% to 24%. Likewise for colorectal cancer: a median 4% lifetime risk, ranging from 0% to 6%, and a median 2% risk over the next 10 years, with personalized risks ranging as high as 13% for lifetime risk and 6% for 10-year colorectal cancer risk.

The risk calculator performed “reasonably well,” according to Dr. van ’t Klooster. She pointed to a C-statistic of 0.74 for lung cancer, 0.63 for total cancer, and 0.64 for colorectal cancer. It’s possible the risk predictor’s performance could be further enhanced by incorporation of several potentially important factors that weren’t available in the UCC-SMART derivation cohort, including race, education level, and socioeconomic status, she added.

Potential applications for the risk calculator in clinical practice require further study, but include using the lifetime risk prediction for cancer as a motivational aid in conversations with patients about the importance of behavioral change in support of a healthier lifestyle. Also, a high predicted 10-year lung cancer risk could potentially be used to lower the threshold for a screening chest CT, resulting in earlier detection and treatment of lung cancer, Dr. van ’t Klooster noted.

In an interview, Bonnie Ky, MD, MSCE, praised the risk prediction study as rigorously executed, topical, and clinically significant.

“This paper signifies the overlap between our two disciplines of cancer and cardiovascular disease in terms of the risks that we face together when we care for this patient population,” said Dr. Ky, a cardiologist at the University of Pennsylvania, Philadelphia.

“Many of us in medicine believe in the importance of risk prediction: identifying who’s at high risk and doing everything we can to mitigate that risk. This paper speaks to that and moves us one step closer to accomplishing that aim,” added Dr. Ky, who is editor in chief of JACC: CardioOncology, which published the study simultaneously with Dr. van ’t Klooster’s presentation at ESC 2020. The paper provides direct access to the risk calculator.

Dr. van ’t Klooster reported having no financial conflicts regarding her study. UCC-SMART is funded by a Utrecht University grant, and CANTOS was funded by Novartis.

bjancin@mdedge.com

SOURCE: van ’t Klooster CC. ESC 2020 and JACC CardioOncol. 2020 Aug. doi: 10.1016/j.jaccao.2020.07.001.

Individualized 10-year and lifetime risks of cancer can now for the first time be estimated in patients with established cardiovascular disease, Cilie C. van ’t Klooster, MD, reported at the virtual annual congress of the European Society of Cardiology.

©sripfoto/Thinkstock.com

She and her coinvestigators have developed an easy-to-use predictive model that generates individualized risk estimates for total cancer, lung cancer, and colorectal cancer. The tool relies on nine readily available clinical variables: age, sex, smoking, weight, height, alcohol use, diabetes, antiplatelet drug use, and C-reactive protein level. The cancer risk calculator factors in an individual’s competing risk of death because of cardiovascular disease (CVD).

The risk calculator was developed using data on 7,280 patients with established CVD enrolled in the ongoing long-term Dutch UCC-SMART (Utrecht Cardiovascular Cohort – Second Manifestations of Arterial Disease) study, then independently validated in 9,322 patients in the double-blind CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes) trial, explained Dr. van ’t Klooster of Utrecht (the Netherlands) University.

Several other prediction models estimate the risk of a specific type of cancer, most commonly breast cancer or lung cancer. But the new Utrecht prediction tool is the first one to estimate total cancer risk. It’s also the first to apply specifically to patients with known CVD, thus filling an unmet need, because patients with established CVD are known to be on average at 19% increased risk of total cancer and 56% greater risk for lung cancer, compared with the general population. This is thought to be caused mainly by shared risk factors, including smoking, obesity, and low-grade systemic inflammation.

As the Utrecht/CANTOS analysis shows, however, that 19% increased relative risk for cancer in patients with CVD doesn’t tell the whole story. While the median lifetime and 10-year risks of total cancer in CANTOS were 26% and 10%, respectively, the individual patient risks for total cancer estimated using the Dutch prediction model ranged from 1% to 52% for lifetime and from 1% to 31% for 10-year risk. The same was true for lung cancer risk: median 5% lifetime and 2% 10-year risks, with individual patient risks ranging from 0% to 37% and from 0% to 24%. Likewise for colorectal cancer: a median 4% lifetime risk, ranging from 0% to 6%, and a median 2% risk over the next 10 years, with personalized risks ranging as high as 13% for lifetime risk and 6% for 10-year colorectal cancer risk.

The risk calculator performed “reasonably well,” according to Dr. van ’t Klooster. She pointed to a C-statistic of 0.74 for lung cancer, 0.63 for total cancer, and 0.64 for colorectal cancer. It’s possible the risk predictor’s performance could be further enhanced by incorporation of several potentially important factors that weren’t available in the UCC-SMART derivation cohort, including race, education level, and socioeconomic status, she added.

Potential applications for the risk calculator in clinical practice require further study, but include using the lifetime risk prediction for cancer as a motivational aid in conversations with patients about the importance of behavioral change in support of a healthier lifestyle. Also, a high predicted 10-year lung cancer risk could potentially be used to lower the threshold for a screening chest CT, resulting in earlier detection and treatment of lung cancer, Dr. van ’t Klooster noted.

In an interview, Bonnie Ky, MD, MSCE, praised the risk prediction study as rigorously executed, topical, and clinically significant.

“This paper signifies the overlap between our two disciplines of cancer and cardiovascular disease in terms of the risks that we face together when we care for this patient population,” said Dr. Ky, a cardiologist at the University of Pennsylvania, Philadelphia.

“Many of us in medicine believe in the importance of risk prediction: identifying who’s at high risk and doing everything we can to mitigate that risk. This paper speaks to that and moves us one step closer to accomplishing that aim,” added Dr. Ky, who is editor in chief of JACC: CardioOncology, which published the study simultaneously with Dr. van ’t Klooster’s presentation at ESC 2020. The paper provides direct access to the risk calculator.

Dr. van ’t Klooster reported having no financial conflicts regarding her study. UCC-SMART is funded by a Utrecht University grant, and CANTOS was funded by Novartis.

bjancin@mdedge.com

SOURCE: van ’t Klooster CC. ESC 2020 and JACC CardioOncol. 2020 Aug. doi: 10.1016/j.jaccao.2020.07.001.

Individualized 10-year and lifetime risks of cancer can now for the first time be estimated in patients with established cardiovascular disease, Cilie C. van ’t Klooster, MD, reported at the virtual annual congress of the European Society of Cardiology.

©sripfoto/Thinkstock.com

She and her coinvestigators have developed an easy-to-use predictive model that generates individualized risk estimates for total cancer, lung cancer, and colorectal cancer. The tool relies on nine readily available clinical variables: age, sex, smoking, weight, height, alcohol use, diabetes, antiplatelet drug use, and C-reactive protein level. The cancer risk calculator factors in an individual’s competing risk of death because of cardiovascular disease (CVD).

The risk calculator was developed using data on 7,280 patients with established CVD enrolled in the ongoing long-term Dutch UCC-SMART (Utrecht Cardiovascular Cohort – Second Manifestations of Arterial Disease) study, then independently validated in 9,322 patients in the double-blind CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes) trial, explained Dr. van ’t Klooster of Utrecht (the Netherlands) University.

Several other prediction models estimate the risk of a specific type of cancer, most commonly breast cancer or lung cancer. But the new Utrecht prediction tool is the first one to estimate total cancer risk. It’s also the first to apply specifically to patients with known CVD, thus filling an unmet need, because patients with established CVD are known to be on average at 19% increased risk of total cancer and 56% greater risk for lung cancer, compared with the general population. This is thought to be caused mainly by shared risk factors, including smoking, obesity, and low-grade systemic inflammation.

As the Utrecht/CANTOS analysis shows, however, that 19% increased relative risk for cancer in patients with CVD doesn’t tell the whole story. While the median lifetime and 10-year risks of total cancer in CANTOS were 26% and 10%, respectively, the individual patient risks for total cancer estimated using the Dutch prediction model ranged from 1% to 52% for lifetime and from 1% to 31% for 10-year risk. The same was true for lung cancer risk: median 5% lifetime and 2% 10-year risks, with individual patient risks ranging from 0% to 37% and from 0% to 24%. Likewise for colorectal cancer: a median 4% lifetime risk, ranging from 0% to 6%, and a median 2% risk over the next 10 years, with personalized risks ranging as high as 13% for lifetime risk and 6% for 10-year colorectal cancer risk.

The risk calculator performed “reasonably well,” according to Dr. van ’t Klooster. She pointed to a C-statistic of 0.74 for lung cancer, 0.63 for total cancer, and 0.64 for colorectal cancer. It’s possible the risk predictor’s performance could be further enhanced by incorporation of several potentially important factors that weren’t available in the UCC-SMART derivation cohort, including race, education level, and socioeconomic status, she added.

Potential applications for the risk calculator in clinical practice require further study, but include using the lifetime risk prediction for cancer as a motivational aid in conversations with patients about the importance of behavioral change in support of a healthier lifestyle. Also, a high predicted 10-year lung cancer risk could potentially be used to lower the threshold for a screening chest CT, resulting in earlier detection and treatment of lung cancer, Dr. van ’t Klooster noted.

In an interview, Bonnie Ky, MD, MSCE, praised the risk prediction study as rigorously executed, topical, and clinically significant.

“This paper signifies the overlap between our two disciplines of cancer and cardiovascular disease in terms of the risks that we face together when we care for this patient population,” said Dr. Ky, a cardiologist at the University of Pennsylvania, Philadelphia.

“Many of us in medicine believe in the importance of risk prediction: identifying who’s at high risk and doing everything we can to mitigate that risk. This paper speaks to that and moves us one step closer to accomplishing that aim,” added Dr. Ky, who is editor in chief of JACC: CardioOncology, which published the study simultaneously with Dr. van ’t Klooster’s presentation at ESC 2020. The paper provides direct access to the risk calculator.

Dr. van ’t Klooster reported having no financial conflicts regarding her study. UCC-SMART is funded by a Utrecht University grant, and CANTOS was funded by Novartis.

bjancin@mdedge.com

SOURCE: van ’t Klooster CC. ESC 2020 and JACC CardioOncol. 2020 Aug. doi: 10.1016/j.jaccao.2020.07.001.

A change in rapid eye movement sleeping pattern as measured by quantitative EEG in patients with major depressive disorder after just a single week on a first-line antidepressant predicts eventual clinical response or nonresponse to the medication weeks later, Thorsten Mikoteit, MD, reported at the virtual congress of the European College of Neuropsychopharmacology.

This finding from a small, randomized, controlled trial opens the door to a novel biomarker-based treatment strategy: namely, an immediate switch to a different antidepressant in predicted nonresponders to the first agent. The goal is to improve the final treatment response rate while collapsing the time required to get there, explained Dr. Mikoteit, a psychiatrist affiliated with the University of Basel (Switzerland).

“In real terms, it means that patients, often in the depths of despair, might not need to wait weeks to see if their therapy is working before modifying their treatment,” he observed.

There is a huge unmet need for a biomarker predictive of response to antidepressant medication in patients with major depression, the psychiatrist added. At present, the treatment response rate is unsatisfactory. Moreover, clinical improvement takes a long time to achieve, often requiring several rounds of therapeutic trials during which patients are exposed to weeks of unpleasant side effects of drugs that are ultimately switched out for lack of efficacy or poor tolerance.

The quantitative EEG biomarker under investigation is prefrontal theta cordance (PTC) during REM sleep. It is computed from the absolute and relative theta power in tonic REM sleep. PTC has been shown to correlate with frontocingulate brain activity and cerebral blood perfusion. In an earlier pilot study, Dr. Mikoteit and coinvestigators demonstrated in 33 patients who were experiencing a depressive episode that an increase in PTC after their first week on an antidepressant was associated a significantly increased treatment response rate at the end of the fourth week on the drug, while nonresponders failed to show such increase (J Psychiatr Res. 2017 Sep;92:64-73).

At ECNP 2020, Dr. Mikoteit presented preliminary results from an ongoing randomized, controlled trial including 37 patients hospitalized for major depressive disorder. All underwent baseline evaluation using the Hamilton Depression Rating Scale (HAMD) and were placed on the first-line antidepressant of their psychiatrist’s choice. After 1 week of therapy, participants underwent polysomnography with PTC measurement during tonic REM sleep.

Twenty-two patients were randomized to the intervention arm, in which investigators informed treating psychiatrists of the PTC results. The clinicians were instructed to change to another antidepressant if the biomarker predicted nonresponse or stay the course if the PTC results were favorable. Polysomnography was repeated 1 week later in the intervention arm, and the second-line antidepressant was either continued or switched out depending on the PTC findings. In the control arm, psychiatrists weren’t informed of the PTC results and patients continued on their initial antidepressant. The intervention and control groups were comparable in terms of age, sex, and severity of depression, with an average baseline HAMD score of 22.

A treatment response was defined as at least a 50% reduction in HAMD score from baseline to week 5. About 86% of patients who switched antidepressants based upon their 1-week quantitative EEG findings were categorized as treatment responders at week 5, compared with 20% of controls.

The overall 5-week response rate in the intervention group was 73%, compared with 60% in the control arm. This favorable trend didn’t achieve statistical significance, presumably because of the study’s sample size; however, the study is continuing to enroll participants in order to achieve a definitive result.

Dr. Mikoteit noted that the cost and inconvenience of spending a night in a sleep laboratory would be worthwhile if it resulted in the ability to give effective treatment much sooner. This would be particularly advantageous in patients at increased risk for suicide.

“If this is confirmed to be effective, it will save lives,” he said.
 

Study could have “enormous implications”

Of note, in the landmark National Institute of Mental Health–sponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, slightly less than half of patients with major depressive disorder achieved a treatment response to their first-line antidepressant, and it took an average of 6 weeks of therapy to do. About one in four nonresponders who chose to switch to a different antidepressant got better.

“The STAR*D trial is still the gold standard for understanding antidepressant response, and so being able to see if an antidepressant works within 1 week would be a real breakthrough,” Catherine Harmer, DPhil, said in an interview.

“Most of the time, patients need to wait for around 4 weeks before they can tell if they are responding to a particular antidepressant or not. This is a hugely disabling and lengthy process, and often a different treatment then needs to be started,” added Dr. Harmer, professor of cognitive neuroscience and director of the Psychopharmacology and Emotional Research Lab at the University of Oxford (England).

“If the study results presented by Dr. Mikoteit are replicated in a larger blinded study, then it would have enormous implications for the future treatment of individuals with depression,” according to Dr. Harmer, who was not involved in the study and has no conflicts of interest related to it.

Dr. Mikoteit reported having no financial conflicts regarding the study, funded by the Psychiatric University Hospital of Basel.

bjancin@mdedge.com

SOURCE: Mikoteit T et al. ECNP 2020, Abstract P.733.

A change in rapid eye movement sleeping pattern as measured by quantitative EEG in patients with major depressive disorder after just a single week on a first-line antidepressant predicts eventual clinical response or nonresponse to the medication weeks later, Thorsten Mikoteit, MD, reported at the virtual congress of the European College of Neuropsychopharmacology.

This finding from a small, randomized, controlled trial opens the door to a novel biomarker-based treatment strategy: namely, an immediate switch to a different antidepressant in predicted nonresponders to the first agent. The goal is to improve the final treatment response rate while collapsing the time required to get there, explained Dr. Mikoteit, a psychiatrist affiliated with the University of Basel (Switzerland).

“In real terms, it means that patients, often in the depths of despair, might not need to wait weeks to see if their therapy is working before modifying their treatment,” he observed.

There is a huge unmet need for a biomarker predictive of response to antidepressant medication in patients with major depression, the psychiatrist added. At present, the treatment response rate is unsatisfactory. Moreover, clinical improvement takes a long time to achieve, often requiring several rounds of therapeutic trials during which patients are exposed to weeks of unpleasant side effects of drugs that are ultimately switched out for lack of efficacy or poor tolerance.

The quantitative EEG biomarker under investigation is prefrontal theta cordance (PTC) during REM sleep. It is computed from the absolute and relative theta power in tonic REM sleep. PTC has been shown to correlate with frontocingulate brain activity and cerebral blood perfusion. In an earlier pilot study, Dr. Mikoteit and coinvestigators demonstrated in 33 patients who were experiencing a depressive episode that an increase in PTC after their first week on an antidepressant was associated a significantly increased treatment response rate at the end of the fourth week on the drug, while nonresponders failed to show such increase (J Psychiatr Res. 2017 Sep;92:64-73).

At ECNP 2020, Dr. Mikoteit presented preliminary results from an ongoing randomized, controlled trial including 37 patients hospitalized for major depressive disorder. All underwent baseline evaluation using the Hamilton Depression Rating Scale (HAMD) and were placed on the first-line antidepressant of their psychiatrist’s choice. After 1 week of therapy, participants underwent polysomnography with PTC measurement during tonic REM sleep.

Twenty-two patients were randomized to the intervention arm, in which investigators informed treating psychiatrists of the PTC results. The clinicians were instructed to change to another antidepressant if the biomarker predicted nonresponse or stay the course if the PTC results were favorable. Polysomnography was repeated 1 week later in the intervention arm, and the second-line antidepressant was either continued or switched out depending on the PTC findings. In the control arm, psychiatrists weren’t informed of the PTC results and patients continued on their initial antidepressant. The intervention and control groups were comparable in terms of age, sex, and severity of depression, with an average baseline HAMD score of 22.

A treatment response was defined as at least a 50% reduction in HAMD score from baseline to week 5. About 86% of patients who switched antidepressants based upon their 1-week quantitative EEG findings were categorized as treatment responders at week 5, compared with 20% of controls.

The overall 5-week response rate in the intervention group was 73%, compared with 60% in the control arm. This favorable trend didn’t achieve statistical significance, presumably because of the study’s sample size; however, the study is continuing to enroll participants in order to achieve a definitive result.

Dr. Mikoteit noted that the cost and inconvenience of spending a night in a sleep laboratory would be worthwhile if it resulted in the ability to give effective treatment much sooner. This would be particularly advantageous in patients at increased risk for suicide.

“If this is confirmed to be effective, it will save lives,” he said.
 

Study could have “enormous implications”

Of note, in the landmark National Institute of Mental Health–sponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, slightly less than half of patients with major depressive disorder achieved a treatment response to their first-line antidepressant, and it took an average of 6 weeks of therapy to do. About one in four nonresponders who chose to switch to a different antidepressant got better.

“The STAR*D trial is still the gold standard for understanding antidepressant response, and so being able to see if an antidepressant works within 1 week would be a real breakthrough,” Catherine Harmer, DPhil, said in an interview.

“Most of the time, patients need to wait for around 4 weeks before they can tell if they are responding to a particular antidepressant or not. This is a hugely disabling and lengthy process, and often a different treatment then needs to be started,” added Dr. Harmer, professor of cognitive neuroscience and director of the Psychopharmacology and Emotional Research Lab at the University of Oxford (England).

“If the study results presented by Dr. Mikoteit are replicated in a larger blinded study, then it would have enormous implications for the future treatment of individuals with depression,” according to Dr. Harmer, who was not involved in the study and has no conflicts of interest related to it.

Dr. Mikoteit reported having no financial conflicts regarding the study, funded by the Psychiatric University Hospital of Basel.

bjancin@mdedge.com

SOURCE: Mikoteit T et al. ECNP 2020, Abstract P.733.

A change in rapid eye movement sleeping pattern as measured by quantitative EEG in patients with major depressive disorder after just a single week on a first-line antidepressant predicts eventual clinical response or nonresponse to the medication weeks later, Thorsten Mikoteit, MD, reported at the virtual congress of the European College of Neuropsychopharmacology.

This finding from a small, randomized, controlled trial opens the door to a novel biomarker-based treatment strategy: namely, an immediate switch to a different antidepressant in predicted nonresponders to the first agent. The goal is to improve the final treatment response rate while collapsing the time required to get there, explained Dr. Mikoteit, a psychiatrist affiliated with the University of Basel (Switzerland).

“In real terms, it means that patients, often in the depths of despair, might not need to wait weeks to see if their therapy is working before modifying their treatment,” he observed.

There is a huge unmet need for a biomarker predictive of response to antidepressant medication in patients with major depression, the psychiatrist added. At present, the treatment response rate is unsatisfactory. Moreover, clinical improvement takes a long time to achieve, often requiring several rounds of therapeutic trials during which patients are exposed to weeks of unpleasant side effects of drugs that are ultimately switched out for lack of efficacy or poor tolerance.

The quantitative EEG biomarker under investigation is prefrontal theta cordance (PTC) during REM sleep. It is computed from the absolute and relative theta power in tonic REM sleep. PTC has been shown to correlate with frontocingulate brain activity and cerebral blood perfusion. In an earlier pilot study, Dr. Mikoteit and coinvestigators demonstrated in 33 patients who were experiencing a depressive episode that an increase in PTC after their first week on an antidepressant was associated a significantly increased treatment response rate at the end of the fourth week on the drug, while nonresponders failed to show such increase (J Psychiatr Res. 2017 Sep;92:64-73).

At ECNP 2020, Dr. Mikoteit presented preliminary results from an ongoing randomized, controlled trial including 37 patients hospitalized for major depressive disorder. All underwent baseline evaluation using the Hamilton Depression Rating Scale (HAMD) and were placed on the first-line antidepressant of their psychiatrist’s choice. After 1 week of therapy, participants underwent polysomnography with PTC measurement during tonic REM sleep.

Twenty-two patients were randomized to the intervention arm, in which investigators informed treating psychiatrists of the PTC results. The clinicians were instructed to change to another antidepressant if the biomarker predicted nonresponse or stay the course if the PTC results were favorable. Polysomnography was repeated 1 week later in the intervention arm, and the second-line antidepressant was either continued or switched out depending on the PTC findings. In the control arm, psychiatrists weren’t informed of the PTC results and patients continued on their initial antidepressant. The intervention and control groups were comparable in terms of age, sex, and severity of depression, with an average baseline HAMD score of 22.

A treatment response was defined as at least a 50% reduction in HAMD score from baseline to week 5. About 86% of patients who switched antidepressants based upon their 1-week quantitative EEG findings were categorized as treatment responders at week 5, compared with 20% of controls.

The overall 5-week response rate in the intervention group was 73%, compared with 60% in the control arm. This favorable trend didn’t achieve statistical significance, presumably because of the study’s sample size; however, the study is continuing to enroll participants in order to achieve a definitive result.

Dr. Mikoteit noted that the cost and inconvenience of spending a night in a sleep laboratory would be worthwhile if it resulted in the ability to give effective treatment much sooner. This would be particularly advantageous in patients at increased risk for suicide.

“If this is confirmed to be effective, it will save lives,” he said.
 

Study could have “enormous implications”

Of note, in the landmark National Institute of Mental Health–sponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, slightly less than half of patients with major depressive disorder achieved a treatment response to their first-line antidepressant, and it took an average of 6 weeks of therapy to do. About one in four nonresponders who chose to switch to a different antidepressant got better.

“The STAR*D trial is still the gold standard for understanding antidepressant response, and so being able to see if an antidepressant works within 1 week would be a real breakthrough,” Catherine Harmer, DPhil, said in an interview.

“Most of the time, patients need to wait for around 4 weeks before they can tell if they are responding to a particular antidepressant or not. This is a hugely disabling and lengthy process, and often a different treatment then needs to be started,” added Dr. Harmer, professor of cognitive neuroscience and director of the Psychopharmacology and Emotional Research Lab at the University of Oxford (England).

“If the study results presented by Dr. Mikoteit are replicated in a larger blinded study, then it would have enormous implications for the future treatment of individuals with depression,” according to Dr. Harmer, who was not involved in the study and has no conflicts of interest related to it.

Dr. Mikoteit reported having no financial conflicts regarding the study, funded by the Psychiatric University Hospital of Basel.

bjancin@mdedge.com

SOURCE: Mikoteit T et al. ECNP 2020, Abstract P.733.