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Psilocybin benefits in severe depression observed up to 12 weeks
NEW ORLEANS –
“This is easily the largest study of a psychedelic drug employing modern randomized controlled trial methodology [with] 22 sites and 10 countries, so it’s not your typical phase 2 trial,” the study’s lead author, Guy M. Goodwin, MD, emeritus professor of psychiatry at the University of Oxford, England, said in an interview.
“Importantly, 94% of the patients in the study were psilocybin naive, which is very important for generalizability,” Dr. Goodwin noted.
Long used as psychedelic ‘magic mushrooms,’ psilocybin has gained increased interest in psychiatry in recent years as a potential treatment for severe depression after showing benefits in patients with life-threatening cancers and others with major depressive disorder (MDD).
To put the therapy to test in a more rigorous, randomized trial, Dr. Goodwin and colleagues conducted the phase 2b study of a proprietary synthetic formulation of psilocybin, COMP360 (COMPASS Pathways), recruiting 233 patients with treatment-resistant depression at 22 centers.
The study was presented at the annual meeting of the American Psychiatric Association.
After a 2-week washout period following the discontinuation of antidepressants, the patients were randomized to one of three groups: A single dose of 25 mg (n = 79), 10 mg (n = 75), or a subtherapeutic comparison of 1 mg (n = 79).
The psilocybin was administered in the presence of specially trained therapists who provided psychological support before, during, and after the 6- to 8-hour session.
Patients were then asked to refrain from antidepressant use for at least 3 weeks following the session, and had periodic follow-up for 12 weeks.
For the primary endpoint, those in the 25-mg group, but not the 10-mg dose, showed a significantly greater reduction in depression from baseline versus the 1-mg group on the Montgomery-Åsberg Depression Rating Scale at week 3 (MADRS; -6.6; P < .001).
The benefit was observed at day 2 and week 1 following administration, “confirming the rapid-acting character of the effect,” the investigators reported.
Sustained responses, defined as at least a 50% change from baseline in MADRS total score, were further observed up to week 12 among 20.3% in the 25-mg group and among 5.3% in the 10-mg groups versus 10.1% in the 1-mg group.
On the day of psilocybin treatment, the treatment-emergent side effects that were reported were headache, nausea, and dizziness, with event rates of 83.5% in the 25-mg group, 74.7% in the 10-mg group, and 72.2% in the 1-mg group.
One participant in the 25-mg group experienced acute anxiety and was treated with lorazepam.
The incidence of treatment-emergent serious adverse events from day 2 to week 3 was 6.3% (five patients) in the 25-mg group, 8.0% (six patients) in the 10-mg group, and 1.3% (one patient) in the 1-mg group.
Serious AEs included suicidal ideation and intentional self-injury among two patients each in the 25-mg group, while in the 10-mg group, two had suicidal ideation and one had hospitalization for severe depression.
There were no significant differences between the groups in terms of vital signs or clinical laboratory tests.
Of note, two patients in the 25-mg group had a change from baseline in QTcF >60 msec on day 2. For one patient, the increase was within normal range, and the other had a QTcF interval duration >500 msec on day 2, but levels returned to normal by day 9.
Improvements in context
Dr. Goodwin noted that the improvements were swift and impressive when compared with those of the STAR*D trial, which is the largest prospective study of treatment outcomes in patients with MDD.
“In the STAR*D trial, third- and fourth-step treatments showed low response rates of under 15% and high relapse rates,” Dr. Goodwin said. “By comparison, our response rates at 12 weeks were 20%-25%, so almost double that seen for probably equivalent treatment steps in STAR*D, with a single treatment with 25 mg, and no additional antidepressant, so no side effect burden.
“We hope to follow up enough of these patients [in the new study] to get some idea of relapse rates,” Dr. Goodwin added. “These have been low in comparable studies with MDD patients: We will see.”
Commenting on the research, Balwinder Singh, MD, of the department of psychiatry and psychology, Mayo Clinic, Rochester, Minn., said the study represents a valuable addition to needed evidence on psilocybin – with some caveats.
“This study adds to the emerging evidence base of psilocybin for treatment-resistant depression, at least in the short term,” he said in an interview. “I think the challenge in the real world would be to have access to 6-8 hours of therapy with psilocybin when patients struggle to find good therapists who could provide even weekly therapy for an hour.”
In addition, Dr. Singh questioned the durability of a single dose of psilocybin in the long term, noting a recent study (N Engl J Med. 2021 Apr 15. doi: 10.1056/NEJMoa2032994) that evaluated two doses of psilocybin (25 mg) 3 weeks apart, and failed to show any significant difference compared with the serotonergic antidepressant escitalopram at 6 weeks.
He further expressed concern about the emergence of suicidal behaviors in some patients, as well as the prolongation of QTc > 60 msec reported in the two patients.
“This is something to be carefully assessed in future studies, due to the risk of arrhythmias,” Dr. Singh said.
The study was sponsored by COMPASS Pathfinder Limited. Dr. Goodwin is chief medical officer for COMPASS Pathways. Dr. Singh had no disclosures to report.
NEW ORLEANS –
“This is easily the largest study of a psychedelic drug employing modern randomized controlled trial methodology [with] 22 sites and 10 countries, so it’s not your typical phase 2 trial,” the study’s lead author, Guy M. Goodwin, MD, emeritus professor of psychiatry at the University of Oxford, England, said in an interview.
“Importantly, 94% of the patients in the study were psilocybin naive, which is very important for generalizability,” Dr. Goodwin noted.
Long used as psychedelic ‘magic mushrooms,’ psilocybin has gained increased interest in psychiatry in recent years as a potential treatment for severe depression after showing benefits in patients with life-threatening cancers and others with major depressive disorder (MDD).
To put the therapy to test in a more rigorous, randomized trial, Dr. Goodwin and colleagues conducted the phase 2b study of a proprietary synthetic formulation of psilocybin, COMP360 (COMPASS Pathways), recruiting 233 patients with treatment-resistant depression at 22 centers.
The study was presented at the annual meeting of the American Psychiatric Association.
After a 2-week washout period following the discontinuation of antidepressants, the patients were randomized to one of three groups: A single dose of 25 mg (n = 79), 10 mg (n = 75), or a subtherapeutic comparison of 1 mg (n = 79).
The psilocybin was administered in the presence of specially trained therapists who provided psychological support before, during, and after the 6- to 8-hour session.
Patients were then asked to refrain from antidepressant use for at least 3 weeks following the session, and had periodic follow-up for 12 weeks.
For the primary endpoint, those in the 25-mg group, but not the 10-mg dose, showed a significantly greater reduction in depression from baseline versus the 1-mg group on the Montgomery-Åsberg Depression Rating Scale at week 3 (MADRS; -6.6; P < .001).
The benefit was observed at day 2 and week 1 following administration, “confirming the rapid-acting character of the effect,” the investigators reported.
Sustained responses, defined as at least a 50% change from baseline in MADRS total score, were further observed up to week 12 among 20.3% in the 25-mg group and among 5.3% in the 10-mg groups versus 10.1% in the 1-mg group.
On the day of psilocybin treatment, the treatment-emergent side effects that were reported were headache, nausea, and dizziness, with event rates of 83.5% in the 25-mg group, 74.7% in the 10-mg group, and 72.2% in the 1-mg group.
One participant in the 25-mg group experienced acute anxiety and was treated with lorazepam.
The incidence of treatment-emergent serious adverse events from day 2 to week 3 was 6.3% (five patients) in the 25-mg group, 8.0% (six patients) in the 10-mg group, and 1.3% (one patient) in the 1-mg group.
Serious AEs included suicidal ideation and intentional self-injury among two patients each in the 25-mg group, while in the 10-mg group, two had suicidal ideation and one had hospitalization for severe depression.
There were no significant differences between the groups in terms of vital signs or clinical laboratory tests.
Of note, two patients in the 25-mg group had a change from baseline in QTcF >60 msec on day 2. For one patient, the increase was within normal range, and the other had a QTcF interval duration >500 msec on day 2, but levels returned to normal by day 9.
Improvements in context
Dr. Goodwin noted that the improvements were swift and impressive when compared with those of the STAR*D trial, which is the largest prospective study of treatment outcomes in patients with MDD.
“In the STAR*D trial, third- and fourth-step treatments showed low response rates of under 15% and high relapse rates,” Dr. Goodwin said. “By comparison, our response rates at 12 weeks were 20%-25%, so almost double that seen for probably equivalent treatment steps in STAR*D, with a single treatment with 25 mg, and no additional antidepressant, so no side effect burden.
“We hope to follow up enough of these patients [in the new study] to get some idea of relapse rates,” Dr. Goodwin added. “These have been low in comparable studies with MDD patients: We will see.”
Commenting on the research, Balwinder Singh, MD, of the department of psychiatry and psychology, Mayo Clinic, Rochester, Minn., said the study represents a valuable addition to needed evidence on psilocybin – with some caveats.
“This study adds to the emerging evidence base of psilocybin for treatment-resistant depression, at least in the short term,” he said in an interview. “I think the challenge in the real world would be to have access to 6-8 hours of therapy with psilocybin when patients struggle to find good therapists who could provide even weekly therapy for an hour.”
In addition, Dr. Singh questioned the durability of a single dose of psilocybin in the long term, noting a recent study (N Engl J Med. 2021 Apr 15. doi: 10.1056/NEJMoa2032994) that evaluated two doses of psilocybin (25 mg) 3 weeks apart, and failed to show any significant difference compared with the serotonergic antidepressant escitalopram at 6 weeks.
He further expressed concern about the emergence of suicidal behaviors in some patients, as well as the prolongation of QTc > 60 msec reported in the two patients.
“This is something to be carefully assessed in future studies, due to the risk of arrhythmias,” Dr. Singh said.
The study was sponsored by COMPASS Pathfinder Limited. Dr. Goodwin is chief medical officer for COMPASS Pathways. Dr. Singh had no disclosures to report.
NEW ORLEANS –
“This is easily the largest study of a psychedelic drug employing modern randomized controlled trial methodology [with] 22 sites and 10 countries, so it’s not your typical phase 2 trial,” the study’s lead author, Guy M. Goodwin, MD, emeritus professor of psychiatry at the University of Oxford, England, said in an interview.
“Importantly, 94% of the patients in the study were psilocybin naive, which is very important for generalizability,” Dr. Goodwin noted.
Long used as psychedelic ‘magic mushrooms,’ psilocybin has gained increased interest in psychiatry in recent years as a potential treatment for severe depression after showing benefits in patients with life-threatening cancers and others with major depressive disorder (MDD).
To put the therapy to test in a more rigorous, randomized trial, Dr. Goodwin and colleagues conducted the phase 2b study of a proprietary synthetic formulation of psilocybin, COMP360 (COMPASS Pathways), recruiting 233 patients with treatment-resistant depression at 22 centers.
The study was presented at the annual meeting of the American Psychiatric Association.
After a 2-week washout period following the discontinuation of antidepressants, the patients were randomized to one of three groups: A single dose of 25 mg (n = 79), 10 mg (n = 75), or a subtherapeutic comparison of 1 mg (n = 79).
The psilocybin was administered in the presence of specially trained therapists who provided psychological support before, during, and after the 6- to 8-hour session.
Patients were then asked to refrain from antidepressant use for at least 3 weeks following the session, and had periodic follow-up for 12 weeks.
For the primary endpoint, those in the 25-mg group, but not the 10-mg dose, showed a significantly greater reduction in depression from baseline versus the 1-mg group on the Montgomery-Åsberg Depression Rating Scale at week 3 (MADRS; -6.6; P < .001).
The benefit was observed at day 2 and week 1 following administration, “confirming the rapid-acting character of the effect,” the investigators reported.
Sustained responses, defined as at least a 50% change from baseline in MADRS total score, were further observed up to week 12 among 20.3% in the 25-mg group and among 5.3% in the 10-mg groups versus 10.1% in the 1-mg group.
On the day of psilocybin treatment, the treatment-emergent side effects that were reported were headache, nausea, and dizziness, with event rates of 83.5% in the 25-mg group, 74.7% in the 10-mg group, and 72.2% in the 1-mg group.
One participant in the 25-mg group experienced acute anxiety and was treated with lorazepam.
The incidence of treatment-emergent serious adverse events from day 2 to week 3 was 6.3% (five patients) in the 25-mg group, 8.0% (six patients) in the 10-mg group, and 1.3% (one patient) in the 1-mg group.
Serious AEs included suicidal ideation and intentional self-injury among two patients each in the 25-mg group, while in the 10-mg group, two had suicidal ideation and one had hospitalization for severe depression.
There were no significant differences between the groups in terms of vital signs or clinical laboratory tests.
Of note, two patients in the 25-mg group had a change from baseline in QTcF >60 msec on day 2. For one patient, the increase was within normal range, and the other had a QTcF interval duration >500 msec on day 2, but levels returned to normal by day 9.
Improvements in context
Dr. Goodwin noted that the improvements were swift and impressive when compared with those of the STAR*D trial, which is the largest prospective study of treatment outcomes in patients with MDD.
“In the STAR*D trial, third- and fourth-step treatments showed low response rates of under 15% and high relapse rates,” Dr. Goodwin said. “By comparison, our response rates at 12 weeks were 20%-25%, so almost double that seen for probably equivalent treatment steps in STAR*D, with a single treatment with 25 mg, and no additional antidepressant, so no side effect burden.
“We hope to follow up enough of these patients [in the new study] to get some idea of relapse rates,” Dr. Goodwin added. “These have been low in comparable studies with MDD patients: We will see.”
Commenting on the research, Balwinder Singh, MD, of the department of psychiatry and psychology, Mayo Clinic, Rochester, Minn., said the study represents a valuable addition to needed evidence on psilocybin – with some caveats.
“This study adds to the emerging evidence base of psilocybin for treatment-resistant depression, at least in the short term,” he said in an interview. “I think the challenge in the real world would be to have access to 6-8 hours of therapy with psilocybin when patients struggle to find good therapists who could provide even weekly therapy for an hour.”
In addition, Dr. Singh questioned the durability of a single dose of psilocybin in the long term, noting a recent study (N Engl J Med. 2021 Apr 15. doi: 10.1056/NEJMoa2032994) that evaluated two doses of psilocybin (25 mg) 3 weeks apart, and failed to show any significant difference compared with the serotonergic antidepressant escitalopram at 6 weeks.
He further expressed concern about the emergence of suicidal behaviors in some patients, as well as the prolongation of QTc > 60 msec reported in the two patients.
“This is something to be carefully assessed in future studies, due to the risk of arrhythmias,” Dr. Singh said.
The study was sponsored by COMPASS Pathfinder Limited. Dr. Goodwin is chief medical officer for COMPASS Pathways. Dr. Singh had no disclosures to report.
AT APA 2022
Antipsychotic safe, effective for resistant depression in phase 3 trial
, new results from a phase 3 study show.
Already approved by the U.S. Food and Drug Administration to treat adults with schizophrenia and manic, mixed, or depressive episodes of bipolar I disorder, cariprazine is under investigation as an add-on therapy for MDD.
“Even patients who appear to be nonresponsive to standard antidepressant drugs have a very good chance of responding” to cariprazine, lead study author Gary Sachs, MD, associate clinical professor of psychiatry at Massachusetts General Hospital, Boston, told this news organization.
He noted that cariprazine, which is a partial agonist at D2 and D3, as well as 5-HT1A, “is an entirely different class” of drugs.
“It’s worth understanding how to use drugs like cariprazine and expanding our nomenclature; instead of referring to these drugs as atypical antipsychotics, perhaps referring to them as atypical antidepressants makes more sense,” Dr. Sachs said.
The findings were presented at the annual meeting of the American Psychiatric Association.
More options critical
MDD is among the most common psychiatric disorders in the United States. In 2020, an estimated 21 million adults had at least one major depressive episode.
Previous research has shown almost half of patients with MDD do not experience satisfactory results from their current treatment regimen. Therefore, research on more options for patients is critical, Dr. Sachs said.
Results from a previously published placebo-controlled study showed adjunctive treatment with cariprazine at 2-mg to 4.5-mg per day doses was more effective than placebo in improving depressive symptoms in adults with MDD.
The new analysis included patients with MDD and an inadequate response to antidepressant therapy, including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants. They were recruited from 116 centers in the United States and Europe.
Dr. Sachs noted that a nonresponse to an adequate dose of an antidepressant typically means having less than a 50% improvement over 6 weeks or more.
Researchers randomly assigned the patients to oral cariprazine 1.5 mg/day, cariprazine 3 mg/day, or placebo. All continued to take their antidepressant monotherapy.
The analysis included 757 mostly White participants (mean age, 44.8 years; 73.4% women). All had experienced depression for a “huge” part of their life (average, about 14 years), “not to mention their adult life,” said Dr. Sachs.
In addition, at the start of the study, the participants had been depressed for almost 8 months on average.
The primary endpoint was change at week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. The mean baseline MADRS total score was 32.5.
Less is sometimes more
Results showed a significantly greater mean reduction in MADRS total score for cariprazine 1.5 mg/day vs. placebo at week 6 (P = .005). Significant differences from placebo were observed as early as week 2 and were maintained at week 4, as well as week 6.
“I can say with great confidence that the 1.5-mg dose met all the standards for efficacy,” Dr. Sachs said.
However, this was not the case for the 3-mg/day dose. Although there was a numerically greater reduction in MADRS total score for this dosage of the drug vs. placebo at week 6, the difference was not statistically significant (P = .07).
At week 6, more patients taking the active drug at 1.5 mg/day than placebo responded to treatment, defined as 50% or greater reduction in MADRS total score (44% vs. 34.9%, respectively; P < .05).
Researchers also assessed scores on the Clinical Global Impressions, finding significantly greater score improvement for both the 1.5-mg/day (P = .0026) and 3-mg/day (P =.0076) groups vs. the placebo group.
Improvement at week 6 in mean total score on the Hamilton Depression Rating Scale (HAM-17) reached nominal significance for cariprazine 1.5 mg/day vs. placebo – but not for 3 mg/day.
The results of this “high-quality” double-blind, randomized, controlled, parallel group study provide “what I regard as proven efficacy,” Dr. Sachs said.
He added that the investigational drug was also relatively safe. “The vast majority of patients tolerated it quite well,” he stressed. In addition, the drop-out rate because of adverse events was “quite low overall.”
The only adverse events (AEs) that occurred with the active treatment at a frequency of 5% or more and double that of placebo were akathisia and nausea. Changes in weight were relatively small, at less than 1 kg, in all treatment groups.
There was one serious AE in each active drug group, one of which was a kidney infection. There were two serious AEs reported in the placebo group, including one patient with multiple sclerosis. There were no deaths.
Dr. Sachs noted an advantage of cariprazine is its long half-life, which makes it more user-friendly because “it forgives you if you miss a dose or two.”
Drug manufacturer AbbVie’s supplemental New Drug Application for cariprazine is currently under review by the FDA for expanded use as adjunctive treatment of MDD. A decision by the agency is expected by the end of this year.
Another potential treatment option
Commenting on the findings, James Murrough, MD, PhD, associate professor of psychiatry and of neuroscience and director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai, New York, said he welcomes research into additional treatments for MDD.
“Each medicine in a particular class has a unique pharmacology, so a larger number of medication options may help the clinician find a good match for a particular patient,” said Dr. Murrough, who was not involved with the research.
He noted cariprazine is “somewhat unique” among the dopamine modulators in “preferring interactions with the D3 receptor, one of many types of dopamine receptors.”
Although the study results showed cariprazine was effective in MDD, it “does not entirely break new ground” because previous research has already established the drug’s efficacy as adjunctive therapy for patients with depression not responding to a standard antidepressant, said Dr. Murrough.
He also noted that the lower dose, but not the higher dose, of the drug was found to be significantly beneficial for patients, compared with placebo.
“This is a good reminder that higher doses of a medication are not always better,” Dr. Murrough said.
The study was funded by AbbVie. Dr. Sachs is a full-time employee of Signant Health, which conducted the training and quality control for this study. Dr. Murrough has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new results from a phase 3 study show.
Already approved by the U.S. Food and Drug Administration to treat adults with schizophrenia and manic, mixed, or depressive episodes of bipolar I disorder, cariprazine is under investigation as an add-on therapy for MDD.
“Even patients who appear to be nonresponsive to standard antidepressant drugs have a very good chance of responding” to cariprazine, lead study author Gary Sachs, MD, associate clinical professor of psychiatry at Massachusetts General Hospital, Boston, told this news organization.
He noted that cariprazine, which is a partial agonist at D2 and D3, as well as 5-HT1A, “is an entirely different class” of drugs.
“It’s worth understanding how to use drugs like cariprazine and expanding our nomenclature; instead of referring to these drugs as atypical antipsychotics, perhaps referring to them as atypical antidepressants makes more sense,” Dr. Sachs said.
The findings were presented at the annual meeting of the American Psychiatric Association.
More options critical
MDD is among the most common psychiatric disorders in the United States. In 2020, an estimated 21 million adults had at least one major depressive episode.
Previous research has shown almost half of patients with MDD do not experience satisfactory results from their current treatment regimen. Therefore, research on more options for patients is critical, Dr. Sachs said.
Results from a previously published placebo-controlled study showed adjunctive treatment with cariprazine at 2-mg to 4.5-mg per day doses was more effective than placebo in improving depressive symptoms in adults with MDD.
The new analysis included patients with MDD and an inadequate response to antidepressant therapy, including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants. They were recruited from 116 centers in the United States and Europe.
Dr. Sachs noted that a nonresponse to an adequate dose of an antidepressant typically means having less than a 50% improvement over 6 weeks or more.
Researchers randomly assigned the patients to oral cariprazine 1.5 mg/day, cariprazine 3 mg/day, or placebo. All continued to take their antidepressant monotherapy.
The analysis included 757 mostly White participants (mean age, 44.8 years; 73.4% women). All had experienced depression for a “huge” part of their life (average, about 14 years), “not to mention their adult life,” said Dr. Sachs.
In addition, at the start of the study, the participants had been depressed for almost 8 months on average.
The primary endpoint was change at week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. The mean baseline MADRS total score was 32.5.
Less is sometimes more
Results showed a significantly greater mean reduction in MADRS total score for cariprazine 1.5 mg/day vs. placebo at week 6 (P = .005). Significant differences from placebo were observed as early as week 2 and were maintained at week 4, as well as week 6.
“I can say with great confidence that the 1.5-mg dose met all the standards for efficacy,” Dr. Sachs said.
However, this was not the case for the 3-mg/day dose. Although there was a numerically greater reduction in MADRS total score for this dosage of the drug vs. placebo at week 6, the difference was not statistically significant (P = .07).
At week 6, more patients taking the active drug at 1.5 mg/day than placebo responded to treatment, defined as 50% or greater reduction in MADRS total score (44% vs. 34.9%, respectively; P < .05).
Researchers also assessed scores on the Clinical Global Impressions, finding significantly greater score improvement for both the 1.5-mg/day (P = .0026) and 3-mg/day (P =.0076) groups vs. the placebo group.
Improvement at week 6 in mean total score on the Hamilton Depression Rating Scale (HAM-17) reached nominal significance for cariprazine 1.5 mg/day vs. placebo – but not for 3 mg/day.
The results of this “high-quality” double-blind, randomized, controlled, parallel group study provide “what I regard as proven efficacy,” Dr. Sachs said.
He added that the investigational drug was also relatively safe. “The vast majority of patients tolerated it quite well,” he stressed. In addition, the drop-out rate because of adverse events was “quite low overall.”
The only adverse events (AEs) that occurred with the active treatment at a frequency of 5% or more and double that of placebo were akathisia and nausea. Changes in weight were relatively small, at less than 1 kg, in all treatment groups.
There was one serious AE in each active drug group, one of which was a kidney infection. There were two serious AEs reported in the placebo group, including one patient with multiple sclerosis. There were no deaths.
Dr. Sachs noted an advantage of cariprazine is its long half-life, which makes it more user-friendly because “it forgives you if you miss a dose or two.”
Drug manufacturer AbbVie’s supplemental New Drug Application for cariprazine is currently under review by the FDA for expanded use as adjunctive treatment of MDD. A decision by the agency is expected by the end of this year.
Another potential treatment option
Commenting on the findings, James Murrough, MD, PhD, associate professor of psychiatry and of neuroscience and director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai, New York, said he welcomes research into additional treatments for MDD.
“Each medicine in a particular class has a unique pharmacology, so a larger number of medication options may help the clinician find a good match for a particular patient,” said Dr. Murrough, who was not involved with the research.
He noted cariprazine is “somewhat unique” among the dopamine modulators in “preferring interactions with the D3 receptor, one of many types of dopamine receptors.”
Although the study results showed cariprazine was effective in MDD, it “does not entirely break new ground” because previous research has already established the drug’s efficacy as adjunctive therapy for patients with depression not responding to a standard antidepressant, said Dr. Murrough.
He also noted that the lower dose, but not the higher dose, of the drug was found to be significantly beneficial for patients, compared with placebo.
“This is a good reminder that higher doses of a medication are not always better,” Dr. Murrough said.
The study was funded by AbbVie. Dr. Sachs is a full-time employee of Signant Health, which conducted the training and quality control for this study. Dr. Murrough has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new results from a phase 3 study show.
Already approved by the U.S. Food and Drug Administration to treat adults with schizophrenia and manic, mixed, or depressive episodes of bipolar I disorder, cariprazine is under investigation as an add-on therapy for MDD.
“Even patients who appear to be nonresponsive to standard antidepressant drugs have a very good chance of responding” to cariprazine, lead study author Gary Sachs, MD, associate clinical professor of psychiatry at Massachusetts General Hospital, Boston, told this news organization.
He noted that cariprazine, which is a partial agonist at D2 and D3, as well as 5-HT1A, “is an entirely different class” of drugs.
“It’s worth understanding how to use drugs like cariprazine and expanding our nomenclature; instead of referring to these drugs as atypical antipsychotics, perhaps referring to them as atypical antidepressants makes more sense,” Dr. Sachs said.
The findings were presented at the annual meeting of the American Psychiatric Association.
More options critical
MDD is among the most common psychiatric disorders in the United States. In 2020, an estimated 21 million adults had at least one major depressive episode.
Previous research has shown almost half of patients with MDD do not experience satisfactory results from their current treatment regimen. Therefore, research on more options for patients is critical, Dr. Sachs said.
Results from a previously published placebo-controlled study showed adjunctive treatment with cariprazine at 2-mg to 4.5-mg per day doses was more effective than placebo in improving depressive symptoms in adults with MDD.
The new analysis included patients with MDD and an inadequate response to antidepressant therapy, including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants. They were recruited from 116 centers in the United States and Europe.
Dr. Sachs noted that a nonresponse to an adequate dose of an antidepressant typically means having less than a 50% improvement over 6 weeks or more.
Researchers randomly assigned the patients to oral cariprazine 1.5 mg/day, cariprazine 3 mg/day, or placebo. All continued to take their antidepressant monotherapy.
The analysis included 757 mostly White participants (mean age, 44.8 years; 73.4% women). All had experienced depression for a “huge” part of their life (average, about 14 years), “not to mention their adult life,” said Dr. Sachs.
In addition, at the start of the study, the participants had been depressed for almost 8 months on average.
The primary endpoint was change at week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. The mean baseline MADRS total score was 32.5.
Less is sometimes more
Results showed a significantly greater mean reduction in MADRS total score for cariprazine 1.5 mg/day vs. placebo at week 6 (P = .005). Significant differences from placebo were observed as early as week 2 and were maintained at week 4, as well as week 6.
“I can say with great confidence that the 1.5-mg dose met all the standards for efficacy,” Dr. Sachs said.
However, this was not the case for the 3-mg/day dose. Although there was a numerically greater reduction in MADRS total score for this dosage of the drug vs. placebo at week 6, the difference was not statistically significant (P = .07).
At week 6, more patients taking the active drug at 1.5 mg/day than placebo responded to treatment, defined as 50% or greater reduction in MADRS total score (44% vs. 34.9%, respectively; P < .05).
Researchers also assessed scores on the Clinical Global Impressions, finding significantly greater score improvement for both the 1.5-mg/day (P = .0026) and 3-mg/day (P =.0076) groups vs. the placebo group.
Improvement at week 6 in mean total score on the Hamilton Depression Rating Scale (HAM-17) reached nominal significance for cariprazine 1.5 mg/day vs. placebo – but not for 3 mg/day.
The results of this “high-quality” double-blind, randomized, controlled, parallel group study provide “what I regard as proven efficacy,” Dr. Sachs said.
He added that the investigational drug was also relatively safe. “The vast majority of patients tolerated it quite well,” he stressed. In addition, the drop-out rate because of adverse events was “quite low overall.”
The only adverse events (AEs) that occurred with the active treatment at a frequency of 5% or more and double that of placebo were akathisia and nausea. Changes in weight were relatively small, at less than 1 kg, in all treatment groups.
There was one serious AE in each active drug group, one of which was a kidney infection. There were two serious AEs reported in the placebo group, including one patient with multiple sclerosis. There were no deaths.
Dr. Sachs noted an advantage of cariprazine is its long half-life, which makes it more user-friendly because “it forgives you if you miss a dose or two.”
Drug manufacturer AbbVie’s supplemental New Drug Application for cariprazine is currently under review by the FDA for expanded use as adjunctive treatment of MDD. A decision by the agency is expected by the end of this year.
Another potential treatment option
Commenting on the findings, James Murrough, MD, PhD, associate professor of psychiatry and of neuroscience and director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai, New York, said he welcomes research into additional treatments for MDD.
“Each medicine in a particular class has a unique pharmacology, so a larger number of medication options may help the clinician find a good match for a particular patient,” said Dr. Murrough, who was not involved with the research.
He noted cariprazine is “somewhat unique” among the dopamine modulators in “preferring interactions with the D3 receptor, one of many types of dopamine receptors.”
Although the study results showed cariprazine was effective in MDD, it “does not entirely break new ground” because previous research has already established the drug’s efficacy as adjunctive therapy for patients with depression not responding to a standard antidepressant, said Dr. Murrough.
He also noted that the lower dose, but not the higher dose, of the drug was found to be significantly beneficial for patients, compared with placebo.
“This is a good reminder that higher doses of a medication are not always better,” Dr. Murrough said.
The study was funded by AbbVie. Dr. Sachs is a full-time employee of Signant Health, which conducted the training and quality control for this study. Dr. Murrough has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM APA 2022
Depressed patients respond faster to IV ketamine than intranasal ketamine
NEW ORLEANS – New research reveals that patients with treatment-resistant depression who were treated with repeated intravenous ketamine show no significant differences in achieving response or remission, compared with those receiving the intranasal formulation of the drug, esketamine – although fewer treatments appear necessary with the intravenous formulation.
“ although at the end, the responses are similar,” said first author Balwinder Singh, MD, of the department of psychiatry and psychology, Mayo Clinic, in Rochester, Minn.
The findings were presented at the annual meeting of the American Psychiatric Association.
Commenting on the study, Roger S. McIntyre, MD, underscored that “this is an important study that addresses the priority questions that everyone wants to know – not only for clinical reasons, but economic reasons.” Dr. McIntyre, a professor of psychiatry and pharmacology at the University of Toronto, and head of the university’s mood disorders psychopharmacology unit, said that “there are implications not only for clinical outcomes and cost, but also implementation because IV is obviously more demanding and complicated.”
As intravenous ketamine increasingly gained interest as a rapid-acting treatment for patients with severe, treatment-resistant depression, the introduction of a more convenient intranasal formulation was seen as a welcome improvement and received approval from the Food and Drug Administration in 2019. However, while the approval ushered in more coverage by insurance companies, the treatment can still be expensive. Intravenous ketamine does not have FDA approval.
With a lack of studies in the real-world setting comparing efficacy of the two formulations, Dr. Singh and his colleagues conducted the observational study, evaluating the responses of 62 adults with treatment-resistant depression who had received either up to six IV ketamine infusions of 0.5 mg/kg, infused over 40 minutes, or up to eight intranasal esketamine treatments of 56/84 mg, as approved by the FDA, at the Mayo Clinic Depression Center.
Of the patients, who had a mean age of 47 years, 59 had major depression and 3 had bipolar depression. Among them, 76% (47) received intravenous ketamine and 24% (15) received esketamine, which Dr. Singh noted reflected the higher number of patients included before esketamine received FDA approval. The patients had similar comorbidity profiles, with the intravenous ketamine group having a higher body mass index at baseline.
Overall, the patients all had significant improvement in their depression at the end of the acute phase of 4 weeks, with a mean change in on the 16-Item Quick Inventory of Depressive Symptomatology (QIDS-SR) scale of –8.6 from baseline (P < .001).
The overall remission rate was 38.7% and overall response rate was 58.1%. Those receiving intravenous ketamine had response and remission rates of 57.4% and 42.6%, versus response and remission rates of 60.0% and 26.7% among the esketamine group, which Dr. Singh said were not significant differences (P > .05).
However, the mean number of treatments necessary to achieve response in the intravenous ketamine group was just 2.3 versus 4.6 with esketamine, and the mean number of treatments to achieve remission were 2.5 versus 6.3, respectively (P = .008).
After a multivariate adjustment, the time to response was determined to be faster with intravenous ketamine versus esketamine (hazard ratio, 2.61; P = .05) and the time to remission was also faster (HR, 5.0; P = .02).
“What this means is you would need fewer treatments to achieve a response or remission with IV ketamine, so there could be an acceleration of patients’ antidepressant response,” Dr. Singh explained.
There were no significant differences between the groups in terms of side effects, and most patients tolerated the treatments well.
Dr. Singh noted the limitation of the study is that it was observational and included a small sample size. Nevertheless, when asked which he would choose if starting treatment when insurance was not an issue, Dr. Singh replied: “I would take patient preference into account, but certainly IV seems to have an advantage.”
Dr. McIntyre noted that, though small, the study’s setting in a real world clinical environment is important.
“Obviously this is observational and not controlled, but the strength is that this involved a real-world cohort of patients and real world applications,” he said. “It’s difficult to have a true comparator head-to-head trial, so that makes this all the more important because it takes into consideration all of the complexities of real world patients.”
Dr. McIntyre emphasized that the study is not “the last word on the story because we need to see a larger sample and replication. But certainly they make an argument that IV ketamine may have an advantage over the speed of onset with intranasal ketamine, which will need to be either replicated or refuted, but it’s a great starting point in the conversation.”
Navigating patient preference
Robert Meisner, MD, founding medical director of the McLean Ketamine Service, Division of Psychiatric Neurotherapeutics, McLean Hospital, Harvard Medical School, in Boston, noted that wide-ranging factors may influence patient as well as clinician decisions about which ketamine treatment approach to use.
“When a patient appears to be equally well-suited for both interventions, I continue to be surprised by why one patient will indicate a preference for intranasal esketamine, while another will lean toward IV racemic ketamine,” he said in an interview.
“Some patients find esketamine’s clear and consistent protocol optimal for scheduling and navigating the logistics of daily life; others value the flexibility offered by certain evidence-based, racemic (IV) protocols,” he said. “Predicting who will prefer each treatment, even with the apparent temporal advantage with IV ketamine, is extremely difficult.”
Likewise, in terms of clinician preference, Dr. Meisner notes that key concerns may sway decisions.
“If I’m concerned with labile pressures or hypertension, for example, or if I have a patient with, say, Erlos Danlos Syndrome without a clear subtype, and hence, some risk of undiscovered aneurysmal vascular disease, I may lean toward racemic IV ketamine.”
On the other hand, “some patients find the simplicity and predictability of the maintenance esketamine protocol comforting and psychologically stabilizing,” he added. “Yet others find that their work or family’s erratic demands on their time make one of the evidence-based racemic regimens preferable – inasmuch as it integrates more flexibility and allows them to remain more fully engaged in the basic activities or work and family.”
Dr. Meisner noted the caveat that efforts to decide which method to use are often complicated by substantial misinformation.
“I can’t emphasize how much misinformation continues to abound regarding appropriate (evidence-based) and safe use of ketamine and esketamine,” he said. “Especially on the IV racemic side, there simply is no substantive evidence base for many of the claims that some providers are preaching.”
The confusion, driven in part by social media, “has diffused into sectors of the field and industry that one might assume are relatively immune (i.e., allied physicians, sophisticated payers, etc),” he added.
“In short, two mantra continue to apply,” Dr. Meisner said. “One – if it sounds too good to be true, it probably is; and two – in pharmacology and interventional psychiatry, we see remarkable progress and potential, but there simply is no such thing as a magic bullet.”
Dr. Singh and Dr. Meisner had no disclosures to report. Dr. McIntyre has received research grant support from Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/National Natural Science Foundation of China, and speaker/consultation fees from Lundbeck, Janssen, Alkermes,Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie, and Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific.
NEW ORLEANS – New research reveals that patients with treatment-resistant depression who were treated with repeated intravenous ketamine show no significant differences in achieving response or remission, compared with those receiving the intranasal formulation of the drug, esketamine – although fewer treatments appear necessary with the intravenous formulation.
“ although at the end, the responses are similar,” said first author Balwinder Singh, MD, of the department of psychiatry and psychology, Mayo Clinic, in Rochester, Minn.
The findings were presented at the annual meeting of the American Psychiatric Association.
Commenting on the study, Roger S. McIntyre, MD, underscored that “this is an important study that addresses the priority questions that everyone wants to know – not only for clinical reasons, but economic reasons.” Dr. McIntyre, a professor of psychiatry and pharmacology at the University of Toronto, and head of the university’s mood disorders psychopharmacology unit, said that “there are implications not only for clinical outcomes and cost, but also implementation because IV is obviously more demanding and complicated.”
As intravenous ketamine increasingly gained interest as a rapid-acting treatment for patients with severe, treatment-resistant depression, the introduction of a more convenient intranasal formulation was seen as a welcome improvement and received approval from the Food and Drug Administration in 2019. However, while the approval ushered in more coverage by insurance companies, the treatment can still be expensive. Intravenous ketamine does not have FDA approval.
With a lack of studies in the real-world setting comparing efficacy of the two formulations, Dr. Singh and his colleagues conducted the observational study, evaluating the responses of 62 adults with treatment-resistant depression who had received either up to six IV ketamine infusions of 0.5 mg/kg, infused over 40 minutes, or up to eight intranasal esketamine treatments of 56/84 mg, as approved by the FDA, at the Mayo Clinic Depression Center.
Of the patients, who had a mean age of 47 years, 59 had major depression and 3 had bipolar depression. Among them, 76% (47) received intravenous ketamine and 24% (15) received esketamine, which Dr. Singh noted reflected the higher number of patients included before esketamine received FDA approval. The patients had similar comorbidity profiles, with the intravenous ketamine group having a higher body mass index at baseline.
Overall, the patients all had significant improvement in their depression at the end of the acute phase of 4 weeks, with a mean change in on the 16-Item Quick Inventory of Depressive Symptomatology (QIDS-SR) scale of –8.6 from baseline (P < .001).
The overall remission rate was 38.7% and overall response rate was 58.1%. Those receiving intravenous ketamine had response and remission rates of 57.4% and 42.6%, versus response and remission rates of 60.0% and 26.7% among the esketamine group, which Dr. Singh said were not significant differences (P > .05).
However, the mean number of treatments necessary to achieve response in the intravenous ketamine group was just 2.3 versus 4.6 with esketamine, and the mean number of treatments to achieve remission were 2.5 versus 6.3, respectively (P = .008).
After a multivariate adjustment, the time to response was determined to be faster with intravenous ketamine versus esketamine (hazard ratio, 2.61; P = .05) and the time to remission was also faster (HR, 5.0; P = .02).
“What this means is you would need fewer treatments to achieve a response or remission with IV ketamine, so there could be an acceleration of patients’ antidepressant response,” Dr. Singh explained.
There were no significant differences between the groups in terms of side effects, and most patients tolerated the treatments well.
Dr. Singh noted the limitation of the study is that it was observational and included a small sample size. Nevertheless, when asked which he would choose if starting treatment when insurance was not an issue, Dr. Singh replied: “I would take patient preference into account, but certainly IV seems to have an advantage.”
Dr. McIntyre noted that, though small, the study’s setting in a real world clinical environment is important.
“Obviously this is observational and not controlled, but the strength is that this involved a real-world cohort of patients and real world applications,” he said. “It’s difficult to have a true comparator head-to-head trial, so that makes this all the more important because it takes into consideration all of the complexities of real world patients.”
Dr. McIntyre emphasized that the study is not “the last word on the story because we need to see a larger sample and replication. But certainly they make an argument that IV ketamine may have an advantage over the speed of onset with intranasal ketamine, which will need to be either replicated or refuted, but it’s a great starting point in the conversation.”
Navigating patient preference
Robert Meisner, MD, founding medical director of the McLean Ketamine Service, Division of Psychiatric Neurotherapeutics, McLean Hospital, Harvard Medical School, in Boston, noted that wide-ranging factors may influence patient as well as clinician decisions about which ketamine treatment approach to use.
“When a patient appears to be equally well-suited for both interventions, I continue to be surprised by why one patient will indicate a preference for intranasal esketamine, while another will lean toward IV racemic ketamine,” he said in an interview.
“Some patients find esketamine’s clear and consistent protocol optimal for scheduling and navigating the logistics of daily life; others value the flexibility offered by certain evidence-based, racemic (IV) protocols,” he said. “Predicting who will prefer each treatment, even with the apparent temporal advantage with IV ketamine, is extremely difficult.”
Likewise, in terms of clinician preference, Dr. Meisner notes that key concerns may sway decisions.
“If I’m concerned with labile pressures or hypertension, for example, or if I have a patient with, say, Erlos Danlos Syndrome without a clear subtype, and hence, some risk of undiscovered aneurysmal vascular disease, I may lean toward racemic IV ketamine.”
On the other hand, “some patients find the simplicity and predictability of the maintenance esketamine protocol comforting and psychologically stabilizing,” he added. “Yet others find that their work or family’s erratic demands on their time make one of the evidence-based racemic regimens preferable – inasmuch as it integrates more flexibility and allows them to remain more fully engaged in the basic activities or work and family.”
Dr. Meisner noted the caveat that efforts to decide which method to use are often complicated by substantial misinformation.
“I can’t emphasize how much misinformation continues to abound regarding appropriate (evidence-based) and safe use of ketamine and esketamine,” he said. “Especially on the IV racemic side, there simply is no substantive evidence base for many of the claims that some providers are preaching.”
The confusion, driven in part by social media, “has diffused into sectors of the field and industry that one might assume are relatively immune (i.e., allied physicians, sophisticated payers, etc),” he added.
“In short, two mantra continue to apply,” Dr. Meisner said. “One – if it sounds too good to be true, it probably is; and two – in pharmacology and interventional psychiatry, we see remarkable progress and potential, but there simply is no such thing as a magic bullet.”
Dr. Singh and Dr. Meisner had no disclosures to report. Dr. McIntyre has received research grant support from Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/National Natural Science Foundation of China, and speaker/consultation fees from Lundbeck, Janssen, Alkermes,Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie, and Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific.
NEW ORLEANS – New research reveals that patients with treatment-resistant depression who were treated with repeated intravenous ketamine show no significant differences in achieving response or remission, compared with those receiving the intranasal formulation of the drug, esketamine – although fewer treatments appear necessary with the intravenous formulation.
“ although at the end, the responses are similar,” said first author Balwinder Singh, MD, of the department of psychiatry and psychology, Mayo Clinic, in Rochester, Minn.
The findings were presented at the annual meeting of the American Psychiatric Association.
Commenting on the study, Roger S. McIntyre, MD, underscored that “this is an important study that addresses the priority questions that everyone wants to know – not only for clinical reasons, but economic reasons.” Dr. McIntyre, a professor of psychiatry and pharmacology at the University of Toronto, and head of the university’s mood disorders psychopharmacology unit, said that “there are implications not only for clinical outcomes and cost, but also implementation because IV is obviously more demanding and complicated.”
As intravenous ketamine increasingly gained interest as a rapid-acting treatment for patients with severe, treatment-resistant depression, the introduction of a more convenient intranasal formulation was seen as a welcome improvement and received approval from the Food and Drug Administration in 2019. However, while the approval ushered in more coverage by insurance companies, the treatment can still be expensive. Intravenous ketamine does not have FDA approval.
With a lack of studies in the real-world setting comparing efficacy of the two formulations, Dr. Singh and his colleagues conducted the observational study, evaluating the responses of 62 adults with treatment-resistant depression who had received either up to six IV ketamine infusions of 0.5 mg/kg, infused over 40 minutes, or up to eight intranasal esketamine treatments of 56/84 mg, as approved by the FDA, at the Mayo Clinic Depression Center.
Of the patients, who had a mean age of 47 years, 59 had major depression and 3 had bipolar depression. Among them, 76% (47) received intravenous ketamine and 24% (15) received esketamine, which Dr. Singh noted reflected the higher number of patients included before esketamine received FDA approval. The patients had similar comorbidity profiles, with the intravenous ketamine group having a higher body mass index at baseline.
Overall, the patients all had significant improvement in their depression at the end of the acute phase of 4 weeks, with a mean change in on the 16-Item Quick Inventory of Depressive Symptomatology (QIDS-SR) scale of –8.6 from baseline (P < .001).
The overall remission rate was 38.7% and overall response rate was 58.1%. Those receiving intravenous ketamine had response and remission rates of 57.4% and 42.6%, versus response and remission rates of 60.0% and 26.7% among the esketamine group, which Dr. Singh said were not significant differences (P > .05).
However, the mean number of treatments necessary to achieve response in the intravenous ketamine group was just 2.3 versus 4.6 with esketamine, and the mean number of treatments to achieve remission were 2.5 versus 6.3, respectively (P = .008).
After a multivariate adjustment, the time to response was determined to be faster with intravenous ketamine versus esketamine (hazard ratio, 2.61; P = .05) and the time to remission was also faster (HR, 5.0; P = .02).
“What this means is you would need fewer treatments to achieve a response or remission with IV ketamine, so there could be an acceleration of patients’ antidepressant response,” Dr. Singh explained.
There were no significant differences between the groups in terms of side effects, and most patients tolerated the treatments well.
Dr. Singh noted the limitation of the study is that it was observational and included a small sample size. Nevertheless, when asked which he would choose if starting treatment when insurance was not an issue, Dr. Singh replied: “I would take patient preference into account, but certainly IV seems to have an advantage.”
Dr. McIntyre noted that, though small, the study’s setting in a real world clinical environment is important.
“Obviously this is observational and not controlled, but the strength is that this involved a real-world cohort of patients and real world applications,” he said. “It’s difficult to have a true comparator head-to-head trial, so that makes this all the more important because it takes into consideration all of the complexities of real world patients.”
Dr. McIntyre emphasized that the study is not “the last word on the story because we need to see a larger sample and replication. But certainly they make an argument that IV ketamine may have an advantage over the speed of onset with intranasal ketamine, which will need to be either replicated or refuted, but it’s a great starting point in the conversation.”
Navigating patient preference
Robert Meisner, MD, founding medical director of the McLean Ketamine Service, Division of Psychiatric Neurotherapeutics, McLean Hospital, Harvard Medical School, in Boston, noted that wide-ranging factors may influence patient as well as clinician decisions about which ketamine treatment approach to use.
“When a patient appears to be equally well-suited for both interventions, I continue to be surprised by why one patient will indicate a preference for intranasal esketamine, while another will lean toward IV racemic ketamine,” he said in an interview.
“Some patients find esketamine’s clear and consistent protocol optimal for scheduling and navigating the logistics of daily life; others value the flexibility offered by certain evidence-based, racemic (IV) protocols,” he said. “Predicting who will prefer each treatment, even with the apparent temporal advantage with IV ketamine, is extremely difficult.”
Likewise, in terms of clinician preference, Dr. Meisner notes that key concerns may sway decisions.
“If I’m concerned with labile pressures or hypertension, for example, or if I have a patient with, say, Erlos Danlos Syndrome without a clear subtype, and hence, some risk of undiscovered aneurysmal vascular disease, I may lean toward racemic IV ketamine.”
On the other hand, “some patients find the simplicity and predictability of the maintenance esketamine protocol comforting and psychologically stabilizing,” he added. “Yet others find that their work or family’s erratic demands on their time make one of the evidence-based racemic regimens preferable – inasmuch as it integrates more flexibility and allows them to remain more fully engaged in the basic activities or work and family.”
Dr. Meisner noted the caveat that efforts to decide which method to use are often complicated by substantial misinformation.
“I can’t emphasize how much misinformation continues to abound regarding appropriate (evidence-based) and safe use of ketamine and esketamine,” he said. “Especially on the IV racemic side, there simply is no substantive evidence base for many of the claims that some providers are preaching.”
The confusion, driven in part by social media, “has diffused into sectors of the field and industry that one might assume are relatively immune (i.e., allied physicians, sophisticated payers, etc),” he added.
“In short, two mantra continue to apply,” Dr. Meisner said. “One – if it sounds too good to be true, it probably is; and two – in pharmacology and interventional psychiatry, we see remarkable progress and potential, but there simply is no such thing as a magic bullet.”
Dr. Singh and Dr. Meisner had no disclosures to report. Dr. McIntyre has received research grant support from Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/National Natural Science Foundation of China, and speaker/consultation fees from Lundbeck, Janssen, Alkermes,Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie, and Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific.
AT APA 2022
Multiple mental health woes? Blame it on genetics
Investigators conducted a genetic analysis of 11 major psychiatric disorders, including schizophrenia and bipolar disorder.
“Our findings confirm that high comorbidity across some disorders in part reflects overlapping pathways of genetic risk,” lead author Andrew Grotzinger, PhD, department of psychology and neuroscience, University of Colorado at Boulder, said in a press release.
The results could lead to the development of treatments that address multiple psychiatric disorders at once and help reshape the way diagnoses are established, the researchers note.
The findings were published online in Nature Genetics.
Common genetic patterns
Using the massive UK Biobank and the Psychiatric Genomics Consortium, the researchers applied novel statistical genetic methods to identify common patterns across 11 major psychiatric disorders: schizophrenia, bipolar disorder, major depressive disorder, anxiety disorder, anorexia nervosa, obsessive-compulsive disorder (OCD), Tourette syndrome, post traumatic stress disorder, problematic alcohol use, attention deficit hyperactive disorder, and autism.
The average total sample size per disorder was 156,771 participants, with a range of 9,725 to 802,939 participants.
In all, the investigators identified 152 genetic variants shared across multiple disorders, including those already known to influence certain types of brain cells.
For example, they found that 70% of the genetic signal associated with schizophrenia was also associated with bipolar disorder.
Results also showed that anorexia nervosa and OCD have a strong, shared genetic architecture and that individuals with a genetic predisposition to low body mass index also tend to have a genetic predisposition to these two disorders.
Not surprisingly, the researchers note, there was a large genetic overlap between anxiety disorder and major depressive disorder.
They also observed that psychiatric disorders that tend to cluster together also tend to share genes that influence how and when individuals are physically active during the day.
For example, patients with internalizing disorders such as anxiety and depression tend to have a genetic architecture associated with low movement throughout the day. On the other hand, those with OCD and anorexia tend to have genes associated with higher movement throughout the day.
“When you think about it, it makes sense,” said Dr. Grotzinger. Depressed individuals often experience fatigue or low energy while those with compulsive disorders may have a tough time sitting still, he noted.
One treatment for multiple disorders?
“Collectively, these results offer key insights into the shared and disorder-specific mechanisms of genetic risk for psychiatric disease,” the investigators write.
Their research is also a first step toward developing therapies that can address multiple disorders with one treatment, they add.
“People are more likely today to be prescribed multiple medications intended to treat multiple diagnoses, and in some instances those medicines can have side effects,” Dr. Grotzinger said.
“By identifying what is shared across these issues, we can hopefully come up with ways to target them in a different way that doesn’t require four separate pills or four separate psychotherapy interventions,” he added.
Dr. Grotzinger noted that, for now, the knowledge that genetics are underlying their disorders may provide comfort to some patients.
“It’s important for people to know that they didn’t just get a terrible roll of the dice in life – that they are not facing multiple different issues but rather one set of risk factors bleeding into them all,” he said.
This research had no commercial funding. Dr. Grotzinger reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
Investigators conducted a genetic analysis of 11 major psychiatric disorders, including schizophrenia and bipolar disorder.
“Our findings confirm that high comorbidity across some disorders in part reflects overlapping pathways of genetic risk,” lead author Andrew Grotzinger, PhD, department of psychology and neuroscience, University of Colorado at Boulder, said in a press release.
The results could lead to the development of treatments that address multiple psychiatric disorders at once and help reshape the way diagnoses are established, the researchers note.
The findings were published online in Nature Genetics.
Common genetic patterns
Using the massive UK Biobank and the Psychiatric Genomics Consortium, the researchers applied novel statistical genetic methods to identify common patterns across 11 major psychiatric disorders: schizophrenia, bipolar disorder, major depressive disorder, anxiety disorder, anorexia nervosa, obsessive-compulsive disorder (OCD), Tourette syndrome, post traumatic stress disorder, problematic alcohol use, attention deficit hyperactive disorder, and autism.
The average total sample size per disorder was 156,771 participants, with a range of 9,725 to 802,939 participants.
In all, the investigators identified 152 genetic variants shared across multiple disorders, including those already known to influence certain types of brain cells.
For example, they found that 70% of the genetic signal associated with schizophrenia was also associated with bipolar disorder.
Results also showed that anorexia nervosa and OCD have a strong, shared genetic architecture and that individuals with a genetic predisposition to low body mass index also tend to have a genetic predisposition to these two disorders.
Not surprisingly, the researchers note, there was a large genetic overlap between anxiety disorder and major depressive disorder.
They also observed that psychiatric disorders that tend to cluster together also tend to share genes that influence how and when individuals are physically active during the day.
For example, patients with internalizing disorders such as anxiety and depression tend to have a genetic architecture associated with low movement throughout the day. On the other hand, those with OCD and anorexia tend to have genes associated with higher movement throughout the day.
“When you think about it, it makes sense,” said Dr. Grotzinger. Depressed individuals often experience fatigue or low energy while those with compulsive disorders may have a tough time sitting still, he noted.
One treatment for multiple disorders?
“Collectively, these results offer key insights into the shared and disorder-specific mechanisms of genetic risk for psychiatric disease,” the investigators write.
Their research is also a first step toward developing therapies that can address multiple disorders with one treatment, they add.
“People are more likely today to be prescribed multiple medications intended to treat multiple diagnoses, and in some instances those medicines can have side effects,” Dr. Grotzinger said.
“By identifying what is shared across these issues, we can hopefully come up with ways to target them in a different way that doesn’t require four separate pills or four separate psychotherapy interventions,” he added.
Dr. Grotzinger noted that, for now, the knowledge that genetics are underlying their disorders may provide comfort to some patients.
“It’s important for people to know that they didn’t just get a terrible roll of the dice in life – that they are not facing multiple different issues but rather one set of risk factors bleeding into them all,” he said.
This research had no commercial funding. Dr. Grotzinger reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
Investigators conducted a genetic analysis of 11 major psychiatric disorders, including schizophrenia and bipolar disorder.
“Our findings confirm that high comorbidity across some disorders in part reflects overlapping pathways of genetic risk,” lead author Andrew Grotzinger, PhD, department of psychology and neuroscience, University of Colorado at Boulder, said in a press release.
The results could lead to the development of treatments that address multiple psychiatric disorders at once and help reshape the way diagnoses are established, the researchers note.
The findings were published online in Nature Genetics.
Common genetic patterns
Using the massive UK Biobank and the Psychiatric Genomics Consortium, the researchers applied novel statistical genetic methods to identify common patterns across 11 major psychiatric disorders: schizophrenia, bipolar disorder, major depressive disorder, anxiety disorder, anorexia nervosa, obsessive-compulsive disorder (OCD), Tourette syndrome, post traumatic stress disorder, problematic alcohol use, attention deficit hyperactive disorder, and autism.
The average total sample size per disorder was 156,771 participants, with a range of 9,725 to 802,939 participants.
In all, the investigators identified 152 genetic variants shared across multiple disorders, including those already known to influence certain types of brain cells.
For example, they found that 70% of the genetic signal associated with schizophrenia was also associated with bipolar disorder.
Results also showed that anorexia nervosa and OCD have a strong, shared genetic architecture and that individuals with a genetic predisposition to low body mass index also tend to have a genetic predisposition to these two disorders.
Not surprisingly, the researchers note, there was a large genetic overlap between anxiety disorder and major depressive disorder.
They also observed that psychiatric disorders that tend to cluster together also tend to share genes that influence how and when individuals are physically active during the day.
For example, patients with internalizing disorders such as anxiety and depression tend to have a genetic architecture associated with low movement throughout the day. On the other hand, those with OCD and anorexia tend to have genes associated with higher movement throughout the day.
“When you think about it, it makes sense,” said Dr. Grotzinger. Depressed individuals often experience fatigue or low energy while those with compulsive disorders may have a tough time sitting still, he noted.
One treatment for multiple disorders?
“Collectively, these results offer key insights into the shared and disorder-specific mechanisms of genetic risk for psychiatric disease,” the investigators write.
Their research is also a first step toward developing therapies that can address multiple disorders with one treatment, they add.
“People are more likely today to be prescribed multiple medications intended to treat multiple diagnoses, and in some instances those medicines can have side effects,” Dr. Grotzinger said.
“By identifying what is shared across these issues, we can hopefully come up with ways to target them in a different way that doesn’t require four separate pills or four separate psychotherapy interventions,” he added.
Dr. Grotzinger noted that, for now, the knowledge that genetics are underlying their disorders may provide comfort to some patients.
“It’s important for people to know that they didn’t just get a terrible roll of the dice in life – that they are not facing multiple different issues but rather one set of risk factors bleeding into them all,” he said.
This research had no commercial funding. Dr. Grotzinger reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM NATURE GENETICS
New insight into how brain stimulation eases major depression
For the first time, researchers understand what happens to the brain when patients with treatment-resistant depression receive repetitive transcranial magnetic stimulation (rTMS).
Using functional magnetic resonance imaging (fMRI), they showed that rTMS induces widespread alterations in functional connectivity in brain regions involved in emotion and motor control.
“‘How does rTMS work?’ is one of the most frequent questions I get in clinic. Providing an accurate explanation and narrative to patients is critical,” senior investigator Fidel Vila-Rodriguez, MD, PhD, director of the Non-Invasive Neurostimulation Therapies Laboratory, University of British Columbia, Vancouver, told this news organization.
“Our findings suggest that rTMS might rely on the brain’s capacity for change (neuroplasticity) to exert its effects and that rTMS effects on the brain are widespread beyond the focal area stimulated (functional network effects),” Dr. Vila-Rodriguez added.
The study was published online in the American Journal of Psychiatry.
Mechanistic insights
Although rTMS has proven efficacy for treatment-resistant depression, the mechanisms behind how it affects the brain are not well understood.
In the current study, researchers used fMRI to assess changes in functional connectivity induced by a single rTMS session in 26 women and 12 men with treatment-resistant depression.
They found that – from managing emotional responses to memory and motor control.
Following a 4-week course of rTMS, these connectivity changes predicted about 30% of the variance of improvement in scores on the Montgomery-Åsberg Depression Rating Scale after rTMS treatment.
The most robust predictive associations involved connections between prefrontal regions and motor, parietal, and insular cortices and between bilateral regions of the thalamus.
“By demonstrating this principle and identifying regions of the brain that are activated by rTMS, we can now try to understand whether this pattern can be used as a biomarker,” Dr. Vila-Rodriguez said in a news release.
“This work provides a mechanistic explanation of what rTMS does to treat depression and supports the notion that for rTMS to treat depressive symptoms a distributed change in brain activity (network or circuit base) is necessary,” he told this news organization.
With funding from the Canadian Institutes of Health Research (CIHR), the team will next see if they can use fMRI to guide rTMS at the individual level, with the ultimate goal of “personalizing” rTMS using individualized functional targets, Dr. Vila-Rodriguez said.
New generation of tms researchers
Reached for comment, Jonathan Downar, MD, PhD, department of psychiatry, University of Toronto, noted that TMS can be “very effective” for treatment-resistant depression, and it has a “very clean side effect profile compared to medications.”
What the field is trying to figure out now is “who it works for and how we can predict more effectively who’s going to benefit from it,” Dr. Downar said in an interview.
He noted that the study’s investigators are part of a “new generation of TMS researchers who are bringing new ideas into the fold and figuring out how to use brain imaging to personalize the treatment.” This study represents “a step” in that direction.
“A challenge for the field is that it’s often pretty easy to demonstrate a change at the group level, but the question is whether we can use that at the individual level. That’s a higher bar to meet, and we’re still not there yet,” Dr. Downar added.
Support for the study was provided by Brain Canada, the Michael Smith Foundation for Health Research and the Vancouver Coastal Health Research Institute. Dr. Vila-Rodriguez has received research support from CIHR, Brain Canada, the Michael Smith Foundation for Health Research, the Vancouver Coastal Health Research Institute, and the Weston Brain Institute for investigator-initiated research and philanthropic support from the Seedlings Foundation; he received in-kind equipment support from MagVenture for this investigator-initiated trial; and he has received honoraria for participation on an advisory board for Janssen. Dr. Downar has served as an adviser for BrainCheck, NeuroStim TMS, and Salience Neuro Health; received research grant from CIHR, National Institute for Mental Health, Brain Canada, Canadian Biomarker Integration Network in Depression, Ontario Brain Institute, Klarman Family Foundation, Arrell Family Foundation and the Edgestone Foundation; received travel stipends from Lundbeck and ANT Neuro; and received in-kind equipment support for investigator-initiated trials from MagVenture.
A version of this article first appeared on Medscape.com.
For the first time, researchers understand what happens to the brain when patients with treatment-resistant depression receive repetitive transcranial magnetic stimulation (rTMS).
Using functional magnetic resonance imaging (fMRI), they showed that rTMS induces widespread alterations in functional connectivity in brain regions involved in emotion and motor control.
“‘How does rTMS work?’ is one of the most frequent questions I get in clinic. Providing an accurate explanation and narrative to patients is critical,” senior investigator Fidel Vila-Rodriguez, MD, PhD, director of the Non-Invasive Neurostimulation Therapies Laboratory, University of British Columbia, Vancouver, told this news organization.
“Our findings suggest that rTMS might rely on the brain’s capacity for change (neuroplasticity) to exert its effects and that rTMS effects on the brain are widespread beyond the focal area stimulated (functional network effects),” Dr. Vila-Rodriguez added.
The study was published online in the American Journal of Psychiatry.
Mechanistic insights
Although rTMS has proven efficacy for treatment-resistant depression, the mechanisms behind how it affects the brain are not well understood.
In the current study, researchers used fMRI to assess changes in functional connectivity induced by a single rTMS session in 26 women and 12 men with treatment-resistant depression.
They found that – from managing emotional responses to memory and motor control.
Following a 4-week course of rTMS, these connectivity changes predicted about 30% of the variance of improvement in scores on the Montgomery-Åsberg Depression Rating Scale after rTMS treatment.
The most robust predictive associations involved connections between prefrontal regions and motor, parietal, and insular cortices and between bilateral regions of the thalamus.
“By demonstrating this principle and identifying regions of the brain that are activated by rTMS, we can now try to understand whether this pattern can be used as a biomarker,” Dr. Vila-Rodriguez said in a news release.
“This work provides a mechanistic explanation of what rTMS does to treat depression and supports the notion that for rTMS to treat depressive symptoms a distributed change in brain activity (network or circuit base) is necessary,” he told this news organization.
With funding from the Canadian Institutes of Health Research (CIHR), the team will next see if they can use fMRI to guide rTMS at the individual level, with the ultimate goal of “personalizing” rTMS using individualized functional targets, Dr. Vila-Rodriguez said.
New generation of tms researchers
Reached for comment, Jonathan Downar, MD, PhD, department of psychiatry, University of Toronto, noted that TMS can be “very effective” for treatment-resistant depression, and it has a “very clean side effect profile compared to medications.”
What the field is trying to figure out now is “who it works for and how we can predict more effectively who’s going to benefit from it,” Dr. Downar said in an interview.
He noted that the study’s investigators are part of a “new generation of TMS researchers who are bringing new ideas into the fold and figuring out how to use brain imaging to personalize the treatment.” This study represents “a step” in that direction.
“A challenge for the field is that it’s often pretty easy to demonstrate a change at the group level, but the question is whether we can use that at the individual level. That’s a higher bar to meet, and we’re still not there yet,” Dr. Downar added.
Support for the study was provided by Brain Canada, the Michael Smith Foundation for Health Research and the Vancouver Coastal Health Research Institute. Dr. Vila-Rodriguez has received research support from CIHR, Brain Canada, the Michael Smith Foundation for Health Research, the Vancouver Coastal Health Research Institute, and the Weston Brain Institute for investigator-initiated research and philanthropic support from the Seedlings Foundation; he received in-kind equipment support from MagVenture for this investigator-initiated trial; and he has received honoraria for participation on an advisory board for Janssen. Dr. Downar has served as an adviser for BrainCheck, NeuroStim TMS, and Salience Neuro Health; received research grant from CIHR, National Institute for Mental Health, Brain Canada, Canadian Biomarker Integration Network in Depression, Ontario Brain Institute, Klarman Family Foundation, Arrell Family Foundation and the Edgestone Foundation; received travel stipends from Lundbeck and ANT Neuro; and received in-kind equipment support for investigator-initiated trials from MagVenture.
A version of this article first appeared on Medscape.com.
For the first time, researchers understand what happens to the brain when patients with treatment-resistant depression receive repetitive transcranial magnetic stimulation (rTMS).
Using functional magnetic resonance imaging (fMRI), they showed that rTMS induces widespread alterations in functional connectivity in brain regions involved in emotion and motor control.
“‘How does rTMS work?’ is one of the most frequent questions I get in clinic. Providing an accurate explanation and narrative to patients is critical,” senior investigator Fidel Vila-Rodriguez, MD, PhD, director of the Non-Invasive Neurostimulation Therapies Laboratory, University of British Columbia, Vancouver, told this news organization.
“Our findings suggest that rTMS might rely on the brain’s capacity for change (neuroplasticity) to exert its effects and that rTMS effects on the brain are widespread beyond the focal area stimulated (functional network effects),” Dr. Vila-Rodriguez added.
The study was published online in the American Journal of Psychiatry.
Mechanistic insights
Although rTMS has proven efficacy for treatment-resistant depression, the mechanisms behind how it affects the brain are not well understood.
In the current study, researchers used fMRI to assess changes in functional connectivity induced by a single rTMS session in 26 women and 12 men with treatment-resistant depression.
They found that – from managing emotional responses to memory and motor control.
Following a 4-week course of rTMS, these connectivity changes predicted about 30% of the variance of improvement in scores on the Montgomery-Åsberg Depression Rating Scale after rTMS treatment.
The most robust predictive associations involved connections between prefrontal regions and motor, parietal, and insular cortices and between bilateral regions of the thalamus.
“By demonstrating this principle and identifying regions of the brain that are activated by rTMS, we can now try to understand whether this pattern can be used as a biomarker,” Dr. Vila-Rodriguez said in a news release.
“This work provides a mechanistic explanation of what rTMS does to treat depression and supports the notion that for rTMS to treat depressive symptoms a distributed change in brain activity (network or circuit base) is necessary,” he told this news organization.
With funding from the Canadian Institutes of Health Research (CIHR), the team will next see if they can use fMRI to guide rTMS at the individual level, with the ultimate goal of “personalizing” rTMS using individualized functional targets, Dr. Vila-Rodriguez said.
New generation of tms researchers
Reached for comment, Jonathan Downar, MD, PhD, department of psychiatry, University of Toronto, noted that TMS can be “very effective” for treatment-resistant depression, and it has a “very clean side effect profile compared to medications.”
What the field is trying to figure out now is “who it works for and how we can predict more effectively who’s going to benefit from it,” Dr. Downar said in an interview.
He noted that the study’s investigators are part of a “new generation of TMS researchers who are bringing new ideas into the fold and figuring out how to use brain imaging to personalize the treatment.” This study represents “a step” in that direction.
“A challenge for the field is that it’s often pretty easy to demonstrate a change at the group level, but the question is whether we can use that at the individual level. That’s a higher bar to meet, and we’re still not there yet,” Dr. Downar added.
Support for the study was provided by Brain Canada, the Michael Smith Foundation for Health Research and the Vancouver Coastal Health Research Institute. Dr. Vila-Rodriguez has received research support from CIHR, Brain Canada, the Michael Smith Foundation for Health Research, the Vancouver Coastal Health Research Institute, and the Weston Brain Institute for investigator-initiated research and philanthropic support from the Seedlings Foundation; he received in-kind equipment support from MagVenture for this investigator-initiated trial; and he has received honoraria for participation on an advisory board for Janssen. Dr. Downar has served as an adviser for BrainCheck, NeuroStim TMS, and Salience Neuro Health; received research grant from CIHR, National Institute for Mental Health, Brain Canada, Canadian Biomarker Integration Network in Depression, Ontario Brain Institute, Klarman Family Foundation, Arrell Family Foundation and the Edgestone Foundation; received travel stipends from Lundbeck and ANT Neuro; and received in-kind equipment support for investigator-initiated trials from MagVenture.
A version of this article first appeared on Medscape.com.
Does suicide risk show up in the blood?
Investigators found patients with MDD who died by suicide had a gene expression signature in blood distinct from patients with MDD who died by other means.
The signature included genes involved in stress response changes, including polyamine metabolism, circadian rhythm, immune dysregulation, and telomere maintenance.
“These blood biomarkers are an important step toward developing blood tests to identify patients with imminent risk of ending their lives,” study investigator Adolfo Sequeira, PhD, associate researcher in the department of psychiatry and human behavior, University of California, Irvine, said in a news release.
“To our knowledge, this is the first study to analyze blood and brain samples in a well-defined population of MDDs demonstrating significant differences in gene expression associated with completed suicide,” Dr. Sequeira added.
The findings were published online in Translational Psychiatry.
A pressing challenge
Suicide rates in the United States have jumped by more than 35% over the past 2 decades, with more than 48,000 deaths by suicide occurring just last year. MDD is the most common diagnosis among completed suicides, and identifying individuals at the highest risk for suicide remains a “pressing challenge,” the researchers noted.
They looked for changes in gene expression associated with suicide in archived postmortem blood and brain samples from adults with MDD who died by suicide (MDD-S) or by other means (MDD-NS), as well as a group of controls with no psychiatric illness.
In total, there were blood and brain samples for 45 adults, including 53 blood samples and 69 dorsolateral prefrontal cortex (DLPFC) tissue samples.
In blood, investigators identified 14 genes that significantly differentiated MDD-S from MDD-NS. The top six genes differentially expressed in blood were PER3, MTPAP, SLC25A26, CD19, SOX9, and GAR1.
In addition, four genes showed significant changes in brain and blood between the MDD-S and MDD-NS groups. SOX9 was decreased and PER3 was increased in MDD-S in both blood and brain samples, while CD19 and TERF1 were increased in blood but decreased in DLPFC.
SOX9, an astrocytic marker in the brain and B-cell marker in blood, has been shown to be decreased in MDD-S compared with controls in the prefrontal cortex.
In the current study, researchers found that SOX9 expression was significantly reduced both in blood and brain in MDD-S compared with MDD-NS, “suggesting similar immune/astrocytic dysregulations in suicide that could be further investigated.”
Potential signatures, potential targets
PER3 is a circadian rhythm gene implicated in sleep disorders associated with shifts in circadian rhythms and is thought to increase susceptibility to MDD.
Mutations in PER3 have been shown previously to alter multiple systems, including response to antidepressants; and increased blood expression of PER1 has been linked to suicidality in women, the researchers noted.
There also were significantly higher levels of two inflammatory markers (CD19 and CD6 genes) in blood of MDD-S patients compared to MDD-NS patients.
Another “significant” finding was the involvement of several mitochondrial genes in suicide, the researchers said.
Two nuclear genes coding for mitochondria-located proteins MTPAP (a mitochondrial poly(A) polymerase) and the mitochondrial polyamine transporter SLC25A26 were increased in blood in MDD-S compared with MDD-NS and controls, suggesting that “mitochondrial alterations could be used as potential signatures to differentiate MDD-S from MDD-NS patients and also from controls.”
The researchers added that the genes found to be dysregulated in suicide represent potential targets for future drug therapies to prevent suicide and could also be used to develop a molecular test to identify individuals at high risk for suicide.
The study was funded by the National Institute of Mental Health, the American Society for Suicide Prevention, and the Pritzker Family Philanthropic Fund. The investigators have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Investigators found patients with MDD who died by suicide had a gene expression signature in blood distinct from patients with MDD who died by other means.
The signature included genes involved in stress response changes, including polyamine metabolism, circadian rhythm, immune dysregulation, and telomere maintenance.
“These blood biomarkers are an important step toward developing blood tests to identify patients with imminent risk of ending their lives,” study investigator Adolfo Sequeira, PhD, associate researcher in the department of psychiatry and human behavior, University of California, Irvine, said in a news release.
“To our knowledge, this is the first study to analyze blood and brain samples in a well-defined population of MDDs demonstrating significant differences in gene expression associated with completed suicide,” Dr. Sequeira added.
The findings were published online in Translational Psychiatry.
A pressing challenge
Suicide rates in the United States have jumped by more than 35% over the past 2 decades, with more than 48,000 deaths by suicide occurring just last year. MDD is the most common diagnosis among completed suicides, and identifying individuals at the highest risk for suicide remains a “pressing challenge,” the researchers noted.
They looked for changes in gene expression associated with suicide in archived postmortem blood and brain samples from adults with MDD who died by suicide (MDD-S) or by other means (MDD-NS), as well as a group of controls with no psychiatric illness.
In total, there were blood and brain samples for 45 adults, including 53 blood samples and 69 dorsolateral prefrontal cortex (DLPFC) tissue samples.
In blood, investigators identified 14 genes that significantly differentiated MDD-S from MDD-NS. The top six genes differentially expressed in blood were PER3, MTPAP, SLC25A26, CD19, SOX9, and GAR1.
In addition, four genes showed significant changes in brain and blood between the MDD-S and MDD-NS groups. SOX9 was decreased and PER3 was increased in MDD-S in both blood and brain samples, while CD19 and TERF1 were increased in blood but decreased in DLPFC.
SOX9, an astrocytic marker in the brain and B-cell marker in blood, has been shown to be decreased in MDD-S compared with controls in the prefrontal cortex.
In the current study, researchers found that SOX9 expression was significantly reduced both in blood and brain in MDD-S compared with MDD-NS, “suggesting similar immune/astrocytic dysregulations in suicide that could be further investigated.”
Potential signatures, potential targets
PER3 is a circadian rhythm gene implicated in sleep disorders associated with shifts in circadian rhythms and is thought to increase susceptibility to MDD.
Mutations in PER3 have been shown previously to alter multiple systems, including response to antidepressants; and increased blood expression of PER1 has been linked to suicidality in women, the researchers noted.
There also were significantly higher levels of two inflammatory markers (CD19 and CD6 genes) in blood of MDD-S patients compared to MDD-NS patients.
Another “significant” finding was the involvement of several mitochondrial genes in suicide, the researchers said.
Two nuclear genes coding for mitochondria-located proteins MTPAP (a mitochondrial poly(A) polymerase) and the mitochondrial polyamine transporter SLC25A26 were increased in blood in MDD-S compared with MDD-NS and controls, suggesting that “mitochondrial alterations could be used as potential signatures to differentiate MDD-S from MDD-NS patients and also from controls.”
The researchers added that the genes found to be dysregulated in suicide represent potential targets for future drug therapies to prevent suicide and could also be used to develop a molecular test to identify individuals at high risk for suicide.
The study was funded by the National Institute of Mental Health, the American Society for Suicide Prevention, and the Pritzker Family Philanthropic Fund. The investigators have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Investigators found patients with MDD who died by suicide had a gene expression signature in blood distinct from patients with MDD who died by other means.
The signature included genes involved in stress response changes, including polyamine metabolism, circadian rhythm, immune dysregulation, and telomere maintenance.
“These blood biomarkers are an important step toward developing blood tests to identify patients with imminent risk of ending their lives,” study investigator Adolfo Sequeira, PhD, associate researcher in the department of psychiatry and human behavior, University of California, Irvine, said in a news release.
“To our knowledge, this is the first study to analyze blood and brain samples in a well-defined population of MDDs demonstrating significant differences in gene expression associated with completed suicide,” Dr. Sequeira added.
The findings were published online in Translational Psychiatry.
A pressing challenge
Suicide rates in the United States have jumped by more than 35% over the past 2 decades, with more than 48,000 deaths by suicide occurring just last year. MDD is the most common diagnosis among completed suicides, and identifying individuals at the highest risk for suicide remains a “pressing challenge,” the researchers noted.
They looked for changes in gene expression associated with suicide in archived postmortem blood and brain samples from adults with MDD who died by suicide (MDD-S) or by other means (MDD-NS), as well as a group of controls with no psychiatric illness.
In total, there were blood and brain samples for 45 adults, including 53 blood samples and 69 dorsolateral prefrontal cortex (DLPFC) tissue samples.
In blood, investigators identified 14 genes that significantly differentiated MDD-S from MDD-NS. The top six genes differentially expressed in blood were PER3, MTPAP, SLC25A26, CD19, SOX9, and GAR1.
In addition, four genes showed significant changes in brain and blood between the MDD-S and MDD-NS groups. SOX9 was decreased and PER3 was increased in MDD-S in both blood and brain samples, while CD19 and TERF1 were increased in blood but decreased in DLPFC.
SOX9, an astrocytic marker in the brain and B-cell marker in blood, has been shown to be decreased in MDD-S compared with controls in the prefrontal cortex.
In the current study, researchers found that SOX9 expression was significantly reduced both in blood and brain in MDD-S compared with MDD-NS, “suggesting similar immune/astrocytic dysregulations in suicide that could be further investigated.”
Potential signatures, potential targets
PER3 is a circadian rhythm gene implicated in sleep disorders associated with shifts in circadian rhythms and is thought to increase susceptibility to MDD.
Mutations in PER3 have been shown previously to alter multiple systems, including response to antidepressants; and increased blood expression of PER1 has been linked to suicidality in women, the researchers noted.
There also were significantly higher levels of two inflammatory markers (CD19 and CD6 genes) in blood of MDD-S patients compared to MDD-NS patients.
Another “significant” finding was the involvement of several mitochondrial genes in suicide, the researchers said.
Two nuclear genes coding for mitochondria-located proteins MTPAP (a mitochondrial poly(A) polymerase) and the mitochondrial polyamine transporter SLC25A26 were increased in blood in MDD-S compared with MDD-NS and controls, suggesting that “mitochondrial alterations could be used as potential signatures to differentiate MDD-S from MDD-NS patients and also from controls.”
The researchers added that the genes found to be dysregulated in suicide represent potential targets for future drug therapies to prevent suicide and could also be used to develop a molecular test to identify individuals at high risk for suicide.
The study was funded by the National Institute of Mental Health, the American Society for Suicide Prevention, and the Pritzker Family Philanthropic Fund. The investigators have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM TRANSLATIONAL PSYCHIATRY
New data support electroconvulsive therapy for severe depression
Advocates and users of electroconvulsive therapy (ECT) have received further scientific backing:
The patient cohort comprised 27,231 men and 40,096 women who had been treated as inpatients. The average age was 45.1 years (range: 18-103 years), and 4,982 patients received ECT. The primary endpoint was death by suicide within 365 days of hospital discharge. The secondary endpoints were death not by suicide and total mortality. The cause-specific hazard ratio (csHR) was calculated for patients with ECT, compared with patients without ECT.
In the propensity score-weighted analysis, ECT was linked to a significantly reduced suicide risk (csHR: 0.53; 95% confidence interval, 0.31-0.92). According to the calculations, ECT was associated with a significantly decreased total mortality risk (hazard ratio, 0.75; 95% CI, 0.58-0.97). However, this was not the case for death from causes other than suicide.
The authors, led by Tyler S. Kaster, PhD, a psychiatrist at Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, concluded that this study underlines the importance of ECT, in particular for people with severe depression.
A well-tested therapy
ECT has been used for decades as a substantial tool for the treatment of patients with severe mental illnesses. Over the past 15 years, new methods for the treatment of severely depressed patients have been tested, such as vagus nerve stimulation, transcranial magnetic stimulation, and intranasal administration of esketamine. However, in a recent review paper in the New England Journal of Medicine, American psychiatrists Randall T. Espinoza, MD, MPH, University of California, Los Angeles, and Charles H. Kellner, MD, University of South Carolina, Charleston, reported that none of these therapies had proven to be an indisputable substitute for ECT for people with severe depression.
Significant clinical benefits
According to these American psychiatrists, the benefit of ECT has been proven many times, and several studies demonstrate the effect on the risk for suicide. Moreover, quality of life is improved, and the rate of new hospital admissions is lowered. ECT can rapidly improve depressive, psychotic, and catatonic symptoms and reduce suicidal urges for certain patient groups.
Studies on ECT involving patients with treatment-refractory depression have shown response rates of 60%-80% and pooled remission rates of 50%-60%. High response rates for ECT have even been reported for patients with psychotic depression or catatonia. In one study that recruited patients with treatment-refractory schizophrenia, the ECT efficacy rates were between 40% and 70%. In some Asian countries, schizophrenia is the main indication for ECT.
Good safety profile
Overall, the psychiatrists consider ECT to be a safe and tolerable therapy. The estimated death rate is around 2.1 deaths per 100,000 treatments. The most common complications are acute cardiopulmonary events, which are estimated to occur in less than 1% of treatments. Rare serious adverse events linked to ECT are arrhythmias, shortness of breath, aspiration, and prolonged seizures. The common but mild side effects are headaches, jaw pain, myalgia, nausea, and vomiting after the procedure, as well as fatigue.
Concerns regarding cognitive impairment still represent an obstacle for the use of ECT. However, in today’s practice, ECT leads to fewer cognitive side effects than previous treatments. The authors stated that it is not possible to predict how an individual patient will be affected, but most patients have only mild or moderate cognitive side effects that generally abate days to weeks after an ECT course has ended.
However, retrograde amnesia linked to ECT can last over a year. In rare cases, acute confusion or delirium can develop that requires interruption or discontinuation of treatment. No indications of structural brain damage after ECT have been detected in neuropathological testing. A Danish cohort study involving 168,015 patients with depression, of whom 3.1% had at least one ECT treatment, did not find a link between ECT with a mean period of almost 5 years and increased onset of dementia.
Bad reputation
Dr. Espinoza and Dr. Kellner criticized the fact that, despite its proven efficacy and safety, ECT is used too little. This judgment is nothing new. Psychiatrists have been complaining for years that this procedure is used too little, including Eric Slade, MD, from the University of Baltimore, in 2017 and German professors Andreas Fallgatter, MD, and Urban Wiesing, MD, PhD, in 2018. Dr. Wiesing and Dr. Fallgatter attribute the low level of use to the fact that ECT is labor-intensive, compared with pharmacotherapy.
Another reason is clearly the bad reputation of this method. However, ECT’s poor image, which has only increased over time, is not a convincing argument to forego today’s ECT as a treatment for patients with severe mental illnesses. According to Dr. Fallgatter and Dr. Wiesing, even the risk of misuse of this method is “not a sufficient argument for categorical refusal, rather for caution at best.” They argued that otherwise, “modern medicine would have to renounce many more therapies.”
This article was translated from Univadis Germany.
Advocates and users of electroconvulsive therapy (ECT) have received further scientific backing:
The patient cohort comprised 27,231 men and 40,096 women who had been treated as inpatients. The average age was 45.1 years (range: 18-103 years), and 4,982 patients received ECT. The primary endpoint was death by suicide within 365 days of hospital discharge. The secondary endpoints were death not by suicide and total mortality. The cause-specific hazard ratio (csHR) was calculated for patients with ECT, compared with patients without ECT.
In the propensity score-weighted analysis, ECT was linked to a significantly reduced suicide risk (csHR: 0.53; 95% confidence interval, 0.31-0.92). According to the calculations, ECT was associated with a significantly decreased total mortality risk (hazard ratio, 0.75; 95% CI, 0.58-0.97). However, this was not the case for death from causes other than suicide.
The authors, led by Tyler S. Kaster, PhD, a psychiatrist at Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, concluded that this study underlines the importance of ECT, in particular for people with severe depression.
A well-tested therapy
ECT has been used for decades as a substantial tool for the treatment of patients with severe mental illnesses. Over the past 15 years, new methods for the treatment of severely depressed patients have been tested, such as vagus nerve stimulation, transcranial magnetic stimulation, and intranasal administration of esketamine. However, in a recent review paper in the New England Journal of Medicine, American psychiatrists Randall T. Espinoza, MD, MPH, University of California, Los Angeles, and Charles H. Kellner, MD, University of South Carolina, Charleston, reported that none of these therapies had proven to be an indisputable substitute for ECT for people with severe depression.
Significant clinical benefits
According to these American psychiatrists, the benefit of ECT has been proven many times, and several studies demonstrate the effect on the risk for suicide. Moreover, quality of life is improved, and the rate of new hospital admissions is lowered. ECT can rapidly improve depressive, psychotic, and catatonic symptoms and reduce suicidal urges for certain patient groups.
Studies on ECT involving patients with treatment-refractory depression have shown response rates of 60%-80% and pooled remission rates of 50%-60%. High response rates for ECT have even been reported for patients with psychotic depression or catatonia. In one study that recruited patients with treatment-refractory schizophrenia, the ECT efficacy rates were between 40% and 70%. In some Asian countries, schizophrenia is the main indication for ECT.
Good safety profile
Overall, the psychiatrists consider ECT to be a safe and tolerable therapy. The estimated death rate is around 2.1 deaths per 100,000 treatments. The most common complications are acute cardiopulmonary events, which are estimated to occur in less than 1% of treatments. Rare serious adverse events linked to ECT are arrhythmias, shortness of breath, aspiration, and prolonged seizures. The common but mild side effects are headaches, jaw pain, myalgia, nausea, and vomiting after the procedure, as well as fatigue.
Concerns regarding cognitive impairment still represent an obstacle for the use of ECT. However, in today’s practice, ECT leads to fewer cognitive side effects than previous treatments. The authors stated that it is not possible to predict how an individual patient will be affected, but most patients have only mild or moderate cognitive side effects that generally abate days to weeks after an ECT course has ended.
However, retrograde amnesia linked to ECT can last over a year. In rare cases, acute confusion or delirium can develop that requires interruption or discontinuation of treatment. No indications of structural brain damage after ECT have been detected in neuropathological testing. A Danish cohort study involving 168,015 patients with depression, of whom 3.1% had at least one ECT treatment, did not find a link between ECT with a mean period of almost 5 years and increased onset of dementia.
Bad reputation
Dr. Espinoza and Dr. Kellner criticized the fact that, despite its proven efficacy and safety, ECT is used too little. This judgment is nothing new. Psychiatrists have been complaining for years that this procedure is used too little, including Eric Slade, MD, from the University of Baltimore, in 2017 and German professors Andreas Fallgatter, MD, and Urban Wiesing, MD, PhD, in 2018. Dr. Wiesing and Dr. Fallgatter attribute the low level of use to the fact that ECT is labor-intensive, compared with pharmacotherapy.
Another reason is clearly the bad reputation of this method. However, ECT’s poor image, which has only increased over time, is not a convincing argument to forego today’s ECT as a treatment for patients with severe mental illnesses. According to Dr. Fallgatter and Dr. Wiesing, even the risk of misuse of this method is “not a sufficient argument for categorical refusal, rather for caution at best.” They argued that otherwise, “modern medicine would have to renounce many more therapies.”
This article was translated from Univadis Germany.
Advocates and users of electroconvulsive therapy (ECT) have received further scientific backing:
The patient cohort comprised 27,231 men and 40,096 women who had been treated as inpatients. The average age was 45.1 years (range: 18-103 years), and 4,982 patients received ECT. The primary endpoint was death by suicide within 365 days of hospital discharge. The secondary endpoints were death not by suicide and total mortality. The cause-specific hazard ratio (csHR) was calculated for patients with ECT, compared with patients without ECT.
In the propensity score-weighted analysis, ECT was linked to a significantly reduced suicide risk (csHR: 0.53; 95% confidence interval, 0.31-0.92). According to the calculations, ECT was associated with a significantly decreased total mortality risk (hazard ratio, 0.75; 95% CI, 0.58-0.97). However, this was not the case for death from causes other than suicide.
The authors, led by Tyler S. Kaster, PhD, a psychiatrist at Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, concluded that this study underlines the importance of ECT, in particular for people with severe depression.
A well-tested therapy
ECT has been used for decades as a substantial tool for the treatment of patients with severe mental illnesses. Over the past 15 years, new methods for the treatment of severely depressed patients have been tested, such as vagus nerve stimulation, transcranial magnetic stimulation, and intranasal administration of esketamine. However, in a recent review paper in the New England Journal of Medicine, American psychiatrists Randall T. Espinoza, MD, MPH, University of California, Los Angeles, and Charles H. Kellner, MD, University of South Carolina, Charleston, reported that none of these therapies had proven to be an indisputable substitute for ECT for people with severe depression.
Significant clinical benefits
According to these American psychiatrists, the benefit of ECT has been proven many times, and several studies demonstrate the effect on the risk for suicide. Moreover, quality of life is improved, and the rate of new hospital admissions is lowered. ECT can rapidly improve depressive, psychotic, and catatonic symptoms and reduce suicidal urges for certain patient groups.
Studies on ECT involving patients with treatment-refractory depression have shown response rates of 60%-80% and pooled remission rates of 50%-60%. High response rates for ECT have even been reported for patients with psychotic depression or catatonia. In one study that recruited patients with treatment-refractory schizophrenia, the ECT efficacy rates were between 40% and 70%. In some Asian countries, schizophrenia is the main indication for ECT.
Good safety profile
Overall, the psychiatrists consider ECT to be a safe and tolerable therapy. The estimated death rate is around 2.1 deaths per 100,000 treatments. The most common complications are acute cardiopulmonary events, which are estimated to occur in less than 1% of treatments. Rare serious adverse events linked to ECT are arrhythmias, shortness of breath, aspiration, and prolonged seizures. The common but mild side effects are headaches, jaw pain, myalgia, nausea, and vomiting after the procedure, as well as fatigue.
Concerns regarding cognitive impairment still represent an obstacle for the use of ECT. However, in today’s practice, ECT leads to fewer cognitive side effects than previous treatments. The authors stated that it is not possible to predict how an individual patient will be affected, but most patients have only mild or moderate cognitive side effects that generally abate days to weeks after an ECT course has ended.
However, retrograde amnesia linked to ECT can last over a year. In rare cases, acute confusion or delirium can develop that requires interruption or discontinuation of treatment. No indications of structural brain damage after ECT have been detected in neuropathological testing. A Danish cohort study involving 168,015 patients with depression, of whom 3.1% had at least one ECT treatment, did not find a link between ECT with a mean period of almost 5 years and increased onset of dementia.
Bad reputation
Dr. Espinoza and Dr. Kellner criticized the fact that, despite its proven efficacy and safety, ECT is used too little. This judgment is nothing new. Psychiatrists have been complaining for years that this procedure is used too little, including Eric Slade, MD, from the University of Baltimore, in 2017 and German professors Andreas Fallgatter, MD, and Urban Wiesing, MD, PhD, in 2018. Dr. Wiesing and Dr. Fallgatter attribute the low level of use to the fact that ECT is labor-intensive, compared with pharmacotherapy.
Another reason is clearly the bad reputation of this method. However, ECT’s poor image, which has only increased over time, is not a convincing argument to forego today’s ECT as a treatment for patients with severe mental illnesses. According to Dr. Fallgatter and Dr. Wiesing, even the risk of misuse of this method is “not a sufficient argument for categorical refusal, rather for caution at best.” They argued that otherwise, “modern medicine would have to renounce many more therapies.”
This article was translated from Univadis Germany.
FROM THE LANCET PSYCHIATRY
Does noninvasive brain stimulation augment CBT for depression?
Results of a multicenter, placebo-controlled randomized clinical trials showed adjunctive transcranial direct current stimulation (tDCS) was not superior to sham-tDCS plus CBT or CBT alone.
“Combining these interventions does not lead to added value. This is an example where negative findings guide the way of future studies. What we learned is that we might change things in a few dimensions,” study investigator Malek Bajbouj, MD, Charité University Hospital, Berlin, told this news organization.
The study was published online in JAMA Psychiatry.
Urgent need for better treatment
MDD affects 10% of the global population. However, up to 30% of patients have an inadequate response to standard treatment of CBT, pharmacotherapy, or a combination of the two, highlighting the need to develop more effective therapeutic strategies, the investigators note.
A noninvasive approach, tDCS, in healthy populations, has been shown to enhance cognitive function in brain regions that are also relevant for CBT. Specifically, the investigators point out that tDCS can “positively modulate neuronal activity in prefrontal structures central for affective and cognitive processes,” including emotion regulation, cognitive control working memory, and learning.
Based on this early data, the investigators conducted a randomized, placebo-controlled trial to determine whether tDCS combined with CBT might have clinically relevant synergistic effects.
The multicenter study included adults aged 20-65 years with a single or recurrent depressive episode who were either not receiving medication or receiving a stable regimen of selective serotonin reuptake inhibitors (SSRIs) or mirtazapine (Remeron).
A total of 148 participants (89 women, 59 men) with a mean age of 41 years were randomly assigned to receive CBT alone (n = 53), CBT+ tDCS (n = 48) or CBT + sham tDCS (n = 47).
Participants attended a 6-week group intervention of 12 sessions of CBT. If assigned, tDCS was applied simultaneously. Active tDCS included stimulation with an intensity of 2 milliamps for 30 minutes.
The study’s primary outcome was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to post treatment in the intention-to-treat sample. A total of 126 patients completed the study.
At baseline, the average MADRS score was 23.0. In each of the study groups, MADRS scores were reduced by a mean of 6.5 points (95% confidence interval, 3.82-9.14 points). The Cohen d value was -0.90 (95% CI, -1.43 to -0.50), indicating a significant effect over time, the researchers report. However, they add that “there was not significant effect of group and no significant interaction of group x time, indicating the estimated additive effects were not statistically significant.”
Results suggest that more research is needed to optimize treatment synchronization to achieve synergies between noninvasive brain stimulation and psychotherapeutic interventions.
Beauty and promise
Commenting on the findings, Mark George, MD, director of the Medical University of South Carolina Center for Advanced Imaging Research and the Brain Stimulation Laboratory, Charleston, described the study as “a really good effort by a great group of researchers.”
It’s unclear, he added, why tDCS failed to augment CBT. “It may be about the nongeneralizability of tDCS to complex functions, it may be that they didn’t get the dose right, or it might be due to a placebo response,” he speculated.
Furthermore, “tDCS is the most simple form of brain stimulation. The beauty and promise of tDCS is that it is so inexpensive and safe,” Dr. George added.
If proven effective, tDCS could potentially be used at home and rolled out as a frontline therapy for depression, he added. “Everybody wants the technology to work as an antidepressant, since it could have a very big positive public health impact,” said Dr. George.
Referring to previous research showing tDCS’ ability to improve specific brain functions in healthy controls, Dr. George noted that the potential of tDCS may be limited to augmenting specific brain functions such as memory but not more complex behaviors like depression.
However, Dr. George believes a more plausible explanation is that the optimal dose for tDCS has not yet been determined.
With other types of neuromodulation, such as electroconvulsive therapy, “we know that we’re in the brain with the right dose. But for tDCS, we don’t know that, and we’ve got to figure that out before it’s ever really going to make it [as a treatment],” he said.
“There have been great advances through the years in the field of brain stimulation and the treatment of depression. But rates of depression and suicide are continuing to grow, and we have not yet made a significant dent in treatment, in part because these technologies require equipment, [and] they’re expensive. So when we figure out tDCS, it will be a very important piece of our toolkit – a real game changer,” Dr. George added.
A version of this article first appeared on Medscape.com.
Results of a multicenter, placebo-controlled randomized clinical trials showed adjunctive transcranial direct current stimulation (tDCS) was not superior to sham-tDCS plus CBT or CBT alone.
“Combining these interventions does not lead to added value. This is an example where negative findings guide the way of future studies. What we learned is that we might change things in a few dimensions,” study investigator Malek Bajbouj, MD, Charité University Hospital, Berlin, told this news organization.
The study was published online in JAMA Psychiatry.
Urgent need for better treatment
MDD affects 10% of the global population. However, up to 30% of patients have an inadequate response to standard treatment of CBT, pharmacotherapy, or a combination of the two, highlighting the need to develop more effective therapeutic strategies, the investigators note.
A noninvasive approach, tDCS, in healthy populations, has been shown to enhance cognitive function in brain regions that are also relevant for CBT. Specifically, the investigators point out that tDCS can “positively modulate neuronal activity in prefrontal structures central for affective and cognitive processes,” including emotion regulation, cognitive control working memory, and learning.
Based on this early data, the investigators conducted a randomized, placebo-controlled trial to determine whether tDCS combined with CBT might have clinically relevant synergistic effects.
The multicenter study included adults aged 20-65 years with a single or recurrent depressive episode who were either not receiving medication or receiving a stable regimen of selective serotonin reuptake inhibitors (SSRIs) or mirtazapine (Remeron).
A total of 148 participants (89 women, 59 men) with a mean age of 41 years were randomly assigned to receive CBT alone (n = 53), CBT+ tDCS (n = 48) or CBT + sham tDCS (n = 47).
Participants attended a 6-week group intervention of 12 sessions of CBT. If assigned, tDCS was applied simultaneously. Active tDCS included stimulation with an intensity of 2 milliamps for 30 minutes.
The study’s primary outcome was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to post treatment in the intention-to-treat sample. A total of 126 patients completed the study.
At baseline, the average MADRS score was 23.0. In each of the study groups, MADRS scores were reduced by a mean of 6.5 points (95% confidence interval, 3.82-9.14 points). The Cohen d value was -0.90 (95% CI, -1.43 to -0.50), indicating a significant effect over time, the researchers report. However, they add that “there was not significant effect of group and no significant interaction of group x time, indicating the estimated additive effects were not statistically significant.”
Results suggest that more research is needed to optimize treatment synchronization to achieve synergies between noninvasive brain stimulation and psychotherapeutic interventions.
Beauty and promise
Commenting on the findings, Mark George, MD, director of the Medical University of South Carolina Center for Advanced Imaging Research and the Brain Stimulation Laboratory, Charleston, described the study as “a really good effort by a great group of researchers.”
It’s unclear, he added, why tDCS failed to augment CBT. “It may be about the nongeneralizability of tDCS to complex functions, it may be that they didn’t get the dose right, or it might be due to a placebo response,” he speculated.
Furthermore, “tDCS is the most simple form of brain stimulation. The beauty and promise of tDCS is that it is so inexpensive and safe,” Dr. George added.
If proven effective, tDCS could potentially be used at home and rolled out as a frontline therapy for depression, he added. “Everybody wants the technology to work as an antidepressant, since it could have a very big positive public health impact,” said Dr. George.
Referring to previous research showing tDCS’ ability to improve specific brain functions in healthy controls, Dr. George noted that the potential of tDCS may be limited to augmenting specific brain functions such as memory but not more complex behaviors like depression.
However, Dr. George believes a more plausible explanation is that the optimal dose for tDCS has not yet been determined.
With other types of neuromodulation, such as electroconvulsive therapy, “we know that we’re in the brain with the right dose. But for tDCS, we don’t know that, and we’ve got to figure that out before it’s ever really going to make it [as a treatment],” he said.
“There have been great advances through the years in the field of brain stimulation and the treatment of depression. But rates of depression and suicide are continuing to grow, and we have not yet made a significant dent in treatment, in part because these technologies require equipment, [and] they’re expensive. So when we figure out tDCS, it will be a very important piece of our toolkit – a real game changer,” Dr. George added.
A version of this article first appeared on Medscape.com.
Results of a multicenter, placebo-controlled randomized clinical trials showed adjunctive transcranial direct current stimulation (tDCS) was not superior to sham-tDCS plus CBT or CBT alone.
“Combining these interventions does not lead to added value. This is an example where negative findings guide the way of future studies. What we learned is that we might change things in a few dimensions,” study investigator Malek Bajbouj, MD, Charité University Hospital, Berlin, told this news organization.
The study was published online in JAMA Psychiatry.
Urgent need for better treatment
MDD affects 10% of the global population. However, up to 30% of patients have an inadequate response to standard treatment of CBT, pharmacotherapy, or a combination of the two, highlighting the need to develop more effective therapeutic strategies, the investigators note.
A noninvasive approach, tDCS, in healthy populations, has been shown to enhance cognitive function in brain regions that are also relevant for CBT. Specifically, the investigators point out that tDCS can “positively modulate neuronal activity in prefrontal structures central for affective and cognitive processes,” including emotion regulation, cognitive control working memory, and learning.
Based on this early data, the investigators conducted a randomized, placebo-controlled trial to determine whether tDCS combined with CBT might have clinically relevant synergistic effects.
The multicenter study included adults aged 20-65 years with a single or recurrent depressive episode who were either not receiving medication or receiving a stable regimen of selective serotonin reuptake inhibitors (SSRIs) or mirtazapine (Remeron).
A total of 148 participants (89 women, 59 men) with a mean age of 41 years were randomly assigned to receive CBT alone (n = 53), CBT+ tDCS (n = 48) or CBT + sham tDCS (n = 47).
Participants attended a 6-week group intervention of 12 sessions of CBT. If assigned, tDCS was applied simultaneously. Active tDCS included stimulation with an intensity of 2 milliamps for 30 minutes.
The study’s primary outcome was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to post treatment in the intention-to-treat sample. A total of 126 patients completed the study.
At baseline, the average MADRS score was 23.0. In each of the study groups, MADRS scores were reduced by a mean of 6.5 points (95% confidence interval, 3.82-9.14 points). The Cohen d value was -0.90 (95% CI, -1.43 to -0.50), indicating a significant effect over time, the researchers report. However, they add that “there was not significant effect of group and no significant interaction of group x time, indicating the estimated additive effects were not statistically significant.”
Results suggest that more research is needed to optimize treatment synchronization to achieve synergies between noninvasive brain stimulation and psychotherapeutic interventions.
Beauty and promise
Commenting on the findings, Mark George, MD, director of the Medical University of South Carolina Center for Advanced Imaging Research and the Brain Stimulation Laboratory, Charleston, described the study as “a really good effort by a great group of researchers.”
It’s unclear, he added, why tDCS failed to augment CBT. “It may be about the nongeneralizability of tDCS to complex functions, it may be that they didn’t get the dose right, or it might be due to a placebo response,” he speculated.
Furthermore, “tDCS is the most simple form of brain stimulation. The beauty and promise of tDCS is that it is so inexpensive and safe,” Dr. George added.
If proven effective, tDCS could potentially be used at home and rolled out as a frontline therapy for depression, he added. “Everybody wants the technology to work as an antidepressant, since it could have a very big positive public health impact,” said Dr. George.
Referring to previous research showing tDCS’ ability to improve specific brain functions in healthy controls, Dr. George noted that the potential of tDCS may be limited to augmenting specific brain functions such as memory but not more complex behaviors like depression.
However, Dr. George believes a more plausible explanation is that the optimal dose for tDCS has not yet been determined.
With other types of neuromodulation, such as electroconvulsive therapy, “we know that we’re in the brain with the right dose. But for tDCS, we don’t know that, and we’ve got to figure that out before it’s ever really going to make it [as a treatment],” he said.
“There have been great advances through the years in the field of brain stimulation and the treatment of depression. But rates of depression and suicide are continuing to grow, and we have not yet made a significant dent in treatment, in part because these technologies require equipment, [and] they’re expensive. So when we figure out tDCS, it will be a very important piece of our toolkit – a real game changer,” Dr. George added.
A version of this article first appeared on Medscape.com.
FROM JAMA PSYCHIATRY
Depression biomarkers: Which ones matter most?
Multiple biomarkers of depression involved in several brain circuits are altered in patients with unipolar depression.
because they suggest neuroimmunological alterations, disturbances in the blood-brain-barrier, hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis, and impaired neuroplasticity as factors in depression pathophysiology.
However, said study investigator Michael E. Benros, MD, PhD, professor and head of research at Mental Health Centre Copenhagen and University of Copenhagen, this is on a group level. “So in order to be relevant in a clinical context, the results need to be validated by further high-quality studies identifying subgroups with different biological underpinnings,” he told this news organization.
Identification of potential subgroups of depression with different biomarkers might help explain the diverse symptomatology and variability in treatment response observed in patients with depression, he noted.
The study was published online in JAMA Psychiatry.
Multiple pathways to depression
The systematic review and meta-analysis included 97 studies investigating 165 CSF biomarkers.
Of the 42 biomarkers investigated in at least two studies, patients with unipolar depression had higher CSF levels of interleukin 6, a marker of chronic inflammation; total protein, which signals blood-brain barrier dysfunction and increased permeability; and cortisol, which is linked to psychological stress, compared with healthy controls.
Depression was also associated with:
- Lower CSF levels of homovanillic acid, the major terminal metabolite of dopamine.
- Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS thought to play a vital role in the control of stress and depression.
- Somatostatin, a neuropeptide often coexpressed with GABA.
- Brain-derived neurotrophic factor (BDNF), a protein involved in neurogenesis, synaptic plasticity, and neurotransmission.
- Amyloid-β 40, implicated in Alzheimer’s disease.
- Transthyretin, involved in transport of thyroxine across the blood-brain barrier.
Collectively, the findings point toward a “dysregulated dopaminergic system, a compromised inhibitory system, HPA axis hyperactivity, increased neuroinflammation and blood-brain barrier permeability, and impaired neuroplasticity as important factors in depression pathophysiology,” the investigators wrote.
“It is notable that we did not find significant difference in the metabolite levels of serotonin and noradrenalin, which are the most targeted neurotransmitters in modern antidepressant treatment,” said Dr. Benros.
However, this could be explained by substantial heterogeneity between studies and the fact that quantification of total CSF biomarker concentrations does not reflect local alteration within the brain, he explained.
Many of the studies had small cohorts and most quantified only a few biomarkers, making it hard to examine potential interactions between biomarkers or identify specific phenotypes of depression.
“Novel high-quality studies including larger cohorts with an integrative approach and extensive numbers of biomarkers are needed to validate these potential biomarkers of depression and set the stage for the development of more effective and precise treatments,” the researchers noted.
Which ones hold water?
Reached for comment, Dean MacKinnon, MD, associate professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, noted that this analysis “extracts the vast amount of knowledge” gained from different studies on biomarkers in the CSF for depression.
“They were able to identify 97 papers that have enough information in them that they could sort of lump them together and see which ones still hold water. It’s always useful to be able to look at patterns in the research and see if you can find some consistent trends,” he told this news organization.
Dr. MacKinnon, who was not part of the research team, also noted that “nonreplicability” is a problem in psychiatry and psychology research, “so being able to show that at least some studies were sufficiently well done, to get a good result, and that they could be replicated in at least one other good study is useful information.”
When it comes to depression, Dr. MacKinnon said, “We just don’t know enough to really pin down a physiologic pathway to explain it. The fact that some people seem to have high cortisol and some people seem to have high permeability of blood-brain barrier, and others have abnormalities in dopamine, is interesting and suggests that depression is likely not a unitary disease with a single cause.”
He cautioned, however, that the findings don’t have immediate clinical implications for individual patients with depression.
“Theoretically, down the road, if you extrapolate from what they found, and if it’s truly the case that this research maps to something that could suggest a different clinical approach, you might be able to determine whether one patient might respond better to an SSRI or an SNRI or something like that,” Dr. MacKinnon said.
Dr. Benros reported grants from Lundbeck Foundation during the conduct of the study. Dr. MacKinnon has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Multiple biomarkers of depression involved in several brain circuits are altered in patients with unipolar depression.
because they suggest neuroimmunological alterations, disturbances in the blood-brain-barrier, hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis, and impaired neuroplasticity as factors in depression pathophysiology.
However, said study investigator Michael E. Benros, MD, PhD, professor and head of research at Mental Health Centre Copenhagen and University of Copenhagen, this is on a group level. “So in order to be relevant in a clinical context, the results need to be validated by further high-quality studies identifying subgroups with different biological underpinnings,” he told this news organization.
Identification of potential subgroups of depression with different biomarkers might help explain the diverse symptomatology and variability in treatment response observed in patients with depression, he noted.
The study was published online in JAMA Psychiatry.
Multiple pathways to depression
The systematic review and meta-analysis included 97 studies investigating 165 CSF biomarkers.
Of the 42 biomarkers investigated in at least two studies, patients with unipolar depression had higher CSF levels of interleukin 6, a marker of chronic inflammation; total protein, which signals blood-brain barrier dysfunction and increased permeability; and cortisol, which is linked to psychological stress, compared with healthy controls.
Depression was also associated with:
- Lower CSF levels of homovanillic acid, the major terminal metabolite of dopamine.
- Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS thought to play a vital role in the control of stress and depression.
- Somatostatin, a neuropeptide often coexpressed with GABA.
- Brain-derived neurotrophic factor (BDNF), a protein involved in neurogenesis, synaptic plasticity, and neurotransmission.
- Amyloid-β 40, implicated in Alzheimer’s disease.
- Transthyretin, involved in transport of thyroxine across the blood-brain barrier.
Collectively, the findings point toward a “dysregulated dopaminergic system, a compromised inhibitory system, HPA axis hyperactivity, increased neuroinflammation and blood-brain barrier permeability, and impaired neuroplasticity as important factors in depression pathophysiology,” the investigators wrote.
“It is notable that we did not find significant difference in the metabolite levels of serotonin and noradrenalin, which are the most targeted neurotransmitters in modern antidepressant treatment,” said Dr. Benros.
However, this could be explained by substantial heterogeneity between studies and the fact that quantification of total CSF biomarker concentrations does not reflect local alteration within the brain, he explained.
Many of the studies had small cohorts and most quantified only a few biomarkers, making it hard to examine potential interactions between biomarkers or identify specific phenotypes of depression.
“Novel high-quality studies including larger cohorts with an integrative approach and extensive numbers of biomarkers are needed to validate these potential biomarkers of depression and set the stage for the development of more effective and precise treatments,” the researchers noted.
Which ones hold water?
Reached for comment, Dean MacKinnon, MD, associate professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, noted that this analysis “extracts the vast amount of knowledge” gained from different studies on biomarkers in the CSF for depression.
“They were able to identify 97 papers that have enough information in them that they could sort of lump them together and see which ones still hold water. It’s always useful to be able to look at patterns in the research and see if you can find some consistent trends,” he told this news organization.
Dr. MacKinnon, who was not part of the research team, also noted that “nonreplicability” is a problem in psychiatry and psychology research, “so being able to show that at least some studies were sufficiently well done, to get a good result, and that they could be replicated in at least one other good study is useful information.”
When it comes to depression, Dr. MacKinnon said, “We just don’t know enough to really pin down a physiologic pathway to explain it. The fact that some people seem to have high cortisol and some people seem to have high permeability of blood-brain barrier, and others have abnormalities in dopamine, is interesting and suggests that depression is likely not a unitary disease with a single cause.”
He cautioned, however, that the findings don’t have immediate clinical implications for individual patients with depression.
“Theoretically, down the road, if you extrapolate from what they found, and if it’s truly the case that this research maps to something that could suggest a different clinical approach, you might be able to determine whether one patient might respond better to an SSRI or an SNRI or something like that,” Dr. MacKinnon said.
Dr. Benros reported grants from Lundbeck Foundation during the conduct of the study. Dr. MacKinnon has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Multiple biomarkers of depression involved in several brain circuits are altered in patients with unipolar depression.
because they suggest neuroimmunological alterations, disturbances in the blood-brain-barrier, hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis, and impaired neuroplasticity as factors in depression pathophysiology.
However, said study investigator Michael E. Benros, MD, PhD, professor and head of research at Mental Health Centre Copenhagen and University of Copenhagen, this is on a group level. “So in order to be relevant in a clinical context, the results need to be validated by further high-quality studies identifying subgroups with different biological underpinnings,” he told this news organization.
Identification of potential subgroups of depression with different biomarkers might help explain the diverse symptomatology and variability in treatment response observed in patients with depression, he noted.
The study was published online in JAMA Psychiatry.
Multiple pathways to depression
The systematic review and meta-analysis included 97 studies investigating 165 CSF biomarkers.
Of the 42 biomarkers investigated in at least two studies, patients with unipolar depression had higher CSF levels of interleukin 6, a marker of chronic inflammation; total protein, which signals blood-brain barrier dysfunction and increased permeability; and cortisol, which is linked to psychological stress, compared with healthy controls.
Depression was also associated with:
- Lower CSF levels of homovanillic acid, the major terminal metabolite of dopamine.
- Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS thought to play a vital role in the control of stress and depression.
- Somatostatin, a neuropeptide often coexpressed with GABA.
- Brain-derived neurotrophic factor (BDNF), a protein involved in neurogenesis, synaptic plasticity, and neurotransmission.
- Amyloid-β 40, implicated in Alzheimer’s disease.
- Transthyretin, involved in transport of thyroxine across the blood-brain barrier.
Collectively, the findings point toward a “dysregulated dopaminergic system, a compromised inhibitory system, HPA axis hyperactivity, increased neuroinflammation and blood-brain barrier permeability, and impaired neuroplasticity as important factors in depression pathophysiology,” the investigators wrote.
“It is notable that we did not find significant difference in the metabolite levels of serotonin and noradrenalin, which are the most targeted neurotransmitters in modern antidepressant treatment,” said Dr. Benros.
However, this could be explained by substantial heterogeneity between studies and the fact that quantification of total CSF biomarker concentrations does not reflect local alteration within the brain, he explained.
Many of the studies had small cohorts and most quantified only a few biomarkers, making it hard to examine potential interactions between biomarkers or identify specific phenotypes of depression.
“Novel high-quality studies including larger cohorts with an integrative approach and extensive numbers of biomarkers are needed to validate these potential biomarkers of depression and set the stage for the development of more effective and precise treatments,” the researchers noted.
Which ones hold water?
Reached for comment, Dean MacKinnon, MD, associate professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, noted that this analysis “extracts the vast amount of knowledge” gained from different studies on biomarkers in the CSF for depression.
“They were able to identify 97 papers that have enough information in them that they could sort of lump them together and see which ones still hold water. It’s always useful to be able to look at patterns in the research and see if you can find some consistent trends,” he told this news organization.
Dr. MacKinnon, who was not part of the research team, also noted that “nonreplicability” is a problem in psychiatry and psychology research, “so being able to show that at least some studies were sufficiently well done, to get a good result, and that they could be replicated in at least one other good study is useful information.”
When it comes to depression, Dr. MacKinnon said, “We just don’t know enough to really pin down a physiologic pathway to explain it. The fact that some people seem to have high cortisol and some people seem to have high permeability of blood-brain barrier, and others have abnormalities in dopamine, is interesting and suggests that depression is likely not a unitary disease with a single cause.”
He cautioned, however, that the findings don’t have immediate clinical implications for individual patients with depression.
“Theoretically, down the road, if you extrapolate from what they found, and if it’s truly the case that this research maps to something that could suggest a different clinical approach, you might be able to determine whether one patient might respond better to an SSRI or an SNRI or something like that,” Dr. MacKinnon said.
Dr. Benros reported grants from Lundbeck Foundation during the conduct of the study. Dr. MacKinnon has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA PSYCHIATRY
Antidepressant study yields controversial findings
Researchers who conducted the study admit this finding was unexpected, and outside experts say no firm conclusions can be drawn from the research.
“Of course we were surprised by the results,” first author Omar Almohammed, PharmD, PhD, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, told this news organization.
“We were expecting to see some positive impact with the use of antidepressant medications on the HRQoL measures when we compared these patients to patients that did not use antidepressant medications,” Dr. Almohammed said.
The study was published online in PLOS ONE.
Controversial impact on quality of life
Depression is known to harm HRQoL. Despite evidence that antidepressants improve depressed mood, their effect on patients’ overall well-being and HRQoL remains controversial.
The researchers examined the effect of antidepressants on HRQoL in adults with depression using 11 years of data from the U.S. Medical Expenditures Panel Survey (MEPS), a large longitudinal survey that tracks health service use in the United States. HRQoL was measured using the 12-item Short Form Health Survey (SF-12).
On average, about 17.5 million adults were diagnosed with depression each year during the study period (2005-2016). More than half (57.6%) of these patients were treated with antidepressants.
Patients with depression had an average age of 48.3 years. Women made up more than two-thirds of the total sample (68%), and more women than men received antidepressants (61% vs. 52%).
Compared with no antidepressant use, antidepressant use was associated with some improvement on the mental, but not physical, component of the SF-12, the researchers report.
However, difference-in-differences (D-I-D) univariate analysis showed no significant difference between adults using and not using antidepressants in the SF-12 physical (-0.35 vs. -0.34; P = .9,595) or mental component (1.28 vs. 1.13; P = .6,405).
“The multivariate D-I-D analyses ensured the robustness of these results,” the researchers note.
The change in HRQoL observed in patients using antidepressants was not significantly different from that seen among peers not using these drugs, the researchers report.
“We are not saying that antidepressant medications are not helpful at all; HRQoL is only one of many measures intended to assess health outcomes,” Dr. Almohammed told this news organization.
“Based on our research design and data, we can only say that patients who used antidepressant medications did not experience better change in terms of HRQoL compared to patients who did not use antidepressant medications,” he said.
“These patients may have had some improvement on other clinical outcome measures, but that clinical improvement did not have a significant positive impact on HRQoL,” he noted.
“We still recommend that patients continue using their antidepressant medications, but they may want to ask their doctors to provide them with other nonpharmacologic interventions as this may have additional impact on their HRQoL,” Dr. Almohammed said.
Further research is needed to address a “gap in knowledge” about the impact of nondrug interventions – alone or in combination with antidepressant medications – on patients’ HRQoL, Dr. Almohammed added.
Experts weigh in
Several experts weighed in on the study in a statement from the British nonprofit Science Media Center.
Gemma Lewis, PhD, with University College London (UCL), noted that “clinical trials with experimental designs have found that antidepressants improve mental health-related quality of life.”
“In this study, the people who received antidepressants had worse quality of life, and are likely to have been more severely depressed, than those who did not. This type of bias is difficult to eliminate in a naturalistic study like this, which does not involve an experimental design,” Dr. Lewis commented.
Eduard Vieta, PhD, with University of Barcelona, noted the “inability to control for severity of depression between the two different groups is a crucial flaw, and therefore, there is little we can learn from this data.”
Echoing Dr. Vieta, David Curtis, MBBS, MD, PhD, with UCL Genetics Institute, said, “One might well assume that the people who were taking antidepressants had been more severely depressed than those who were not.”
“From this point of view, one could argue that it seems that the antidepressants were effective and that with their use people who had presented with more severe depression did not have markedly reduced quality of life,” Dr. Curtis said.
“However, the reality is that this kind of observational study tells us nothing about causation. For that, clinical trials are required, and numerous such trials have demonstrated that, on average, antidepressants are effective in terms of treating depressive illness and in improving the quality of life of patients with significant depression,” he added.
Michael Sharpe, MD, with University of Oxford, said the study highlights the importance of measuring the long-term outcomes of treatments for depression. “However, this study has no clear implication for the care of patients with depression and certainly should not discourage patients who may benefit from taking these drugs.”
Livia de Picker, MD, PhD, with University of Antwerp, Belgium, said, “What these data do point towards is the persistent treatment gap for depression in the United States, with only 57.6% of patients with major depressive disorder receiving treatment with antidepressants over a 2-year follow-up.”
Funding for the study was provided by King Saud University, Riyadh, Saudi Arabia. Dr. Almohammed, Dr. de Picker, Dr. Curtis, Dr. Lewis, and Dr. Sharpe have disclosed no relevant financial relationships. Dr. Vieta has participated in clinical trials of antidepressants and advisory boards for Angelini, Biogen, Janssen, and Lundbeck.
A version of this article first appeared on Medscape.com.
Researchers who conducted the study admit this finding was unexpected, and outside experts say no firm conclusions can be drawn from the research.
“Of course we were surprised by the results,” first author Omar Almohammed, PharmD, PhD, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, told this news organization.
“We were expecting to see some positive impact with the use of antidepressant medications on the HRQoL measures when we compared these patients to patients that did not use antidepressant medications,” Dr. Almohammed said.
The study was published online in PLOS ONE.
Controversial impact on quality of life
Depression is known to harm HRQoL. Despite evidence that antidepressants improve depressed mood, their effect on patients’ overall well-being and HRQoL remains controversial.
The researchers examined the effect of antidepressants on HRQoL in adults with depression using 11 years of data from the U.S. Medical Expenditures Panel Survey (MEPS), a large longitudinal survey that tracks health service use in the United States. HRQoL was measured using the 12-item Short Form Health Survey (SF-12).
On average, about 17.5 million adults were diagnosed with depression each year during the study period (2005-2016). More than half (57.6%) of these patients were treated with antidepressants.
Patients with depression had an average age of 48.3 years. Women made up more than two-thirds of the total sample (68%), and more women than men received antidepressants (61% vs. 52%).
Compared with no antidepressant use, antidepressant use was associated with some improvement on the mental, but not physical, component of the SF-12, the researchers report.
However, difference-in-differences (D-I-D) univariate analysis showed no significant difference between adults using and not using antidepressants in the SF-12 physical (-0.35 vs. -0.34; P = .9,595) or mental component (1.28 vs. 1.13; P = .6,405).
“The multivariate D-I-D analyses ensured the robustness of these results,” the researchers note.
The change in HRQoL observed in patients using antidepressants was not significantly different from that seen among peers not using these drugs, the researchers report.
“We are not saying that antidepressant medications are not helpful at all; HRQoL is only one of many measures intended to assess health outcomes,” Dr. Almohammed told this news organization.
“Based on our research design and data, we can only say that patients who used antidepressant medications did not experience better change in terms of HRQoL compared to patients who did not use antidepressant medications,” he said.
“These patients may have had some improvement on other clinical outcome measures, but that clinical improvement did not have a significant positive impact on HRQoL,” he noted.
“We still recommend that patients continue using their antidepressant medications, but they may want to ask their doctors to provide them with other nonpharmacologic interventions as this may have additional impact on their HRQoL,” Dr. Almohammed said.
Further research is needed to address a “gap in knowledge” about the impact of nondrug interventions – alone or in combination with antidepressant medications – on patients’ HRQoL, Dr. Almohammed added.
Experts weigh in
Several experts weighed in on the study in a statement from the British nonprofit Science Media Center.
Gemma Lewis, PhD, with University College London (UCL), noted that “clinical trials with experimental designs have found that antidepressants improve mental health-related quality of life.”
“In this study, the people who received antidepressants had worse quality of life, and are likely to have been more severely depressed, than those who did not. This type of bias is difficult to eliminate in a naturalistic study like this, which does not involve an experimental design,” Dr. Lewis commented.
Eduard Vieta, PhD, with University of Barcelona, noted the “inability to control for severity of depression between the two different groups is a crucial flaw, and therefore, there is little we can learn from this data.”
Echoing Dr. Vieta, David Curtis, MBBS, MD, PhD, with UCL Genetics Institute, said, “One might well assume that the people who were taking antidepressants had been more severely depressed than those who were not.”
“From this point of view, one could argue that it seems that the antidepressants were effective and that with their use people who had presented with more severe depression did not have markedly reduced quality of life,” Dr. Curtis said.
“However, the reality is that this kind of observational study tells us nothing about causation. For that, clinical trials are required, and numerous such trials have demonstrated that, on average, antidepressants are effective in terms of treating depressive illness and in improving the quality of life of patients with significant depression,” he added.
Michael Sharpe, MD, with University of Oxford, said the study highlights the importance of measuring the long-term outcomes of treatments for depression. “However, this study has no clear implication for the care of patients with depression and certainly should not discourage patients who may benefit from taking these drugs.”
Livia de Picker, MD, PhD, with University of Antwerp, Belgium, said, “What these data do point towards is the persistent treatment gap for depression in the United States, with only 57.6% of patients with major depressive disorder receiving treatment with antidepressants over a 2-year follow-up.”
Funding for the study was provided by King Saud University, Riyadh, Saudi Arabia. Dr. Almohammed, Dr. de Picker, Dr. Curtis, Dr. Lewis, and Dr. Sharpe have disclosed no relevant financial relationships. Dr. Vieta has participated in clinical trials of antidepressants and advisory boards for Angelini, Biogen, Janssen, and Lundbeck.
A version of this article first appeared on Medscape.com.
Researchers who conducted the study admit this finding was unexpected, and outside experts say no firm conclusions can be drawn from the research.
“Of course we were surprised by the results,” first author Omar Almohammed, PharmD, PhD, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, told this news organization.
“We were expecting to see some positive impact with the use of antidepressant medications on the HRQoL measures when we compared these patients to patients that did not use antidepressant medications,” Dr. Almohammed said.
The study was published online in PLOS ONE.
Controversial impact on quality of life
Depression is known to harm HRQoL. Despite evidence that antidepressants improve depressed mood, their effect on patients’ overall well-being and HRQoL remains controversial.
The researchers examined the effect of antidepressants on HRQoL in adults with depression using 11 years of data from the U.S. Medical Expenditures Panel Survey (MEPS), a large longitudinal survey that tracks health service use in the United States. HRQoL was measured using the 12-item Short Form Health Survey (SF-12).
On average, about 17.5 million adults were diagnosed with depression each year during the study period (2005-2016). More than half (57.6%) of these patients were treated with antidepressants.
Patients with depression had an average age of 48.3 years. Women made up more than two-thirds of the total sample (68%), and more women than men received antidepressants (61% vs. 52%).
Compared with no antidepressant use, antidepressant use was associated with some improvement on the mental, but not physical, component of the SF-12, the researchers report.
However, difference-in-differences (D-I-D) univariate analysis showed no significant difference between adults using and not using antidepressants in the SF-12 physical (-0.35 vs. -0.34; P = .9,595) or mental component (1.28 vs. 1.13; P = .6,405).
“The multivariate D-I-D analyses ensured the robustness of these results,” the researchers note.
The change in HRQoL observed in patients using antidepressants was not significantly different from that seen among peers not using these drugs, the researchers report.
“We are not saying that antidepressant medications are not helpful at all; HRQoL is only one of many measures intended to assess health outcomes,” Dr. Almohammed told this news organization.
“Based on our research design and data, we can only say that patients who used antidepressant medications did not experience better change in terms of HRQoL compared to patients who did not use antidepressant medications,” he said.
“These patients may have had some improvement on other clinical outcome measures, but that clinical improvement did not have a significant positive impact on HRQoL,” he noted.
“We still recommend that patients continue using their antidepressant medications, but they may want to ask their doctors to provide them with other nonpharmacologic interventions as this may have additional impact on their HRQoL,” Dr. Almohammed said.
Further research is needed to address a “gap in knowledge” about the impact of nondrug interventions – alone or in combination with antidepressant medications – on patients’ HRQoL, Dr. Almohammed added.
Experts weigh in
Several experts weighed in on the study in a statement from the British nonprofit Science Media Center.
Gemma Lewis, PhD, with University College London (UCL), noted that “clinical trials with experimental designs have found that antidepressants improve mental health-related quality of life.”
“In this study, the people who received antidepressants had worse quality of life, and are likely to have been more severely depressed, than those who did not. This type of bias is difficult to eliminate in a naturalistic study like this, which does not involve an experimental design,” Dr. Lewis commented.
Eduard Vieta, PhD, with University of Barcelona, noted the “inability to control for severity of depression between the two different groups is a crucial flaw, and therefore, there is little we can learn from this data.”
Echoing Dr. Vieta, David Curtis, MBBS, MD, PhD, with UCL Genetics Institute, said, “One might well assume that the people who were taking antidepressants had been more severely depressed than those who were not.”
“From this point of view, one could argue that it seems that the antidepressants were effective and that with their use people who had presented with more severe depression did not have markedly reduced quality of life,” Dr. Curtis said.
“However, the reality is that this kind of observational study tells us nothing about causation. For that, clinical trials are required, and numerous such trials have demonstrated that, on average, antidepressants are effective in terms of treating depressive illness and in improving the quality of life of patients with significant depression,” he added.
Michael Sharpe, MD, with University of Oxford, said the study highlights the importance of measuring the long-term outcomes of treatments for depression. “However, this study has no clear implication for the care of patients with depression and certainly should not discourage patients who may benefit from taking these drugs.”
Livia de Picker, MD, PhD, with University of Antwerp, Belgium, said, “What these data do point towards is the persistent treatment gap for depression in the United States, with only 57.6% of patients with major depressive disorder receiving treatment with antidepressants over a 2-year follow-up.”
Funding for the study was provided by King Saud University, Riyadh, Saudi Arabia. Dr. Almohammed, Dr. de Picker, Dr. Curtis, Dr. Lewis, and Dr. Sharpe have disclosed no relevant financial relationships. Dr. Vieta has participated in clinical trials of antidepressants and advisory boards for Angelini, Biogen, Janssen, and Lundbeck.
A version of this article first appeared on Medscape.com.