Major Depressive Disorder

The first randomized controlled trial testing the safety and efficacy of long-term antidepressant maintenance therapy after remission of a depressive episode in adults with bipolar I disorder has yielded mixed results.

Continuing antidepressant therapy for 52 weeks, as opposed to stopping it at 8 weeks, was not more beneficial with regard to the primary outcome of occurrence of any mood episode.

However, a prespecified sensitivity analysis of the primary outcome and of the secondary analyses suggests that continuing antidepressant therapy for 52 weeks may prolong the time to a depressive relapse.

“Because the primary outcome is negative and the prespecified sensitivity analysis is positive and the secondary outcomes are positive, some clinicians will pick the position that they work and some that they don’t work,” lead investigator Lakshmi Yatham, MBBS, with University of British Columbia, Vancouver, told this news organization.

University of British Columbia

Controversial issue

Adjunctive antidepressant therapy – alongside mood stabilizers and/or second-generation antipsychotic medications – are often used to treat acute depressive episodes in patients with bipolar I disorder.

Currently, the Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) advise discontinuing antidepressant treatment 8 weeks after remission of depression.

Yet, the duration of antidepressant therapy for bipolar depression is “highly controversial,” due to a lack of evidence and concerns that antidepressants may induce mania, mixed states, or rapid cycling between mania and depression, Dr. Yatham said.

Dr. Yatham and colleagues assessed the safety and efficacy of continuing adjunctive antidepressant treatment (escitalopram or bupropion XL) for 52 weeks after remission, compared with discontinuing antidepressant therapy at 8 weeks after remission.

The final analysis included 177 patients (mean age 41 years, 48% men) with bipolar I disorder who had remission of depression; 90 patients continued treatment with an antidepressant for 52 weeks and 87 were switched to placebo at 8 weeks. All were taking a mood stabilizer or a second-generation antipsychotic or both.

The primary outcome, assessed in a time-to-event analysis, was any mood episode, as defined by scores on scales measuring symptoms of hypomania or mania, depression, suicidality, and mood-episode severity; additional treatment or hospitalization for mood symptoms; or attempted or completed suicide.

At 52 weeks, 28 patients (31%) in the 52-week group had experienced any mood episode (primary outcome), compared with 40 patients (46%) in the 8-week group.

The primary outcome did not reach statistical significance (hazard ratio, 0.68; 95% confidence interval, 0.43-1.10; P = .12).

The researchers note that the decision by the study team to include relapses that occurred during the first 6 weeks of the study may have affected the primary outcome.

“During the first 6 weeks, both groups were getting the same treatment, and we thought there shouldn’t be any difference in relapse, but sadly, there were more relapses in the 52-week group even though the treatments were identical,” Dr. Yatham said.

However, in a sensitivity analysis of the primary outcome after week 6, when treatment between the two groups differed, patients continuing antidepressant treatment were 40% less likely to experience a relapse of any mood event (HR, 0.60) and 59% less likely to experience a depressive episode (HR, 0.41) relative to the placebo group.

“From the point where the two groups began receiving different treatments, we see a significant benefit for patients who continued treatment with antidepressants,” Dr. Yatham said in a news release.

“Treating depression in bipolar disorder is challenging. Reducing the risk of relapse is important because it can provide patients with a great deal of stability that ultimately lets them get back to the activities they enjoy and can greatly improve their quality of life,” he added.

Although fewer patients in the 52-week group than 8-week group had a depressive episode within 52 weeks (17% vs. 40%; HR, 0.43), more had a manic or hypomanic event (12% vs. 6%; HR, 2.28).

The estimated probability of remaining free of a depressive episode at 52 weeks was 72% in the 52-week group versus 53% in the 8-week group. The estimated probability of remaining free of a manic episode at 52 weeks was 81% and 92%, respectively.

The incidence of adverse events was similar in the two groups, with a low rate of discontinuation due to adverse events and no serious adverse events. Clinically significant weight gain (≥ 7% increase in body weight) was observed in 14% of patients in the 52-week group and 7% of patients in the 8-week group.

Limitations of the trial include the fact that it was stopped early, before the planned sample size was reached, owing to slow recruitment and funding issues.

Other limitations include a lack of ethnic diversity (only 12% were White and < 1% Black) and overrepresentation of patients from India, which may limit generalizability. 

In addition, the findings may not be applicable to treatment with antidepressants other than escitalopram and buproprion XL. Finally, the study population was also enriched for patients who responded to these antidepressants.
 

Need for an individualized approach

Commenting on the study, Roger McIntyre, MD, professor of psychiatry in pharmacology, University of Toronto, noted the study was not easy to conduct, and the investigators should be credited for conducting a maintenance study in bipolar depression.

“Although the study reports, as it should, that there is no evidence of maintenance effect, the secondary analysis, which was not adjusted for multiplicity, does suggest that there is a benefit,” said Dr. McIntyre, who was not associated with this research.

“However, the authors are also correct in stating that one cannot draw a conclusion because it was not the primary question and was not adjusted for multiplicity,” he added.

“If anything,” said Dr. McIntyre, “what these results do support is the notion that antidepressants are unlikely to destabilize all patients. Instead, the risk of destabilization seems to be largely limited to some persons, and there is a suggestion, based on the secondary outcome of this study, that maintenance antidepressant benefits can be seen in some people. But again that’s a testable hypothesis.”

Also weighing in on the research, Madhukar H. Trivedi, MD, professor of psychiatry and director, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas, said the study is “interesting,” adding that it was “unfortunate that the researchers had to curtail recruitment and reduce the size of the trial.”

University of Texas Southwestern Medical Center

A version of this article first appeared on Medscape.com.

The first randomized controlled trial testing the safety and efficacy of long-term antidepressant maintenance therapy after remission of a depressive episode in adults with bipolar I disorder has yielded mixed results.

Continuing antidepressant therapy for 52 weeks, as opposed to stopping it at 8 weeks, was not more beneficial with regard to the primary outcome of occurrence of any mood episode.

However, a prespecified sensitivity analysis of the primary outcome and of the secondary analyses suggests that continuing antidepressant therapy for 52 weeks may prolong the time to a depressive relapse.

“Because the primary outcome is negative and the prespecified sensitivity analysis is positive and the secondary outcomes are positive, some clinicians will pick the position that they work and some that they don’t work,” lead investigator Lakshmi Yatham, MBBS, with University of British Columbia, Vancouver, told this news organization.

University of British Columbia

Controversial issue

Adjunctive antidepressant therapy – alongside mood stabilizers and/or second-generation antipsychotic medications – are often used to treat acute depressive episodes in patients with bipolar I disorder.

Currently, the Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) advise discontinuing antidepressant treatment 8 weeks after remission of depression.

Yet, the duration of antidepressant therapy for bipolar depression is “highly controversial,” due to a lack of evidence and concerns that antidepressants may induce mania, mixed states, or rapid cycling between mania and depression, Dr. Yatham said.

Dr. Yatham and colleagues assessed the safety and efficacy of continuing adjunctive antidepressant treatment (escitalopram or bupropion XL) for 52 weeks after remission, compared with discontinuing antidepressant therapy at 8 weeks after remission.

The final analysis included 177 patients (mean age 41 years, 48% men) with bipolar I disorder who had remission of depression; 90 patients continued treatment with an antidepressant for 52 weeks and 87 were switched to placebo at 8 weeks. All were taking a mood stabilizer or a second-generation antipsychotic or both.

The primary outcome, assessed in a time-to-event analysis, was any mood episode, as defined by scores on scales measuring symptoms of hypomania or mania, depression, suicidality, and mood-episode severity; additional treatment or hospitalization for mood symptoms; or attempted or completed suicide.

At 52 weeks, 28 patients (31%) in the 52-week group had experienced any mood episode (primary outcome), compared with 40 patients (46%) in the 8-week group.

The primary outcome did not reach statistical significance (hazard ratio, 0.68; 95% confidence interval, 0.43-1.10; P = .12).

The researchers note that the decision by the study team to include relapses that occurred during the first 6 weeks of the study may have affected the primary outcome.

“During the first 6 weeks, both groups were getting the same treatment, and we thought there shouldn’t be any difference in relapse, but sadly, there were more relapses in the 52-week group even though the treatments were identical,” Dr. Yatham said.

However, in a sensitivity analysis of the primary outcome after week 6, when treatment between the two groups differed, patients continuing antidepressant treatment were 40% less likely to experience a relapse of any mood event (HR, 0.60) and 59% less likely to experience a depressive episode (HR, 0.41) relative to the placebo group.

“From the point where the two groups began receiving different treatments, we see a significant benefit for patients who continued treatment with antidepressants,” Dr. Yatham said in a news release.

“Treating depression in bipolar disorder is challenging. Reducing the risk of relapse is important because it can provide patients with a great deal of stability that ultimately lets them get back to the activities they enjoy and can greatly improve their quality of life,” he added.

Although fewer patients in the 52-week group than 8-week group had a depressive episode within 52 weeks (17% vs. 40%; HR, 0.43), more had a manic or hypomanic event (12% vs. 6%; HR, 2.28).

The estimated probability of remaining free of a depressive episode at 52 weeks was 72% in the 52-week group versus 53% in the 8-week group. The estimated probability of remaining free of a manic episode at 52 weeks was 81% and 92%, respectively.

The incidence of adverse events was similar in the two groups, with a low rate of discontinuation due to adverse events and no serious adverse events. Clinically significant weight gain (≥ 7% increase in body weight) was observed in 14% of patients in the 52-week group and 7% of patients in the 8-week group.

Limitations of the trial include the fact that it was stopped early, before the planned sample size was reached, owing to slow recruitment and funding issues.

Other limitations include a lack of ethnic diversity (only 12% were White and < 1% Black) and overrepresentation of patients from India, which may limit generalizability. 

In addition, the findings may not be applicable to treatment with antidepressants other than escitalopram and buproprion XL. Finally, the study population was also enriched for patients who responded to these antidepressants.
 

Need for an individualized approach

Commenting on the study, Roger McIntyre, MD, professor of psychiatry in pharmacology, University of Toronto, noted the study was not easy to conduct, and the investigators should be credited for conducting a maintenance study in bipolar depression.

“Although the study reports, as it should, that there is no evidence of maintenance effect, the secondary analysis, which was not adjusted for multiplicity, does suggest that there is a benefit,” said Dr. McIntyre, who was not associated with this research.

“However, the authors are also correct in stating that one cannot draw a conclusion because it was not the primary question and was not adjusted for multiplicity,” he added.

“If anything,” said Dr. McIntyre, “what these results do support is the notion that antidepressants are unlikely to destabilize all patients. Instead, the risk of destabilization seems to be largely limited to some persons, and there is a suggestion, based on the secondary outcome of this study, that maintenance antidepressant benefits can be seen in some people. But again that’s a testable hypothesis.”

Also weighing in on the research, Madhukar H. Trivedi, MD, professor of psychiatry and director, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas, said the study is “interesting,” adding that it was “unfortunate that the researchers had to curtail recruitment and reduce the size of the trial.”

University of Texas Southwestern Medical Center

A version of this article first appeared on Medscape.com.

The first randomized controlled trial testing the safety and efficacy of long-term antidepressant maintenance therapy after remission of a depressive episode in adults with bipolar I disorder has yielded mixed results.

Continuing antidepressant therapy for 52 weeks, as opposed to stopping it at 8 weeks, was not more beneficial with regard to the primary outcome of occurrence of any mood episode.

However, a prespecified sensitivity analysis of the primary outcome and of the secondary analyses suggests that continuing antidepressant therapy for 52 weeks may prolong the time to a depressive relapse.

“Because the primary outcome is negative and the prespecified sensitivity analysis is positive and the secondary outcomes are positive, some clinicians will pick the position that they work and some that they don’t work,” lead investigator Lakshmi Yatham, MBBS, with University of British Columbia, Vancouver, told this news organization.

University of British Columbia

Controversial issue

Adjunctive antidepressant therapy – alongside mood stabilizers and/or second-generation antipsychotic medications – are often used to treat acute depressive episodes in patients with bipolar I disorder.

Currently, the Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) advise discontinuing antidepressant treatment 8 weeks after remission of depression.

Yet, the duration of antidepressant therapy for bipolar depression is “highly controversial,” due to a lack of evidence and concerns that antidepressants may induce mania, mixed states, or rapid cycling between mania and depression, Dr. Yatham said.

Dr. Yatham and colleagues assessed the safety and efficacy of continuing adjunctive antidepressant treatment (escitalopram or bupropion XL) for 52 weeks after remission, compared with discontinuing antidepressant therapy at 8 weeks after remission.

The final analysis included 177 patients (mean age 41 years, 48% men) with bipolar I disorder who had remission of depression; 90 patients continued treatment with an antidepressant for 52 weeks and 87 were switched to placebo at 8 weeks. All were taking a mood stabilizer or a second-generation antipsychotic or both.

The primary outcome, assessed in a time-to-event analysis, was any mood episode, as defined by scores on scales measuring symptoms of hypomania or mania, depression, suicidality, and mood-episode severity; additional treatment or hospitalization for mood symptoms; or attempted or completed suicide.

At 52 weeks, 28 patients (31%) in the 52-week group had experienced any mood episode (primary outcome), compared with 40 patients (46%) in the 8-week group.

The primary outcome did not reach statistical significance (hazard ratio, 0.68; 95% confidence interval, 0.43-1.10; P = .12).

The researchers note that the decision by the study team to include relapses that occurred during the first 6 weeks of the study may have affected the primary outcome.

“During the first 6 weeks, both groups were getting the same treatment, and we thought there shouldn’t be any difference in relapse, but sadly, there were more relapses in the 52-week group even though the treatments were identical,” Dr. Yatham said.

However, in a sensitivity analysis of the primary outcome after week 6, when treatment between the two groups differed, patients continuing antidepressant treatment were 40% less likely to experience a relapse of any mood event (HR, 0.60) and 59% less likely to experience a depressive episode (HR, 0.41) relative to the placebo group.

“From the point where the two groups began receiving different treatments, we see a significant benefit for patients who continued treatment with antidepressants,” Dr. Yatham said in a news release.

“Treating depression in bipolar disorder is challenging. Reducing the risk of relapse is important because it can provide patients with a great deal of stability that ultimately lets them get back to the activities they enjoy and can greatly improve their quality of life,” he added.

Although fewer patients in the 52-week group than 8-week group had a depressive episode within 52 weeks (17% vs. 40%; HR, 0.43), more had a manic or hypomanic event (12% vs. 6%; HR, 2.28).

The estimated probability of remaining free of a depressive episode at 52 weeks was 72% in the 52-week group versus 53% in the 8-week group. The estimated probability of remaining free of a manic episode at 52 weeks was 81% and 92%, respectively.

The incidence of adverse events was similar in the two groups, with a low rate of discontinuation due to adverse events and no serious adverse events. Clinically significant weight gain (≥ 7% increase in body weight) was observed in 14% of patients in the 52-week group and 7% of patients in the 8-week group.

Limitations of the trial include the fact that it was stopped early, before the planned sample size was reached, owing to slow recruitment and funding issues.

Other limitations include a lack of ethnic diversity (only 12% were White and < 1% Black) and overrepresentation of patients from India, which may limit generalizability. 

In addition, the findings may not be applicable to treatment with antidepressants other than escitalopram and buproprion XL. Finally, the study population was also enriched for patients who responded to these antidepressants.
 

Need for an individualized approach

Commenting on the study, Roger McIntyre, MD, professor of psychiatry in pharmacology, University of Toronto, noted the study was not easy to conduct, and the investigators should be credited for conducting a maintenance study in bipolar depression.

“Although the study reports, as it should, that there is no evidence of maintenance effect, the secondary analysis, which was not adjusted for multiplicity, does suggest that there is a benefit,” said Dr. McIntyre, who was not associated with this research.

“However, the authors are also correct in stating that one cannot draw a conclusion because it was not the primary question and was not adjusted for multiplicity,” he added.

“If anything,” said Dr. McIntyre, “what these results do support is the notion that antidepressants are unlikely to destabilize all patients. Instead, the risk of destabilization seems to be largely limited to some persons, and there is a suggestion, based on the secondary outcome of this study, that maintenance antidepressant benefits can be seen in some people. But again that’s a testable hypothesis.”

Also weighing in on the research, Madhukar H. Trivedi, MD, professor of psychiatry and director, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas, said the study is “interesting,” adding that it was “unfortunate that the researchers had to curtail recruitment and reduce the size of the trial.”

University of Texas Southwestern Medical Center

A version of this article first appeared on Medscape.com.

New research calls into question the established method of assessing patient response to antidepressant treatment and expands the concepts of “responder” and “nonresponder.” 

Investigators assessed more than 800 patients with major depressive disorder (MDD) attending a partial hospital program. The patients completed questionnaires about depressive symptoms as well as functioning and broader measures of quality of life (QoL).

Brown University

Although fewer than 40% were classified as treatment responders on the basis of depressive symptoms, as measured by the Remission from Depression Questionnaire (RDQ), two-thirds met criteria as responders on the Patient Global Rating of Improvement (PGI) scale, which takes into consideration broader domains of life satisfaction.

“The treatments we’re offering patients may be doing a better job than we think in treating depression, because many patients say they feel significantly better, even if their depression symptoms haven’t been diminished by the arbitrary threshold of 50% or greater improvement,” study investigator Mark Zimmerman, MD, professor of psychiatry and human behavior, Brown University, Providence, R.I., told this news organization.

“Many of these patients – even if they have ongoing depressive symptoms – nevertheless say treatment has been very or extremely helpful, which is picked by other emphasizes in outcome, such as functioning, quality of life, coping abilities, and positive mental health,” added Dr. Zimmerman, director of the outpatient division at the Partial Hospital Program, Rhode Island Hospital.

The study was published online in the Annals of Clinical Psychiatry.

What’s the best tool?

“Almost all studies of depression treatment rely on measures of symptom severity to evaluate outcome – which is understandable, because a diagnosis of MDD requires a minimum number of symptoms for a sustained period of time,” said Dr. Zimmerman.

However, while important, symptom reduction is only one component of depression treatment. Improving overall function, QoL, and ability to deal with life’s stressors are equally important, he said.

Dr. Zimmerman emphasized he’s an “advocate, supporter, and practitioner of measurement-based care.” This approach, he said, “increases efficiency of the visit and directs me to the areas I should be inquiring about and the areas that need less time for inquiry.”

Measurement tools also enable numerical documentation of how a patient is doing and helps them understand and recognize their improvement.

The question is which tool captures improvements most effectively. Several surveys show that patients value improved functioning and QoL as primary treatment goals, which “is different from the emphasis of symptom improvement found in research,” said Dr. Zimmerman.

A multidimensional questionnaire that assesses functioning, QoL, and coping ability as well as symptoms is more likely to reflect patients’ treatment goals than simply measuring symptoms, he said.

Dr. Zimmerman and his coauthor reported on findings from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) Project, which “examined the concordance between patients’ global rating of improvement from treatment and responder status, based on a depression symptoms severity scale.”
 

Doing better than we think

The study was conducted in Rhode Island Hospital’s department of psychiatry partial hospital program, where 844 patients with MDD (65.2% women; mean [SD] age, 36.8 [13.9] years) completed the RDQ – a self-report measure that “assesses constructs that patients consider to be relevant for assessing treatment outcome.” This questionnaire assesses symptom and nonsymptom domains that people consider important when evaluating treatment effectiveness.

To the original 41-item questionnaire, the researchers added 19 items. The final 60-item questionnaire included the following:

• 14 depressive symptoms.
• 11 nondepressive symptoms.
• 5 coping ability/stress tolerance items (for instance, “I had trouble handling pressure”).
• 12 positive mental health items (for instance, “I saw myself as a person of value”).
• 10 functioning items (for instance, “I was socially withdrawn”).
• 8 general well-being/life satisfaction items (for instance, “I was engaging in life rather than hiding from it”).

Patients were divided into three groups:

• Symptom responders (whose scores on the RDQ depressive symptom subscale improved by ≥ 50% from admission to discharge).
• PGI responders, who weren’t symptom responders – that is, who reported global improvement but didn’t improve ≥ 50% on the depression symptom subscale.
• Nonresponders (that is, patients who didn’t respond on the PGI and the depressive symptom subscale).

The researchers compared the three groups on the four symptom domains of the RDQ. Patients also completed the PGI on discharge, and the researchers compared these responses to responses to the RDQ.

Only 38.7% were responders on the depressive symptoms subscale, while 67.4% were PGI responders.

Most patients (91.4%) who were responders on the depressive symptom subscale were also PGI responders, while 32% were PGI responders but not responders on the depressive symptom subscale.

Although 29.2% were nonresponders on both measures, 70.8% were responders on one scale or the other.

As far as the nonsymptom domains, response rates varied between 30% (life satisfaction) to 33.1% (positive mental health).

“If you’re using a measurement tool in practice, I’d recommend one that goes beyond symptom improvement and also captures broader domains,” Dr. Zimmerman said.
 

‘Better enough’

Commenting on the study, Philip Muskin, MD, professor of psychiatry, Columbia University Medical Center, New York, said the use of symptom-driven rating scales to measure depression response originated in mandates of the U.S. Food and Drug Administration to determine whether a drug being tested in a clinical trial is superior to placebo.

Columbia University Medical Center

“But there has been, for a long time, the question of whether these people are really better,” said Dr. Muskin, who was not involved with the current study. “Symptomatically, they may show improvement, but do they actually perceive themselves as better?”

Some patients might report, “I’m about 75% myself, but not back to 100%.” Dr. Muskin doesn’t “take these to be hard-and-fast numbers, but patients can tell you how they perceive themselves. This study suggests that if you’re wedded to [symptom measurement] scales, you may not realize that patients are actually getting better. And who decides if a patient is better, or better enough? The patient decides that.”

He added that some patients won’t achieve complete remission. “Even if I can’t get the person to be 100% better, I’m glad if I can help them become ‘better enough’ to function in life, do things, go to work, and improve in quality-of-life domains.”

The study received no outside funding. Dr. Zimmerman and his coauthor and Dr. Muskin report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

New research calls into question the established method of assessing patient response to antidepressant treatment and expands the concepts of “responder” and “nonresponder.” 

Investigators assessed more than 800 patients with major depressive disorder (MDD) attending a partial hospital program. The patients completed questionnaires about depressive symptoms as well as functioning and broader measures of quality of life (QoL).

Brown University

Although fewer than 40% were classified as treatment responders on the basis of depressive symptoms, as measured by the Remission from Depression Questionnaire (RDQ), two-thirds met criteria as responders on the Patient Global Rating of Improvement (PGI) scale, which takes into consideration broader domains of life satisfaction.

“The treatments we’re offering patients may be doing a better job than we think in treating depression, because many patients say they feel significantly better, even if their depression symptoms haven’t been diminished by the arbitrary threshold of 50% or greater improvement,” study investigator Mark Zimmerman, MD, professor of psychiatry and human behavior, Brown University, Providence, R.I., told this news organization.

“Many of these patients – even if they have ongoing depressive symptoms – nevertheless say treatment has been very or extremely helpful, which is picked by other emphasizes in outcome, such as functioning, quality of life, coping abilities, and positive mental health,” added Dr. Zimmerman, director of the outpatient division at the Partial Hospital Program, Rhode Island Hospital.

The study was published online in the Annals of Clinical Psychiatry.

What’s the best tool?

“Almost all studies of depression treatment rely on measures of symptom severity to evaluate outcome – which is understandable, because a diagnosis of MDD requires a minimum number of symptoms for a sustained period of time,” said Dr. Zimmerman.

However, while important, symptom reduction is only one component of depression treatment. Improving overall function, QoL, and ability to deal with life’s stressors are equally important, he said.

Dr. Zimmerman emphasized he’s an “advocate, supporter, and practitioner of measurement-based care.” This approach, he said, “increases efficiency of the visit and directs me to the areas I should be inquiring about and the areas that need less time for inquiry.”

Measurement tools also enable numerical documentation of how a patient is doing and helps them understand and recognize their improvement.

The question is which tool captures improvements most effectively. Several surveys show that patients value improved functioning and QoL as primary treatment goals, which “is different from the emphasis of symptom improvement found in research,” said Dr. Zimmerman.

A multidimensional questionnaire that assesses functioning, QoL, and coping ability as well as symptoms is more likely to reflect patients’ treatment goals than simply measuring symptoms, he said.

Dr. Zimmerman and his coauthor reported on findings from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) Project, which “examined the concordance between patients’ global rating of improvement from treatment and responder status, based on a depression symptoms severity scale.”
 

Doing better than we think

The study was conducted in Rhode Island Hospital’s department of psychiatry partial hospital program, where 844 patients with MDD (65.2% women; mean [SD] age, 36.8 [13.9] years) completed the RDQ – a self-report measure that “assesses constructs that patients consider to be relevant for assessing treatment outcome.” This questionnaire assesses symptom and nonsymptom domains that people consider important when evaluating treatment effectiveness.

To the original 41-item questionnaire, the researchers added 19 items. The final 60-item questionnaire included the following:

• 14 depressive symptoms.
• 11 nondepressive symptoms.
• 5 coping ability/stress tolerance items (for instance, “I had trouble handling pressure”).
• 12 positive mental health items (for instance, “I saw myself as a person of value”).
• 10 functioning items (for instance, “I was socially withdrawn”).
• 8 general well-being/life satisfaction items (for instance, “I was engaging in life rather than hiding from it”).

Patients were divided into three groups:

• Symptom responders (whose scores on the RDQ depressive symptom subscale improved by ≥ 50% from admission to discharge).
• PGI responders, who weren’t symptom responders – that is, who reported global improvement but didn’t improve ≥ 50% on the depression symptom subscale.
• Nonresponders (that is, patients who didn’t respond on the PGI and the depressive symptom subscale).

The researchers compared the three groups on the four symptom domains of the RDQ. Patients also completed the PGI on discharge, and the researchers compared these responses to responses to the RDQ.

Only 38.7% were responders on the depressive symptoms subscale, while 67.4% were PGI responders.

Most patients (91.4%) who were responders on the depressive symptom subscale were also PGI responders, while 32% were PGI responders but not responders on the depressive symptom subscale.

Although 29.2% were nonresponders on both measures, 70.8% were responders on one scale or the other.

As far as the nonsymptom domains, response rates varied between 30% (life satisfaction) to 33.1% (positive mental health).

“If you’re using a measurement tool in practice, I’d recommend one that goes beyond symptom improvement and also captures broader domains,” Dr. Zimmerman said.
 

‘Better enough’

Commenting on the study, Philip Muskin, MD, professor of psychiatry, Columbia University Medical Center, New York, said the use of symptom-driven rating scales to measure depression response originated in mandates of the U.S. Food and Drug Administration to determine whether a drug being tested in a clinical trial is superior to placebo.

Columbia University Medical Center

“But there has been, for a long time, the question of whether these people are really better,” said Dr. Muskin, who was not involved with the current study. “Symptomatically, they may show improvement, but do they actually perceive themselves as better?”

Some patients might report, “I’m about 75% myself, but not back to 100%.” Dr. Muskin doesn’t “take these to be hard-and-fast numbers, but patients can tell you how they perceive themselves. This study suggests that if you’re wedded to [symptom measurement] scales, you may not realize that patients are actually getting better. And who decides if a patient is better, or better enough? The patient decides that.”

He added that some patients won’t achieve complete remission. “Even if I can’t get the person to be 100% better, I’m glad if I can help them become ‘better enough’ to function in life, do things, go to work, and improve in quality-of-life domains.”

The study received no outside funding. Dr. Zimmerman and his coauthor and Dr. Muskin report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

New research calls into question the established method of assessing patient response to antidepressant treatment and expands the concepts of “responder” and “nonresponder.” 

Investigators assessed more than 800 patients with major depressive disorder (MDD) attending a partial hospital program. The patients completed questionnaires about depressive symptoms as well as functioning and broader measures of quality of life (QoL).

Brown University

Although fewer than 40% were classified as treatment responders on the basis of depressive symptoms, as measured by the Remission from Depression Questionnaire (RDQ), two-thirds met criteria as responders on the Patient Global Rating of Improvement (PGI) scale, which takes into consideration broader domains of life satisfaction.

“The treatments we’re offering patients may be doing a better job than we think in treating depression, because many patients say they feel significantly better, even if their depression symptoms haven’t been diminished by the arbitrary threshold of 50% or greater improvement,” study investigator Mark Zimmerman, MD, professor of psychiatry and human behavior, Brown University, Providence, R.I., told this news organization.

“Many of these patients – even if they have ongoing depressive symptoms – nevertheless say treatment has been very or extremely helpful, which is picked by other emphasizes in outcome, such as functioning, quality of life, coping abilities, and positive mental health,” added Dr. Zimmerman, director of the outpatient division at the Partial Hospital Program, Rhode Island Hospital.

The study was published online in the Annals of Clinical Psychiatry.

What’s the best tool?

“Almost all studies of depression treatment rely on measures of symptom severity to evaluate outcome – which is understandable, because a diagnosis of MDD requires a minimum number of symptoms for a sustained period of time,” said Dr. Zimmerman.

However, while important, symptom reduction is only one component of depression treatment. Improving overall function, QoL, and ability to deal with life’s stressors are equally important, he said.

Dr. Zimmerman emphasized he’s an “advocate, supporter, and practitioner of measurement-based care.” This approach, he said, “increases efficiency of the visit and directs me to the areas I should be inquiring about and the areas that need less time for inquiry.”

Measurement tools also enable numerical documentation of how a patient is doing and helps them understand and recognize their improvement.

The question is which tool captures improvements most effectively. Several surveys show that patients value improved functioning and QoL as primary treatment goals, which “is different from the emphasis of symptom improvement found in research,” said Dr. Zimmerman.

A multidimensional questionnaire that assesses functioning, QoL, and coping ability as well as symptoms is more likely to reflect patients’ treatment goals than simply measuring symptoms, he said.

Dr. Zimmerman and his coauthor reported on findings from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) Project, which “examined the concordance between patients’ global rating of improvement from treatment and responder status, based on a depression symptoms severity scale.”
 

Doing better than we think

The study was conducted in Rhode Island Hospital’s department of psychiatry partial hospital program, where 844 patients with MDD (65.2% women; mean [SD] age, 36.8 [13.9] years) completed the RDQ – a self-report measure that “assesses constructs that patients consider to be relevant for assessing treatment outcome.” This questionnaire assesses symptom and nonsymptom domains that people consider important when evaluating treatment effectiveness.

To the original 41-item questionnaire, the researchers added 19 items. The final 60-item questionnaire included the following:

• 14 depressive symptoms.
• 11 nondepressive symptoms.
• 5 coping ability/stress tolerance items (for instance, “I had trouble handling pressure”).
• 12 positive mental health items (for instance, “I saw myself as a person of value”).
• 10 functioning items (for instance, “I was socially withdrawn”).
• 8 general well-being/life satisfaction items (for instance, “I was engaging in life rather than hiding from it”).

Patients were divided into three groups:

• Symptom responders (whose scores on the RDQ depressive symptom subscale improved by ≥ 50% from admission to discharge).
• PGI responders, who weren’t symptom responders – that is, who reported global improvement but didn’t improve ≥ 50% on the depression symptom subscale.
• Nonresponders (that is, patients who didn’t respond on the PGI and the depressive symptom subscale).

The researchers compared the three groups on the four symptom domains of the RDQ. Patients also completed the PGI on discharge, and the researchers compared these responses to responses to the RDQ.

Only 38.7% were responders on the depressive symptoms subscale, while 67.4% were PGI responders.

Most patients (91.4%) who were responders on the depressive symptom subscale were also PGI responders, while 32% were PGI responders but not responders on the depressive symptom subscale.

Although 29.2% were nonresponders on both measures, 70.8% were responders on one scale or the other.

As far as the nonsymptom domains, response rates varied between 30% (life satisfaction) to 33.1% (positive mental health).

“If you’re using a measurement tool in practice, I’d recommend one that goes beyond symptom improvement and also captures broader domains,” Dr. Zimmerman said.
 

‘Better enough’

Commenting on the study, Philip Muskin, MD, professor of psychiatry, Columbia University Medical Center, New York, said the use of symptom-driven rating scales to measure depression response originated in mandates of the U.S. Food and Drug Administration to determine whether a drug being tested in a clinical trial is superior to placebo.

Columbia University Medical Center

“But there has been, for a long time, the question of whether these people are really better,” said Dr. Muskin, who was not involved with the current study. “Symptomatically, they may show improvement, but do they actually perceive themselves as better?”

Some patients might report, “I’m about 75% myself, but not back to 100%.” Dr. Muskin doesn’t “take these to be hard-and-fast numbers, but patients can tell you how they perceive themselves. This study suggests that if you’re wedded to [symptom measurement] scales, you may not realize that patients are actually getting better. And who decides if a patient is better, or better enough? The patient decides that.”

He added that some patients won’t achieve complete remission. “Even if I can’t get the person to be 100% better, I’m glad if I can help them become ‘better enough’ to function in life, do things, go to work, and improve in quality-of-life domains.”

The study received no outside funding. Dr. Zimmerman and his coauthor and Dr. Muskin report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

One of the most controversial issues today is whether a physician should be permitted, or even obligated, to assist patients with a terminal or incurable illness to end their life – a process known as medical assistance in dying (MAID) or physician-assisted suicide (PAS.)

Until recently, this contentious issue applied only to patients with physical illnesses who want to end their suffering and who seek out a physician willing to assist with that objective. In the United States and other countries, this is the patient population who may be able to avail themselves of this option.

However, newly proposed legislation in Canada – which has the largest number of physician-assisted deaths worldwide – would expand the indication for MAID to include serious mental illness. Originally set to be passed in March 2023, the law has been deferred for final decision until March 2024.

A recent commentary by psychiatrist Dinah Miller, MD, explored the ethics of this proposed legislation for mental health professionals. “To offer the option of death facilitated by the very person who is trying to get [patients with serious mental illness] better seems so counter to everything I have learned and contradicts our role as psychiatrists who work so hard to prevent suicide,” Dr. Miller wrote. “As psychiatrists, do we offer hope to our most vulnerable patients, or do we offer death? Do we rail against suicide, or do we facilitate it?”

Dr. Miller’s piece garnered a huge amount of reader response that included many laudatory comments: a “nuanced and open-ended inquiry here,” “timely and honest,” and “beautifully written.” One reader thanked the author for “this thoughtful, questioning, and open reflection on what it means to be a psychiatrist facing a thorny and deeply personal practice and philosophical question.”
 

Cognitive distortion or objective reality?

Many readers were opposed to any type of physician involvement in hastening a patient’s death, regardless of whether the condition is medical or psychiatric. “Let others who wish to die make their own arrangement without the aid of the medical profession,” one reader wrote.

But others felt that for those with terminal physical illnesses or intractable pain, it is justified for medical professionals to either facilitate death or, at the very least, withhold life-prolonging treatments.

A critical-care physician described responding to families’ accusations that withdrawal of life-sustaining measures means “playing God.” On the contrary, the physician wrote, “there is a limit to our abilities; and withdrawing those life-prolonging interventions allows nature or God or whatever to play a role and take its course.”

Another U.S. reader pointed out that “multiple polls in this country have shown that the majority of the general public, physicians in general and psychiatrists in particular, support the option of MAID for the terminally ill. They do not find it at variance with their calling as physicians.”

“I and many of my elderly friends don’t fear death but fear prolonged dementia with its dependency and lack of quality of life,” one reader wrote. “We would be much more at peace if we could put in our advanced directive that we request MAID once some point of dependency has been reached.”

Another wrote that in the event of entering a state of “degrading dependency and hardship on the family, please let me go peacefully, without burdening others, into that good night [of death].”

Many felt that not only physical illness but also the prospect of cognitive degeneration – specifically dementia – also justifies assisting patient death.
 

“Enormous suffering”

One Canadian reader noted that provisions for advance consent are now in place in Canada for those facing the prospect of neurodegenerative disease and who are still mentally competent to make such decisions.

But therein lies the rub – the concept of an advanced directive goes to the question of decisional capacity. Dr. Miller noted that “depression distorts cognition and leads many patients to believe that they would be better off dead and that their loves ones would be better off without them.”

The concept of “cognitive distortion” implies that the illness itself may impede the decisional capacity required for an advanced directive or a decision made in the moment, in the absence of such a directive. Dr. Miller asked, “How do we determine whether patients with serious mental illness are competent to make such a decision or whether it is mental illness that is driving their perception of a future without hope?”

One reader attested to this from personal experience. “As both a physician and a sufferer of severe, often profound depression for 50 years, I can confidently say that ... the pursuit of death is the result of an impaired mental state, which simultaneously prevents a rational decision.”

Another agreed. “As a psychiatrist, I treated suicidal patients almost every day of my 27-year career. I believe in making every effort to prevent the suicide of a healthy depressed person and I do not support MAID for psychiatric conditions. But I do support MAID for the terminally ill.”

Other readers disagreed. In the words of one commentator, “I think that if we are going to help mentally ill people, we have to consider their choices. The stress imposed by a severe/intractable mental illness is as bad as any other devastating medical illness. If no one is going to hold their hand in life (as support services are limited and psychiatric treatments often fail), allow a medical professional to hold their hand through their final moments.”

A psychiatrist described very ill patients with treatment-resistant bipolar disorder who had not only received medications, including ketamine, but had also received electroconvulsive therapy and still did not respond.

“Their suffering is enormous and the truth is that there is no improvement for more than a few days or weeks and later they return to their hell. Appreciating that they would be better off dead for themselves and their families is not always a cognitive distortion but an objective evaluation of their reality.”

However, as another reader pointed out, an issue with the argument presented here is that it presupposes that MAID requires “clinical justification.” But in Canada, “MAID ... is understood as an expression of personal autonomy. Rooted in liberal political philosophy of individualism ... approval for death need not be based on a clinical assessment.” Instead, “death is seen as a ‘right’ that the state must therefore provide.”
 

Another form of eugenics?

Dr. Miller raised the ethical implications of racial and socioeconomic factors playing a role in the consideration of MAID for those with psychiatric illness.

“Might those who are poor, who have less access to expensive treatment options and social support, be more likely to request facilitated death?” she asks. “Do we risk facilitating a patient’s demise when other options are unavailable because of a lack of access to treatment or when social and financial struggles exacerbate a person’s hopelessness? Should we worry that psychiatric euthanasia will turn into a form of eugenics where those who can’t contribute are made to feel that they should bow out?”

Several readers agreed. “Looking at the disproportionate burden of illness, rates of imprisonment, and application of the death penalty indicates to me that race and socioeconomic status will be an immediate factor in how, where, and with whom MAID for mental illness would be practice in much, if not all, of the U.S.,” wrote one physician.

A Canadian reader expressed similar concerns. “I’ve seen a handful of people, including someone I considered a good friend, opt for MAID because it was easier than living as a disabled person in poverty without adequate mental health care.”

Another Canadian clinician noted that offering people good care can make all the difference. “As a Canadian mental health clinician who served youth with severe mental illness for over 20 years through our socialized medical network, I can attest to the difference good care usually makes in shifting clients from despair and a commitment to death to embracing life once again. Let’s not, as clinicians, embrace easing a government/state-sanctioned pathway to death.”

Some readers believe that these types of issues can’t be solved with a blanket approach, noting that each case is different. “Real life is always more complicated than academic discussions. Having served on a hospital ethics committee, I know that each case is unique,” one reader noted.

Another reader added, “I think all we can do as physicians is to let people decide for themselves and participate only if our conscience allows.”
 

A version of this article first appeared on Medscape.com.

One of the most controversial issues today is whether a physician should be permitted, or even obligated, to assist patients with a terminal or incurable illness to end their life – a process known as medical assistance in dying (MAID) or physician-assisted suicide (PAS.)

Until recently, this contentious issue applied only to patients with physical illnesses who want to end their suffering and who seek out a physician willing to assist with that objective. In the United States and other countries, this is the patient population who may be able to avail themselves of this option.

However, newly proposed legislation in Canada – which has the largest number of physician-assisted deaths worldwide – would expand the indication for MAID to include serious mental illness. Originally set to be passed in March 2023, the law has been deferred for final decision until March 2024.

A recent commentary by psychiatrist Dinah Miller, MD, explored the ethics of this proposed legislation for mental health professionals. “To offer the option of death facilitated by the very person who is trying to get [patients with serious mental illness] better seems so counter to everything I have learned and contradicts our role as psychiatrists who work so hard to prevent suicide,” Dr. Miller wrote. “As psychiatrists, do we offer hope to our most vulnerable patients, or do we offer death? Do we rail against suicide, or do we facilitate it?”

Dr. Miller’s piece garnered a huge amount of reader response that included many laudatory comments: a “nuanced and open-ended inquiry here,” “timely and honest,” and “beautifully written.” One reader thanked the author for “this thoughtful, questioning, and open reflection on what it means to be a psychiatrist facing a thorny and deeply personal practice and philosophical question.”
 

Cognitive distortion or objective reality?

Many readers were opposed to any type of physician involvement in hastening a patient’s death, regardless of whether the condition is medical or psychiatric. “Let others who wish to die make their own arrangement without the aid of the medical profession,” one reader wrote.

But others felt that for those with terminal physical illnesses or intractable pain, it is justified for medical professionals to either facilitate death or, at the very least, withhold life-prolonging treatments.

A critical-care physician described responding to families’ accusations that withdrawal of life-sustaining measures means “playing God.” On the contrary, the physician wrote, “there is a limit to our abilities; and withdrawing those life-prolonging interventions allows nature or God or whatever to play a role and take its course.”

Another U.S. reader pointed out that “multiple polls in this country have shown that the majority of the general public, physicians in general and psychiatrists in particular, support the option of MAID for the terminally ill. They do not find it at variance with their calling as physicians.”

“I and many of my elderly friends don’t fear death but fear prolonged dementia with its dependency and lack of quality of life,” one reader wrote. “We would be much more at peace if we could put in our advanced directive that we request MAID once some point of dependency has been reached.”

Another wrote that in the event of entering a state of “degrading dependency and hardship on the family, please let me go peacefully, without burdening others, into that good night [of death].”

Many felt that not only physical illness but also the prospect of cognitive degeneration – specifically dementia – also justifies assisting patient death.
 

“Enormous suffering”

One Canadian reader noted that provisions for advance consent are now in place in Canada for those facing the prospect of neurodegenerative disease and who are still mentally competent to make such decisions.

But therein lies the rub – the concept of an advanced directive goes to the question of decisional capacity. Dr. Miller noted that “depression distorts cognition and leads many patients to believe that they would be better off dead and that their loves ones would be better off without them.”

The concept of “cognitive distortion” implies that the illness itself may impede the decisional capacity required for an advanced directive or a decision made in the moment, in the absence of such a directive. Dr. Miller asked, “How do we determine whether patients with serious mental illness are competent to make such a decision or whether it is mental illness that is driving their perception of a future without hope?”

One reader attested to this from personal experience. “As both a physician and a sufferer of severe, often profound depression for 50 years, I can confidently say that ... the pursuit of death is the result of an impaired mental state, which simultaneously prevents a rational decision.”

Another agreed. “As a psychiatrist, I treated suicidal patients almost every day of my 27-year career. I believe in making every effort to prevent the suicide of a healthy depressed person and I do not support MAID for psychiatric conditions. But I do support MAID for the terminally ill.”

Other readers disagreed. In the words of one commentator, “I think that if we are going to help mentally ill people, we have to consider their choices. The stress imposed by a severe/intractable mental illness is as bad as any other devastating medical illness. If no one is going to hold their hand in life (as support services are limited and psychiatric treatments often fail), allow a medical professional to hold their hand through their final moments.”

A psychiatrist described very ill patients with treatment-resistant bipolar disorder who had not only received medications, including ketamine, but had also received electroconvulsive therapy and still did not respond.

“Their suffering is enormous and the truth is that there is no improvement for more than a few days or weeks and later they return to their hell. Appreciating that they would be better off dead for themselves and their families is not always a cognitive distortion but an objective evaluation of their reality.”

However, as another reader pointed out, an issue with the argument presented here is that it presupposes that MAID requires “clinical justification.” But in Canada, “MAID ... is understood as an expression of personal autonomy. Rooted in liberal political philosophy of individualism ... approval for death need not be based on a clinical assessment.” Instead, “death is seen as a ‘right’ that the state must therefore provide.”
 

Another form of eugenics?

Dr. Miller raised the ethical implications of racial and socioeconomic factors playing a role in the consideration of MAID for those with psychiatric illness.

“Might those who are poor, who have less access to expensive treatment options and social support, be more likely to request facilitated death?” she asks. “Do we risk facilitating a patient’s demise when other options are unavailable because of a lack of access to treatment or when social and financial struggles exacerbate a person’s hopelessness? Should we worry that psychiatric euthanasia will turn into a form of eugenics where those who can’t contribute are made to feel that they should bow out?”

Several readers agreed. “Looking at the disproportionate burden of illness, rates of imprisonment, and application of the death penalty indicates to me that race and socioeconomic status will be an immediate factor in how, where, and with whom MAID for mental illness would be practice in much, if not all, of the U.S.,” wrote one physician.

A Canadian reader expressed similar concerns. “I’ve seen a handful of people, including someone I considered a good friend, opt for MAID because it was easier than living as a disabled person in poverty without adequate mental health care.”

Another Canadian clinician noted that offering people good care can make all the difference. “As a Canadian mental health clinician who served youth with severe mental illness for over 20 years through our socialized medical network, I can attest to the difference good care usually makes in shifting clients from despair and a commitment to death to embracing life once again. Let’s not, as clinicians, embrace easing a government/state-sanctioned pathway to death.”

Some readers believe that these types of issues can’t be solved with a blanket approach, noting that each case is different. “Real life is always more complicated than academic discussions. Having served on a hospital ethics committee, I know that each case is unique,” one reader noted.

Another reader added, “I think all we can do as physicians is to let people decide for themselves and participate only if our conscience allows.”
 

A version of this article first appeared on Medscape.com.

One of the most controversial issues today is whether a physician should be permitted, or even obligated, to assist patients with a terminal or incurable illness to end their life – a process known as medical assistance in dying (MAID) or physician-assisted suicide (PAS.)

Until recently, this contentious issue applied only to patients with physical illnesses who want to end their suffering and who seek out a physician willing to assist with that objective. In the United States and other countries, this is the patient population who may be able to avail themselves of this option.

However, newly proposed legislation in Canada – which has the largest number of physician-assisted deaths worldwide – would expand the indication for MAID to include serious mental illness. Originally set to be passed in March 2023, the law has been deferred for final decision until March 2024.

A recent commentary by psychiatrist Dinah Miller, MD, explored the ethics of this proposed legislation for mental health professionals. “To offer the option of death facilitated by the very person who is trying to get [patients with serious mental illness] better seems so counter to everything I have learned and contradicts our role as psychiatrists who work so hard to prevent suicide,” Dr. Miller wrote. “As psychiatrists, do we offer hope to our most vulnerable patients, or do we offer death? Do we rail against suicide, or do we facilitate it?”

Dr. Miller’s piece garnered a huge amount of reader response that included many laudatory comments: a “nuanced and open-ended inquiry here,” “timely and honest,” and “beautifully written.” One reader thanked the author for “this thoughtful, questioning, and open reflection on what it means to be a psychiatrist facing a thorny and deeply personal practice and philosophical question.”
 

Cognitive distortion or objective reality?

Many readers were opposed to any type of physician involvement in hastening a patient’s death, regardless of whether the condition is medical or psychiatric. “Let others who wish to die make their own arrangement without the aid of the medical profession,” one reader wrote.

But others felt that for those with terminal physical illnesses or intractable pain, it is justified for medical professionals to either facilitate death or, at the very least, withhold life-prolonging treatments.

A critical-care physician described responding to families’ accusations that withdrawal of life-sustaining measures means “playing God.” On the contrary, the physician wrote, “there is a limit to our abilities; and withdrawing those life-prolonging interventions allows nature or God or whatever to play a role and take its course.”

Another U.S. reader pointed out that “multiple polls in this country have shown that the majority of the general public, physicians in general and psychiatrists in particular, support the option of MAID for the terminally ill. They do not find it at variance with their calling as physicians.”

“I and many of my elderly friends don’t fear death but fear prolonged dementia with its dependency and lack of quality of life,” one reader wrote. “We would be much more at peace if we could put in our advanced directive that we request MAID once some point of dependency has been reached.”

Another wrote that in the event of entering a state of “degrading dependency and hardship on the family, please let me go peacefully, without burdening others, into that good night [of death].”

Many felt that not only physical illness but also the prospect of cognitive degeneration – specifically dementia – also justifies assisting patient death.
 

“Enormous suffering”

One Canadian reader noted that provisions for advance consent are now in place in Canada for those facing the prospect of neurodegenerative disease and who are still mentally competent to make such decisions.

But therein lies the rub – the concept of an advanced directive goes to the question of decisional capacity. Dr. Miller noted that “depression distorts cognition and leads many patients to believe that they would be better off dead and that their loves ones would be better off without them.”

The concept of “cognitive distortion” implies that the illness itself may impede the decisional capacity required for an advanced directive or a decision made in the moment, in the absence of such a directive. Dr. Miller asked, “How do we determine whether patients with serious mental illness are competent to make such a decision or whether it is mental illness that is driving their perception of a future without hope?”

One reader attested to this from personal experience. “As both a physician and a sufferer of severe, often profound depression for 50 years, I can confidently say that ... the pursuit of death is the result of an impaired mental state, which simultaneously prevents a rational decision.”

Another agreed. “As a psychiatrist, I treated suicidal patients almost every day of my 27-year career. I believe in making every effort to prevent the suicide of a healthy depressed person and I do not support MAID for psychiatric conditions. But I do support MAID for the terminally ill.”

Other readers disagreed. In the words of one commentator, “I think that if we are going to help mentally ill people, we have to consider their choices. The stress imposed by a severe/intractable mental illness is as bad as any other devastating medical illness. If no one is going to hold their hand in life (as support services are limited and psychiatric treatments often fail), allow a medical professional to hold their hand through their final moments.”

A psychiatrist described very ill patients with treatment-resistant bipolar disorder who had not only received medications, including ketamine, but had also received electroconvulsive therapy and still did not respond.

“Their suffering is enormous and the truth is that there is no improvement for more than a few days or weeks and later they return to their hell. Appreciating that they would be better off dead for themselves and their families is not always a cognitive distortion but an objective evaluation of their reality.”

However, as another reader pointed out, an issue with the argument presented here is that it presupposes that MAID requires “clinical justification.” But in Canada, “MAID ... is understood as an expression of personal autonomy. Rooted in liberal political philosophy of individualism ... approval for death need not be based on a clinical assessment.” Instead, “death is seen as a ‘right’ that the state must therefore provide.”
 

Another form of eugenics?

Dr. Miller raised the ethical implications of racial and socioeconomic factors playing a role in the consideration of MAID for those with psychiatric illness.

“Might those who are poor, who have less access to expensive treatment options and social support, be more likely to request facilitated death?” she asks. “Do we risk facilitating a patient’s demise when other options are unavailable because of a lack of access to treatment or when social and financial struggles exacerbate a person’s hopelessness? Should we worry that psychiatric euthanasia will turn into a form of eugenics where those who can’t contribute are made to feel that they should bow out?”

Several readers agreed. “Looking at the disproportionate burden of illness, rates of imprisonment, and application of the death penalty indicates to me that race and socioeconomic status will be an immediate factor in how, where, and with whom MAID for mental illness would be practice in much, if not all, of the U.S.,” wrote one physician.

A Canadian reader expressed similar concerns. “I’ve seen a handful of people, including someone I considered a good friend, opt for MAID because it was easier than living as a disabled person in poverty without adequate mental health care.”

Another Canadian clinician noted that offering people good care can make all the difference. “As a Canadian mental health clinician who served youth with severe mental illness for over 20 years through our socialized medical network, I can attest to the difference good care usually makes in shifting clients from despair and a commitment to death to embracing life once again. Let’s not, as clinicians, embrace easing a government/state-sanctioned pathway to death.”

Some readers believe that these types of issues can’t be solved with a blanket approach, noting that each case is different. “Real life is always more complicated than academic discussions. Having served on a hospital ethics committee, I know that each case is unique,” one reader noted.

Another reader added, “I think all we can do as physicians is to let people decide for themselves and participate only if our conscience allows.”
 

A version of this article first appeared on Medscape.com.

Among military veterans who die by suicide, those who experience a traumatic brain injury (TBI) during service take their lives 21% sooner after deployment than those without a TBI history, a new study shows.

Investigators also found that increases in new mental health diagnoses are significantly higher in soldiers with a history of TBI – in some cases, strikingly higher. For example, cases of substance use disorder rose by 100% among veterans with TBI compared to just 14.5% in those with no brain injury.

Veterans Health Administration

“We had had pieces of these findings for a long time but to be able to lay out this longitudinal story over time is the part that’s new and important to really switch the focus to people’s whole lives and things that happen over time, both psychological and physical,” lead author Lisa Brenner, PhD, director of the Veterans Health Administration (VHA) Rocky Mountain Mental Illness Research Education and Clinical Center, Aurora, Colo., said in an interview.

“If we take that life-course view, it’s a very different way about thinking about conceptualizing exposures and conceptualizing risk and it’s a different way of thinking about treatment and prevention,” added Dr. Brenner, professor of physical medicine and rehabilitation, psychiatry, and neurology at the University of Colorado, Aurora. “I think that definitely applies to civilian populations.”

The findings were published online in JAMA Network Open.
 

Largest, longest study to date

Researchers have long suspected that TBI and a higher rate of new mental illness and a shorter time to suicide are all somehow linked. But this study examined all three components longitudinally, in what is thought to be the largest and longest study on the topic to date, including more than 860,000 people who were followed for up to a decade.

Investigators studied health data from the Substance Use and Psychological Injury Combat Study database on 860,892 U.S. Army soldiers who returned from deployment in Iraq or Afghanistan between 2008 and 2014 and were 18-24 years old at the end of that deployment. They then examined new mental health diagnoses and suicide trends over time.

Nearly 109,000 (12.6%) experienced a TBI during deployment, and 2,695 had died by suicide through the end of 2018.

New-onset diagnoses of anxiety, mood disorders, posttraumatic stress disorder, alcohol use, and substance use disorder (SUD) after deployment were all more common in soldiers who experienced PTSD while serving compared with those with no history of TBI.

There was a 67.7% increase in mood disorders in participants with TBI compared with a 37.5% increase in those without TBI. The increase in new cases of alcohol use disorder was also greater in the TBI group (a 31.9% increase vs. a 10.3% increase).

But the sharpest difference was the increase in substance use disorder among those with TBI, which rose 100% compared with a 14.5% increase in solders with no history of TBI.
 

Sharp differences in time to suicide

Death by suicide was only slightly more common in those with TBI compared with those without (0.4% vs. 0.3%, respectively). But those with a brain injury committed suicide 21.3% sooner than did those without a head injury, after the researchers controlled for sex, age, race, ethnicity, and fiscal year of return from deployment.

Time to suicide was faster in those with a TBI and two or more new mental health diagnoses and fastest among those with TBI and a new SUD diagnosis, who took their own lives 62.8% faster than did those without a TBI.

The findings offer an important message to medical professionals in many different specialties, Dr. Brenner said.

“Folks in mental health probably have a lot of patients who have brain injury in their practice, and they don’t know it and that’s an important thing to know,” she said, adding that “neurologists should screen for depression and other mental health conditions and make sure those people have evidence-based treatments for those mental health conditions while they’re addressing the TBI-related symptoms.”
 

Applicable to civilians?

“The complex interplay between TBI, its potential effects on mental health, and risk of suicide remains a vexing focus of ongoing investigations and academic inquiry,” Ross Zafonte, DO, president of Spaulding Rehabilitation Hospital Network and professor and chair of physical medicine and rehabilitation at Harvard Medical School, Boston, and colleagues, wrote in an accompanying editorial.

The study builds on earlier work, they added, and praised the study’s longitudinal design and large cohort as key to the findings. The data on increased rates of new-onset substance use disorder, which was also associated with a faster time to suicide in the TBI group, were of particular interest.

“In this work, Brenner and colleagues identified substance use disorder as a key factor in faster time to suicide for active-duty service members with a history of TBI compared with those without TBI and theorized that a multiple stress or exposure burden may enhance risk,” they wrote. “This theory is reasonable and has been postulated among individuals with medical sequelae linked to TBI.”

However, the authors caution against applying these findings in military veterans to civilians.

“While this work is critical in the military population, caution should be given to avoid direct generalization to other populations, such as athletes, for whom the linkage to suicidal ideation is less understood,” they wrote.

The study was funded by National Institute of Mental Health and Office of the Director at National Institutes of Health. Dr. Brenner has received personal fees from Wolters Kluwer, Rand, American Psychological Association, and Oxford University Press and serves as a consultant to sports leagues via her university affiliation. Dr. Zafonte reported receiving royalties from Springer/Demos; serving as a member of the editorial boards of Journal of Neurotrauma and Frontiers in Neurology and scientific advisory boards of Myomo, Nanodiagnostics, Onecare.ai, and Kisbee; and evaluating patients in the MGH Brain and Body-TRUST Program, which is funded by the National Football League Players Association.
 

A version of this article first appeared on Medscape.com.

Among military veterans who die by suicide, those who experience a traumatic brain injury (TBI) during service take their lives 21% sooner after deployment than those without a TBI history, a new study shows.

Investigators also found that increases in new mental health diagnoses are significantly higher in soldiers with a history of TBI – in some cases, strikingly higher. For example, cases of substance use disorder rose by 100% among veterans with TBI compared to just 14.5% in those with no brain injury.

Veterans Health Administration

“We had had pieces of these findings for a long time but to be able to lay out this longitudinal story over time is the part that’s new and important to really switch the focus to people’s whole lives and things that happen over time, both psychological and physical,” lead author Lisa Brenner, PhD, director of the Veterans Health Administration (VHA) Rocky Mountain Mental Illness Research Education and Clinical Center, Aurora, Colo., said in an interview.

“If we take that life-course view, it’s a very different way about thinking about conceptualizing exposures and conceptualizing risk and it’s a different way of thinking about treatment and prevention,” added Dr. Brenner, professor of physical medicine and rehabilitation, psychiatry, and neurology at the University of Colorado, Aurora. “I think that definitely applies to civilian populations.”

The findings were published online in JAMA Network Open.
 

Largest, longest study to date

Researchers have long suspected that TBI and a higher rate of new mental illness and a shorter time to suicide are all somehow linked. But this study examined all three components longitudinally, in what is thought to be the largest and longest study on the topic to date, including more than 860,000 people who were followed for up to a decade.

Investigators studied health data from the Substance Use and Psychological Injury Combat Study database on 860,892 U.S. Army soldiers who returned from deployment in Iraq or Afghanistan between 2008 and 2014 and were 18-24 years old at the end of that deployment. They then examined new mental health diagnoses and suicide trends over time.

Nearly 109,000 (12.6%) experienced a TBI during deployment, and 2,695 had died by suicide through the end of 2018.

New-onset diagnoses of anxiety, mood disorders, posttraumatic stress disorder, alcohol use, and substance use disorder (SUD) after deployment were all more common in soldiers who experienced PTSD while serving compared with those with no history of TBI.

There was a 67.7% increase in mood disorders in participants with TBI compared with a 37.5% increase in those without TBI. The increase in new cases of alcohol use disorder was also greater in the TBI group (a 31.9% increase vs. a 10.3% increase).

But the sharpest difference was the increase in substance use disorder among those with TBI, which rose 100% compared with a 14.5% increase in solders with no history of TBI.
 

Sharp differences in time to suicide

Death by suicide was only slightly more common in those with TBI compared with those without (0.4% vs. 0.3%, respectively). But those with a brain injury committed suicide 21.3% sooner than did those without a head injury, after the researchers controlled for sex, age, race, ethnicity, and fiscal year of return from deployment.

Time to suicide was faster in those with a TBI and two or more new mental health diagnoses and fastest among those with TBI and a new SUD diagnosis, who took their own lives 62.8% faster than did those without a TBI.

The findings offer an important message to medical professionals in many different specialties, Dr. Brenner said.

“Folks in mental health probably have a lot of patients who have brain injury in their practice, and they don’t know it and that’s an important thing to know,” she said, adding that “neurologists should screen for depression and other mental health conditions and make sure those people have evidence-based treatments for those mental health conditions while they’re addressing the TBI-related symptoms.”
 

Applicable to civilians?

“The complex interplay between TBI, its potential effects on mental health, and risk of suicide remains a vexing focus of ongoing investigations and academic inquiry,” Ross Zafonte, DO, president of Spaulding Rehabilitation Hospital Network and professor and chair of physical medicine and rehabilitation at Harvard Medical School, Boston, and colleagues, wrote in an accompanying editorial.

The study builds on earlier work, they added, and praised the study’s longitudinal design and large cohort as key to the findings. The data on increased rates of new-onset substance use disorder, which was also associated with a faster time to suicide in the TBI group, were of particular interest.

“In this work, Brenner and colleagues identified substance use disorder as a key factor in faster time to suicide for active-duty service members with a history of TBI compared with those without TBI and theorized that a multiple stress or exposure burden may enhance risk,” they wrote. “This theory is reasonable and has been postulated among individuals with medical sequelae linked to TBI.”

However, the authors caution against applying these findings in military veterans to civilians.

“While this work is critical in the military population, caution should be given to avoid direct generalization to other populations, such as athletes, for whom the linkage to suicidal ideation is less understood,” they wrote.

The study was funded by National Institute of Mental Health and Office of the Director at National Institutes of Health. Dr. Brenner has received personal fees from Wolters Kluwer, Rand, American Psychological Association, and Oxford University Press and serves as a consultant to sports leagues via her university affiliation. Dr. Zafonte reported receiving royalties from Springer/Demos; serving as a member of the editorial boards of Journal of Neurotrauma and Frontiers in Neurology and scientific advisory boards of Myomo, Nanodiagnostics, Onecare.ai, and Kisbee; and evaluating patients in the MGH Brain and Body-TRUST Program, which is funded by the National Football League Players Association.
 

A version of this article first appeared on Medscape.com.

Among military veterans who die by suicide, those who experience a traumatic brain injury (TBI) during service take their lives 21% sooner after deployment than those without a TBI history, a new study shows.

Investigators also found that increases in new mental health diagnoses are significantly higher in soldiers with a history of TBI – in some cases, strikingly higher. For example, cases of substance use disorder rose by 100% among veterans with TBI compared to just 14.5% in those with no brain injury.

Veterans Health Administration

“We had had pieces of these findings for a long time but to be able to lay out this longitudinal story over time is the part that’s new and important to really switch the focus to people’s whole lives and things that happen over time, both psychological and physical,” lead author Lisa Brenner, PhD, director of the Veterans Health Administration (VHA) Rocky Mountain Mental Illness Research Education and Clinical Center, Aurora, Colo., said in an interview.

“If we take that life-course view, it’s a very different way about thinking about conceptualizing exposures and conceptualizing risk and it’s a different way of thinking about treatment and prevention,” added Dr. Brenner, professor of physical medicine and rehabilitation, psychiatry, and neurology at the University of Colorado, Aurora. “I think that definitely applies to civilian populations.”

The findings were published online in JAMA Network Open.
 

Largest, longest study to date

Researchers have long suspected that TBI and a higher rate of new mental illness and a shorter time to suicide are all somehow linked. But this study examined all three components longitudinally, in what is thought to be the largest and longest study on the topic to date, including more than 860,000 people who were followed for up to a decade.

Investigators studied health data from the Substance Use and Psychological Injury Combat Study database on 860,892 U.S. Army soldiers who returned from deployment in Iraq or Afghanistan between 2008 and 2014 and were 18-24 years old at the end of that deployment. They then examined new mental health diagnoses and suicide trends over time.

Nearly 109,000 (12.6%) experienced a TBI during deployment, and 2,695 had died by suicide through the end of 2018.

New-onset diagnoses of anxiety, mood disorders, posttraumatic stress disorder, alcohol use, and substance use disorder (SUD) after deployment were all more common in soldiers who experienced PTSD while serving compared with those with no history of TBI.

There was a 67.7% increase in mood disorders in participants with TBI compared with a 37.5% increase in those without TBI. The increase in new cases of alcohol use disorder was also greater in the TBI group (a 31.9% increase vs. a 10.3% increase).

But the sharpest difference was the increase in substance use disorder among those with TBI, which rose 100% compared with a 14.5% increase in solders with no history of TBI.
 

Sharp differences in time to suicide

Death by suicide was only slightly more common in those with TBI compared with those without (0.4% vs. 0.3%, respectively). But those with a brain injury committed suicide 21.3% sooner than did those without a head injury, after the researchers controlled for sex, age, race, ethnicity, and fiscal year of return from deployment.

Time to suicide was faster in those with a TBI and two or more new mental health diagnoses and fastest among those with TBI and a new SUD diagnosis, who took their own lives 62.8% faster than did those without a TBI.

The findings offer an important message to medical professionals in many different specialties, Dr. Brenner said.

“Folks in mental health probably have a lot of patients who have brain injury in their practice, and they don’t know it and that’s an important thing to know,” she said, adding that “neurologists should screen for depression and other mental health conditions and make sure those people have evidence-based treatments for those mental health conditions while they’re addressing the TBI-related symptoms.”
 

Applicable to civilians?

“The complex interplay between TBI, its potential effects on mental health, and risk of suicide remains a vexing focus of ongoing investigations and academic inquiry,” Ross Zafonte, DO, president of Spaulding Rehabilitation Hospital Network and professor and chair of physical medicine and rehabilitation at Harvard Medical School, Boston, and colleagues, wrote in an accompanying editorial.

The study builds on earlier work, they added, and praised the study’s longitudinal design and large cohort as key to the findings. The data on increased rates of new-onset substance use disorder, which was also associated with a faster time to suicide in the TBI group, were of particular interest.

“In this work, Brenner and colleagues identified substance use disorder as a key factor in faster time to suicide for active-duty service members with a history of TBI compared with those without TBI and theorized that a multiple stress or exposure burden may enhance risk,” they wrote. “This theory is reasonable and has been postulated among individuals with medical sequelae linked to TBI.”

However, the authors caution against applying these findings in military veterans to civilians.

“While this work is critical in the military population, caution should be given to avoid direct generalization to other populations, such as athletes, for whom the linkage to suicidal ideation is less understood,” they wrote.

The study was funded by National Institute of Mental Health and Office of the Director at National Institutes of Health. Dr. Brenner has received personal fees from Wolters Kluwer, Rand, American Psychological Association, and Oxford University Press and serves as a consultant to sports leagues via her university affiliation. Dr. Zafonte reported receiving royalties from Springer/Demos; serving as a member of the editorial boards of Journal of Neurotrauma and Frontiers in Neurology and scientific advisory boards of Myomo, Nanodiagnostics, Onecare.ai, and Kisbee; and evaluating patients in the MGH Brain and Body-TRUST Program, which is funded by the National Football League Players Association.
 

A version of this article first appeared on Medscape.com.

For the first time, the Food and Drug Administration approved a pill taken once daily for 14 days to help women manage the often strong, sometimes overpowering symptoms of postpartum depression.

Several experts in mental health and women’s health offered their views of this new treatment option for a condition that affects an estimated 1 in 8 women in the United States. What will it mean for easing symptoms such as hopelessness, crankiness, and lack of interest in bonding with the baby or, in the case of multiples, babies – and in some cases, thoughts of death or suicide?
 

A fast-acting option

“We don’t have many oral medications that are fast-acting antidepressants, so this is incredibly exciting,” said Sarah Oreck, MD, a psychiatrist in private practice in Los Angeles who specializes in reproductive psychiatry. The rapid response is likely because the medication targets the hormonal mechanism underlying postpartum depression, she added.

Zuranolone (Zurzuvae, Biogen/Sage) is different from most other antidepressants – it is designed to be taken for a shorter period. Also, Because zuranolone is a pill, it is more convenient to take than the other FDA-approved treatment, the IV infusion brexanolone (Zulresso, Sage).

“It’s obviously game changing to have something in pill form. The infusion has to be done at an infusion center to monitor people for any complications,” said Kimberly Yonkers, MD, a psychiatrist specializing in women’s health, a Distinguished Life Fellow of the American Psychiatric Association (APA), and the Katz Family Chair of Psychiatry at the University of Massachusetts Chan Medical School/UMass Memorial Medical Center in Worcester.

Women may experience improvement in postpartum depression in as soon as 3 days after starting the medication. In contrast, “typical antidepressants can take up to 2 weeks before patients notice a difference and 4 to 8 weeks to see a full response. A fast-acting pill that can be taken orally could be an ideal option for the 15% to 20% of women who experience postpartum depression,” said Priya Gopalan, MD, a psychiatrist with UPMC Western Psychiatric Hospital and Magee-Womens Hospital in Pittsburgh.

The medical community, and reproductive psychiatrists in particular, has always suspected differences in the biological underpinnings of postpartum depression and major depressive disorder, Dr. Oreck said. “We know that postpartum depression looks different from major depressive disorder and that hormonal shifts during pregnancy and postpartum are a huge risk factor for postpartum depression,” she said.

Although selective serotonin reuptake inhibitors (SSRIs) are helpful and currently the standard of care for treating moderate to severe postpartum depression in combination with therapy, Dr. Oreck added, early studies suggest that zuranolone may work faster and potentially be more effective than SSRIs in treating the condition.

Zuranolone is a version of a naturally occurring hormone called allopregnanolone, a metabolite of progesterone. Concentrations of allopregnanolone rise dramatically during pregnancy and then drop precipitously after childbirth. Zuranolone works through modulating GABA-A, a neurotransmitter implicated in the development of depression.

“It is encouraging that postpartum individuals may now have more options to manage a debilitating condition that affects them and their families,” said Christopher Zahn, MD, interim CEO and chief of clinical practice and health equity and quality for the American College of Obstetricians and Gynecologists (ACOG).

ACOG recommends women be screened for depression at least three times – during early pregnancy, later in pregnancy, and again after delivery. A decision to start this or any other medicine should be individualized and based on shared decision-making between a patient and doctor, Dr. Zahn added.

The cost of zuranolone is not yet known. Dr. Yonkers said cost of the infusion can serve as a cautionary tale for the manufacturer. Some reports put the infusion cost at $34,000. “Cost is going to be an important component to this. The previous intervention was priced so high that it was not affordable to many people and it was difficult to access.”
 

Beyond ‘baby blues’

The APA has changed the name from “postpartum depression” to “peripartum depression” because evidence suggests feelings and symptoms also can start late in pregnancy. “It means you don’t have to wait until somebody delivers to screen for depression. We have to recognize that depression can occur during pregnancy,” Dr. Yonkers said. “In fact it is not uncommon during the third trimester.”

No matter when it starts, the condition can be “very serious,” particularly if the person already experiences depression, including bipolar disorder, Dr. Yonkers added.

Postpartum depression “is more than just ‘baby blues.’ It is a potentially debilitating illness that causes feelings of intense sadness and worthlessness, making it difficult to care for and bond with your newborn,” Dr. Gopalan said.
 

Can be a medical emergency

Severe postpartum depression requires immediate attention and treatment.

“One of the things we have to be cautious about is for people with previous predisposition to hurt themselves,” Dr. Yonkers said. “It is therefore important to consider somebody’s medical and behavioral health history as well.

“For an individual with recurring depression or severe episodes of depression, this may not be sufficient, because they are just going to get these 14 days of therapy,” Dr. Yonkers said. “They may need ongoing antidepressants.

“It may not be the right pill for everybody,” Dr. Yonkers added. She recommended everyone be followed closely during and after treatment “to make sure they are responding and to monitor for relapse.”
 

The science that led to approval

The clinical trials showed early response in patients with severe postpartum depression. Researchers conducted two studies of women who developed a major depressive episode in the third trimester of pregnancy or within 4 weeks of delivery. They found women who took zuranolone once in the evening for 14 days “showed significantly more improvement in their symptoms compared to those in the placebo group.”

The antidepressant effect lasted at least 4 weeks after stopping the medication.

Drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection were the most common side effects. The label has a boxed warning noting that the medication can affect a person’s ability to drive and perform other potentially hazardous activities. Use of zuranolone may also cause suicidal thoughts and behavior, according to an FDA news release announcing the approval.
 

The start of more help for mothers?

Zuranolone is not a cure-all. As with most psychiatric prescriptions, the medication likely will work best in conjunction with behavioral health treatments such as psychotherapy, use of other medications, behavioral management, support groups, and self-care tools such as meditation, exercise, and yoga, Dr. Gopalan said.

Dr. Oreck said she hopes this first pill approval will lead to more discoveries. “I hope this is the beginning of more innovation and development of novel treatments that can target women’s mental health issues specifically – female reproductive hormones impact mental health in unique ways and it’s exciting to finally see research and development dollars dedicated to them,” she said. “The FDA approval of this pill provides the potential to improve the lives of millions of Americans suffering from postpartum depression.”

Dr. Oreck, Dr. Yonkers, Dr. Gopalan, and Dr. Zahn have disclosed no relevant financial relationships.
 

A version of this article first appeared on Medscape.com.

For the first time, the Food and Drug Administration approved a pill taken once daily for 14 days to help women manage the often strong, sometimes overpowering symptoms of postpartum depression.

Several experts in mental health and women’s health offered their views of this new treatment option for a condition that affects an estimated 1 in 8 women in the United States. What will it mean for easing symptoms such as hopelessness, crankiness, and lack of interest in bonding with the baby or, in the case of multiples, babies – and in some cases, thoughts of death or suicide?
 

A fast-acting option

“We don’t have many oral medications that are fast-acting antidepressants, so this is incredibly exciting,” said Sarah Oreck, MD, a psychiatrist in private practice in Los Angeles who specializes in reproductive psychiatry. The rapid response is likely because the medication targets the hormonal mechanism underlying postpartum depression, she added.

Zuranolone (Zurzuvae, Biogen/Sage) is different from most other antidepressants – it is designed to be taken for a shorter period. Also, Because zuranolone is a pill, it is more convenient to take than the other FDA-approved treatment, the IV infusion brexanolone (Zulresso, Sage).

“It’s obviously game changing to have something in pill form. The infusion has to be done at an infusion center to monitor people for any complications,” said Kimberly Yonkers, MD, a psychiatrist specializing in women’s health, a Distinguished Life Fellow of the American Psychiatric Association (APA), and the Katz Family Chair of Psychiatry at the University of Massachusetts Chan Medical School/UMass Memorial Medical Center in Worcester.

Women may experience improvement in postpartum depression in as soon as 3 days after starting the medication. In contrast, “typical antidepressants can take up to 2 weeks before patients notice a difference and 4 to 8 weeks to see a full response. A fast-acting pill that can be taken orally could be an ideal option for the 15% to 20% of women who experience postpartum depression,” said Priya Gopalan, MD, a psychiatrist with UPMC Western Psychiatric Hospital and Magee-Womens Hospital in Pittsburgh.

The medical community, and reproductive psychiatrists in particular, has always suspected differences in the biological underpinnings of postpartum depression and major depressive disorder, Dr. Oreck said. “We know that postpartum depression looks different from major depressive disorder and that hormonal shifts during pregnancy and postpartum are a huge risk factor for postpartum depression,” she said.

Although selective serotonin reuptake inhibitors (SSRIs) are helpful and currently the standard of care for treating moderate to severe postpartum depression in combination with therapy, Dr. Oreck added, early studies suggest that zuranolone may work faster and potentially be more effective than SSRIs in treating the condition.

Zuranolone is a version of a naturally occurring hormone called allopregnanolone, a metabolite of progesterone. Concentrations of allopregnanolone rise dramatically during pregnancy and then drop precipitously after childbirth. Zuranolone works through modulating GABA-A, a neurotransmitter implicated in the development of depression.

“It is encouraging that postpartum individuals may now have more options to manage a debilitating condition that affects them and their families,” said Christopher Zahn, MD, interim CEO and chief of clinical practice and health equity and quality for the American College of Obstetricians and Gynecologists (ACOG).

ACOG recommends women be screened for depression at least three times – during early pregnancy, later in pregnancy, and again after delivery. A decision to start this or any other medicine should be individualized and based on shared decision-making between a patient and doctor, Dr. Zahn added.

The cost of zuranolone is not yet known. Dr. Yonkers said cost of the infusion can serve as a cautionary tale for the manufacturer. Some reports put the infusion cost at $34,000. “Cost is going to be an important component to this. The previous intervention was priced so high that it was not affordable to many people and it was difficult to access.”
 

Beyond ‘baby blues’

The APA has changed the name from “postpartum depression” to “peripartum depression” because evidence suggests feelings and symptoms also can start late in pregnancy. “It means you don’t have to wait until somebody delivers to screen for depression. We have to recognize that depression can occur during pregnancy,” Dr. Yonkers said. “In fact it is not uncommon during the third trimester.”

No matter when it starts, the condition can be “very serious,” particularly if the person already experiences depression, including bipolar disorder, Dr. Yonkers added.

Postpartum depression “is more than just ‘baby blues.’ It is a potentially debilitating illness that causes feelings of intense sadness and worthlessness, making it difficult to care for and bond with your newborn,” Dr. Gopalan said.
 

Can be a medical emergency

Severe postpartum depression requires immediate attention and treatment.

“One of the things we have to be cautious about is for people with previous predisposition to hurt themselves,” Dr. Yonkers said. “It is therefore important to consider somebody’s medical and behavioral health history as well.

“For an individual with recurring depression or severe episodes of depression, this may not be sufficient, because they are just going to get these 14 days of therapy,” Dr. Yonkers said. “They may need ongoing antidepressants.

“It may not be the right pill for everybody,” Dr. Yonkers added. She recommended everyone be followed closely during and after treatment “to make sure they are responding and to monitor for relapse.”
 

The science that led to approval

The clinical trials showed early response in patients with severe postpartum depression. Researchers conducted two studies of women who developed a major depressive episode in the third trimester of pregnancy or within 4 weeks of delivery. They found women who took zuranolone once in the evening for 14 days “showed significantly more improvement in their symptoms compared to those in the placebo group.”

The antidepressant effect lasted at least 4 weeks after stopping the medication.

Drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection were the most common side effects. The label has a boxed warning noting that the medication can affect a person’s ability to drive and perform other potentially hazardous activities. Use of zuranolone may also cause suicidal thoughts and behavior, according to an FDA news release announcing the approval.
 

The start of more help for mothers?

Zuranolone is not a cure-all. As with most psychiatric prescriptions, the medication likely will work best in conjunction with behavioral health treatments such as psychotherapy, use of other medications, behavioral management, support groups, and self-care tools such as meditation, exercise, and yoga, Dr. Gopalan said.

Dr. Oreck said she hopes this first pill approval will lead to more discoveries. “I hope this is the beginning of more innovation and development of novel treatments that can target women’s mental health issues specifically – female reproductive hormones impact mental health in unique ways and it’s exciting to finally see research and development dollars dedicated to them,” she said. “The FDA approval of this pill provides the potential to improve the lives of millions of Americans suffering from postpartum depression.”

Dr. Oreck, Dr. Yonkers, Dr. Gopalan, and Dr. Zahn have disclosed no relevant financial relationships.
 

A version of this article first appeared on Medscape.com.

For the first time, the Food and Drug Administration approved a pill taken once daily for 14 days to help women manage the often strong, sometimes overpowering symptoms of postpartum depression.

Several experts in mental health and women’s health offered their views of this new treatment option for a condition that affects an estimated 1 in 8 women in the United States. What will it mean for easing symptoms such as hopelessness, crankiness, and lack of interest in bonding with the baby or, in the case of multiples, babies – and in some cases, thoughts of death or suicide?
 

A fast-acting option

“We don’t have many oral medications that are fast-acting antidepressants, so this is incredibly exciting,” said Sarah Oreck, MD, a psychiatrist in private practice in Los Angeles who specializes in reproductive psychiatry. The rapid response is likely because the medication targets the hormonal mechanism underlying postpartum depression, she added.

Zuranolone (Zurzuvae, Biogen/Sage) is different from most other antidepressants – it is designed to be taken for a shorter period. Also, Because zuranolone is a pill, it is more convenient to take than the other FDA-approved treatment, the IV infusion brexanolone (Zulresso, Sage).

“It’s obviously game changing to have something in pill form. The infusion has to be done at an infusion center to monitor people for any complications,” said Kimberly Yonkers, MD, a psychiatrist specializing in women’s health, a Distinguished Life Fellow of the American Psychiatric Association (APA), and the Katz Family Chair of Psychiatry at the University of Massachusetts Chan Medical School/UMass Memorial Medical Center in Worcester.

Women may experience improvement in postpartum depression in as soon as 3 days after starting the medication. In contrast, “typical antidepressants can take up to 2 weeks before patients notice a difference and 4 to 8 weeks to see a full response. A fast-acting pill that can be taken orally could be an ideal option for the 15% to 20% of women who experience postpartum depression,” said Priya Gopalan, MD, a psychiatrist with UPMC Western Psychiatric Hospital and Magee-Womens Hospital in Pittsburgh.

The medical community, and reproductive psychiatrists in particular, has always suspected differences in the biological underpinnings of postpartum depression and major depressive disorder, Dr. Oreck said. “We know that postpartum depression looks different from major depressive disorder and that hormonal shifts during pregnancy and postpartum are a huge risk factor for postpartum depression,” she said.

Although selective serotonin reuptake inhibitors (SSRIs) are helpful and currently the standard of care for treating moderate to severe postpartum depression in combination with therapy, Dr. Oreck added, early studies suggest that zuranolone may work faster and potentially be more effective than SSRIs in treating the condition.

Zuranolone is a version of a naturally occurring hormone called allopregnanolone, a metabolite of progesterone. Concentrations of allopregnanolone rise dramatically during pregnancy and then drop precipitously after childbirth. Zuranolone works through modulating GABA-A, a neurotransmitter implicated in the development of depression.

“It is encouraging that postpartum individuals may now have more options to manage a debilitating condition that affects them and their families,” said Christopher Zahn, MD, interim CEO and chief of clinical practice and health equity and quality for the American College of Obstetricians and Gynecologists (ACOG).

ACOG recommends women be screened for depression at least three times – during early pregnancy, later in pregnancy, and again after delivery. A decision to start this or any other medicine should be individualized and based on shared decision-making between a patient and doctor, Dr. Zahn added.

The cost of zuranolone is not yet known. Dr. Yonkers said cost of the infusion can serve as a cautionary tale for the manufacturer. Some reports put the infusion cost at $34,000. “Cost is going to be an important component to this. The previous intervention was priced so high that it was not affordable to many people and it was difficult to access.”
 

Beyond ‘baby blues’

The APA has changed the name from “postpartum depression” to “peripartum depression” because evidence suggests feelings and symptoms also can start late in pregnancy. “It means you don’t have to wait until somebody delivers to screen for depression. We have to recognize that depression can occur during pregnancy,” Dr. Yonkers said. “In fact it is not uncommon during the third trimester.”

No matter when it starts, the condition can be “very serious,” particularly if the person already experiences depression, including bipolar disorder, Dr. Yonkers added.

Postpartum depression “is more than just ‘baby blues.’ It is a potentially debilitating illness that causes feelings of intense sadness and worthlessness, making it difficult to care for and bond with your newborn,” Dr. Gopalan said.
 

Can be a medical emergency

Severe postpartum depression requires immediate attention and treatment.

“One of the things we have to be cautious about is for people with previous predisposition to hurt themselves,” Dr. Yonkers said. “It is therefore important to consider somebody’s medical and behavioral health history as well.

“For an individual with recurring depression or severe episodes of depression, this may not be sufficient, because they are just going to get these 14 days of therapy,” Dr. Yonkers said. “They may need ongoing antidepressants.

“It may not be the right pill for everybody,” Dr. Yonkers added. She recommended everyone be followed closely during and after treatment “to make sure they are responding and to monitor for relapse.”
 

The science that led to approval

The clinical trials showed early response in patients with severe postpartum depression. Researchers conducted two studies of women who developed a major depressive episode in the third trimester of pregnancy or within 4 weeks of delivery. They found women who took zuranolone once in the evening for 14 days “showed significantly more improvement in their symptoms compared to those in the placebo group.”

The antidepressant effect lasted at least 4 weeks after stopping the medication.

Drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection were the most common side effects. The label has a boxed warning noting that the medication can affect a person’s ability to drive and perform other potentially hazardous activities. Use of zuranolone may also cause suicidal thoughts and behavior, according to an FDA news release announcing the approval.
 

The start of more help for mothers?

Zuranolone is not a cure-all. As with most psychiatric prescriptions, the medication likely will work best in conjunction with behavioral health treatments such as psychotherapy, use of other medications, behavioral management, support groups, and self-care tools such as meditation, exercise, and yoga, Dr. Gopalan said.

Dr. Oreck said she hopes this first pill approval will lead to more discoveries. “I hope this is the beginning of more innovation and development of novel treatments that can target women’s mental health issues specifically – female reproductive hormones impact mental health in unique ways and it’s exciting to finally see research and development dollars dedicated to them,” she said. “The FDA approval of this pill provides the potential to improve the lives of millions of Americans suffering from postpartum depression.”

Dr. Oreck, Dr. Yonkers, Dr. Gopalan, and Dr. Zahn have disclosed no relevant financial relationships.
 

A version of this article first appeared on Medscape.com.

The Food and Drug Administration is considering approving a postpartum depression medication that can start working rapidly – in as little as 3 days. Promising results for the drug, zuranolone, were published recently in The American Journal of Psychiatry.

Approximately 17% of women are affected by postpartum depression (PPD) during pregnancy or after birth, study authors noted. The condition often results in reduced breastfeeding, poor maternal-infant bonding, and hindering behavioral, emotional and brain development of the baby. Severe PPD can lead to suicide of the mother, which accounts for 20% of all postpartum deaths, they wrote.

The study included 196 people who had given birth in the past year, and were between the ages of 18 and 45 years old. Participants had major depression that began in the 3rd trimester of pregnancy or during the first 4 weeks of the postpartum period. Among participants, 22% were Black and 38% were Hispanic.

Of those who took zuranolone, 57% had significantly improved depression symptoms after taking the drug for 14 days, and 27% were in remission at the conclusion of the 14-day treatment. The average time it took for symptoms to significantly decline was 9 days. Most people who saw improvements had them continue for the entire 45-day follow-up period. The most common side effects were drowsiness, dizziness, and sleepiness.

Currently, PPD treatment includes taking antidepressants, which can take up to 12 weeks to work. 

Researchers noted that the limitations of the study were that it only included women with severe PPD, and that women with a history of bipolar or psychotic disorders were excluded. Women in the study were not allowed to breastfeed, so the effect of zuranolone on lactation is unknown, they wrote.

A February news release from drugmaker Biogen indicated the FDA may decide whether to approve the medicine by Aug. 5.

A version of this article first appeared on WebMD.com.

The Food and Drug Administration is considering approving a postpartum depression medication that can start working rapidly – in as little as 3 days. Promising results for the drug, zuranolone, were published recently in The American Journal of Psychiatry.

Approximately 17% of women are affected by postpartum depression (PPD) during pregnancy or after birth, study authors noted. The condition often results in reduced breastfeeding, poor maternal-infant bonding, and hindering behavioral, emotional and brain development of the baby. Severe PPD can lead to suicide of the mother, which accounts for 20% of all postpartum deaths, they wrote.

The study included 196 people who had given birth in the past year, and were between the ages of 18 and 45 years old. Participants had major depression that began in the 3rd trimester of pregnancy or during the first 4 weeks of the postpartum period. Among participants, 22% were Black and 38% were Hispanic.

Of those who took zuranolone, 57% had significantly improved depression symptoms after taking the drug for 14 days, and 27% were in remission at the conclusion of the 14-day treatment. The average time it took for symptoms to significantly decline was 9 days. Most people who saw improvements had them continue for the entire 45-day follow-up period. The most common side effects were drowsiness, dizziness, and sleepiness.

Currently, PPD treatment includes taking antidepressants, which can take up to 12 weeks to work. 

Researchers noted that the limitations of the study were that it only included women with severe PPD, and that women with a history of bipolar or psychotic disorders were excluded. Women in the study were not allowed to breastfeed, so the effect of zuranolone on lactation is unknown, they wrote.

A February news release from drugmaker Biogen indicated the FDA may decide whether to approve the medicine by Aug. 5.

A version of this article first appeared on WebMD.com.

The Food and Drug Administration is considering approving a postpartum depression medication that can start working rapidly – in as little as 3 days. Promising results for the drug, zuranolone, were published recently in The American Journal of Psychiatry.

Approximately 17% of women are affected by postpartum depression (PPD) during pregnancy or after birth, study authors noted. The condition often results in reduced breastfeeding, poor maternal-infant bonding, and hindering behavioral, emotional and brain development of the baby. Severe PPD can lead to suicide of the mother, which accounts for 20% of all postpartum deaths, they wrote.

The study included 196 people who had given birth in the past year, and were between the ages of 18 and 45 years old. Participants had major depression that began in the 3rd trimester of pregnancy or during the first 4 weeks of the postpartum period. Among participants, 22% were Black and 38% were Hispanic.

Of those who took zuranolone, 57% had significantly improved depression symptoms after taking the drug for 14 days, and 27% were in remission at the conclusion of the 14-day treatment. The average time it took for symptoms to significantly decline was 9 days. Most people who saw improvements had them continue for the entire 45-day follow-up period. The most common side effects were drowsiness, dizziness, and sleepiness.

Currently, PPD treatment includes taking antidepressants, which can take up to 12 weeks to work. 

Researchers noted that the limitations of the study were that it only included women with severe PPD, and that women with a history of bipolar or psychotic disorders were excluded. Women in the study were not allowed to breastfeed, so the effect of zuranolone on lactation is unknown, they wrote.

A February news release from drugmaker Biogen indicated the FDA may decide whether to approve the medicine by Aug. 5.

A version of this article first appeared on WebMD.com.

Twice-weekly subcutaneous ketamine injections are safe and highly effective for treatment-resistant depression (TRD), results of a randomized controlled phase 3 trial show.
 

University of New South Wales

“In this severely treatment-resistant population, of which 24% had failed to respond to treatment with electroconvulsive therapy, adequately dosed racemic ketamine produced benefits that were large, being both clinically and statistically superior to midazolam,” report the researchers, led by Colleen Loo, MD, MBBS, with Black Dog Institute, University of New South Wales, Sydney.

The study was published online in the British Journal of Psychiatry.


 

Individualized dosing

“Previously, most studies of racemic ketamine [administered] it by intravenous infusion over half an hour to several hours, which is a much more medically complex and expensive procedure,” Dr. Loo said in an interview.

The fact that subcutaneously administered ketamine was “highly effective” given by this practical and feasible route is a “major contribution to the field,” said Dr. Loo.

The Ketamine for Adult Depression trial assessed the acute efficacy and safety of a 4-week course of twice-weekly subcutaneous injections of racemic ketamine or midazolam (active control) in 174 adults with TRD.

Initially, the trial tested a fixed dose of 0.5 mg/kg ketamine vs. 0.025 mg/kg midazolam (cohort 1; 68 patients). Dosing was subsequently revised, after the data safety monitoring board recommended flexible-dose ketamine (0.5-0.9 mg/kg) or midazolam (0.025-0.045 mg/kg) with response-guided dosing increments (cohort 2; 106 patients).

The primary outcome was remission defined as Montgomery-Åsberg Rating Scale for Depression (MADRS) score ≤ 10 at week 4.

On this outcome, in the fixed-dose cohort, there was no statistically significant difference in remission rates between ketamine and midazolam (6.3% and 8.8%; odds ratio, 1.34; 95% CI, 0.22-8.21; P = .76).

However, there was a significant difference in remission in the flexible-dose cohort, with remission rates 19.6% for ketamine vs. just 2% for midazolam (OR, 12.11; 95% CI, 2.12-69.17; P = .005).

“The study showed that individualized dose adjustment, based on clinical response, was very important in optimizing the benefit of ketamine,” said Dr. Loo.

“It meant that one, you are more likely to respond as you receive a higher dose if needed, and two, you don’t receive a higher dose than needed, given that side effects are also dose-related,” she said.

Results also favored flexible-dose ketamine over midazolam for the secondary outcomes of response (≥ 50% reduction in MADRS: 29% vs. 4%; P = .001) and remission defined by a less rigid definition (MADRS ≤ 12: 22% vs. 4%; P = .007).

The results also confirm that the antidepressant effects of ketamine are not sustained when treatment stops.

“The study included careful follow-up for 4 weeks after the end of treatment. This is an important contribution to the literature, as it shows that ongoing treatment beyond the 4 weeks will be necessary for most people to maintain the benefits of ketamine treatment if you respond to the treatment. This study provided clear evidence of this, for racemic ketamine,” said Dr. Loo.

Overall, ketamine was well-tolerated, with the well-established acute effects of ketamine observed in both cohorts. The acute effects resolved or returned to pretreatment levels within the 2-hour observation period. No one required medical intervention, and there was no evidence of cognitive impairment.
 

Rigorous research, compelling data

Reached for comment, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the mood disorders psychopharmacology unit, said the data are “compelling with respect to efficacy and safety of subcutaneous ketamine in adults with major depression.”

Dr. McIntyre said the data are “highly relevant” for several reasons. “First, it is the most rigorous study conducted to date with subcutaneous administration of ketamine for adults living with treatment-resistant depression.”

Second, it “demonstrates the efficacy and safety of this route of delivery, which until now has not been studied with this level of rigor and which is a more scalable and accessible approach to administer ketamine to suitable candidates,” Dr. McIntyre said.

The study was funded by a competitive research grant from the Australian National Health and Medical Research Council. Dr. Loo has disclosed relationships with Douglas Pharmaceuticals and Janssen Cilag and is the medical director of neurostimulation and interventional psychiatry at Ramsay Health Care. Dr. McIntyre has received 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, Viatris, AbbVie, and Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.

Twice-weekly subcutaneous ketamine injections are safe and highly effective for treatment-resistant depression (TRD), results of a randomized controlled phase 3 trial show.
 

University of New South Wales

“In this severely treatment-resistant population, of which 24% had failed to respond to treatment with electroconvulsive therapy, adequately dosed racemic ketamine produced benefits that were large, being both clinically and statistically superior to midazolam,” report the researchers, led by Colleen Loo, MD, MBBS, with Black Dog Institute, University of New South Wales, Sydney.

The study was published online in the British Journal of Psychiatry.


 

Individualized dosing

“Previously, most studies of racemic ketamine [administered] it by intravenous infusion over half an hour to several hours, which is a much more medically complex and expensive procedure,” Dr. Loo said in an interview.

The fact that subcutaneously administered ketamine was “highly effective” given by this practical and feasible route is a “major contribution to the field,” said Dr. Loo.

The Ketamine for Adult Depression trial assessed the acute efficacy and safety of a 4-week course of twice-weekly subcutaneous injections of racemic ketamine or midazolam (active control) in 174 adults with TRD.

Initially, the trial tested a fixed dose of 0.5 mg/kg ketamine vs. 0.025 mg/kg midazolam (cohort 1; 68 patients). Dosing was subsequently revised, after the data safety monitoring board recommended flexible-dose ketamine (0.5-0.9 mg/kg) or midazolam (0.025-0.045 mg/kg) with response-guided dosing increments (cohort 2; 106 patients).

The primary outcome was remission defined as Montgomery-Åsberg Rating Scale for Depression (MADRS) score ≤ 10 at week 4.

On this outcome, in the fixed-dose cohort, there was no statistically significant difference in remission rates between ketamine and midazolam (6.3% and 8.8%; odds ratio, 1.34; 95% CI, 0.22-8.21; P = .76).

However, there was a significant difference in remission in the flexible-dose cohort, with remission rates 19.6% for ketamine vs. just 2% for midazolam (OR, 12.11; 95% CI, 2.12-69.17; P = .005).

“The study showed that individualized dose adjustment, based on clinical response, was very important in optimizing the benefit of ketamine,” said Dr. Loo.

“It meant that one, you are more likely to respond as you receive a higher dose if needed, and two, you don’t receive a higher dose than needed, given that side effects are also dose-related,” she said.

Results also favored flexible-dose ketamine over midazolam for the secondary outcomes of response (≥ 50% reduction in MADRS: 29% vs. 4%; P = .001) and remission defined by a less rigid definition (MADRS ≤ 12: 22% vs. 4%; P = .007).

The results also confirm that the antidepressant effects of ketamine are not sustained when treatment stops.

“The study included careful follow-up for 4 weeks after the end of treatment. This is an important contribution to the literature, as it shows that ongoing treatment beyond the 4 weeks will be necessary for most people to maintain the benefits of ketamine treatment if you respond to the treatment. This study provided clear evidence of this, for racemic ketamine,” said Dr. Loo.

Overall, ketamine was well-tolerated, with the well-established acute effects of ketamine observed in both cohorts. The acute effects resolved or returned to pretreatment levels within the 2-hour observation period. No one required medical intervention, and there was no evidence of cognitive impairment.
 

Rigorous research, compelling data

Reached for comment, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the mood disorders psychopharmacology unit, said the data are “compelling with respect to efficacy and safety of subcutaneous ketamine in adults with major depression.”

Dr. McIntyre said the data are “highly relevant” for several reasons. “First, it is the most rigorous study conducted to date with subcutaneous administration of ketamine for adults living with treatment-resistant depression.”

Second, it “demonstrates the efficacy and safety of this route of delivery, which until now has not been studied with this level of rigor and which is a more scalable and accessible approach to administer ketamine to suitable candidates,” Dr. McIntyre said.

The study was funded by a competitive research grant from the Australian National Health and Medical Research Council. Dr. Loo has disclosed relationships with Douglas Pharmaceuticals and Janssen Cilag and is the medical director of neurostimulation and interventional psychiatry at Ramsay Health Care. Dr. McIntyre has received 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, Viatris, AbbVie, and Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.

Twice-weekly subcutaneous ketamine injections are safe and highly effective for treatment-resistant depression (TRD), results of a randomized controlled phase 3 trial show.
 

University of New South Wales

“In this severely treatment-resistant population, of which 24% had failed to respond to treatment with electroconvulsive therapy, adequately dosed racemic ketamine produced benefits that were large, being both clinically and statistically superior to midazolam,” report the researchers, led by Colleen Loo, MD, MBBS, with Black Dog Institute, University of New South Wales, Sydney.

The study was published online in the British Journal of Psychiatry.


 

Individualized dosing

“Previously, most studies of racemic ketamine [administered] it by intravenous infusion over half an hour to several hours, which is a much more medically complex and expensive procedure,” Dr. Loo said in an interview.

The fact that subcutaneously administered ketamine was “highly effective” given by this practical and feasible route is a “major contribution to the field,” said Dr. Loo.

The Ketamine for Adult Depression trial assessed the acute efficacy and safety of a 4-week course of twice-weekly subcutaneous injections of racemic ketamine or midazolam (active control) in 174 adults with TRD.

Initially, the trial tested a fixed dose of 0.5 mg/kg ketamine vs. 0.025 mg/kg midazolam (cohort 1; 68 patients). Dosing was subsequently revised, after the data safety monitoring board recommended flexible-dose ketamine (0.5-0.9 mg/kg) or midazolam (0.025-0.045 mg/kg) with response-guided dosing increments (cohort 2; 106 patients).

The primary outcome was remission defined as Montgomery-Åsberg Rating Scale for Depression (MADRS) score ≤ 10 at week 4.

On this outcome, in the fixed-dose cohort, there was no statistically significant difference in remission rates between ketamine and midazolam (6.3% and 8.8%; odds ratio, 1.34; 95% CI, 0.22-8.21; P = .76).

However, there was a significant difference in remission in the flexible-dose cohort, with remission rates 19.6% for ketamine vs. just 2% for midazolam (OR, 12.11; 95% CI, 2.12-69.17; P = .005).

“The study showed that individualized dose adjustment, based on clinical response, was very important in optimizing the benefit of ketamine,” said Dr. Loo.

“It meant that one, you are more likely to respond as you receive a higher dose if needed, and two, you don’t receive a higher dose than needed, given that side effects are also dose-related,” she said.

Results also favored flexible-dose ketamine over midazolam for the secondary outcomes of response (≥ 50% reduction in MADRS: 29% vs. 4%; P = .001) and remission defined by a less rigid definition (MADRS ≤ 12: 22% vs. 4%; P = .007).

The results also confirm that the antidepressant effects of ketamine are not sustained when treatment stops.

“The study included careful follow-up for 4 weeks after the end of treatment. This is an important contribution to the literature, as it shows that ongoing treatment beyond the 4 weeks will be necessary for most people to maintain the benefits of ketamine treatment if you respond to the treatment. This study provided clear evidence of this, for racemic ketamine,” said Dr. Loo.

Overall, ketamine was well-tolerated, with the well-established acute effects of ketamine observed in both cohorts. The acute effects resolved or returned to pretreatment levels within the 2-hour observation period. No one required medical intervention, and there was no evidence of cognitive impairment.
 

Rigorous research, compelling data

Reached for comment, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the mood disorders psychopharmacology unit, said the data are “compelling with respect to efficacy and safety of subcutaneous ketamine in adults with major depression.”

Dr. McIntyre said the data are “highly relevant” for several reasons. “First, it is the most rigorous study conducted to date with subcutaneous administration of ketamine for adults living with treatment-resistant depression.”

Second, it “demonstrates the efficacy and safety of this route of delivery, which until now has not been studied with this level of rigor and which is a more scalable and accessible approach to administer ketamine to suitable candidates,” Dr. McIntyre said.

The study was funded by a competitive research grant from the Australian National Health and Medical Research Council. Dr. Loo has disclosed relationships with Douglas Pharmaceuticals and Janssen Cilag and is the medical director of neurostimulation and interventional psychiatry at Ramsay Health Care. Dr. McIntyre has received 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, Viatris, AbbVie, and Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.

Two-thirds of Americans support regulated use of psychedelics for therapeutic purposes, results of a new poll show.

It is a surprisingly large percentage, said officials at the University of California, Berkeley, Center for the Science of Psychedelics, which conducted the online survey of 1,500 registered voters in early June.

Courtesy Alia Malley

“That is a stunning number,” said Michael Pollan, cofounder of the center, and author of “How to Change Your Mind,” a book that explored potential uses of psychedelics.

In a briefing with reporters, Mr. Pollan said that he believes the large support base, in part, reflects campaigns that have “been successful by highlighting the effectiveness of psychedelics as therapy for mental illness.”

However, the poll also showed that 61% of voters said that they do not perceive psychedelics as “good for society,” and 69% do not perceive them as “something for people like me.”

These negative sentiments “suggest a fragile kind of support – the kind of support where you’re only hearing one side of the story,” said Mr. Pollan.

Still, poll respondents supported other potential policy changes, including 56% in support of the U.S. Food and Drug Administration vetting and approving psychedelics so they could be available by prescription.
 

50% have tried psychedelics

Almost 80% said that it should be easier for researchers to study psychedelics, and just under one-half said that they backed removing criminal penalties for personal use and possession.

The poll results also show that almost half of respondents had heard about psychedelics recently, with 48% saying they had heard about the drugs’ use in treating mental illness.

Respondents who were most familiar with and positive about psychedelics tended to be White, male, aged 30-50 years, liberal, highly educated, living in a Western state, and have little to no religious or spiritual practice.

Overall, 52% of survey respondents said that they or someone close to them had used a psychedelic, with almost half of that use coming in the past 5 years. Some 40% said that the use had been more than a decade ago.

Almost three-quarters of psychedelic use was reported as recreational, but the second-biggest category was therapeutic use at 39%. About one-third of respondents said that they or someone close to them had microdosed.

Conservative voters had lower levels of awareness and first-degree connection use as well as the least amount of support for regulated therapeutic use, with only 45% saying they would back such a policy, compared with 80% of liberal voters and 66% of moderate voters.

Black individuals were the least likely to be familiar with psychedelics: Just 29% said that they had heard a little or a lot about the drugs, compared with 39% of Latinx individuals and 51% of White individuals. And just one-quarter reported first-degree use, compared with half of Latinx individuals and 56% of White individuals.
 

Who should be eligible?

When asked who should be eligible for treatment with psychedelics, 80% said that they were comfortable with its use for those with terminal illnesses. More than two-thirds expressed comfort with the drugs being used to help veterans and people with treatment-resistant depression and anxiety.

Less than one-half of respondents said that psychedelics should be available to everyone older than 21 years. And voters seemed to be less inclined to say psychedelics should be used to treat people with addiction, with just 45% indicating that they were very or somewhat comfortable with that use.

Mr. Pollan said that reflects perhaps some lack of knowledge or education.

“The story about addiction and psychedelics hasn’t gotten out,” he said. “I kind of get that intuitively the idea of using a drug to treat a drug doesn’t sound right to a lot of people. But in fact, there’s good evidence it works,” Mr. Pollan said.

Respondents said that doctors, nurses, and scientists were the most trusted source of information about psychedelics, whereas the FDA received lower confidence. Law enforcement was least trusted by liberals and most trusted by conservatives.

Mr. Pollan noted the reversal in attitudes, with Americans mostly now looking to the scientific and medical establishment for guidance on psychedelics.

“We went from a counterculture drug to something that is being taken seriously by scientists as a potential therapy,” he said.

The poll’s margin of error was ± 2.5%.

A version of this article first appeared on Medscape.com.

Two-thirds of Americans support regulated use of psychedelics for therapeutic purposes, results of a new poll show.

It is a surprisingly large percentage, said officials at the University of California, Berkeley, Center for the Science of Psychedelics, which conducted the online survey of 1,500 registered voters in early June.

Courtesy Alia Malley

“That is a stunning number,” said Michael Pollan, cofounder of the center, and author of “How to Change Your Mind,” a book that explored potential uses of psychedelics.

In a briefing with reporters, Mr. Pollan said that he believes the large support base, in part, reflects campaigns that have “been successful by highlighting the effectiveness of psychedelics as therapy for mental illness.”

However, the poll also showed that 61% of voters said that they do not perceive psychedelics as “good for society,” and 69% do not perceive them as “something for people like me.”

These negative sentiments “suggest a fragile kind of support – the kind of support where you’re only hearing one side of the story,” said Mr. Pollan.

Still, poll respondents supported other potential policy changes, including 56% in support of the U.S. Food and Drug Administration vetting and approving psychedelics so they could be available by prescription.
 

50% have tried psychedelics

Almost 80% said that it should be easier for researchers to study psychedelics, and just under one-half said that they backed removing criminal penalties for personal use and possession.

The poll results also show that almost half of respondents had heard about psychedelics recently, with 48% saying they had heard about the drugs’ use in treating mental illness.

Respondents who were most familiar with and positive about psychedelics tended to be White, male, aged 30-50 years, liberal, highly educated, living in a Western state, and have little to no religious or spiritual practice.

Overall, 52% of survey respondents said that they or someone close to them had used a psychedelic, with almost half of that use coming in the past 5 years. Some 40% said that the use had been more than a decade ago.

Almost three-quarters of psychedelic use was reported as recreational, but the second-biggest category was therapeutic use at 39%. About one-third of respondents said that they or someone close to them had microdosed.

Conservative voters had lower levels of awareness and first-degree connection use as well as the least amount of support for regulated therapeutic use, with only 45% saying they would back such a policy, compared with 80% of liberal voters and 66% of moderate voters.

Black individuals were the least likely to be familiar with psychedelics: Just 29% said that they had heard a little or a lot about the drugs, compared with 39% of Latinx individuals and 51% of White individuals. And just one-quarter reported first-degree use, compared with half of Latinx individuals and 56% of White individuals.
 

Who should be eligible?

When asked who should be eligible for treatment with psychedelics, 80% said that they were comfortable with its use for those with terminal illnesses. More than two-thirds expressed comfort with the drugs being used to help veterans and people with treatment-resistant depression and anxiety.

Less than one-half of respondents said that psychedelics should be available to everyone older than 21 years. And voters seemed to be less inclined to say psychedelics should be used to treat people with addiction, with just 45% indicating that they were very or somewhat comfortable with that use.

Mr. Pollan said that reflects perhaps some lack of knowledge or education.

“The story about addiction and psychedelics hasn’t gotten out,” he said. “I kind of get that intuitively the idea of using a drug to treat a drug doesn’t sound right to a lot of people. But in fact, there’s good evidence it works,” Mr. Pollan said.

Respondents said that doctors, nurses, and scientists were the most trusted source of information about psychedelics, whereas the FDA received lower confidence. Law enforcement was least trusted by liberals and most trusted by conservatives.

Mr. Pollan noted the reversal in attitudes, with Americans mostly now looking to the scientific and medical establishment for guidance on psychedelics.

“We went from a counterculture drug to something that is being taken seriously by scientists as a potential therapy,” he said.

The poll’s margin of error was ± 2.5%.

A version of this article first appeared on Medscape.com.

Two-thirds of Americans support regulated use of psychedelics for therapeutic purposes, results of a new poll show.

It is a surprisingly large percentage, said officials at the University of California, Berkeley, Center for the Science of Psychedelics, which conducted the online survey of 1,500 registered voters in early June.

Courtesy Alia Malley

“That is a stunning number,” said Michael Pollan, cofounder of the center, and author of “How to Change Your Mind,” a book that explored potential uses of psychedelics.

In a briefing with reporters, Mr. Pollan said that he believes the large support base, in part, reflects campaigns that have “been successful by highlighting the effectiveness of psychedelics as therapy for mental illness.”

However, the poll also showed that 61% of voters said that they do not perceive psychedelics as “good for society,” and 69% do not perceive them as “something for people like me.”

These negative sentiments “suggest a fragile kind of support – the kind of support where you’re only hearing one side of the story,” said Mr. Pollan.

Still, poll respondents supported other potential policy changes, including 56% in support of the U.S. Food and Drug Administration vetting and approving psychedelics so they could be available by prescription.
 

50% have tried psychedelics

Almost 80% said that it should be easier for researchers to study psychedelics, and just under one-half said that they backed removing criminal penalties for personal use and possession.

The poll results also show that almost half of respondents had heard about psychedelics recently, with 48% saying they had heard about the drugs’ use in treating mental illness.

Respondents who were most familiar with and positive about psychedelics tended to be White, male, aged 30-50 years, liberal, highly educated, living in a Western state, and have little to no religious or spiritual practice.

Overall, 52% of survey respondents said that they or someone close to them had used a psychedelic, with almost half of that use coming in the past 5 years. Some 40% said that the use had been more than a decade ago.

Almost three-quarters of psychedelic use was reported as recreational, but the second-biggest category was therapeutic use at 39%. About one-third of respondents said that they or someone close to them had microdosed.

Conservative voters had lower levels of awareness and first-degree connection use as well as the least amount of support for regulated therapeutic use, with only 45% saying they would back such a policy, compared with 80% of liberal voters and 66% of moderate voters.

Black individuals were the least likely to be familiar with psychedelics: Just 29% said that they had heard a little or a lot about the drugs, compared with 39% of Latinx individuals and 51% of White individuals. And just one-quarter reported first-degree use, compared with half of Latinx individuals and 56% of White individuals.
 

Who should be eligible?

When asked who should be eligible for treatment with psychedelics, 80% said that they were comfortable with its use for those with terminal illnesses. More than two-thirds expressed comfort with the drugs being used to help veterans and people with treatment-resistant depression and anxiety.

Less than one-half of respondents said that psychedelics should be available to everyone older than 21 years. And voters seemed to be less inclined to say psychedelics should be used to treat people with addiction, with just 45% indicating that they were very or somewhat comfortable with that use.

Mr. Pollan said that reflects perhaps some lack of knowledge or education.

“The story about addiction and psychedelics hasn’t gotten out,” he said. “I kind of get that intuitively the idea of using a drug to treat a drug doesn’t sound right to a lot of people. But in fact, there’s good evidence it works,” Mr. Pollan said.

Respondents said that doctors, nurses, and scientists were the most trusted source of information about psychedelics, whereas the FDA received lower confidence. Law enforcement was least trusted by liberals and most trusted by conservatives.

Mr. Pollan noted the reversal in attitudes, with Americans mostly now looking to the scientific and medical establishment for guidance on psychedelics.

“We went from a counterculture drug to something that is being taken seriously by scientists as a potential therapy,” he said.

The poll’s margin of error was ± 2.5%.

A version of this article first appeared on Medscape.com.

The risks of common postpartum mental health (PMH) problems may soon be more predictable, thanks to a new comprehensive index for identifying mothers’ 1-year risk at time of delivery.

Developed by Canadian researchers, the easily implementable PMH CAREPLAN index “creates a framework for clinically actionable risk stratification that could assist patients and providers in determining an individual’s level of risk for common postpartum mental health disorders and direct them to appropriate intervention,” wrote a group led by Simone N. Vigod, MD, MSc, head of the department of psychiatry at Women’s College Hospital, Toronto, in the British Journal of Psychiatry.

courtesy Women&#039;s College Hospital

After giving birth, women are especially vulnerable to major depression, anxiety, PTSD, and obsessive-compulsive disorder, which have a general postpartum prevalence of 7%-20%.

Common PMH disorders are to be distinguished from the more rare but severe PMH disorders such as postpartum psychosis and bipolar disorder, the researchers stressed.

“We know there are interventions that can prevent these disorders, but these seem to work best in people who are at high risk for developing the illnesses, “ Dr. Vigod said. “So, we wanted to be able to determine the level of risk that a person might actually experience them.”

In an ideal world, she continued, physicians might be able to say to a patient: “You have a 50% chance of developing postpartum depression and anxiety, so it may be worth investing your time and resources in a course of preventive psychotherapy.” Or: “You have a 90% chance of developing these disorders, so it might be worth going back on your medications even though you are breastfeeding.” Or: “You have only a 1% chance of developing them, so probably it’s not worthwhile to go back on your medication prophylactically.”

A need for a new assessment tool, akin to the Framingham Risk Score for 10-year cardiovascular events and the FRAX scoring system for 10-year fracture risk, was evident since previous indices based largely on patient self-reporting have had moderate predictive capacity, and have not been adopted in clinical practice, Dr. Vigod and associates noted.
 

Split-cohort design

Using population-based health administrative data and hospital birth records from Ontario during 2012-2015, Dr. Vigod’s group created and internally validated a predictive model for common PMH disorders in a cohort of 152,362 mothers. They then converted it to a risk index after validation in an additional cohort of 75,772 mothers. The women had delivered live infants during 2012-2014.

A common PMH disorder occurred in 13,608 mothers, while 214,526 were unaffected.

Independently associated PMH variables were many: prenatal care provider, mental health diagnosis history and medications during pregnancy, psychiatric hospital admissions or ED visits, conception type and complications, and apprehension of newborn by child services. Other factors were region of maternal origin, extremes of gestational age at birth, primary maternal language, lactation intention, maternal age, and number of prenatal visits.

Based on a broad span of scores from 0 to 39, 1-year common PMH disorder risk ranged from 1.5% to 40.5%, with an overall 1-year prevalence of 6%, consistent with previous studies. That included 11,262 (5%) mothers with an anxiety or related disorder, 3,392 (1.5%) with a depressive episode, and 1,046 (0.5%) with both. The best trade-off of sensitivity/specificity for risk appeared to be at a screening threshold score of 17 or above.
 

Risk drivers

PMH-affected mothers were slightly younger than unaffected women (mean age, 29.9 years vs. 30.6 years), more likely to be primiparous (45.2% vs. 42%), and less likely to be recent immigrants (16.7% vs. 27.2%).

They were also more likely to have previously experienced postpartum depression (4.4% vs. 1.4%), any depression (15.3% vs. 4.4%), and any anxiety disorder (13.8% vs. 4.3%).

As to lifestyle, smoking was more common in women with PMH (15.0% vs. 10.2%), as were the use of nonprescribed substances (3% vs. 1.4%) and intimate partner violence in pregnancy (2.7% vs. 1.5%).

In addition, the affected group experienced more pregnancy complications than their unaffected peers (16% vs. 13.9%), preterm birth (8.2% vs. 6.8%), and Apgar scores below 7 at 1 or 5 minutes (10.5% vs. 7.6%).

Low income did not appear to have an impact since just over 20% in either group fell into the lowest neighborhood income quintile.

courtesy Northwestern Medicine

Commenting on the index but not involved in developing it, LaTasha D. Nelson, MD, an associate professor or medicine and a maternal-fetal medicine specialist at Northwestern Medicine in Chicago, doubted the Canadian model would work as well in the more fragmented U.S. health care system, compared with Canada’s universal model with its large provincial health databases.

She also found the large number of variables and broad score range potentially problematic, especially if the risk threshold is set at less than half the maximum score at 17, at which some low-risk mothers might get screening and perhaps intervention. “Are we going to use up the resources we have for those who might not need help, or are we going to treat someone who really needs it?” she asked.

Another concern is the postpartum timing of assessment. At Dr. Nelson’s center, mothers are checked for mental health at two points during pregnancy and those with higher scores are triaged for further care.

Dr. Nelson was also puzzled by the score-lowering impact of prenatal care given by a nurse practitioner and “other” provider : –5 and –2, respectively, versus +3 for a midwife and +1 for a family doctor. “This may capture more relaxed, easy-going multiparous mothers who felt comfortable turning to an NP,” she said.

It may indeed reflect that the risk level of a person who sees those providers is overall lower, Dr. Vigod agreed. “This is one reason why we would want to see replication of these results in other jurisdictions and by other ways of diagnosis before putting it out into clinical practice.”

As to the score-lowering effect of not speaking English as the primary tongue, Dr. Nelson wondered, “is that because we’re taking better care of mothers who speak the main language and missing those who speak other languages? Are they not getting the same level of interrogation?”

It may be that individuals in these groups were less likely to access mental health care, Dr. Vigod agreed, or it might reflect the so-called healthy immigrant effect or culturally different levels of postpartum support. “It might mean that there are more people who benefit from community-level protective factors in these groups. We know that social support is an important protective factor.”

Despite her reservations about the index, Dr. Nelson said that increasing attention to the pre- and postnatal mental health of mothers is an important part of maternal care. “This is an issue that needs to be recognized.”

The next step, Dr. Vigod said, is to determine whether the index holds up in other populations. “Then, we would want to test it out to see if recommending interventions based on a certain level of risk improves outcomes. At what percentage risk would starting an antidepressant medication result in a reduced risk for postpartum depression or anxiety – 90%, 80%, 70%, or less?”

The study received funding from the Canadian Institutes of Health Research. Data were analyzed by ICES, an independent nonprofit research organization that holds population-based data. Dr. Vigod reported royalties from UpToDate for materials related to depression and pregnancy. Dr. Nelson disclosed no relevant competing interests.

The risks of common postpartum mental health (PMH) problems may soon be more predictable, thanks to a new comprehensive index for identifying mothers’ 1-year risk at time of delivery.

Developed by Canadian researchers, the easily implementable PMH CAREPLAN index “creates a framework for clinically actionable risk stratification that could assist patients and providers in determining an individual’s level of risk for common postpartum mental health disorders and direct them to appropriate intervention,” wrote a group led by Simone N. Vigod, MD, MSc, head of the department of psychiatry at Women’s College Hospital, Toronto, in the British Journal of Psychiatry.

courtesy Women&#039;s College Hospital

After giving birth, women are especially vulnerable to major depression, anxiety, PTSD, and obsessive-compulsive disorder, which have a general postpartum prevalence of 7%-20%.

Common PMH disorders are to be distinguished from the more rare but severe PMH disorders such as postpartum psychosis and bipolar disorder, the researchers stressed.

“We know there are interventions that can prevent these disorders, but these seem to work best in people who are at high risk for developing the illnesses, “ Dr. Vigod said. “So, we wanted to be able to determine the level of risk that a person might actually experience them.”

In an ideal world, she continued, physicians might be able to say to a patient: “You have a 50% chance of developing postpartum depression and anxiety, so it may be worth investing your time and resources in a course of preventive psychotherapy.” Or: “You have a 90% chance of developing these disorders, so it might be worth going back on your medications even though you are breastfeeding.” Or: “You have only a 1% chance of developing them, so probably it’s not worthwhile to go back on your medication prophylactically.”

A need for a new assessment tool, akin to the Framingham Risk Score for 10-year cardiovascular events and the FRAX scoring system for 10-year fracture risk, was evident since previous indices based largely on patient self-reporting have had moderate predictive capacity, and have not been adopted in clinical practice, Dr. Vigod and associates noted.
 

Split-cohort design

Using population-based health administrative data and hospital birth records from Ontario during 2012-2015, Dr. Vigod’s group created and internally validated a predictive model for common PMH disorders in a cohort of 152,362 mothers. They then converted it to a risk index after validation in an additional cohort of 75,772 mothers. The women had delivered live infants during 2012-2014.

A common PMH disorder occurred in 13,608 mothers, while 214,526 were unaffected.

Independently associated PMH variables were many: prenatal care provider, mental health diagnosis history and medications during pregnancy, psychiatric hospital admissions or ED visits, conception type and complications, and apprehension of newborn by child services. Other factors were region of maternal origin, extremes of gestational age at birth, primary maternal language, lactation intention, maternal age, and number of prenatal visits.

Based on a broad span of scores from 0 to 39, 1-year common PMH disorder risk ranged from 1.5% to 40.5%, with an overall 1-year prevalence of 6%, consistent with previous studies. That included 11,262 (5%) mothers with an anxiety or related disorder, 3,392 (1.5%) with a depressive episode, and 1,046 (0.5%) with both. The best trade-off of sensitivity/specificity for risk appeared to be at a screening threshold score of 17 or above.
 

Risk drivers

PMH-affected mothers were slightly younger than unaffected women (mean age, 29.9 years vs. 30.6 years), more likely to be primiparous (45.2% vs. 42%), and less likely to be recent immigrants (16.7% vs. 27.2%).

They were also more likely to have previously experienced postpartum depression (4.4% vs. 1.4%), any depression (15.3% vs. 4.4%), and any anxiety disorder (13.8% vs. 4.3%).

As to lifestyle, smoking was more common in women with PMH (15.0% vs. 10.2%), as were the use of nonprescribed substances (3% vs. 1.4%) and intimate partner violence in pregnancy (2.7% vs. 1.5%).

In addition, the affected group experienced more pregnancy complications than their unaffected peers (16% vs. 13.9%), preterm birth (8.2% vs. 6.8%), and Apgar scores below 7 at 1 or 5 minutes (10.5% vs. 7.6%).

Low income did not appear to have an impact since just over 20% in either group fell into the lowest neighborhood income quintile.

courtesy Northwestern Medicine

Commenting on the index but not involved in developing it, LaTasha D. Nelson, MD, an associate professor or medicine and a maternal-fetal medicine specialist at Northwestern Medicine in Chicago, doubted the Canadian model would work as well in the more fragmented U.S. health care system, compared with Canada’s universal model with its large provincial health databases.

She also found the large number of variables and broad score range potentially problematic, especially if the risk threshold is set at less than half the maximum score at 17, at which some low-risk mothers might get screening and perhaps intervention. “Are we going to use up the resources we have for those who might not need help, or are we going to treat someone who really needs it?” she asked.

Another concern is the postpartum timing of assessment. At Dr. Nelson’s center, mothers are checked for mental health at two points during pregnancy and those with higher scores are triaged for further care.

Dr. Nelson was also puzzled by the score-lowering impact of prenatal care given by a nurse practitioner and “other” provider : –5 and –2, respectively, versus +3 for a midwife and +1 for a family doctor. “This may capture more relaxed, easy-going multiparous mothers who felt comfortable turning to an NP,” she said.

It may indeed reflect that the risk level of a person who sees those providers is overall lower, Dr. Vigod agreed. “This is one reason why we would want to see replication of these results in other jurisdictions and by other ways of diagnosis before putting it out into clinical practice.”

As to the score-lowering effect of not speaking English as the primary tongue, Dr. Nelson wondered, “is that because we’re taking better care of mothers who speak the main language and missing those who speak other languages? Are they not getting the same level of interrogation?”

It may be that individuals in these groups were less likely to access mental health care, Dr. Vigod agreed, or it might reflect the so-called healthy immigrant effect or culturally different levels of postpartum support. “It might mean that there are more people who benefit from community-level protective factors in these groups. We know that social support is an important protective factor.”

Despite her reservations about the index, Dr. Nelson said that increasing attention to the pre- and postnatal mental health of mothers is an important part of maternal care. “This is an issue that needs to be recognized.”

The next step, Dr. Vigod said, is to determine whether the index holds up in other populations. “Then, we would want to test it out to see if recommending interventions based on a certain level of risk improves outcomes. At what percentage risk would starting an antidepressant medication result in a reduced risk for postpartum depression or anxiety – 90%, 80%, 70%, or less?”

The study received funding from the Canadian Institutes of Health Research. Data were analyzed by ICES, an independent nonprofit research organization that holds population-based data. Dr. Vigod reported royalties from UpToDate for materials related to depression and pregnancy. Dr. Nelson disclosed no relevant competing interests.

The risks of common postpartum mental health (PMH) problems may soon be more predictable, thanks to a new comprehensive index for identifying mothers’ 1-year risk at time of delivery.

Developed by Canadian researchers, the easily implementable PMH CAREPLAN index “creates a framework for clinically actionable risk stratification that could assist patients and providers in determining an individual’s level of risk for common postpartum mental health disorders and direct them to appropriate intervention,” wrote a group led by Simone N. Vigod, MD, MSc, head of the department of psychiatry at Women’s College Hospital, Toronto, in the British Journal of Psychiatry.

courtesy Women&#039;s College Hospital

After giving birth, women are especially vulnerable to major depression, anxiety, PTSD, and obsessive-compulsive disorder, which have a general postpartum prevalence of 7%-20%.

Common PMH disorders are to be distinguished from the more rare but severe PMH disorders such as postpartum psychosis and bipolar disorder, the researchers stressed.

“We know there are interventions that can prevent these disorders, but these seem to work best in people who are at high risk for developing the illnesses, “ Dr. Vigod said. “So, we wanted to be able to determine the level of risk that a person might actually experience them.”

In an ideal world, she continued, physicians might be able to say to a patient: “You have a 50% chance of developing postpartum depression and anxiety, so it may be worth investing your time and resources in a course of preventive psychotherapy.” Or: “You have a 90% chance of developing these disorders, so it might be worth going back on your medications even though you are breastfeeding.” Or: “You have only a 1% chance of developing them, so probably it’s not worthwhile to go back on your medication prophylactically.”

A need for a new assessment tool, akin to the Framingham Risk Score for 10-year cardiovascular events and the FRAX scoring system for 10-year fracture risk, was evident since previous indices based largely on patient self-reporting have had moderate predictive capacity, and have not been adopted in clinical practice, Dr. Vigod and associates noted.
 

Split-cohort design

Using population-based health administrative data and hospital birth records from Ontario during 2012-2015, Dr. Vigod’s group created and internally validated a predictive model for common PMH disorders in a cohort of 152,362 mothers. They then converted it to a risk index after validation in an additional cohort of 75,772 mothers. The women had delivered live infants during 2012-2014.

A common PMH disorder occurred in 13,608 mothers, while 214,526 were unaffected.

Independently associated PMH variables were many: prenatal care provider, mental health diagnosis history and medications during pregnancy, psychiatric hospital admissions or ED visits, conception type and complications, and apprehension of newborn by child services. Other factors were region of maternal origin, extremes of gestational age at birth, primary maternal language, lactation intention, maternal age, and number of prenatal visits.

Based on a broad span of scores from 0 to 39, 1-year common PMH disorder risk ranged from 1.5% to 40.5%, with an overall 1-year prevalence of 6%, consistent with previous studies. That included 11,262 (5%) mothers with an anxiety or related disorder, 3,392 (1.5%) with a depressive episode, and 1,046 (0.5%) with both. The best trade-off of sensitivity/specificity for risk appeared to be at a screening threshold score of 17 or above.
 

Risk drivers

PMH-affected mothers were slightly younger than unaffected women (mean age, 29.9 years vs. 30.6 years), more likely to be primiparous (45.2% vs. 42%), and less likely to be recent immigrants (16.7% vs. 27.2%).

They were also more likely to have previously experienced postpartum depression (4.4% vs. 1.4%), any depression (15.3% vs. 4.4%), and any anxiety disorder (13.8% vs. 4.3%).

As to lifestyle, smoking was more common in women with PMH (15.0% vs. 10.2%), as were the use of nonprescribed substances (3% vs. 1.4%) and intimate partner violence in pregnancy (2.7% vs. 1.5%).

In addition, the affected group experienced more pregnancy complications than their unaffected peers (16% vs. 13.9%), preterm birth (8.2% vs. 6.8%), and Apgar scores below 7 at 1 or 5 minutes (10.5% vs. 7.6%).

Low income did not appear to have an impact since just over 20% in either group fell into the lowest neighborhood income quintile.

courtesy Northwestern Medicine

Commenting on the index but not involved in developing it, LaTasha D. Nelson, MD, an associate professor or medicine and a maternal-fetal medicine specialist at Northwestern Medicine in Chicago, doubted the Canadian model would work as well in the more fragmented U.S. health care system, compared with Canada’s universal model with its large provincial health databases.

She also found the large number of variables and broad score range potentially problematic, especially if the risk threshold is set at less than half the maximum score at 17, at which some low-risk mothers might get screening and perhaps intervention. “Are we going to use up the resources we have for those who might not need help, or are we going to treat someone who really needs it?” she asked.

Another concern is the postpartum timing of assessment. At Dr. Nelson’s center, mothers are checked for mental health at two points during pregnancy and those with higher scores are triaged for further care.

Dr. Nelson was also puzzled by the score-lowering impact of prenatal care given by a nurse practitioner and “other” provider : –5 and –2, respectively, versus +3 for a midwife and +1 for a family doctor. “This may capture more relaxed, easy-going multiparous mothers who felt comfortable turning to an NP,” she said.

It may indeed reflect that the risk level of a person who sees those providers is overall lower, Dr. Vigod agreed. “This is one reason why we would want to see replication of these results in other jurisdictions and by other ways of diagnosis before putting it out into clinical practice.”

As to the score-lowering effect of not speaking English as the primary tongue, Dr. Nelson wondered, “is that because we’re taking better care of mothers who speak the main language and missing those who speak other languages? Are they not getting the same level of interrogation?”

It may be that individuals in these groups were less likely to access mental health care, Dr. Vigod agreed, or it might reflect the so-called healthy immigrant effect or culturally different levels of postpartum support. “It might mean that there are more people who benefit from community-level protective factors in these groups. We know that social support is an important protective factor.”

Despite her reservations about the index, Dr. Nelson said that increasing attention to the pre- and postnatal mental health of mothers is an important part of maternal care. “This is an issue that needs to be recognized.”

The next step, Dr. Vigod said, is to determine whether the index holds up in other populations. “Then, we would want to test it out to see if recommending interventions based on a certain level of risk improves outcomes. At what percentage risk would starting an antidepressant medication result in a reduced risk for postpartum depression or anxiety – 90%, 80%, 70%, or less?”

The study received funding from the Canadian Institutes of Health Research. Data were analyzed by ICES, an independent nonprofit research organization that holds population-based data. Dr. Vigod reported royalties from UpToDate for materials related to depression and pregnancy. Dr. Nelson disclosed no relevant competing interests.

Transcranial direct current stimulation (tDCS) provides no additional benefit when added to selective serotonin reuptake inhibitor therapy for adults with major depressive disorder (MDD), results of a triple-blind, randomized, sham-controlled trial show.

The study showed no difference in mean improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) scores at 6 weeks between active and sham tDCS.

“Our trial does not support the efficacy of tDCS as an additional treatment to SSRIs in adults with MDD,” the investigators, led by Frank Padberg, MD, department of psychiatry and psychotherapy, Ludwig-Maximilians-University Munich, write.

The study was published online in The Lancet.

Rigorous trial

Because it neurophysiologically modulates prefrontal cortex connectivity, tDCS has been proposed as a potential treatment for MDD.

Yet evidence for its efficacy has been inconsistent, and there is a scarcity of multicenter trial data, the researchers note.

The DepressionDC trial assessed the efficacy of tDCS in combination with SSRIs in 160 adults with MDD. Participants had a score of at least 15 on the Hamilton Depression Rating Scale (21-item version); their conditions had not responded to at least one antidepressant trial in their current depressive episode; and they had received treatment with an SSRI at a stable dose for at least 4 weeks. The SSRI was continued at the same dose during stimulation.

Eighty-three patients were allocated to undergo 30 min of 2-mA bifrontal tDCS every weekday for 4 weeks, then two tDCS sessions per week for 2 weeks; 77 patients were assigned to receive matching sham stimulation. Randomization was stratified by baseline MADRS score of less than 31 or 31 and higher.

In intention-to-treat analysis, there was no between-group difference in mean improvement on the MADRS at week 6 (–8.2 with active and –8.0 with sham tDCS; difference, 0.3; 95% confidence interval, –2.4 to 2.9).

There was also no significant difference for all secondary outcomes, including response and remission rates, patient-reported depression, and functioning, as well as at 18-week and 30-week follow-up visits.

There were significantly more mild adverse events reported in the active tDCS group than in the sham group (60% vs. 43%; P = .028). The most common adverse events were headaches, local skin reactions, and sleep-related problems.

Still reason for optimism

These findings call into question the efficacy of tDCS as add-on therapy to SSRI treatment for individuals with MDD and highlight the need for supportive evidence from multicenter studies, the investigators write.

Yet Dr. Padberg said it’s not the end of the road for tDCS for depression.

tDCS exerts a “rather subtle and nonfocal effect on neuronal activity. Thus, tDCS may need to be combined with specific behavioral or cognitive interventions which functionally involve the brain region where tDCS is targeted at,” he said.

Another “promising avenue” is personalization of tDCS by “individual MRI-based computational modeling of tDCS-induced electric fields,” he noted.

The coauthors of an accompanying commentary note that the DepressionDC trial was “carefully designed” and “well executed.”

And while the results did not show the superiority of active tDCS over sham stimulation as an additional treatment to SSRI therapy, “clinicians and researchers should not disregard this treatment for people with MDD,” write Daphne Voineskos, MD, PhD, and Daniel Blumberger, MD, with the University of Toronto.

“Specifically, further exploration of placebo response in less heterogeneous MDD samples and the evaluation of tDCS as an earlier treatment option for people with MDD are important areas of future research,” they suggest.

“Moreover, elucidating the effects of interindividual anatomical variability on electrical current distribution might lead to tDCS protocols that individualize treatment to optimize therapeutic effects as opposed to a so-called one-size-fits-all approach.

“Overall, there is reason for optimism about the potential to individualize tDCS and deliver it outside of the clinical setting,” Dr. Voineskos and Dr. Blumberger conclude.

Funding for the study was provided by the German Federal Ministry of Education and Research. Several authors disclosed relationships with the pharmaceutical industry. A complete list of disclosures of authors and comment writers is available with the original article.

A version of this article first appeared on Medscape.com.

Transcranial direct current stimulation (tDCS) provides no additional benefit when added to selective serotonin reuptake inhibitor therapy for adults with major depressive disorder (MDD), results of a triple-blind, randomized, sham-controlled trial show.

The study showed no difference in mean improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) scores at 6 weeks between active and sham tDCS.

“Our trial does not support the efficacy of tDCS as an additional treatment to SSRIs in adults with MDD,” the investigators, led by Frank Padberg, MD, department of psychiatry and psychotherapy, Ludwig-Maximilians-University Munich, write.

The study was published online in The Lancet.

Rigorous trial

Because it neurophysiologically modulates prefrontal cortex connectivity, tDCS has been proposed as a potential treatment for MDD.

Yet evidence for its efficacy has been inconsistent, and there is a scarcity of multicenter trial data, the researchers note.

The DepressionDC trial assessed the efficacy of tDCS in combination with SSRIs in 160 adults with MDD. Participants had a score of at least 15 on the Hamilton Depression Rating Scale (21-item version); their conditions had not responded to at least one antidepressant trial in their current depressive episode; and they had received treatment with an SSRI at a stable dose for at least 4 weeks. The SSRI was continued at the same dose during stimulation.

Eighty-three patients were allocated to undergo 30 min of 2-mA bifrontal tDCS every weekday for 4 weeks, then two tDCS sessions per week for 2 weeks; 77 patients were assigned to receive matching sham stimulation. Randomization was stratified by baseline MADRS score of less than 31 or 31 and higher.

In intention-to-treat analysis, there was no between-group difference in mean improvement on the MADRS at week 6 (–8.2 with active and –8.0 with sham tDCS; difference, 0.3; 95% confidence interval, –2.4 to 2.9).

There was also no significant difference for all secondary outcomes, including response and remission rates, patient-reported depression, and functioning, as well as at 18-week and 30-week follow-up visits.

There were significantly more mild adverse events reported in the active tDCS group than in the sham group (60% vs. 43%; P = .028). The most common adverse events were headaches, local skin reactions, and sleep-related problems.

Still reason for optimism

These findings call into question the efficacy of tDCS as add-on therapy to SSRI treatment for individuals with MDD and highlight the need for supportive evidence from multicenter studies, the investigators write.

Yet Dr. Padberg said it’s not the end of the road for tDCS for depression.

tDCS exerts a “rather subtle and nonfocal effect on neuronal activity. Thus, tDCS may need to be combined with specific behavioral or cognitive interventions which functionally involve the brain region where tDCS is targeted at,” he said.

Another “promising avenue” is personalization of tDCS by “individual MRI-based computational modeling of tDCS-induced electric fields,” he noted.

The coauthors of an accompanying commentary note that the DepressionDC trial was “carefully designed” and “well executed.”

And while the results did not show the superiority of active tDCS over sham stimulation as an additional treatment to SSRI therapy, “clinicians and researchers should not disregard this treatment for people with MDD,” write Daphne Voineskos, MD, PhD, and Daniel Blumberger, MD, with the University of Toronto.

“Specifically, further exploration of placebo response in less heterogeneous MDD samples and the evaluation of tDCS as an earlier treatment option for people with MDD are important areas of future research,” they suggest.

“Moreover, elucidating the effects of interindividual anatomical variability on electrical current distribution might lead to tDCS protocols that individualize treatment to optimize therapeutic effects as opposed to a so-called one-size-fits-all approach.

“Overall, there is reason for optimism about the potential to individualize tDCS and deliver it outside of the clinical setting,” Dr. Voineskos and Dr. Blumberger conclude.

Funding for the study was provided by the German Federal Ministry of Education and Research. Several authors disclosed relationships with the pharmaceutical industry. A complete list of disclosures of authors and comment writers is available with the original article.

A version of this article first appeared on Medscape.com.

Transcranial direct current stimulation (tDCS) provides no additional benefit when added to selective serotonin reuptake inhibitor therapy for adults with major depressive disorder (MDD), results of a triple-blind, randomized, sham-controlled trial show.

The study showed no difference in mean improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) scores at 6 weeks between active and sham tDCS.

“Our trial does not support the efficacy of tDCS as an additional treatment to SSRIs in adults with MDD,” the investigators, led by Frank Padberg, MD, department of psychiatry and psychotherapy, Ludwig-Maximilians-University Munich, write.

The study was published online in The Lancet.

Rigorous trial

Because it neurophysiologically modulates prefrontal cortex connectivity, tDCS has been proposed as a potential treatment for MDD.

Yet evidence for its efficacy has been inconsistent, and there is a scarcity of multicenter trial data, the researchers note.

The DepressionDC trial assessed the efficacy of tDCS in combination with SSRIs in 160 adults with MDD. Participants had a score of at least 15 on the Hamilton Depression Rating Scale (21-item version); their conditions had not responded to at least one antidepressant trial in their current depressive episode; and they had received treatment with an SSRI at a stable dose for at least 4 weeks. The SSRI was continued at the same dose during stimulation.

Eighty-three patients were allocated to undergo 30 min of 2-mA bifrontal tDCS every weekday for 4 weeks, then two tDCS sessions per week for 2 weeks; 77 patients were assigned to receive matching sham stimulation. Randomization was stratified by baseline MADRS score of less than 31 or 31 and higher.

In intention-to-treat analysis, there was no between-group difference in mean improvement on the MADRS at week 6 (–8.2 with active and –8.0 with sham tDCS; difference, 0.3; 95% confidence interval, –2.4 to 2.9).

There was also no significant difference for all secondary outcomes, including response and remission rates, patient-reported depression, and functioning, as well as at 18-week and 30-week follow-up visits.

There were significantly more mild adverse events reported in the active tDCS group than in the sham group (60% vs. 43%; P = .028). The most common adverse events were headaches, local skin reactions, and sleep-related problems.

Still reason for optimism

These findings call into question the efficacy of tDCS as add-on therapy to SSRI treatment for individuals with MDD and highlight the need for supportive evidence from multicenter studies, the investigators write.

Yet Dr. Padberg said it’s not the end of the road for tDCS for depression.

tDCS exerts a “rather subtle and nonfocal effect on neuronal activity. Thus, tDCS may need to be combined with specific behavioral or cognitive interventions which functionally involve the brain region where tDCS is targeted at,” he said.

Another “promising avenue” is personalization of tDCS by “individual MRI-based computational modeling of tDCS-induced electric fields,” he noted.

The coauthors of an accompanying commentary note that the DepressionDC trial was “carefully designed” and “well executed.”

And while the results did not show the superiority of active tDCS over sham stimulation as an additional treatment to SSRI therapy, “clinicians and researchers should not disregard this treatment for people with MDD,” write Daphne Voineskos, MD, PhD, and Daniel Blumberger, MD, with the University of Toronto.

“Specifically, further exploration of placebo response in less heterogeneous MDD samples and the evaluation of tDCS as an earlier treatment option for people with MDD are important areas of future research,” they suggest.

“Moreover, elucidating the effects of interindividual anatomical variability on electrical current distribution might lead to tDCS protocols that individualize treatment to optimize therapeutic effects as opposed to a so-called one-size-fits-all approach.

“Overall, there is reason for optimism about the potential to individualize tDCS and deliver it outside of the clinical setting,” Dr. Voineskos and Dr. Blumberger conclude.

Funding for the study was provided by the German Federal Ministry of Education and Research. Several authors disclosed relationships with the pharmaceutical industry. A complete list of disclosures of authors and comment writers is available with the original article.

A version of this article first appeared on Medscape.com.