SAGE-547 for depression: Cause for caution and optimism

The importance of postpartum depression, both in terms of its prevalence and the need for appropriate screening and effective treatments, has become an increasingly important area of focus for clinicians, patients, and policymakers. This derives from more than a decade of data on the significant prevalence of the condition, with roughly 10% of women meeting the criteria for major or minor depression during the first 3-6 months post partum.

Over the last 5 years, interest has centered around establishing mechanisms for appropriate perinatal depression screening, most notably the January 2016 recommendation from the U.S. Preventive Services Task Force that all adults should be screened for depression, including the at-risk populations of pregnant and postpartum women. In 2015, the American College of Obstetricians and Gynecologists endorsed screening women for depression and anxiety symptoms at least once during the perinatal period using a validated tool. Unfortunately, we still lack data to support whether screening is effective in getting patients referred for treatment and if it leads to women accessing therapies that will actually get them well.

As we wait for that data and consider ways to best implement enhanced screening, it’s important to take stock of the available treatments for postpartum depression.

Seeking a rapid treatment

The current literature supports efficacy for nonpharmacologic therapies, such as interpersonal psychotherapy and cognitive-behavioral therapy, as well as several antidepressants. The efficacy of antidepressants – such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors – has been demonstrated for postpartum depression, but these agents carry the typical limitations and concerns in terms of side effects and the amount of time required to ascertain if there is benefit. While these are the same challenges seen in treating depression in general, the time to response – often 4-8 weeks – is particularly problematic for postpartum women where the impact of depression on maternal morbidity and child development is so critical.

The field has been clamoring for agents that work more quickly. One possibility in that area is ketamine, which is being studied as a rapid treatment in major depression. The National Institutes of Health also has an initiative underway called RAPID (Rapidly Acting Treatments for Treatment-Resistant Depression), aimed at identifying and testing pharmacologic and nonpharmacologic treatments that produce a response within days rather than weeks.

Recently, considerable interest has focused on SAGE-547, manufactured by Sage Therapeutics, which is a different type of antidepressant. The so-called neurosteriod is an allosteric modulator of the GABA_A (gamma-aminobutyric acid type A) receptors. The product was granted fast-track status by the Food and Drug Administration to speed its development as a possible treatment for superrefractory status epilepticus, but it also is being studied for its potential in treating severe postpartum depression.

Approximately a year ago, there was preliminary evidence from an open-label study suggesting rapid response to SAGE-547 for women who received this medicine intravenously in a controlled hospital environment. And in July 2016, the manufacturer announced in a press release unpublished positive results from a small phase II controlled trial of SAGE-547 for the treatment of severe postpartum depression.

Specifically, this was a placebo-controlled, double-blind randomized trial for 21 women who had severe depressive symptoms with a baseline score of at least 26 on the Hamilton Rating Scale for Depression (HAM-D). For some of the women, postpartum depression was not of new onset, but rather was an extension of depression that had manifested no earlier than the third trimester of pregnancy. A total of 10 women received the drug, while 11 received placebo. Both groups received continuous intravenous infusion over a 60-hour period.

Consistent with the earlier report, participants receiving the active agent had a statistically significant reduction in HAM-D scores at 24 hours, compared with women who received the placebo. Seven out of 10 women who received the active drug achieved remission from depression at 60 hours, compared with only 1 of the 11 patients who received placebo. Even though the results derived from an extremely small sample, the signal for efficacy appears promising.

Of particular interest, there appeared to be a duration of benefit at 30 days’ follow-up. The medicine was well tolerated with no discontinuations due to adverse events, which were most commonly dizziness, sedation, or somnolence. The adverse events were about the same in both the drug and placebo groups.

Next steps

These early results have generated excitement, if not a “buzz,” in the field, given the rapid onset of antidepressant benefit and the apparent duration of the effect. But readers should be mindful that to date, the findings have not been peer reviewed and are available only through a company-issued press release. It is also noteworthy that on clinicaltrials.gov, the projected enrollment was 32, but 21 women enrolled. This may speak to the great difficulty in enrolling the sample and may ultimately reflect on the generalizability of the findings.

One significant challenge with SAGE-547 is the formulation. It’s hardly feasible for severely ill postpartum women to come to the hospital for 60 hours of treatment. The manufacturer will have to produce a reformulated compound that is able to sustain the efficacy signaled in this proof of concept study.

But even more importantly, we will need to see how the drug performs in a larger, rigorous phase IIB or phase III study to know if the signal of promise really translates into a potential viable treatment option for women with severe postpartum depression. When we have results from a randomized controlled trial with a substantially larger number of patients, then we’ll know whether the excitement is justified. It would be a significant advance for the field if this were to be the case.

The field of depression, in general, has been seeking an effective, rapid treatment for some time, and the role of neurosteriods has been spoken about for more than 2 decades. If postpartum women are in fact a subgroup who respond to this class of agents, then that would be an example of truly personalized medicine. But we won’t know that until the manufacturer does an appropriate large trial, which could take 2-4 years.

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information and resources and conducts clinical care and research in reproductive mental health. He has no financial relationship with SAGE Therapeutics, but he has been a consultant to manufacturers of psychiatric medications.

The importance of postpartum depression, both in terms of its prevalence and the need for appropriate screening and effective treatments, has become an increasingly important area of focus for clinicians, patients, and policymakers. This derives from more than a decade of data on the significant prevalence of the condition, with roughly 10% of women meeting the criteria for major or minor depression during the first 3-6 months post partum.

Over the last 5 years, interest has centered around establishing mechanisms for appropriate perinatal depression screening, most notably the January 2016 recommendation from the U.S. Preventive Services Task Force that all adults should be screened for depression, including the at-risk populations of pregnant and postpartum women. In 2015, the American College of Obstetricians and Gynecologists endorsed screening women for depression and anxiety symptoms at least once during the perinatal period using a validated tool. Unfortunately, we still lack data to support whether screening is effective in getting patients referred for treatment and if it leads to women accessing therapies that will actually get them well.

As we wait for that data and consider ways to best implement enhanced screening, it’s important to take stock of the available treatments for postpartum depression.

Seeking a rapid treatment

The current literature supports efficacy for nonpharmacologic therapies, such as interpersonal psychotherapy and cognitive-behavioral therapy, as well as several antidepressants. The efficacy of antidepressants – such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors – has been demonstrated for postpartum depression, but these agents carry the typical limitations and concerns in terms of side effects and the amount of time required to ascertain if there is benefit. While these are the same challenges seen in treating depression in general, the time to response – often 4-8 weeks – is particularly problematic for postpartum women where the impact of depression on maternal morbidity and child development is so critical.

The field has been clamoring for agents that work more quickly. One possibility in that area is ketamine, which is being studied as a rapid treatment in major depression. The National Institutes of Health also has an initiative underway called RAPID (Rapidly Acting Treatments for Treatment-Resistant Depression), aimed at identifying and testing pharmacologic and nonpharmacologic treatments that produce a response within days rather than weeks.

Recently, considerable interest has focused on SAGE-547, manufactured by Sage Therapeutics, which is a different type of antidepressant. The so-called neurosteriod is an allosteric modulator of the GABA_A (gamma-aminobutyric acid type A) receptors. The product was granted fast-track status by the Food and Drug Administration to speed its development as a possible treatment for superrefractory status epilepticus, but it also is being studied for its potential in treating severe postpartum depression.

Approximately a year ago, there was preliminary evidence from an open-label study suggesting rapid response to SAGE-547 for women who received this medicine intravenously in a controlled hospital environment. And in July 2016, the manufacturer announced in a press release unpublished positive results from a small phase II controlled trial of SAGE-547 for the treatment of severe postpartum depression.

Specifically, this was a placebo-controlled, double-blind randomized trial for 21 women who had severe depressive symptoms with a baseline score of at least 26 on the Hamilton Rating Scale for Depression (HAM-D). For some of the women, postpartum depression was not of new onset, but rather was an extension of depression that had manifested no earlier than the third trimester of pregnancy. A total of 10 women received the drug, while 11 received placebo. Both groups received continuous intravenous infusion over a 60-hour period.

Consistent with the earlier report, participants receiving the active agent had a statistically significant reduction in HAM-D scores at 24 hours, compared with women who received the placebo. Seven out of 10 women who received the active drug achieved remission from depression at 60 hours, compared with only 1 of the 11 patients who received placebo. Even though the results derived from an extremely small sample, the signal for efficacy appears promising.

Of particular interest, there appeared to be a duration of benefit at 30 days’ follow-up. The medicine was well tolerated with no discontinuations due to adverse events, which were most commonly dizziness, sedation, or somnolence. The adverse events were about the same in both the drug and placebo groups.

Next steps

These early results have generated excitement, if not a “buzz,” in the field, given the rapid onset of antidepressant benefit and the apparent duration of the effect. But readers should be mindful that to date, the findings have not been peer reviewed and are available only through a company-issued press release. It is also noteworthy that on clinicaltrials.gov, the projected enrollment was 32, but 21 women enrolled. This may speak to the great difficulty in enrolling the sample and may ultimately reflect on the generalizability of the findings.

One significant challenge with SAGE-547 is the formulation. It’s hardly feasible for severely ill postpartum women to come to the hospital for 60 hours of treatment. The manufacturer will have to produce a reformulated compound that is able to sustain the efficacy signaled in this proof of concept study.

But even more importantly, we will need to see how the drug performs in a larger, rigorous phase IIB or phase III study to know if the signal of promise really translates into a potential viable treatment option for women with severe postpartum depression. When we have results from a randomized controlled trial with a substantially larger number of patients, then we’ll know whether the excitement is justified. It would be a significant advance for the field if this were to be the case.

The field of depression, in general, has been seeking an effective, rapid treatment for some time, and the role of neurosteriods has been spoken about for more than 2 decades. If postpartum women are in fact a subgroup who respond to this class of agents, then that would be an example of truly personalized medicine. But we won’t know that until the manufacturer does an appropriate large trial, which could take 2-4 years.

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information and resources and conducts clinical care and research in reproductive mental health. He has no financial relationship with SAGE Therapeutics, but he has been a consultant to manufacturers of psychiatric medications.

The importance of postpartum depression, both in terms of its prevalence and the need for appropriate screening and effective treatments, has become an increasingly important area of focus for clinicians, patients, and policymakers. This derives from more than a decade of data on the significant prevalence of the condition, with roughly 10% of women meeting the criteria for major or minor depression during the first 3-6 months post partum.

Over the last 5 years, interest has centered around establishing mechanisms for appropriate perinatal depression screening, most notably the January 2016 recommendation from the U.S. Preventive Services Task Force that all adults should be screened for depression, including the at-risk populations of pregnant and postpartum women. In 2015, the American College of Obstetricians and Gynecologists endorsed screening women for depression and anxiety symptoms at least once during the perinatal period using a validated tool. Unfortunately, we still lack data to support whether screening is effective in getting patients referred for treatment and if it leads to women accessing therapies that will actually get them well.

As we wait for that data and consider ways to best implement enhanced screening, it’s important to take stock of the available treatments for postpartum depression.

Seeking a rapid treatment

The current literature supports efficacy for nonpharmacologic therapies, such as interpersonal psychotherapy and cognitive-behavioral therapy, as well as several antidepressants. The efficacy of antidepressants – such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors – has been demonstrated for postpartum depression, but these agents carry the typical limitations and concerns in terms of side effects and the amount of time required to ascertain if there is benefit. While these are the same challenges seen in treating depression in general, the time to response – often 4-8 weeks – is particularly problematic for postpartum women where the impact of depression on maternal morbidity and child development is so critical.

The field has been clamoring for agents that work more quickly. One possibility in that area is ketamine, which is being studied as a rapid treatment in major depression. The National Institutes of Health also has an initiative underway called RAPID (Rapidly Acting Treatments for Treatment-Resistant Depression), aimed at identifying and testing pharmacologic and nonpharmacologic treatments that produce a response within days rather than weeks.

Recently, considerable interest has focused on SAGE-547, manufactured by Sage Therapeutics, which is a different type of antidepressant. The so-called neurosteriod is an allosteric modulator of the GABA_A (gamma-aminobutyric acid type A) receptors. The product was granted fast-track status by the Food and Drug Administration to speed its development as a possible treatment for superrefractory status epilepticus, but it also is being studied for its potential in treating severe postpartum depression.

Approximately a year ago, there was preliminary evidence from an open-label study suggesting rapid response to SAGE-547 for women who received this medicine intravenously in a controlled hospital environment. And in July 2016, the manufacturer announced in a press release unpublished positive results from a small phase II controlled trial of SAGE-547 for the treatment of severe postpartum depression.

Specifically, this was a placebo-controlled, double-blind randomized trial for 21 women who had severe depressive symptoms with a baseline score of at least 26 on the Hamilton Rating Scale for Depression (HAM-D). For some of the women, postpartum depression was not of new onset, but rather was an extension of depression that had manifested no earlier than the third trimester of pregnancy. A total of 10 women received the drug, while 11 received placebo. Both groups received continuous intravenous infusion over a 60-hour period.

Consistent with the earlier report, participants receiving the active agent had a statistically significant reduction in HAM-D scores at 24 hours, compared with women who received the placebo. Seven out of 10 women who received the active drug achieved remission from depression at 60 hours, compared with only 1 of the 11 patients who received placebo. Even though the results derived from an extremely small sample, the signal for efficacy appears promising.

Of particular interest, there appeared to be a duration of benefit at 30 days’ follow-up. The medicine was well tolerated with no discontinuations due to adverse events, which were most commonly dizziness, sedation, or somnolence. The adverse events were about the same in both the drug and placebo groups.

Next steps

These early results have generated excitement, if not a “buzz,” in the field, given the rapid onset of antidepressant benefit and the apparent duration of the effect. But readers should be mindful that to date, the findings have not been peer reviewed and are available only through a company-issued press release. It is also noteworthy that on clinicaltrials.gov, the projected enrollment was 32, but 21 women enrolled. This may speak to the great difficulty in enrolling the sample and may ultimately reflect on the generalizability of the findings.

One significant challenge with SAGE-547 is the formulation. It’s hardly feasible for severely ill postpartum women to come to the hospital for 60 hours of treatment. The manufacturer will have to produce a reformulated compound that is able to sustain the efficacy signaled in this proof of concept study.

But even more importantly, we will need to see how the drug performs in a larger, rigorous phase IIB or phase III study to know if the signal of promise really translates into a potential viable treatment option for women with severe postpartum depression. When we have results from a randomized controlled trial with a substantially larger number of patients, then we’ll know whether the excitement is justified. It would be a significant advance for the field if this were to be the case.

The field of depression, in general, has been seeking an effective, rapid treatment for some time, and the role of neurosteriods has been spoken about for more than 2 decades. If postpartum women are in fact a subgroup who respond to this class of agents, then that would be an example of truly personalized medicine. But we won’t know that until the manufacturer does an appropriate large trial, which could take 2-4 years.

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information and resources and conducts clinical care and research in reproductive mental health. He has no financial relationship with SAGE Therapeutics, but he has been a consultant to manufacturers of psychiatric medications.