Postpartum Depression Pill Zuralonone Shows Promise in Women With Severe Symptoms

Women with severe postpartum depression may experience improvements within a few days of taking the oral medication zuranolone (a neuroactive steroid), suggests a report published today in The American Journal of Psychiatry. These improvements continued even after the women stopped the 14-day medication regimen.

The study was funded by Sage Therapeutics and Biogen, which are involved in the development of the medication.

Postpartum depression affects an estimated 17% of women worldwide, according to Kristina M. Deligiannidis, M.D., of Zucker Hillside Hospital and colleagues. This disorder can lead to multiple challenges for mothers and infants, including poor maternal-infant bonding, increased risk of infant behavioral problems, and suicidal ideation in mothers. “Current treatment options often include standard-of-care antidepressants; however, achieving response to treatment can take up to 12 weeks,” Deligiannidis and colleagues wrote. “Given the deleterious effects of untreated [postpartum depression], identification of rapid and effective treatment options is critical.”

Zuranolone is a rapid-acting medication in development for the treatment of postpartum depression; it has been granted priority review by the Food and Drug Administration. A previous trial found zuranolone at the 30 mg/day dose to be effective and generally well tolerated.

For the current phase 3 trial, 196 women aged 18 to 45 with severe postpartum depression were randomized to zuranolone (50 mg/day) or placebo pills for 14 days. To be included in the trial, the participants had to have a baseline score of at least 26 on the 17-item Hamilton Depression Rating Scale (HAM-D), experienced a major depressive episode with onset during the third trimester of pregnancy or up to four weeks after giving birth, and were within the postpartum period of 12 months or less. The researchers evaluated the participants using multiple assessments over the course of the 45-day trial, including the HAM-D total score, Clinical Global Impressions severity (CGI-S) score, Hamilton Anxiety Rating Scale (HAM-A), 9-item Patient Health Questionnaire (PHQ-9), and more.

“Patients receiving zuranolone demonstrated robust, clinically meaningful, and rapid improvements in depressive symptoms, as assessed by change from baseline HAM-D score, which were evident as early as day 3 and were maintained through day 45,” Deligiannidis and colleagues wrote. The women also showed improvements in anxiety and symptom severity from baseline to day 15.

The most common side effects reported by patients were somnolence, dizziness, sedation, and headache.

“Given the prevalence and substantial adverse maternal and infant outcomes associated with [postpartum depression], its appropriate management is essential,” Deligiannidis and colleagues wrote. “Therefore, if approved, zuranolone would be the first short-course, rapid-acting, oral treatment for patients with PPD.”

For related information, see the Psychiatric News article “Perinatal Treatment Requires Careful Risks, Benefit Consideration.”

(Image: iStock/Fly View Productions)

---

Nominations Open for APA Components and Board of Trustees

APA’s success hinges on the expertise, knowledge, and input of its members. Learn more about APA leadership opportunities and nominate yourself or a colleague by Tuesday, August 15, for component service and Friday, September 1, for the Board of Trustees.

LEARN MORE

Five-Day TMS Treatment Rapidly Reduces Depression Symptoms

A condensed five-day transcranial magnetic stimulation (TMS) protocol appears to reduce symptoms of treatment-resistant depression safely and effectively, according to a report published today in AJP in Advance. Compared with patients receiving a sham stimulation, those who received Stanford neuromodulation therapy (SNT) showed significantly greater improvements in depressive symptoms within one day of finishing the five-day treatment; these effects were sustained for four weeks. Current TMS protocols typically require six weeks of treatment.

“Open-label trials of our SNT protocol have shown a remission rate of ~90%, even in treatment-resistant individuals, which is almost double the remission rate of ECT [electroconvulsive therapy] for treatment-resistant depression (~48%), the current gold-standard treatment,” wrote Eleanor J. Cole, Ph.D., of Stanford University and colleagues. “However, the efficacy of SNT has not been investigated in a randomized sham-controlled trial.”

Cole and colleagues recruited adults aged 22 to 80 who had treatment-resistant depression and were experiencing a moderate to severe depressive episode (scores ≥20 on both the Hamilton Depression Rating Scale [HAM-D] and the Montgomery-Åsberg Depression Rating Scale [MADRS]) for the trial. (Patients who had any previous exposure to TMS were excluded from the trial.) A total of 29 participants were randomly assigned to either an active or sham SNT protocol, which involved 10 stimulation sessions per day for five consecutive days. Stimulation sessions took place hourly, beginning with 10 minutes of magnetic stimulation (or noise mimicking stimulation for the sham stimulation group) followed by a 50-minute rest. Prior to starting treatment, all participants received MRI scans to identify the optimal target location for stimulation.

The researchers evaluated the participants’ symptom changes using the HAM-D and MADRS before and after the five-day stimulation period, as well as one, two, three, and four weeks later.

After five days of treatment, MADRS scores dropped from baseline by 62.0% among participants in the SNT group compared with 14.3% in the sham stimulation group. The effects were sustained at four weeks, with scores reduced 52.5% in the SNT group compared with 11.1% in the sham group. Additionally, 11 of the 14 participants in the SNT group achieved remission (MADRS score of 10 or less) in at least one assessment during the four-week follow-up, compared with 2 of the 15 participants in the sham group, the authors noted. Similar results showing that SNT was superior to sham stimulation were seen when looking at HAM-D scores.

No severe side effects were observed during the trial, and headaches appeared to be the only side effect that was more prevalent in the SNT group than the sham stimulation group.

“The short duration and high antidepressant efficacy of SNT presents an opportunity to treat patients in the emergency or inpatient settings, where a compressed time course is necessary,” Cole and colleagues concluded.

To read more on the Stanford neuromodulation protocol, see the Psychiatric News article “New TMS Protocol Turns Six Weeks of Treatment Into One.”

(Image: iStock/Henrik5000)

---

Don't miss out! To learn about newly posted articles in Psychiatric News, please sign up here.

Follow Psychiatric News on Twitter!

Patients With Treatment-Resistant OCD Found to Improve After Deep Brain Stimulation

Deep brain stimulation (DBS) may lead to improvements in patients with treatment-resistant obsessive-compulsive disorder (OCD), reports a study published today in AJP in Advance.

In the open study of 70 OCD patients who received DBS of a region called the ventral anterior limb of the internal capsule (vALIC), Damiaan Denys, M.D., Ph.D., of the University of Amsterdam and colleagues found that during the first year following the procedure, patients on average experienced significant improvements in symptoms of OCD, anxiety, and depression. The findings support the results of a DBS trial involving 16 OCD patients reported in 2010, the authors noted.

Although pharmacotherapy and cognitive-behavioral therapy (CBT) have been shown to benefit many patients with OCD, 10% of patients experience treatment-resistant OCD, Damiaan Denys, M.D., Ph.D., of the University of Amsterdam and colleagues wrote. DBS uses electrical pulses from implanted electrodes to regulate activity in specific regions of the brain. 

To be included in the trial, patients had to have a primary diagnosis of OCD and a five-year history of OCD. The patients also had a history of “no or insufficient response” to multiple treatments, including two selective serotonin reuptake inhibitors (SSRIs) at maximum dosages, at least one attempt at augmenting SSRIs with an atypical antipsychotic, and CBT, the authors wrote. DBS electrodes were implanted bilaterally into the vALIC of all patients included in the trial, and two weeks after surgery, DBS was activated.

The researchers assessed the patients’ responses to DBS every two weeks to optimize the treatment, such as adjusting the voltage of the electrodes or contact point configurations. They used the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) to assess OCD symptoms before DBS surgery, two weeks after the DBS implantation, monthly up to six months after surgery, and at a follow-up at 12 months. The researchers also assessed anxiety symptoms in the patients using the Hamilton Anxiety Rating Scale (HAM-A) and depression symptoms using the Hamilton Depression Rating Scale (HAM-D). The patients were asked about side effects at each visit.

The authors reported that from baseline to follow-up at 12-months, the patients’ mean Y-BOCS score decreased by 40%. Over this same period, the mean HAM-A score decreased by 55%, and the mean HAM-D scores decreased by 54%. 

The researchers categorized the patients as responders if they experienced a ≥35% decrease in scores on the Y-BOCS; partial responders if the Y-BOCS score decreased between 25% and 34%; and nonresponders if the Y-BOCS score decreased less than 25%. At 12 months, 52% of the patients met the criteria for responders; 17%, partial responders; and 31%, nonresponders. The most common side effects reported by patients included hypomania, agitation, impulsivity, and sleeping disorders, but most of these symptoms resolved within weeks, the authors wrote.

“Our study confirms our previous finding that DBS of the vALIC is an effective and tolerable treatment for refractory OCD,” Denys and colleagues concluded.  “Investigating predictors of success could improve DBS selection …,” they added. 

For related information, see the chapter “Brain Stimulation Treatments for Mood Disorders” in Gabbard’s Treatments of Psychiatric Disorders.

(Image: SvedOliver/Shutterstock)

Follow Psychiatric News on Twitter!

And check out the new Psychiatric News Brief on Alexa-enabled devices.

Study Highlights Long-Term Benefits of Deep Brain Stimulation for Refractory Depression

Deep brain stimulation (DBS) of a region called the subcallosal cingulate appears to be safe and effective at reducing symptoms of depression in patients with treatment-resistant depression over time, according to a small study in AJP in Advance.

Previous studies suggest that up to one-third of all patients with major depression have treatment-resistant depression (that is, they fail to experience symptom improvements during two or more antidepressant trials). “Given that patients with treatment-resistant depression are highly susceptible to recurrent depressive episodes, the ability of DBS or any treatment to support long-term maintenance of antidepressant response and prevention of relapse in severe and intractable depression would be an important treatment advance,” wrote Andrea Crowell, M.D., of Emory University School of Medicine and colleagues.

Crowell and colleagues analyzed long-term follow-up data from an open-label trial of 28 patients aged 27 to 65 who underwent subcallosal cingulate DBS surgery. (The subcallosal cingulate is a small brain region rich in serotonin transporters that is believed to be a key regulator of mood.) Of this group, 20 had been diagnosed with major depressive disorder, and seven had been diagnosed with bipolar II disorder; one patient in the major depression subgroup was later reclassified as having bipolar II disorder. To be included in the trial, patients were required to have a score ≥20 on the 17-item Hamilton Depression Rating Scale (HAM-D) and a score <50 on the Global Assessment of Functioning Scale (GAF). Patients with a history of psychosis, personality disorders, or imminent risk for suicide were not included in the trial.

A psychiatrist evaluated study participants weekly for 32 weeks, beginning about four weeks prior to DBS surgery. After this point, a psychiatrist assessed study participants every six months for two to eight years. All 28 participants who underwent DBS surgery completed at least one year of follow-up. Fourteen participants completed at least eight years of study participation.

After two years, the average HAM-D scores of the patients dropped by over 50% (from about 23 to 10) and remained steady over the remaining years. Likewise, the average GAF score rose from about 34 (indicating major impairment in several areas of functioning) to 70 (indicating mild symptoms but with overall good functioning) after two years and remained steady. Crowell and colleagues noted that 20 participants (71%) “demonstrated consistent improvement of ≥25% from baseline depression severity ratings throughout the study. … Among the eight patients with bipolar disorder, five showed a favorable response pattern, and three exhibited limited antidepressant response over time.”

While no adverse events were attributable to acute or chronic stimulation, 19 serious adverse events were related to surgery, or 0.7 events per participant—a medical complication rate “comparable to that seen with DBS for other indications,” they continued.

Crowell and colleagues concluded, “Identifying factors associated with long-term response is an important next step in [subcallosal cingulate] DBS research. … Beyond this, more qualitative studies of DBS patient characteristics and the quality of patients’ experience of depression before and after DBS are needed in order to optimize patient selection for DBS in the [subcallosal cingulate] and other brain targets.”

For more on deep brain stimulation, see the Journal of Neuropsychiatry and Clinical Neurosciences article “Deep Brain Stimulation and Cognitive Outcomes Among Patients With Parkinson’s Disease: A Historical Cohort Study.”

(Image: iStock/Hank Grebe)

Follow Psychiatric News on Twitter!

And check out the new Psychiatric News Brief on Alexa-enabled devices.

New Drug Shows Promising Results in Treatment of Postpartum Depression

In a small sample of women with severe postpartum depression, infusion of the compound brexanolone resulted in rapid, significant reduction in symptoms, according to a study published online this week in The Lancet.

The findings “demonstrate a substantial treatment effect of brexanolone” in a group of patients “for which there are no currently approved pharmacological therapies,” Steven Kanes, M.D., of Sage Therapeutics and colleagues wrote. Sage Therapeutics funded this research, and assisted in the study design, data collection, data analysis, data interpretation and writing of the report.

For the double-blind, randomized, controlled trial, the researchers assigned 21 women with severe postpartum depression (Hamilton Depression Rating Scale [HAM-D] score of at least 26) to a 60-hour, continuous intravenous dose of brexanolone or placebo. To make the sample as representative as possible, the researchers recruited patients from urban, suburban, and rural settings in the United States to receive treatment at four research sites.

By 60 hours, seven (70%) women had achieved remission (HAM-D total score of ≤7) compared to one (9%) in the placebo group. Furthermore, mean HAM-D scores for the women who received brexanolone remained significantly lower for a follow-up period of 30 days compared with the placebo group.

Brexanolone is an allosteric modulator of both synaptic and extra-synaptic GABA-A receptors. The results support the rationale for targeting GABA-A receptors in the development of therapies for the estimated 10% to 20% of birth mothers who suffer from postpartum depression, wrote the researchers.

“Our findings provide the first placebo-controlled clinical support for the role of extrasynaptic GABA-A receptors in the modulation of mood and affective states in any clinical population,” wrote the authors. A treatment with rapid onset of action is considered important in severe postpartum depression because of the adverse impact of the depression on the mother, infant, and family.

Brexanolone, a formulation of the neuroactive steroid allopregnanolone, was found to be generally well tolerated among the study participants. There were no deaths, serious adverse events, or discontinuations. The most commonly reported adverse events in the brexanolone group were dizziness (two brexanolone-treated subjects; three placebo-treated subjects) and somnolence (two brexanolone-treated subjects; no placebo-treated subjects).

The author of an accompanying commentary published in The Lancet commented on the study’s “potentially important implication for our understanding of the pathophysiology of postpartum mood disorders,” but he also raised questions such as “Is this a treatment for postpartum episodes specifically or could it be used generally in depression?”

Brexanolone is currently being evaluated in a phase 3 clinical program under way at various other sites across the country.

For related information, see the Psychiatric News article “Synthetic Oxytocin May Increase Risk of Postpartum Depression, Anxiety” and the Psychiatric Services article “Collaborative Care for Perinatal Depression Among Socioeconomically Disadvantaged Women: Adverse Neonatal Birth Events and Treatment Response.”

(Image: iStock/SolStock)

Patient Expectations of Antidepressants May Mediate Placebo Effects

How well a patient responds to medication may be partially mediated by his or her expectation about whether and how much he or she will improve, according to a study published in AJP in Advance. The findings, say the study authors, suggest that developing interventions capable of modifying patient expectancy may not only help to reduce placebo response in clinical trials, but also improve treatment outcomes in clinical practice.

To examine the relationship between patient expectancy and placebo effects, Bret Rutherford, M.D., of Columbia University College of Physicians and Surgeons and colleagues enrolled 54 patients with major depressive disorder (aged 24 to 65) in an eight-week citalopram trial. Before being randomly assigned to the placebo-controlled or open group, participants were asked questions to assess how much they believed depression symptoms would improve by the end of the trial. 

In an effort to manipulate patient expectancy, the participants were informed of their group assignment before starting medication but instructed to refrain from revealing this assignment to anyone in the study group. Expectancy of treatment outcome was then measured once again before patients began taking citalopram (20 mg/day) or pill placebo for eight weeks.

Participants were assessed using the Hamilton Rating Scale for Depression (HAM-D) throughout the trial. Treatment response was defined as decrease of 50% or more from the baseline HAM-D score; patients who had a HAM-D score of 7 or less at week 8 were considered to be in remission.

Although mean prerandomization expectancy scores did not differ significantly between the open group (mean=11.2 [SD=1.1]) and placebo-controlled group (10.8 [SD=1.9]), postrandomization expectancy scores were significantly higher in the open group (mean=12.1 [SD=2.1]) compared with the placebo-controlled group (mean=11.0 [SD=2.0]), when adjusted for baseline HAM-D scores. This, according to the authors, suggests “the experimental design succeeded in manipulating expectancies.”

The authors found that response rates were 25% for placebo-controlled placebo, 45% for placebo-controlled citalopram, and 53.8% for open citalopram. Remission rates were 0% for placebo-controlled placebo, 20% for placebo-controlled citalopram, and 34.6% for open citalopram. After adjusting for covariates, the average participant treated with citalopram in the open group experienced 6.2 points of additional improvement in HAM-D score by week 8 compared with the average participant treated with citalopram in the placebo-controlled group.

“Strikingly, despite receiving the identical antidepressant medication, being treated by the same study clinicians, and visiting the same treatment site, depressed subjects who knew they were receiving citalopram improved on average 6 HAM-D points more than those receiving citalopram who were aware they had a chance of receiving placebo,” the authors wrote. 

“To the extent that expectancy mediates placebo responses in antidepressant studies, limiting patient expectancy may be a useful strategy to reduce placebo response in phase III trials. ... Conversely, the optimal strategy in clinical practice may be to combine active medication with a presentation that enhances patient expectancy, leading to greater medication response,” they concluded.

For related information, see the Psychiatric News PsychoPharm article “Unraveling the Mystery Behindthe Nocebo Effect: Placebo’s Evil Twin.” 

Reanalysis of JAACAP Study on Paroxetine Sparks Controversy

A reanalysis of data from a 2001 study that concluded paroxetine to be generally well tolerated and effective for treating major depression in adolescents has raised questions over the safety and effectiveness of the drug in this patient population, according to a paper published Wednesday in the BMJ.

The original study, published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP), describes an eight week, double-blind randomized control trial that compared the safety and effectiveness of paroxetine (20 mg to 40 mg) and imipramine (gradual upward titration to 200 mg to 300 mg) with placebo in 275 adolescents aged 12 to 18 with major depression.

In the paper, Martin Keller, M.D., of Brown University and colleagues reported that after eight weeks, those in the paroxetine group demonstrated significantly greater improvement compared with placebo on the Hamilton Rating Scale for Depression (HAM-D) total score, HAM-D depressed mood item, depression item of the Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version depressed mood item, and Clinical Global Impression score.

For the BMJ study, Jon Jureidini, M.B.B.S., of the University of Adelaide, and colleagues reanalyzed the data from the 2001 study, including a review of primary data from the original trial supplied by GlaxoSmithKline. (The reanalysis was part of an initiative called RIAT [Restoring Invisible and Abandoned Trials], which calls on “funders and investigators of abandoned [unpublished] or misreported trials to publish undisclosed outcomes or correct misleading publications,” according to the study authors.)

Based on the reanalysis, the authors reported, “The efficacy of paroxetine and imipramine was not significantly different from placebo for any prespecified primary or secondary outcome.” The authors also described “clinically significant increases in harms, including suicidal ideation and behavior and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group.”

“That one can do better reanalyzing adverse-event data using refinements in approach that have accrued in the 15 years since a study’s publication is unsurprising and not a valid critique of our study as performed and presented,” Keller and his colleagues noted in a letter in response to the BMJ article. The authors concluded, “In summary, to describe our trial as 'misreported' is pejorative and wrong, both from consideration of best research practices at the time, and in terms of a retrospective from the standpoint of current best practices.

“This new reanalysis has sparked a healthy discussion over the value of open access to clinical trial data, the importance of following protocol specified analyses, and the risks of confirmation bias, which is a tendency to search for information that confirms the investigator's preconceptions,” Mark Olfson, M.D., M.P.H., a professor of psychiatry at Columbia University Medical Center who was not involved with either study, told Psychiatric News. “However, the new reanalyses does not alter the totality of clinical trial evidence that continues to support the safety and efficacy of SSRIs for adolescent depression.”

Daniel Pine, M.D., chief of NIMH's Section on Development and Affective Neuroscience, added, “We have known for some time that antidepressant medications have both significant benefits for some children as well as significant risks for other children. This new analysis really does nothing to change this knowledge, and provides no new insights into what we have known about these medications for the past few years.”

“AACAP supports transparency in clinical trial reporting and welcomes the RIAT initiative, which enables publicly available primary data to be reanalyzed and published as new, potentially revised reports,” Paramjit T. Joshi, M.D., President of the American Academy of Child and Adolescent Psychiatry, told Psychiatric News. “JAACAP is a forum for scientific reporting and scholarly discussion. The scientific process builds on itself over time through a cycle of new research, analysis, and ongoing dialog. This process stimulates debate and moves the field forward toward a better understanding of critical issues.”

(Image: Shutterstock.com/Paul Matthew Photography)