medication

Concerns That May Limit the Utility of Zuranolone

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On August 4, 2023, the US Food and Drug Administration (FDA) granted marketing authorization for zuranolone (Zurzuvae) for postpartum depression. Prior to this recent approval, patients with postpartum depression had only 1 FDA-approved option: brexanolone, an intravenous medication requiring infusion across multiple days, with a cost of $34 000 for a single course of treatment.1 Zuranolone thus fills an important niche as an oral option. However, there are several features of the design and conduct of the drug’s pivotal trials that undermine confidence in this agent, which should give physicians pause in prescribing it. Here, we explore the evidence base of the FDA approval of zuranolone.

Postpartum depression is a subset of major depressive disorder that meets the diagnostic criteria of major depressive disorder but occurs with onset during pregnancy or within 4 weeks of delivery. Current guidelines advise the mainstays of major depressive disorder therapy for individuals with postpartum depression. For instance, first-line treatment is psychotherapy. The American College of Obstetricians and Gynecologists (ACOG) recommends a selective serotonin reuptake inhibitor (SSRI) as first-line pharmacotherapy for women with postpartum depression.2 For women with no previous exposure to SSRI or serotonin and norepinephrine reuptake inhibitor treatment, sertraline and escitalopram are considered reasonable first-line agents.

Zuranolone is a neuroactive steroid that is a positive modulator of the GABAAR (γ-aminobutyric acid “A” receptor). The drug works by increasing the inhibitory tone of the central nervous system. Zuranolone exerts its effect via the same receptor as benzodiazepines and barbiturates. Although it is similar to brexanolone in action, zuranolone is an oral formulation.

The drug’s mechanism of action underpins its adverse effect profile (somnolence, dizziness, sedation) and may explain the black box warning stating that patients should not drive a motor vehicle or engage in potentially hazardous behavior within 12 hours of taking this medication. The similarity to other GABA-ergic compounds may also explain why the drug demonstrated a dose-dependent misuse potential comparable with that of alprazolam (Xanax)3 and why human participants have been shown to exhibit symptoms of withdrawal after cessation of zuranolone in clinical trials. This is specifically stated in the FDA’s package leaflet, which states that “Adverse reactions reported upon discontinuation of zuranolone in healthy subjects who received 50 mg of zuranolone for 5 to 7 days (on the 7th day subjects received 50 mg or 100 mg) included: insomnia, palpitations, decreased appetite, nightmare, nausea, hyperhidrosis, and paranoia. These adverse reactions indicate a potential for physical dependence with zuranolone.”3

There are significant safety concerns regarding zuranolone’s use in both pregnant and breastfeeding individuals. Trial participants were required to abstain from breastfeeding from the first dose administered through 7 days following the last dose of the 14-day treatment. They were also required to be receiving effective contraception. These precautions seem appropriate, given that preclinical animal models demonstrated neurotoxic effects on the developing brain. According to the FDA package insert, “Oral administration of zuranolone to rats during pregnancy and lactation resulted in developmental toxicity in the offspring, including, perinatal mortality, at maternal exposures similar to that in humans at the [maximum recommended human dose].”3

There are 2 trials that support the use of this drug. The first study, ROBIN, examined the effect of 30-mg capsules of zuranolone, once per day (evening with meal), vs placebo in patients with severe postpartum depression.4 Severity was determined with inclusion criteria that required a baseline Hamilton Depression Rating Scale (HAMD)-17 score of 26 or higher. Thus, the trial is restricted to individuals with severe postpartum depression. The mean baseline score was just above 28 in both groups. Although the drug achieved statistical significance, there was a marked placebo effect. The primary end point (change from baseline in HAMD-17 score at day 15) improved in the placebo group by 13.6 points, three-quarters of the 17.8-point improvement seen with zuranolone.

The second registration study, SKYLARK, had an almost identical trial design, testing a higher dose of zuranolone (50 mg). Participants similarly had severe depressive episodes, with mean baseline HAMD-17 scores higher than 28. A similar result was shown, with 74% of the improvement at day 15 achieved with placebo vs zuranolone.5

There are at least 3 concerns with the trials used to support this approval. First, the use of placebo control is inappropriate. Multiple guidelines endorse treatment of severe postpartum depression with SSRIs and psychotherapy. Yet, in ROBIN and SKYLARK, just 20% and 15% of women, respectively, were using antidepressants at baseline. Patients were required to delay the start or alteration of any psychotropic treatment regimens until after day 15 in ROBIN and until after day 45 in SKYLARK. Each participant should have been prescribed an SSRI and psychotherapy based on the current standard of care. The median length of time to response expected with these interventions does not justify withholding treatment from the control group. We are unable to assess whether the improvement in the treatment group would have been observed vs standard of care.

Second, these trials assessed drug efficacy in individuals with severe postpartum depression. Meanwhile, the FDA’s drug approval does not qualify its indication for individuals with postpartum depression of this severity, instead granting a blanket approval for milder forms of postpartum depression—an indication that lacks evidence.

Third, the placebo effect and/or regression to the mean is a large effect. In fact, roughly 75% of the effect of the product occurred with placebo in both trials. Patients with postpartum depression in this study tended to get better, regardless of treatment. The authors suggest this could be due to the high number of study visits, although another potential contribution is regression to the mean. To enter either study, patients needed a HAMD-17 score of 26 or greater. Any participant needed to achieve this both on initial screening and day 0. Thus, a person whose score improved between these points, eg, from day 28 to 24, would be excluded from the study. Data are not provided on the reason for screening failures. We do know that 44% of patients in ROBIN who were enrolled and screened were excluded prior to randomization and 60% were excluded in SKYLARK. This raises the possibility that a substantial number of eligible individuals were improving without any intervention prior to day 0.

Zuranolone failed to gain approval for major depressive disorder. Two trials failed to achieve the primary end point and the third trial achieved the primary end point statistically, but the magnitude of improvement vs placebo was an underwhelming 1.7-point reduction in HAMD-17 score at day 15.6 Sage representatives have stated that they planned to price the 14-day course less than $10 000 only if it was also approved for major depressive disorder. Analysts estimate the price will be $10 000 to $30 000 for the 2-week course.1 Whether the cost of this medication will impact accessibility remains to be seen.

The FDA saw fit to approve zuranolone based on modest efficacy data in trials that compared it with substandard medical care. This medication has significant limitations, including misuse potential, impaired psychomotor functioning, lack of compatibility with breastfeeding, and anticipated exorbitant cost. We suggest that the FDA require control groups that reflect standards of care to better inform and equip physicians with medications that might improve the health of patients, and we caution the current use of zuranolone.

Remission From ‘Treatment-Resistant’ Schizophrenia Possible With Underutilized Drug

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Bethany Yeiser is now free of severe schizophrenia symptoms after starting clozapine in 2008, allowing her to graduate college and start the CURESZ Foundation.

Remission From ‘Treatment-Resistant’ Schizophrenia Possible With Underutilized Drug: Psychiatrist
Bethany Yeiser reached remission from schizophrenia on the antipsychotic drug, clozapine, allowing her to finish her degree and start the CURESZ Foundation. (Courtesy of Bethany Yeiser)

Before the onset of severe, treatment-resistant schizophrenia, Bethany Yeiser was a star honors student. She won a half-tuition scholarship to study biochemistry and molecular biology at the University of Southern California in 1999 and managed to publish three papers as an undergraduate, with one appearing in the prestigious journal Proceedings of the National Academy of Sciences of the United States of America (PNAS).

Amid the initial success, a storm was brewing in Ms. Yeiser’s mind, threatening to unravel every facet of her life. After her grades slowly declined her first three years of college, she took a two-and-a-half-month trip to Africa. The journey became an obsession, making the isolated undergrad forget her studies.

But soon, her preoccupation with Africa shifted to grander ideas. Suddenly Ms. Yeiser believed she would become a billionaire, run a nonprofit that would replace the United Nations, win a Nobel Peace Prize, and live the life of a prophet, the “next Mother Teresa,” she said.

“I couldn’t study any more. Work—not possible—no way. You know, if you’re going to work, you need a healthy body and also a healthy mind. And my mind was just shattered,” Ms. Yeiser told The Epoch Times.

She dropped out of college and was homeless for four years, sustained by her “delusions,” she said. When Ms. Yeiser finally sought medical help in 2007, the exchange with the first psychiatrist did not go as expected.

“When I was diagnosed [with schizophrenia], within about 36 hours of knowing me, the doctor said I was just permanently and totally disabled,” she said.

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But Ms. Yeiser persisted, even as she began to believe the doctor’s forecast.

“I spent 12 months trying five different medications, up to two at a time, and I started to think he’s right, you know, all I can do is sit at home and lay down on the couch. I had terrible side effects. I was sleeping 16 hours a night—very restless and still very symptomatic,” she said.

That all changed in 2008 when she met Henry A. Nasrallah, MD, a psychiatrist who believed in Ms. Yeiser’s potential.

Dr. Nasrallah studied her background. He saw a talented and high performing young woman with a university background in biochemistry who had more publications than some graduate students.

“Dr. Nasrallah was not settled. He wasn’t done with me until I would reach recovery. He wanted me to go back to school and hopefully score high grades again, graduate, and work,” Ms. Yeiser said.

An exterior view of the University of California Irvine (UC Irvine) Medical Center is seen in Orange, Calif., on Oct. 15, 2021. (App Gomes/AFP via Getty Images)
An exterior view of the University of California Irvine (UC Irvine) Medical Center is seen in Orange, Calif., on Oct. 15, 2021. (App Gomes/AFP via Getty Images)

Recovery with Clozapine

He recommended the drug clozapine to Ms. Yeiser, an atypical antipsychotic medication used for treatment-resistant schizophrenia, according to the National Library of Medicine (NLM).

The NLM defines “treatment-resistant schizophrenia” as “persistent or moderate delusions or hallucinations after failing two trials of antipsychotic medicines.”

The medication changed Ms. Yeiser’s life. She went back to college and earned a molecular biology degree from the University of Cincinnati before publishing her memoir, “Mind Estranged: My Journey from Schizophrenia and Homelessness to Recovery” in 2014.

Ms. Yeiser and Dr. Nasrallah founded the CURESZ Foundation in 2018 to help schizophrenia patients receive the treatment they need to live healthy and fulfilling lives.

“So many patients are just told by their doctor or nurse practitioner on day one that this is a hopeless condition, that people do not get better,” she said.

Ms. Yeiser hoped to give patients the tools and information to not just speak with their doctors about their disorder but to also have the strength to find a new physician if the current one does not believe remission is possible.

With clozapine, Ms. Yeiser has few if any “breakthrough symptoms,” which are recurring schizophrenia symptoms that can persist after treatment but are otherwise not severe enough to affect a patient’s day-to-day functioning.

However, there are risks with the drug. According to a study from the NLM, the fatality rate for clozapine overdose is 12 percent, and the drug causes seizures, myocarditis, constipation, excessive salivation, pulmonary embolism, and metabolic syndrome in some of its users.

Physicians recommend patients receive regular blood tests to monitor for any side effects.

But Dr. Nasrallah said that schizophrenia, like cancer, is a life-or-death medical crisis. Chemotherapy comes with greater dangers than clozapine, but if more cancer patients rejected chemo-treatments purely out of fear of the side effects, they would likely die, he said.

Not only are death rates higher for schizophrenia patients compared to all other psychiatric disorders, but Dr. Nasrallah notes that 80 to 90 percent of untreated patients do not understand or realize that they are sick, preventing them from living fulfilling lives.

Some NLM studies have noted a gradual rise in schizophrenia between 1990 and 2017 but Dr. Nasrallah disagrees.

Unlike cases of autism, which have largely risen due to public awareness and understanding of the disorder, particularly with the discovery Autism Spectrum Disorder, the prevalence for schizophrenia has remained at one percent of the population globally, Dr. Nasrallah told The Epoch Times.

He said northern regions of the globe with less sunlight see roughly 1.5 percent of schizophrenia cases across the general population while sunny regions near the equator see 0.5 percent.

Roughly 80 percent of schizophrenia cases are genetic by nature, with the remaining 20 percent due to environmental factors, Dr. Nasrallah said.

The most common environmental factors that lead to schizophrenia are “disruption of fetal brain development during pregnancy (infections, diabetes, severe vitamin D deficiency, substance abuse, asphyxia during delivery, etc.) as well as severe physical, sexual, or emotional abuse or neglect in the first five years of life when the brain is still developing and the trauma disrupts the brain development via epigenetic changes,” he added.

Other Forms of Treatment

While many were taught for years that remission was next to impossible with treatment-resistant schizophrenia, Dr. Nasrallah said that 40 to 50 percent of patients recover on clozapine.

The remaining 50 percent who do not recover while taking clozapine typically respond well to electroconvulsive therapy (ECT), also known as shock treatment.

“Many studies have shown that ECT regrows brain tissue which is lost during psychotic episodes, because psychosis actually destroys brain tissue, kills millions and millions of brain cells. And ECT can actually regrow many parts of the brain so it’s an excellent treatment. No, it doesn’t fry your brain, it actually rejuvenates and replenishes the brain,” Dr. Nasrallah said.

He explained that ECT is also effective with severe depression and patients with bipolar disorder.

“It’s actually one of the best treatments in medicine—very safe. We give it to people in their 80s and 90s with very good results,” Dr. Nasrallah added.

For some patients, taking medications daily is difficult. An initial resistance towards the drugs is exacerbated by symptoms that could convince the patient they are improving so much they no longer “need” the medications, causing a relapse and a more treatment-resistant case of schizophrenia.

Dr. Nasrallah said that luckily, doctors have access to long-acting injectable medications that can be administered in a patient’s muscle tissue once every month, two months, three months, or even once a year with a new medication that was recently developed.

“Patients don’t have to take any pills, it guarantees that the medication reaches their brain slowly, oozing from the muscle, going into the blood, and to the brain,” he said.

Dr. Nasrallah explained that doctors were resistant to these drugs for decades because some feared they were encroaching on their patients’ “civil liberties” as the shots are not self-administered and are sometimes given before a patient reaches lucidity, or self-awareness that they actually have schizophrenia.

(Illustration by The Epoch Times, Shutterstock)
(Illustration by The Epoch Times, Shutterstock)

But in 2001, researchers discovered that psychotic episodes lead to brain atrophy, resulting in millions of dead brain cells and a worsening of symptoms. The long-acting injectables can prevent not just relapse but also a downward spiral into psychosis that worsens with each subsequent episode, Dr. Nasrallah said.

The ‘Myth’ of Schizophrenia and Violent Crime

He also discussed a public misconception or “myth” that sufferers from the disorder are more “violent” or more likely to commit crimes than people with average mental health stability.

A man was recently charged with stabbing two teenage tourists from Paraguay inside New York’s Grand Central Terminal on Christmas Day. A woman alleging to be his “ex-girlfriend” made statements that the suspect was schizophrenic and had refused to take medication to treat it.

Dr. Nasrallah said it is a “myth” because “less than one percent” of patients with schizophrenia commit crimes under the influence of hallucinations, paranoid delusions, or by the command of voices in their head.

“Unfortunately, the media exaggerates it and makes it frontline news when one person with psychosis commits a crime, but there are hundreds and thousands of crimes being committed by non-schizophrenic patients. The jails and prisons are full of [people with] antisocial personality [disorder], who can do all the killing. But if one person with psychosis does it, it gets far more media attention. And that perpetuates and disseminates unfortunately this myth. Psychosis or schizophrenia [patients] are far more victims of crime, rather than perpetrators of crime,” he said.

COVID-19 and Social Isolation

(Leonid Sorokin/Shutterstock)
(Leonid Sorokin/Shutterstock)

Patients also struggle with social isolation, which was worsened by the COVID-19 pandemic. A recent study out of California found that emergency room visits for “schizophrenia spectrum disorders,” which include schizophrenia and schizoaffective disorder, increased by 15 percent at five University of California campus hospitals during the initial phase of the pandemic.

Ms. Yeiser said she believes this could be the result of several forces coming into play simultaneously.

“If you take someone with a predisposition [for schizophrenia] and put them in a small apartment, where they’re not seeing anybody else for long periods of time, that is a huge trigger. So maybe some people who would not have developed it would develop it again because of this isolation. I’ve seen people lose jobs; I’ve seen people get really anxious and depressed. The anxiety is often really severe, you know, maybe people are experiencing worse anxiety than they ever have in their lives,” she said.

There are other factors, too.

“With the pandemic, you’re probably seeing some people experience symptoms that are new, you know, they haven’t seen a psychiatrist yet. And maybe their loved one is saying, ‘My son, my daughter, or my relative, is acting erratic, I haven’t seen him or her like this before, we need help. We don’t know what to do.’ And those people are going to the emergency room,” she said.

Emergency tents are set up outside the University of California–Irvine Medical Center in Orange, Calif., on Dec. 16, 2020. (John Fredricks/The Epoch Times)
Emergency tents are set up outside the University of California–Irvine Medical Center in Orange, Calif., on Dec. 16, 2020. (John Fredricks/The Epoch Times)

Ms. Yeiser recounted how she was in the ER on five separate occasions after her first psychiatrist dropped her as a patient in 2007.

“I think the reason you’re seeing more people go to the ER, again, is because this is new, and their mom, dad, relative is saying, ‘What on earth is going on? They need help [or] I need help now.’ And another problem in psychiatry is there’s a shortage of psychiatrists … often, you have to wait three months or four months, or for some people, it’s six months. Some people have the option of going to a family doctor much more quickly, and sometimes getting a prescription for an antipsychotic. But a lot of family doctors will not do that,” she added.

Need for Compassion and Hope

Krissy Williams, pictured with her brother, lives with schizophrenia. The disruption to her school and health services caused by COVID-19 worsened her mental health. In October, she tried to take her own life. (Patricia Williams)
Krissy Williams, pictured with her brother, lives with schizophrenia. The disruption to her school and health services caused by COVID-19 worsened her mental health. In October, she tried to take her own life. (Patricia Williams)

Both Ms. Yeiser and Dr. Nasrallah agree that treatment of schizophrenia would improve with better public awareness.

For Dr. Nasrallah, this involves increasing compassion and empathy among the general population.

“I would like them to know that it’s a brain disorder. Millions of data generated from neurophysiology, neurochemistry, neuropathology, brain imaging, genetics—all of that shows that it’s just as like a brain disorder, like stroke. People look at stroke and they develop compassion to people who develop stroke; they do not do that to patients with schizophrenia, even though their brain is destroyed with psychosis. Just like people with a stroke or with heart disease, I regard psychosis as a brain attack, just like a heart attack,” he explained.

Along with compassion by the public, patients also need “urgency for treatment by the psychiatric community.”

For Ms. Yeiser, hope is also required.

“Never, ever give up on your loved one with schizophrenia. If your doctor tells you that they are just permanently and totally disabled, and that’s it, it may be time to look for a new nurse practitioner or psychiatrist. Because there is hope today. I mean, I was sick and as treatment resistant as you can possibly be, and I still did get better,” she said.

What the Hell Is Light Therapy and Does It Really Work?

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In high school, Kristen Inman, now 23, started noticing patterns in her mood.

Struggling with undiagnosed depression, anxiety and self-harm, she became more conscious of how the seasons affected her. “I noticed that things typically got worse as the weather got colder and the days got shorter,” she says.

Like Inman, about 5 percent of the U.S. population experiences a form of seasonal mood disorder and depression known as seasonal affective disorder, or SAD. People affected by SAD typically experience symptoms like fatigue, hopelessness and withdrawal for about 40 percent of the year, particularly during the winter, according to a 2012 study.

 

One popular treatment for SAD? Light therapy, a process that involves exposure to a lamp that mimics sunlight to improve your mood. While light therapy may sound like a gimmick (at least, it did to me), it actually works — if used properly, says Kathryn Roecklein, an associate professor of psychology at the University of Pittsburgh who has studied SAD.

What to know about SAD

SAD isn’t just the “winter blues,” which involves feeling fatigued and less interested in typical activities during colder months. Also known as “subsyndromal SAD,” the winter blues is much more common, affecting about 14 percent of U.S. adults, but they don’t technically meet the current medical criteria for SAD, Roecklein says. SAD is more serious than that. In fact, it’s considered a subset of clinical depression, not a separate disorder, Roecklein says.

“Unlike major depression, though, SAD is characterized by its predictability: It sets in when the seasons change — usually from summer to winter — and it returns in the same pattern for at least two years in a row,” she says. “A person with SAD will experience consistent depressive symptoms most of the day for at least two weeks.”

Symptoms of SAD usually occur during the fall and winter months when there’s less sunlight, particularly in January and February for those in the U.S. Some people also experience SAD in the summer, but that’s less common, according to the American Psychiatric Association. For people who experience SAD, symptoms can affect daily routines and functioning.

“I feel tired and unmotivated but have trouble falling asleep because I’m also agitated,” Inman says. “It alleviates in the spring, which, like last year, could be as early as February or sometimes as late as April.”

Researchers still don’t know the exact causes of SAD, but there is a strong correlation between SAD and sunlight, Roecklein says. “Some of this can be attributed to daylight saving time. When it gets darker earlier, our bodies produce more melatonin, a hormone that regulates sleep, which can throw off circadian rhythms, leaving people feeling more tired than usual.”

Certain people are more likely to experience SAD: those who live closer to the poles than in climates with less seasonal change; those with a family history of depression and SAD; women, who are four times more likely to report having SAD than men; and children and teens.

Light therapy and how it works

The use of light therapy to treat SAD is relatively new. Researchers coined the term seasonal affective disorder in 1982 and two years later discovered it could be effectively treated with bright therapeutic light.

In the years since, research has continued to confirm that light therapy can be effective. The treatment requires you to sit in front of a 10,000-lux light box (that’s about 100 times brighter than normal indoor lighting) for 20 minutes to an hour first thing in the morning every day during the months you experience SAD, Roecklein says. The idea is to replace the natural sunlight you’re not getting.

Inman has been using light therapy successfully for years, but she was skeptical at first. “I read about light therapy online during the fall of my junior year of college, but I didn’t initially purchase one because they were expensive to me, and I was not sure if they worked in the first place or if it was some sort of pseudo-science fad or placebo,” she says.

But she was seeing a licensed counselor and a psychiatrist by that point, so she asked her psychiatrist: Does it really work? “He reassured me that the science behind them had merit and recommended that I try one. By that winter, if I was sitting at my desk at home, the light box was also on.”

Because it requires a time commitment each day and a routine, a study conducted by Roecklein found that only about 12 percent of people with SAD who are given a light box will actually continue using it the next winter. “Light therapy can be effective if done properly, but it must be used as directed, every day, in order to feel its full effects,” Roecklein says. When used correctly, the treatment can take effect within a week. However, even for those who try it, it’s not a guarantee. Research has found about a 50 percent chance that a dawn simulator — a timed light that gradually increases in intensity early in the morning — or a light box will work as a treatment for SAD, Roecklein says.

If you experience SAD, though, it’s worth trying. Inman still uses a light box, along with increased medication and vitamin D supplements, with success. “I’m going on two and a half years free of self-harm, and I’ve become proactive about my ‘winter’ needs,” she says.

Likewise, Eileen Cotter Wright, a 32-year-old American living in London, says “the glow of the SAD light brightened up my room and gave me more than just light therapy. I was doing something productive, actionable, to try to feel better. While working from home, it gave me routine and a daily task to accomplish, which also helped morale. I love the SAD therapy and almost feel bummed when it’s time to put it away for the spring.”

For those suffering from subsyndromal SAD, or the winter blues, light therapy could work for them, too. But treatment — even light therapy, which doesn’t require a prescription — should be discussed with a doctor, Roecklein says. “The reason is that light has similar effects in the brain as medication, and surely no one would start antidepressant medication treatment for depression without a doctor, even if their symptoms were less severe.”

Other treatments exist

Sticking to a daily routine of sitting near a light for a certain amount of time probably isn’t for everyone. Plus, light boxes can be pricey. Thankfully, other treatment options exist for SAD, including anti-depression medication and cognitive behavioral therapy. “These therapies have the patient identify negative thoughts and work to replace them with more positive, self-serving ways of thinking and behaving,” Roecklein says.

The treatments can be used individually or together.

Vitamin D, though popular among those who experience SAD, has had inconclusive research results as a form of treatment compared to light therapy, Roecklein says. “People with SAD often have low levels of Vitamin D, which could be caused either by lack of sun exposure or by not getting enough of it in their diet. Vitamin D isn’t currently recommended by itself as a sufficient treatment for SAD, but it can be used in combination with light therapy, medication or psychotherapy.”

For Inman, the combination of three treatments — light therapy, increased medication and vitamin D — has worked, and she thinks light therapy specifically has made all the difference. “Even though I still feel the effects of SAD, they are milder than they would be without it,” she says. “It makes me feel better, during times when I miss the sunlight, to have my own personal sun.”