Postpartum depression

Beyond SSRIs: How the Newest Antidepressants Work

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Antidepressants are medications that can help relieve depression symptoms, like fatigue and emotional numbness.

Several different kinds of antidepressants exist, but the most commonly prescribed are selective serotonin reuptake inhibitors (SSRIs).

Fluoxetine (Prozac) entered the market in 1988Trusted Source as the first SSRI, and for the next 30 years, many experts considered SSRIs the “modern” antidepressant.

In 2019, the Food and Drug Administration (FDA) approved two new antidepressants, brexanoloneTrusted Source and esketamineTrusted Source. There’s also been renewed interest in agomelatine, an antidepressant not currently available in the United States.

Read on to learn more about these new antidepressants, including how they compare to SSRIs, their side effects, and how to try them.

Brexanolone

In 2019, the FDA approved brexanolone (Zulresso) as the first drug specifically designed to treat moderate to severe postpartum depression (PPD).

Experts consider some SSRIs safe to take while pregnant or nursing, but these medications may not lead to much improvement for several weeksTrusted Source. When you have PPD, symptoms don’t just affect your own well-being — they can also have long-term effects on your bond with your baby.

Brexanolone, however, begins to take effect immediately. According to two randomized clinical trialsTrusted Source published in 2018, this medication can significantly reduce PPD symptoms — benefits that held when researchers followed up with participants 30 days after treatment.

How it works

Brexanolone raises brain levels of the neurotransmitter gamma aminobutyric acid (GABA).

In a nutshell, GABA dampens the chemical activity in your neurons, almost like a dimmer switch for certain cells.

Scientists aren’t sure exactly how brexanolone treats PPD symptoms, but one theoryTrusted Source suggests that with PPD, your GABA levels don’t recover quickly enough from pregnancy to manage your stress. Essentially, cortisol hormones rise unchecked, contributing to symptoms of depression. Brexanolone, then, may offer a “reset” by restoring your GABA levels.

You receive this medication as a one-time IV treatment over the course of 2 and a half daysTrusted Source. You’ll remain in your healthcare center for the entire 60-hour treatment for monitoring.

Safety and side effects

Like other drugs that affect GABA levels, brexanolone can cause sedation. Roughly 1 in 4 peopleTrusted Source experience sedation-related side effects in the first 24 hours of treatment.

You may feel:

  • extremely sleepy, even during the day
  • unfocused and distractible
  • dizzy or faint

Your care team will check on you every 2 hours for extreme symptoms like fainting. If you experience serious side effects, they’ll stop the infusion. Sedation-related symptoms should stop within 15 minutesTrusted Source after the IV infusion stops.

How to get a prescription

You can only receive this treatment from approved healthcare centers, and you’ll need a doctor’s referral to join the treatment program.

The treatment can cost up to $34,000Trusted Source, though health insurance can help offset some of the cost. Companies like Aetna and Cigna require pre-authorization, so you’ll want to make sure your insurance provider covers the treatment before you check in to your clinic.

Keep in mind, too, that most insurance companies only cover one round of treatment, as research has yet to explore the potential benefits of additional rounds of treatment.

The company that makes brexanolone also offers several financial assistance programs, which could be worth considering if the price tag puts it out of reach.

Esketamine

Esketamine (Spravato) is a chemical cousin of the anesthetic ketamine. The FDA approved esketamine in 2019 to treat treatment-resistant depression, or depression that persists after you try at least two different antidepressant treatments.

During clinical trials, doctors gave participants a nasal esketamine spray or a placebo spray. All participants also took an oral antidepressant they hadn’t tried before. Compared to people who took an oral antidepressant and used a placebo spray, those who used the esketamine spray reported greater symptom relief and longer symptom-free periodsTrusted Source.

How it works

Esketamine sets off a chain reaction of chemicals that ultimately raises your levels of brain-derived neurotrophic factor (BDNF). BDNF helps your neurons make new connections, which in turn enables you to form memories, learn new information, and develop different habits.

Depression typically involves low BDNF levels, and your brain may have difficulty adapting to changes. Esketamine helps restore BDNF levels, along with overall brain plasticity.

As with brexanolone, you have to take esketamine in the presence of a healthcare professional. Your doctor or clinician will give you a dose between 56–84 milligrams (mg), which you spray into your nostrils. You then relax in a chair for 2 hours. Your care team will monitor your blood pressure and heart rate during this time.

This medication works quickly, with many people noticing relief right away. Treatment requires multiple sessions, typically twice a week for the first 28 days and then spaced out over time. The effects usually last until your next dose.

Safety and side effects

In clinical trials, participants tended to report mild to moderate side effects. You may feel sleepy, dizzy, or a bit “out of it” during your treatment session. These side effects often go away within 90 minutes after you take your dose.

On rare occasions, people have reported more severe side effects like:

  • vomiting
  • anxiety and confusion
  • worsening depression or suicidal thoughts

Esketamine can also lead to significant increases in blood pressure during the treatment session, which is why you’ll need monitoring for 2 hours. If you have hypertension or another vascular condition, make sure to tell your doctor before receiving treatment.

How to get a prescription

You can only receive this treatment at an approved healthcare center, so you’ll need to ask your doctor or psychiatrist if you’d like to try esketamine.

The course of treatment instead depends on the severity of your symptoms — and how much you’re able to pay. As of 2021, a standard 56-mg dose of esketamine costs $590, and a large dose of 84 mg costs $885.

The initial month of therapy is often the most expensive since treatment guidelines recommend twice-weekly treatment for the first month. This first month can cost anywhere from $4,800 and $6,800 dollars.

To date, no official guidelines set an ideal length of treatment.

According to the company that produces Spravato, some insurance programs cover most of the cost of esketamine. You’ll only need to pay a $10 copay per session until you hit the benefits cap of $7,150 per year.

Agomelatine

Agomelatine (Valdoxan), an oral antidepressant, has been available in some other countries since 2009, though you can’t get this medication in the United States.

You take agomelatine as a 25-mg pill once a day at bedtime. If your depression symptoms don’t respond, a doctor may increase the dose to 50 mg per day.

Agomelatine may have particular benefit for depression that:

How it works

Agomelatine has two main effectsTrusted Source on your brain. It increases activity at melatonin nerve receptors, which helps you sleep. It also decreases activity at specific serotonin receptors and helps increase dopamine and norepinephrine in the frontal cortex.

Increasing melatonin levels can improve sleep-related issues. In a small 2018 study that included 24 young adults, researchers found that the more agomelatine shifted the participants’ circadian rhythms, the more their depression symptoms improved.

Experts don’t yet know exactly how decreasing serotonin fits into the picture.

That said, older animal research from 2014Trusted Source suggests boosting melatonin and decreasing serotonin binding to receptors simultaneously may help protect newly created neurons by shielding them from the damage caused by chronic stress.

Safety and side effects

Agomelatine may cause:

  • nausea and vomiting
  • constipation, stomach pain, and diarrhea
  • drowsiness or difficulty sleeping
  • headaches

But many people only experience mild side effects while taking agomelatine, which may partially explain the renewed interest in this antidepressant.

After all, if you don’t experience severe side effects, you’ll probably feel more inclined to continue taking the medication.

How agomelatine compares

A2018 reviewTrusted Sourceincluding 522 trials with a total of 116,477 participants compared 21 antidepressants.

When the review authors considered dropout rates specifically due to adverse reactions, they discovered all included antidepressants had a higher dropout rate than the placebo — except agomelatine.

Incidentally, researchers also listed agomelatine as one of seven most effective antidepressants among those studied.

With many antidepressants, you may experience flu-like symptoms if you suddenly stop taking the medication. This phenomenon, called discontinuation syndrome, doesn’t occur with agomelatine. You can easily stop even long-term agomelatine useTrusted Source.

So, you might wonder: If this medication works so well, what’s holding up approval in the United States?

Agomelatine does have the potential to cause one very severe side effect: liver toxicity. The medication raises the levels of liver amino acids called transaminases, causing liver damage for up to 4.6%Trusted Source of people who take it. People taking this medication need to have their liver function tested at weeks 3, 6, 12, and 24 of treatment.

Other antidepressants can have a similar impact on your liver, but at much lower ratesTrusted Source:

  • placebo: 2.1%
  • escitalopram (Lexapro): 1.4%
  • paroxetine (Paxil): 0.6%
  • fluoxetine (Prozac): 0.4%

How to get a prescription

Currently, you can’t get a prescription for agomelatine in the United States or Canada, as regulatory agencies have deemed the risk of liver injury too high to allow the drug on the market.

It’s possible that agomelatine could become more widely available in the future if researchers identify a way to minimize the risk of liver toxicity.

Doctors in Europe and Australia may prescribe this medication.

The bottom line

Brexanolone and esketamine appear to have the most benefit for postpartum depression and treatment-resistant depression, respectively. These medications also come with a high price tag that can make them harder to access.

Agomelatine can effectively treat a wider range of depression subtypes. But it also carries a risk of liver toxicity, and it hasn’t been approved for use in the United States.

To sum up, these medications likely won’t replace SSRIs as the first line of treatment for other types of depression anytime soon. Still, their existence opens up possibilities for future advances in depression treatment.

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.

Pill for Postpartum Depression Submitted for FDA Review

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A pill that could change the way postpartum depression is treated has been submitted to the U.S. Food and Drug Administration for priority review, pharmaceutical companies Sage Therapeutics and Biogen announced.

The drug, zuranolone, would be taken once-a-day for two weeks and could replace other postpartum depression treatments that take much longer to have any effect. Because the FDA is giving the application priority review, the drug might be approved this calendar year.

“Most current approved therapies may take weeks or months to work. We are committed to advancing treatments that could help physicians and patients by addressing depression symptoms quickly,” Laura Gault, MD, chief medical officer at Sage, said in a news release. “We believe zuranolone, if approved, could offer a new way for physicians to support patients.”

About one in eight U.S. women giving birth experience postpartum depression, or about 500,000 annually, the drug companies said. The pill also could be used to treat major depressive disorder, which is diagnosed in about 14 million people yearly.

A clinical study of 200 women with PPD found depression decreased for about 26.5% of them in three days when they took zuranolone, compared to 12.5% who got a placebo. In two weeks, those figures went up to 57% for those getting zuranolone and 38.9% who got the placebo.

In 2019 the FDA approved a Sage Therapeutics drug that was the first anti-depressant specifically designed for PPD, The Boston Globe reported. That drug, Zulresso, was given intravenously and was a commercial failure because of its high price, about $34,000 per patient, The Globe said.

But the effectiveness of Zulresso motivated pharmaceutical companies to start new research into postpartum depression, which has been often under-studied for years, The Globe reported.

Postpartum Depression Is More Than Baby Blues

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Summary: Symptoms of postpartum depression usually begin to arise three weeks after the birth of a child and are defined by differences in mood and anxiety levels. PPD can last for a year or longer. Baby blues, by contrast, typically last for two weeks.

Source: Mayo Clinic

Postpartum depression is real. The Centers for Disease Control and Prevention says 1 out of every 10 new moms suffer from it. It’s much more than what’s called the “baby blues” because it lasts longer and tends to be more severe.

Symptoms include mood swings, anxiety, sadness, crying irritability and feeling overwhelmed. Prompt treatment is important, and Mayo Clinic experts say it works.

It’s been a month since you welcomed your new baby into the world. You’re supposed to be elated. Instead, you feel sad, lonely, irritable and depressed.

“Postpartum depression is typically defined as mood symptoms, anxiety that presents in women—usually within three weeks or longer, say up to the first year after delivery of their child,” says Dr. Summer Allen, a Mayo Clinic family physician.

This shows a mom and newborn
Dr. Allen says that postpartum depression is different than the baby blues, which typically lasts about two weeks

Dr. Allen says that postpartum depression is different than the baby blues, which typically lasts about two weeks.

“Postpartum depression, or maternal mental health as it’s being referred to now, is normal and happens to a lot of women, and can have a varying degree of severity,” she says.

Credit: Mayo Clinic

Help and support are key to coping. Get as much rest as you can, accept help from family and friends, connect with other new moms, carve out time for yourself and avoid alcohol.

Talk to your health care team if you have any symptoms because treatment can help.

Anxiety, depression persist despite antidepressant use in pregnancy, postpartum

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Women who took antidepressant medication had persistent depressive and anxiety symptoms during pregnancy and postpartum, with some women experiencing increased anxiety symptoms, data showed.

“Sustaining remission through the use of medication of perinatal major depressive disorder (MDD) is essential for achieving optimal maternal and offspring health,” Gabrielle A. Mesches, MS, of the department of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine, and colleagues wrote in Psychiatric Research & Clinical Practice. “Given the high comorbidity, clinical guidelines recommend screening for anxiety disorders in women with perinatal MDD, [and] the individual symptom trajectories of anxiety and depression vary across pregnancy to postpartum.”

Despite taking a selective serotonin reuptake inhibitor, women experienced similar levels of depressive and anxiety symptoms throughout pregnancy and after birth. Source: Adobe Stock
Despite taking a selective serotonin reuptake inhibitor, women experienced similar levels of depressive and anxiety symptoms throughout pregnancy and after birth. Source: Adobe Stock

Treatment for MDD typically includes selective serotonin reuptake inhibitors (SSRIs), though existing studies have not provided concrete evidence on the efficacy of SSRIs in pregnancy, the researchers wrote.

“Our goal is to analyze the depressive and anxiety symptom trajectories across pregnancy and after birth in women who did not have syndromal MDD at entry and who were maintained on one of the four commonly prescribed SSRI antidepressants that have equivalent effectiveness,” they said.

Enrollment and assessment

Mesches and colleagues enrolled 88 pregnant women (89% white) by 18 weeks’ gestation who had a diagnosis of MDD and were currently taking sertraline (n = 47), fluoxetine (n = 10), citalopram (n = 9) or escitalopram (n =22). Participants continued using their initial SSRI for the entire study period.

Researchers conducted interviews at baseline and every 4 weeks through delivery, and continued follow-up with 77 women at 6 and 14 weeks postpartum. To assess MDD, anxiety and physical health at each interview, they used the 10-item Edinburgh Postnatal Depression Scale (EPDS), the 16-item Quick Inventory of Depressive Symptoms (QIDS), the 7-item Generalized Anxiety Disorder Scale (GAD-7) and the 10-item Patient-Reported Outcomes Measurement Information System Global Health (PROMIS-GH) T-scores. Scores were used to identify and group participants with similar symptom progression.

Depression, anxiety continue

Trajectories of EPDS scores — categorized as minimal (18%), mild (50%) and subthreshold (32%) by increasing severity — remained relatively stable throughout pregnancy and postpartum, with the exception of subthreshold levels, which started high, decreased by 9 months’ gestation and increased postpartum. SSRI dose increase was not significantly associated with any depression trajectory, the researchers said.

QIDS scores confirmed the three EPDS trajectories, although there was a different progression of depressive symptoms. However, this difference was not significant.

Of note, the presence of an eating disorder was predictive of QIDS group membership, with 4% of the minimal group, 26% of the mild group and 11% of the subthreshold group reporting an eating disorder.

Regarding anxiety, the GAD-7 scores followed four trajectories — asymptomatic (7%); minimal (53%); breakthrough, or increasing symptoms (18%); and mild (23%). In general, the anxiety trajectories were positively associated with the EPDS trajectory groups, according to the researchers. The asymptomatic and minimal trajectories identified through GAD-7 scores remained stable through pregnancy and after birth. The breakthrough trajectory revealed a trend of increasing anxiety symptoms over the duration of study, while there was a decrease in symptoms for the mild trajectory.

“Our findings demonstrate that the treatment goal to achieve full resolution of maternal depression symptoms remains a clinical challenge,” Mesches and colleagues said. “Despite maintenance treatment, pregnant women with MDD frequently had residual symptoms at enrollment and throughout pregnancy and postpartum.”

Because the study consisted mainly of white women and only evaluated SSRIs, the researchers emphasized the need for more research.

“Additional intervention research is needed to enhance the effectiveness of maintenance medication, especially for women in the highest scoring QIDS and EPDS trajectories, respectively,” they said.

Postpartum thoughts of infant-related harm, OCD unrelated to risk of maternal aggression

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Postpartum unwanted intrusive thoughts based on intentional infant-related harm or obsessive-compulsive disorder were not associated with elevated risk of harm to infants, according to a study published in the Journal of Clinical Psychiatry.

“UITs of infant-related harm are a core feature of postpartum OCD,” Nichole Fairbrother, PhD, assistant professor of psychiatry at the University of British Columbia, and colleagues wrote.

Sad Woman with Sad Baby

“Further, although it is widely accepted that OCD is not associated with an increased risk of violence and that sufferers are not at risk of acting on the content of their obsessions, this assertion has not been formally assessed.”

Researchers sought to evaluate the connection between new mothers’ UITs of intentional harm and OCD with maternal aggression toward their infants, and to document the prevalence of the same.

It is estimated that 1 in 4 American children suffer from some form of maltreatment, the authors note. Referrals to child protective services suggest a prevalence rate of 9 per 1,000 cases.

The study drew from a prospective, province-wide sample of 763 English-speaking women who had just given birth and were aged 19 years and older. A total of 388 participants responded. Study enrollees completed two questionnaires and interviews postpartum to gauge incidence of UITs of infant-related harm, OCD (based on DSM-5 criteria), and maternal aggression toward their infant. Data were collected from February 2014 to February 2017.

Fairbrother and colleagues found 2.9% (95% CI, 1.5% to 4.7%) of participants (n = 11) reported non-ideated aggressive behavior toward their child. The estimated prevalence of experiencing UITs within the first 9 months postpartum was 44.4% (95% CI, 32.9% to 49.7%).

Mothers who reported UITs of intentional, infant-related harm were not more likely to report aggression toward their newborn compared with women who did not report this ideation. The same held true for women with and without OCD.

“The findings from this study provide critical and reassuring information regarding the relation between new mothers’ UITs of intentional harm and the risk of violence toward the infant,” the researchers wrote.

Important Facts on Depression: Types, Symptoms and Treatment

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Story at-a-glance

  • Depression is a widespread global problem, with over 300 million people dealing with this severe mood disorder today
  • Depression does not discriminate between gender, race or social status — anyone can be predisposed to it

It’s normal for people to sometimes feel sad, disappointed or disheartened, especially when they experience low points in their life. However, these “blues” usually go away when any happy circumstances occur.

But in some people, this low mood becomes persistent and lasts a long time — for weeks, months or even years. And if it comes with other hallmark symptoms, such as lack of interest in enjoyable activities, a feeling of hopelessness or thoughts about self-harm or even suicide, then watch out: You may be suffering from depression.

depressed woman in a dark room

Depression Defined: Know the Facts

The Mayo Clinic defines depression, also called clinical depression or major depressive disorder (MDD), as “a mood disorder that causes a persistent feeling of sadness and loss of interest.” This debilitating condition affects you entirely — how you behave, think and feel — and paves the way for emotional and physical problems to arise. Depressed individuals usually struggle with completing their day-to-day tasks, feeling as if there’s no more point in living.1

According to the Australian nonprofit organization Beyond Blue, there are different subtypes of depression depending on the symptoms, the intensity and their triggers. Some of the most common ones include manic depression, bipolar disorder, dysthymia, seasonal affective disorder (SAD) or “the winter blues” and antepartum and postpartum depression (occurs specifically in pregnant women and new mothers).2

Depression is a widespread global problem, with over 300 million people dealing with this severe mood disorder today.3 Even in developed, industrialized countries, depression is rampant. In fact, in the United States, between 2013 and 2016, 8.1 percent of Americans who were 20 years old and older suffered from depression in a given two-week period.4

This Disorder Is Now a Prevalent Problem

Depression is not a simple condition that you can “snap out of.” If not addressed immediately, it can damage your physical health, leading to low immunity and worsened pain, or worse, substance abuse. According to a study published in Current Opinion in Psychiatry, up to 33 percent of people suffering from clinical depression are prone to drug or alcohol problems.5

Even more alarming is the link between depression and suicide. According to the American Association of Suicidology, depression is the psychiatric diagnosis that is most commonly linked to suicide.6 It’s said that 30 to 70 percent of people who commit suicide suffer from major depression or bipolar disorder.7,8

Keep an Eye Out for the Signs — Before It’s Too Late

Depression does not discriminate between gender, race or social status. Anyone can be predisposed to it. Given its potentially dangerous effects, it’s only wise to take the necessary precautions to address and treat this disorder before it spirals out of control. But a word to the wise: Antidepressants and other medications are NOT the best solution for depression, and may even have more debilitating and long-term side effects.

Read these articles and learn important facts about depression, including its hallmark symptoms, devastating effects and how to avoid it. Plus, learn natural yet useful remedies that will help alleviate this disorder but will not put you at risk for side effects, unlike conventional antidepressant medications. Stay informed now, so you can avoid or address this mental disorder immediately.

There Could Be a Biological Mechanism Behind Postpartum Depression, Says Study

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Postpartum depression (PPD) is a devastating condition, affecting somewhere between 11 and 20 percent of women who give birth. Yet it’s complicated, and poorly understood.

Now, using mouse models, researchers have identified what could be an actual biological cause for the condition – at least in some patients. It all has to do with a pathway in the body that regulates stress.

 

When that pathway breaks down, the new study from Tufts University suggests that mothers are more likely to develop PPD.

PPD is distinct from the “baby blues,” a low mood that may hang around for a few days after giving birth. Not only is it longer lasting, but it can deepen into a sense of worthlessness, fatigue, anxiety, inability to bond with the baby and even suicidal thoughts.

It doesn’t just affect mothers either – postpartum depression correlates strongly with developmental and behavioural difficulties in infants.

Right now, up to 85 percent of mothers do not seek or receive help for PPD. This is partly because of the fact the condition is still so poorly understood.

But the discovery of a biological mechanism underlying postpartum depression could finally give scientists a better understanding of what causes some women to develop the condition and not others – and could also lead to more effective medication.

The new study revolves around a stress pathway in the body known as the hypothalamic-pituitary-adrenal (HPA) axis. This pathway is responsible for triggering the famous fight-or-flight response, but during pregnancy it’s supposed to be suppressed to protect the foetus from stress.

One of the main drivers of this pathway is a hormone known as corticotropin-releasing hormone (CVH), which is released by the brain during times of stress.

Previous studies had shown a link between PPD, CVH, and the HPA axis, but until now no one had ever been able to figure out exactly how they all worked together.

The team used mouse models to show for the first time that when the HPA axis isn’t functioning normally, it can actually trigger PPD-like behaviours in mice.

“Our new study provides the first empirical evidence supporting the clinical observations of HPA axis dysfunction in patients with postpartum depression,” said one of the team, neuroscientist Jamie Maguire from Tufts University.

The first part of the experiment involved looking at a protein in the brain called KCC2. KCC2 is known to regulate how much CVN the brain releases, and therefore how much stress mice experience.

The team found that in virgin mice that were exposed to stress, KCC2 was suppressed, which indicated that CVN was unregulated.

But in stressed out pregnant and postpartum mice, KCC2 was active, which suggests it was stifling the stress response in the mothers.

Next, they developed mice that completely lacked KCC2, and compared these “knockout” mice with normal mice.

The knockout mice were much more stressed during pregnancy, and did not show a reduction in anxiety after giving birth, which would have been normal for the postpartum period. They also were more reluctant to mother their pups, approaching them more slowly, and spending less time with them.

To investigate further, the team then silenced the brain cells that usually secrete the stress-driving hormone CVN, and found that the mice without those active brain cells were less stressed and interacted more normally with their pups.

In other words, when CVN was blocked in pregnant mice through a number of different actions, mice were less likely to experience PPD-like symptoms.

This mechanism hasn’t yet been demonstrated in humans, but there have been clinical observations of a dysfunctional HPA axis and postpartum depression, so it’s definitely worth further investigation.

If the same link exists in humans, it could lead to a more effective way to treat the disease.

But, importantly, the researchers caution that the condition is highly complex and has several contributing mechanisms, so it’s unlikely that one treatment would work across all women.

The researchers next hope they will be able to develop a biological marker that can identify women vulnerable to postpartum depression because of a dysfunctional stress axis.

“There is much more we need to learn, but we believe our model will be useful for testing novel therapeutic compounds for postpartum depression,” Maguire said.

Neuroscientists shed light on causes of postpartum depression using new research model

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Neuroscientists shed light on causes of postpartum depression using new research model
Tufts University neuroscientists Jamie Maguire (left) and Laverne Melón have generated a novel preclinical model of postpartum depression and demonstrated involvement of the neuroendocrine system that mediates physiological response to …more

Postpartum depression strikes nearly one in five new mothers, who may experience anxiety, severe fatigue, inability to bond with their children and suicidal thoughts. Such depression has also been associated with infants’ developmental difficulties. Although stress has been identified as a significant risk factor for postpartum depression, this complex disorder is still poorly understood. Now neuroscientists at Tufts University School of Medicine have generated a novel preclinical model of postpartum depression and demonstrated involvement of the neuroendocrine system that mediates physiological response to stress, called the hypothalamic-pituitary-adrenal (HPA) axis, which is normally suppressed during and after pregnancy. The findings in mice provide the first empirical evidence that disruption of this system engenders behaviors that mimic postpartum depression in humans.

This study, to be published in the journal Psychoneuroendocrinology and now available online, provides a much-needed research model for further investigation into the causes of and treatment for , which has largely relied on correlational studies in humans because of the scarcity of animal models.

Stress is known to activate the HPA axis, which triggers the fight or flight response seen in many species. During and after pregnancy such activation is normally blunted – helping to insulate developing offspring from  – and dysregulation of the HPA axis has been suggested as playing a role in the physiology of postpartum .

The effects of stress on postpartum behavior are thought to be mediated by stress hormones because animal experiments show that stress and exogenous stress hormones can induce abnormal postpartum behaviors. However, clinical data on  in women with postpartum depression has been inconsistent. To date, research has not directly demonstrated a role for corticotropin-releasing hormone (CRH)—the main driver of the stress response, which is primarily secreted by a cluster of neurons in the hypothalamus called the paraventricular nucleus (PVN)—or for inappropriate activation of the HPA axis in postpartum depression.

“Some clinical studies show a relationship between CRH, HPA axis function and postpartum depression, but others fail to replicate these findings. Direct investigation into this relationship has been hindered due to the lack of useful animal models of such a complex disorder,” said Jamie Maguire, Ph.D., corresponding author on the new study, assistant professor in the Department of Neuroscience at Tufts University School of Medicine, and a member of the Neuroscience and Pharmacology & Experimental Therapeutics program faculties at Tufts’ Sackler School of Graduate Biomedical Sciences.

“Using a mouse model that we developed, our new study provides the first empirical evidence supporting the clinical observations of HPA axis dysfunction in patients with postpartum depression and shows for the first time that dysregulation of the HPA axis and a specific protein in the brain, KCC2, can be enough to induce postpartum depression-like behaviors and deficits in maternal care,” she continued.

Maguire’s lab had previously shown a critical role for KCC2 in regulating CRH neurons and the physiological response to stress. The recent study investigated the specific role of KCC2 in regulating the HPA axis during and after pregnancy. Maguire and her colleagues assessed KCC2 expression in the PVN in virgin, pregnant and postpartum mice. They observed suppression (downregulation) of KCC2 in virgin mice exposed to stress but not in pregnant or postpartum mice. They propose that this contributes to the protective HPA hypofunction prior to birth, which is consistent with lower glucocorticoid levels observed in pregnant and postpartum mice and similar to findings in humans.

To further test the role of KCC2, the researchers developed mice that completely lacked KCC2 in CRH neurons and compared HPA axis function in these “knockout” mice with their normal (wildtype) littermates. Knockout mice demonstrated significantly more stress reactivity during the peripartum period, did not show the reduced anxiety typical of the , and exhibited abnormal maternal care compared with postpartum wildtype mice. Utilizing novel chemogenetic strategies to specifically activate or silence the CRH neurons in the PVN, researchers were able to pinpoint these abnormal behaviors to the activity of these specific neurons, which govern the HPA axis.

Identifying molecular targets and biological markers for postpartum depression”Pregnancy obviously involves great changes to a woman’s body, but we’re only now beginning to understand the significant unseen adaptations occurring at the neurochemical and circuitry level that may be important to maintaining mental health and maternal behavior in the first few weeks to months following delivery,” said Laverne Camille Melón, Ph.D., first author on the paper and postdoctoral fellow in the Maguire laboratory. “By uncovering the role for stability of KCC2 in the regulation of CRH neurons, the postpartum stress axis, and maternal behavior, we hope we have identified a potential molecular target for the development of a new class of compounds that are more effective for women suffering from postpartum depression and anxiety.”

Melón and Maguire do not believe that HPA axis dysfunction is the only pathological mechanism at work. “Many psychiatric and neurological disorders are a constellation of symptoms and represent an unfortunate synergy of heterogeneous maladaptations. The mechanisms underlying one woman’s postpartum depression may differ from another’s,” said Melón.

The researchers hope that continued work will enable them to identify a biological marker that characterizes women who may be vulnerable to postpartum depression because of dysregulation of the stress axis, potentially leading to new treatment options.

“There is much more we need to learn,” said Maguire, “but we believe our model will be useful for testing novel therapeutic compounds for postpartum depression. Such studies could also be relevant to other conditions in which KCC2 deficits are implicated, such as epilepsy, chronic pain and autism, and to other stress and anxiety related disorders.”

Saffron: A Safe and Effective Treatment for Postpartum Depression

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Depression is a common health condition, with few conventional treatment options. Forced to choose between talk therapy and medication, many people choose to be treated with drugs. But what about new mothers, whose desire to breastfeed means they are not candidates for psychiatric meds? Nature is providing hope in the form of a delicate flower: saffron

Postpartum depression is a mood disorder that affects as many as 1 in 7 new mothers. Characterized by deep mood swings, low energy, and a loss of interest in daily activities, postpartum depression may be caused by the sudden drops in estrogen and progesterone that occur in a woman’s body immediately after giving birth.[1]  Currently, the only approved medical treatments for postpartum depression are talk therapy and psychiatric medications. If a mother wishes to breastfeed, the pharmaceutical path is contraindicated due to contaminating breast milk with medication metabolites. Now, thanks to an exotic spice, there is another choice that demonstrates the power of nature to heal from within.

In December 2017, the journal Phytomedicine published the results of a clinical trial on saffron stigma for treating mothers suffering from postpartum depression. Saffron stigma are crimson-covered threads that are produced by the flowers of Crocus sativus L., commonly referred to as “saffron crocus.” A highly valued cooking spice, saffron is one of the world’s most expensive spices by weight.[2] Beyond saffron’s delicate flavor, often described as sweet and “hay like”, and rich golden hue used in traditional dyes, saffron’s use as a medicinal herb has been documented for more than 4,000 years.

In this study, researchers wanted to identify a non-pharmaceutical treatment option for breastfeeding mothers suffering from mild-to-moderate postpartum depressive disorder (PPD). A double-blind, randomized, placebo-controlled trial was conducted on 60 new mothers diagnosed with PPD using the Beck Depression Inventory-Second Edition (BDI-II). Participants were randomly assigned to either saffron or placebo group, with saffron group receiving a 15-mg per day dose of the powdered herb. After 8 weeks, new BDI-II scores were taken and compared to the baseline scores. Results showed that the saffron group experienced a 96% remission rate for postpartum depression, more than double the remission rate of placebo group. BDI-II scores decreased significantly for the women consuming saffron (from 20.3 ± 5.7 to 8.4 ± 3.7), while the placebo group experienced only a modest decrease in symptom scores (19.8 ± 3.2 to 15.1 ± 5.4). Researchers concluded that saffron can have a safe and significant mood-elevating impact for those suffering from postpartum depression who want to safely breast-feed their newborns.[3]

Other researchers have produced similarly encouraging findings about saffron’s potential as a natural antidepressant. A 2014 meta-analysis titled “Saffron for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action” analyzed six studies on saffron for treating depression. Researchers determined conclusively that “saffron had large treatment effects” on depression. When compared with antidepressant medications, saffron was found to have similar efficacy – without the side effects.  Saffron’s antidepressant properties have been attributed to its “serotonergic, antioxidant, anti-inflammatory, neuro-endocrine, and neuroprotective effects.”[4]

It is a commonly held misbelief that holistic treatments for depression are only viable when a person is experiencing mild-to-moderate depression symptoms. Another meta-analysis of saffron for major depressive disorders dispels this concern. In this 2013 review of five studies on saffron for major depressive disorder, researchers noted that a “large effect” was seen in saffron-treated patients versus placebo, concluding that “saffron supplementation can improve symptoms of depression in adults with major depressive disorder.”[5]

Saffron’s impressive ability to elevate mood is backed-up by at least seven additional proven health benefits. Rich in B vitamins and manganese, adding this beautiful spice to your diet also provides a nutritional boost.