Depression affects over 300 million people globally.
Current treatments have limited efficacy for many patients.
Exciting new research highlights the potential of allopregnanolone agonists like brexanolone and zuranolone as more targeted, rapid-acting antidepressants.
Key Facts:
- Allopregnanolone is a neurosteroid that regulates mood and is decreased in depression. Its agonists boost allopregnanolone activity.
- Brexanolone is the first FDA-approved allopregnanolone agonist for postpartum depression. Zuranolone shows promise for major depressive disorder.
- These drugs act within days, unlike weeks for standard antidepressants. Remission rates are higher.
- Side effects like sedation must be monitored but are generally mild. More studies are underway.
Source: Cureus
The Search for Better Antidepressants
Depression is a leading cause of disability worldwide.
Available treatments like SSRIs can take weeks to improve symptoms in only around half of patients. Even then, residual symptoms often persist.
This highlights an unmet need for more effective, rapid-acting antidepressants with fewer side effects.
Research is uncovering new ways to achieve this.
One approach involves targeting the neurosteroid allopregnanolone and its role in regulating mood and GABA signaling in the brain.
What is Allopregnanolone and How is it Linked to Depression?
Allopregnanolone is a metabolite of the hormone progesterone made in the brain.
It acts on GABA receptors, the brain’s main inhibitory neurotransmitters.
This calms neuronal activity and explains its anti-anxiety and sedative effects.
Studies find allopregnanolone levels are decreased in depression, PMDD, PTSD and other stress-related conditions.
This impairs GABA signaling and mood regulation.
Animal research shows boosting allopregnanolone quickly improves depressive behaviors.
This suggests restoring normal levels could have antidepressant effects in humans too.
Introducing Synthetic Allopregnanolone Agonists
Since allopregnanolone itself has poor bioavailability when given orally, scientists developed synthetic analogs that mimic its effects on GABA receptors.
The first FDA-approved drug in this new class of allopregnanolone agonists is brexanolone (Zulresso). It is administered intravenously and used for postpartum depression.
Zuranolone (Sage-217) is another orally active allopregnanolone agonist now in phase 3 trials for major depressive disorder.
Both aim to rapidly enhance GABAergic transmission and normalize mood pathways disrupted in depression.
How Do Allopregnanolone Agonists Compare to Standard Antidepressants?
In clinical trials, allopregnanolone agonists act significantly faster than conventional antidepressants like SSRIs.
While SSRIs take 2-4 weeks to work, improvements in depressive symptoms are seen in just 3 days with zuranolone.
Effects persist for weeks after short 2-week treatment courses.
Remission rates are also twice as high – around 30-50% of patients versus 15-20% on placebo pills in comparative studies.
This faster action and higher remission is a major advance.
Faster relief of depressive symptoms could lower suicide risk during the gradual onset of standard antidepressants.
Brexanolone: The First-Approved Allopregnanolone Agonist
Several randomized trials found brexanolone slashes depression scores by over 50% within 30 days in women with severe postpartum depression.
Placebo groups had smaller improvements.
Infusions of brexanolone start working within 24-48 hours.
Remission rates were also higher – 26-34% on brexanolone versus 14% on placebo.
This led the FDA to approve brexanolone in 2019 as the first allopregnanolone agonist for PPD.
It offers new hope to women reluctant to take antidepressants while breastfeeding.
However, brexanolone requires 60-hour IV infusions under medical supervision due to risks like excessive sedation or sudden loss of consciousness.
This limits its use to specialized clinics.
Oral Zuranolone for Major Depressive Disorder
Unlike brexanolone, zuranolone is an oral capsule tested for major depression at 30-50 mg daily doses.
Multiple phase 2 and 3 trials demonstrate rapid improvements in depressive symptoms versus placebo within 1-2 weeks of starting zuranolone.
In one 6-month study, over 50% of those on 30 mg zuranolone achieved remission versus 35% on placebo.
This is a major advance for hard-to-treat depression.
Zuranolone was also very well tolerated with mild side effects like headaches and dizziness.
It is not associated with withdrawal symptoms after discontinuing treatment.
If approved, zuranolone could be prescribed by regular doctors without the need for infusions or hospital stays.
This widens accessibility of this innovative new class of antidepressants.
Are Allopregnanolone Agonists the Answer for Treatment-Resistant Depression?
Around 30% of those with major depression fail to respond to at least two different antidepressant medications.
This treatment-resistant depression is a huge unmet need.
Some clinical trials specifically enrolled patients who previously failed to respond to drugs like SSRIs.
Brexanolone and zuranolone both improved depressive symptoms better than placebo in these hard-to-treat groups.
While more research is needed, this indicates allopregnanolone agonists may provide hope for patients out of options.
Their novel mechanism of modulating GABA activity appears beneficial even in those who did not respond to other mechanisms.
Combination Strategies to Enhance Efficacy
More studies are looking at combining allopregnanolone agonists with other agents that have antidepressant properties through different pathways.
For instance, zuranolone plus standard antidepressants further improves response rates compared to placebos.
Other experimental combo therapies like buprenorphine/samidorphan also outperformed single drugs for major depression.
Using allopregnanolone agonists together with complementary medications that boost serotonin, dopamine or glutamate signaling could maximize benefits.
Safety and Side Effects
Brexanolone can cause excessive sedation requiring medical monitoring.
Zuranolone has milder side effects like drowsiness and dizziness.
There are some concerns with rare complications like suicidal ideation, confusion, insomnia and liver damage.
However, large trials generally report good safety and tolerance.
While allopregnanolone agonists show low abuse potential, some precautions are advised in vulnerable populations prone to substance misuse.
Overall, the safety profile appears acceptable and generally better than older antidepressants.
Proper patient selection and vigilance for adverse effects remain important.
Future Outlook: A Paradigm Shift in Antidepressant Therapy?
In summary, allopregnanolone agonists represent game-changing new additions to the antidepressant arsenal after decades of minimal innovation.
Their ability to lift mood within days rather than weeks addresses an urgent need for faster relief of depressive symptoms.
Higher remission rates are another key advantage over current medications, which fail to induce remission in nearly half of patients.
While more research on long-term safety and optimal treatment regimens is needed, allopregnanolone agonists offer new hope to the millions suffering from major depression worldwide.
References
- Study: Exploring novel therapeutic approaches for depressive disorders: the role of allopregnanolone agonists
- Authors: Najeeha Ahmad Bhatti et al. (2023)
