Summary: A synthetic neurosteroid called allopregnanolone is one of the first drugs approved in its class. It works about as well as SSRIs. But unlike those drugs, it brings long remission and a very low relapse rate. It seems to work in a very different way, by changing brain waves in the amygdala. Major depressive disorder (MDD) is now the top mental health problem. It is only expected to grow. There are many drugs for it, but treatment falls far short. SSRIs are the drugs most often prescribed for MDD. But depression often comes back on them. Now researchers seem to have found a drug that may not only treat depression but also keep it away for a long time.
Major depressive disorder (MDD) is now the most common mental health problem in the world. It affects about 5% of people. It is also expected to become the top cause of disability in adults. Many drugs treat MDD. But they are slow to act, often do not work, and depression often comes back1.
Today, most doctors start treating depression with SSRIs (selective serotonin reuptake inhibitors) like fluoxetine (Prozac). They are very safe, but they often cause side effects. SSRIs cause sexual problems, sleep problems, weight gain, appetite changes, headaches, and much more. They also take several weeks to start working. Worse, MDD comes back in more than 80% of cases once the drug stops2.
Because of these limits, doctors, including chronic pain specialists, are looking at other therapies and combined plans. The goal is better results and fewer relapses.
What is allopregnanolone, and can it treat depression?
Many side effects, slow action, and a very high relapse rate show an urgent need. We need an antidepressant that is safer and lasts longer. Researchers seem to have found it in allopregnanolone.
It is a neurosteroid (a steroid made in the nervous system) found almost a century ago. It was first found in the adrenal gland. Then, in 1981, researchers found that the brain makes it too. Over the next 25 years, they learned how it is made. They learned the role of enzymes like 5α-reductase type I (5α-RI) and 3α-hydroxysteroid dehydrogenase (3α-HSD)3.
Researchers also found that it is very active in certain brain centers. It is key to keeping the amygdala working. The amygdala is the brain center that runs emotional responses. It is central to handling fear or threat signals. In depression, this handling is changed.
That led to the approval of allopregnanolone to treat depression. It is now better known as brexanolone and sold as Zulresso.
How does allopregnanolone cause lasting remission of depression?
Synthetic allopregnanolone is approved for use, and it is known to bring long remission of depression. But researchers have struggled to explain how it works.
They knew that it changes how active the amygdala is, forever or at least for a long time. They also knew that it works by tuning GABA receptors in that part of the brain. But how tuning GABA receptors in the amygdala brings remission of the disease was a mystery.
The new study in rodents seems to have found how this new neurosteroid works. It helped correct certain brain waves that had gone off track. And these changes last. It seems that allopregnanolone boosts high theta waves (6–12 Hz) in the amygdala4.
Figure 1 Novel neurosteroid causes prolonged depression remission3
Treatment with allopregnanolone helps shield the brain from stress. It causes lasting changes in behavior.
In the clinical studies, 60 hours of brexanolone infusion (synthetic allopregnanolone) helped treat post-partum depression. It kept it from coming back for as long as 30 days. That is quite unlike SSRIs or other antidepressants. With those, depression mostly comes back fast once the drug stops.
Researchers know many things can affect brain waves. Still, these findings add to what we know about how the brain works. They also open a door to other therapies that target brain waves.
Frequently asked questions
What does allopregnanolone do in the body?
Allopregnanolone is a neurosteroid that is very active in certain brain centers. It is key to keeping the amygdala working right. That is the part of the brain that handles emotions and fear and threat signals. It works by tuning GABA receptors there. In depression, that fear and threat handling is changed.
Where does allopregnanolone come from?
The body makes it. Allopregnanolone was found almost a century ago, first in the adrenal gland. In 1981, researchers found that the brain makes it too. Over the next 25 years they worked out how it is made. That includes the role of two enzymes: 5α-reductase type I and 3α-hydroxysteroid dehydrogenase.
What is brexanolone (Zulresso)?
Brexanolone is synthetic allopregnanolone, sold as Zulresso and approved to treat depression. It is given as an infusion. In clinical studies, a 60-hour brexanolone infusion treated postpartum depression. It kept it from coming back for as long as 30 days. SSRIs and other antidepressants are different: depression usually comes back fast once the drug stops.
How is allopregnanolone different from SSRIs?
Both work about equally well, but they act very differently. SSRIs such as fluoxetine (Prozac) take several weeks to start working. They often cause side effects such as sexual problems, sleep problems and weight gain. And depression returns in more than 80% of cases when they are stopped. Allopregnanolone brings long remission with a very low relapse rate.
References
- Clevenger SS, Malhotra D, Dang J, Vanle B, IsHak WW. The role of selective serotonin reuptake inhibitors in preventing relapse of major depressive disorder. Ther Adv Psychopharmacol. 2018;8(1):49-58. doi:10.1177/2045125317737264
- Ferguson JM. SSRI Antidepressant Medications: Adverse Effects and Tolerability. Prim Care Companion J Clin Psychiatry. 2001;3(1):22-27.
- Pinna G. Allopregnanolone, the Neuromodulator Turned Therapeutic Agent: Thank You, Next? Front Endocrinol (Lausanne). 2020;11:236. doi:10.3389/fendo.2020.00236
- Antonoudiou P, Colmers PLW, Walton NL, et al. Allopregnanolone Mediates Affective Switching Through Modulation of Oscillatory States in the Basolateral Amygdala. Biological Psychiatry. 2021;0(0). doi:10.1016/j.biopsych.2021.07.017
Dr. Gurpreet Singh Padda, MD, MBA, MHP
