Summary: Major depressive disorder (MDD) is now the leading mental health issue. Its prevalence is only expected to grow. Although there are numerous medications to manage the condition, but treatment is far from satisfactory. SSRs are the most commonly prescribed drugs to treat MDD. However, they have a high relapse rate. Fortunately, it seems researchers have found a medication that may not only effectively treat depression but also lead to its prolonged remission. A synthetic neurosteroid called allopregnanolone is one of the first drugs approved in its class. It has efficacy comparable to SSRIs. However, unlike these medications, it causes prolonged remission, has a very low relapse rate. It appears to work very differently by changing oscillations in the amygdala.
Keywords: major depressive disorder, MDD, SSRIs, Prozac, allopregnanolone, brain oscillations, amygdala
Major depressive disorder (MDD) is now the most common mental health issue in the world. It affects about 5% of the population. Furthermore, it is projected to become the leading cause of disability in adults. Although many medications are available to treat MDD, they are slow to act, do not work in many cases, and have a high relapse rate1.
At present, most doctors would start treating depression with SSRIs (selective serotonin reuptake inhibitors) like fluoxetine (Prozac). Unfortunately, although they are highly safe, they often cause side effects. For example, SSRIs cause sexual dysfunction, sleep disorders, weight gain, changes in appetite, headaches, and much more. In addition, they take several weeks to start working. Even worse, MDD would relapse in more than 80% of cases on discontinuation of drug therapy2.
A novel way to manage depression
A high number of side effects, slow mechanism of action, and extremely high relapse rate only show an urgent need to find an antidepressant that is safer and has prolonged action. It seems that researchers have found that ideal antidepressant in the form of allopregnanolone.
It is a neurosteroid discovered almost a century ago. It was first identified in the adrenal gland. However, in 1981, researchers found that it is also produced in the brain. In the next 25 years, researchers could understand how it is produced and the role of enzymes like 5α-reductase type I (5α-RI) and 3α-hydroxysteroid dehydrogenase (3α-HSD), in its production3.
Further, researchers discovered that it has high activity in specific brain centers. It is especially important for maintaining the activity of the amygdala, a brain center responsible for emotional responses. Amygdala is especially central to processing fear or threat signals. And, in depression, alteration in this processing is present.
It has led to the approval of allopregnanolone for the treatment of depression. It is now better known as brexanolone and marketed as Zulresso.
A new study shows how the novel neurosteroid may cause prolonged depression remission
Although synthetic allopregnanolone is approved for clinical use, it is known that it causes prolonged remission of depression. However, researchers have been struggling to explain how it works.
They knew that it changes the activity level of the amygdala for ever or at least for a prolonged time. They also knew that it works by modulation GABA receptors in the part of the brain. But, how modulating GABA receptors in the amygdala causes remission of the disease remains a mystery.
The new study in rodents appears to have found how this novel neurosteroid works. Researchers found that it helped correct specific altered brain oscillations. And these changes are pretty persistent. Thus, it seems that allopregnanolone enhances high theta oscillations (6–12 Hz) in the amygdala4.
Treatment with allopregnanolone helps protect the brain from various stressors, causing prolonged behavioral changes.
In the clinical studies, 60 hours of brexanolone infusion (synthetic allopregnanolone) could help treat and prevent relapse of post-partum depression for as many as 30 days. Thus, it is quite unlike SSRIs or other antidepressants, in which case relapse occurs in most cases quickly on the discontinuation of the drugs.
Researchers know that there could be many factors affecting brain oscillations. Nonetheless, these findings increase our knowledge of how the brain works. It also opens a door for finding other therapies targeting brain oscillations.
1. 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
2. Ferguson JM. SSRI Antidepressant Medications: Adverse Effects and Tolerability. Prim Care Companion J Clin Psychiatry. 2001;3(1):22-27.
3. Pinna G. Allopregnanolone, the Neuromodulator Turned Therapeutic Agent: Thank You, Next? Front Endocrinol (Lausanne). 2020;11:236. doi:10.3389/fendo.2020.00236
4. 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