A minimum of 1 episode of major depression is reported by 19.4 million US people who are 18 years of age and older per year.1 With 10% of US people experiencing a mood disorder episode in 2021, major depressive disorder (MDD) and its related mood disorders are the most often diagnosed mental illnesses.2 Hence, there is a need for an effective therapeutic intervention that would help improve the quality of life for patients living with MDD.
What is major depressive disorder?
MDD is a neuropsychiatric disorder characterized by suicidal thoughts, a depressed mood, and a loss of interest in enjoyable activities. According to the World Health Organization (WHO), 5% of the world's population is impacted by MDD. Around 0.8 million individuals commit suicide annually, and more than 90% of them have a psychiatric diagnosis, according to a WHO 2020 study. There are no reliable physiological or molecular indicators for psychiatric diseases despite decades of research. Therefore, questionnaire-based psychiatric evaluation is the primary method used to diagnose these diseases. The criteria for diagnosing psychiatric diseases are constantly changing.3
According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5, 2013), at least five of these symptoms must be present throughout the full two-week period in order to diagnose MDD: chronic sadness, feeling empty, and hopelessness; markedly decreased interest in enjoyable activities; significant weight loss or gain; increased or decreased appetite; insomnia or hypersomnia; exhaustion; feelings of worthlessness; excessive or inappropriate guilt; diminished ability to think or concentrate; indecision; recurrent thoughts of death and suicidal ideation without a specific plan; and psychomotor agitation.4
Gamma-Aminobutyric Acid (GABA): A Key Neurotransmitter
The central nervous system's principal inhibitory neurotransmitter, GABA, is essential for regulating the balance of neuronal activity in the brain, and maintaining the homeostasis of neuronal activity.5 An imbalance between neural excitation and inhibition leads to several illnesses, such as spasticity, sleeplessness, anxiety, and convulsions.5
Based on research done on depressive individuals, MDD is associated with decreased levels of the inhibitory neurotransmitter GABA in the brain, as well as changes to the subunit makeup of the main GABA-A receptors, which mediate GABAergic inhibition.6 Additionally, there is strong evidence that GABA plays a significant role in how the brain regulates stress, which is a major risk factor for mood disorders. Additionally, preclinical data suggest that nonpharmacological treatments and currently prescribed antidepressant medicines (ADs) intended to change monoaminergic transmission may eventually work to compensate for GABAergic deficiencies.6 The modulation of hippocampal neurogenesis and neural maturation, which are now recognized as the biological substrates of the majority, if not all, antidepressant treatments, is particularly influenced by GABAergic transmission.6
The Current and Future Therapies for MDD
Tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRIs) have all been used to treat MDD.7 The glutamate and GABA-A neurotransmitter system have most recently been implicated as major participants in MDD illnesses, according to research conducted in the last 25 years.8 A new extra-synaptic GABA called zuranolone (SAGE217), which is an experimental new medication that is an oral modulator, was successfully submitted as a first-in-class compound in 2013.2
What is zuranolone, and how is it effective against MDD?
Zuranolone (SAGE-217) is a brand-new, synthetic, clinical-stage neuroactive steroid with positive GABA-A receptor allosteric modulation capabilities intended for oral daily dose. At nine distinct human recombinant receptor subtypes, including representative receptors for both synaptic (containing subunits) and extrasynaptic (containing subunits) configurations, zuranolone increased GABA-A receptor current in vitro.5 Zuranolone and the benzodiazepine diazepam together potentiated GABA currents at a typical synaptic subunit configuration, which is consistent with the non-competitive action and different binding sites of the two classes of drugs at synaptic receptors.5 Zuranolone caused a sustained rise in GABA currents in a brain slice preparation that is compatible with metabotropic trafficking of GABA-A receptors to the cell surface.3
Initially, the pharmacokinetics of zuranolone in rodents showed promise, with a decent 24-hour exposure via both IV and PO in the mouse.2 By preventing chemo-convulsant seizures in a mouse model and boosting electroencephalogram -frequency power in rats, zuranolone demonstrated significant activity in vivo, showing its capacity to activate GABA-A receptors in the central nervous system (CNS) following oral administration. All these findings show zuranolone to be a powerful and effective neuroactive steroid that is GABA-A receptor positive, and an allosteric modulator with drug-like characteristics and CNS exposure in preclinical models.5 Brexanolone is the first medication approved particularly for the treatment of postpartum depression (PPD), and recent clinical data confirm the therapeutic promise of neuroactive steroids as GABA-A receptor positive modulators for the treatment of mood disorders.5 For the treatment of major depressive episodes ( MDEs) in MDD, PPD, and bipolar depression (BD), zuranolone is now being studied in clinical trials.5 The Food and Drug Administration (FDA) awarded fast track designation to zuranolone in 2017 and breakthrough therapy designation for MDD in 2018. In 2022, the FDA also gave PPD fast track designation.9
1. US Census Bureau, Population Division. Annual estimates of the resident population by single year of age and sex for the United States: April 1, 2010 to July 1, 2019. June 2020. Accessed December 24, 2022. https://www2.census.gov/programs-surveys/popest/tables/2010-2019/national/asrh/nc-est2019-syasexn.xlsx (2020)
2. Beresis, Richard T. Sage 217 (Zuranolone) for treatment of major depressive disorder. In: Beresis RT; Li JJ, ed. Current Drug Synthesis. 1st ed. John Wiley & Sons, Inc; 2022. Accessed December 24, 2022. https://doi.org/10.1002/9781119847281.ch14
3. Mullins N, Bigdeli TB, Borglum AD, et al. GWAS of suicide attempt in psychiatric disorders and association with major depression polygenic risk scores. Am J Psychiatry. 2019;176(8):651–60. doi: 10.1176/appi.ajp.2019.18080957
4. American Psychiatric Association, DSM-5 Task Force. Diagnostic and statistical manual of mental disorders: DSM-5. 5th ed. American Psychiatric Publishing, Inc; 2013. https://doi.org/10.1176/appi.books.9780890425596
5. Althaus AL, Ackley MA, Belfort GM, et al. Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator. Neuropharmacology. 2020;181:108333. doi: 10.1016/j.neuropharm.2020.108333
6. Luscher B, Shen Q, Sahir, N. The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry. 2011;16(4):383-406. doi: 10.1038/mp.2010.120
7. 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.
8. Sarawagi A, Soni ND, Patel AB. Glutamate and GABA homeostasis and neurometabolism in major depressive disorder. Front Psychiatry. 2021;12:637863. doi: 10.3389/fpsyt.2021.637863.
9. Biogen and Sage Therapeutics complete rolling submission of new drug application for zuranolone in the treatment of major depressive disorder and postpartum depression. News release. Biogen Inc; December 6, 2022. Accessed December 24, 2022. http://media.biogen.com/news-releases/news-release-details/biogen-and-sage-therapeutics-complete-rolling-submission-new