Alison Wakeford, PhD, Scientist, Allucent
Marcus S. Delatte, PhD, VP Regulatory Strategy, Allucent
Background
According to the World Health Organization, depression is a common mood disorder, affecting approximately 280 million people globally.1 Depression is characterized by persistent feelings of sadness and loss of interest, occurs across almost all age groups, and manifests in various forms ranging in severity from mild to debilitating. In addition to the exceedingly complex nature of this illness, the estimated yearly costs for depression to US employers are staggering – $134 billion in health care (including mental health), $20.9 billion in absenteeism, and $32.9 billion in lost productivity.2 Therefore, the development of safe and effective medications is not only critical for the well-being of many individuals globally, especially those in which current medications are ineffective (e.g., treatment-resistant depression), but represents a significant financial concern for employers across all sectors.
What You Need to Know
When evaluating the landscape for developing anti-depressant medications, the areas discussed below should be considered as part of work.
Public Health Concerns
- Depression is associated with significant morbidity and suicidality in adults and adolescents. The 2021 National Survey on Drug Use and Health indicated that, in the US, 21 million adults (≥ 18 years old) and 5 million adolescents (12 to 17 years old) had at least one major depressive episode in the past year
- The number of US adolescents experiencing depression in the past year represents 20% of the US adolescent population
- Unfortunately, within this same survey, an estimated 39% of adults and almost 60% of adolescents received no treatment for this disorder in the past year. 3
Regulatory Developments
- Regulating therapeutics and products intended to treat depression is challenging, given the numerous unapproved and misbranded products currently marketed to individuals4 in addition to the toxicity profile of many FDA-approved products.
- Despite FDA approval of products for the treatment of depression, some of these medications may produce severe adverse effects that complicate long-term treatment. These adverse effects include QT prolongation, serotonin syndrome, suicidal behavior and thoughts, embryo-fetal toxicities, abuse liability, and convulsions.
- In addition, the toxicity profiles for these medications can be worsened by potential drug interactions between approved products and other non-approved products used by these populations.
- Compliance with anti-depressant medications is also limited by reduced efficacy in many populations. According to the Clevland Clinic, approximately 30% of people diagnosed with major depressive disorder have treatment-resistant depression5. The lack of treatments for these individuals represents a unique and challenging therapeutic landscape and highlights the need for new treatments that act via novel mechanisms.
Drug Discovery and Development Achievements
- In the last 5 years, the FDA has approved several new molecular entities (NME) for the treatment of depression. These NMEs are believed to produce therapeutic effects via novel target sites, including GABAA receptor complexes, 5HT1A receptors, and non-competitive NMDA receptors.
- In particular, these products are indicated for use in patients with refractory depression (Spravato) and postpartum depression (Zuranolone), both populations having historically limited or no effective treatment options.
- Mounting evidence also suggests that psychedelics may be effective in treating major depression and treatment-resistant depression without serious side effects.6,7,8,9 Together, these findings support the development of NMEs that act at novel mechanisms to safely and effectively treat depression.
Recently Approved Medications for the Treatment of Depression
Product | Indication | Mechanism of Action | Source Document |
Zurzuvae (zuranolone; oral; 2023) | Post-partum depression (≥ 18 years old) | Positive modulation of GABAA receptor complex | |
Exxua (gepirone; oral; 2023) | Major Depressive Disorder (≥ 18 years old) | Modulation of serotonergic activity in the CNS via 5HT1A receptors | |
Zulresso (brexanolone; intravenous; 2019) | Post-partum depression (≥ 15 years old) | Positive modulation of GABAA receptor complex | |
Spravato (esketamine; PO; 2019) | Treatment-resistant depression (≥ 18 years old) Depressive symptoms in adults with major depressive disorder with acute suicidal ideation of behavior | Block non-competitive NMDA receptors |
Conclusion
This blog provides evidence supporting a significant need to develop medications that are safer and more effective than the existing FDA-approved products for the treatment of depression. Specifically, the identification of novel targets for therapeutic development represents a new and exciting avenue of product development in a treatment landscape that has been historically limited by severe toxicities and reduced efficacy.
Allucent’s Comprehensive Expertise in Anti-depressant Medication Development
Allucent’s experts maintain comprehensive and robust expertise in central nervous system (CNS) medication development. Specifically, Allucent’s experts demonstrate:
- Over 17 years of research experience in CNS pharmacology and behavior
- Expertise in the use of products that target GABAergic and central serotonergic (i.e., 5HT1A, 5HT2C/A) pathways relevant to the development of new candidate medications, in addition to work with psychedelics (3,4-methylenedioxymethamphetamine, “MDMA”)
- Over 11 years of service as a senior pharmacology/toxicology reviewer who advised sponsors on developing CNS therapeutic products and supported review teams in deciding if numerous IND were allowed to proceed and NDA applications were approved.
For more information about the specifics of the current treatment landscape related to depression, Allucent’s regulatory team is here to offer guidance and solutions. Contact us today!
Allucent brings new therapies to light by solving the distinct challenges of small and mid-sized biotech companies. We are a global provider of comprehensive drug development solutions, including regulatory consulting, clinical operations, biometrics, and clinical pharmacology across a variety of therapeutic areas. Our individualized partnership approach provides experience-driven insights and expertise to assist clients in successfully navigating the complexities of delivering novel treatments to patients. Learn more about how the A-Team can support your drug development programs.
References
1. World Health Organization (WHO). (2023, March 31). Depressive disorder (depression). https://www.who.int/news-room/fact-sheets/detail/depression Depressive disorder (depression) (who.int)
2. Meadows Mental Health Policy Institute. (2023). The Cost of Depression. https://mmhpi.org/topics/educational-resources/the-cost-of-depression/ The Cost of Depression – MMHPI – Meadows Mental Health Policy Institute
3. National Institute of Mental Health. (2023, July). Major Depression. https://www.nimh.nih.gov/health/statistics/major-depression NIMH » Major Depression (nih.gov)
4. U.S. Food & Drug Administration. (2023, November). Warning Letters. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters Warning Letters | FDA
5. Cleveland Clinic. (2023). Treatment-Resistant Depression. https://my.clevelandclinic.org/health/diseases/24991-treatment-resistant-depression Treatment-Resistant Depression: What It Is & Symptoms (clevelandclinic.org)
6. Robin L Carhart-Harris, Mark Bolstridge, James Rucker, Camilla M J Day, David Erritzoe, Mendel Kaelen, Michael Bloomfield, James A Rickard, Ben Forbes, Amanda Feilding, David Taylor, Steve Pilling, Valerie H Curran, David J Nutt. Psilocybin with Psychological Support for Treatment-Resistant Depression: An Open-Label Feasibility Study. Lancet Psychiatry. 2016 July; 3(7):619-27. doi: 10.1016/S2215-0366(16)30065-7. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study – PubMed (nih.gov)
7. R L Carhart-Harris, M Bolstridge, C M J Day, J Rucker, R Watts, D E Erritzoe, M Kaelen, B Giribaldi, M Bloomfield, S Pilling, J A Rickard, B Forbes, A Feilding, D Taylor, H V Curran, D J Nutt. Psilocybin with Psychological Support for Treatment-Resistant Depression: Six-Month Follow-Up. Psychopharmacology. 2018 February; 235(2):399-408. doi: 10.1007/s00213-017-4771-x. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up – PubMed (nih.gov)
8. Alan K Davis, Frederick S Barrett, Darrick G May, Mary P Cosimano, Nathan D Sepeda, Matthew W Johnson, Patrick H Finan, Roland R Griffiths. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2021 May 1; 78(5):481-489. doi: 10.1001/jamapsychiatry.2020.3285. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial – PubMed (nih.gov)
9. Natalie Gukasyan, Alan K Davis, Frederick S Barrett, Mary P Cosimano, Nathan D Sepeda, Matthew W Johnson, Roland R Griffiths. Efficacy and Safety of Psilocybin-Assisted Treatment for Major Depressive Disorder: Prospective 12-Month Follow-up. Journal of Psychopharmacology. 2022 February; 36(2): 151-158. doi:10.1177/02698811211073759. Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up – PubMed (nih.gov)