This newsletter focuses on promising drugs and new applications of known drugs that may play a significant role in mental health treatment by 2024. Each drug is explored along with the available evidence supporting its efficacy.
We also share key points from an interview on depression, anxiety, and delirium in patients with cancer; a presentation on psychodynamic psychopharmacology; and our practical research summaries of adult psychiatry (Quick Takes).
Upcoming Psychiatric Drugs for 2024
The constant quest for new and improved treatment methods is critical in the ever-evolving field of psychiatry. The development of medication that can effectively manage and potentially cure mental disorders is a priority in the psychiatric community. What promising drugs or new applications of known drugs can we anticipate for 2024?
Drugs Seeking Approval for New Indications
Zuranolone (Zurzuvae) for Major Depressive Disorder (MDD)
- Therapeutic Application Proposal:
- Zuranolone—approved in 2023 for postpartum depression—is currently being studied for the treatment of MDD.
- Available evidence:
- The phase 3 CORAL study demonstrated that zuranolone, combined with a standard antidepressant, significantly reduced depressive symptoms within 3 days, with effects lasting up to 2 weeks.
- Contrastingly, in a previous phase 3 study, zuranolone did not show any significant difference from placebo in terms of its effectiveness.
- Highlights:
- Last year, the FDA announced the new drug application (NDA) for MDD did not offer significant evidence of effectiveness. Thus, more research is needed.
- If approved, zuranolone would represent a new approach to treating MDD.
- Unlike most current treatments, which can take 6–8 weeks to take effect, zuranolone is designed as a 14-day treatment.
Lumateperone (Caplyta) for MDD
- Therapeutic Application Proposal:
- Lumateperone—initially approved for schizophrenia and depressive episodes in bipolar disorder—is being studied for the treatment of MDD.
- Available evidence:
- Lumateperone has shown significant improvement in the total score on the Montgomery Asberg Depression Rating Scale compared with placebo.
- These results have bolstered confidence in its potential as a treatment for MDD, with the manufacturer planning to seek approval for this use in 2024.
- Highlights:
- Lumateperone works on both dopamine and serotonin receptors.
- It could potentially be beneficial for patients who have not responded well to other antidepressant treatments.
Dextromethorphan/bupropion (Auvelity) for Agitation in Alzheimer’s Disease
- Therapeutic Application Proposal:
- Dextromethorphan/bupropion—already approved for treating MDD—is currently being researched for its potential use in treating agitation in patients with Alzheimer’s disease.
- Auvelity is an oral N-methyl D-aspartate receptor antagonist.
- Available evidence:
- Auvelity demonstrated promising results in the phase 3 ACCORD trial, where it met both primary and secondary endpoints.
- The drug significantly delayed the time to relapse and prevented relapse of agitation in Alzheimer’s patients.
- Highlights:
- It has shown substantial effectiveness against agitation symptoms in Alzheimer’s disease and now is awaiting the decision on the next steps to submit an NDA.
Novel Drugs Seeking for Approval
ALTO-100 for MDD and Posttraumatic Stress Disorder (PTSD)
- Therapeutic Application Proposal:
- ALTO-100 is currently being evaluated for the treatment of MDD and PTSD.
- It works through brain-derived neurotrophic factor, which is involved in brain plasticity.
- The hypothesis is that in depression, disrupted brain plasticity influences cognition.
- Available evidence:
- In a phase 2a study, ALTO-100 showed clear evidence of efficacy and a favorable safety profile in MDD. It is now being assessed in a phase 2b trial.
- Highlights:
- ALTO-100 is being developed based on artificial intelligence.
- Developers are looking for biomarkers with machine-learning models to optimize the selection of patients who will benefit most from this medication.
- ALTO-100 aims to treat patients struggling with cognition problems due to depression by restoring neural plasticity, thus enhancing the brain’s ability to adapt and learn.
Xanomeline–Trospium (KarXT) for Schizophrenia
- Therapeutic Application Proposal:
- KarXT is a novel drug that aims to treat both positive and negative symptoms of schizophrenia.
- It works as an agonist of muscarinic acetylcholine 1 receptors M1 and M4.
- Available evidence:
- KarXT has shown promising results in 3 trials, meeting its primary endpoint of reducing symptom severity on the Positive and Negative Syndrome Scale (PANSS).
- However, it failed to meet a secondary endpoint in decreasing negative symptoms compared with placebo at week 5 but did significantly reduce negative symptoms on 2 other scales after 4 weeks.
- Highlights:
- If approved, KarXT would be the first new class of medicine for schizophrenia in over 50 years.
- The drug could revolutionize the treatment of schizophrenia, as it targets not just positive symptoms but also negative symptoms, such as social withdrawal, lack of motivation, and apathy.
- It is also being studied for treating psychosis in Alzheimer’s disease.
Emraclidine for Schizophrenia
- Therapeutic Application Proposal:
- Emraclidine is a promising drug designed to treat the symptoms of schizophrenia.
- It acts as a positive allosteric modulator that selectively targets M4 receptors, capitalizing on the potential antipsychotic benefits associated with these receptors.
- Available evidence:
- Emraclidine is currently in phase 2 trials, having successfully shown meaningful improvement in PANSS total score at 6 weeks in a phase 1b study.
- The drug was generally well-tolerated compared with placebo.
- Highlights:
- Like KarXT, emraclidine targets M4 receptors.
- Emraclidine aims to offer the antipsychotic benefits associated with M4 receptors while minimizing side effects linked with pan-muscarinic agonists.
Troriluzole for Obsessive-Compulsive Disorder (OCD)
- Therapeutic Application Proposal:
- Troriluzole is an innovative drug being developed to treat OCD and spinocerebellar ataxia.
- It is a novel chemical entity and a tripeptide prodrug of the active metabolite riluzole, which is approved to treat amyotrophic lateral sclerosis (ALS).
- Available evidence:
- The use of troriluzole in OCD is supported by clinical data from riluzole in open-label and placebo-controlled clinical trials.
- Highlights:
- This drug represents an extension of riluzole’s application from treating ALS to potentially treating OCD.
Fasedienol for Social Anxiety Disorder (SAD)
- Therapeutic Application Proposal:
- Fasedienol is an investigational drug for the treatment of SAD.
- Available evidence:
- Initial trials (PALISADE-1) did not meet the primary endpoint; however, recent positive results have emerged from a second phase 3 trial (PALISADE-2).
- In the PALISADE-2 study, participants using the fasedienol nasal spray experienced a significantly greater reduction in their Subjective Units of Distress Scale score.
- Highlights:
- After initial setbacks, fasedienol shows promise in treating SAD based on positive results from recent trials.
- If successful, it could mark significant progress in the field, given that PALISADE-2 is the first positive U.S. phase 3 study of an investigational SAD therapy in over 15 years.
Depression, Anxiety, and Delirium in Patients With Cancer With Jaroslava Salman, M.D.
In this interview, Dr. Yara Salman explores depression, anxiety, and delirium in patients with cancer. She delves into critical topics like differentiating between depression and grief in cancer patients, understanding demoralization, and providing top prescribing tips for various situations. She also discusses the effective management of cancer-related fatigue, highlighting the use of stimulants to significantly enhance quality of life and functionality.
Interview highlights include the following:
- For the management of fatigue associated with cancer or its treatment, consider stimulants to help restore quality of life and functioning.
- Some cancer treatments, such as steroids and chemotherapy, can induce depression in patients. Consider using antidepressants to manage symptoms during those periods.
Learn more and earn 0.5 CME credits here.
Psychodynamic Psychopharmacology: Alliance, Communication, and Psychotherapy Skills
In this presentation, Dr. Mintz continues the journey through the intricate principles of psychodynamic psychopharmacology. With an expert touch, he unveils the science behind the art of psychopharmacotherapy and sheds light on the implications of the biological theory of illness. Furthermore, he delves into the relevance of enhancing the pharmacotherapy alliance with our patients, substantiating the importance of respecting their treatment preferences and fostering effective communication.
Pharmacotherapy Alliance, Treatment Preferences, and Communication
- The pharmacotherapeutic alliance exerts a greater effect on treatment outcomes than medication.
- The prescriber can improve outcomes by attending to evidence-based factors that enhance the alliance.
- Warmth, empathy, and respect for treatment preferences contribute to better outcomes.
Learn more and earn 1 CME credit here.
Quick Takes: Research, Digested
Use of Daridorexant for the Management of Chronic Insomnia
- Dual orexin receptor antagonists, such as daridorexant, treat insomnia by inhibiting wakefulness, in contrast with other hypnotics that enhance sleep through inhibitory neurotransmission.
- Daridorexant may be effective in improving sleep, with 78% of patients showing significant improvement in insomnia severity index scores after switching from other medication. Learn more.
Listen to or read the full volume and earn 0.5 CME credits here.
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References
- Clayton, A. H., Lasser, R., Parikh, S. V., Iosifescu, D. V., Jung, J., Kotecha, M., Forrestal, F., Jonas, J., Kanes, S. J., & Doherty, J. (2023). Zuranolone for the treatment of adults with major depressive disorder: A randomized, placebo‐controlled phase 3 trial. American Journal of Psychiatry, 180(9), 676-684.
- Intra-Cellular Therapies. (2023). Intra-cellular therapies announces positive topline results from study 403 evaluating lumateperone as monotherapy in patients with major depressive disorder with mixed features and bipolar depression with mixed features. https://ir.intracellulartherapies.com/node/12896/pdf
- Axsome Therapeutics. (2022, September 8). Axsome therapeutics initiates ADVANCE-2 phase 3 trial of AXS-05 in Alzheimer’s disease agitation. https://axsometherapeuticsinc.gcs-web.com/node/10521/pdf
- Alto neuroscience announces positive results for ALTO-100 in phase 2 study supporting advancement of first-in-class mechanism for treating depression. (2023, January 10). Alto Neuroscience. https://www.altoneuroscience.com/press-releases/alto-neuroscience-announces-positive-results-for-alto-100-in-phase-2-study-supporting-advancement-of-first-in-class-mechanism-for-treating-depression
- Kaul, I., Sawchak, S., Correll, C. U., Kakar, R., Breier, A., Zhu, H., Miller, A. C., Paul, S. M., & Brannan, S. K. (2024). Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline–trospium) in schizophrenia (EMERGENT-2) in the USA: Results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. The Lancet, 403(10422), 160-170.
- Krystal, J. H., Kane, J. M., Correll, C. U., Walling, D. P., Leoni, M., Duvvuri, S., Patel, S., Chang, I., Iredale, P., Frohlich, L., Versavel, S., Perry, P., Sanchez, R., & Renger, J. (2022). Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: A two-part, randomised, double-blind, placebo-controlled, phase 1b trial. The Lancet, 400(10369), 2210-2220.
- Glutamate modulation platform | Biohaven. (2023, October 6). Biohaven, Ltd. https://www.biohaven.com/pipeline/clinical-programs/glutamate/
- Vistagen Therapeutics. (2023, August 7). Vistagen announces positive top-line results from phase 3 PALISADE-2 trial of fasedienol (PH94B) nasal spray in social anxiety disorder. Vistagen Therapeutics, Inc. https://www.vistagen.com/news-releases/news-release-details/vistagen-announces-positive-top-line-results-phase-3-palisade-2
