​​FDA watch: 4 psychiatric agents in the pipeline

By Samar Mahmoud, PhD | Medically reviewed by Amanda Zeglis, DO, MBA
Published July 21, 2022

Key Takeaways

  • Mental disorders constitute a significant disease burden worldwide.

  • While many pharmaceutical companies have diverted resources from psychiatric drugs, the market for mental disorder therapeutics is expected to increase by 2028.

  • Psychiatric agents in the current developmental pipeline include drugs to treat schizophrenia, postpartum depression, and major depressive disorder.

Untreated mental disorders account for a considerable disease burden worldwide, yet there’s been a shift away from psychiatric drug discovery. Many pharmaceutical companies have downplayed the development of psychiatric drugs—possibly due to limited understanding of the neurobiological mechanisms that underlie these disorders, and multiple late-stage failures for psychiatric drug candidates in recent years.[]

But now that may be changing. The market for central nervous system (CNS) therapeutics, driven by unmet need as well as government initiatives, is expected to take a turn for the better.[] A report from Grand View Research estimates that the CNS drug market size is predicted to be $205 billion by 2028.[] This is an increase from its value of $116.2 billion in 2020.

Here's a list of four psychiatric drugs currently in the developmental pipeline that have demonstrated promise in offering patients new, effective treatments.


Kar-XT is a combination of the drugs xanomeline and trospium. Xanomeline is a muscarinic receptor agonist that is selective for the M1 and M4 receptor subtypes.[] Clinical trials have demonstrated that xanomeline leads to improvements of both positive and negative schizophrenia symptoms. However, patients who received xanomeline as a monotherapy did not tolerate it well, due to adverse effects which included vomiting, diarrhea, and nausea. To circumvent this issue, xanomeline was combined with trospium, a peripheral muscarinic antagonist incapable of crossing the blood-brain barrier.

Kar-XT showed positive results in a phase 2 trial, leading to a decrease in negative and positive schizophrenia symptoms. In addition, the drug was well-tolerated in patients.

SAGE-217, also known as Zuranolone

Allopregnanolone is a naturally occurring neurosteroid that acts as a positive allosteric modulator of the GABA type A receptor. In 2019, the Food and Drug Administration (FDA) approved brexanolone, which is an IV forumlation of allopregnanolone, for the treatment of postpartum depression as a first-in-class medication. Allopregnanolone is thought to function by intensifying GABAergic signaling in the brain which leads to an improvement in symptoms, such as depression and anxiety.

Unlike brexanolone, SAGE-217 is an oral version of allopregnanolone that is currently being evaluated for the treatment of major depressive disorder (MDD) in males and females as well as postpartum depression.


AXS-05 is a combination of two FDA approved drugs, dextromethorphan and bupropion. Dextromethorphan, a cough suppressant, was approved by the FDA in 1954 and was then approved as an over-the-counter drug in 1958. It acts as a NMDA-glutamate antagonist, a sigma-1 receptor agonist, and non-selective serotonin reuptake inhibitor. Bupropion was approved by the FDA in 1985 as the first selective norepinephrine and dopamine reuptake inhibitor. It is approved for the treatment of MDD, nicotine dependence, and seasonal affective disorder. Bupropion was also found to be a strong inhibitor of the cytochrome P450 2D6 enzyme, which is involved in the metabolism of dextromethorphan. The combination of these two drugs allows dextromethorphan to persist for a longer time in the body. Prolonged dextromethorphan serum levels in combination with the norepinephrine and dopamine reuptake inhibition characteristics of bupropion are what create the antidepressant qualities of AXS-05.

Phase 3 clinical trials in patients with MDD found that, after 6 weeks, AXS-05 improved the Montgomery Asberg Depression Rating Scale (MADRS) by 4.7 points in comparison to the placebo.


In March 2019, the FDA approved intranasal esketamine, an enantiomer of ketamine, for the treatment of MDD. Esketamine is approved for the treatment of depressive symptoms in patients who have MDD with suicidal ideation as well as for treatment-resistant depression in adults. Esketamine is a potent antidepressant, improving symptoms within 24 hours. While its mechanism of action is unknown, it is thought to exert its antidepressant effects by increasing the activity of mTOR. The two enantiomers of ketamine are metabolized to hydroxynorketamine, which functions by activating the AMPA glutamate ion channel, leading to an increase in mTOR activity. In animal models, hydroxynorketamine worked rapidly to decrease depressive symptoms.

This is promising because unlike ketamine and esketamine, hydroxynorketamine does not have dissociative effects and has no potential for abuse.

What this means for you

Mental disorders are highly prevalent and contribute to a significant disease burden across the globe, highlighting the need for more effective therapeutics to treat mental health concerns. There are currently promising psychiatric agents being developed to treat various mental disorders, including schizophrenia and major depressive disorder. These novel agents shed new light on brain functioning and show promise in improving the quality of life for patients suffering from psychiatric conditions.

Read Next: Adverse effects of 4 drugs approved in 2021
Share with emailShare to FacebookShare to LinkedInShare to Twitter