​​FDA watch: 4 psychiatric agents in the pipeline

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.

Kar-XT

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.

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.

AXS-05

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.

Hydroxynorketamine

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.