A Look at the Psychopharmacology Pipeline

Over the past decade, there have been developments in psychopharmacology, and the possibility of treating psychiatric conditions has improved enormously. During a presentation at the Neuroscience Education Institute Max! Virtual Meeting, Andrew J. Cutler, MD, a clinical professor in the Department of Psychiatry at SUNY Upstate Medical, discussed neurobiology, etiology, genetics, diagnosis, and treatment recommendations for various mental health conditions.

Unmet treatment needs for psychopharmacology include drugs that treat more symptoms, drugs that provide improved options for treatment-resistant disease, drugs with enhanced safety profiles, and drugs that increase compliance.

There are 29 stimulant preparations and three non-stimulant preparations that are FDA-approved for attention deficit/hyperactivity disorder. The stimulant pipeline includes AR19, a manipulation resistant amphetamine, which has a forthcoming PDUFA date. Centanafadine, CX717 (an AMPA modulator), eltoprazine, and other non-stimulants are also in development.

Mood disorder spectrum includes bipolar depression and bipolar mania. “Unfortunately, a majority of our antidepressants don’t do a great job,” he said, as only one in three patients will achieve remission on their first antidepressant. Two-thirds of patients (67%) require four antidepressant trials before symptoms remit. “There’s quite an unmet need for the treatment of depression,” he said.

A number of monotherapies target multiple receptors for the treatment of depression, including mirtazapine, nefazodone, trazodone (and trazodone ER), vilazodone, and vortioxetine. Other targets for depression treatment include acetylcholine release inhibitor and neuromuscular blocking agent, such as onabotulinum toxin A; acetylcholine muscarinic receptor antagonist such as scopolamine; glucocorticoid receptor antagonists, for which three agents are in development — mifepristone, metyrapone, and org-34517; and other somatic treatments, including deep transcranial magnetic stimulation, repetitive transcranial magnetic stimulation, synchronized transcranial magnetic stimulation, low field magnetic stimulation, and intermittent theta-burst stimulation.

Treatments in the pipeline for major depressive disorder include the NMDA modulator AV-101, the kappa opioid antagonist BTRX-335140, the ephedrine nasal spray PH10, and the GABA-A modulator SAGE-217, among others.

Treatments under consideration for bipolar depression include lumateperone, which is currently FDA-approved for schizophrenia, and NRX-101 (lurasidone/cycloserine), which is under investigation for bipolar depression with suicidal ideation and behavior.

Dr. Cutler noted that during the COVID-19 pandemic, there are potential interactions that occur between psychotropics and organ systems effected by COVID-19. For instance, use caution with psychotropics that may impact white blood cell production, may cause liver injury, and may lower seizure threshold.

“We have a lot of activity in the schizophrenia field,” he said. Unmet treatment needs for schizophrenia include drugs that treat negative symptoms, enhance cognition, provide improved options for treatment- resistant patients, have enhanced safety profiles — “maybe even with non-dopaminergic profiles” — and drugs that increase compliance.

“We’d like to use drugs that target different types of circuitry,” he said, noting that each symptom may be related to certain malfunctioning brain circuits. “We don’t have any drugs that address these different circuits in the brain.” A number of dopaminergic antipsychotics are in development, including eltoprazine, stepholidine, YKP1358, and more. Beyond dopamine, lumateperone was approved by the FDA in December 2019. Other non-dopaminergic agents in development include pimavanserin, KarXT (xanomeline plus trospium), and SEP-363856.

Lastly, Dr. Cutler talked about sleep disorders. There are many current pharmacologic treatments for insomnia, including benzodiazepine hypnotics, antidepressants, hypocretin/orexin antagonists, and a melatonin receptor agonist. Blocking orexin receptors with antagonist agents may help to promote sleep, he said. Lemborexant blocks the orexin system and is FDA-approved for insomnia. The other FDA-approved orexin-blocking agent is suvorexant.

Presentation: Into the Pipeline: The Latest in Psychopharmacology. Presented at the Neuroscience Education Institute Max! Virtual Meeting, Nov. 5-8, 2020.