The psychiatric medication pipeline: What’s the latest?

FFor some, psychiatric medications are the difference between life and death. For others, they are the difference between life and chaos. The stakes are high for many people and that is why it is crucial to follow the medication process.

We will start as we did in the first part…

One in five American adults is believed to use psychiatric medications. The UK figures are similar.

Now, there are those who claim that psychiatric medications are not only useless, but also harmful. But for the sake of the people who believe in them (and trust them), as well as continuing the search for greater efficacy and fewer side effects, we must do it.

As you can imagine, we are dealing with a lot of information and there is no way to do it justice in one piece.

That’s why we covered generalized anxiety disorder, major depressive disorder, and post-traumatic stress disorder in part one. And here we will review attention deficit/hyperactivity disorder and schizophrenia.

While we’re on the subject, if you’re interested in participating in a US Food and Drug Administration (FDA) clinical trial for a drug in development anywhere in the world, hit the database. The UK offers the same in ScanMedicine.

Let’s get busy…

The psychiatric medication line: the latest

I tried to keep the information you’re about to read simple and brief, but I’ll tell you from the beginning: the details of schizophrenia are intense.

If you want every detail, there are links to my sources at the end.

Attention-deficit/hyperactivity disorder (ADHD)

Two medications – stimulants – are the most effective pharmacological treatments for ADHD: methylphenidate (Ritalin, Concerta, others) used since the 1960s and amphetamine (Adderall, Evekeo, others) used since the 1970s.

Two other classes of medications are available: presynaptic α2 adrenergic receptor agonists: extended-release clonidine (Kapvay), extended-release guanfacine (Intuniv), and primary norepinephrine reuptake inhibitors (NRIs): atomoxetine (Strattera) and extended-release viloxazine prolonged (Qelbree). .

Options are a good thing. As effective as stimulants can be, they are not for everyone. Furthermore, although two of the non-stimulants are NRIs, they have very different secondary mechanisms of action and pharmacokinetics.

Centanafadine

Centanafadine is a new inhibitor of the reuptake of norepinephrine, dopamine and serotonin: “triple reuptake inhibitor”.

The most common adverse events in phase 3 Studies that occurred in less than 7% of cases were headache and decreased appetite.

Centanafadine is in the final stages of development by Osaka Pharmaceutical. Completed Phase 3 studies indicate it could soon join the family of ADHD medications.

Schizophrenia

There are currently five prominent medications in development for the treatment of schizophrenia. And those who try to live with it fully deserve the attention.

Schizophrenia is an ultra-complicated disease, and that makes it difficult to explain the action of its medications on development.

But we can do this, so come on…

acetylcholine

Interesting: in the evolutionary history of the nervous system, it is believed that acetylcholine (ACh) is our original neurotransmitter. It is also the main neurotransmitter of our parasympathetic nervous systemthat orchestrates the “rest” and digest.”

Now we’ll get “scientific.” There are two types of neuronal receptors for ACh: nicotinic and muscarinic. Both have been considered targets for drug development. Here we will focus on muscarinic receptors (MAChR).

Muscaniric ACh M1 receptor agonism It has been associated with improved cognition, attention, and memory consolidation.

The key here is the fact that M4 receptors are selectively expressed in the striatumthe part of the brain believed to be the source of psychosis due to an imbalance of dopamine and ACh.

The molecule xanomeline is an agonist of the muscarinic acetylcholine receptor with selectivity (binding preference) at the M1 and M4 receptors.

When xanomeline agonizes M4 receptors, the flow of ACh into the synapse is inhibited, which is thought to ultimately result in a decrease in dopamine, which exacerbates psychosis, in the striatum.

So this is the preferred method of controlling dopamine-2 receptors at the source, rather than having to block them chemically at the synapse.

karxt

Karuna Therapeutics hypothesized and clinically confirmed that by adding trospium ion, a well-established mAChR antagonist, as a combination molecule with xanomeline, the core benefits of mAChR agonism could be maintained while trospium would buffer adverse effects by antagonizing mAChRs. peripherals. .

The resulting combination of xanomeline and trospium was compared to a placebo in a phase 2 trial. The results showed significant improvement. The phase 2 results were recently replicated by two phase 3 trials.

The most common adverse effects included constipation, nausea, dry mouth, indigestion, and vomiting.

In September 2023, Karuna Therapeutics submitted a new drug application to the FDA for karxt for the treatment of schizophrenia in adults. It was accepted.

Potential FDA approval of KarXT later this year would be huge. You see, all current FDA-approved antipsychotics share the property of antagonizing postsynaptic dopamine-2 receptors.

This leads to terrible adverse effects: movement disorders, elevated prolactin, cognitive dullness, and emotional dullness.

Yes, KarXT can be a game changer.

Emraclidine

Cerevel Therapeutics is developing its own muscarinic receptor agonist for the treatment of schizophrenia. Emraclidine It is highly specific for M4 receptors.

In a recent phase 1b trial, emraclidine produced clinically and statistically significant improvement. Two phase 2 trials are currently underway.

Iclepertin

Schizophrenia has three types of symptoms…

1. Positive: hallucinations, delusions, confused thoughts/disorganized speech, difficulty concentrating
2. Negatina: lack of pleasure, problems with speech, flattening, social withdrawal, difficulty with activities of daily living.
3. Cognitive: affects learning, storage and use of information: working memory, attention, organization of thoughts, decision making. They are known as cognitive impairments associated with schizophrenia (CIAS).

Unfortunately, there are no FDA-approved medications to treat CIAS. Boehinger Ingelheim aims to remedy this injustice with the nootropic iclepertin.

I’ll tell you what, this one is super complicated, so we’ll run it with the bare minimum. Schizophrenia is characterized by abnormalities in glutamatergic pathways related to NMDA receptor hypofunction..

Inhibition of glycine transporter-1 (GlyT1) in the presynaptic membrane or astrocytes is hypothesized to increase wisteria levels within the synapse. NMDA receptor function can be improved by increasing levels of its co-agonist, glycine, within the synaptic cleft, which may lead to improvements in cognitive function.

Iclepertin is a GlyT1 inhibitor.

A phase 2 trial demonstrated significant cognitive improvement. Iclepertin was found to be safe and well tolerated.

Three multinational phase 3 trials are underway.

roluperidone

Reducing the negative symptoms of schizophrenia (reference above) remains a huge unmet need.

roluperidone, developed by Minerva Neurosciences, is a novel molecule that antagonizes the 5-HT2A (serotonin), sigma-2 and α-1A adrenergic receptors. It was specifically designed to prevent activity in dopamine receptors, to reduce or eliminate the disabling adverse effects we reviewed above.

Roluperidone has been investigated in two trials and both demonstrated improvement over placebo. Two extension studies showed continued improvement in negative symptoms.

It looks like FDA approval could come later this year.

Evenamide

Treatment-resistant schizophrenia (TRS) is defined as lack of (or inadequate) symptom response after treatment with two antipsychotic medications for an appropriate dose and duration.

TRS is a major and devastating clinical challenge for the patient and their family, especially after clozapine (Clozaril), the only FDA-approved medication for TRS, failed to arrive.

Glutamatergic dysfunction has long been hypothesized to contribute to treatment resistance.

Newton Pharmaceuticals evenamide It is a selective inhibitor of voltage-gated Na+ channels. It has been shown to normalize glutamate release, demonstrating improvements in animal models of psychosis as monotherapy and as an adjunct to other antipsychotics, including clozapine.

A recent phase 2 study, with some limitations, using evenamide as an adjunct to a current antipsychotic showed significant and consistent improvement and was well tolerated.

Evenamide is in a very early stage of development, but is considered a drug to watch.

That will do it

Just like when I finished the first part, I’m wiping my forehead. There is so much complex information to review.

I’m excited that schizophrenia is getting so much attention. If you don’t have it, can you imagine what it could be like?

That will be enough for the series. I hope you learned a few things. More importantly, I hope the series has provided some comfort in knowing that the investigation continues and help is on the way.

Generalized anxiety disorder, major depressive disorder, post-traumatic stress disorder: be sure to read the first part.

Primary information sources: Psychiatric Times: Drug Pipeline: Schizophrenia and Post-Traumatic Stress Disorder, Channeling of medications; Antidepressants and ADHD Rx

Image content: the original charger was Nrets on English Wikipedia. The file is licensed under the Creative Commons Attribution-ShareAlike License 3.0 Unported. Subject to disclaimers. No changes were made.

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Bill White is not a doctor and provides this information for educational purposes only. Always contact your doctor if he has questions, advice or recommendations.

After a decades-long battle with panic, generalized anxiety, mood swings and alcohol dependence; Bill finally found his passion and life’s work: lending a hand to those in the same boat. At age 49 he entered graduate school and earned his counseling credentials. And he continues his service through Chipur and other projects.