Emerging Schizophrenia Drugs Target Negative Symptoms

Ted Bosworth

June 17, 2021

Late-stage trials of new antipsychotic drugs are showing promise in the control of negative symptoms, according to an overview presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

Dr Henry A. Nasrallah

The progress in these trials deserves attention, because control of negative symptoms is "a major unmet need in schizophrenia," according to Henry A. Nasrallah, MD, director of the schizophrenia program at the University of Cincinnati.

The novel mechanisms of the agents in development are credited with the promise. Not least, several antipsychotic agents with activity against both positive and negative symptoms "are completely devoid of dopamine receptor blockade," Nasrallah said at the virtual meeting, presented by MedscapeLive!

The xanomeline portion of the investigational treatment xanomeline-trospium is one example. Xanomeline is a muscarinic receptor agonist with no activity on dopamine D2 receptors. The role of trospium, a muscarinic receptor antagonist, is to reduce peripheral cholinergic side effects.

Xanomeline-Trospium: Negative vs Positive Symptoms

In a recently published placebo-controlled, double-blind, phase 2 trial, the reductions relative to placebo after 5 weeks on the negative subscale of the Positive and Negative Syndrome Scale (PANSS) tool (–3.9 vs –1.3; P < .001) was about as robust as that achieved on the positive subscale (–5.6 vs –3.2; P < .001).

These subscales were secondary endpoints. Relative to placebo, xanomeline-trospium was also effective on the primary endpoint of the PANSS total score (–17.9 vs –5.9; P < .001).

The presence of trospium did not eliminate cholinergic side effects, which included constipation, dry mouth, and nausea, but the therapy strengthens the evidence that newer agents with novel mechanisms of action, including those without dopamine blockade, can achieve meaningful clinical effects.

SEP-363856, another example of an experimental agent without direct dopamine blockade, was also recently tested in placebo-controlled, double-blind study.

"This is the first agonist of the TAAR1 [trace amine-associated receptor 1] and 5-HT1A [serotonin 5-hydroxytryptamine type 1A receptor] to reach clinical trials," said Nasrallah, calling this an interesting agent for its range of clinical activity, which appears to include antianxiety effects.

SEP-363856: Negative vs Positive Symptoms

It also appears to include activity against negative symptoms. While the primary endpoint of total PANSS score favored SEP-363856 over placebo at the end of 4 weeks (–17.2 points vs –9.7; P = .001), the reductions in the subscales for negative (–3.1 vs –1.6) and positive (–5.5 vs 3.9) symptoms were also substantial even if statistical differences were not calculated.

The rates of side effects on SEP-3638656 were low, according to Nasrallah. The most common complaints, such as somnolence, agitation, and nausea, were observed in fewer than 10% of patients.

Roluperidone, another agent with no direct dopamine blockade, has reached phase 3 trials. The activity of this agent is attributed to antagonist activity on the serotonin 5-HT2A and sigma2 receptors. In a multinational, phase 2b study cited by Nasrallah, both of two study doses of roluperidone were superior to placebo for the negative symptom dimensions of expressive deficit and experiential deficit. Patients enrolled in the trial were required to have baseline PANSS negative symptom subscale scores of 20 points or greater.

Pimavanserin, an inverse agonist of 5-HT2A receptors, is already approved for the treatment of psychosis in Parkinson's disease, but it is now attracting interest for its potential efficacy against negative symptoms in schizophrenia, according to Nasrallah, who cited a poster presented last November at the Psych Congress 2020.

The poster provided results of ADVANCE, a double-blind, placebo-controlled, phase 2 study that associated pimavanserin with significant improvement across several types of negative symptoms, Nasrallah said. The drug was well tolerated with a side-effect profile "similar to placebo."

Traditional antipsychotic therapies are generally associated with limited effect against negative symptoms, but it has never been proven that the interaction of treatments on the dopaminergic system is the reason. Indeed, in his list of therapies being pursued for potential benefit against negative symptoms, Nasrallah cited a clinical study with cariprazine, an agent with multiple effects on dopamine and serotonin signaling.

"Cariprazine is a partial agonist at D2, D3, and 5-HT1A receptors and an antagonist at 5-HT2c and 5-HT7 receptors, but it has the highest affinity to the D3 receptor," Nasrallah reported.

Cariprazine is already approved for schizophrenia, acute mania, and bipolar depression, but the authors of a recent review claim evidence of activity against negative symptoms. Furthermore, they speculate that this activity might be mediated by agonism of the D3 receptor.

Despite the evidence that these agents might control negative symptoms, the relative roles will be defined by clinical experience, not just clinical trials, Nasrallah said. However, he did indicate that there appears to be meaningful progress in this area.

Potential progress in this area is important, because "negative symptoms are a largely unaddressed treatment target in people with schizophrenia," reported Christoph U. Correll, MD, professor of psychiatry, Hofstra University, Hempstead, N.Y. These symptoms deserve attention for their "important potential to improve interpersonal, educational, and work function."

Correll agreed that the newer drugs with mechanisms other than postsynaptic dopamine blockade could be a very important advance in the treatment of schizophrenia.

"Promising new medications with potential efficacy for negative symptoms, either based on their pharmacological profile and/or emerging data, include cariprazine, lumateperone, ulotaront [SEP-363856], and xanomeline plus trospium," he said. Efficacy for negative symptoms, if proven, will address an "elusive goal."

MedscapeLive! and this news organization are owned by the same parent company. Nasrallah reported financial relationships with Acadia Pharmaceuticals, Alkermes, Avanir, Intra-Cellular Therapies, Indivior, Janssen, Neurocrine, and Teva. Correll listed financial relationships with more than 25 pharmaceutical companies, including several developing medications with potential activity against negative symptoms.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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