Novel Compound Shows Promise in Treating Negative Symptoms of Schizophrenia

A promising new agent, MIN-101, has emerged in the search for a medication that can treat the debilitating negative symptoms of schizophrenia. These symptoms often persist long after the psychotic symptoms have been stabilized.

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Unlike current antipsychotic medications, MIN-101 has no direct affinity for dopamine receptors. It targets neural pathways that rely on glutamate, serotonin, or calcium signals.

In a phase 2b clinical study involving 244 adults with schizophrenia, MIN-101 was found to be superior to placebo at improving negative symptom ratings at both 32 mg/day and 64 mg/day doses. There were no statistically significant differences in positive symptoms between the MIN-101 and placebo groups. The results were published July 28 in AJP in Advance.

MIN-101 is not the first drug to demonstrate some potential in managing negative symptoms of schizophrenia. In particular, the FDA-approved antipsychotic cariprazine has produced some favorable data in this regard. However, Michael Davidson, M.D., chief medical officer at Minerva Biosciences, which developed MIN-101 and funded this study, told Psychiatric News that it’s not yet settled that cariprazine has direct effects on negative symptomology.

Davidson pointed out that the clinical studies involving cariprazine and negative symptoms have shown that cariprazine is superior to risperidone, but it is still debatable whether negative symptom improvements are an indirect result of fewer positive symptoms and better mood.

Davidson said there are two main findings from the trial that make him feel confident that MIN-101 specifically targets negative symptoms. First, patients taking MIN-101 showed significant improvements in negative symptoms such as apathy, social isolation, and blunted emotions on two variations of the Positive and Negative Symptom Scale (PANSS), compared with patients taking placebo. In contrast, there was no difference in positive symptom changes between the MIN-101 and placebo groups.

“Of course, for most antipsychotic trials you can always turn around and say that patients or clinicians were unblinded during the study when adverse effects emerged, which skews the reporting,” Davidson said. For example, if a patient in a clinical trial starts gaining weight, the patient might conclude he or she is not on placebo and then think more favorably about his symptoms.

“In this case, there were no revealing side effects,” Davidson said, making it less likely clinicians or patients knew who was receiving MIN-101 or placebo. No clinically significant changes were observed in vital signs, routine laboratory values, weight, metabolic indices, and Abnormal Involuntary Movement Scale scores between the groups.

“A relevant clinical question is whether the improvement in negative symptoms reported here is specific and clinically meaningful. Indeed, it is possible that MIN-101 has a beneficial effect on mood. However, the effect on negative symptoms was maintained after controlling for depression, which suggests the effect was not synonymous with improvement in mood,” Davidson and colleagues wrote.

“This is definitely a promising advance, when you consider this drug had a good effect size, improved both negative symptoms and CGI scores, and does not involve dopamine,” said Stephen Marder, M.D., a professor of psychiatry and biobehavioral sciences at UCLA’s David Geffen School of Medicine, who studies the pharmacology of antipsychotics.

“An important qualification of this study, though, is that the investigators had to recruit a specific population with elevated negative symptoms and low positive symptoms. So how these results will translate to the typical schizophrenia population is unclear,” continued Marder, who was not involved with this study.

Marder also pointed out that the trial was limited to 12 weeks; this duration might not be long enough to assess the degree to which positive symptoms reemerge. Marder said understanding how MIN-101 affects positive symptoms is important to gauge whether this novel agent could be used as a monotherapy or as an adjunct to a conventional antipsychotic.

Further tests will be needed, and Davidson said Minerva is in the process of launching a phase 3 study before the end of 2017; the trial will seek to enroll at least 500 participants in sites across Europe and the United States (the phase 2b trial was solely in Europe) and will retain the 12-week study design, with an optional 36-week extension phase in which all participants will receive MIN-101.

If all goes well, Davidson envisions great potential for this new medication. While negative symptoms are a core component of schizophrenia, they are not specific to this disorder. Many other disorders such as dementias, depression, or autism include strong negative components, which suggest many potential indications for MIN-101.

All of the authors on the AJP study have financial ties to Minerva Neurosciences, manufacturer or MIN-101. ■