Schizophrenia Spectrum and Psychotic Disorders

Negative Symptoms In Schizophrenia Reduced By Novel Therapy

Tori Rodriguez, MA, LPC
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Patients with schizophrenia in the MIN-101 trial demonstrated lower negative factor scores than a placebo group.

Findings reported in the American Journal of Psychiatry demonstrate the efficacy of a novel therapy in reducing negative symptoms of schizophrenia.1

Negative symptoms affect the majority of patients with schizophrenia throughout their lives.2 While current antipsychotic therapies reduce positive symptoms in approximately two-thirds of patients with acute illness, there is insufficient data to support a recommendation for a pharmacologic treatment targeting negative symptoms.3 In addition, current treatments are associated with a high risk of adverse effects that can cause or exacerbate negative symptoms, as well as other effects such as metabolic abnormalities.

A novel cyclic amide derivative called MIN-101 “has high equipotent affinities for sigma-2 and 5-hydroxytryptamine 2A (5-HT2A) receptors…. and binding affinity for a1-adrenergic receptors but low or no affinity for muscarinic, cholinergic, and histaminergic receptors,” wrote the investigators in the present study. Results of rodent studies suggest that MIN-101 may have antipsychotic effects and reduces negative symptoms without the sedative effects linked with other treatments.

Previously, the researchers conducted a phase 2a randomized placebo-controlled proof-of concept study of MIN-101 in patients with acute schizophrenia, as indicated by a score ≥60 on the Positive and Negative Syndrome Scale (PANSS; pentagonal structure model) and a severity rating of ≥4 on the Clinical Global Impressions Scale (CGI).4 There were significant improvements in negative symptoms after the 12-week course of treatment.

In the current phase 2b trial, they aimed to confirm and expand upon those results in 244 patients with schizophrenia (per DSM-5 criteria; age 18 to 60) with stable symptoms at 36 sites across 6 countries in Europe. Patients were required to have a baseline score of ≥20 on the PANSS negative subscale. After being withdrawn from all psychotropic drugs, patients were randomly assigned to 12 weeks of either placebo or oral MIN-101 32 mg/day or 64 mg/day in a 1:1:1 ratio.

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The findings show that the 2 treatment groups had significantly lower PANSS negative factor scores (pentagonal structure model) compared with placebo (effect sizes: d=0.45, P ≤.024 for MIN-101 32 mg/day; d=0.57, P ≤.004 for MIN-101 64 mg/day). Similar effects were observed for multiple secondary outcomes, including the PANSS total, negative “classic” symptom, and activation factor scores, as well as CGI severity and the Brief Negative Symptom Scale. There were no significant changes in vital signs, weight, metabolic or routine laboratory values, or scores on the Abnormal Involuntary Movement Scale, indicating a high degree of tolerability.

“The effect of MIN-101 on symptoms of schizophrenia can probably be attributed to the synergistic effects on 5-HT2A and sigma-2 pathways,” according to the investigators. This is the first study to report on “a non-D2-receptor-blocking drug with specific therapeutic effects on negative symptoms of schizophrenia.”

References

  1. Davidson M, Saoud J, Staner C. Efficacy and safety of MIN-101: a 12-week randomized, double-blind, placebo-controlled trial of a new drug in development for the treatment of negative symptoms in schizophrenia [published online July 28, 2017]. Am J Psychiatry. doi:10.1176/appi.ajp.2017.17010122
  2. Millan MJ, Fone K, Steckler T, et al. Negative symptoms of schizophrenia: clinical characteristics, pathophysiological substrates, experimental models, and prospects for improved treatment. Eur Neuropsychopharmacol. 2014;24(5):645-692. doi:10.1016/j.euroneuro.2014.03.008
  3. Kreyenbuhl J, Buchanan RW, Dickerson FB, et al. The schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2009. Schizophr Bull. 2010; doi:10.1093/schbul/sbp130
  4. Staner C, Davidson M, Noel N, et al. Results of an exploratory phase 2a study with MIN-101, a 5-HT2A/sigma-2 antagonist, for the treatment of schizophrenia. Presented at the Sixth Biennial Schizophrenia International Research Society Conference, Florence, 2016.