MIN-101, an investigational antipsychotic, appears to be safe and effective for the treatment of negative symptoms of schizophrenia, new research shows.
Investigators led by Michael Davidson, MD, professor of psychiatry, Sackler School of Medicine, Tel Aviv University, Israel, compared two different doses of MIN-101 (32 mg/day and 64 mg/day) to placebo in patients with schizophrenia.
At 12 weeks, they found a statistically significant difference in negative factor score on the Positive and Negative Syndrome Scale (PANSS), with lower scores for the MIN-101 groups compared with the placebo group. Similar improvements were seen in scores on Other measures of negative symptoms, including the Brief Negative Symptom Scale.
“For the majority of schizophrenia patients, negative symptoms persist long after positive symptoms improve or remit and are responsible for the poor social and vocational abilities of these individuals,” Dr Davidson told Medscape Medical News.
“For the first time, there is a real possibility that a drug could ameliorate negative symptoms without the adverse effects of the currently available drugs used to treat schizophrenia,” he said.
The study was published online July 28 in the American Journal of Psychiatry.
Alternative to Dopaminergic Agents
“Currently available antipsychotic drugs, all of which to varying degrees have antidopaminergic activity, ameliorate positive symptoms in about two-thirds of acutely ill patients,” but do not sufficiently address negative symptoms, the authors write.
Although amisulpride, asenapine, and cariprazine have been regarded as beneficial for negative symptoms, “their specificity and advantages in this regard remain debatable.” Moreover, some dopamine D2 receptor blocking agents produce secondary negative symptoms.
MIN-101 is a novel cyclic amide derivative that has high equipotent affinities for sigma-2 and 5-hydroxytryptamine2A (5-HT2A) receptors but has no direct dopamine affinities.
The authors hypothesize that sigma-2 receptors may be involved in counteracting dysregulations in key dopamine and glutamate neurotransmitter pathways. Moreover, “5-HT2A receptors may be implicated in schizophrenia, hence blocking these receptors may contribute to MIN-101’s therapeutic effect.”
A previous phase 2a randomized, placebo-controlled study of patients with acute schizophrenia found that MIN-101 yielded statistically significant improvements in negative symptoms, as compared to placebo.
The current phase 2b trial “was designed to confirm and extend the findings of the phase 2a trial in symptomatically stable schizophrenia patients,” the authors state.
“While benefiting positive symptoms, currently available antipsychotic drugs possess effects which are very similar to negative symptoms, and as such, no FDA-approved drug targeting negative symptoms exists, making the development of drugs for negative symptoms an unmet need and a research priority,” Dr Davidson said.
Spurious Findings Unlikely
To investigate the efficacy, safety, and tolerability of MIN-101 in patients with schizophrenia who have negative symptoms, the researchers studied 244 patients (aged 18-60 years) who were symptomatically stable and had had negative symptoms for less than 3 months prior to entering the trial.
Patients were required at baseline to have at least “moderately severe” negative symptoms, defined as a score of ≥20 on the “classic” seven-item negative symptom scaled of the PANSS (items N1 – N7). In addition, they were required to have scored <4 on six PANSS items (excitement, hyperactivity, hostility, suspiciousness, uncooperativeness, and poor impulse control).
Patients with arrhythmias, such as long QT syndrome, were excluded. Also excluded were patients who had been diagnosed with another mental disorder, had experienced suicidality, had an unstable medical disorder, or had engaged in substance abuse within 3 months of the screening.
Patients underwent a washout period prior to the study onset. Those being treated with depot antipsychotics were withdrawn from their treatment for at least 1 month, were hospitalized, and were then withdrawn from all psychotropic drugs for at least 5 days prior to randomization. Close to 70% of patients had been treated with oral second-generation antipsychotics prior to entering the trial.
No psychotropic drugs other than MIN-101 were allowed during the trial. However, patients were allowed to take rescue medications for insomnia or agitation. Anticholinergic agents were also discontinued at baseline but were allowed for patients who experienced emergent extrapyramidal symptoms (EPS).
Patients were randomly assigned in a 1:1:1 ratio to receive either placebo or oral MIN-101 (32 mg/day or 64 mg/day) for 12 weeks. The researchers assessed efficacy and safety at baseline before the first dose of medication, at weeks 2, 4, 8, and 12, or on premature termination. Outpatients were contacted by telephone or at weeks 6 and 10 to ascertain safety and adherence to the study medication.
The researchers selected the negative factor score of the PANSS from the pentagonal structure model as the primary outcome measure (items N1 – N4, G5 – G8, G13, G14).
Secondary outcome measures were the PANSS total score, PANSS positive, negative, and general psychopathology scale scores, the individual pentagonal factors of the PANSS, the Brief Negative Symptom Scale score, CGI severity and improvement scores, Brief Assessment of Cognition in Schizophrenia (BACS) score, and Calgary Depression Scale for Schizophrenia (CDSS) score. The Abnormal Involuntary Movement Scale (AIMS) was used to evaluate EPS.
At the end of 12 weeks, the researchers found a statistically significant reduction in the primary endpoint — ie, the PANSS negative symptom pentagonal structure factor score for the MIN-101 32 mg/day and 64 mg/day groups, as compared with the placebo group (P ≤ .024, d = 0.45; and P ≤ .004, d = 0.57, respectively).
The MIN-101 32 mg/day group showed statistically significant improvements at 2 weeks, and both MIN-101 dosage groups at showed statistically significant improvement at 8 weeks. Benefit was maintained throughout the 12-week period. Similar findings were obtained in the PANSS negative “classic” (N1 – N7) scale and the PANSS total score.
The researchers conducted a per-protocol analysis of the primary outcome measure and found a statistically significant reduction for the MIN-101 32 mg/day group and the 64 mg/day group, compared with the placebo group.
Clinically Meaningful?
MIN-101 displayed statistically significant superiority over placebo with regard to the PANSS total score and the PANSS five-factor activation score. The 64 mg/day group displayed improvement on the PANSS five-factor and dysphoric mood scores, CGI severity and improvement scores, Brief Negative Symptom Scale score, and CDSS score.
Additional post hoc analyses found low correlation between changes in depression and negative symptoms, “supporting the view that improvement in negative symptoms was not synonymous with improvement in mood,” the researchers report. The effect size on the PANSS negative pentagonal factor decreased only minimally when they controlled for change in depression.
There were no significant differences between the groups in PANSS positive symptom scores at week 12, and also no significant worsening, compared with baseline.
All three groups displayed no changes in body weight from baseline, and all demonstrated a similar decrease in prolactin plasma level. There were likewise no changes in vital signs, routine laboratory test values, suicidality, and EPS symptom ratings.
Treatment-emergent adverse events were reported by 57.5% of patients in the MIN-101 32 mg/day group, 57.1% in the MIN-101 64 mg/day group, and 43.4% in the placebo group. The most common adverse events reported by patients in the MIN-101 groups were headache, anxiety, insomnia, schizophrenia symptoms, asthenia, nausea, and somnolence.
“Because of the early stage of development of MIN-101, it is difficult to weigh the clinical meaningfulness of the results,” the authors write. “Yet there was a noticeable and statistically significantly greater change in CGI severity and improvement scores in the MIN-101 64 mg/day group compared with the placebo group.”
Additionally, “the effect sizes for negative symptoms reported here are higher than those of currently marketed drugs indicated for schizophrenia and of many drugs utilized to treat chronic diseases in general medicine.”
Dr Davidson noted several strengths of the study, including achieving statistically significant superiority over placebo on the primary outcome and on additional secondary measurements reflecting negative symptoms. “This makes the probability of a spurious finding extremely low.”
Moreover, “because currently available drugs used to treat schizophrenia have well-known and identifiable adverse effects, too often in trials patients and/or investigators are aware who was assigned to drug and who to placebo, which in turn reduces the methodological rigor of a blinded, placebo controlled trial.” However, MIN-101 “has not such identifiable adverse effects, making the trial truly placebo controlled,” he said.
Lastly, psychotropic drugs often bring improvement in delusions and hallucinations, leading to improved interaction with others and secondary improvement in negative symptoms. By contrast, “in this trial, the delusions and hallucinations did not change, such that a direct and specific improvement can be attributed to MIN-101,” he stated.
Enemy of the State
Commenting on the study for Medscape Medical News, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Canada, called the study a “worthwhile enterprise” and said the study was “well designed and executed.”
He noted that the negative symptoms of schizophrenia are more impairing than the positive symptoms. “Negative symptoms are the enemy of the state, and the existing pharmacopia is underwhelming.”
He expressed concern that prominent depressive symptoms and prominent EPS were not noted to be exclusion criteria. “These two phenomena can masquerade as negative symptoms.”
Dr Davidson explained that the researchers “kept exclusion criteria to a minimum, essential to make the results as generalizable as possible,” and they measured EPS and depression before and during the trial.
He acknowledged that there could be “biological and/or psychometric overlap between aspects of depression and aspects of negative symptoms.” However, “There was no change in AIMS scores between baseline and end of study. Hence, EPS improvement could not affect the results.”
Additionally, “when we reanalyzed the data, controlling for depression, the significant superiority of MIN-101 over placebo was maintained.”
Dr McIntyre praised the study for “bringing more attention to negative symptoms,” adding that “we need new treatment options because we do not have a gold-standard treatment for negative symptoms, and there is a pressing need.”
The study results “give reasons to believe that this novel agent may in fact be capable of offering some benefit for patients in this area that is not addressed in current treatments.”
Dr Davidson agreed, speculating on the role that MIN-101 might play in future treatment of schizophrenia.
“Currently, individuals who have manifested psychotic symptoms are treated with antipsychotic drugs during the acute phase of the illness. After the psychotic symptoms improve or remit, the same treatment is continued for months and even years in an attempt to reduce the risk of reemergence of psychosis,” he said.
“Most probably, the acute phase of the illness will continue to be treated with currently available antipsychotic drugs. However, once the psychosis improves or remits, it is possible that patients could be switched to MIN-101 to address the residual negative symptoms and, hopefully, the social and vocational abilities of the patient.”
This study was funded by Minerva Neurosciences. The original article contains a list of the authors’ relevant financial relationships. Dr McIntyre has received research grants from numerous pharmaceutical companies.
Am J Psychiatry. Published online July 28, 2017. Abstract
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