Treating negative symptoms in schizophrenia has always been a challenge for clinicians. Currently there are no drugs approved by the US Food and Administration (FDA) for this specific indication. But recent research findings may offer new hope.
Although antipsychotic medications help treat main/primary positive symptoms of schizophrenia, such as hallucinations and delusions, they have not been effective in treating primary negative symptoms, such as apathy, lack of emotion, and poor social functioning.
However, recently published results from a phase 2b trial of 244 patients showed that those who received either 32 mg/day or 64 mg/day of the investigational antipsychotic MIN-101 (Minerva Neurosciences) had lower scores at 12 weeks on the Positive and Negative Syndrome Scale (PANSS) than those receiving placebo.
This follows research presented in June at the annual meeting of the American Society of Clinical Psychopharmacology and published in Lancet showing positive results for the antipsychotic cariprazine, which has a different mechanism of action than MIN-101.
Commenting on these new findings for Medscape Medical News, William T Carpenter, MD, University of Maryland School of Medicine and the Maryland Psychiatric Research Center, Baltimore, said that although more research is needed, there’s reason for cautious optimism right now, especially regarding MIN-101.
Dr William Carpenter
“What will be interesting is whether this mechanism really is independent of the dopaminergic mechanism,” said Dr Carpenter, who is also a past president of the American College of Neuropsychopharmacology.
“There is for sure an unmet therapeutic need. It’s been a stagnant field for schizophrenia, so it’s exciting to see something of a novel mechanism.”
On the Other Hand…
Former President of the American Psychiatric Association Jeffrey Lieberman, MD, is more skeptical.
“I would caution anybody against exuding too much enthusiasm,” said Dr Lieberman, professor and chair of psychiatry at Columbia University and chief at the New York Presbyterian Hospital Columbia Medical Center, New York City.
Dr Jeffrey Lieberman
“Negative symptoms are a prevalent dimension of schizophrenia, and, while not distressing, they are certainly disabling in terms of limiting functioning. And while there have been a number of shots on goal in terms of treating these symptoms, nothing’s worked,” he said.
Cariprazine (Vraylar, Forest Research Institute) is a dopamine D3/D3 receptor partial agonist that was approved by the FDA for the overall treatment of schizophrenia. The phase 3b study, which was published earlier this year in the Lancet included 460 patients, showed greater improvement in negative symptoms for those receiving cariprazine than for those receiving risperidone (Risperdal, Jannsen).
Amisulpride (multiple brands) and asenapine (Saphris, Forest Laboratories) have also been suggested as being beneficial in the treatment of negative symptoms of schizophrenia. But there’s been some debate about the specificity of that benefit ― is the benefit just a trickle-down effect from the treatment of positive symptoms?
In addition, antipsychotics that are currently available have at least some antidopaminergic activity; and some dopamine D2 receptor blockers can produce adverse events that appear similar to negative symptoms.
In the recent cariprazine trial, the investigators “couldn’t exclude the possibility that dopaminergic mechanisms were involved” in the treatment effect, said Dr Carpenter.
Dr Lieberman went further, saying he didn’t see any “real therapeutic effect” from the drug on negative symptoms. “If someone wanted to pursue this further in a really rigorous design, great; it would be nice to see those results. But based on the data up until now, the benefits have been overstated,” he said.
“There’s no plausible pharmacologic rationale as to why it would be particularly effective based on what we know about the underlying pathophysiology of negative symptoms.”
On the other hand, MIN-101 is a cyclic amide derivative that has high equipotent affinities for sigma-2 and 5-hydroxytryptamine2A (5-HT2A) receptors; and it has no direct dopamine affinities.
“This one seems to have a completely novel mechanism involved,” Dr Carpenter noted.
Primary Outcome Met
A phase 2a proof-of-concept trial in patients with acute schizophrenia showed that those who received MIN-101 had significant improvements in negative symptoms, as determined on the basis of PANSS score, at 12 weeks compared with the participants who received placebo.
The recent phase 2b randomized trial was conducted at 36 sites in six European countries. It included adult patients aged 18 to 60 years with symptomatically stable schizophrenia and moderately severe negative symptoms.
The results met the primary outcome, with a significant reduction at 12 weeks in PANSS negative symptom scores for those receiving MIN-101 at 32 mg/day (P < .02) and 64 mg/day (P < .004) vs the placebo group. Improvements were also shown at 8 weeks for both doses and at 2 weeks for the 32 mg/day group.
Interestingly, there were no between-group differences in PANSS positive symptom scores at 12 weeks, showing that the “direct and specific improvement” in negative symptoms can be attributed to MIN-101, lead author Michael Davidson, MD, chief medical officer at Minerva and professor of psychiatry at the Sackler School of Medicine at Tel Aviv University, Israel, said at the time.
“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,” added Dr Davidson.
He later told Medscape Medical News that, on the basis of phase 2b results and after talks with the FDA, the company plans to start a 501-patient phase 3 trial before the end of this year. “We had an ‘end of phase 2 meeting’ with them,” he said. Multiple countries will participate in the upcoming study, including the United States.
“Unequivocally, there’s definitely reason for optimism,” said Dr Davidson. “There’s no other compound that was really positive for negative symptoms. Right now it’s ‘wait and see’ for clinicians while we wait for our phase 3 results, but I’m very optimistic.”
Reason for Optimism?
Dr Carpenter, who was not involved with this research, noted that many negative-symptom studies showed only modest effects.
“There’s virtually never a design that lets you isolate on negative symptoms; and if you do that design, there’s no evidence for having effective treatment,” he said.
“I like this study because they use many elements of the agreed-upon design that’s necessary if you want to get an indication from the FDA for efficacy for negative symptoms.”
He added, though, that a lot can happen between phase 2 trials and phase 3 trials. “We all get nervous, but if I were them, I would be optimistic,” said Dr Carpenter.
Although he has some lingering concerns about the phase 2 study, including questions about the dropout rate and the fact that the Brief Negative Symptom Scale is a better, more detailed measure than the PANSS, “I think they went a lot further than most past study designs have done.”
However, Dr Lieberman isn’t impressed. “Sometimes, when results seem to be construable as positive, a compound gets advanced. And that’s the case with this one from Minerva,” he said.
“It’s ultimately not going to produce any scientific or clinical value based on the compound’s pharmacology. There’s no clear rationale for why it would be therapeutic for negative symptoms. And there’s nothing from the preclinical and clinical data that gives me even a modicum of hope.”
Still at Square One
The goal of treating schizophrenia’s negative symptoms effectively has been elusive for many years, reiterated Dr Carpenter.
Some antipsychotic medications, while focusing on positive symptoms, have shown some effect on negative symptoms, “which is a nice clinical advantage, but it’s not efficacy. And that’s a mistake that’s been widely made,” he said.
Dr Lieberman noted that in the 1990s, the National Institute of Mental Health and the neuropsychopharmacology section of the FDA agreed to work together to create “a drug development pathway for treatments that focused on nonpsychotic symptoms of schizophrenia,” including cognitive impairment and negative symptoms.
“This provided a well-marked pathway and an incentive to pharmaceutical companies. Although antipsychotics had been the cornerstone of treatment for this condition, it was well known that those treatments did nothing for negative symptoms. So there was a need for adjunctive medications.”
He said that he wouldn’t necessarily call it “the start of the gold rush,” but it did provide an incentive that many companies responded to. “Yet, everything thus far has failed or at least not fulfilled expectations.”
To show real efficacy for a potential therapeutic treatment, secondary negative symptoms from psychosis need to be separated from primary negative symptoms. “And the study that was done by Minerva didn’t demonstrate that in a conclusive way,” said Dr Lieberman.
“Overall, I’d say we’re still at ground zero, or square one. It’s not that all hope is dashed, but it is caveat emptor. This is a worthy goal to pursue, but we have not yet found the key to unlock the pathology.”
The MIN-101 study was funded by Minerva Neurosciences. Dr Davidson is an employee of Minerva. Dr Carpenter reported no relevant financial relationships but did at once time provide guidance to a consulting firm on hypothetical data for schizophrenia treatment. Dr Lieberman has received research grants from Alkermes, Biomarin, EnVivo/Forum, Genentech, Novartis/Novation, and Sunovion. He also writes an ongoing column for Medscape Medical News.
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