Trying to assess the value of an idea that first appealed to the research community in the 1970s, a team of investigators has published a careful statistical analysis of 30 past clinical trials in which people with schizophrenia were treated with a class of medicines called opioid antagonists. These medicines, which block the body’s naturally occurring opioid receptors, were invented to treat opiate overdoses.

The meta-analysis (as studies of multiple past studies are called) found that four opioid antagonists, approved by the FDA in the 1970s, ‘80s and ‘90s, likely have some “significant” degree of effectiveness in treating the so-called positive symptoms of schizophrenia, and perhaps negative symptoms as well. The findings appeared in the journal Neuropsychopharmacology.

In schizophrenia, positive symptoms refer to hallucinations and delusions as well as confused or disorganized thinking. Negative symptoms refer to flat affect, social withdrawal, and the inability to experience pleasure, among other symptoms.

In the 1970s, during clinical testing of opiate medicines designed to relieve pain, it was noted that some healthy volunteers experienced hallucinations and delusions similar to those experienced by people with schizophrenia and other illnesses with psychotic symptoms. This led to the question of whether blocking the cellular receptors for opioids would have some impact in reducing positive symptoms in schizophrenia patients.

A team led by Samuel Clark, M.D., Ph.D., the founder and CEO of Terran Biosciences, set out to review and assess clinical tests between 1979 and 2019 of opioid antagonists in patients with schizophrenia and related illnesses including schizoaffective disorder. The team’s senior member was Anissa Abi-Dargham, M.D., a member of BBRF’s Scientific Council, winner of BBRF’s 2018 Lieber Prize for Outstanding Achievement in Schizophrenia Research, and a 2008 BBRF Distinguished Investigator, 2000 Independent Investigator, and 1997 and 1993 Young Investigator. Dr. Abi-Dargham, a professor at Stony Brook University, is on Terran Biosciences’ Board of Scientific Advisors.

The idea of using opioid antagonists to treat positive symptoms in schizophrenia, after many clinical tests, was abandoned by some academic researchers when the results proved to be mixed—substantial efficacy was shown in some trials, minimal efficacy in others, and no benefit in still others. Trying to make sense of this, Drs. Clark, Abi-Dargham and colleagues applied a set of stringent criteria to published reports, reducing thousands of academic references to 27 published papers reporting on 30 clinical trials.

For this meta-analysis the team only considered trials in which there was a “control” group, and in which doctors and participants were “blinded,” i.e., did not know which participants were receiving an opioid antagonist and which were not. The 30 trials passing these and other quality-control criteria included 434 patients. In 28 of the 30 trials, two opioid antagonists, naloxone and naltrexone, were tested; one used nalmefene and another used buprenorphine.

One limitation of the meta-analysis of the 30 trials is that they varied considerably in their designs: in the kinds of patients they recruited (different ages, medication history, history of illness); in the way patients in the trials were assessed (e.g., the number of hours following administration of the drug or placebo at which they were assessed, as well as the assessment scales that were employed); and choice of study-endpoints (i.e., what defined a “response” in each trial).

Despite these differences, the team found that across the 30 trials, “significant decreases in symptoms following treatment with opioid antagonists were observed.” Among these, they found significant improvements in participants' positive symptoms. Although there was some evidence of impact on negative symptoms, this evidence was “underpowered,” meaning considerably more patients, data, and results are needed to make a meaningful assessment.

Many of the patients in the 30 trials were already taking antipsychotic medicines. There was evidence that the higher an individual patient’s dose, the more muted any additional benefit of an opioid antagonist would be on positive symptoms. Still, the team suggested that the evidence across the 30 trials supplies sufficient rationale for a modern, carefully controlled clinical trial or trials to attempt to quantify and specify: if and how much benefit is to be gained from opioid antagonists, which patients might be most helped, and which antagonist(s) are likely to have the greatest therapeutic impact.

“These findings remain preliminary, but provide a strong rationale for a systematic effort to resolve the potential efficacy of opioid antagonists either alone or as adjunctive treatment, both for positive and negative symptoms,” the team wrote.

Dr. Clark, whose company is developing a candidate medicine that specifically blocks one of the three main opioid receptors, believes the concept “could represent a paradigm shift” in schizophrenia treatment. In some patients, he believes, they might supplement or supplant antipsychotics, which block the D2 receptor for dopamine. Dr. Clark theorizes that kappa opioid receptors malfunction in schizophrenia, impacting the regulation of the dopamine system—hence his company’s drug to block that specific receptor.

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