Opioid antagonists are associated with a reduction in the symptoms of schizophrenia: a meta-analysis of controlled trials

Abstract

Current treatments for the symptoms of schizophrenia are only effective for positive symptoms in some individuals, and have considerable side effects that impact compliance. Thus, there is a need to investigate the efficacy of other compounds in treating both positive and negative symptoms. We conducted a meta-analysis of English language placebo-controlled clinical trials of naloxone, naltrexone, nalmefene, and buprenorphine in patients with schizophrenia to determine whether opioid antagonists have therapeutic efficacy on positive, negative, total, or general symptoms. We searched online databases Ovid Medline and PsychINFO, PubMed, EMBASE, Scopus, Cochrane library/CENTRAL, Web of Science, and Google Scholar from 1970 through February 2019. Following PRISMA guidelines, Hedges g was calculated for each study. Primary study outcomes were the within-subject change on any symptom assessment scale for positive, negative, total, or general symptoms of schizophrenia between active drug and placebo conditions. Thirty studies were included with 434 total patients. We found a significant effect of all drugs on all scales combined with both a standard random effects model: (g = 0.26; P = 0.02; k = 22; CI = 0.03–0.49) and a more inclusive bootstrap model: (g = 0.26; P = 0.0002; k = 30; CI = 0.11–0.51) and a significant effect on total scales with the bootstrap model (g = 0.25288; P = 0.015; k = 19; CI = 0.04–0.35). We also observed a significant effect of all drugs on all positive scales combined with both the random effects (g = 0.33; P = 0.015; k = 17; CI = 0.07–0.60) and bootstrap models (g = 0.32; P < 0.0001; k = 21; CI = 0.13–1.38). This evidence provides support for further testing in randomized clinical trials of a new class of non-D2-receptor drugs, based on opioid mechanisms, for the treatment of positive and negative symptoms of schizophrenia.

Relevance of the Kappa Dynorphin System to Schizophrenia and Its Therapeutics

“…Based on this evidence from preclinical studies and in light of the excess striatal dopamine function in schizophrenia underlying psychosis and its response to D2 blockade [ 37 ], and the evidence for supersensitized D2 receptors from imaging studies of comorbid schizophrenia and addiction [ 38 ], we propose that KORs may contribute to the positive symptoms of schizophrenia by interacting at least partly with the dopaminergic system to produce increased dopamine release and supersensitized D2 receptors and may be uniquely positioned to play a therapeutic role. This view is supported by studies of KOR agonists and antagonists that we summarize briefly below, and a meta-analysis that we have recently published [ 39 ]. A dopaminergic mediated effect of KOR agonists does not exclude potentially other non dopaminergic mechanisms that may lead to psychosis.…”

“…Naloxone, naltrexone, and nalmefene, antagonists at the kappa, mu, and delta receptor, and buprenorphine, a dual KOR antagonist and mu partial agonist, have been tested in the treatment of SCZ with various results. We have recently reviewed these studies [ 2 ] and also performed a meta-analysis of all trials which showed a therapeutic signal for KOR antagonism [ 39 ]. Intravenous (IV) naloxone at dosages higher than 4 mg [ 44 , 57 - 63 ] produced significant improvement on the Brief Psychiatric Rating Scale (BPRS), while subcutaneous administration did not [ 64 - 68 ], possibly due to lower bioavailability [ 69 ].…”

The Role of Dynorphin and the Kappa Opioid Receptor in Schizophrenia and Major Depressive Disorder: A Translational Approach

“…To date, there have been more clinical trials of nonselective opioid antagonists for schizophrenia than any other mood disorder, with over 50 clinical trials as well as a number of case reports spanning 4 nonselective opioid antagonists: buprenorphine, nalmefene, naloxone, and naltrexone (Clark et al 2020). The premise for these studies was based on an initial study performed by Gunne and colleagues in 1977 who reported an acute antipsychotic effect of naloxone injection in 4 out of 6 patients with schizophrenia (Gunne et al 1977).…”

“…Overall, approximately half of these trials did not find any significant effect which makes it difficult to derive any definitive results from any individual trial (Clark and Abi-Dargham 2019). To address this, a recent meta-analysis was conducted on the double-blind placebocontrolled trials of opioid antagonists in patients with schizophrenia (Clark et al 2020). Pooling the trials together resulted in a dataset of 434 patients from 30 trials.…”

A meta-analysis comparing short-term weight and cardiometabolic changes between olanzapine/samidorphan and olanzapine

“…First, samidorphan has no drug-drug interaction with olanzapine 14 . Second, opioid antagonists are safe for schizophrenia and may modestly reduce psychotic symptoms 15 . Third, olanzapine/samidorphan is superior to placebo and as effective as olanzapine for the treatment of schizophrenia 16 .…”