A Randomized Clinical Trial of Histamine 2 Receptor Antagonism in Treatment-Resistant Schizophrenia

Abstract

Histamine has important functions as regulator of several other key neurotransmitters. Patients with schizophrenia have lower histamine H1 receptor levels. Since a case report in 1990 of an effect of the H2 antagonist famotidine on negative symptoms in schizophrenia, some open-label trials have been performed, but no randomized controlled trial. Recently, it was shown that clozapine is a full inverse agonist at the H2 receptor. We performed a researcher-initiated, academically financed, double-blind, placebo-controlled, parallel-group, randomized trial with the histamine H2 antagonist famotidine in treatment-resistant schizophrenia. Thirty subjects with schizophrenia were randomized to have either famotidine (100 mg twice daily, n = 16) or placebo (n = 14) orally, added to their normal treatment regimen for 4 weeks. They were followed up weekly with the Scale for the Assessment of Negative Symptoms (SANS), the PANSS (Positive and Negative Syndrome Scale), and Clinical Global Impression (CGI) Scale. In the famotidine group, the SANS score was reduced by 5.3 (SD, 13.1) points, whereas in the placebo group the SANS score was virtually unchanged (mean change, +0.2 [SD, 9.5]). The difference did not reach statistical significance (P = 0.134) in Mann-Whitney U analysis. However, the PANSS Total score and the General subscore as well as the CGI showed significantly (P < 0.05) greater change in the famotidine group than in the placebo group. No significant adverse effects were observed. This is the first placebo-controlled, randomized clinical trial showing a beneficial effect of histamine H2 antagonism in schizophrenia. H2 receptor antagonism may provide a new alternative for the treatment of schizophrenia.

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…Although one small open-label study (Whiteford et al, 1995) reported no significant effects, two larger studies (Rosse et al, 1990;Deutsch et al, 1993) reported significant therapeutic effects in a group of patients with schizophrenia. A recent randomized double-blind, placebo-controlled study with famotidine in treatment-resistant schizophrenia showed statistically significant improvement in the positive and negative syndrome scale (Meskanen et al, 2013). H 2 receptor agonism blocks accommodation of firing and causes long-term potentiation in hippocampus and cortex (Selbach et al, 1997;Haas and Panula, 2003), which may lead to cognitive enhancement and be worthy of further study.…”

Association of Histamine N-Methyltransferase Thr105Ile Polymorphism with Parkinson’s Disease and Schizophrenia in Han Chinese: A Case-Control Study

“…It may be no coincidence that antipsychotic drugs such as clozapine and olanzapin act, in least in part, through histamine receptors [36]. Indeed, a new generation of non-dopaminergic drugs to treat both PD and SCZ bind to histamine H2 receptors[6,13]. …”

“…In addition, levels of the histamine metabolite tele-methylhistamine in the cerebrospinal fluid are 2.6-fold higher in SCZ patients than in healthy individuals, suggesting abnormally high histamine turnover [12]. Histamine H2 antagonist therapy has shown clinical benefits for patients with SCZ without significant adverse effects in a recent placebo-controlled randomized clinical trial[13]. The same type of therapy has proven effective at treating levodopa-induced dyskinesia in an animal model of PD and in patients with PD [6,14].…”

Famotidine Augmentation in Schizophrenia: Hope or Hype?

“…3. Three RCTs on famotidine augmentation in refractory schizophrenia 2,13,15 reported benefits on different outcome measures and to different extents (10%-27% superiority over placebo). 4.…”

“…Of the remaining 3 RCTs, 2,13,15 all with results favoring famotidine augmentation in antipsychotic-refractory schizophrenia, 1 13 could not be evaluated because the full text was not in English. One found that famotidine outperformed placebo by a large margin (27%), 15 and 1 found that famotidine outperformed placebo by only a small margin (10%), 2 which falls well below the threshold of most definitions of treatment response even in refractory schizophrenia. Only 1 RCT 2 presented a sound statistical plan, and no RCT corrected for type I errors arising from multiple testing.…”