Benzoate and not benzodiazepines for antipsychotic augmentation

Dr. Jari Tiihonen, Professor of Clinical Neuroscience at the Karolinska Institure in Stockholm, Sweden, discussed findings from his research on polypharmacy in people with schizophrenia on September 20 at the 7th Annual Pacific Psychopharmacology Conference. Using national databases in Finland, his team examined prescription medications and all-cause mortality in a cohort of 2,588 patients during 7 years. Antipsychotic polypharmacy was not associated with increased mortality, and antidepressant use was associated with a decreased risk of death by suicide. In contrast, benzodiazepine use was associated with an increase in suicide and all-cause mortality. Dr. Tiihonen speculated that the sedative effects of benzodiazepines may predispose to unintentional injuries, and withdrawal symptoms may increase agitation and dysphoria which could elevate the risk of suicide.

As for new findings in treatment-resistant schizophrenia, Dr. Tiihonen mentioned the recently published clinical trial of famotidine (see my blog post of July 14). His group is now attempting a replication for which they plan to recruit 140 patients. He also called attention to a randomized clinical trial of sodium benzoate at a dose of 1 gram daily which was presented at the December, 2012 meeting of the American College of Neuropsychopharmacology. The researchers added benzoate or placebo to treatment of 52 patients with chronic schizophrenia “stabilized with antipsychotics for 3 months or longer.” According to the abstract posted on the ACNP Web site, at 6 weeks of treatment, the benzoate group showed significant improvement in PANSS total, positive, and negative scales, as well as in overall neurocognition. The effect size on PANSS total was 1.76, which is very large. It’s not clear if these patients met the usual definition of treatment resistance, i.e. poor response to adequate trials of two antipsychotics, but we should know more soon as the study is in press.

Reference

Tsai GE, Lane H-Y, Green MF. A randomized, double-blind, placebo-controlled add-on treatment of benzoate, a D-amino acid oxidase Inhibitor, for schizophrenia. Neuropsychopharmacology. 2012; 38: S198-S313. Available at: http://www.nature.com/npp/journal/v38/n1s/full/npp2012220a.html (poster T162)

Famotidine for treatment-resistant schizophrenia

Psychiatrists regard the histamine-receptor antagonism of antipsychotics mostly as a nuisance given its relationship to sedation and weight gain. Some evidence, including research on animal models and preliminary human investigations, suggest that in fact it has a therapeutic role for schizophrenia. Recent research has found that clozapine is an inverse agonist at H2 receptors, meaning that it reduces H2 receptor activity below its baseline (1).

A Finnish team has completed a four-week randomized, controlled, and double-masked trial of famotidine, a selective H2 antagonist now marketed as an over-the-counter remedy for heartburn (2). They recruited 30 patients with treatment-resistant schizophrenia, mean age about 51 years, who were on a variety of antipsychotics and had residual functional impairment; 11 of them were on clozapine. They assessed them with the Scale for Assessment of Negative Symptoms (SANS), the Positive and Negative Syndrome Scale (PANNS), and the CGI. The active-treatment group received 100 mg of famotidine twice daily; no significant adverse reactions occurred, but 3 subjects receiving placebo dropped out “for unclear reasons.”

In comparison with the placebo group, the famotidine group had a significant reduction in mean PANSS total score and PANSS general subscale score and in mean CGI. The mean total PANSS score decreased 11% in the famotidine group and 1% in the placebo group. The researchers acknowledged that their study was too brief and had too few subjects to adequately investigate famotidine, and they suggested a follow-up trial with at least 80 subjects for 8 to 10 weeks to test the potential of this well-tolerated medication in treatment-resistant patients.

References

1. Humbert-Claude M, Davenas E, Gbahou F, et al. Involvement of histamine receptors in the atypical antipsychotic profile of clozapine: a reassessment in vitro and in vivo. Psychopharmacology. 2012;220:225-241.

2. Meskanen K, Ekelund H, Laitinen J et al. A randomized clinical trial of histamine 2 receptor antagonism in treatment-resistant schizophrenia. J Clin Psychopharmacol. 2013;33:472-478.