Sabine Itani

Introduction: Atypical antipsychotic drugs play a key role in the treatment of schizophrenia, bipolar disorder, and depression.¹ In the US, over 50% of adults over the age of 70 use anti-psychotic drugs.² Weight gain has been identified as one of the major side effects caused by atypical antipsychotic drugs and is believed to be caused by the blockade of H₁ receptors, which increase triglyceride levels in blood.³ Both the synthesis and release of histamine are controlled by presynaptic H₃ Receptors. Due to the belief that blockade of histamine action by H₁R antagonism may be responsible for the adverse side effects of antipsychotic drug use, the possible solution might be connected with H₃R ligands.⁴  Methods: To determine the effects of olanzapine with and without a H₃R antagonist (pitolisant), a forced swim test was conducted. Additionally, mice were fed a high fat diet with and without pitolisant treatment and their plasma levels of triglycerides and cholesterol were determined. Moreover, a double-blind placebo-controlled study was conducted to evaluate the effects of treatment with betahistine (H₃R antagonist) on appetite and fasting glucose-lipid and leptin levels in patients treated with anti-psychotic drugs who gained weight during treatment or had a high body-mass-index (BMI). Results: Daily olanzapine treatment induced sedation, prolonged immobility time in forced swim tests, and elevated triglyceride levels, while administration of pitolisant subsequent to olanzapine opposed these adverse effects.⁵ Mice that were fed a high-fat diet without pitosilant treatment showed more weight gain than those treated with pitolisant.⁶ In the group treated with pitolisant, glucose levels were significantly lower than glucose levels of control obese mice.⁷ The plasma triglyceride levels in pitolisant-treated mice were significantly lower compared to those in control obese group.⁸ In patients treated with olanzapine, betahistine was significantly better than placebo in preventing increases in weight and BMI.⁹  Conclusions: H₃ histamine antagonism can be a promising alternative for counteracting some of the antipsychotic-drug associated behavioral and metabolic side effects. Pitosilant and betahistine both have favorable influences on body weight, improve glucose tolerance, and decrease triglyceride levels. This could be a potential therapeutic for the metabolic side effects associated with anti-psychotic drug use. Additionally, co-administration of a histaminergic agonist with olanzapine is useful in decreasing the adverse metabolic effects associated with anti-psychotic drug use in patients.

1. Olfson M, King M, Schoenbaum M. Antipsychotic treatment of adults in the United States. J Clin Psychiatry. 2015 Oct;76(10):1346-53. doi: 10.4088/JCP.15m09863. PMID: 26528641.
2. Malhotra K, Vu P, Wang DH, Lai H, Faziola LR: Olanzapine-Induced Neutropenia. Ment Illn. 2015 Jun 23;7(1):5871. doi: 10.4081/mi.2015.5871. eCollection 2015 Feb 24.
3. Misiak B, Frydecka D, Łaczmański Ł, et al. (2015) Effects of second-generation antipsychotics on selected markers of one-carbon metabolism and metabolic syndrome components in first-episode schizophrenia patients. Eur J Clin Pharmacol 70:1433–1441. doi:10.1007/s00228-014-1762-2
4. Grinchii D, Dremencov E. Mechanism of Action of Atypical Antipsychotic Drugs in Mood Disorders. Int J Mol Sci. 2020 Dec 15;21(24):9532. doi: 10.3390/ijms21249532. PMID: 33333774; PMCID: PMC7765178.
5. Dudek M, Kuder K, Kołaczkowski M, et al. H3 Histamine Receptor Antagonist Pitolisant Reverses Some Sub-Chronic Disturbances Induced by Olanzapine in Mice. Metab Brain Dis. 2016;31(5):1023-1029. doi:10.1007/s11011-016-9840-z
6. Kotańska M, Kuder KJ, Szczepańska K, Sapa J, Kieć-Kononowicz K. The Histamine H₃Receptor Inverse Agonist Pitolisant Reduces Body Weight in Obese Mice. Naunyn Schmiedebergs Arch Pharmacol. 2018;391(8):875-881. doi:10.1007/s00210-018-15162
7. Singh R, Bansal Y, Sodhi RK, Saroj P, Medhi B, Kuhad A. Modeling of antipsychotic-induced metabolic alterations in mice: An experimental approach precluding psychosis as a predisposing factor. Toxicol Appl Pharmacol. 2019 Sep 1;378:114643. doi: 10.1016/j.taap.2019.114643. Epub 2019 Jun 26. PMID: 31254565.
8. Lian J, Huang XF, Pai N, Deng C. Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications. Pharmacol Res. 2016 Apr;106:51-63. doi: 10.1016/j.phrs.2016.02.011. Epub 2016 Feb 15. PMID: 26892184
9. Smith RC, Maayan L, Wu R, et al. Betahistine Effects on Weight-Related Measures in Patients Treated with Antipsychotic Medications: A Double-Blind Placebo-Controlled Study. Psychopharmacology (Berl). 2018;235(12):3545-3558. doi:10.1007/s00213-018-5079-1.