Mitigating Adverse Side Effects of Atypical Anti-Psychotic Drugs by Targeting the Histamine, H3, Receptor Subtype
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.
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