Histamine and Weight

The role of the histaminergic system in eating habits has been established in numerous animal and human studies. Histamine is best known as an allergic / inflammatory mediator; however, peripherally - produced histamine does not penetrate the blood-brain barrier (BBB) and its activities in the brain are independent of its peripheral actions. In the brain, histamine acts as a neurotransmitter and plays a major role in eating, alertness and cognition. Histamine activation of the post-synaptic H1 receptor decreases food consumption, an activity which can be mimicked by H1 agonists. In contrast, inhibition of the H1 receptor results in increased food consumption and consequent weight gain, as well as increased somnolence. This is reflected in the side effect profiles of anti-inflammatory/allergenic drugs and the second generation anti-psychotic drugs. The pre-synaptic H3 receptor has an auto-regulatory role on histamine production. Thus, inhibition of the H3 receptor may also decrease food intake.

Betahistine, the active pharmaceutical ingredient of Histalean^®

Betahistine, a dual-action H1 receptor agonist and partial H3 receptor antagonist, is a generic prescription drug used on a worldwide basis, except in the US, to treat Ménière's disease (vertigo). With over 35 years of treatment in more than 100 million patients, betahistine has an excellent safety profile. In the US, the drug was approved for Ménière's by the FDA in 1967; however, after the manufacturer failed to provide additional satisfactory efficacy data, the drug approval was withdrawn without voicing any concern regarding safety. Moreover, a post-marketing surveillance review, published in November 2006, indicates that after more than 130 million patient exposures, only about 500 reports have been filed.

Pharmacology of Second-generation Antipsychotic Drugs - Olanzapine

The second-generation antipsychotic (SGA) belong to the thienobenzodiazepine class of drugs and act as monoaminergic antagonists. As a drug class they show binding to multiple receptors, including serotonin type 2, dopamine, histamine H1 and adrenergic α1, with variable affinities. Their therapeutic benefits have mainly been attributed to their anti-dopaminergic and anti-serotonergic actions; whereas their binding to the other receptors is believed to contribute to their side effects.

Indeed, treatment with SGA is associated with significant side effects which adversely impact patient health, quality of life and compliance with medication. These include:

· Rapid increase in body weight in the first few months of therapy due to increased caloric consumption, driven by increased appetite. This dramatic weight gain has been associated with an increased risk of developing hyperglycemia, insulin resistance and diabetes and, ultimately, cardiovascular disease.

· Increased sleepiness, particularly in the daytime (somnolence) that can seriously interfere with patients’ capacity to function in the community, including the capacity to drive, operate heavy machinery, pursue education or perform any task requiring concentration.

The variability in weight gain exerted by the different SGA shows a significant correlation with their respective affinity to the H1 receptor. Clozapine and olanzapine, with the highest H1 affinities, have the highest propensity to induce weight gain, followed by quetiapine >risperidone>aripiprazole>ziprasidone. Recently, studies have further established the antagonism of the H1R as the main mechanism for SGA-associated weight gain.

Of all the first line SGA, olanzapine (Zyprexa^®) carries the highest risk for inducing serious weight gain. A review of the safety and efficacy data from four clinical trials, in which olanzapine was compared with placebo and/or haloperidol in nearly 3,000 patients, showed that patients treated with olanzapine had a dose-related increase in weight, with a mean weight gain of approximately 12 kg after one year at approved standard doses (12.5–17.5 mg/day. Moreover, a recent report of a study in children treated with one of four SGA (olanzapine, quetiapine, aripiprazole and risperidone) showed standard olanzapine doses to exert the greatest weight gain, with a mean of about 8.5 kg or 15% of their baseline body weight, in just 12 weeks of treatment.