The antipsychotic drug market has exponentially grown from <$1 billion to >$15 billion, since the launch of the second generation antipsychotic (SGA) drugs in the mid 1990s. With an improved efficacy and less extrapyramidal and side effects, they are being used for treatment of schizophrenia, controlling bipolar disorders and major depression, in adults and adolescents, and even in children, psychiatric disorders that afflict >5% of the population. However, full market realization is still constrained by serious concerns of stakeholders (regulators, physicians and patient groups) about the exposure of the psychiatric patients to acute side effects associated with their required antipsychotic medications. Of these, weight gain and somnolence are of key importance in causing patients to discontinue medication and have a relapse. Moreover, their consequences weigh heavily in prescription choices, making them a risk-liability for the pharmaceutical manufacturers:

· Weight Gain: A dramatic and rapid weight gain and the consequent risk of exposure to obesity, diabetes and cardiovascular disease co-morbidity is a major concern for some of the most effective SGA drugs. . In a recently published study encompassing almost 300 children, the top selling antipsychotic drugs were shown to cause mean weight gains of 4 – 8.5 kg, in just 3 months of treatment. The most “notorious” being Zyprexa^® (Eli Lilly & Co.) triggering an average weight gain of 8.5 kg (about 15% of baseline weight); Seroquel^® (AstraZeneca PL) and Risperdal^® (Johnson & Johnson), caused a lower, yet clinically significant, weight gain (6 kg and 4.5 kg, respectively). The drugs were also found to raise the children’s’ plasma levels of blood sugar, cholesterol, insulin and triglycerides, all highly correlated with cardio-metabolic diseases. Abilify^® (Bristol-Myers Squibb Co. and Otsuka Pharmaceutical Co.) caused much less weight gain, and Geodon^® (Pfizer Inc.) was not tested. Notably, the latter two drugs are also considered less effective.

· Somnolence: Excessive somnolence (daytime drowsiness) is considered beneficial in the control of the acute psychotic episode; however, it becomes a liability in patients on maintenance therapy, negatively impacting patients' quality of life. Patients are prohibited from driving, operating heavy machinery and are at risk even when performing common house hold tasks such as cooking or watching children, let alone learning. This makes it hard for them to return to the community, hold a job or continue with their education.

The antipsychotic benefits of this drug class are thought to be mediated via binding and inhibition of multiple dopaminergic and/or serotonergic receptors. In contrast, both the weight gain and the somnolence induction are attributed to their antihistaminic activity as inverse agonists of the H1 histamine receptor¹ ².

Newly introduced antipsychotic drugs have yet to gain market acceptance; although they show less side effects, they seem to be less effective when compared to Zyprexa^® - which, were it not for the weight gain, would be the first drug of choice. There is therefore a great need for antipsychotic drug treatment with improved efficacy to risk ratio, including adjunctive therapy that would safely mitigate or prevent the side effects.

There is excessive weight-gain, as high as 20- 25 lbs over the initial 24 weeks of treatment, associated with the use of the atypical anti-psychotics, such as olanzapine and clozapine. This is a major problem in psychiatric patient treatment since it not only impairs treatment due to reduced compliance, but also exposes patients to risk from metabolic disease. This is also a risk liability to the manufacturing pharma companies.

The direct cause of the weight gain in anti-psychotic drug treated patients is still not known. However, there is a direct correlation between the weight gain induced by the various agents and their ability to inhibit the histaminergic H1 receptor1. This has been further validated in a molecular interactions study.

1. Wirshing et. al., Journal of Clinical Psychiatry (1999), 358-363.
2. Kim et. al., Proc Ad Nat Sci (2007) 3456-3459