Do Histamine receptor 3 antagonists have a place in the therapy for schizophrenia?

In spite of almost 60 years of experience with the pharmacological treatment of schizophrenia, there is still a large unmet medical need for better control of especially the negative and cognitive symptoms of schizophrenia. One potential new avenue is the selective blockade of histamine H3 receptors (H3R). Based on a large basis of preclinical data, H3R antagonists or inverse agonists have been suggested to improve cognition in a variety of neurological and psychiatric indications. The aim of the present paper is to review the potential usefulness of H3R antagonists for the treatment of schizophrenia. Although, so far no H3R antagonist has been marketed and many phase II and III studies are still underway, the available data seem to indicate that H3R antagonists may not be primarily effective against the positive symptoms (i.e. the psychotic symptoms such as hallucinations and delusions) but may hold a promise as add-on therapy for selectively improving cognitive and perhaps negative symptoms.

The other side of the histamine H3 receptor.

Although histamine H3 receptors are predominantly known as presynaptic receptors, regulating the release of neurotransmitters such as dopamine, acetylcholine, and histamine, in the striatal complex the vast majority of these receptors are actually located on the other side, in other words postsynaptically. Given their strategic location, they can crucially affect signaling throughout the basal ganglia. We describe the anatomy and function of H3 receptors within the basal ganglia with a specific focus on their colocalization with dopamine D1 and D2 receptors. Because the basal ganglia are centrally involved in several major neurological and psychiatric disorders, we also discuss the therapeutic potential of drugs targeting H3 receptors in the treatment of Parkinson disease (PD), schizophrenia, and addiction.