[Recent advance of treatments for narcolepsy and hypersomnia]

It was discovered in 2000 that a deficit of hypocretin/orexin neurons is responsible for causing narcolepsy. Today, agonists for orexin receptors are being explored in order to establish an orexin replacement therapy, but the process is still at the stage of research. On the other hand, orexin antagonists are now undergoing clinical trials as a hypnotic. Activation of the dopamine system is effective against hypersomnia, and activation of the noradrenaline system is effective against cataplexy. Therefore, these two types of drugs have been used for treatment. Methylphenidate was mainly used, but recently modafinil has become mainstream. The action mechanism of methylphenidate is reuptake inhibition and release stimulation of dopamine. The action mechanism of modafinil is not fully explained, but is thought to be reuptake inhibition of dopamine. When methylphenidate was used for disorders other than narcolepsy, such as depression, dependence on the drug and abuse became an issue, and methylphenidate is no longer available for depression. It has been said that narcoleptic patients have a tendency to control the doses of methylphenidate at a low level of their own accord, and that they have a significantly low risk of developing a dependency on the drug. It has also been observed in mice with orexin deficit produced by molecular genetics that they have a significantly low development of dependency on amphetamine, a relative compound of methylphenidate. On the other hand, modafinil has been found to cause very little dependence, and is chosen as the principal drug in treatment. It was recently discovered that the histamine neurons, which are downstream of orexin neurons, are responsible for controlling arousal. It was also discovered that the CSF histamine was low in narcolepsy and other hypersomnia of central origin. Histamine H3 antagonists are being explored as a treatment for hypersomnia. H3 receptors are auto receptors located in the brain histamine neuron, and agonists act for suppression, antagonists for activation. They have shown good results in the animal experiments and phase 2 of clinical experiments.