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.