Hypocretin/orexin and narcolepsy: new basic and clinical insights.

Narcolepsy is a chronic sleep disorder, characterized by excessive daytime sleepiness (EDS), cataplexy, sleep paralysis and hypnagogic hallucinations. Both sporadic (95%) and familial (5%) forms of narcolepsy exist in humans. The major pathophysiology of human narcolepsy has been recently discovered based on the discovery of narcolepsy genes in animals; the genes involved in the pathology of the hypocretin/orexin ligand and its receptor. Mutations in hypocretin-related genes are rare in humans, but hypocretin ligand deficiency is found in a large majority of narcolepsy with cataplexy. Hypocretin ligand deficiency in human narcolepsy is probably due to the post-natal cell death of hypocretin neurones. Although a close association between human leucocyte antigen (HLA) and human narcolepsy with cataplexy suggests an involvement of autoimmune mechanisms, this has not yet been proved. Hypocretin deficiency is also found in symptomatic cases of narcolepsy and EDS with various neurological conditions, including immune-mediated neurological disorders, such as Guillain-Barre syndrome, MA2-positive paraneoplastic syndrome and neuromyelitis optica (NMO)-related disorder. The findings in symptomatic narcoleptic cases may have significant clinical relevance to the understanding of the mechanisms of hypocretin cell death and choice of treatment option. The discoveries in human cases lead to the establishment of the new diagnostic test of narcolepsy (i.e. low cerebrospinal fluid hypocretin-1 levels for 'narcolepsy with cataplexy' and 'narcolepsy due to medical condition'). As a large majority of human narcolepsy patients are ligand deficient, hypocretin replacement therapy may be a promising new therapeutic option, and animal experiments using gene therapy and cell transplantations are in progress.

Subjective experience and related symptoms in schizophrenia.

We had previously extracted two types of subjective experience of schizophrenia (SES); first, a feeling of inadequacy in stream of speech, thought, and action, associated with a distorted sense of self, and second, a feeling that excessive thoughts are filling and sticking to one's head, causing negative affective burden such as misery and oppression. This study tried to validate their content using conventional symptom clusters as external validators. Subjects were 63 patients from two hospitals in Tokyo meeting ICD-10 criteria for schizophrenia. Positive, negative, and depressive psychopathology were measured by the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of the Negative Symptoms (SANS), and Hamilton's Depression Scale (HDS). The two types of SES were measured by an original scale. The first type of SES correlated significantly with the negative symptoms of alogia, avolition, and attention, whereas the second correlated with positive and depressive symptoms. To analyze how schizophrenia is experienced by patients, qualitative and comprehensive descriptions, such as indicated by our subjective factors, will be useful.