Narcolepsy type 1 (NT1) and schizophrenia are debilitating diseases that are often diagnosed during adolescence, and limited evidence suggests that 5% to 13% of individuals with NT1 have comorbid schizophrenia.1 NT1 is a “relatively homogeneous clinical syndrome of hypothalamic deficiency in hypocretin-1 (orexin) producing neurons,” and human leukocyte antigen DQB1*06:02 positivity has been found in up to 98% of patients, according to an article published in June 2018 in Pediatric Neurology.1
Individuals with both disorders are exposed to an increased prevalence of various risk factors and worse clinical outcomes compared with individuals with either disorder alone. A 2014 case-control study compared adolescents with NT1 and secondary schizophrenia (study group) to those with NT1 only (control group 1) and another group with schizophrenia only (control group 2).2 Those in the study group were found to have a higher body mass index (BMI) than control group 1, more severe psychotic symptoms compared with control group 2, more frequent depressive symptoms and hospitalization, and lower treatment response to multiple trials of antipsychotic medications. These patients developed schizophrenia after a mean of 2.55 ± 1.8 years following narcolepsy onset.
Shared neural pathways and autoimmune pathology between the disorders has been proposed. “Disordered mesocorticolimbic system dopamine neurotransmission has been considered to be the pathologic mechanism of schizophrenia,” wrote the authors of the 2018 paper.1 “Notably, dopaminergic activity within the ventral tegmental area, prefrontal cortex, and nucleus accumbens is regulated by hypocretin neurotransmission, which may explain the shared pathophysiology of psychotic symptoms within both disorders.”
The substantial disease burden associated with both narcolepsy and schizophrenia underscores the importance of early diagnosis and treatment. Based on various study results, the following considerations may provide valuable clinical guidance.
- While delusions are a core feature of schizophrenia, they are very rare in narcolepsy.
- Auditory hallucinations are uncommon in narcolepsy, and the multisensory hallucinations that affect these patients occur exclusively during transitions between sleep and wakefulness.3-5
- Psychotic symptoms have been observed following initiation of psychostimulants for treatment of narcolepsy.6-7
- In patients with comorbid narcolepsy and schizophrenia, initiation of psychotropic medications for schizophrenia may exacerbate hypersomnia in narcolepsy.
Additional investigation into these disorders “may lead to considerable advances in understanding the complex interplay of neuronal pathways in both conditions,” the authors concluded.1 “Successful therapeutic interventions hinge on establishing the correct diagnosis and the recognition that these entities may coexist.”
To learn more about the link between schizophrenia and narcolepsy, related clinical implications, and research challenges, Psychiatry Advisor checked in with Emmanuel Mignot, MD, PhD, professor of psychiatry and behavioral sciences at Stanford University and director of the Stanford Center for Sleep Sciences and Medicine. In 1999, Dr Mignot and colleagues identified hypocretin deficiency as the cause of narcolepsy.8
Psychiatry Advisor: What is known or suspected about the link between schizophrenia and narcolepsy, and what are the proposed underlying mechanisms?
Dr Mignot: It is a complex link. First, it can co-occur just by chance, as schizophrenia is common and narcolepsy is not so rare, affecting 1.0% and 0.05% of the population, respectively. Second, narcolepsy is very destabilizing to any personality – patients suddenly gain a lot of weight, have very vivid dreams, etc, so it can trigger schizophrenia the same way any huge life change or drugs can sometimes precipitate schizophrenia in the context of a susceptible background.
Third, although it is not proven, narcolepsy [appears to be] an autoimmune disease, and schizophrenia involves genes of the immune system. It has even been suggested that some cases of schizophrenia are autoimmune as well. So, it could be that in certain cases, the autoimmune process of narcolepsy affects not only hypocretin cells, but also other brain cells that cause schizophrenia.
Fourth, the symptoms of narcolepsy and schizophrenia have some commonality: Narcolepsy patients can experience hallucinations that are dreams while awake, and they also experience their dreams more vividly and real than normal subjects. From there to believing that these dreams are actual reality, the border is sometimes thin and the symptoms can mimic schizophrenia. Finally, the drugs used to treat narcolepsy can trigger psychosis; stimulants generally [are associated with] more persecution delusions that are reversible but not always, and Xyrem® [is linked with] all kinds of psychiatric reactions.
Psychiatry Advisor: What are the treatment implications for clinicians who may encounter these patients?
Dr Mignot: Clinicians need to be cautious and monitor patients closely when using certain narcolepsy drugs – notably Xyrem – for a patient with a fragile personality. Comorbid narcolepsy and schizophrenia is very hard to treat because the narcolepsy treatment can make schizophrenia worse and vice versa.
These patients are also very challenging to manage. They are often children or adolescents, and it always breaks my heart because it is so hard for the family. I am trained as a psychiatrist, and I have a few of these patients. A few do very well, but many not as well.
Psychiatry Advisor: What are some of the most pressing research needs remaining in this area?
Dr Mignot: Research regarding the autoimmune causes of narcolepsy and schizophrenia are needed. Novel therapies should also be tried in these patients – maybe even immunosuppressive therapies. But I should note that the National Institutes of Health (NIH) does not fund any research on human narcolepsy anymore. I have had no funding for 3 years, even though I found the cause of the disorder and new drugs have resulted from our research. It is unlikely that any such studies in this area will be funded by the government in the near future.
- Cavalier Y, Kothare SV. The association of schizophrenia and narcolepsy in adolescents.Pediatr Neurol. 2018;83:56-57.
- Huang YS, Guilleminault C, Chen CH, Lai PC, Hwang FM. Narcolepsy-cataplexy and schizophrenia in adolescents.Sleep Med. 2014;15(1):15-22.
- Dahmen N, Kasten M, Mittag K, Muller MJ. Narcoleptic and schizophrenic hallucinations. Implications for differential diagnosis and pathophysiology. Eur J Health Econ. 2002;3(Suppl 2):S94-S98.
- Fortuyn HA, Lappenschaar GA, Nienhuis FJ, et al. Psychotic symptoms in narcolepsy: phenomenology and a comparison with schizophrenia. Gen Hosp Psychiatry. 2009;31(2):146–154.
- Vourdas A, Shneerson JM, Gregory CA, et al. Narcolepsy and psychopathology: is there an association?Sleep Med. 2002;3(4):353-360.
- Kishi Y, Konishi S, Koizumi S, Kudo Y, Kurosawa H, Kathol RG. Schizophrenia and narcolepsy: a review with a case report.Psychiatry Clin Neurosci. 2004;58:117-124.
- Canellas F, Lin L, Julià MR, et al. Dual cases of type 1 narcolepsy with schizophrenia and other psychotic disorders.J Clin Sleep Med. 2014;10(9):1011-1018.
- Stanford Medicine News Center. Narcolepsy is an autoimmune disorder, Stanford researcher says. 2009. https://med.stanford.edu/news/all-news/2009/05/narcolepsy-is-an-autoimmune-disorder-stanford-researcher-says.html Accessed August 9, 2018.