Circadian Rhythm and Sleep Disruption: Causes, Metabolic Consequences and Countermeasures.

Circadian (∼ 24 hour) timing systems pervade all kingdoms of life, and temporally optimize behaviour and physiology in humans. Relatively recent changes to our environments, such as the introduction of artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behaviour and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these too are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally-driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioural and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important

Successful Targeted Treatment of a Medically Actionable Mutation in Psychotic Disorders

Background: The identification of mutations in specific genes could enable personalized, “medically actionable” treatment interventions. We identified a potentially informative mutation, a rare structural rearrangement that includes a triplication of the glycine decarboxylase gene (GLDC). GLDC is the enzyme that catabolizes glycine, a co-agonist of the NMDA receptor (NMDAR). Four copies of GLDC would be expected to accelerate the degradation of glycine, resulting in low levels of brain glycine and NMDAR-mediated hypofunction, which has been strongly implicated in the pathophysiology of psychotic disorders. Carriers of this mutation may especially benefit from augmentation of psychotropic drug treatment with glycine or other NMDAR co-agonist site modulators. Methods: We carried out a double-blind placebo-controlled clinical trial (six weeks per arm), followed by six weeks of open-label glycine, in two related individuals who are carriers of the GLDC mutation, one with a diagnosis of bipolar disorder with psychotic features and the other with a diagnosis of schizo-affective disorder. Clinical assessments were carried out every two weeks using the PANSS, BPRS, YMRS, HAM-D, and CGI. Results: Here, we report that the subjects showed dramatic clinical improvements while on glycine both during blinded and open label glycine treatment. Both subjects relapsed when glycine augmentation was discontinued. Subsequent resumption of glycine augmentation restored the symptom remission observed previously. Conclusion: Other carriers of duplications or triplications of GLDC, or carriers of other genetic variants resulting in NMDAR hypofunction, also may benefit from augmentation with glycine or other NMDAR positive modulators, regardless of clinical phenotype

Targeted Treatment of Individuals With Psychosis Carrying a Copy Number Variant Containing a Genomic Triplication of the Glycine Decarboxylase Gene

BACKGROUND: The increased mutational burden for rare structural genomic variants in schizophrenia and other neurodevelopmental disorders has so far not yielded therapies targeting the biological effects of specific mutations. We identified two carriers (mother and son) of a triplication of the gene encoding glycine decarboxylase, GLDC, presumably resulting in reduced availability of the N-methyl-D-aspartate receptor coagonists glycine and D-serine and N-methyl-D-aspartate receptor hypofunction. Both carriers had a diagnosis of a psychotic disorder. METHODS: We carried out two double-blind, placebo-controlled clinical trials of N-methyl-D-aspartate receptor augmentation of psychotropic drug treatment in these two individuals. Glycine was used in the first clinical trial, and D-cycloserine was used in the second one. RESULTS: Glycine or D-cycloserine augmentation of psychotropic drug treatment each improved psychotic and mood symptoms in placebo-controlled trials. CONCLUSIONS: These results provide two independent proof-of-principle demonstrations of symptom relief by targeting a specific genotype and explicitly link an individual mutation to the pathophysiology of psychosis and treatment response