How changes in time are a stressor in bipolar disorder | Charles Raison
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NPAS2, a gene polymorphism involved in circadian rhythm regulation, is also associated with the risk of bipolar disorder. People with bipolar disorder are sensitive to fluctuations in circadian patterns, including sleep deprivation and time zone changes. Chronotherapy, which involves maintaining regular sleep/wake cycles, has been used as a treatment for bipolar disorder. In this clip, Dr. Charles Raison describes how changes in time zones or sleep/wake patterns can be a stressor for people with bipolar disorder.
- Rhonda: Are you familiar with some of the gene polymorphisms, the snps in... There’s one gene that, I think it’s NPAS2, I think, that is involved in circadian rhythm, but also there is susceptibility to bipolar disorder when it’s dis-regulated. So again, sort of this...
- Charles: Yes. Well, especially bipolar disorder. You know, if depression, if regular depression is sort of an evolved human response to the adversity of a relationship, bipolar disorder is a response to the adversity of time.
- Rhonda: What do you mean by that?
- Charles: Well, what you see with bipolar disorder is that the many, so folks with bipolar disorder are also, they can be set off into either manias or depressions by stress, right? But they’re also exquisitely sensitive to fluctuations in circadian patterns. So the great way to induce a manic episode is to just keep people awake. There’s wonderful data from the 1980s from the National Institute of Mental Health where they’d keep really very ill bipolar patients in psychiatric wards for years and study every, you know, every episode. And always, depressive but especially, manic episodes would be triggered by a night of sleep deprivation. You see this clinically. So time is an adversity because it’s, you know, it’s constantly threatening homeostasis. So, you know, the things we’re talking about, the sun comes up, the sun goes down, this happens, that happened, this happened, and your body went up and down. Any time things move, there’s always a risk of things coming off the rails and breaking, right? So bipolar folks are so profoundly vulnerable to disruptions in their circadian sleep/wake cycles, in their activity cycles. Helen Frank was one of the originators of this, called “Chronotherapy.” It came out of University of Pittsburgh, where they actually, you know, as a therapeutic thing for bipolar sort of, part of it was education about, you always go to sleep at the same time, you get up at the same time. You know, be careful about air travel. There is a beautiful study from Heathrow showing that, you know, that there’s a hugely increased risk of people showing up at Heathrow with a psychotic mania if they come from America to Heathrow, than if they come from Asia to Heathrow. And the reason is because it’s a sleep deprivation thing if you’re coming from here, that’s why you’re always exhausted when you land in Europe. You’ve missed a night of sleep. Oh, so many manic patients I saw in my years running the emergency psychiatry at UCLA. Many of them were activated by getting on a plane.
- Rhonda: Wow.
- Charles: “I was normal till I got on the plane. I got off the plane, and the world looked different.” And then they’re off and gone.
- Rhonda: That’s what patients would say?
- Charles: Oh, yeah.
- Rhonda: Wow.
- Charles: And the first episodes were often induced. I mean, people really developed life-long psychotic disorders in response to...
- Rhonda: Do you think those people that are having that are a little more sensitive to the, like their circadian, they maybe have some snp and...?
- Charles: Yeah, that’s probably NPAS, which is one of the great kind of drivers or regulators of the circadian things, is a particular bipolar disorders, because, you know, it’s a condition where time, the changes of time, the recurrent changes of time are just a big stressor for that disorder.
- Rhonda: Yeah. And probably lots of genes are not being regulated properly, right?
- Charles: That’s right.
- Rhonda: And it’s like a transcription factor, regulating a whole host of genes, and so their response to things are very different because they’re not activating all those pathways that you’re supposed to activate, you know?
- Charles: Yeah. Whereas, you know, it’s interesting is, if you don’t have that bipolar risk, most of us do not end up in the psych hospital because we missed a night of sleep, right?
- Rhonda: Yeah, right.
- Charles: We end up in a psych hospital because the person we cared about dumped us, or somebody died, or we lost, or we were shamed, or... You know, it’s just the things, when something tees it off, it’s a different register of things that tee it off. Which is so interesting, it’s one of the main differences between...
- Rhonda: When I’m missing out in sleep, like if I’m traveling abroad, I certainly feel strange when I land in Heathrow, or any other airport in Europe, or even Asia. But I certainly don’t feel...
- Charles: You’re not.
- Rhonda: Yeah. It feels kind of weird.
- Charles: Right. But you’re not psychotic.
- Rhonda: No. I don’t actually have that snp so.
- Charles: Yeah.
The body’s 24-hour cycles of biological, hormonal, and behavioral patterns. Circadian rhythms modulate a wide array of physiological processes, including the body’s production of hormones that regulate sleep, hunger, metabolism, and others, ultimately influencing body weight, performance, and susceptibility to disease. As much as 80 percent of gene expression in mammals is under circadian control, including genes in the brain, liver, and muscle.[1] Consequently, circadian rhythmicity may have profound implications for human healthspan.
- ^ Dkhissi-Benyahya, Ouria; Chang, Max; Mure, Ludovic S; Benegiamo, Giorgia; Panda, Satchidananda; Le, Hiep D., et al. (2018). Diurnal Transcriptome Atlas Of A Primate Across Major Neural And Peripheral Tissues Science 359, 6381.
A mood disorder characterized by profound sadness, fatigue, altered sleep and appetite, as well as feelings of guilt or low self-worth. Depression is often accompanied by perturbations in metabolic, hormonal, and immune function. A critical element in the pathophysiology of depression is inflammation. As a result, elevated biomarkers of inflammation, including the proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha, are commonly observed in depressed people. Although selective serotonin reuptake inhibitors and cognitive behavioral therapy typically form the first line of treatment for people who have depression, several non-pharmacological adjunct therapies have demonstrated effectiveness in modulating depressive symptoms, including exercise, dietary modification (especially interventions that capitalize on circadian rhythms), meditation, sauna use, and light therapy, among others.
An organism’s ability to maintain its internal environment within defined limits that allow it to survive. Homeostasis involves self-regulating processes that return critical bodily systems to a particular “set point” within a narrow range of operation, consistent with the organism’s survival.
A change in one nucleotide DNA sequence in a gene that may or may not alter the function of the gene. SNPs, commonly called "snips," can affect phenotype such as hair and eye color, but they can also affect a person's disease risk, absorption and metabolism of nutrients, and much more. SNPs differ from mutations in terms of their frequency within a population: SNPs are detectable in >1 percent of the population, while mutations are detectable in <1 percent.
A protein that binds to specific DNA sequences, thereby controlling the rate of transcription of genetic information from DNA to messenger RNA. A defining feature of transcription factors is that they contain one or more DNA-binding domains, which attach to specific sequences of DNA adjacent to the genes that they regulate.
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