A growing body of research suggests that mood disorders such as depression and bipolar disorder may sometimes be driven not just by brain chemistry but by hidden problems with insulin and disrupted sleep rhythms. New findings open the door to earlier detection and a radically new way to treat these disorders.
For decades, doctors have known that some people with depression or bipolar disorder do not improve through typical antidepressants such as selective serotonin reuptake inhibitors.
An interdisciplinary team of researchers including psychiatrists and geneticists thinks that they have found the reason why: for some, these mood disorders may have unexpected roots in insulin resistance and disruption of the circadian rhythm.
“We have been thinking of sleep cycle disruptions as a symptom of mood disorders and metabolic changes as a side-effect of medication,” explains Ian Hickie, Professor of Psychiatry at the Brain and Mind Centre, University of Sydney, Australia who researches major mood disorders. “But our research suggests that the sleep disruption and metabolic changes may actually come first.”
Hickie and colleagues sketch out a potential vicious circle between mood disorders, metabolic changes and circadian rhythm disruption in a recent article in Nature Mental Health. “Mood disorders are a whole-health issue and not just a one-organ problem,” Hickie says.
Understanding this dynamic could have profound implications for treating depression and bipolar disorder – and even help to identify people at risk for mood disorders before symptoms develop.
When mood disorders begin in the body and not the brain
About one in 20 people worldwide live with depression or bipolar disorder, two of the most common mood disorders.
“We all have normal fluctuations in our sense of well-being, our sense of energy and our sense of reactivity with the environment,” Hickie notes. A mood disorder is when that range gets too narrow – “being stuck at one particular area of the spectrum, no longer responsive in a normal way to ordinary life circumstances,” he explains.
Hickie and his co-authors think that scientists have underestimated the role of metabolic problems in mood disorders. When researchers first observed high insulin levels among people being treated for mood disorders, they assumed that this was a side-effect of medication – that prescription antidepressant and antipsychotic drugs cause weight gain, leading to insulin resistance.
“Our work over the last decade indicates that this is not true,” Hickie said. “A lot of people with mood disorders have insulin resistance before treatment starts. This is not picked up because healthcare providers only measure blood sugar and not insulin.”
When the brain runs out of fuel
Insulin is a hormonal signal that instructs cells to absorb glucose (sugar) from the bloodstream after a meal. The body can use the glucose sugar right away as fuel for its cells – or store it for later as glycogen in the liver and muscles, and as fat in the body. When cells become insulin resistant, they do not listen appropriately to the instruction to take in glucose or need more insulin to get the message.
Hickie says that researchers are only beginning to understand how insulin resistance affects the brain. Since the brain does not store fat for back-up energy, it requires a constant glucose supply. Insulin is like a key that unlocks little doors (called GLUT4 transporters) on brain cells, letting sugar in for fuel. If the lock becomes rusty from insulin resistance, fewer doors open. This means that vital brain areas such as the prefrontal cortex and hippocampus – which govern mood and motivation – do not get the energy they need.
In a 2019 study of more than 1,000 young people seeking mental healthcare at the University of Sydney, Hickie’s team found that about 30% showed clinical insulin resistance, measured with a standard test called homeostatic model assessment for insulin resistance (HOMA-IR) that estimates how hard the body has to work to keep blood sugar under control, even before starting any psychotropic medication.
When the body clock goes off track, so does the mind
“Disruption to the sleep cycle – including altered timing, fragmentation, irregularity and abnormal duration – is a hallmark of mood disorders, but existing medications do not do much to restore the circadian rhythm. This is a clue that there is a pathway that scientists have missed,” explains co-author Mirim Shin, a postdoctoral research fellow at the Brain and Mind Centre, University of Sydney who researches the circadian rhythm among young people with mood disorders.
“The circadian clock orchestrates our internal body rhythms,” Shin says. “For humans, it is roughly a 24-hour cycle aligned with the light–dark cycles created by the Earth’s rotation.”
The circadian rhythm governs far more than sleep. A master clock at the centre of the brain (the suprachiasmatic nucleus) keeps the body’s time. It uses special clock genes (with names like PER and BMAL1) that act like gears in a watch – making sure that hormones, metabolism and even the immune system run on schedule. When the gears slip, the whole system ticks at the wrong time.
As Frédéric Gachon, Professor of Medical Chronobiology at Aarhus University, notes: “These molecular clock gears are not just timers for sleep – they also synchronise metabolism. When they go off track, energy regulation and mood regulation can both unravel.”
When the body clock breaks, the brain and body unravel
When the suprachiasmatic nucleus gets out of sync, these genes fire at the wrong times, disrupting metabolism and mood-regulating circuits. Sleeping too much, not enough or at the wrong times can confuse the timetables for other bodily functions.
“Scientists know from studies with shift workers that an irregular sleep–wake cycle can reduce insulin sensitivity. “Just eight days of disruption to the sleep–wake cycle can cause glucose regulation to drop by 27%,” Shin notes. Fred Gachon adds: “this shows how tightly the circadian clock and insulin signalling are wired together – the disruption is fast and measurable.”
The circadian clock also gates the immune system, which also runs on a timetable. It releases small messenger proteins (such as interleukin-6 and tumour necrosis factor-alpha) in carefully timed bursts to clear out waste and to repair tissue. If the body clock breaks, these messengers flood the system nonstop – like demolition workers who do not clock off – and damage healthy brain cells.
"Constant inflammation also jams the body’s wiring. It blocks the normal chain of signals (the insulin receptor substrate-1 (IRS-1)/AKT pathway) that carry insulin’s message inside cells. That makes insulin resistance worse and scrambles the circuits in the brain that help to keep mood in balance. According to Frédéric Gachon: “circadian disruption itself worsens this inflammatory jamming, creating a molecular double hit on insulin pathways and brain circuits.”
New ways to break the cycle
The researchers believe that understanding this vicious circle will help to identify new opportunities for treating people with atypical depression and bipolar disorder. “They might need multiple and somewhat different interventions than what we currently prescribe,” Hickie adds.
Strategies for boosting insulin sensitivity could put the brakes on the vicious circle. Exercise, a well-supported interventions for depression, also improves insulin resistance. Studies are in progress to test whether drugs developed to treat other metabolic problems, including metformin and glucagon-like peptide-1 (GLP-1) agonists, could improve the symptoms of mood disorders.
Interventions that target circadian rhythm disruptions are sorely needed, Shin says. That could mean counselling patients on behavioural changes, prescribing existing medications such as melatonin or developing new drugs.
Catching the warning signs before illness begins
Any totally novel treatments are many years away. The researchers agree that much work remains to be done to pin down the mechanisms – including specific proteins, transmitters and genes – connecting these systems.
But even with this incomplete understanding of this vicious circle, there is an opportunity to act on the knowledge right now, Hickie says: screening young people for high insulin levels. “We are really making a fuss where we failed in the past, to get people to focus on insulin resistance,” Shin explains.
Screening for insulin levels could help healthcare providers identify young people at higher risk of developing mood disorders, perhaps even before mental health symptoms arise. “We really need to target young people early enough to determine whether they have metabolic or circadian dysfunction before they proceed down the path to mood disorders,” Shin says.
“We are trying to use available tests plus new combinations of tests to find out who among the young people we see has the highest risk and would benefit from a different type of treatment,” Hickie concludes.
