Stress increases the risk of psychiatric illnesses such as major depression and post-traumatic stress disorder. Not everyone who experiences stress goes on to develop these illnesses, though. Researchers are currently trying to find out why, exploring treatments that might increase resilience and prevent mental illnesses.
Animal research is often used to study depression. Mice exposed to certain stressors behave in ways that resemble human depression—like giving up faster when they’re forced to tread water, or withdrawing from activities they once enjoyed, like eating sucrose. In a recent study by researcher Christine Denny and colleagues, mice were injected with either saline or ketamine, a rapid-acting antidepressant, and one week later they were exposed to triggers that typically produce a depressive response. Mice who received the saline injection still got depressed when, for example, they were repeatedly forced to confront a dominant mouse. But mice who received ketamine injections did better, maintaining their motivation and not showing signs of depressive behavior following the stress. The researchers concluded that ketamine may have a protective effect against stress.
Editor’s Note: These results are remarkable because ketamine’s effects are typically short-lived.
At the 2015 meeting of the American Academy of Child and Adolescent Psychiatry, researcher Charles Popper reviewed the literature to date about broad-spectrum micro-nutrient treatments for psychiatric disorders in young people, concluding that these formulations of vitamins and minerals can reduce symptoms of aggressive and disordered conduct, attention deficit hyperactivity disorder, mood disorders, anxiety, and stress. Four randomized controlled trials showed that micronutrient formulas reduced violence and major misconduct in children.
Popper warned that while these micronutrients can be helpful in treating children who have never been prescribed psychiatric medication, they can interact dangerously with psychiatric medications in children who do take them.
At the same meeting, researcher Bonnie Kaplan reported that six randomized controlled trials of broad-spectrum micro-nutrients and B-complex vitamins in adults with and without psychiatric disorders showed that both of the formulas reduced anxiety and stress following natural disasters (which are associated with the development of post-traumatic stress disorder (PTSD)).
A collaboration between Norwegian and French researchers led by Bruno Etain has clarified the pathway by which childhood trauma is linked to worse outcomes among people with bipolar disorder. The researchers, who presented their work in a poster at the 2015 meeting of the Society of Biological Psychiatry, replicated earlier findings by this editor (Robert Post) that patients who experienced trauma as a child had a more adverse course of bipolar disorder. Etain and colleagues found a link between childhood trauma and an earlier age of onset of bipolar disorder, rapid cycling, suicide attempts, and cannabis misuse.
The researchers identified more than 550 patients with bipolar disorder, who answered questionnaires about their history of bipolar disorder and childhood trauma. Their DNA was also analyzed, and the researchers found that the effect of childhood trauma on age of onset was mediated by the presence of common genetic variants in proteins related to stress (the serotonin transporter) and immune function (Toll-like receptors). They also found that the traits of mood lability (or moodiness) and impulsivity mediated the effects of trauma on clinical outcomes.
The lasting epigenetic effects of child maltreatment and adversity noted in the above abstract are consistent with a large literature showing more epigenetic effects in these individuals than in controls. While genetics are important, the impact of the environment is also substantial.
Studies of primates suggest that the amygdala plays an important role in the development of anxiety disorders. Researcher Ned Kalin suggested at the 2015 meeting of the Society of Biological Psychiatry that the pathology of anxiety begins early in life. When a child with anxiety faces uncertainty, the brain increases activity in the amygdala, the insula, and the prefrontal cortex. Children with an anxious temperament, who are sensitive to new social experiences, are at almost sevenfold risk of developing a social anxiety disorder, and later experiencing depression or substance abuse.
A study by Patrick H. Roseboom and colleagues presented at the meeting was based on the finding that corticotropin-releasing hormone (CRH) plays a role in stress and is found in the central nucleus of the amygdala (as well as in the hypothalamus). The researchers used viral vectors to increase CRH in the central nucleus of the amygdala in young rhesus monkeys, hoping to determine what impact increased CRH has on a young brain. Rhesus monkeys and humans share similar genetic and neural structures that allow for complex social and emotional functioning.
Roseboom and colleagues compared the temperaments of five monkeys who received injections increasing the CRH in their amygdala region to five monkeys who received control injections. As expected, the monkeys with increased CRH showed increases in anxious temperament. Brain scans also revealed increases in metabolism not only in the central nucleus of the amygdala, but also in other parts of the brain that have been linked to anxiety, including the orbitofrontal cortex, the hippocampus, and the brainstem, in the affected monkeys. The degree of increase in amygdala metabolism was directly proportional to the increase in anxious temperament in the monkeys, further linking CRH’s effects in the amygdala to anxiety.
Dysregulation of the brain in early life can have lasting effects, and the effects of stress and depression can also accumulate. At the 2015 meeting of the Society of Biological Psychiatry, researcher Huda Akil explained that behavioral pathology can “take on a life of its own, leading to deteriorating course of illness and treatment resistance.” She illustrated how preclinical work in animals can help clarify the molecular biology of depression and develop new targets for therapeutics.
Early Life Experiences are Key
Akil discuss studies of rodents in which she used new molecular genetic techniques to increase the number of glucocorticoid receptors in the hippocampus early in life (prior to weaning). Glucocorticoid receptors mediate the effects of the stress hormone cortisol in people and corticosterone in rodents. More receptors help shut off cortisol secretion after a stressful event. People with post-traumatic stress disorder (PTSD) have high levels of glucocorticoid receptors while people with depression have low levels, leading to over-secretion of cortisol in depression.
The increased glucocorticoid receptors led to a long-term increase in anxiety behaviors and response to stimulants. When Akil carried out the same manipulation on rats that had already been weaned, it had no long-lasting effects, showing that there is a vulnerability window for some long-lasting effects on behavior.
CLOCK Genes and Circadian Rhythms
Akil also studied CLOCK genes in rodents. These genes, including BMAL-1, Per 1, Per 2, and Per3, play a role in circadian rhythms, and their transcription induces these 24-hour cycles. In rodents who were induced into a depression-like state, the CLOCK genes were dysregulated and did not correspond to normal circadian rhythms. These data show that depressive states can induce changes in CLOCK genes and circadian rhythms. Others have shown the converse, that abnormal CLOCK genes can induce behavioral abnormalities including mania-like behaviors.
Fibroblast Growth Factor
Levels of fibroblast growth factor 2 (FGF2) in the hippocampus are low in people with depression. In rodents, FGF2 inhibits anxiety. Decreases in FGF2 are seen in the hippocampus of animals in a depression-like state following repeated defeat by a larger animal. It appears that FGF2 is an endogenous antidepressant (i.e. one that is produced by the brain). When the rodent brain is manipulated to eliminate FGF2, the animals become anxious.
In addition, animals bred to have high stress, low social responsivity, and resistance to new learning also have low FGF2. Treatment with FGF2 reversed these behavioral abnormalities and also increased the production of new neurons. For the stressed rats, receiving FGF2 on their second day of life increased new neuron production, decreased anxiety, decreased proneness to social defeat stress and increased the bonding hormone oxytocin in the amygdala into adulthood.
FGF2 had no effect on rats bred for low stress and high social responsivity, indicating that it only worked for the rats that needed it. Akil compared FGF2 to “personalized medicine for rats.”
Defeat stress affects the way genes are transcribed, and FGF2 was able to reverse one of these specific transcriptional effects, suggesting it could potentially ameliorate some of the long-lasting effects of stress and depression.
The Human Brain
Akil also studied the brains of people who had died of depression, bipolar disorder, or schizophrenia. In bipolar disorder, the nucleus accumbens, the reward center of the brain, was enlarged.
In contrast, Akil described the brains of those people who had died with depression as being “low on fertilizer.” That is, they showed less cell growth, less production of new neurons, more abnormalities in cell shape, and more cell death. Akil said that by the time someone is severely ill, the pathology is all over the brain. The changes Akil saw in the brains of people who were depressed are also consistent with data indicating that several neuroprotective factors, including BDNF and VEG-F, are low in the frontal cortex and the hippocampus of depressed people (while BDNF is high in the nucleus accumbens).
Certain nutritional supplements may help people cope following natural disasters. Following a 7.1 magnitude earthquake in Christchurch, New Zealand, in 2010, researchers there who were working on a clinical trial of a broad spectrum mineral and vitamin formula for ADHD realized that they could compare participants who had been taking the nutritional supplements at the time of the earthquake with those who had either already completed the trial or had not yet begun it. Two weeks after the quake, those who had been taking the multivitamin at the time of the quake were less anxious and stressed than those who hadn’t been taking the formula.
When another large earthquake struck five months later, the researchers implemented a randomized trial comparing two doses of the same broad spectrum supplement with a B Complex vitamin formula that had previously shown efficacy for stress and anxiety. Those participants taking any supplement showed fewer symptoms of post-traumatic stress disorder (PTSD) a month after the second quake compared to controls, and those taking the higher dose of the broad spectrum formula had greater improvements in mood and anxiety than those taking the B Complex supplement.
More recently, in Alberta, Canada, flooding forced many people from their homes. Researchers there who were studying the effects of micronutrients on stress and anxiety realized they had the opportunity to replicate the research from New Zealand in a different type of environmental disaster.
Researcher Bonnie J. Kaplan and colleagues recruited adults who had been affected by the flood, and randomized the participants to receive different types of supplements: vitamin D (1 pill/day); a B complex vitamin containing B6, B12, and several other nutrients (1 pill/day); or a broad spectrum supplement containing 24 vitamins and minerals and several botanical extracts (4 pills/day). No placebo was used—it was considered unethical to deny participants access to a potentially helpful treatment.
In a 2015 article in the journal Psychiatry Research, the Alberta team reported that while all of the nutrient supplements minimized stress after the flood, patients randomized to the B complex vitamin or the broad spectrum formula had less stress and anxiety following the flood than those randomized to vitamin D.
We have previously described a broad spectrum vitamin preparation called EMPowerplus, used by psychiatrist Charles Popper and psychologist Mary A. Fristad to treat children with treatment-resistant bipolar disorder. This may be the same formula used in the Alberta study. We await larger trials of this preparation in children with bipolar disorder.
Enduring stressful life events in childhood can affect children long-term. Children who experience neglect can show increased levels of cortisol, a stress hormone. Family interventions can reduce these levels, and a new study shows that the impact of these interventions can be lasting. The study, by Kristin Bernard and colleagues in the journal JAMA Pediatrics, included 115 children whose families had been referred to Child Protective Services after allegations of neglect. After an incident of neglect in early childhood, the families received either an experimental intervention called ABC (focused on increasing parental nurturance to child distress, increasing synchronous interactions, and decreasing frightening parental behavior) or a control intervention (which provided educational information about child development). When the children reached preschool age about three years later, the researchers collected the children’s cortisol levels at waking and bedtime on three different days.
The children whose families received the ABC intervention had more typical cortisol levels than those whose families had received the control intervention. The ABC children had higher morning cortisol, with a steeper decline throughout the day, compared to a more blunted cortisol rhythm in the control group children. These patterns resembled differences in the two groups observed three months after the initial intervention. The authors concluded that the ABC intervention has long-term effects on children’s physiological stress system, helping them maintain health and adjustment.
Adolescence may be a period of particular vulnerability to the effects of stress. New research by Shannon Gourley indicates a possible mechanism for this vulnerability. When Gourley exposed adolescent mice to low levels of the stress hormone corticosterone (the equivalent to human cortisol), they developed habit-based rather than goal-oriented decision-making, leading to behaviors that resembled human depression, which lasted into adulthood. Adult mice that were exposed to the low levels of corticosterone were not affected by it.
Gourley also used an alternative method of producing these stress responses a second time by silencing the trkB receptor for brain-derived neurotrophic factor (BDNF) in the amygdala and hippocampus of the mice. The depression-like behaviors that resulted, such as lack of motivation, were able to be reversed by treating the mice with 7,8-dihydroxyflavone, a drug that activated the trkB receptor. In the adolescent mice, this treatment had antidepressant effects that lasted into adulthood, even though the treatment stopped earlier.
Mice subjected to chronic defeat stress (being placed in the home cage of a larger, more aggressive mouse) behave in ways that resemble human anxiety and depression. In new research by Miles Herkenham and colleagues at the National Institute of Mental Health, in which they explored the adaptive immune system’s affect on mood, mice exposed to this type of stress showed increases in inflammatory cytokines in the blood (including TNFalpha, IL-1beta, IL-2, IL-3, IL-6, IL-17, and IFNgamma) compared to a control group. Interestingly, when white blood cells (lymphocytes) from stressed animals were transferred to a new set of animals, the recipient mice seemed to benefit from greater resilience to stress in a variety of ways.
Mice that received white blood cells from defeat-stressed animals had lower levels of TNFalpha, IL-1beta, IL-2, IL-3, and IL-17 than a control group that received white blood cells from unstressed mice. The recipient mice also exhibited reduced anxious and depressive behaviors in a litany of behavioral tests compared to both the group that received white blood cells from unstressed mice and a group that received a saline injection instead. Lastly, the recipients of the white blood cells from stressed animals showed more new neurons in the dentate gyrus of the hippocampus. (Hippocampal neurogenesis is decreased by stressors and increased by antidepressants.)
Herkenham and colleagues concluded that psychopathology is not just a downward spiral—the immune system plays an active role in adapting to stress, with lymphocytes being programmed by stress to provide antidepressant functions.
Editor’s Note: These data add a new twist to the studies of Scott Russo, who found that IL-6 secreted by white cells of animals subject to defeat stress was the cause of the depressive-like behaviors they exhibited. If IL-6 was blocked, the behaviors did not occur. Now it would appear from Herkenham’s work that something about the timing, the type of cytokines, or the transfer of the white cells conveyed protective antidepressant-like effects in this case.
Researchers hope to map out the neurocircuitry by which stress leads to compulsive drug taking. A recent study by Klaus Miczek and colleagues examined different rodents’ responses to the stress of being repeatedly placed in the cage of a larger, more aggressive rodent, developing what is known as defeat stress, a set of behaviors that mimic human depression. Mice and rats showed increases in the stress hormone corticosterone that did not diminish over repeated run-ins with a larger animal. Rodents who were exposed to this stress became sensitized to cocaine or amphetamine, showing hyperactivity that increased each time they accessed the drug (the opposite of a tolerance response). Some also “binged” on cocaine, which they were able to self-administrate by pushing a lever to receive infusions. The mice and rats that went through the social defeat showed elevated levels of dopamine in the nucleus accumbens, the brain’s reward center. Levels were related to the severity of their stressful experience.
Later the rodents had a choice between water and a 20% alcohol solution. The researchers determined what type of stress led the rodents to consume the alcohol solution instead of the water. The maximal effect was seen in two types of mice that suffered an attack of less than five minutes that resulted in a moderate number of attack bites (30); this resulted in the mice consuming large amounts (15–30 g/kg/day) of the alcohol solution. Earlier sensitization to cocaine or amphetamine did not predict later alcohol or cocaine self-administration.
When the researchers injected the rodents with antagonists of the receptors for corticotropin-releasing factor, a hormone and neurotransmitter important in stress response, prior to each episode of social defeat, the rodents did not escalate their cocaine or alcohol self-administration, indicating that CRF plays an essential role in the process by which stress makes animals prone to using substances.
In related research by Camilla Karlsson and colleagues, IL-1R1 and TNF-1R, the receptors for two inflammatory cytokines, mediated the effects of social stress on escalated alcohol use in mice.