Researcher Andrea Danese discussed the influence of childhood maltreatment on inflammation in a symposium at the 2014 meeting of the American Academy of Child and Adolescent Psychiatry. Danese indicated that inflammation is part of the normal immune system, which includes the blood brain barrier, recognition of self- versus non-self proteins, activation of cytokines and endothelial cells, and response by phagocytes and acute phase proteins. In an acute phase inflammatory response, the liver secretes proteins including c-reactive protein (CRP) and fibrinogen into the blood, where their levels can be measured.
Normal amounts of inflammation can be protective, while excessive or persistent inflammation can be damaging and pathological. The inflammatory cytokines interferon gamma and tumor necrosis factor (TNF alpha) induce an enzyme called indoleamine oxidase (IDO) that shunts the amino acid tryptophan away from its normal path, which yields serotonin, so that it instead yields kynurenine and then kynurenic acid, which inhibits the action of glutamate at NMDA receptors. Kynurenine can also be hydroxylated and turned into quinolinic acid, which activates glutamate NMDA receptors and causes toxicity.
In addition, inflammatory cytokines such as interleukin six (Il-6) can cross the blood brain barrier and directly influence neurotransmission. Meta-analyses have shown that inflammatory markers CRP, IL-6, IL-1, and IL-1 Ra all increase significantly in depression. A direct demonstration of the relationship between inflammation and depression is the finding that when hepatitis C is treated using the inflammatory treatment interferon gamma, there is about a 30% incidence of depression, which responds to the antidepressant paroxetine.
Stress can also increase the activity of the sympathetic nervous system, driving inflammation, and decrease parasympathetic activity, resulting in further inflammation. In addition, glucocorticoid receptor resistance can develop, enhancing depression, and increasing inflammation. Thus there are multiple ways inflammation can develop.
Danese described a study from New Zealand in which 1000 participants were observed over several decades—from childhood through age 38. The small percentage of participants who experienced maltreatment as children (aged three to eleven) showed a linear increase in CRP in adulthood as a function of their histories of previous child maltreatment. The maltreatment included parental rejection in 14%, sexual abuse in 12%, harsh discipline in 10%, changing caretakers in 6%, and physical abuse in 4%. Childhood maltreatment was also associated with some unfortunate outcomes in adulthood, including lower socioeconomic status, more major depression, more persistent depression, more cardiovascular risk, and more smoking. In other studies, Danese found that compared with controls, patients with depression alone, and patients with maltreatment alone, a greater number of patients with both depression and maltreatment (about 30%) had elevated CRP.
Danese noted that in a study by Ford et al. (2004), recurrent depressions, but not single depressions, were also significantly associated with increased CRP. In a meta-analysis by Nanni et al. in the American Journal of Psychiatry in 2012, Danese and colleagues found that across multiple studies, childhood maltreatment was associated with a twofold increase in the incidence of depression and a twofold increase in the persistence of depression (chronic depression or treatment resistance). The traditional optimal treatment for depression, combined psychotherapy and pharmacotherapy, was also significantly less effective in those with histories of childhood maltreatment. However, psychotherapy alone was equally effective in those with and without childhood maltreatment.
Together these data suggest that childhood maltreatment, partly through an inflammatory pathway, results in multiple difficulties in adulthood, including depression and treatment resistance. These data speak to the importance of attempting to prevent maltreatment in the first place, and ameliorating its consequences should it occur.
Editor’s Note: In a 2014 article in the Journal of Nervous and Mental Disorders, this editor Robert Post and colleagues reported that childhood adversity (verbal, physical, or sexual abuse) is associated with increases in medical comorbidities in adult patients with bipolar illness, and it is likely that inflammation could play a role in some of these medical conditions.
At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Booij reported that in humans, there is an interaction between adversity experienced during childhood, and an epigenetic variation in the short form of the serotonin transporter (5HT-T ss, or SLC6A4), which can influence hippocampal volume during depression.
Epigenetics refers to environmental influences on the way genes are transcribed. The impact of life experiences such as stress is not registered in DNA sequences, but can influence the structure of DNA or tightness of its packaging. Early life experiences, particularly psychosocial stress, can lead to the accumulation of methyl groups on DNA (a process called methylation), which generally constricts DNA’s ability to start transcription (turning on) of genes and the synthesis of the proteins the genes encode. DNA is tightly wound around proteins called histones, which can also be methylated or acetylated based on events in the environment. When histones are acetylated, meaning that acetyl groups are attached to them, DNA is wound around them more loosely, facilitating gene transcription (i.e. the reading out of the DNA code into messenger RNA, which then arranges amino acids in order to construct proteins). Conversely, histone methylation usually tightens the winding of DNA and represses transcription.
Booij followed 33 children who had experienced some form of adversity at a young age until they were 15 or 16, examining methylation of the serotonin transporter in their T cells and monocytes compared to 36 children who had not experienced adversity during childhood. He found that in children who had experienced abuse in childhood, the degree of that abuse was correlated with methylation of the serotonin transporter and was inversely related to the volume of the hippocampus, as measured using magnetic resonance imaging (MRI). Thus, child abuse yields lasting epigenetic effects (methylation of the serotonin transporter) and has anatomical consequences in teenagers, as seen in smaller hippocampi. These data parallel converse findings by Joan Luby et al. published in the journal PNAS in 2012, in which increased maternal warmth directed toward a child aged 4-7 was associated with increased volume of the hippocampus several years later.
A symposium at the 2014 meeting of the American Psychiatric Association suggested that resilience may hold the key to healthy aging, and overcoming trauma and stress.
Resilience in Aging
Former APA president Dilip Jeste began the symposium with a discussion of successful aging. He noted the importance of optimism, social engagement, and wisdom (or healthy social attitudes) in aging. In a group of 83-year-olds, those with an optimistic attitude had fewer cardiovascular illnesses, less cancer, fewer pain syndromes, and lived longer. Those with high degrees of social engagement had a 50% increase in survival rate. Wisdom comprises skills such as seeing aging in a positive light, and having a memory that is biased toward the positive (the opposite of what happens in depression, where negatives are selectively recalled and remembered). Jeste encouraged psychiatrists to focus not just on the treatment of mental illness, but on behavioral change and the enhancement of wellbeing. He suggested asking patients not just, “How do you feel?” but instead, “How do you want to feel?”
Resilience in the Military
Researcher Dennis Charney gave a talk on resilience based on his work with people in the military, some of whom experienced post-traumatic stress disorder (PTSD). He cited a series of important principles that could enhance resilience. The first principle was to reframe adversity—assimilating, accepting and recovering from it. The second principle was that failure is essential to growth. The third principle was that altruism helps, as does a mission for the survivor of trauma. Charney suggested that a personal moral compass is also critical, whether this is based on religion or general moral principles. Other factors that are important for resilience include having a role model, facing one’s fears, developing coping skills, having a support network, increasing physical well-being, and training regularly and rigorously in multiple areas.
Charney and colleagues studied Navy SEALS who went through SERE (Survival, Evasion, Resistance, Escape) training. Those SEALS who had the highest resilience during this severe training exercise had the highest levels of the neurotransmitter norepinephrine and NPY (an antianxiety neuropeptide). NPY levels are low in people with PTSD. Charney and colleagues reasoned that giving a peptide that acted on the NPY-1 receptors intranasally (so that it could cross the blood brain barrier) might be therapeutic. In a rodent model of PTSD, the peptide prevented and reversed PTSD-like behaviors. Further clinical development of the peptide is now planned.
The Effects of Stress
Researcher Owen Wolkowitz described how stress accelerates the mental and physical aspects of aging. Telomeres are strands of DNA at the end of each chromosome that protect the DNA during each cell replication. Telomere length decreases with stress and aging. Read more
A recent study in the UK compared students whose schools instituted the 9-week international Mindfulness in Schools Program (MiSP) curriculum to those who were taught a standard curriculum. Students at schools with MiSP were taught techniques for sustaining attention aimed at changing their thoughts, actions, and feelings.
Students who participated in MiSP training had fewer depressive symptoms immediately after the training and three months later. They also reported lower stress and greater well-being at follow-up. Those students using the techniques they learned in the program more consistently had better scores for depression, stress, and well-being than their peers who used the techniques less often. The study by Kuyken et al., which was published in the British Journal of Psychiatry in 2013, included 522 students between the ages of 12 and 16.
Psychological well-being has been linked to better learning and performance in school, in addition to better social relationships. Researchers suggested that because this kind of mindfulness training is designed to help students deal with everyday stressors and experiences, it has benefits for all students, regardless of their level of well-being.
Elizabeth Blackburn (who won the Nobel Prize for medicine in 2009) gave a spectacular plenary lecture at the 2013 meeting of the American Psychiatric Association, in which she described the role of telomeres in psychiatric and other medical disorders. Telomeres are the strands of DNA at the end of each chromosome that protect the integrity of the DNA each time the cell replicates. The end is capped to prevent damage, degeneration, and genetic instability. A minimum length must be maintained for the protection of the cells.
Telomeres shorten with aging and with each cell replication. They also shorten as a function of childhood adversity, stressors in adulthood, and number of episodes of depression. When a cell’s telomeres get too short, the cell enters a period of senescence, meaning it no longer replicates. Senescence is associated with a variety of adverse events, including the possibility of apoptosis (cell death), pro-inflammatory effects, and pro-tumor effects. The cell can begin to resemble a rotten apple that spreads its ill effects to others nearby. These effects can predispose a person to diseases such as diabetes, depression, attention deficit hyperactivity disorder (ADHD), anxiety disorders, pulmonary fibrosis, aplastic anemia, cardiovascular disorders (stroke and heart attack), osteoarthritis, immune abnormalities, dementia (in women), and premature aging.
Certain lifestyle alterations can increase telomere length, such as mindfulness/yoga training, exercise, sleep, omega-3 fatty acids, and having a positive purpose or meaning in life. Telomeres can also be lengthened by a synthetic enzyme called telomerase.
Other lifestyle factors can shorten telomeres or make telomerase less effective. Chronic stress can decrease the activity of telomerase by 50%. For people serving as the caregiver of a loved one, the longer the duration of this stress, the shorter the length of telomeres. High levels of what Blackburn described as cynical hostility also decrease telomere length.
Editor’s Note: Here we have more evidence that stress can affect our genes. We have written before about epigenetics, the study of the process by which environmental events such as stress can leave behind methyl and acetyl groups on DNA and histones that affect how easily DNA is turned on or off. Now it seems that stress can also have profound effects on the telomeres that cap each strand of DNA and keep it stable. An overly high proportion of short chromosomes is associated with a range of psychiatric and medical illnesses. This type of non-hereditary influence on genes could mediate some of the long-term effects of the environment on health. The good news for patients with bipolar disorder is that M. Schalling et al. found that treatment with lithium lengthened telomeres. Perhaps the bottom line of this whole collection of fascinating data is: Take good care of your telomeres, and they will take care of you.
At the 2012 meeting of the Collegium Internationale Neuro-Psychopharmacologicum (CINP), a symposium was held to discuss fibromyalgia and chronic fatigue syndrome, two illnesses that remain mysterious.
Fibromyalgia is more common in women than in men and is characterized by aching all over, decreased sleep, stiffness upon waking, and most prominently, being tired all day, as well as a host of other symptoms including headache, dizziness, and gastrointestinal upset. Researcher Siegried Kasper suggested that treating fibromyalgia requires more than just medication. His approach is known as MESS, which stands for medication, exercise, sleep management, and stress management.
Medications to treat the illness include milnacipran (not available in the US), duloxetine (Cymbalta, a serotonin-norepinephrine reuptake inhibitor or SNRI), or pregabalin (Lyrica), and if tolerated, low doses of the tricyclic amitriptyline (Elavil).
According to Kasper, SSRIs and anti-inflammatory drugs don’t work, and benzodiazepines decrease the deepest phase of sleep (stage 4) and can exacerbate the syndrome.
Recommended exercise is moderate, graded (to a pulse of about 120, or at a level where the patient can still talk, but can’t sing), and should be done in the early morning rather than the late afternoon where it might interfere with sleep.
Good sleep hygiene is recommended, such as keeping the same sleep schedule every day and abstaining from caffeine (even in the morning).
Working on developing active coping strategies for stressors that are likely to occur is a good idea. Mindfulness and other meditative techniques may also be helpful. Joining a support group (that encourages exercise rather than discouraging it) was also recommended.
Chronic Fatigue Syndrome
At the CINP meeting researcher Simon Wessely discussed chronic fatigue syndrome (CFS), which has many overlaps with fibromyalgia. He reported that careful controlled study of more than 15,000 individuals has not indicated that the illness is associated with a viral infection. Just as many people with and without chronic fatigue syndrome were found to be infected with a virus.
However, like the myth that vaccines cause autism, the myth that chronic fatigue is associated with a virus remains popular despite the lack of evidence. A large randomized study validated Wessely’s treatment techniques, but he has continued to be vilified for the position that the illness is not virally based. The study showed that patients who participated in cognitive behavior therapy and graded exercise improved more than those who received conventional medical management.
Wessely thought the most important cognitive change to make was accepting that exercise is not harmful for patients with chronic fatigue syndrome, and is in fact helpful and therapeutic. Many older treatment approaches had advocated rest, rest, and more rest, or even “intensive rest.” However, Wessely indicated that this would be counter-productive, as the patient would lose muscle mass and cardiovascular conditioning, and would become even more tired and chronically fatigued.
This editor (RM Post) in collaboration with Jacqueline Fleming and Flavio Kapczinski published the article “Neurobiological mechanisms of illness progression in the recurrent affective disorders” in the Journal of Psychiatric Research this year. The article built on several themes about the progression of bipolar illness that had been explored in previous research.
These themes include:
- The likely acceleration of repeated episodes as a function of the number of prior episodes (episode sensitization)
- The increased responsivity of the illness to repeated stressors (stress sensitization)
- The increased behavioral reactivity to repeated use of psychomotor stimulants such as cocaine (stimulant-induced behavioral sensitization)
Not only are these observations well documented in the scientific literature, but recent observations also suggest that each type of sensitization can show cross-sensitization to the other two types. That is, individuals exposed to repeated stressors are more likely both to experience affective illness episodes and to adopt comorbid substance abuse. In a similar way, episodes of an affective disorder and stressors may also be associated with the relapse into drug administration in those who have been abstinent.
In addition to these mechanisms of illness progression in the recurrent affective disorders, the new article reviews the literature showing that the number of affective episodes or the duration of the illness appear to be associated with a variety of other clinical and neurobiological variables.
The number of affective episodes a patient experiences is associated with the degree of cognitive dysfunction present in their bipolar illness, and experiencing more than 4 episodes of unipolar or bipolar depression is a risk factor for dementia in late life. A relative lack of response to most treatments is also correlated with the number of prior episodes, and this holds true for response to naturalistic treatment in general. While most of these data are correlational and the direction of causality cannot be ascertained for certain, it is likely that the number of affective episodes and/or their duration could account for and drive difficulties with treatment and with cognitive function.
If this were the case, one would expect to see a variety of neurobiological correlates with the number of prior episodes or duration of illness, and in the article we summarize those that have been found in unipolar and bipolar disorder. Considerable data indicate that cortical volume and degrees of prefrontal cortical dysfunction can vary as a function of number of prior episodes. There is evidence that increased activity of the amygdala and the nucleus accumbens are also related to episodes or duration of illness. In those with unipolar depression, the volume of the hippocampus is decreased with longer duration of illness. Read more
Epigenetics is a relatively new area of study that examines changes in DNA regulation and structure that can come about as a result of environmental events, as opposed to the genetic inheritance (DNA sequence) people receive through their parents’ genes. Epigenetic effects occur when an environmental stressor or chemical causes methyl or acetyl groups to attach to DNA or to histones (around which DNA are wound). These epigenetic changes determine how difficult it is to turn on genes coded in the DNA (see here for more information about the way the environment produces these epigenetic effects).
After the jump: Several studies presented at the 65th Annual Scientific Convention of the Society of Biological Psychiatry earlier this year suggested a link between environmental stress and both inflammation and abnormalities in DNA.
It has been thought that one fundamental principle of genetics is that the impact of environment factors cannot be passed from one generation to the next via the genetic code. New data suggest this may not be true.
In an emerging field called epigenetics, researchers are finding that while the impact of environment and life experiences is not registered in DNA sequences, environmental factors can influence the structure of DNA or tightness of its packaging. Early life experiences, particularly psychosocial stress, can lead to the accumulation of methyl groups on DNA (a process called methylation), which generally constricts DNA’s ability to start transcription (turning on) of genes and the synthesis of the proteins the genes encode. DNA is tightly wound around proteins called histones, which can also be methylated or acetylated based on events in the environment. When histones are acetylated, meaning that acetyl groups are attached to them, DNA is wound around them more loosely, facilitating gene transcription (i.e. the reading out of the DNA code into messenger RNA, which then arranges amino acids in order to construct proteins). Conversely, histone methylation usually tightens the winding of DNA and represses transcription.