Depression has been linked to increases in medical problems such as cardiovascular disease. A new study shows that depression is linked to increased risk of stroke, even when symptoms of depression are in remission.
The 2015 study, by Paola Gilsanz and colleagues in the Journal of the American Heart Association, focused on health and retirement. It included over 16,000 adults aged 50 and up who were interviewed every two years about their health history.
Previous studies have shown a link between depression and stroke risk. Like those studies, the study by Gilsanz and colleagues found that people who were depressed during two consecutive interviews were more than twice as likely to have a stroke in the subsequent two-year period than those who reported few depressive symptoms in the first two visits.
What is new is that in this study, people who were depressed in the first interview but not in the second interview were still at 66% greater risk for a stroke than those with no depression. Those who were depressed only during the second interview not at greater risk for a stroke, implying that depression takes more than two years to affect stroke risk.
Gilsanz and colleagues suggest that they don’t know how depression, remission, and stroke risk interact over the longer term. It is possible that stroke risk diminishes the longer a patient’s depression stays in remission.
It is not clear why depression increases strokes, though some have speculated that depression causes irregular heartbeats. There is not as yet any support for that theory, but high blood pressure, rigid veins, or sticky platelets may be other explanations.
DNA has several ways of repairing itself. Serious damage, including breaks to both strands of the double helix and problems with replication, prompt a process known as DNA damage repair, or DDR. Researcher Stephen J. Elledge of Harvard Medical School won the 2015 Albert Lasker Basic Medical Research Award for his findings about DDR. He summarized these findings in a September article in the journal JAMA.
DDR occurs because of DNA’s remarkable self-awareness. Through the DDR process, DNA can detect when it has been damaged and prompt the right kind of repair. When damage occurs, DDR allows for the activation of enzymes that can remodel DNA to maintain the integrity of the genome.
When DDR pathways are activated, they can alter more than 1000 different proteins. DDR can affect immune function, blood and bone marrow, viral response, cancer, aging, and brain development.
Mutations in components of the DDR pathway can lead to problems with brain development, including Seckel syndrome (characterized by dwarfism, brain and facial abnormalities, and mental retardation) and ataxia telangiectasia (loss of control of bodily movements along with weakened immune system).
DDR is particularly relevant to cancer, since properly functioning DDR promotes a stable genome. Classic cancer treatments such as radiation and chemotherapy also rely on DDR to prompt cell death.
DDR also plays a role in aging. When we get older or have certain illnesses, telomeres, bits of material at the end of DNA strands that protect the DNA during replication, get shorter. This prompts DDR to engage in tumor prevention measures, either killing off the cells or changing them into what’s called senescent cells. Senescent cells prevent tumors, but their accumulation is associated with chronic inflammation, aging, and age-related diseases.
Editor’s Note: You can protect your telomeres and possibly hold off the age-related effects of DDR. Healthy diet, exercise, meditation, goal setting, and making positive contributions to society all help maintain telomere length. Lithium treatment also directly increases telomere length.
At the 2015 meeting of the Society of Biological Psychiatry in May, researcher Daniel Blumberger reported to this editor (Robert M. Post) that he has found repeated transcranial magnetic stimulation (rTMS) to be effective for depression in late life. Blumberger noted that it may be necessary to use higher intensity stimulation (i.e. at 120% of motor threshold instead of the usual 110% of motor threshold) in the elderly in order to overcome the gap between the skull and the brain, which can grow with age due to brain atrophy.
Blumberger has also successfully used rTMS as a followup treatment to a successful course of electroconvulsive therapy (ECT), administering rTMS twice a week for up to 66 treatments in a given patient in order to maintain remission of their depression.
In a new study by ESM Eurelings and colleague in the journal International Psychogeriatrics, the inflammatory marker C-reactive protein differentiated between older people with symptoms of apathy versus symptoms of depression. Higher levels of C-reactive protein were found in those with symptoms of apathy. The researchers concluded that apathy may be a manifestation of mild inflammation in elderly people.
Type 2 diabetes can damage the brain, particularly by reducing volume of the hippocampus, and frequently occurs in patients with bipolar disorder. A recent study of patients with bipolar disorder and abnormal glucose metabolism showed that patients with bipolar disorder who also had insulin resistance, glucose intolerance, or type 2 diabetes had smaller hippocampi than both patients with bipolar disorder and normal glucose function and normal control participants without a psychiatric disorder. In those with bipolar disorder and glucose abnormalities, age was associated with lower hippocampal volume to a greater extent than in bipolar patients with normal glucose function.
In the study, published by Tomas Hajek et al. in the journal Neuropsychopharmacology, not only did diabetes or prediabetes reduce the size of the hippocampus, but also reduced gray matter in the cerebral cortex, including the insula.
The researchers hope that treating diabetes, or possibly even its initial symptoms, more effectively may prevent these gray matter losses and slow brain aging in patients with bipolar disorder.
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 decades-long study called Cardiovascular Risk Factors, Aging and Dementia (CAIDE) observed older participants for signs of dementia, and collected data on participants’ levels of cynical distrust, for example, the belief that others will lie or cheat for personal gain and that it’s safer not to trust anyone.
A 2014 study by Elisa Neuvonen et al. in the journal Neurology reported that after adjusting for demographic and other factors, those participants with the highest levels of cynical distrust of others were at higher risk for dementia as they aged. This relationship was not explained by depressive symptoms. The authors suggest that a positive attitude may protect the brain.
The researchers acknowledge that it is possible the distrust may be a result of brain changes leading to dementia, rather than the cause of it.
Those with the highest levels of cynical distrust were also at higher risk for death, but this association disappeared when the researchers controlled for socioeconomic factors and health behaviors such as smoking.
The researchers hope to investigate whether having a cynical attitude early in life is more robustly linked to mortality. It would be exciting to determine whether a shift to a more positive attitude earlier in life could prevent dementia.
Editor’s Note: A high level of chronic anger is associated with shorter telomeres. Telomeres sit at the end of DNA strands and shorten with each cell replication. Shorter telomeres are linked to multiple medical and psychiatric disorders. It may be that cynical distrust shortens telomeres, and is thus associated with dementia.
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.