In a 2013 article in the journal European Psychiatry, in which researcher Valery V. Gafarov examined depression’s influence on cardiovascular health in Russia, an astonishing 55.2% of women aged 25–64 years in the study were diagnosed with depression. The study, in which 870 women in the city of Novosibirsk were surveyed over 16 years from 1995 to 2010, was part of a World Health Organization program called “MONICA-psychosocial.”
The researchers collected information on the incidence of myocardial infarction (heart attack), arterial hypertension, and stroke among the women. Over the 16 years of the study, 2.2% of the women had heart attacks and 5.1% had strokes. Women with depression were 2.53 times more likely to have a heart attack and 4.63 times more likely to have a stroke than women without depression.
Among women with average education levels, married women with depression were more likely to have heart attacks, hypertension, and strokes. Hypertension was more likely among women who worked as managers or light manual laborers.
C-reactive protein, or CRP, is a protein found in blood plasma, the levels of which rise in response to inflammation. In a recent study, levels of CRP were able to predict which of two antidepressants a patient was more likely to respond to.
The 2014 article by Rudolph Uher et al. in the American Journal of Psychiatry reported that low levels of CRP (<1 mg/L) predicted a good response to the selective serotonin reuptake inhibitor (SSRI) escitalopram (Lexapro) while higher levels of CRP predicted a good response to the tricyclic antidepressant nortriptyline, a blocker of norepinephrine reuptake.
The research was part of the Genome-Based Therapeutic Drugs for Depression (GENDEP) study, a multicenter open-label randomized clinical trial. CRP was measured in the blood of 241 adult men and women with major depressive disorder. In the article the researchers say that CRP and its interaction with medication explained more than 10% of the individual variance in response to the two antidepressants.
If these findings can be replicated with these and similarly acting drugs, it would be a very large step in the direction of personalized medicine and the ability to predict individual response to medications.
Some people have found that gluten-free or casein-free diets have improved their intestinal, autoimmune, or neurological symptoms. (Casein is a protein found in mammals’ milk. Cow milk is high in casein while human milk proteins are 20–45% casein.) One explanation for the good effects of these diets is that peptides that are released during digestion of these foods can create epigenetic changes in gene expression, adding methyl groups to DNA strands that increase inflammation.
As infants transition from getting all of their nutrition from the placenta to using their gastrointestinal tract, their diet may lead to epigenetic modifications that affect their health later in life. Epigenetics refers to changes in genes that do not affect the inherited sequence of DNA, but affect how easily the DNA is transcribed to produce proteins. Methyl or acetyl groups can be added to DNA or the histones around which it is wound.
When a person digests casein (from either human or animal milk) or gliaden (a protein derived from wheat), peptides are released that activate opioid receptors, modulating the uptake of the amino acid cysteine in neurons and in the gastrointestinal tract. This decrease in cysteine uptake is associated with drop in the antioxidant glutathione and a methyl donor (a molecule with a reactive methyl group that can easily become part of another molecule) called S-Adenosyl methionine.
In addition to decreasing cysteine uptake, the peptides also increase DNA methylation and create epigenetic changes in genes involved in redox (changes in oxidation) and methylation homeostasis.
These processes are described in a 2014 article by Malav S.Trivedi et al. in the Journal of Nutritional Biology. Trivedi et al. conclude that milk and wheat can change antioxidant activity and gene expression. Differences in the peptides in human and cow milk may explain developmental differences between children who are breastfed and those who receive formula.
The decrease in antioxidants caused by peptides from wheat and milk can predispose people to inflammation and oxidation, explaining why wheat- or casein-free diets might be useful.
Epidemiological studies have linked methamphetamine use to risk of Parkinson’s disease, and animal studies of the illicit drug have shown that it harms dopamine neurons. A 2014 study by Sara Ares-Santos et al. in the journal Neuropsychopharmacology compared the effects of repeated low or medium doses to those of a single high dose on mice. Loss of dopaminergic terminals, where dopamine is released, was greatest after three injections of 10mg/kg given at three-hour intervals, followed by three injections of 5 mg/kg at three-hour intervals, and a one-time dose of 30mg/kg. All of the dosages produced similar rates of degeneration of dopamine neurons via necrosis (cell destruction) and apoptosis (cell suicide) in the substantia nigra pars compacta (the part of the brain that degenerates in Parkinson’s disease) and the striata.
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
Not everyone who experiences trauma develops post-traumatic stress disorder (PTSD) immediately. Researchers are discovering that some people go on to develop symptoms like flashbacks or intrusive thoughts, anxiety, and withdrawal, sometimes after long periods of being asymptomatic. Two studies provide hints about the mechanism of this late-onset (or delayed-type) PTSD.
In an article by Danny Horesh et al. published in the journal Psychiatry Research in 2013, a reported 16.5% of 675 Israeli veterans of the 1982 conflict with Lebanon developed late-onset PTSD after a completely non-symptomatic period. The number of deployments soldiers were sent on and the number of terror incidents they experienced within Israel after the war were correlates of the late-onset PTSD, while continuous post-war employment was a protective factor reducing late-onset PTSD.
In a study of 260 older adults (above age 60) who survived the destruction around Galveston Bay, Texas by Hurricane Ike in 2008, Robert H. Pietrzak et al. reported in the Journal of Psychiatry Research in 2013 that 5.3% developed late-onset PTSD. In this case as well, a greater number of subsequent traumatic and stressful life events (and in particular financial difficulties) was associated with late onset of PTSD. The majority of participants in Pietrzak’s study (78.7 %) had no to few PTSD symptoms, while 16.0% had chronic PTSD symptoms from the outset persisting through assessments at three months and 15 months.
Editor’s Note: These two studies reveal that upon prospective follow-up, a small but substantial group of patients (5–16%) develop a late-onset type of PTSD. Acute onset PTSD has been closely linked to new trauma in adulthood, especially following the occurrence of previous (childhood) traumas. The late-occurring variety of PTSD seems to appear after an incubation period, and appears to be closely associated with the occurrence of new traumatic events during the well interval. These new events may result in a kindling-like effect, where repetition of subthreshold stimuli come to evoke a full-blown episode. PTSD appearing after repeated traumatic experiences may operate in a similar fashion to seizures that gradually emerge following repeated electrical stimulation of the amygdala (i.e. amygdala kindling). Read more
Links between inflammation and depression continue to be identified in new research. Researcher N. Vogelzangs et al. reported in a 2014 article in Neuropharmacology that inflammatory and metabolic dysregulation in antidepressant users predicted an outcome of depression two years later. Elevated levels of the marker of inflammation Il-6, low HDL (or “good”) cholesterol, high triglycerides, and high blood sugar were associated with poor response to medication and chronicity of depression. Of 315 people treated with antidepressants (average age 43), 138 were in remission at 2 years, while 177 (56.2%) were still depressed. People with four or more types of inflammatory or metabolic dysregulations had a 90% chance of still being depressed at 2 years.
Among inflammatory markers including CRP and TNF-alpha, IL-6 alone was associated with chronic depression. Il-6 can cross the blood-brain barrier. We have previously reported that researcher Scott Russo found that in rats in a depression-like state known as defeat stress (brought about by repeated defeat by a larger rodent), blocking Il-6 can prevent depressive behaviors such as social avoidance or loss of preference for sucrose.
Like inflammation, metabolic abnormalities also complicate depression. Lipid dysregulation and hyperglycemia are associated not only with depression persistence, but also with the new onset of depression in humans.
Vogelzangs et al. conclude that these data “ suggest that inflammatory and metabolic dysregulation worsens depression course owing to reduced [antidepressant] response and that alternative intervention treatments may be needed for depressed persons with inflammatory and metabolic dysregulation.”
It is noteworthy that a 2014 meta-analysis of the anti-inflammatory drug celecoxib (Celebrex) published by Farhad Faridhosseini et al. in Human Psychopharmacology, showed that the drug, often prescribed for arthritis, is effective for unipolar depression when added to patients’ regular treatment.
It remains to be ascertained whether celecoxib’s effects are seen in depression in general, or if they pertain only to the 30% of depressed patients who show inflammation at baseline. Typical markers of inflammation include Il-6, CRP, TNFa, and Il-1.
Statins, prescribed to lower cholesterol, also have anti-inflammatory effects, and are also effective in preventing depression.
Determining treatment approaches for those patients showing signs of inflammation or metabolic irregularities remains a high priority for study. The preliminary data noted here suggest that treating these dysregulations in those with depression may be useful.
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.
An epigenetic finding from a study of twins may shed light on why some people develop bipolar disorder and others don’t.
Epigenetics refers to changes in genes that do not affect the inherited sequence of DNA, but affect how easily the DNA is transcribed to produce proteins. Environmental events such as stress or exposure to chemicals can bring about epigenetic changes by adding or subtracting acetyl or methyl groups from strands of DNA or the histones around which it is wound. In this way twins’ DNA can differ—not in its sequence but in its physical structure and the ease with which it produces proteins.
At the 2014 meeting of the International Society for Bipolar Disorders, researcher J. Ayers Ringlera et al. presented their study of pairs of twins in which one twin had bipolar disorder and the other didn’t. The ill twins showed more methylation of SLC1A2, the gene for the excitatory amino acid transporter 2 (EAAT2), which clears the excitatory neurotransmitter glutamate from the synapse of neurons. Methylation of the gene suppresses the amount of transporter expressed, so less glutamate gets cleared.
Editor’s Note: Glutamate abnormalities play a role in bipolar disorder. This finding by Ringlera et al. may explain why the drug N-acetylcysteine (NAC) works in bipolar disorder—NAC increases the number of glial glutamate transporters and helps clear excess glutamate from the synapse.
A 2014 study by Sarah E. Canetta et al. in the American Journal of Psychiatry suggests that children whose mothers had influenza during pregnancy are at higher risk for bipolar disorder with psychotic features. The same researchers had previously found that maternal influenza during pregnancy increased a child’s risk of developing schizophrenia, suggesting that there is a link between maternal influenza and psychotic symptoms in the offspring.
In the current study, influenza infections were identified by measuring levels of flu antibodies in blood. In a previous study, participants were considered to have influenza if they had been diagnosed clinically. Possibly due to this difference, that study showed a link between maternal flu infections and bipolar disorder in general (not just psychotic cases).