Mysteries Remain in the Relationship Between Inflammation and Depression
At the 2017 meeting of the American College of Psychiatrists, researchers Charles L. Raison and Vladimir Maletic gave a plenary lecture on the role of inflammation in depression. Meta-analyses have confirmed that inflammatory markers including Il-1, Il-6, TNF alpha, and CRP are elevated in about 1/3 of depressed patients. However, Raison and Maletic made the point that anti-inflammatory medications are not for everyone. While patients with elevated levels of CRP at baseline responded to an anti–TNF alpha antibody, patients with low CRP values at baseline actually got worse.
Raison and Maletic cited three studies that have also linked CRP to differential response to traditional antidepressants. In unipolar depression, those with low CRP respond well to selective serotonin reuptake inhibitor (SSRI) antidepressants, while those with elevated blood levels of CRP seem to respond better to a dopamine-active antidepressant such as bupropion or a noradrenergic-active antidepressant such as nortriptyline or the serotonin norepinephrine reuptake inhibitor (SNRI) antidepressant duloxetine. Patients with high inflammation at baseline also seem to respond better to intravenous ketamine and oral doses of omega-3 fatty acids.
Studies of animals have suggested that inflammation throughout the body is implicated in depression. Studies in which rodents are repeatedly defeated by larger animals show that these animals have increased inflammation from lymphocites (a type of white blood cells) in the blood, and monocytes (another type of white blood cells) from the bone marrow and spleen. This inflammation can induce depression-like behaviors in the rodents, which is prevented if the inflammatory mechanisms are blocked. These data suggest that depression is not just in the brain—inflammation from all over the body plays an important role.
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How Stress Triggers Inflammation and Depression
Depression and bipolar disorder are associated with increases in markers of inflammation that can be found in the brain and blood. It is increasingly clear that the mechanisms that cause depression are not just in the brain, but actually throughout the body. These include two signaling systems that begin in the bone marrow and the spleen.
When a small mouse is repeated defeated by a larger animal, they show depression-like symptoms known as defeat stress. Animal studies have shown that stress and danger signals are perceived and relayed to the amygdala and the hypothalamus. The sympathetic nervous system releases the neurotransmitter norepinephrine into bone marrow, where stem cells are turned into activated monocytes (a type of white blood cells) that are then released into the blood. The monocytes travel to the brain, leading to the activation of more inflammatory cells.
Blocking part of this process can prevent the depression-like behaviors from occurring. If the bone marrow monocytes are blocked from entering the brain, inflammation and defeat stress behaviors like social avoidance do not occur. However, if there is a second bout of defeat stress, primed monocytes that have been stored in the spleen are released and travel to the brain, producing further increases in inflammatory cells and even more defeat stress behaviors.
If these monocytes from the spleen are blocked, the inflammation and the reaction to the new stressor do not occur.
Stress also activates lymphocytes (another type of white blood cells) to secrete the inflammatory cells Il-6. If this Il-6 secretion is inhibited, defeat stress behaviors can be prevented.
Defeat stress also leads to the release of the neurotransmitter glutamate. Some of this cascade begins in the brain, which evaluates stressors and releases IL-1 beta, another type of inflammatory cell. It slows down the production of glutamate, while IL-6 can endanger neurons and is associated with anhedonia—loss of interest in pleasurable activities. This cascade also leads to the production of another type of inflammatory cell, TNF-alpha, which has adverse effects on biochemistry, brain, and behavior.
This understanding of the role of the brain and body provides new targets for drug development. If inflammatory processes are blocked, defeat stress behaviors do not occur. Researcher Michael D. Weber and colleagues described this process in detail in the journal Neuropsychopharmacology Reviews in 2017.
Together these observations suggest that inflammatory processes in the body are crucial to the development of some stress- and inflammation-related depressive behaviors.
Certain Types of Inflammation and BMI Predict Depression
At the 2016 meeting of the Society of Biological Psychiatry, researcher Femke Lamers and colleagues presented findings from the Netherlands Study of Depression and Anxiety. The inflammatory markers interleukin-6 and CRP were elevated in people with current major depression. These measures were correlated with BMI, a measure of body weight. High levels of interleukin-6 at the beginning of the study predicted who would have a chronic course of illness.
Editor’s Note: Previous studies have found that elevated levels of CRP predicted a future mood episode in people at high risk for bipolar disorder due to a family history of the illness.
These studies suggest that it might be useful to assess levels of these inflammatory markers (CRP, interleukin-1, interleukin-6, and TNF-alpha) in young people who are at high risk for bipolar disorder. Factors that put someone at high risk include a family history of depression or bipolar disorder, a history of adversity in childhood (abuse, neglect, loss of a parent, etc.), and preliminary symptoms.
Several interventions are available that may reduce the likelihood that someone at risk for bipolar disorder will go on to develop the illness. Family interventions such as the Family Focused Therapy developed by researcher David Miklowitz are helpful. In a 2013 study in the Journal of the American Academy of Child and Adolescent Psychiatry, Miklowitz reported that Family Focused Therapy outperformed treatment as usual for youth at risk for bipolar disorder.
Measures of inflammation might provide additional rationale for beginning interventions in youth at high risk for mood disorders. In addition to family interventions, omega-3 fatty acid supplementation is a low-risk option that is supported by some positive data. Since BMI was implicated in the study by Lamers and colleagues, keeping weight under control might also have some benefit.
For adults with depression who want to keep their weight under control, the combination of the antidepressant bupropion XR (150–300mg/day) and naltrexone (50mg/day), an opiate antagonist medication normally used to fight addictions, has been effective.
Children of Bipolar Parents in US More Ill than Those in the Netherlands
New research shows that bipolar disorder risk is higher in the US than in the Netherlands. At the 2015 meeting of the American Academy of Child and Adolescent Psychiatry, researchers Manon Hillegers and Esther Mesman described a study in which they compared the offspring of mothers with bipolar disorder in the US to those in the Netherlands. The offspring ranged in age from 10–18.
In the US, the mothers had, on average, an earlier age of onset, more substance abuse comorbidity, and were more likely to have been diagnosed with bipolar II disorder. Among the US offspring, 66% had been diagnosed with a psychiatric illness compared to 44% of the Dutch offspring. This included significantly higher rates of anxiety, ADHD, and disruptive behavior disorders in the US offspring. Among the offspring who had been diagnosed with a mood disorder, 80% of those in the US had other additional psychiatric disorders, but only 34% of the Dutch did. Bipolar disorder is more rare among children under the age of 12 in the Netherlands compared to the US.
Dutch children and adolescents were typically treated with lithium and with only one drug at a time. In the US, lithium is less widely used, and simultaneous treatment with several medications (usually including atypical antipsychotics) is common.
Editor’s Note: The research by Hillegers and Mesman replicates research by this editor (Robert M. Post) and colleagues that compared bipolar disorder incidence and severity in the US, Germany, and the Netherlands. Other comparisons have been made between the US and Europe. A 2014 article by Frank Bellivier and colleagues in the World Journal of Biological Psychiatry also showed that bipolar disorder onset occurs earlier in the US than in 10 different European countries, while Bruno Etain and colleagues found that bipolar disorder onset occurs earlier in the US than in France in a 2012 article in the Journal of Clinical Psychiatry.
Together this research shows that bipolar disorder is more serious in the US than in a number of European countries. Two-thirds of adults with bipolar disorder report that their illness began in childhood or adolescence. Most of these cases are not properly diagnosed or treated. A concerted effort must be made by the medical establishment and healthcare policymakers in the US to provide better and earlier treatment of bipolar illness.
Mixed Depression
Mixed depression describes a state of depression accompanied by a few symptoms typically associated with mania. At the 2015 meeting of the International Society for Bipolar Disorders, researcher Roger McIntyre shared some findings about mixed depression.
People with mixed depression have higher levels of MHPG, which is produced as the neurotransmitter norepinephrine breaks down. They also have higher levels of the stress hormone cortisol and their depressions are more difficult to treat. Those with unipolar mixed depression may respond poorly to traditional antidepressants.
There are also medical risks associated with mixed depression. People with mixed depression are more susceptible to cardiovascular disease than are people with depressive symptoms alone.
The drugs lurasidone, olanzepine, and ziprasidone have each shown efficacy in mixed depression.
Reduced Cognitive Function and Other Abnormalities in Pediatric Bipolar Disorder
At the 2015 meeting of the International Society for Bipolar Disorders, Ben Goldstein described a study of cognitive dysfunction in pediatric bipolar disorder. Children with bipolar disorder were three years behind in executive functioning (which covers abilities such as planning and problem-solving) and verbal memory.
There were other abnormalities. Youth with bipolar disorder had smaller amygdalas, and those with larger amygdalas recovered better. Perception of facial emotion was another area of weakness for children (and adults) with bipolar disorder. Studies show increased activity of the amygdala during facial emotion recognition tasks.
Goldstein reported that nine studies show that youth with bipolar disorder have reduced white matter integrity. This has also been observed in their relatives without bipolar disorder, suggesting that it is a sign of vulnerability to bipolar illness. This could identify children who could benefit from preemptive treatment because they are at high risk for developing bipolar disorder due to a family history of the illness.
There are some indications of increased inflammation in pediatric bipolar disorder. CRP, a protein that is a marker of inflammation, is elevated to a level equivalent to those in kids with juvenile rheumatoid arthritis before treatment (about 3 mg/L). CRP levels may be able to predict onset of depression or mania in those with minor symptoms, and is also associated with depression duration and severity. Goldstein reported that TNF-alpha, another inflammatory marker, may be elevated in children with psychosis.
Goldstein noted a study by Ghanshyam Pandey that showed that improvement in pediatric bipolar disorder was related to increases in BDNF, a protein that protects neurons. Cognitive flexibility interacted with CRP and BDNF—those with low BDNF had more cognitive impairment as their CRP increased than did those with high BDNF.
Benefits of a Healthy Lifestyle
In a talk at the 2015 meeting of the International Society for Bipolar Disorder, researcher Michael Berk suggested that a healthy lifestyle may improve mood disorder symptoms.
Diet is important. A study of more than 20,000 mothers revealed that those with unhealthy diets had children with more externalizing disorders, such as attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder, and mania. Diets high in fat and sugar were linked to depression. The Nurses’ Health Study, a long-term epidemiological study of 50,000 women, showed that people who exercised more were less likely to be depressed, while lower muscle mass was associated with greater depression. Exercise also has anti-inflammatory effects.
Avoiding smoking has benefits, too. A study by Pasco and colleagues showed that people who smoke are at increased risk for a new onset of a mood disorder. Smoking is associated with onset of a more severe mood disorder earlier in life, suicide attempts, alcohol and substance abuse, and decreased response to treatment. Fortunately, quitting smoking can reverse some of these risks.
Diabetes Complicates Bipolar Disorder
People with bipolar disorder are three times more likely than the general population to develop type 2 diabetes. Type 2 diabetes typically occurs in adulthood and is associated with insulin resistance, as opposed to type 1, which is usually diagnosed in childhood and is associated with insulin deficiency.
In a talk at the 2015 meeting of the Society of Biological Psychiatry, researcher Tomas Hajek reported that in a large group of bipolar patients, 13% reported a history of type 2 diabetes, 21% were diagnosed with type 2 diabetes upon laboratory evaluation, and 32.2% had pre-diabetes without realizing it. Thus, about half of these patients with bipolar disorder were either affected by diabetes or at risk for it, many without knowing it.
The Bad News
Diabetes complicates the course of bipolar illness. Type 2 diabetes is associated with poorer response to treatment, atrophy of the hippocampus, cognitive impairment, and higher rates of conversion from mild cognitive impairment to full-blown dementia.
The main effect of type 2 diabetes is insulin resistance. The body produces enough insulin, but insulin’s effects at its receptors are impaired. Diabetes also causes deficits in growth factors, increases in the enzyme GSK3B, decreases in mitochondria and brain-derived neurotrophic factor (BDNF, which protects neurons), and glucose toxicity.
Recent research by Hajek and colleagues shows that diabetes has several other detrimental effects on the brain in bipolar disorder. On magnetic resonance spectroscopy (MRS) scans, people with type 2 diabetes had lower levels of NAA, a marker of neuronal integrity, in the prefrontal cortex. This can indicate impaired functioning. People with type 2 diabetes also had lower levels of creatine, indicating impaired energy metabolism. In addition, hippocampal volume decreases with aging, and type 2 diabetes accelerated this age-related decline.
Some of diabetes’ effects on the brain are mediated by other health factors, including obesity, cerebral blood vessel disease (which affects white matter integrity), and side effects from medications.
What You Can Do
Start early with a good diet and exercise, and have regular checkups with a doctor, who can tell you if you have diabetes or are at risk for it. If so, start long-term preventative treatment with the most effective and easy-to-tolerate medications, and periodically have your fasting blood sugar tested. If these tests are abnormal, have your hemoglobin A1c (HbA1c) checked. This is a measure of good glucose control, and should be under 6. If it creeps upward toward 6 (a sign of pre-diabetes), the drug metformin may be able to prevent the onset of type 2 diabetes. If you have type 2 diabetes, there are several types of effective medications that can minimize its effects.
Omega-3 Fatty Acids Prevent Conversion to Psychosis
A new long-term study of omega-3 polyunsaturated fatty acids for psychosis prevention shows that almost seven years after a 3-month stint of receiving these dietary supplements daily, adolescents and young adults at high risk for psychosis showed fewer symptoms of conversion to full-blown psychosis than those who received placebo during the same period.
The research team, led by Paul Amminger, originally found that among 81 youth (mean age 16.5) at high risk of developing psychosis due to their family histories, the 41 who received 12 weeks of daily supplementation with 700mg of eicosapentaenoic acid (EPA) omega-3s and 480 mg of docosahexaenoic acid (DHA) omega-3s showed reduced likelihood of conversion to psychosis one year later than the 40 who received placebo.
The team followed up an average of 6.7 years later with 71 of the original 81 participants. Among those who had received the omega-3 intervention, 9.8% had developed psychosis. Among the placebo group, 40% had developed psychosis, and they had done so earlier.
In addition, the omega-3 participants were better functioning, they had required less antipsychotic medication, and they had lower rates of any psychiatric disorder than the placebo group.
Amminger wrote in the journal Nature Communications, “Unlike antipsychotics, fish oil tablets have no side effects and arent’s stigmatizing to patients.”
Editor’s Note: Because of their lack of side effects, a good case can be made for omega-3 fatty acids for patients at high risk for psychosis. The novel thing about this study is that short-term treatment with omega-3 fatty acids had preventive effects almost 7 years later.
A Note on Genetic Inheritance
Genetic inheritance is not everything, according to J. Craig Venter, pioneering genetic scientist responsible for sequencing the human genome in 2001:
“Human biology is actually far more complicated than we imagine. Everybody talks about the genes that they received from their mother and father, for this trait or the other. But in reality, those genes have very little impact on life outcomes. Our biology is far too complicated for that and deals with hundreds of thousands of independent factors. Genes are absolutely not our fate. They can give us useful information about the increased risk of a disease, but in most cases they will not determine the actual cause of the disease, or the actual incidence of somebody getting it. Most biology will come from the complex interaction of all the proteins and cells working with the environmental factors, not driven directly by the genetic code.”
