Untreated Episodes of Bipolar Disorder Worsen Over Time, But Prevention is Possible
A 2017 literature review by researcher Lars V. Kessing and Per K. Andersen in the journal Acta Psychiatrica Scandinavica reports that the greater a patient’s number of previous episodes of bipolar disorder, the more likely that patient is to have a more difficult course of illness and poorer outcomes. The number of episodes was associated with more rapid recurrences, duration and severity of episodes, more automatic episodes (i.e. not triggered by stress), risk of dementia, treatment resistance, lack of recovery between episodes, and brain volume losses.
In an article in the journal Bipolar Disorders in 2016, BNN Editor-in-Chief Robert M. Post described the value of preventive treatment in reducing episodes and protecting the brain from the damage that accompanies them.
Given that episodes, stressors, and bouts of substance abuse can affect the way genes are transcribed via a phenomenon known as epigenetics, preventing these occurrences could lead to an easier course of illness and improved outcomes. Patients should provide their physicians with feedback about their response to prior medications and any side effects they experience over time so that their medication regime can be adjusted until it is maximally effective.
Patients with severe illness and multiple previous episodes may need a complex medication regimen that includes multiple types of medications that target different systems of neurotransmitters.
This philosophy of treatment is presented in several publications, including the 2008 book Treatment of Bipolar Illness: A Casebook for Clinicians and Patients by Post and Gabrielle Leverich, and more recently in the article “Treatment of Bipolar Depression: Evolving Recommendations” in the journal Psychiatric Clinics of North America. An open access article by Post, “New Perspectives on the Course and Treatment of Bipolar Disorders,” published in the journal Edizioni Minerva Medica S.p.A. in 2017, describes the need for early and sometimes complex combination therapy, including the non-intuitive idea that more medications (carefully prescribed) can actually produce fewer side effects than large doses of a single medication.
Another good resource for patients is a daily personal calendar that can be used to track ongoing symptoms, side effects, and response to medications. We offer several types of these calendars free here. My Mood Monitor, or What’s My M3, is a validated screening instrument that can detect depression, anxiety disorders, and mania in response to weekly self-reports. It is available online and as an app, and can be used to track illness course and response to treatment.
Alterations in Amino Acids in Blood That Affect Metabolism May Help Explain Chronic Fatigue
Chronic fatigue syndrome, more recently known as myalgic encephalopathy, is a debilitating and somewhat mysterious illness. However, a 2016 article in the Journal of Clinical Investigation Insight suggests that low blood levels of amino acids related to oxidative metabolism, the process by which oxygen is used to make energy from sugars, may play a role in the illness. High levels of amino acids related to the breakdown of proteins were also seen.
The study by Øystein Fluge and colleagues compared blood concentrations of 20 amino acids in 200 patients with chronic fatigue and 102 healthy participants. There were shortages in 6 amino acids that fuel oxidative metabolism in those with chronic fatigue, particularly women. Men with chronic fatigue had high levels of a different amino acid related to protein catabolism, the breaking down of complex molecules, a process that releases energy.
The differences between men and women with the illness might be because men use muscle tissue as a source for amino acids, while women, who have less muscle mass, use amino acids from blood as fuel.
The changes in both sexes suggest a functional impairment in pyruvate dehydrogenase (PDH), an enzyme that is important for the conversion of carbohydrates into energy. If PDH fails to work and cells turn elsewhere to create energy, muscles may suddenly weaken and lactate may build up, which patients experience as a burning in their muscles after the slightest exertion.
Fluge and colleagues are cancer researchers. They stumbled into chronic fatigue research when they noticed that people with chronic fatigue who were treated for cancer with the drug rituximab saw reductions in their fatigue. Rituximab, which is also used to treat some autoimmune diseases, is a monoclonal antibody directed at B cells. When it binds, it induces cell death. The researchers hope to clarify the link between the immune system and the problems with energy metabolism they have identified in people with chronic fatigue.
Levels of Amino Acid Proline Interact with COMT Genotype to Affect Negative Symptoms
In a 2016 article, researcher Catherine L. Clelland and colleagues reported that a patient’s levels of the amino acid proline interact with their genetic profile to influence the seriousness of their negative symptoms. Negative symptoms of schizophrenia and bipolar disorder include flat affect and lack of volition and can be some of the hardest symptoms to treat.
High levels of proline in the central nervous system have been linked to schizophrenia. Proline is a precursor to the neurotransmitter glutamate, and high proline levels have been found to alter glutamate and dopamine signaling in mice. This is one of the factors affecting negative symptoms.
The other factor affecting negative symptoms is the COMT gene. The enzyme catechol-o-methlyl transferase (COMT) metabolizes dopamine in the prefrontal cortex. There are several common versions of the gene for COMT. The most efficient is known as val-158-val, identifying that the gene has two valine amino acids at position 158. People with high proline levels and the val-158-val version of the COMT gene had fewer negative symptoms than people with high proline levels and another version of the gene, val-158-met (indicating one valine and one methionine amino acid at position 158).
Clelland and colleagues hypothesized that high proline levels may actually counteract the dopamine shortages common in the prefrontal cortex in people with the val-158-val genotype of COMT, which is more efficient at breaking down dopamine in this region.
The mood stabilizer valproate increases proline levels. In the study, which was published in Translational Psychiatry, people with schizophrenia and the val-val genotype had fewer negative symptoms when treated with valproate than those with the val-met genotype who received the same treatment.
Adherence to Antidepressants Associated with Lower Mortality
A large study from Israel suggests that over a 4-year period, people who regularly took their prescribed antidepressants were less likely to die of any cause during that period.
The study, published in the Journal of Clinical Psychiatry in 2016, used data from an Israeli health provider that covers 53% of the nation’s population. It included 251,745 patients aged 40 and up who filled a prescription for an antidepressant at least once between 2008 and 2011.
Researchers led by Amir Krivoy looked at how much of the time people actually filled their prescriptions. Patients who filled their prescriptions more of the time were less likely to die during the study period than those who did not fill their prescriptions regularly.
Editor’s Note: This study by Krivoy and colleagues provides more evidence of the benefit of long-term antidepressants. People who have had two or three episodes of unipolar depression should consider long-term prevention with antidepressants over the course of their lifetime, in the way that people take blood pressure medications long-term to prevent heart attacks. In addition to lowering mortality, antidepressants also reduce the rate of relapse by 75% compared to placebo. More time on antidepressants also preserves hippocampal volume with aging.
Immune Response to Repeated Stress Alters Behavior in Mice
In research presented at the 2016 meeting of the Society of Biological Psychiatry, Jonathan P. Godbout described how an immune reaction to repeated stressors may lead to anxious behaviors in mice.
Mice were repeatedly defeated by a larger animal, a form of stress that produces a depression-like state. This provoked an immune response in the mice—the release of a type of white blood cells called monocytes from the bone marrow into the circulatory system. These inflammatory monocytes then traveled to the brain and spleen, attracted by signaling proteins called chemokines. The monocytes in turn produced inflammatory marker interleukin-1beta.
The defeat stress also provoked a reaction in the central nervous system, where microglia were activated.
These changes produced inflammation and anxiety-like behaviors in the mice. Blocking the microglial activation, monocyte recruitment to the brain, or interleukin-1beta signaling each reversed the anxiety-like behaviors.
Another researcher, Scott Russo, has shown that leukocytes, another type of white blood cells, secrete inflammatory interleukin-6 following defeat stress, and blocking this secretion prevents defeat stress–related behaviors.
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.
