Early Precursors of Mood Disorders in Young Children of Parents with Bipolar or Unipolar Disorder

July 24, 2020 · Posted in Course of Illness, Risk Factors · Comment 

At the 2020 meeting of the International Society for Bipolar Disorders, researcher Caroline Vandeleur presented findings from a 13-year study of children in Switzerland who have a parent with bipolar disorder or major depressive disorder. In contrast to findings from the US presented by Danella Hafeman, Vandeleur and colleagues found no evidence of psychopathology in 4 year-olds. They did find that in 7-year-olds, children of a parent with major depressive disorder were four times more likely to have a separation anxiety disorder. In an overall sample of 449 children with a mean age of 10 who were followed up for 13 years, major depression tended to be preceded by anxiety disorders. Participants who went on to be diagnosed with bipolar disorder had earlier symptoms of depression, subthreshold hypomania, conduct disorders, and drug abuse. These were especially common in those who had a parent with bipolar disorder.

Editor’s Note: These data indirectly confirm other observations in which children at high risk for mood disorders in the US showed earlier signs of psychopathology than those in other countries including the Netherlands and Canada.

Clinical Risk Prediction in Youth at Risk for Bipolar Spectrum Disorder and Relapse

July 21, 2020 · Posted in Course of Illness, Diagnosis, Risk Factors · Comment 

Researchers from two 15-year studies of bipolar youth, COBY (The Coarse and Outcome of Bipolar Youth Study) and BIOS (Bipolar Offspring Family Study), have used the longitudinal data from their studies in order to create a risk calculator that can predict an individual’s likelihood of illness.

At the 2020 meeting of the International Society for Bipolar Disorders, researcher Danella Hafeman presented research on a risk calculator that predicts the 5-year risk for onset of a bipolar disorder spectrum diagnosis (BPSD) in young people at high risk and can reasonably distinguish those who will receive a diagnosis from those who will not.

Some of the factors used in the risk calculator include dimensional measures of mania, depression, anxiety, and mood lability; psychosocial functioning; and the age at which parents were diagnosed with a mood disorder.

Hafeman reported that there was a 25% risk that offspring of a bipolar parent would develop a bipolar disorder spectrum diagnosis. In a population ranging in age from 6 to 18 years, Hafeman and colleagues found that anxiety and depression symptoms were a sign of vulnerability to a bipolar spectrum disorder, while subthreshold manic symptoms indicated that a bipolar spectrum disorder could soon emerge. Sudden or exaggerated changes in mood were also an important predictor of BPSD.

Hafeman and colleauges noted that even in children as young as 2 to 5 years old, there were already signs of anxiety, aggression, attention problems, depression, and sudden mood changes in those who would go on to receive a diagnosis of bipolar spectrum disorder.

The researchers were also able to predict which patients with BPSD would have a relapse. According to Hafeman and colleagues, “The most influential recurrence risk factors were shorter recovery lengths, younger age at assessment, earlier mood onset, and more severe prior depression.”

Editor’s Note: Offspring of a parent with bipolar disorder are at high risk for anxiety, depression, attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder, and bipolar disorder. Parents should be alert for the symptoms of these illnesses and seek evaluation and treatment for their children as necessary. Parents should also be aware of the risk factors above that contributed to the risk calculator.

Parents can aid physicians in their evaluation by joining our Child Network and keeping weekly ratings of their children’s symptoms of depression, anxiety, ADHD, oppositional behavior, and mania.

Danish Population-Based Study Identifies New Drug Candidates for Bipolar Disorder

July 17, 2020 · Posted in Potential Treatments · Comment 
Aspirin was one of the drugs that looked promising as a potential treatment for bipolar disorder, along with statins and angiotensin agents.

At the 2020 meeting of the International Society for Bipolar Disorders, Lars Kessing of the Psychiatric Center Copenhagen described a study that examined incidence of bipolar disorder among a total of 1,605,365 participants who purchased one of six common medications over a ten-year-period, with the goal of identifying drugs that might be repurposed to prevent or treat bipolar illness. The drugs were non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs such as ibuprofen), low-dose aspirin, high-dose aspirin, statins, allopurinol, and angiotensin.

Because Denmark has population-based healthcare data, the researchers were able to identify participants who purchased these medications between 2005 and 2015, and could also assess these participants for two outcome measures: 1) whether they had received a diagnosis of mania or bipolar disorder as an inpatient or outpatient at a psychiatric hospital, and 2) a combined measure of whether they had received a diagnosis for mania or bipolar disorder in any setting or initiated lithium use. The data on these participants were compared to a random sample of 30% of the population of Demark.

Kessing and colleagues found that among those with steady use of low-dose aspirin, statins (used to lower blood cholesterol), and angiotensin agents (which can lower blood pressure), there was a significant decreased incidence of mania/bipolar disorder on both outcome measures.

In contrast, among those taking non-aspirin NSAIDs and high-dose aspirin, there was an increased incidence of bipolar disorder. (There were no statistically significant findings with regard to allopurinol, which is used to treat gout and kidney stones.)

The researchers concluded that population-based studies such as these can be used to identify drugs that may have secondary benefits, in this case low-dose aspirin, statins, and angiotensin agents, which have already been identified as potentially therapeutic in other research.

Increased Risk for Dementia in Bipolar Disorder

July 14, 2020 · Posted in Comorbidities, Risk Factors · Comment 

At the 2020 meeting of the International Society for Bipolar Disorders, researcher Flavio Kapczinski described a recent meta-analysis of 10 studies that found that bipolar disorder is a risk factor for dementia, and that lithium treatment can decrease the incidence of dementia in people with bipolar disorder.

The ten studies included a total of 6,859 participants with bipolar disorder and 487,966 healthy control participants. People with bipolar disorder were 2.96 times more likely to develop dementia than those without bipolar disorder. Five of the studies included information about  treatment with lithium, which was found to decrease the risk of dementia among those with bipolar disorder by a little more than half (0.54).

Five studies also revealed that the risk of progression to dementia was higher among those with bipolar disorder than among those with major depressive disorder. In addition, one of the ten studies explored predictors of dementia in people with bipolar disorder and found that those who experienced more mood episodes had a higher risk of dementia.

Editor’s Note: It appears that the number of mood episodes a person experiences predicts dementia, and it has previously been found to predict the emergence of cognitive impairment. Prevention is the name of the game, and lithium is the best defense. My new mantra: “Prevent Episodes, Protect the Brain, Use More Lithium.”

Cognitive Abnormalities in Patients Recently Diagnosed with Bipolar Disorder

July 10, 2020 · Posted in Course of Illness · Comment 

At the 2020 meeting of the International Society for Bipolar Disorders, researcher Kamilla Miskowiak described a study in which she and her colleagues grouped 158 patients in remission from recently diagnosed bipolar disorder into groups based on their neurocognitive functioning and particularly their emotional processing, and also observed cognitive function in 52 first-degree relatives of those with bipolar disorder. These groups were compared to 110 healthy control participants.

Miskowiak and colleagues identified three clusters among the patients with bipolar disorder: 23% were globally impaired, 31% were selectively impaired, and 46% had normal cognition. Those who were globally impaired had problems recognizing facial expressions in social scenarios. Cognitive impairment has previously been documented in patients who have had a longer duration or more episodes of bipolar illness.

First-degree relatives of cognitively impaired patients had impaired recognition of facial expressions, but their cognition in non-emotional areas was normal. Miskowiak and colleagues concluded that the impaired affective cognition in relatives of patients with neurocognitive impairment was an indication of inherited risk for bipolar disorder.

Editor’s Note: Children with bipolar disorder also have this deficit in facial emotion recognition. That 23% of recently diagnosed patients with bipolar disorder were globally impaired indicates that some cognitive impairments can emerge early in the course of bipolar disorder. Researcher Lakshmi Yatham has previously found that cognition improves after a first episode of mania only if no further episodes occur in the one year following, indicating that episode prevention is crucial even after a patient’s first episode.

White Matter Disturbances in Bipolar Disorder

July 7, 2020 · Posted in Brain Imaging, Neurobiology · Comment 

At the 2020 meeting of the International Society for Bipolar Disorders, researcher Clare Beasley described the cellular and molecular underpinnings of the white matter abnormalities typically seen in children and adults with bipolar disorder. Researchers consistently see white matter abnormalities in neuroimaging studies of bipolar disorder, but not much is understood about what creates these deficits.

Beasley and colleagues studied autopsy specimens and found that compared to controls, people with bipolar disorder had a number of abnormalities affecting glial cells, lipid composition, and axons.

The researchers found increased density of oligodendrocytes (glial cells that produce the myelin that wraps around axons, the long fibers of nerve cells where impulses travel out to other cells) and an associated protein called CNP in the prefrontal cortex.  The myelin is what makes up white matter, while gray matter consists of cell bodies of neurons and glial cells.

People with bipolar disorder also had differently-shaped astrocytes, another type of glial cell that abuts synapses. The researchers found changes in lipid composition, including phospholipid and fatty acid levels, in the white matter of people with bipolar disorder. There were also problems with axons. Beasley and colleagues noted lower density of axon-associated proteins, which are involved in transport of substances along the axons in people with bipolar disorder.

The authors conclude that these data implicate specific disturbances in oligodendrocytes and axonal function associated with the white matter alterations usually seen in neuroimages of people with bipolar disorder.

Bipolar Disorder in Pregnancy and the Postpartum Period

July 3, 2020 · Posted in Risk Factors · Comment 

At the 2020 meeting of the International Society for Bipolar Disorders, researcher Veerle Bergink reported several findings from a recent meta-analysis of articles on pregnancy and bipolar disorder. Bergink and colleagues found that pregnant women with bipolar disorder have a 37% risk of a postpartum relapse, more than twice the risk of postpartum mental disorders in the general population.

Using lithium as a treatment in the first trimester of pregnancy increased risk of congenital malformations in the fetus, but the risk was much smaller than previously thought and could be monitored by ultrasound.

Bergink and colleagues also reported that in a sample of 645 women with first-onset postpartum psychosis who received followup over a period of 7 to 25 years, 43% had no subsequent severe episodes outside of the postpartum period.

Another finding was that women with postpartum severe depression or mania had abnormalities in T cells, which are important in immune response.

Childbirth and Bipolar Disorder

June 30, 2020 · Posted in Risk Factors · Comment 

In an abstract for virtual presentation at the 2020 meeting of the International Society for Bipolar Disorders, researcher Ian Jones presented evidence that childbirth may trigger onset of bipolar disorder.

Jones found that 15% of women who experience postpartum mood disorders shortly after childbirth will go on to develop bipolar disorder over time. A previous diagnosis of bipolar affective disorder is the biggest predictor that a woman will be readmitted for treatment of postpartum mental illness.

In addition, one of the biggest risk factors for postpartum mental disorders is a family history of bipolar disorder in first-degree relatives. The risk of postpartum mental disorders also increases when first-degree relatives have a psychiatric illness of any kind.

Editor’s Note:  These data are consistent with research on sensitization/kindling, the idea that while early mood episodes may be triggered by psychosocial stress and other endocrine factors, later episodes may emerge more spontaneously.  In this case, the stress associated with childbirth can lead to a subsequent bipolar diagnosis (with or without a precipitating stressor) in the future.

The psychosocial stress of childbirth and subsequent sleep deprivation can be severe, and those with a history of a mood disorder should seek additional support during such a time.

Neurotransmitters Can Also Function As Epigenetic Marks

June 2, 2020 · Posted in Genetics, Peer-Reviewed Published Data · Comment 
lab rat

The most common epigenetic marks involve methylation of DNA (which usually inhibits gene transcription) and the acetylation and methylation of histones. Acetylation opens or loosens the winding of DNA around the histones and facilitates transcription, while methylation of histones leaves the DNA tightly wound and inhibits transcriptional activation.

Researcher Ashley E. Lepack and colleagues have identified a surprising type of epigenetic mechanism involving neurotransmitters. They report in a 2020 article in the journal Science that neurotransmitters such as serotonin and dopamine can act as epigenetic marks. Dopamine can bind to histone H3, a process called called dopaminylation (H3Q5dop). In rats undergoing withdrawal from cocaine, Lepack and colleagues found increased levels of H3Q5dop in dopamine neurons in a part of the midbrain called the ventral tegmental area (VTA), a part of the brain’s reward system. When the investigators reduced H3Q5dop, this decreased dopamine release in the reward area of the brain (the nucleus accumbens) and reduced cocaine seeking. Thus, dopamine can be both an important transmitter conveying messages between neurons and a chemical mark on histones that alters DNA binding and transcriptional regulation.

Researcher Jean-Antoine Girault provided commentary on the article by Lepack and colleagues, writing that “[t]he use of the same monoamine molecule as a neurotransmitter and a histone modification in the same cells illustrates that evolution proceeds by molecular tinkering, using available odds and ends to make innovations.”

Editor’s Note: Epigenetic marks may remain stable and influence behavior over long periods of time. They are involved in the increased reactivity or sensitization to repeated doses of cocaine through DNA methylation. Such sensitization can last over a period of months or longer. If the methylation inhibitor zebularine is given, animals fail to show sensitization. Now a newly identified epigenetic process, dopaminylation, is found to alter histones and is associated with long-term changes in cocaine-seeking.

The clinical message for a potential cocaine user is ominous. Cocaine not only creates a short-term “high,” but its repeated use rewires the brain not only at the level of changes in neurotransmitter release and receptor sensitivity, but also at the genetic and epigenetic level, changes that could persist indefinitely.

The sensitization to motor hyperactivity and euphoria that occur with cocaine use can progress to paranoia and panic attacks and eventually even seizures (through a process known as kindling).

The dopaminylation of histones in the VTA could lead to persistent increases in drug craving and addiction that may not be easily overcome. Thus, the appealing short-term effects of cocaine can spiral into increasingly adverse behaviors and drug-seeking can become all consuming. While these adversities do not emerge for everyone, the best way to ensure that they do not is to avoid cocaine from the start.

Manic episodes that include a feeling of invincibility, increased social contacts, and what the DSM-5 describes as “excessive involvement in pleasurable activities that have a high potential for painful consequences” are a time that many are at risk for acquiring a substance problem. For the adolescent who has had a manic episode, ongoing counseling about avoiding developing this type of additional long-term, difficult-to-treatment psychiatric illness could be lifesaving. Describing the epigenetic consequences of substance use may or may not be helpful, but may be worth a try.

Environment Can Leave “Molecular Scars” Via Epigenetic Processes

May 29, 2020 · Posted in Genetics, Peer-Reviewed Published Data · Comment 
DNA

A 2020 review article by researchers Julia Richetto and Urs Meyer in the journal Biological Psychiatry provides a good overview of the role epigenetic modifications play in schizophrenia and related disorders.

The article provides a powerful understanding of how the environment can induce long-lasting changes in the structure of DNA (not only in schizophrenia, but also in bipolar disorder). This process, known as epigenetics, can have life-long influences on brain chemistry and behavior, and remarkably, some of these epigenetic changes can even be transmitted to the next generation.

While the sequence of DNA that one inherits from one’s parents does not change over the course of one’s life, what can change is how loosely or tightly the DNA is wound around proteins called histones, making it easier or harder to transcribe the genetic material held there. The addition of a methyl group to DNA usually inhibits transcription, while the addition of an acetyl group to histones usually facilitates transcription. These alterations in the shape of the DNA that result from environmental exposures or behavior can be passed on through generations.

Richetto and Meyer describe these chemical changes to DNA as “molecular scars,” which are left when environmental stress occurs during sensitive developmental periods. For example, patients with schizophrenia who experienced stressors in early life have higher levels of the enzyme histone deacetylase than patients who had stress or trauma later in life. Histone deacetylase would remove the acetyl groups on histones, which would inhibit gene transcription.

Other factors that have been implicated in epigenetic modifications in schizophrenia, such as DNA methylation of key developmental pathways, include pre- or post-natal stress, a challenge to a mother’s immune system during pregnancy, pre- and post-natal nutrition, exposure to drugs or toxic substances, and cannabis use in adolescence.

Richetto and Meyer suggest that epigenetics may explain why schizophrenia (and we would add bipolar disorder) can differ so much across individuals, and may help researchers and clinicians determine how best to treat different individuals.

Editor’s Note: This editor has written about how epigenetic changes can mediate sensitization to the recurrence of life stressors, episodes of mood disorder, and bouts of substance abuse, each of which can drive illness exacerbation and progression in bipolar disorder (see the 2016 article by Robert M. Post in the journal Bipolar Disorders, “Epigenetic basis of sensitization to stress, affective episodes, and stimulants: implications for illness progression and prevention”).

The chemical changes to our DNA, histones, and microRNA emphasize how important it is to begin long-term preventative treatment starting after a first episode of mania. This not only helps limit episode recurrence and the accumulation of stressors and bouts of substance use that can cause illness deterioration, but also limit the placement of these “molecular scars” on our DNA. The key to treating bipolar disorder is: prevent episodes, protect the person and the brain.

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