Depression Associated with Increased DNA Methylation
Epigenetics is an emerging field where researchers are studying the ways environmental events and biochemical changes can affect the structure of DNA. Chemicals such as methyl groups can accumulate on DNA (a process called methylation), which usually results in suppression of genes in that area. DNA is tightly wound around proteins called histones, which can also be methylated or acetylated (when acetyl groups accumulate) based on events in the environment, including stressors and drug use. The environmental events do not change the genetic inheritance people receive from their parents, but instead change the ease with which genes are transcribed (or switched on).
At the 2012 meeting of the Society of Biological Psychiatry, Dr. Yurong Xin et al. presented an abstract that indicates that depressed patients may have much more DNA methylation at CpG sites on genes. CpG sites occur in many genes and refer to a place where a cytosine and a guanine (two of the four building blocks of DNA) sit next to each other on the same strand of DNA (the ‘p’ refers to the chemical bond between the two). CpG sites can become methylated. Xin and colleagues measured 27,578 CpG sites across 14,000 genes in the human genome. They found an eightfold increase in DNA methylation at these CpG sites in depressed patients compared to controls.
Editor’s Note: Previous research has found that early life experiences like psychosocial stress can lead to epigenetic changes. The new findings by Dr. Xin indicate that DNA methylation may occur and accumulate across the lifespan and suggests that DNA methylation may be associated with the emergence and progression of depression. Future treatments for depression could target this DNA hypermethylation, but determining how to do that selectively without affecting normal functioning may be a challenge.
Epigenetics Update
In the BNN we have previously written about the role of epigenetics in the onset and course of bipolar disorder. Epigenetics refers to the idea that events and substances in the environment can affect the structure of DNA by adding chemicals (often methyl or acetyl groups) onto DNA and histones (structures around which DNA is wound) in such a way that the DNA is more or less likely to be transcribed and activated to produce new proteins. Thus our DNA is shaped not only by the genetic inheritance we receive from our parents, but also by events in the environment (which do not alter the sequence of DNA but can influence how easily the DNA gets turned on to produce proteins in our bodies.)
Researcher David Sweatt published a review article on epigenetics and memory in the journal Neuropsychopharmacology in 2012. In it he examined research on rodents who show epigenetic changes after repeatedly being exposed to stimuli such as a fear-inducing environment or cocaine.
Sweatt made two main points abut the mechanisms by which the environment influences gene expression. The first is about the effects that histone deacetylase (HDAC) inhibitors can have on epigenetics. Contextual fear conditioning (when a rodent experiences danger in a particular place and begins to associate fear with that particular physical environment) can be augmented by histone deacetylase (HDAC) inhibitors, which include sodium butyrate and valproate. In rodents who have been given cocaine and whose interest in cocaine is associated with the physical environment they were in while receiving the cocaine, Marcelle Wood reported that extinction of this context-dependent cocaine-induced place preference could also be enhanced with an HDAC inhibitor.
Sweatt’s second point was that DNA methylation is necessary for long-term memory, and traumatic learning like that of the rodent avoiding the place it encountered danger can actually be erased using zebularine, an inhibitor of DNA methylation.
Editor’s Note: Zebularine can also reverse other lifelong responses to neonatal trauma such as decreases in brain-derived neurotrophic factor (BDNF), a neuroprotective factor necessary for long-term memory, in the prefrontal cortex. Zebularine can also block the long-lasting increases in motor activity in response to repeated cocaine use, i.e. cocaine sensitization. Thus, it looks like much of what one learns or responds to in the environment is coded at the level of epigenetics when DNA or histones are methylated and/or acetylated (among other chemical modifications).
Amazingly, some of these epigenetic marks on our DNA and histones can even be transmitted to the next generation! Read more
Cardiovascular Problems in Bipolar Disorder May Begin in Adolescence
Adults with bipolar disorder have higher rates of cardiovascular disease and premature death from cardiovascular illness than the general population. At the 2012 meeting of the American Academy of Child and Adolescent Psychiatry, Benjamin Goldstein presented a poster in which he showed that youth with bipolar disorder may also have abnormal cardiovascular function.
When a tourniquet is applied, blood vessels normally expand to make up for the period of oxygen deprivation. This does not happen as readily in patients with mood disorders. This lack of flexibility and compensatory response could be one of the reasons for increased cardiovascular difficulties in those with mood disorders.
In Goldstein’s study, noninvasive ultrasound imaging was used to measure the thickness of the walls of the carotid artery and flow mediated dilation of the artery in adolescents with bipolar disorder and those without the illness. The data was collected by a certified ultrasound technologist who remained blind to the patients’ diagnostic and symptom status.
Goldstein found highly abnormal results in 14 adolescents aged 14 to 19 with bipolar disorder compared to controls. He concluded that reducing cardiovascular risk in bipolar disorder is a pressing clinical and public health challenge and that treating these patients while they are adolescents may offer considerable advantages both for prevention and for understanding the progression of cardiovascular problems in patients with bipolar disorder.
Irritability and Unipolar Depression in Kids
At the 2012 Pediatric Bipolar conference sponsored by the Ryan Licht Sang Foundation, Graham J. Emslie gave a talk on irritable mood and unipolar depression in youth.
Irritability is common in unipolar depression. Emslie suggested that if a child’s irritability is severe and the child destroys objects and denies being irritable, bipolar disorder might be likely. Irritable unipolar depressed children will generally acknowledge being irritable.
Emslie reported that 96% of youth in his randomized placebo-controlled studies of selective serotonin reuptake inhibitor antidepressants (SSRIs) recovered from their unipolar depression, but 46.6% relapsed. Those children with residual depressive symptoms were at double the risk for relapse into a depression compared to those who remitted completely. In those without residual depressive symptoms, there were no relapses if the children stayed on their medications.
Children were excluded from Emslie’s study if they had a positive family history of bipolar disorder, and perhaps because of this, very few participants switched into mania with antidepressants.
MORAL: Treat to remission and stay on the antidepressants associated with the remission. This has previously been found to be important for adults as well. (Emslie added that he would advise that a child stay on an antidepressant for at least a year after a remission was achieved, and longer if the child had difficulties in academic performance or relationships at school.)
Children with unipolar major depression who had a few manic symptoms at a subsyndromal level had poorer outcomes in Emslie’s study. The presence of subsyndromal manic symptoms in bipolar depressed adults is a risk factor for increased switching into mania when antidepressants are added to a mood stabilizer.
Comorbid substance abuse is another risk factor for poor outcome in childhood depression.
Anxiety and Depressive Disorders Often Precede the Onset of Bipolar Disorder in Those At High Risk Due to Family History
At the 2012 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) meeting, Anne Duffy and Gabrielle A. Carlson sponsored a symposium on the association between anxiety and minor mood disorders and subsequent bipolar disorder in those at high risk. Researchers presenting at the symposium consistently found that there is a sequence in which young people at high risk for bipolar disorder develop increasingly severe illnesses: first anxiety, then mood disorders, then bipolar illness.
One difference: the incidence of childhood-onset bipolar disorders in those at high risk because a parent has the disorder was lower in Canada, Switzerland, and the Netherlands than it was in the US.
Duffy, a professor of psychiatry in Calgary, noted that bipolar disorder is highly heritable even though most adults with bipolar illness do not have a family history of bipolar illness among their first-degree relatives. She shared estimates that if one parent has bipolar disorder their offspring have a 5% lifetime risk of developing bipolar disorder. If both parents have bipolar disorder their offspring have a 25% risk of developing bipolar disorder and a 35% incidence of developing any affective disorder (although other data by Lapalme et al. suggest it may be as high as 60%).
Duffy found that when parents responded well to lithium, their children tended to do the same. Lithium-responsive patients tended to be those without anxiety disorder and substance abuse and who had classic bipolar episodes and clear well intervals between episodes. Read more
Substance Use Among Canadian Adolescents with Bipolar Disorder: The Critical Need for Intervention and Prevention
At the 2012 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), Antoinette Scavone presented a poster on correlates of substance use disorders among Canadian adolescents with bipolar disorder. Participants were 62 adolescents aged 14 to 19 with bipolar disorder. Twenty-three participants (37.1%) had a substance abuse disorder.
Those with a comorbid substance use disorder were more likely to have a comorbid panic disorder or an oppositional defiant disorder. They also had higher rates of police contact or arrest, were more likely to have been involved in assault, and were more impulsive. In addition they had experienced more stressful life events.
Editor’s Note: These data from a Canadian sample replicate previous findings in the US and again indicate the critical importance of preventing the onset of substance abuse in adolescents at especially high risk because of their bipolar disorder.
Family Environment, Cognitive Functioning, and Quality of Life Among Depressed Adolescents with Bipolar Disorder
At the 2012 meeting of the American Academy of Child and Adolescent Psychiatry, Arman Danielyan presented a poster on psychosocial, cognitive, and behavioral characteristics of youth in a depressive phase of bipolar disorder. These adolescents had lower scores on a variety of measures.
Adolescents with bipolar depression had significantly lower scores on 7 of 10 family environment scales measuring the quality of family interaction, communication, and emotional tone. They also exhibited significant impairment in cognitive function, particularly executive functioning, and all domains of psychosocial health were substantially lower than US normative data.
The authors concluded that bipolar depression affects multiple domains of adolescents’ lives including their cognitive, psychosocial, and family functioning. This suggests that the involvement of the whole family in the treatment process would be beneficial.
The impaired cognitive functioning these young people face is associated with lower quality of life, and ways of addressing this better are clearly needed.
Editor’s Note: In a previous BNN we reported on the efficacy of Family Focused Therapy (FFT), which was pioneered by David Miklowitz. This therapy is effective for adolescents and adults with bipolar disorder and for adolescents who are at high risk for the disorder because of two factors: having a parent with the disorder and having preliminary symptoms of bipolar disorder not otherwise specified (BP-NOS), depression, or an anxiety disorder. Kiki Chang, a respected authority on child and adolescent psychiatry, recommends FFT for children and adolescents with bipolar disorder and those at high risk for it.
It Appears Antidepressants and Stimulants Do Not Hasten the Onset of Bipolar Disorder in Children
It is a common clinical assumption that early treatment of depression with antidepressants may be a risk factor for hastening the onset of subsequent bipolar disorder. Accumulating evidence indicates that this may not be the case. At a symposium at the 2012 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) researchers in the field shared the latest findings on antidepressant-induced manic symptoms in youth (AIMS), and there was a surprising consensus that antidepressants do not increase the risk of subsequent bipolar disorder onset when used for the treatment of childhood-onset depression.
Symposium speakers Kiki Chang, Melissa P. DelBello, and David Axelson all agreed that antidepressant treatment was not a risk factor for bipolar disorder.
DelBello shared data from a study in which antidepressant treatment was associated with a lower likelihood of mania during follow-up. Antidepressants were typically discontinued if the patient switched into manic-like symptoms or increased irritability or aggression. These symptoms tended to occur in children who were younger, who had a smaller volume of the amygdala, and in those who had a positive family history for bipolar disorder in first-degree relatives.
Axelson indicated that his data represented only a “bird’s-eye view,” but suggested that antidepressants do not cause or hasten the onset of bipolar disorder when used for treating depression in children. He also reported results from a naturalistic study in which stimulants also did not increase the risk of subsequent bipolarity.
Several of the presenters discussed how they would treat children with an early-onset depression when there is a family history of bipolar disorder. Read more
Long Delays to First Treatment Are Crippling Many with Bipolar Disorder: What You Can Do
An article published by N. Drancourt et al. in the journal Acta Psychiatra Scandinavica this year examined the duration of the period between a first mood episode and treatment with a mood stabilizer among 501 patients with bipolar disorder. The time between a first episode of depression, mania, or hypomania and first treatment averaged 9.7 years. The authors conclude that more screening, better recognition of the early stages of the illness, and greater awareness are needed to decrease this long delay.
Editor’s Note: The article by Dancourt et al. replicates earlier findings of an average treatment delay of 10 years among bipolar patients from the treatment network in which this editor (Robert Post) is an investigator (formerly the Stanley Foundation Bipolar Network, now called the Bipolar Collaborative Network). The duration of the untreated interval (DUP) for patients with bipolar disorder is unacceptably long and carries a heavy price.
Those with the earliest age of onset experience the longest delay to first treatment. Early onset is associated with poor outcome compared to adult onset bipolar disorder, and the duration of time untreated adds a separate, independent risk of a worse outcome in adulthood, especially more frequent and severe depression, more episodes, and less time well.
What patients and doctors can do to shorten this interval to first treatment: Know the risk factors for early onset bipolar disorder so you can seek evaluation and advise treatment as appropriate. Read more
The Impact of Obesity on Brain and Behavior
In an abstract presented at the 5th Biennial Conference of the International Society for Bipolar Disorders, K. Sim and colleagues discussed the impact of increased body mass index on the integrity of white matter in the brain during a first episode of mania. The researchers found significant abnormalities in white matter integrity in the temporal pole and occipital brain regions in overweight and obese patients compared to patients of normal weight. These data highlight the need to clarify the neural mechanisms that link obesity and poorer functional outcomes in bipolar disorder.
Other investigators have reported that bipolar patients with obesity have a less robust response to naturalistic treatment compared to those of normal weight. At least one study suggested that patients with overweight and obesity experience more cognitive difficulties.
Editor’s Note: The pathophysiological mechanisms involved in the relationship between weight and brain function are not yet clear, although one possibility is that in obese patients, some fat cells in the abdominal area become too big to survive and are scavenged by other cytokine-producing cells. These inflammatory cytokines are then able to cross the blood-brain barrier, enter the brain, and affect neuronal functioning. Whether a mechanism like this is at play in relation to these particular findings remains for further investigation.
Nonetheless, these data suggest the importance of good diet, exercise, and other means of maintaining a good body weight in order to attempt to avoid some of the adverse associations of obesity with deficits in cognition, white matter integrity, and treatment outcome.
