Cognitive Abnormalities in Patients Newly Diagnosed with Bipolar Disorder

September 24, 2020 · Posted in Course of Illness, Genetics, Risk Factors · 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.

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.

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.

Inflammation Associated With Duration of Untreated Unipolar Depression

February 14, 2019 · Posted in Brain Imaging, Course of Illness, Neurobiology · Comment 

depressed woman

Researcher Sophia Attwells and colleagues reported at a 2018 scientific meeting that the longer the time that a patient went without treatment for depression, the more inflammation they exhibited on positron emission tomography (PET) scans. Attwells and colleagues used the PET scans to assess the total distribution volume of TSPO, which is a marker of brain microglial activation, a form of inflammation.

Strikingly, in participants who had untreated major depressive disorder for 10 years or longer, TSPO distribution volume was 29–33% greater in the prefrontal cortex, anterior cingulate cortex, and insula than in participants who were untreated for 9 years or less. TSPO distribution volume was 31–39% greater in these three important regions of gray matter in participants with long durations of untreated major depressive disorder than in healthy control participants.

Editor’s Note: In schizophrenia, the duration of untreated interval (DUI) is associated with a poor prognosis, but not with inflammation. Researcher Yvette Sheline has also reported that less time on antidepressants compared to more time treated with them was associated with greater hippocampal volume loss with aging in patients with major depression.

Given Attwells and colleagues’ remarkable finding about the adverse effects of the DUI in depression, including inflammation and brain volume loss, and other findings that associate more episodes with poorer functioning, cognition, and treatment responsiveness, physicians and patients should think hard about committing to long-term antidepressant treatment to prevent episodes, beginning early in the course of illness.

This editor (Robert M. Post) would propose that if a second depressive episode occurs after a first depression that responded well to treatment, this would be an appropriate time to start antidepressant prophylaxis. Most guidelines suggest that prophylaxis be started after a third episode, but these recommendations generally do not account for newer data on the pernicious effects of experiencing repeated depressive episodes. In addition to causing dysfunction and disability, going through four depressive episodes doubles the risk of dementia in old age, and this risk increases further with each successive episode, according to researcher Lars Kessing.

Having too many depressions is bad for the brain. In Kessing’s studies, two episodes of unipolar or bipolar depression did not increase the risk of dementia compared to the general population, while four depressions did. One could compare the effects of repeated depressions on the brain to the effects of heart attacks on the heart muscle. A heart might still function well after one or even two heart attacks, but the chances of significant loss of function and the risk of congestive heart failure increase as a function of the number of heart attacks. After even one heart attack, most patients change their lifestyle and/or go on prophylactic medications to reduce risk factors such as elevated blood pressure, cholesterol, triglycerides, weight, blood sugar, and smoking. The benefits of reducing heart attacks are a no brainer. Trying to prevent recurrent depression with pharmacotherapy and adjunctive psychotherapy after a second depressive episode should be a no brainer too.

In addition, if antidepressants are not effective enough in preventing depressions, lithium is an option, even in unipolar depression, for preventing both episodes and suicide. The evidence of efficacy in both instances is very strong according to an article by Mohammed T. Abou-Saleh in the International Journal of Bipolar Disorders in 2017.  The renowned psychiatrist Jules Angst’s recommendation as to when to start lithium treatment was that if a patient had had one episode or more in the previous five years in addition to the present episode, then they were likely to have two further episodes in the following five years, and lithium prophylaxis would be recommended.

Early Intervention Improves Outcomes in Early-Stage Schizophrenia

 

doctor with teen boy

A recent meta-analysis of 10 studies found that early intervention after a first episode of psychosis or in the early stages of a schizophrenia spectrum disorder led to better patient outcomes than treatment as usual.
The meta-analysis by researcher Christoph U. Correll and colleagues appeared in the journal JAMA Psychiatry in 2018. The 10 studies that were included had randomized a total of 2,176 patients to receive either treatment as usual or early intervention services, which typically include efforts at early detection of symptoms, early treatment with low doses of antipsychotic medication, interventions to prevent relapse, and strategies to help patients return to normal work and social activities.

Those patients who received early intervention services were less likely to discontinue treatment, were less likely to have a psychiatric hospitalization, were more involved in school or work, and had less severe symptoms, including both positive and negative symptoms of schizophrenia.

The authors called for better funding and implementation of early intervention services in early psychosis or the beginning stages of schizophrenia.

Editor’s Note: This finding with regard to schizophrenia spectrum disorders emphasizes the enormous disparity in allocation of research resources for the study of early psychosis versus early bipolar disorder, where almost no studies of this kind have been done.

The mean age of the patients in this psychosis meta-analysis was 27.5 years. Symptoms of bipolar disorder can often begin earlier, in childhood, and early onset of bipolar disorder predicts poor long-term outcomes into adulthood and is associated with a high risk of substance abuse and suicide. This editor (Robert M. Post) and many colleagues have witnessed two decades of scientific literature on early-onset bipolar disorder. We know that early intervention is necessary, but more treatment studies are needed at the early stages of the illness, and calls for funding treatment-focused research have gone unheeded.

More advocacy is needed among families affected by bipolar disorder and advocacy groups interested in better treatment of bipolar disorder. We must try to change the abysmal status quo and campaign publicly, privately, and politically for more funds and public health attention to be directed toward early intervention in bipolar disorder.

Longer Periods of Untreated Depression Linked to More Brain Inflammation

June 27, 2018 · Posted in Course of Illness, Risk Factors · Comment 

depressed womanA 2018 study by researchers Elaine Setiawan, Sophia Attwells and colleagues reports that inflammation seems to increase with duration of untreated unipolar depression. This implies that depression may be a progressive illness, and later stage depression may require different treatments than early stage depression, such as those that directly target inflammation.

The study published in the journal The Lancet Psychiatry used positron emission tomography (PET scan) to examines levels of translocator protein in the brain. Higher levels of translocator protein indicate activation of microglia, the brain’s immune cells, which can respond to trauma or injury.

The study included 80 participants between the ages of 18 and 75. Ten had a history of more than 10 years of depression, ten had experienced fewer than 10 years of depression, and 30 comprised a healthy comparison group.

The best predictors of high levels of translocator protein were duration of untreated major depressive disorder, total illness duration, and duration of antidepressant exposure. These three factors explained about half of the variation in translocator protein levels. Those participants whose depression went untreated for 10 years or longer had inflammation levels 29–33% higher than those whose depression was untreated for 9 years or less.

Participants who had received antidepressant treatment appeared to avoid an average yearly increase in the extent of their microglial activation.

The study took place at Canada’s Centre for Addiction and Mental Health.

Editor’s Note: Since inflammation is a predictor of poorer response to antidepressants, these data add a further neurochemical rationale to the already strong clinical rationale for earlier and more sustained antidepressant treatment and prevention. Virtually all treatment guidelines suggest that after two or three prior unipolar depressions, patients should receive long-term (lifelong) antidepressant treatment.

There is now a large body of data, including a 2012 article by this editor Robert M. Post and colleagues in the Journal of Psychiatric Research that too many episodes can hurt the brain, and the current study adds to this perspective. Avoiding preventive treatment for too long may actually foster the development of more episodes and more treatment resistance. A good mantra is “prevent episodes, protect the brain.”

Consensus is now also building that comprehensive long-term treatment is indicated after a first manic episode. A 2013 article by Lars Kessing and colleagues in the British Journal of Psychiatry suggested that high quality initial treatment can improve the long-term course of illness. Moreover, a 2016 article by Jan-Marie Kozicky and colleagues and a 2017 article by Christine Demmo and colleagues, both in the journal Bipolar Disorders, suggest that after a first mania, cognition recovers over the next year only if no further episodes occur in that time.

Untreated Episodes of Bipolar Disorder Worsen Over Time, But Prevention is Possible

September 18, 2017 · Posted in Course of Illness · Comment 

Pensive man

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

September 7, 2017 · Posted in Course of Illness · Comment 

exhausted woman

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

May 24, 2017 · Posted in Course of Illness, Genetics, Neurobiology · Comment 

DNAIn 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.

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