Predicting Onset of Bipolar Disorder in Children at High Risk: Part I

April 3, 2020 · Posted in Diagnosis, Risk Factors · Comment 

teenage boy sitting on floor with arms on kneesAt the 2019 meeting of the American Academy of Child and Adolescent Psychiatry, one symposium was devoted to new research on predicting onset of bipolar disorder in children who have a family history of the disorder. Below are some of the findings that were reported.

Symptom Progression

In offspring of parents with bipolar disorder, researcher Anne Cecilia Duffy found that symptoms in the children tended to progress in a typical sequence. Childhood sleep and anxiety disorders were first to appear, then depressive symptoms, then bipolar disorder.

Different Types of Illness May Respond Best to Different Medications

Duffy’s research also suggested links between illness features and a good response to specific medications. Those offspring who developed a psychotic spectrum disorder responded best to atypical antipsychotic medication. Those with classical episodic bipolar I disorder responded well to lithium, especially if there was a family history of lithium responsiveness. Those offspring with bipolar II (and anxiety and substance abuse) responded well to anticonvulsant medications.
If parents with bipolar disorder had experienced early onset of their illness, their children were more likely to receive a diagnosis of bipolar disorder.

The offspring of lithium-responsive parents tended to be gifted students, while those from lithium non-responders tended to be poorer students.

Comparing Risk Factors for Bipolar Disorder and Unipolar Depression

Researcher Martin Preisig and colleagues also showed that parental early onset of bipolar disorder (before age 21) was a risk factor for the offspring receiving a diagnosis of bipolar disorder. Parental oppositional defiant disorder (ODD) was also a risk factor for bipolar disorder in the offspring. The emergence of depression, conduct disorder, drug use, and sub-syndromal hypomanic symptoms also predicted the onset of mania during childhood.

Conversely, sexual abuse and witnessing violence were strong risk factors associated with a diagnosis of major (unipolar) depressive disorder. Being female and experiencing separation anxiety were also factors that predicted unipolar depression.

Predicting Conversion to Mania

Researcher Danella M. Hafeman reported that mood swings (referred to in the literature as “affective lability”), depression/anxiety, and having a parent who had an early onset of bipolar disorder were linked to later diagnoses of mania. Immediate risk factors that predicted an imminent onset of mania included affective lability, substance abuse, and the presence of sub-threshold manic symptoms.

7-Year-Olds At Risk for Schizophrenia, But Not Bipolar Disorder, Show Specific Types of Cognitive Dysfunction

March 16, 2020 · Posted in Diagnosis · Comment 

young boy with question marks on a chalk boardA large Danish study investigated whether children at risk for schizophrenia and bipolar disorder would show signs of cognitive problems. The study by researcher Nicoline Hemager and colleagues was published in the journal JAMA Psychiatry in 2018.

The researchers identified 7-year-olds,197 who had family members with schizophrenia, 118 who had family members with bipolar disorder, and 199 control 7-year-olds with no family history of these illnesses. Those children at risk for schizophrenia had significantly more cognitive deficits and behavioral disorders than the controls, while those children at risk for bipolar disorder did not differ significantly from the controls. The deficits among the children at risk for schizophrenia were in the areas of processing speed and working memory, executive and visuospatial functions, and declarative memory and attention.

The researchers indicated that the neurocognitive profile seen in the children at risk for schizophrenia could help clinicians identify these children for early intervention.

Adolescents with Bipolar Disorder May Have Higher Levels of Vitamin D–Binding Protein

May 7, 2019 · Posted in Diagnosis, Risk Factors · Comment 
illustration of vitamin D binding protein

Vitamin D binding protein. Illustration: Emw [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)]

A 2018 article by Brawnie Petrov and colleagues in the journal Translational Psychiatry suggests that adolescents with bipolar disorder have higher levels of vitamin D–binding protein than adolescents without a mood disorder. The researchers wrote that vitamin D–binding protein “responds early to cellular damage by binding…structural proteins and activating inflammatory cells.”

This pilot study suggests that measuring levels of vitamin D–binding protein could be a useful marker of bipolar disorder. The study was small, with only 12 participants who had bipolar disorder, 11 who had unipolar depression, and 13 with no mood disorder. The researchers hope to follow up with larger studies in adolescents and adults using blood that has already been collected from people with bipolar disorder.

Vitamin D–binding protein is not measured by a standard blood test. The study authors used a technique where they “fished” for inflammatory factors that might be linked to mood disorders. The researchers began by looking for a link between other inflammatory markers in the blood and bipolar disorder, which have repeatedly been found in other studies, but they did not find any such association. There also did not seem to be a link between bipolar illness and vitamin D levels in the blood, only vitamin D–binding protein levels.

It can be especially difficult to distinguish early bipolar disorder from unipolar depression, and if the results of this small study are replicated, a blood test might eventually help to identify people with bipolar disorder earlier.

Pediatric Bipolar Disorder Diagnoses Much More Common in US than England

April 19, 2018 · Posted in Diagnosis, Political Commentary · Comment 

Outline of the USA 2014 article by Anthony James and colleagues in the Journal of the American Academy of Child and Adolescent Psychiatry reported that hospitalizations for pediatric bipolar disorder are 72.1 times higher in the US than in England.

The researchers determined that there were 100.9 diagnoses of pediatric bipolar disorder per 100,000 people in the US, but only 1.4 cases per 100,000 people in Britain. The discrepancy in diagnoses for adult bipolar disorder and for other childhood psychiatry illnesses were smaller but still notable: While 158.2 adults per 100,000 in the US were diagnosed with bipolar disorder, only 22.1 adults per 100,000 in England received such a diagnosis, making the diagnosis of bipolar disorder in adults 7.2 times more common in the US. Diagnoses of childhood attention-deficit hyperactivity disorder (ADHD) were 13.0 times more common in the US than in England, while cases of childhood depression were 4.2 times more common in the US.

James and colleagues hypothesized several potential reasons for the dramatic difference in diagnosis rates at hospital discharge of bipolar disorder in children in the US versus England. The lower hospitalization rates for pediatric bipolar disorder in England may reflect the better availability of community or outpatient treatment options there. Diagnostic practices may also differ. James and colleagues suggested that in the US, pediatric diagnoses of bipolar disorder are often used to describe children and adolescents with irritability and frequent mood shifts, whereas English diagnostic practices rely more on episodic bouts of euphoria to diagnose bipolar disorder in children.

However, children in the US may simply be more likely to have a variety of childhood psychiatric disorders than those from England.

Editor’s Note: Epidemiological data support the view that bipolar disorder not otherwise specified (BP-NOS), which is often the earliest manifestation of bipolar disorder, is indeed much more common in the US than multiple other countries.

Even if there are some diagnostic differences that contribute to the immense 72.1 fold higher rates of hospitalization for childhood bipolar in the US compared to Britain, one cannot overlook the findings that these children are requiring hospitalization for something resembling bipolar disorder and are in need of treatment. Read more

Marker of Heart Failure May Predict Brain Deterioration

July 27, 2017 · Posted in Diagnosis · Comment 

heartA protein released into the blood in response to heart failure may be able to predict brain deterioration before clinical symptoms appear. The protein, N-terminal pro-B-type natriuretic peptide (NT-proBNP), is released when cardiac walls are under stress. High levels of NT-proBNP in the blood are a sign of heart disease. A 2016 Dutch study indicated that high levels of NT-proBNP in the blood are also linked to smaller brain volume, particularly small gray matter volume, and to poorer organization of the brain’s white matter. The study by researcher Hazel I. Zonneveld and colleagues, published in the journal Neuroradiology, assessed heart and brain health in 2,397 middle-aged and elderly people with no diagnosed heart or cognitive problems.

Researchers are working to clarify the relationship between cardiac dysfunction and preliminary brain disease, but researcher Meike Vernooij says it is likely cardiac dysfunction comes first and leads to brain damage. Measuring biomarkers such as NT-proBNP may help identify brain diseases such as stroke and dementia earlier and allow for earlier treatment and lifestyle changes that can slow or reverse the course of disease.

In Case Control Study, Two-Thirds of Patients With Severe Depression Had Underlying Metabolic Abnormalities

July 18, 2017 · Posted in Diagnosis, Risk Factors · Comment 

depressed manA recent study suggests that potentially treatable metabolic abnormalities in the central nervous system may underlie a large proportion of cases of severe, treatment-resistant depression. These abnormalities, such as folate deficiency in the cerebrospinal fluid, are not screened for regularly, as they require a spinal tap to diagnose.

Researchers led by Lisa A. Pan were inspired to assess metabolic function in people with treatment-resistant depression after a young patient with severe, persistent depression who had attempted suicide several times improved dramatically after being diagnosed with a tetrahydrobiopterin deficiency in his cerebrospinal fluid and treated for the deficiency. Tetrahydrobiopterin is critical to the production of monoamine neurotransmitters.

The researchers carried out a case-control study of 33 teen and young adult patients who had had treatment-resistant depression since childhood and 16 healthy control participants. Twenty-one of the 33 patients with severe depression had metabolic abnormalities in their cerebrospinal fluid. Twelve had cerebral folate deficiencies (but no folate deficiency in blood tests). Those who took folinic acid for at least six weeks (1–2 mg/kg/day) in addition to their regular medications showed sometimes dramatic improvement in their depression.

Other metabolic issues identified in the patients with severe depression included abnormal levels of acylcarnitine in five patients, low tetrahydrobiopterin intermediates in one, low guanidinoacetate in another, and unusual creatine/creatinine ratios in three patients. None of the healthy participants had any metabolic abnormality.

While the study, published in the American Journal of Psychiatry in 2017, was small, it suggests that the underlying causes of some severe depression cases are going undiagnosed and untreated. The authors suggest that assessment of metabolic function should be more common in cases of severe treatment-resistant depression.

Measuring Inflammation in Neuropsychiatric Disorders May Shed Light on Treatment

March 14, 2017 · Posted in Diagnosis · Comment 

testing for inflammatory markers in blood

Meta-analyses have found links between elevated levels of inflammatory markers and many neuropsychiatric disorders, including depression, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD) and traumatic brain injury.  Multiple studies also show that those with elevated inflammatory markers such as interleukin-1, interleukin-6, tumor necrosis factor (TNF) alpha, and c-reactive protein (CRP) also respond less well to typical treatments than those with normal levels of these markers in the blood.

These links suggest that it could be useful to measure levels of these inflammatory markers in the blood of people who are responding poorly to medications. If one or more of these markers are elevated, it might be a sign that treatment with an anti-inflammatory agent could be helpful. Preliminary studies have shown that some neuropsychiatric disorders may improve after treatment with anti-inflammatory drugs such as aspirin, celecoxib (Celebrex), and the antibiotic minocycline, among others.

Anxiety, Depression, Unstable Mood, and Low-Level Mania Best Predictors of Bipolar Disorder

May 4, 2016 · Posted in Diagnosis, Risk Factors · Comment 

kids at high risk for bipolar disorder

Researchers are looking for better ways of predicting whether children at risk for bipolar disorder will go on to develop the illness. A 2015 study by David Axelson and colleagues in the American Journal of Psychiatry reported that in the offspring of parents with bipolar disorder, diagnoses of sub-threshold mania, depression, and disruptive behavior disorders were associated with subsequent diagnosis of full-blown Bipolar I or Bipolar II disorders six to seven years later.

More recently, in an article by Danella M. Hafeman and colleagues in the American Journal of Psychiatry, the same group of investigators has examined how symptoms (rather than categorical diagnoses, as in the earlier study) predict the development of bipolar disorder. In children and adolescents at high risk for bipolar disorder (because they have a parent with the disorder) three types of symptoms were the best predictors of later bipolar disorder: anxiety/depression at the time participants entered the study, unstable mood or irritability both when entering the study and shortly before a bipolar diagnosis, and low-level manic symptoms observed shortly before diagnosis.

The earlier the age at which a parent was diagnosed with a mood disorder, the greater the risk that the offspring would also be diagnosed with bipolar disorder. Youth with all four risk factors (anxiety or depression, mood changes, low-level mania, and a parent who was diagnosed with a mood disorder at an early age) had a 49 percent chance of developing bipolar disorder, compared to a 2 percent chance among those without those risk factors.

Childhood onset of bipolar disorder and long delays until first treatment for depression or mania are both significant predictors of a poor outcome in adulthood compared to adult onsets and shorter delays to treatment. Read more

Changes in Sense of Humor May Be Warning Sign of Dementia

April 6, 2016 · Posted in Diagnosis, Risk Factors · Comment 

senior man laughingA change in a person’s sense of humor could be an early indicator of dementia, according to a 2015 article by Jason Warren and colleagues in the Journal of Alzheimer’s Disease. The changes can appear as early as 10 years before a diagnosis of dementia. Almost all participants who would go on to be diagnosed with frontotemporal dementia showed an increased preference for slapstick humor over satirical or absurdist compared with those who would not. In contrast, changes in sense of humor appeared in less than half of those who would go on to be diagnosed with Alzheimer’s disease, indicating that changes in sense of humor may allow doctors to distinguish between different types of dementia.

The study has some limitations. It was small (48 patients) and relied on patients’ memory of what kind of humor they enjoyed 15 years earlier. More research is needed to clarify the link between changes in humor preferences and dementia.

Warren suggests that changes in humor appear before other warning signs of dementia, such as memory loss. He called humor a type of “stress test” for the brain, since getting a joke can require a quick shift in perspective.

Diagnosing PANS

February 24, 2016 · Posted in Diagnosis · Comment 

psychiatric symptoms following an infection

Pediatric Acute-Onset Neuropsychiatric Syndrome, or PANS, describes a condition in which a child develops acute onset of psychiatric symptoms following an infection. At the 2015 meeting of the American Academy of Child and Adolescent Psychiatry, researcher Tanya K. Murphy reported on symptoms that differentiate PANS from other childhood-onset illnesses. Kids with PANS are more likely to have:

  • sudden onset of symptoms
  • earlier age of onset
  • personality changes
  • new onset of attention deficit hyperactivity disorder (ADHD) symptoms
  • food refusal and weight loss
  • behavioral regression
  • deterioration in handwriting
  • severe sleep disruption
  • psychosis
  • memory problems
  • frequent urination
  • dilated pupils
  • an infection at the time of onset, particularly a group A streptococcal infection

A child with sudden onset of these symptoms following an infection may have PANS. It is important to differentiate PANS from traditional psychiatric diagnoses because treatment of PANS often consists of antibiotics, anti-inflammatory medications, and other treatments that target the immune system. See our case report about a boy with PANS.

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