The Course and Outcome of Bipolar Youth study, or COBY, has been collecting information on young people with bipolar disorder and tracking their symptoms into adulthood since 2000. A 2015 study by Benjamin I. Golstein in the Journal of Clinical Psychiatry analyzed COBY data, identifying links between higher than average levels of inflammatory markers measured in the blood and participants’ histories of illness and familial risk factors.
High levels of the inflammatory marker hsCRP were associated with longer duration of illness, substance use disorder, and family history of suicide attempts or completed suicides. High levels of TNF-alpha were linked to suicide attempts, self-injury behaviors, and family history of substance use disorders. IL-6 was also linked to family history of substance use disorders.
There were also links between inflammatory markers and participants’ symptoms over the 6 months leading up to the blood tests. Levels of the inflammatory marker TNF-alpha were linked to the percentage of weeks patients had psychotic symptoms. Levels of IL-6 were associated with percentage of weeks with subthreshold mood symptoms and also with any suicide attempt. Levels of HsCRP were linked to maximum severity of depressive symptoms.
It is possible that targeting the elevated levels of inflammatory markers with anti-inflammatory treatments could improve patients’ response to treatments, but this topic requires further study.
In the past decade, several studies have indicated that people with bipolar disorder have less ability to recognize the emotions expressed on people’s faces than do healthy controls. A 2013 meta-analysis by Cecilia Samamé and colleagues concluded that facial emotion recognition was deficient in people with bipolar disorder regardless of their current state. A 2011 quantitative review article by Christian G. Kohler and colleagues revealed that this difficulty distinguishing emotions is general, rather than specific to any one emotion.
A 2015 study by Esther Vierck and colleagues in the journal Psychiatry Research showed that both euthymic patients with bipolar disorder and their first-degree relatives without bipolar disorder performed worse on tests of emotion recognition than did normal controls. The findings in healthy relatives suggest that the deficit may be a familial risk factor for the development of bipolar disorder.
These deficits in facial emotion recognition have also been seen in 4 out of 5 studies of children with early-onset bipolar disorder, including those who are euthymic. 2008 studies by Melissa A. Brotman and colleagues showed that even children just at high risk for bipolar disorder due to a family history of the disorder had deficient emotion recognition.
This literature indicates that deficiencies in facial emotion recognition consistently accompany bipolar disorder and may also be a sign that a child or teenager is at risk for bipolar disorder. Since these deficits can create social and interpersonal difficulties, it may be useful to teach better emotion recognition skills to people with bipolar disorder or those at high risk for the illness.
N-acetylcysteine (NAC), an antioxidant available without a prescription in health food stores, has shown remarkable effectiveness when added to regular treatments for schizophrenia, bipolar disorder, and the substance abuse that often accompanies these illnesses.
A 2008 article by Michael Berk and colleagues in the journal Biological Psychiatry reported that compared to placebo, 2 grams/day of NAC reduced both positive symptoms of schizophrenia (hallucinations, delusions) and negative symptoms (social withdrawal, difficulty planning and problem-solving). A 2013 study by Mehdi Farokhnia found that 2 grams/day of NAC improved negative symptoms in 42 patients with schizophrenia. Two other studies found that NAC improved deficits in auditory sensory processing in people with schizophrenia.
NAC also improves symptoms of bipolar disorder. A 2008 study by Berk and a 2011 study by Pedro Vieira da Silva Magalhães showed that NAC improved bipolar depression, and a small 2013 study by Magalhães showed that it improved mania in 15 patients. After 24 weeks, 60% of those who took NAC were in remission, compared to 15% of those taking placebo.
NAC is also effective at reducing habitual behaviors such as substance abuse, which is common in patients with schizophrenia and bipolar disorder. Studies have shown that NAC can reduce patients’ use of marijuana, cocaine, alcohol, and nicotine. It is relatively safe with minimal side effects, and fights oxidative stress, which is also common in severe mental illness.
NAC comes in 500mg or 600mg capsules. Dosing typically begins with one capsule twice a day for a week, followed by two tablets twice a day thereafter. As with any recommendations in the BNN, these should not be acted on without guidance from a treating physician.
At the 2015 meeting of the International Society for Bipolar Disorders, researcher Martin McInnis described how stem cells can be used to identify biochemical abnormalities in patients with bipolar disorder. In this research, the stem cells, or IPSCs (for induced pluripotential stem cells), are created when cells from skin fibroblasts, which produce connective tissue, are treated with chemicals that cause them to de-differentiate back into stem cells.
McInnis identified several abnormalities in the stem cells of patients with bipolar disorder. Stem cells with the gene CACNA1C, which is associated with vulnerability to bipolar disorder, fired more rapidly than non-CACNA1C stem cells. There were other abnormalities at the NMDA glutamate receptor and an imbalance of the neurotransmitter GABA in the cells. When the cells were treated with lithium, some of these abnormalities were reversed. In the cells with the CACNA1C gene, lithium normalized the firing rate. Lithium aslo re-balanced the distribution of GABA in the cells.
McInnis hopes that this stem cell research will shed light on the abnormalities associated with bipolar disorder, help explain how lithium corrects some of these, and lead to the development of new therapeutic approaches.
At the 2015 meeting of the International Society for Bipolar Disorders, Ben Goldstein described a study of cognitive dysfunction in pediatric bipolar disorder. Children with bipolar disorder were three years behind in executive functioning (which covers abilities such as planning and problem-solving) and verbal memory.
There were other abnormalities. Youth with bipolar disorder had smaller amygdalas, and those with larger amygdalas recovered better. Perception of facial emotion was another area of weakness for children (and adults) with bipolar disorder. Studies show increased activity of the amygdala during facial emotion recognition tasks.
Goldstein reported that nine studies show that youth with bipolar disorder have reduced white matter integrity. This has also been observed in their relatives without bipolar disorder, suggesting that it is a sign of vulnerability to bipolar illness. This could identify children who could benefit from preemptive treatment because they are at high risk for developing bipolar disorder due to a family history of the illness.
There are some indications of increased inflammation in pediatric bipolar disorder. CRP, a protein that is a marker of inflammation, is elevated to a level equivalent to those in kids with juvenile rheumatoid arthritis before treatment (about 3 mg/L). CRP levels may be able to predict onset of depression or mania in those with minor symptoms, and is also associated with depression duration and severity. Goldstein reported that TNF-alpha, another inflammatory marker, may be elevated in children with psychosis.
Goldstein noted a study by Ghanshyam Pandey that showed that improvement in pediatric bipolar disorder was related to increases in BDNF, a protein that protects neurons. Cognitive flexibility interacted with CRP and BDNF—those with low BDNF had more cognitive impairment as their CRP increased than did those with high BDNF.
Bipolar disorder in childhood or adolescence can destroy academic, family, and peer relationships and increase vulnerability to drug use, unsafe sexual encounters, disability, and suicide. Treatment is critical to avoid cognitive decline. Given the potential tragic outcomes of undertreating bipolar illness, it is concerning that 40–60% of children and adolescents with bipolar disorder are not in treatment.
In a talk at the 2015 meeting of the International Society for Bipolar Disorder, researcher Cristian Zeni reviewed the existing research on the treatment of bipolar disorder in children and adolescents. A 2012 study by Geller reported response rates of 68% for the atypical antipsychotic risperidone, 35% for lithium and 24% for valproate. Risperidone was linked to weight gain and increases in prolactin, a protein secreted by the pituitary gland, while lithium was linked to more discontinuations and valproate to sedation.
For children or adolescents with aggression, researcher Robert Kowatch recommends quetiapine, aripiprazole, and risperidone. For those with a family history of bipolar disorder, he recommends lithium or alternatively, valproate plus an atypical antipsychotic.
Reseacher Robert Findling has found that lamotrigine has positive effects in childhood mania, and Duffy et al. found in a study of 21 children with mania that 13 remained stable on monotherapy with quetiapine for 40 weeks without relapse, while 5 others required combination treatment with more than one drug. In studies by Karen Wagner, oxcarbazepine was significantly better than placebo at reducing mania in younger children (ages 7–12), but not older children (13–18).
Studies by Duffy and colleagues in 2007 and 2009 recommend lithium for those with a family history of bipolar disorder, atypical antipsychotics for children with no family history of bipolar disorder, and lamotrigine for those with a family history of anxiety disorders.
In children with bipolar disorder and comorbid attention deficit hyperactivity disorder, there is universal agreement that mood should be stabilized first, and then small amounts of stimulants may be added for residual ADHD symptoms. Too often, the opposite occurs, with stimulants given prior to mood stabilization with lithium, anticonvulsants (valproate, lamotrigine, carbamazepine/oxcarbazepine) and/or an atypical antipsychotic. Read more
A new longitudinal study of 391 youth at risk for bipolar disorder revealed some predictors of the disorder. The study by Danella M. Hafeman and colleagues was presented at the 2015 meeting of the Society of Biological Psychiatry. The participants were aged 6–18 and each had a parent with bipolar disorder. Over the course of the study, 40 developed an illness on the bipolar spectrum, including 21 who developed bipolar I or II. The participants were assessed for various descriptive characteristics and those who developed bipolar disorder were compared to those who developed major depressive disorder.
The most important predictors of bipolar disorder were parental assessment of internalizing symptoms of anxiety or depression, self-assessment of mood changeability, and self-assessment of hostility. A diagnosis of bipolar disorder not otherwise specified (BP-NOS) was the only predictor of a later diagnosis of bipolar I or II.
Editors Note: These data resemble findings from a 2015 study by David Axelson and colleagues in the American Journal of Psychiatry that used the same cohort of participants. The Axelson study indicated that a categorical diagnosis of a major psychiatric disorder occurred in 74% of the offspring of a bipolar parent compared to about 50% in a control group from the community. Depression, anxiety, attention deficit hyperactivity disorder (ADHD), and oppositional disorders were even more common than bipolar disorder in the at-risk population.
The presence of a major psychiatric diagnosis in about three-quarters of the offspring of a parent with bipolar disorder suggests the importance of early vigilance. One way to track symptoms of depression, anxiety, ADHD, oppositional behavior, and bipolar disorder is to join the Child Network, a secure online platform for rating children’s moods, medications, and side effects. These weekly ratings can be collected longitudinally and printed out to help parents and clinicians assess mood difficulties in their children.
People with bipolar disorder are three times more likely than the general population to develop type 2 diabetes. Type 2 diabetes typically occurs in adulthood and is associated with insulin resistance, as opposed to type 1, which is usually diagnosed in childhood and is associated with insulin deficiency.
In a talk at the 2015 meeting of the Society of Biological Psychiatry, researcher Tomas Hajek reported that in a large group of bipolar patients, 13% reported a history of type 2 diabetes, 21% were diagnosed with type 2 diabetes upon laboratory evaluation, and 32.2% had pre-diabetes without realizing it. Thus, about half of these patients with bipolar disorder were either affected by diabetes or at risk for it, many without knowing it.
The Bad News
Diabetes complicates the course of bipolar illness. Type 2 diabetes is associated with poorer response to treatment, atrophy of the hippocampus, cognitive impairment, and higher rates of conversion from mild cognitive impairment to full-blown dementia.
The main effect of type 2 diabetes is insulin resistance. The body produces enough insulin, but insulin’s effects at its receptors are impaired. Diabetes also causes deficits in growth factors, increases in the enzyme GSK3B, decreases in mitochondria and brain-derived neurotrophic factor (BDNF, which protects neurons), and glucose toxicity.
Recent research by Hajek and colleagues shows that diabetes has several other detrimental effects on the brain in bipolar disorder. On magnetic resonance spectroscopy (MRS) scans, people with type 2 diabetes had lower levels of NAA, a marker of neuronal integrity, in the prefrontal cortex. This can indicate impaired functioning. People with type 2 diabetes also had lower levels of creatine, indicating impaired energy metabolism. In addition, hippocampal volume decreases with aging, and type 2 diabetes accelerated this age-related decline.
Some of diabetes’ effects on the brain are mediated by other health factors, including obesity, cerebral blood vessel disease (which affects white matter integrity), and side effects from medications.
What You Can Do
Start early with a good diet and exercise, and have regular checkups with a doctor, who can tell you if you have diabetes or are at risk for it. If so, start long-term preventative treatment with the most effective and easy-to-tolerate medications, and periodically have your fasting blood sugar tested. If these tests are abnormal, have your hemoglobin A1c (HbA1c) checked. This is a measure of good glucose control, and should be under 6. If it creeps upward toward 6 (a sign of pre-diabetes), the drug metformin may be able to prevent the onset of type 2 diabetes. If you have type 2 diabetes, there are several types of effective medications that can minimize its effects.
At the 2015 meeting of the Transcranial Magnetic Stimulation Society in May, researcher Stephanie Ameis discussed the dearth of medication studies in children, particularly for depression but also for schizophrenia and autism spectrum disorders, which share the symptom of impaired executive functioning, which can include skills such as planning and problem solving.
Ameis noted that in a literature review, there were a total of 1046 controlled pharmacological treatment studies in adults compared to only 106 in children, which reflects a relative absence of treatment knowledge, especially for depression (where there were 303 studies in adults versus only 17 in children) and bipolar disorder (where there were 174 studies of adults and 24 of children).
Ameis then reviewed the few studies of rTMS for depression in young people. She identified several series with only a total of 33 children and adolescents who had been treated with rTMS. She is beginning to study rTMS in patients with high-functioning autism (40 patients aged 16 to 25 have been randomized in her study). Ameis also described a 2013 study of rTMS in which patients with schizophrenia showed improved performance on a test of working memory published by Mera S. Barr and colleagues in the journal Biological Psychiatry. Ameis cited this as a rationale for studying rTMS’s effect on cognitive performance in people with autism.
Verbal Abuse in Childhood, Like Physical and Sexual Abuse, Linked to Earlier Onset and More Difficult Course of Bipolar Disorder
Earlier research has shown that childhood adversity is linked to earlier age of onset of bipolar disorder and more difficult course of illness. Physical and sexual abuse are associated with both earlier age of onset and more difficulties such as anxiety disorders and substance abuse. Now, new research by this editor (Robert M. Post) and colleagues links verbal abuse (even in the absence of physical and sexual abuse) to earlier onset of bipolar disorder and to more severe and complicated course of illness.
The study, published in the journal Bipolar Disorders, was based on the self-reports of 634 adult outpatients with bipolar disorder at four sites in the US. These participants were interviewed about their history of illness and the frequency of adverse events they experienced in childhood, adolescence, and adulthood, including physical, sexual, and verbal abuse. Twenty-four percent of these participants reported having experienced verbal abuse occasionally or frequently in childhood, but not other forms of abuse, while another 35% had a history of verbal abuse as well as physical or sexual abuse, for a total of 59% with a history of verbal abuse.
The greater the frequency of verbal abuse in childhood, the earlier the average age of onset of bipolar disorder. Participants with no history of abuse had a mean age of onset of 20.6 years, but verbal abuse by itself reduced the mean age of onset to 16.5 years, and verbal abuse plus sexual abuse reduced the mean age of onset to 15.3 years. (The mean age of onset for participants who experienced sexual abuse alone was 17.5 years.) It was impossible to determine the combined effect of verbal and physical abuse because verbal abuse was almost always present when physical abuse occurred. For the 14% of the participants who had experienced verbal, physical, and sexual abuse in childhood, the mean age of onset of bipolar disorder was 13.1 years.
Those who were verbally (but not physically or sexually) abused in childhood had more anxiety disorders, drug abuse, and rapid cycling than those who were not abused, but not more alcohol abuse. Those who were verbally abused also showed increasing severity of illness, including increased frequency of cycling.
Genetics can also play a role. Having a parent with a mood disorder also contributed to an earlier age of onset of bipolar disorder.
Editor’s Note: Researcher David J. Miklowitz and colleagues have shown that family focused therapy (FFT), which emphasizes illness education and communication enhancement within the family, is more effective than treatment as usual for children with a family history of bipolar disorder and a diagnosis of depression, cyclothymia, or bipolar not otherwise specified (BP NOS).
FFT was particularly effective in reducing symptoms in children from families with high expressed emotion, suggesting that this kind of family-based intervention could reduce levels of verbal abuse.