Reduced Cognitive Function and Other Abnormalities in Pediatric Bipolar Disorder
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.
Benefits of a Healthy Lifestyle
In a talk at the 2015 meeting of the International Society for Bipolar Disorder, researcher Michael Berk suggested that a healthy lifestyle may improve mood disorder symptoms.
Diet is important. A study of more than 20,000 mothers revealed that those with unhealthy diets had children with more externalizing disorders, such as attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder, and mania. Diets high in fat and sugar were linked to depression. The Nurses’ Health Study, a long-term epidemiological study of 50,000 women, showed that people who exercised more were less likely to be depressed, while lower muscle mass was associated with greater depression. Exercise also has anti-inflammatory effects.
Avoiding smoking has benefits, too. A study by Pasco and colleagues showed that people who smoke are at increased risk for a new onset of a mood disorder. Smoking is associated with onset of a more severe mood disorder earlier in life, suicide attempts, alcohol and substance abuse, and decreased response to treatment. Fortunately, quitting smoking can reverse some of these risks.
Diabetes Complicates Bipolar Disorder
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.
Omega-3 Fatty Acids Prevent Conversion to Psychosis
A new long-term study of omega-3 polyunsaturated fatty acids for psychosis prevention shows that almost seven years after a 3-month stint of receiving these dietary supplements daily, adolescents and young adults at high risk for psychosis showed fewer symptoms of conversion to full-blown psychosis than those who received placebo during the same period.
The research team, led by Paul Amminger, originally found that among 81 youth (mean age 16.5) at high risk of developing psychosis due to their family histories, the 41 who received 12 weeks of daily supplementation with 700mg of eicosapentaenoic acid (EPA) omega-3s and 480 mg of docosahexaenoic acid (DHA) omega-3s showed reduced likelihood of conversion to psychosis one year later than the 40 who received placebo.
The team followed up an average of 6.7 years later with 71 of the original 81 participants. Among those who had received the omega-3 intervention, 9.8% had developed psychosis. Among the placebo group, 40% had developed psychosis, and they had done so earlier.
In addition, the omega-3 participants were better functioning, they had required less antipsychotic medication, and they had lower rates of any psychiatric disorder than the placebo group.
Amminger wrote in the journal Nature Communications, “Unlike antipsychotics, fish oil tablets have no side effects and arent’s stigmatizing to patients.”
Editor’s Note: Because of their lack of side effects, a good case can be made for omega-3 fatty acids for patients at high risk for psychosis. The novel thing about this study is that short-term treatment with omega-3 fatty acids had preventive effects almost 7 years later.
A Note on Genetic Inheritance
Genetic inheritance is not everything, according to J. Craig Venter, pioneering genetic scientist responsible for sequencing the human genome in 2001:
“Human biology is actually far more complicated than we imagine. Everybody talks about the genes that they received from their mother and father, for this trait or the other. But in reality, those genes have very little impact on life outcomes. Our biology is far too complicated for that and deals with hundreds of thousands of independent factors. Genes are absolutely not our fate. They can give us useful information about the increased risk of a disease, but in most cases they will not determine the actual cause of the disease, or the actual incidence of somebody getting it. Most biology will come from the complex interaction of all the proteins and cells working with the environmental factors, not driven directly by the genetic code.”
Chronic Drug Use and Recovery
George Koob, Director of the National Institute on Alcohol Abuse and Alcoholism, discussed the neuroscience of chronic drug use at the 2015 meeting of the Society of Biological Psychiatry. His basic message was that chronic drug use is associated with A) loss of the reward value of the drug and B) a progressive increase in dysphoria and stress when off the drug. Both factors drive craving and drug seeking.
Access to high as opposed to moderate doses of a drug lead to an escalation in drug intake, and associated persistent increases in withdrawal dysphoria, which Koob called “the dark side.”
Koob explained that a month of detoxification is not sufficient, and that people quitting a drug need more time to let dopamine increase and to let levels of corticotropin releasing factor (CRF), which drives the anxiety and dysphoria of withdrawal, normalize. He stressed that for people addicted to opiates, it is important to taper levels of the drug to minimize withdrawal symptoms.
In addition to CRF, dynorphin also plays a role in chronic drug abuse. This opiate peptide acts at kappa opiate receptors and is associated with anxiety, dysphoria, and psychosis as opposed to morphine, which acts at mu opiate receptors and is associated with euphoria and decreased pain. Koob found that administration of the kappa opiate antagonist norbinaltorphimine (nor-BNI) blocks dose escalation of methamphetamine and brings abstinence-related compulsive drug seeking back to baseline.
Surprisingly, Adult ADHD Is Distinct From Childhood ADHD
In a longitudinal study of 1,037 people born in Dunedin, New Zealand in 1972 and 1973, most participants with attention deficit hyperactivity disorder (ADHD) in adulthood did not have the disorder as children. The study by Terrie E. Moffitt and colleagues in the American Journal of Psychiatry is the first prospective longitudinal study to describe the childhood of adults with ADHD.
When the study participants were children, about 6% were diagnosed with ADHD (mostly males). These children also had comorbid disorders, neurocognitive deficits, multiple genes associated with risk for ADHD, and some life impairment when they reached adulthood.
In adulthood, about 3% of the participants had ADHD (roughly equal between men and women), and 90% of these participants had no history of ADHD in childhood. The participants with ADHD in adulthood also had substance dependence and life impairment, and had sought treatment for the disorder. The researchers were surprised to find that these participants with adult ADHD did not show neuropsychological deficits in childhood, nor did they have the genetic risk factors associated with childhood ADHD.
If the findings of this study are replicated, researchers will have to rethink the current classification of ADHD as a neurodevelopment disorder that begins in childhood, and begin to determine how adult ADHD develops.
Editor’s Note: Before the publication of this article, most investigators (including this editor Robert M. Post) thought that virtually all ADHD in adulthood evolved from the childhood disorder, and if it did not begin in childhood, the diagnosis was suspect. I still believe the ADHD that appears in adulthood in patients with bipolar disorder is likely attributable to residual depression and anxiety or hypomania and that more concerted treatment of the patient to full remission will often result in much better attention, concentration, and ability to follow through and stay on task.
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.
Recovery and Relapse After a First Mania
The timeframe during which recovery and recurrence occur in people with a first episode of mania are somewhat variable. A meta-analysis by Andréanne Gignac and colleagues published in the Journal of Clinical Psychiatry in 2015 offers some new information. The meta-analysis included eight studies with a total of 734 participants in a first episode of mania. Syndromal recovery rates (when patients no longer met diagnostic criteria for bipolar disorder) were 77.4% at six months after first episode of mania and 84.2% at one year after. However, some symptoms lingered, and only 62.1% of patients reached a period of symptomatic recovery within one year.
Recurrence rates were 25.7% within six months, 41.0% within one year, and 59.7% by four years. Those who were younger at the time of the first episode were at higher risk for relapse within one year.
Editor’s Note: On the positive side, most recovered, but on the negative side, at one year, 60% remained symptomatic and 40% had a recurrence. What is not clear is how intensively patients were treated and monitored. The main message of this study is that a first episode of mania is not trivial and deservces concerted acute and long-term treatment. When expert multimodal treatment is given results are vastly more superior than treatment as usual (Kessing et al. British Journal of Psychiatry 2013).
Childhood Onset of Bipolar Illness More Difficult than Adolescent and Adult Onset
Research on early-onset bipolar disorder sometimes lumps childhood-onset in with adolescent onset. Researcher Terence Ketter et al. explored differences in illness among 502 patients at the Stanford Bipolar Disorder Clinic. The 107 patients with childhood onsets (before age 13) had a more difficult course of illness in almost all domains compared to the 238 patients with adolescent onsets (age 13–18) or the 157 patients with illness onset in adulthood (after age 18).
Considered separately, both patients with childhood-onset illness and patients with adolescent-onset illness had more comorbid anxiety disorders, alcohol use disorders, eating disorders, prior suicide attempts, rapid cycling in the prior year, and at least five mood episodes over the course of their lifetimes than those patients whose illness began in adulthood. Patients whose illness began in childhood had higher rates of each of these unfavorable illness characteristics and were more likely to have a first-degree relative with a mood disorder.
These data mirror those from the Bipolar Collaborative Network in which this editor (Robert Post) is an investigator, and the larger STEP-BD network led by Perlis et al. All three suggest that in the US, two-thirds of the bipolar disorder seen in adults begins in childhood and adolescence, with about a quarter beginning before age 13.
Ketter suggests that research should not combine childhood and adolescent onset illnesses, which come with different rates of anxiety, alcohol, and eating disorder comorbidity, rapid cycling, and prior episodes. The statistical relevance of some findings can be diluted when the two groups are combined.
Editor’s Note: However, the primary message is that childhood onset bipolar disorder is a more severe version of the illness that deserves greater attention, treatment, and research so that its course can be made more benign. It is a problem that there are no Federal Drug Administration–approved treatments for children under 10 years of age with bipolar disorder.
