In a 2017 article in the Journal of Clinical Psychiatry, researcher Paul E. Croarkin and colleagues describe findings from their study of genetic risk factors for early-onset bipolar disorder. The researchers focused on single nucleotide polymorphisms (SNPs), which are variations in a single base pair of a DNA sequence. SNPs are normal variations or copying errors that occur when DNA is replicated. Croarkin and colleagues tracked 8 SNPs that had been linked to bipolar disorder in previous studies. They examined 69 patients from a study of early-onset mania, 732 adult patients with bipolar disorder (including 192 with early-onset illness), and 776 healthy controls. The researchers compared patients with early-onset illness to controls, and also looked for connections between specific SNPs and early-onset illness.
The SNPs analyzed in the study map to three genes that have repeatedly been associated with the risk for bipolar disorder in other studies. These include CACNA1C (one of several genes that create calcium channels), ANK3, and ODZ4. Croarkin and colleagues determined that the presence of these SNPs, particularly the ones that involved the CACNA1C gene, were associated with early-onset bipolar disorder.
Editor’s Note: These findings may lead to better treatment for early-onset bipolar disorder. The CACNA1C calcium influx gene that has repeatedly been connected to bipolar illness can be blocked by the calcium channel blocker nimodipine. Nimodipine has lithium-like effects in mania and depression in adults. One case report by Pablo A. Davanzo in the Journal of Child and Adolescent Psychopharmacology described success using nimodipine and the thyroid medication levothyroxine to treat a 13-year-old boy with very rapid cycling bipolar disorder that had previously failed to respond to multiple medications.
Nimodipine deserves further study in children showing symptoms of bipolar disorder. The company Genomind provides testing for the CACNA1C gene. We hope it will soon be determined whether the presence of this SNP predicts a good response to nimodipine.
Being able to predict who will get bipolar disorder is a long way off. However, there are some clear risk factors. Young people from families that have had several generations of bipolar disorder or related disorders are at increased risk for bipolar disorder. This risk increases for children who experience adversity in childhood, such as abuse or neglect. The presence of early mild symptoms of mania, depression, or disruptive behavior further increase this risk.
For doctors, a patient’s clinical history of these three types of risk factors can help identify whether they are at increased risk of developing bipolar disorder. Patients with several risk factors should be observed closely and treated with psychotherapy or medication as needed.
Parents of children between the ages of 2 and 12 who have shown some signs of mood or behavioral symptoms are encouraged to join our Child Network. We provide a secure online platform where parents record their children’s symptoms of anxiety, depression, attention-deficit hyperactivity disorder (ADHD), oppositional behavior, and mania on a weekly basis. Symptoms are charted over time in a graphical depiction that can be shared with the child’s doctor. For more information, see page 11 of this issue. To join, visit our website bipolarnews.org and click on the tab for the Child Network.
It has been clear for some time that the volume of the hippocampus, a brain region implicated in mood and memory processing, plays a role in bipolar disorder. A 2017 article by researcher Bo Cao and colleagues in the journal Molecular Psychiatry links loss of volume in specific sub-regions of the hippocampus with bipolar disorder.
The study by Cao and colleagues used magnetic resonance imaging (MRI) and a special segmentation technique to compare the volume of certain hippocampal sub-regions across people with bipolar disorder, people with major depression, and healthy control participants.
Participants with bipolar disorder had lower volumes in subfield 4 of the cornu ammonis, two cellular layers (the granule cell layer and the molecular layer), and the tail part of the seahorse-shaped hippocampus compared to the other subjects. Participants with bipolar I disorder had particularly severe volume loss in these areas.
Cao and colleagues also found that volume loss progressed along with the illness. The volumes of the right cornu ammonis, the molecular layer, and the subiculum decreased further in patients who had bipolar disorder for longer. As manic episodes increased, the volume of both sides of the cornu ammonis and the hippocampal tail decreased.
A 2017 meta-analysis published in the British Journal of Psychiatry indicates that psychosocial interventions were linked to reduced relapse rates, better adherence to medication, and other benefits in people with bipolar disorder. The meta-analysis by researcher Mary Lou Chatterton and colleagues evaluated data from 41 studies with a total of 3,119 participants. The studies examined psychosocial interventions such as cognitive-behavioral therapy, psychoeducation, and family-focused therapy compared to treatment as usual.
Chatterton and colleagues found that interventions that targeted family members who act as caregivers reduced manic and depressive relapse rates. Combined psychoeducation and cognitive-behavioral therapy was more successful than any other intervention, and had a large effect in reducing symptoms of mania. This combination also improved general functioning. Psychoeducation alone and in combination with cognitive behavioral therapy reduced medication non-adherence. Unfortunately, no intervention reduced depressive symptoms.
Meta-Analysis Shows Inflammation is Common in Unipolar Depression, Bipolar Depression, and Schizophrenia
In a symposium at the 2016 meeting of the Society of Biological Psychiatry, Mark Hyman Rapaport described the results of his research group’s meta-analysis of studies comparing levels of inflammation in the blood of people with unipolar depression, bipolar depression, and schizophrenia. Rapaport and colleagues determined that people acutely ill with any of the three illnesses showed abnormally high levels of certain inflammatory proteins. These included: interleukin-1beta, interleukin-6, TNF alpha, and c-reactive protein. Those who were chronically ill showed elevations in interleukin-6.
These data are consistent with increasing evidence that inflammation also occurs in the brain. Brain inflammation can be observed by measuring translocator protein binding, a measure of brain microglial activation, using positron emission tomography (PET) scans.
Bipolar disorder has been linked to cardiovascular disease. New research by Jessica Hatch and colleagues shows that inflammation may be at the root of this connection. At the 2016 meeting of the Society of Biological Psychiatry, the researchers showed that teens with bipolar disorder have higher levels of inflammatory marker interleukin 6.
Hatch and colleagues assessed the blood of 60 teens with bipolar I or II disorder and 20 healthy controls for a variety of biomarkers, including the inflammatory proteins interleukin 6, interleukin 10, and TNF alpha; VEGF, which is responsible for the production of new blood vessels; and brain-derived neurotrophic factor (BDNF), which protects neurons. The researchers also assessed the participants’ cardiovascular health, performing the carotid intima media thickness test to estimate how much plaque is in the arteries, and measuring how well the patients’ arteries dilate in response to changes in bloodflow.
Participants with bipolar disorder had higher levels of interleukin 6 than healthy controls, regardless of whether their bipolar illness was symptomatic. Low BDNF was linked to greater carotid intima thickness in participants with symptomatic bipolar disorder, and vascular measurements suggest a possible mechanism by which bipolar disorder increases cardiovascular risk.
At the 2016 meeting of the Society of Biological Psychiatry, researcher Femke Lamers and colleagues presented findings from the Netherlands Study of Depression and Anxiety. The inflammatory markers interleukin-6 and CRP were elevated in people with current major depression. These measures were correlated with BMI, a measure of body weight. High levels of interleukin-6 at the beginning of the study predicted who would have a chronic course of illness.
Editor’s Note: Previous studies have found that elevated levels of CRP predicted a future mood episode in people at high risk for bipolar disorder due to a family history of the illness.
These studies suggest that it might be useful to assess levels of these inflammatory markers (CRP, interleukin-1, interleukin-6, and TNF-alpha) in young people who are at high risk for bipolar disorder. Factors that put someone at high risk include a family history of depression or bipolar disorder, a history of adversity in childhood (abuse, neglect, loss of a parent, etc.), and preliminary symptoms.
Several interventions are available that may reduce the likelihood that someone at risk for bipolar disorder will go on to develop the illness. Family interventions such as the Family Focused Therapy developed by researcher David Miklowitz are helpful. In a 2013 study in the Journal of the American Academy of Child and Adolescent Psychiatry, Miklowitz reported that Family Focused Therapy outperformed treatment as usual for youth at risk for bipolar disorder.
Measures of inflammation might provide additional rationale for beginning interventions in youth at high risk for mood disorders. In addition to family interventions, omega-3 fatty acid supplementation is a low-risk option that is supported by some positive data. Since BMI was implicated in the study by Lamers and colleagues, keeping weight under control might also have some benefit.
For adults with depression who want to keep their weight under control, the combination of the antidepressant bupropion XR (150–300mg/day) and naltrexone (50mg/day), an opiate antagonist medication normally used to fight addictions, has been effective.
In a recent study by researcher Dan V. Iosifescu and colleagues, the drug galantamine, which is used to treat dementia, did not improve cognitive function in euthymic people with bipolar disorder. The drug had done so in earlier studies. Seventy-two participants with bipolar disorder that was in remission were randomized to receive either a placebo or galantamine extended release for a period of two weeks. Doses of galantamine ranged from 8 to 24 mg/day.
The participants took several tests of attention and memory over the course of the study. After 16 weeks of treatment, those taking galantamine did not show significant improvements in functioning compared to those who received placebo.
This research was presented at the 2016 meeting of the Society of Biological Psychiatry.
Depression and Bipolar Disorder in Adolescence Linked to Early-Onset Cardiovascular Disease and Hardening of the Arteries
The link between mood disorders and cardiovascular illnesses has been clear for some time. Now there is evidence that this link begins early in life. In 2015, the American Heart Association issued a statement that adolescents with major depressive disorder and bipolar disorder are at increased risk for both accelerated atherosclerosis (narrowing and hardening of the arteries) and early-onset cardiovascular disease.
In the statement, the American Heart Association recommended that major depressive disorder and bipolar disorder be classified as “tier II” conditions (which also include HIV and chronic inflammatory disease) that confer a moderate risk of disease.
Until recently, it had been assumed that the increased risk of cardiovascular disease among people with depression or bipolar disorder was a result of behaviors linked to these illnesses, such as higher rates of smoking, obesity, or diabetes, which increases heart disease. Some psychiatric medication can also bring about risk factors for cardiovascular problems. It turns out that these types of factors could not fully explain the increased risk of atherosclerosis and cardiovascular disease among people who had depression or bipolar disorder in their teens.
It is not clear why depression and bipolar disorder make cardiovascular illness more likely, though it may be due to blood vessel damage resulting from inflammation or oxidative stress.
The American Heart Association recommends that pediatricians and cardiologists pay particular attention to this link by identifying and treating mental illness as early as possible and by making sure that their colleagues understand the role of mental illnesses in cardiovascular risk.
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
Studies have shown that therapy can be helpful for people with bipolar disorder. In a 2016 article in the British Journal of Psychiatry, researchers led by M. Oud described the findings of their systematic review of studies evaluating different types of therapy for bipolar disorder. The research team reviewed the findings of 55 randomized controlled trials of psychotherapeutic interventions that included a total of 6,010 adult participants with bipolar disorder. The team found moderate-quality evidence that psychological interventions reduced relapses following treatment, and that collaborative care reduced hospital admissions for adults with bipolar disorder. Oud and colleagues found lower-quality evidence that group interventions reduced depression relapses following treatment, and that family psychoeducation reduced symptoms of depression and mania.
The reseachers concluded that there is evidence that therapy can be helpful for people with bipolar disorder. Since some of the evidence was of low quality, more research is needed to identify the most effective therapies for different phases of bipolar disorder.
Editor’s Note: The data are clear that therapy is helpful. In particular, one approach worth emulating is that described in an article by Lars V. Kessing and colleagues in the British Journal of Psychiatry in 2013. They found that comprehensive care in an outpatient mood disorder clinic, which included psychotherapy, psychoeducation, mood monitoring, and drug treatment, reduced relapses significantly compared to treatment as usual.