Possible Interventions for At-Risk Children in Addition to Family Focused Therapy
Our editor Robert M. Post recommends that in the absence of good care in the community for children at high risk for bipolar disorder because a parent has the disorder, adult psychiatrists of parents with bipolar disorder who have children with the disorder should fill this gap by treating the children themselves. If the child has only early symptoms, family focused therapy as developed by David Miklowitz would be recommended.
Here are some other suggestions in addition to family focused therapy:
- Good Diet, Exercise, Sleep Hygiene
- Omega-3 Fatty Acids
- Check Vitamin D3 levels and Add Supplement if Needed
- Melatonin for Insomnia
- N-acetylcysteine (NAC) for Irritability (as in studies of children with autism spectrum disorders)
- Folate for Depression and/or Elevated Homocysteine
- Check for Evidence of Inflammation (Increased IL-6 or CRP)
Options with Some Side Effects:
- Minocycline (an anti-inflammatory neuroprotective antibiotic)
Important Reminders from the APA Symposium on Special Topics in Bipolar Disorder
Our editor Robert M. Post served as discussant at a symposium on special topics in bipolar disorder at the 2013 meeting of the American Psychiatic Association. Here are some of the findings that were presented at the symposium.
Michael Gitlin of the University of California, Los Angeles (UCLA) emphasized the importance of treating patients until remission in order to achieve functional recovery and prevent cognitive impairment.
Michael Bauer of Dresden, Germany reviewed data showing that early onset of the illness and long delays to first treatment are important predictors of poor response to treatment.
Mark Frye of the Mayo Clinic discussed the promise of pharmacogenomics to aid in the selection of the best medicine for a given individual (i.e. personalized medicine). Currently the presence of one of a few relatively rare gene variations—HLA-B 1502 (in Asian populations) and HLA-A 3101 (in European populations)—can predict that an individual may develop a severe rash when taking the anticonvulsant carbamazepine. Researcher J. Rybakowski has found that a somewhat common variant in the gene responsible for producing brain-derived neurotrophic factor (the val-66-met allele for proBDNF) is associated with a good response to lithium. This may be explained by the fact that lithium increases BDNF, and this could be crucial in those with the val-66-met allele, which functions less efficiently than the more common and better functioning allele val-66-val.
David Miklowitz, also of UCLA, reviewed data that strongly indicates psychotherapy is effective in the treatment and prevention of bipolar depression. He and Kiki Chang of Stanford University found that family focused therapy (FFT) was effective in treating early syndromes that sometimes lead to bipolar disorder (including depression, anxiety, or BP-NOS) in children at high risk for bipolar disorder because of a family history that includes bipolar disorder in a first degree relative. Yesterday we shared the 8 key ingredients to family focused therapy.
In his discussion, Post emphasized several points from each presentation. Among these was the recommendation by both Gitlin and Bauer that patients use a personal calendar to monitor symptoms and side effects. (We offer an easy download of a personal calendar.)
Post also endorsed Bauer’s emphasis on the need for early intervention, since delay to first treatment is an independent risk factor for a poor outcome in adulthood. (This finding has been replicated in three studies — Franchini et al. in 1999, Post et al. in 2010, and Drancourt et al. in 2012.
Each of these factors and family focused therapy need greater attention in the US, since Post noted that all aspects of bipolar disorder are more difficult for patients in the US compared to those in Germany, the Netherlands, and many other European countries. About two-thirds of the adults with bipolar disorder in the US had onset of the illness before age 19, while in most European countries, only about one-third of adult patients had an early onset. These data are also consistent with the low incidence of bipolar disorder in children at high risk for the disorder because of a parent with bipolar disorder in studies from the Netherlands, Switzerland, and Germany. In contrast, similar studies of children with at least on parent diagnosed with bipolar disorder in the US (by Chang et al., Nurnberger et al., Wozniak et al., and Birmaher et al.) show a higher incidence of the illness. Canadian studies by Duffy et al. and studies of an isolated Amish community in Pennsylvania by Egeland et al. show a low incidence much like the Europeans.
Given the great need for care of children with signs of bipolar disorder in the US and the shortage of child psychiatrists and pediatricians knowledgeable about bipolar disorder, Post recommended that in the absence of other alternatives, adult psychiatrists of parents with bipolar disorder who have children with the disorder should fill this gap by treating the children themselves. If the child has only early symptoms, family focused therapy as described by Miklowitz above would be recommended.
Tomorrow and Friday we’ll share tables with recommendations for the treatment of parents with bipolar disorder and their children.
Family Focused Therapy
Family focused therapy (FFT), developed by David Miklowitz, a professor of psychiatry at the University of California, Los Angeles, has been effective in treating early syndromes that sometimes lead to bipolar disorder (including depression, anxiety, or BP-NOS) in children at high risk for bipolar disorder because of a family history that includes bipolar disorder in a first degree relative. There are 8 key ingredients to family focused therapy.
- Consistent monitoring of the illness and developing an early warning system with a plan for responding if early symptoms emerge
- Stress management
- Development of a relapse prevention plan
- Emphasis on sleep hygiene and the importance of regular sleep patterns
- Work on medication adherence
- Development of self-regulatory skills
- Improvement of family relationships
- Avoidance of substances of abuse
Obesity and Bipolar Disorder
David Bond presented research at the 2013 meeting of the International Society of Bipolar Disorder about the connections between obesity and the course of bipolar disorder. Bipolar disorder has some of the highest rates of obesity among all psychiatric illnesses. Obese patients with bipolar disorder have more episodes of depression, more suicide attempts, worse response to psychiatric medications, and more cognitive impairment between episodes of illness.
Bond also found that higher body mass index (BMI) was associated with reduced white and gray matter volume in the brain, greater cognitive impairment, increased risk of Alzheimer’s disease, and increased glutamate concentration in the hippocampus (which is potentially neurotoxic) and decreased NAA (a marker of neuronal integrity). Those with 7% weight gain or higher in the first year of treatment show a greater loss of volume in the frontal and temporal lobes.
Editor’s Note: These data again speak to the importance of maintaining good lifestyle habits such as proper diet and exercise to attempt to slow or prevent the development of obesity. Also avoiding medications for bipolar disorder with the greatest liability for weight gain and using some that can help with weight loss would be good topics for discussion with a treating physician.
Preventing Cognitive Decline in Bipolar Disorder
Here are some suggestions from BNN Editor-in-Chief Robert M. Post, MD for preventing cognitive decline in patients with bipolar disorder.
1. Prevent Episodes with Long-term Prophylaxis
2. Remove Sedating or Impairing Drugs
3. Add Folate to Decrease Homocysteine
4. Treat Depression to Remission
5. Consider Adding:
a. Bupropion (Wellbutrin) for Mood and ADHD
b. Modafinil (Provigil) for Attention and ADHD
c. A Stimulant for ADHD
6. Add Lithium at 150mg/day for Neuroprotection in Mild Cognitive Impairment
7. Add Levitiracetam at 125mg/day to Decrease Hippocampal Hyperactivity
8. Treat Dementia Symptoms Early with:
a. Memantine (Namenda) AND/OR
b. Acetylcholine Esterase Inhibitors Such As Donepezil (Aricept)
9. Consider Adding an Anti-inflammatory Agent
Lithium Increases Hippocampal Volume
There is some evidence that lithium can affect brain structure, particularly the size of various parts of the brain. A study by Hajek et al. presented at the 2013 meeting of the International Society of Bipolar Disorders examined patients with bipolar disorder who had either received lithium for at least two years (37 patients) or had received under three months of treatment with lithium (19 patients), and compared the size of the hippocampus in these two groups and one control group (50 people). The patients with bipolar disorder all had the disorder for at least 10 years (25 years on average) and had had a minimum of five episodes.
Those treated with lithium long-term had greater hippocampal volume than the non-lithium patients (despite having spent more time in episodes of illness), and equal volume to healthy controls. Measurements were collected via magnetic resonance imaging (MRI), and analyses were done two different ways to avoid being confounded by the changes lithium may have on water balance in the brain, a phenomenon that was recently found to affect MRI images.
Editor’s Note: These data add to the large number of studies in animals and humans indicating that lithium, in addition to preventing episodes and suicides, may have neurotrophic and neuroprotective effects.
Childhood Illness Onset Produces Worse Outcomes
There is more evidence that childhood onset of bipolar illness means a more difficult course of illness. In a study published in World Psychiatry in 2012, Baldessarini et al. pooled data from 1,665 adult patients with bipolar I disorder at seven international sites and compared their family history of bipolar disorder, outcomes, and age of onset. Among these patients, 5% had onset in childhood (age <12 years), 28% during adolescence (12-18), and 53% during a peak period from age 15-25.
Patients who were younger at onset had more episodes per year, more co-morbidities, and a greater likelihood of a family history of the illness. Patients who were older at onset were more likely to have positive functional outcomes in adulthood, like being employed, living independently, and having a family.
Youth at High Risk for Bipolar Disorder Show White Matter Tract Abnormalities
At a recent scientific conference, researcher Donna Roybal presented research showing that children at high risk of developing bipolar disorder due to a positive family history of the illness had some abnormalities in important white matter tracts in the brain. Prior to illness onset, there was increased fractional anisotropy (FA), a sign of white matter integrity, but following the onset of full-blown bipolar illness there were decreases in FA.
Roybal postulated that these findings show an increased connectivity of brain areas prior to illness onset, but some erosion of the white matter tracts with illness progression.
Editor’s Note: It will be critical to replicate these findings in order to better define who is at highest risk for bipolar disorder so that attempts at prevention can be explored.
Lamotrigine Not Helpful as Add-on to Lithium and Valproate in Rapid Cycling Bipolar Disorder
A 2012 study by Kemp et al. in the journal Bipolar Disorders found that lamotrigine added to combination treatment with lithium and valproate was no more effective than placebo in patients with rapid cycling bipolar disorder. Only 14% (19 out of 133) of rapid cycling patients stabilized upon initial treatment with the open combination of lithium and valproate, a startlingly low rate. In the next phase of the study, 49 patients who were not stabilized were given adjunctive treatment with either lamotrigine (n=23) or placebo (n=26) on a double-blind basis, but no significant difference was observed.
Editor’s Note: This study has two pieces of not-so-good news. The first is that it was so difficult to stabilize these patients with rapid cycling bipolar disorder. The second is that the add-on of lamotrigine, which is highly effective in the prevention of depressions in bipolar disorder, was in this case no more effective than placebo.
This study again demonstrates that rapid cycling bipolar disorder is difficult to treat, and even the use of three proven mood stabilizers in combination is not always effective. Many doctors would recommend an atypical antipsychotic as the next clinical option.
Acquired Lithium Resistance
Lithium is one of the most important treatments available for bipolar disorder. A small percentage of patients who initially respond well to lithium may develop resistance to the drug over time. Some develop tolerance to the drug’s therapeutic effects over a period of years, seen as a gradual breaking through of manic or depressive episodes that increase in severity or frequency. Others who are good long-term responders to lithium, but stop taking lithium and then suffer relapses, fail to respond as well as they had before. In a few instances, the drug no longer helps at all. This latter form of acquired lithium resistance is called lithium discontinuation-induced refractoriness.
In a review article published in the Journal of Affective Disorders in 2011, this editor (Robert Post) analyzed case series and case reports that depicted these two different types of acquired lithium resistance and reported that each must be addressed in a different way. In the case of tolerance development, a temporary break from lithium may theoretically restore its effectiveness, but the typical way to treat this situation is to add additional drugs with different mechanisms of action that are not affected by the tolerance.
In those who stop effective lithium treatment and experience relapses that are no longer responsive when lithium is re-instituted, it is not clear what the best treatment approaches are. Therefore the most conservative approach to preventive treatment with lithium is to avoid discontinuing the drug. This would appear to be a generally sound principle for the treatment of recurrent unipolar or bipolar illness. When things are going well, do not change the regimen; leave well-enough alone. Conversely, when treatment is not optimal, as in the case of loss of drug responsiveness via tolerance, a more aggressive exploration of treatment options would be warranted.
Patients should be aware of the multiple dangers of stopping effective treatment with lithium. These include: likely relapse, perhaps the necessity of hospitalization, an increased risk of suicide, and the loss of responsiveness to lithium that appears to occur in approximately 15% of patients who stop lithium when it is working effectively.
