Jules Angst on the Long-Term Progressive Course of Mood Disorders
Jules Angst
At a symposium celebrating the retirement of Willem Nolen, a researcher who spent 40 years studying unipolar and bipolar disorder, from his position at Groningen Hospital in the Netherlands, his colleague Jules Angst discussed some recent findings. Angst is perhaps the world’s leading authority on the long-term course of unipolar and bipolar disorders based on his multiple prospective follow-up studies, some lasting 20-30 years.
The Sensitization-Kindling Model
Angst described evidence that supports the sensitization-kindling model of recurrent mood disorders, which this editor (Robert Post) described in 1992. Episodes tend to recur faster over time, i.e. the well interval between episodes becomes progressively shorter. While stressors often precipitate initial episodes, after multiple occurrences, episodes also begin to occur spontaneously (in the absence of apparent stressors).
This type of progressive increase in response to repetition of the same stimulus was most clearly seen in animal studies, where repeated daily electrical stimulation of the amygdala eventually produced major motor seizures (i.e. amygdala kindling). Daily electrical stimulation of rodents’ amygdala for one second initially produced no behavioral change, but eventually, minor and then full-blown seizures emerged. Once enough of the stimulated full-blown amygdala-kindled seizures had occurred, seizures began to occur spontaneously (i.e. in the absence of the triggering stimulation).
The analogy to human mood disorders is indirect, but kindling provides a model not only for how repeated triggers eventually result in full-blown depressive episodes, but also for how these triggered depressive episodes may eventually occur spontaneously as well.
Long-Term Treatment of Mood Disorders
Angst also discussed long-term treatment of mood disorders. He has found that long-term lithium treatment not only reduces suicides in patients with bipolar disorder, but also reduces the medical mortality that accompanies bipolar disorder.
Angst noted his previous surprising observations that in unipolar disorder, long-term maintenance treatment, even with low doses of tricyclic antidepressants, prevents suicide. Previously, researchers Ellen Frank and David Kupfer of Western Psychiatric Institute and Clinic at the University of Pittsburgh Medical Center had found that when patients with recurrent unipolar depression who had been stable for 5 years on the tricyclic antidepressant nortriptyline were blindly switched to half their original dose, about 90% rapidly relapsed into a new episode of depression. Their data helped establish the prevailing view that maintenance treatment with the full-dose regimen required to achieve a good initial acute response is also the optimal approach to long-term continuation and prophylactic treatment.
Angst found good results even at low doses, but his data may not be in conflict with Frank and Kupfer’s, as a person who responds well acutely to low doses may also be able to maintain good enough response to them to prevent recurrences in the long term.
Incidence of Bipolar Disorder in Adolescents Similar to Incidence in Adults
Angst also presented data from the Adolescent Supplement to the National Comorbidity Study (NCS-A), which analyzed interviews with approximately 10,000 adolescents (aged 13-17) in the US. He found a 7.6% incidence of major depression, a 2.5% incidence of bipolar I or II disorder, and a 1.7% incidence of mania. There was an even higher incidence of sub-threshold bipolar disorder, when there are not enough symptoms or a long enough duration of symptomatology to meet diagnostic criteria for bipolar I or II disorder. These data published by Merikangas et al. in 2009 provide clear epidemiological data that there is a substantial incidence of bipolar disorder in adolescents in the US, roughly similar to that seen in adults.
Bipolar Illness is Worse in the US than in Germany and the Netherlands
At a symposium celebrating the retirement of Willem Nolen, a researcher who spent 40 years studying unipolar and bipolar disorder, from his position at Groningen Hospital in the Netherlands, this editor (Robert Post) discussed progress in the treatment of bipolar disorder over the past 40 years. Despite the availability of lithium; many new mood stabilizers (carbamazepine, valproate, lamotrigine); and many atypical antipsychotics, all of which are anti-manic and some of which are antidepressant (quetiapine and lurasidone), there is still a very high rate of continued illness and treatment resistance, especially in the US.
In fact, research from the Bipolar Collaborative Network, a treatment research network including sites around the US (one run by this editor) and in Germany and the Netherlands, shows that almost everything about bipolar disorder is worse in the US. Americans have more genetic vulnerability because more of their parents have bipolar disorder, and they are more likely to have environmental vulnerability as a result of childhood adversity. Patients in the US also reported having had more stressors at the onset of their illness and more stressors prior to the last episode they had before entering the network at an average age of 40.
Age at illness onset is much lower in the US than in the Netherlands and Germany. About two-thirds of American patients had onset in childhood or adolescence (under 19 years), while only about one-third of the European patients in this study showed these early onsets.
The course of illness is also more difficult in the US. There is more anxiety, substance abuse, and medical comorbidity, and there are more episodes and more rapid cycling. All this resulted in more US patients than European ones who did not respond to naturalistic treatment in our treatment network despite being prescribed multiple medications.
The implication of these data is that we need a new and more concerted approach to bipolar disorder in the US, beginning with early diagnosis and treatment during childhood and adolescence, instead of the 10- to 15-year average delay that was typical about twenty years ago. The duration of the delay to first treatment with a drug to treat mania or depression was an independent predictor of a worse outcome in adulthood. Early intervention should also include therapy and education.
Family-Focused Treatment (FFT), a method pioneered by researchers David Miklowitz and Kiki Chang, has been shown to be much more effective than treatment as usual in children who are at high risk for developing bipolar disorder because they have a family history of the illness and symptoms of an anxiety or depressive disorder or bipolar not otherwise specified (BP-NOS). In this way it may even be possible to head off the full-blown illness before it starts in those children at highest risk.
Adversity May Increase Risk of Mood Disorders
In adults with bipolar disorder, adversity in childhood has been associated with an earlier onset of bipolar disorder compared to those who did not experience some form of adversity such as verbal abuse, physical abuse, sexual abuse, loss of a parent, abandonment, or neglect. At the 2013 meeting of the Society of Biological Psychiatry, Nancy Low et al. reported that the number of these stressful life events a child experienced was associated with the number of their anxiety symptoms, psychiatric disorders, and lifetime substance abuse. Having experienced 3 or more adversities was associated with a 3.5-fold increased risk for developing a mood disorder and a 3-fold increase in anxiety disorders and alcohol or drug abuse.
While the study has not yet been published in a peer-reviewed journal, the abstract (#194) may be found in the meeting supplement, Volume 73, Number 9S of the journal Biological Psychiatry.
Editor’s Note: Low’s study is the first to report that childhood adversity is a risk factor for the onset of bipolar disorder in the general population.
Given the increasing evidence for the persistence of epigenetic marks on DNA and histones (which can’t change the sequence of genes but can change their structure) in those who have experienced such stressors in childhood, this could provide a mechanism for the long-term vulnerability of these children to the development of mood disorders and a variety of physical illnesses.
Loss of Appetite or Weight in Depressed Parents Predicts Depression in Children
Depression in a parent is one of the factors that best predicts whether a young person will develop depression. Since depression symptoms can vary greatly from person to person and some symptoms are known to be more heritable than others, new research is investigating whether a parent’s profile of symptoms affects their child’s likelihood of developing the illness. A 2013 study by Mars et al. in the Journal of Clinical Psychiatry suggests that loss of appetite or weight in a parent with depression is the symptom that most strongly predicts new onset of depression and depressive symptoms in their offspring.
The study observed 337 parent-child pairs. The parents (mostly mothers), who had a history of recurrent unipolar depression, ranged in age from 25–55 years, and their children ranged from 9–17 years. The study lasted four years, during which the families participated in three assessments. Parents’ symptoms were recorded and children were also assessed for symptoms or new development of depression. Thirty percent of the offspring whose parents reported weight loss or low appetite were found to have new onset of depression at followup, compared to nine percent of the offspring whose parents did not have these symptoms.
There are nine symptoms used to diagnose depression in the Diagnostic and Statistical Manual for Mental Disorders: low mood, loss of interest (anhedonia), loss of energy, change in appetite or weight, change in sleep, low self-esteem or guilt, suicidality, psychomotor slowing (retardation), and loss of concentration or indecisiveness. Of these, parental loss of appetite or weight was the only symptom that predicted depression in a child. Interestingly, the severity of parental depression or the presence of other health problems in the parent did not account for the emergence of illness in the children.
Suggestions for Physicians Treating Parents with Bipolar Disorder
- Support Pregnant Women with Bipolar Disorder
A. Depression during pregnancy is more common among women with bipolar disorder than among controls–consider cognitive behavioral therapy, omega-3 fatty acids, folate, & rTMS
B. 52% incidence of post-partum depression (3x higher than controls)–Monitor closely and treat accordingly - Ask Your Affectively Ill Patients About Their Children
- Encourage Good Diet and Exercise in These Children
- Encourage Watchful Waiting in Families with Children at High Risk
- If a Child becomes Symptomatic, Suggest:
A. Family Focused Therapy (FFT), or other Family-Based Treatment
B. Low-Risk Interventions Like Nutrition and Sleep Hygiene - If a Child Develops BP-NOS, Encourage:
A. Mainstream Pharmacotherapy
B. Increased Social Support (Family, Friends, Advocacy) - If a Child Develops BP-I, Encourage Ongoing Monitoring & Medication
- If an Adolescent Becomes Manic, Educate About Substance Abuse and Attempt Primary Prevention of a Substance Abuse Disorder
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
More Evidence That Regular Antidepressants Do Not Work in Bipolar Depression
Psychiatrists most commonly prescribe antidepressants for bipolar depression, but mounting evidence shows that the traditional antidepressants that are effective in unipolar depression are not effective in bipolar disorder. At the 2013 meeting of the American Psychiatric Association, researcher Jessica Lynn Warner reported that among 377 patients with Bipolar I Disorder who were discharged from a hospital, those who were prescribed an antidepressant at discharge were just as likely to be remitted for a new depression than those not given an antidepressant.
The average time to readmission also did not differ across the two groups and was 205 +/- 152 days. Those patients prescribed the serotonin and norepinephrine reuptake inhibitor (SNRI) drug venlafaxine (Effexor) were three times more likely to be readmitted than those not prescribed antidepressants.
These naturalistic data (generated from observations of what doctors normally do and information in the hospital’s clinical notes) resemble those from controlled studies. In the most recent meta-analysis of antidepressants in the treatment of bipolar depression (by researchers Sidor and MacQueen), there appeared to be no benefit to adding antidepressants to ongoing treatment with a mood stabilizer over adding placebo. Randomized studies by this editor Post et al. and Vieta et al. have shown that venlafaxine is more likely to bring about switches into mania than other types of antidepressants such as bupropion or selective serotonin reuptake inhibitors (SSRIs).
In addition, a naturalistic study published by this editor Post et al. in the Journal of Clinical Psychiatry in 2012 showed that the number of times antidepressants were prescribed prior to a patient’s entrance into a treatment network (the Bipolar Collaborative Network) at an average age of 40 was related to their failure to achieve a good response or a remission for a duration of at least six months during prospective treatment.
Editor’s Note: Antidepressants are still the most widely used treatments for bipolar depression, and their popularity over more effective treatments (mood stabilizers and some atypical antipsychotics) probably contributes to the fact that patients with bipolar disorder receiving typical treatment in their communities spend three times as much time in depressions than in manic episodes. Using other treatments first before an antidepressant would appear to do more to prevent bipolar depression. These treatments include mood stabilizers (lithium, lamotrigine, carbamazepine, and valproate); the atypical antipsychotics that are FDA-approved for monotherapy in bipolar depression, lurasidone (Latuda) and quetiapine (Seroquel); and the combination of olanzapine and fluoxetine that goes by the trade name Symbiax.
Evidence from several sources suggests that the SNRI venlafaxine may be a risk factor for switches into mania and lead to re-hospitalizations. Other data suggest that in general, in bipolar depression, augmentation treated with antidepressants should be avoided in several cases: in childhood-onset bipolar depression, in mixed states, and in those with a history of rapid cycling (4 or more episodes per year).
FDA Approves Lurasidone for Bipolar Depression
Last year the BNN summarized two presentations from the 2012 meeting of the American Psychiatric Association showing the antidepressant efficacy of the atypical antipsychotic lurasidone (Latuda) in bipolar depression. Lurasidone was more effective than placebo both when prescribed alone (monotherapy) and when prescribed as an add-on to the mood stabilizers lithium or valproate.
In June 2013, the Federal Drug Administration (FDA) approved lurasidone as both a monotherapy and as an adjunctive therapy with lithium or valproate for bipolar depression. Previously the only FDA-approved agents for bipolar depression were the atypical antipsychotic quetiapine (Seroquel) and the combination of the atypical antipsychotic olanzapine and fluoxetine.
Lurasidone’s precise role in therapeutics remains to be explored, but its side effects profile is of particular interest, as it appears to be less sedating than the other atypical antipsychotics noted above. It also appears to have fewer side effects in the realm of weight gain, cholesterol or triglyceride increases, and increases in blood sugar and insulin resistance.
