--Janice Papolos and Demitri F. Papolos, M.D.
A mother from New Jersey wrote and
described a scene that occurred not long ago as she was driving her nine-year-old
son to soccer practice. A commercial for an anxiety clinic came on the radio
and the announcer asked: “Do you worry a lot about things that don’t
seem to bother other people? Are you afraid of having anxiety or panic attacks?;
Are you worried that bad things may happen to people you love?; Do you feel
nervous when you are out with other people—even if you know them?….”
The youngster’s symptoms of early-onset bipolar disorder were understood
and well-treated pharmacologically, so this mother was shocked to hear her son
murmur in response to the questions: “I have all of those.”
With his mood swings, raging, and
periods of hypersexuality all controlled by medications, and his learning disabilities
discovered and treated by the school professionals and tutors, the mother hadn’t
realized he was still suffering with more than his fair share of anxiety.
Indeed, there is a surprisingly
robust scientific literature that documents the frequent co-morbidity or association
between bipolar disorder and a number of anxiety disorders, but this association
is frequently overlooked when a differential diagnosis is made. Instead, anxiety
disorders are often seen as diagnoses existing all by themselves--divorced from
the possibility of a co-existing mood disorder. Thus, a child frequently receives
a diagnosis of generalized anxiety disorder—GAD—or an adolescent
frequently gets the diagnosis of panic disorder, and the anxiety disorders are
not viewed as a possible pre-cursor to a mood disorder or as a possibly co-occurring
condition.
In cases where the bipolar disorder
is recognized, the primary focus of treatment becomes the stabilizing of the
moods and the modulation of the aggression, and the evaluation of residual anxiety
is not high on the list of priorities. In many situations, anxiety is viewed
as the least of the problem—more of a benign condition-- and not the pernicious
one that eats away at a child’s feeling of safety and self-esteem. Dr.
Ira Glovinsky co-author of Bipolar Patterns in Children told us that
he works with children who describe anxiety as “a tornado inside my body
that my body just can’t hold inside.”; and “It’s bigger
than my body and it seeps out the side seams.” Dr. Glovinsky added: “Many
of these children are just hemorrhaging anxiety. When one thinks about it, it
is easy to see how chronic anxiety would contribute to irritability, lack of
concentration, and hyperactivity.”
Therefore, we thought it might be
a good idea to focus this issue on this common co-occurrence of mood disorders
and the anxiety disorders.
How Does the DSM-IV Define Anxiety
Disorders?
The DSM-IV devotes 51 pages to the
anxiety disorders which, if we leave aside anxiety induced by substances or
by a general medical condition, broadly includes:
Panic Attack
Agoraphobia
Specific Phobia
Social Phobia
Obsessive –Compulsive Disorder
Posttraumatic Stress Disorder
Acute Stress Disorder
Generalized Anxiety Disorder
Separation anxiety, so commonly seen
in children with bipolar disorder, is not listed with the anxiety disorders
but under the category “Disorders Usually First Diagnosed in Infancy,
Childhood, or Adolescence.”
What Does the Scientific Literature
Conclude About the Interface of Anxiety Disorders and Mood Disorders?
There is no dearth of good studies
linking mood disorders and anxiety disorders. In 1995, Peter Lewinsohn and colleagues,
in a community study of high school students with any form of anxiety disorder,
reported that anxious youths were seven times more likely to have comorbid bipolar
disorder than students without any anxiety disorder.
Panic disorder represents one of
the most extreme manifestations of anxiety in both adults and children. The
association between both panic attacks and panic disorder and major depression
has been well documented. In addition, in adults, panic disorder has been shown
to be associated with bipolar disorder, with 13-to-23% of adults with panic
disorder having a comorbid bipolar disorder. Conversely, in adults with bipolar
disorder, the lifetime rates of comorbid panic disorder range from 36-to-80%.
The association between anxiety disorders
and bipolar disorder is “particularly marked in pediatric samples,”
says Dr. Janet Wozniak, assistant professor of psychiatry at Harvard Medical
School. She notes that “studies of children and adolescents with bipolar
disorder report that 56% of these children have multiple anxiety disorders.”
Dr. Joseph Biederman, also of Harvard Medical School, found that 52% of the
children diagnosed with panic disorder in his study had a co-occurrring bipolar
disorder.
Dr. Boris Birmaher of Western Psychiatric
Institute and Clinic at the University of Pittsburgh School of Medicine published
a paper in the Journal of Clinical Psychiatry entitled: “Is Bipolar
Disorder Specifically Associated with Panic Disorder in Youths?” It was
a large study of 2025 youths aged 5-19, and patients were grouped into those
with panic disorder (N=42); those with non-panic disorder anxiety disorders
(N=407); and psychiatric controls with no anxiety disorders (N=1576).
The results of this study showed
that youths with panic disorder were more likely to exhibit co-morbid bipolar
disorder (N=8; 19%) than youths with either non-panic disorder anxiety disorders
(N=22, 5.4%) or non-anxious psychiatric disorders (N=112, 7.1%). The conclusions
reached by the investigators were that “The presence of either panic disorder
or bipolar disorder in youths made the co-occurrence of the other condition
more likely, as has been noted in adults.”
Actress Patty Duke, who was diagnosed
with manic-depression years after her illness began recalls “a fear of
death so powerful it precipitated anxiety attacks from the early 1950s to 1983.
I was obsessed, truly obsessed with my mortality. All of a sudden the absolute
realization of my mortality would hit and I just felt impelled to scream. Sometimes
it was what I’d call a bloody-murder scream, sometimes words like ‘No!
No! No! No!’ Inevitably though, it happened at night, on the way to sleep.
I’d scream every night of my life. I was overtaken by abject terror.”
Dr. Birmaher and his collegues wonder
in their article referenced above if children and adolescents with panic disorder
are at higher risk for the development of a bipolar disorder, but state that
no such prospective studies have been done yet. They do, however warn that if
it turns out that panic disorder is a marker for bipolar disorder, then before
patients with panic disorder are treated with antidepressants, “a personal
and family history should be elicited, and they should be closely monitored
for the emergence of mania.”
They then go on to state:
Because children with panic disorder
often have somatic complaints such as shortness of breath or chest pain, they
often present first to primary care or specialty physicians. When treating
patients who present in the primary care sector, the challenge is two-fold:
making the diagnosis and, if pharmacotherapy is initiated, carefully monitoring
for the onset of manic symptoms. Therefore, any physician who makes a diagnosis
of panic disorder must make a conscious effort to rule out bipolar disorder
before medication is initiated or risk exacerbating a “hidden”
manic/hypomanic state.
In other words, if a bipolar disorder
is co-occurring, it could be worsened by the medical treatment used for panic
or anxiety disorder, specifically the SSRIs such as Paxil and Zoloft. (We will
discuss the treatment of panic disorders and other anxiety disorders toward
the end of this newsletter.)
A Closer look at Some of the Anxiety
Disorders
SEPARATION ANXIETY
Many mothers have described their
children’s inability to be separated from them—in the early days
of infanthood, and well beyond. One mother told us she called her child “the
Velcro Kid.” Others remember “cleaning chicken with her in a Snugli”;
“vacuuming with her in a sling”; and another mother described being
“mauled with his nails scraping down my chest as he struggled against
being withdrawn by his father, who was trying to take him from me so that I
could take a shower.”
A mother from Illinois emailed us
about the separation anxiety her son was experiencing and had this to say:
Right now Jamison can’t
be separated from me—it’s like the umbilical cord grew back! I
can’t get him out of my room at night. If he falls asleep anywhere else,
he ends up there eventually. I’ve stepped on him in the middle of the
night many times. He hides under the bed with only his head sticking out.
But he gets so anxious, and this relieves some of it.
How Does Separation Anxiety Affect
the Child and Family Members?
In almost all instances, the mother
is most affected by the child’s powerful attachment demands; but as the
child’s exclusive desire for her companionship begins to rule the roost,
others in the family will also be affected. Some fathers may be entirely excluded
from this intense relationship and viewed by the children as intruders. Mothers
who remain identified with the role of satisfying the child’s needs are
easily drawn into perpetual motherhood. They too find it hard to separate, particularly
if they have inherited a bipolar disorder or temperament, and their own fears
of separation and abandonment fuse with those of the child.
There are no formulas for dealing
with these particular problems, but it is abundantly clear that managing the
separation anxiety in the child and becoming aware of its effects on the family
should become a primary therapeutic goal of the treatment of the condition.
Crucial is helping the child who
experiences this level of fear and terror to understand that the sense of imminent
loss of control (by becoming isolated from the mother) is not based on reality.
The parents and therapists need to help the verbal child to grasp the range
and intensity of his feelings—anxiety and anger as well as elation and
depression—and to express these feelings openly on a regular basis. Any
exercise that helps a child to label feelings and talk about them in play gives
order, definition, and a feeling of self-control that would counter the prevailing
tendency to believe that feelings are overwhelming and unmanageable—a
tendency likely to impede emotional growth and maturation.
OBSESSIVE-COMPULSIVE DISORDER
(OCD)
A study by Daniel Geller that focused
on 217 children with obsessive-compulsive disorder at the McLean Hospital/Massachusetts
Pediatric OCD clinic, found that a full 69 percent of the study sample also
carried diagnoses of mood disorders. The Epidemiological Catchment Area database
supports the conclusion that the lifetime rate of comorbidity for obsessive-compulsive
disorder is particularly high among bipolar subjects.
Children with OCD have recurrent
and intrusive thoughts of impending harm that can be allayed only by some compulsive
act. They feel compelled to perform repetitive acts or rituals to ward off the
discomfort and anxiety they experience, but these acts can cause the child shame
and embarrassment as well as make it hard to get out of the house and go about
a typical kid’s day.
Some examples of repetitive acts
or rituals designed to reduce the anxiety and keep a dreaded event from occurring
include: placing objects just right; touching things a self-specified number
of times; checking behaviors….Some children count or repeat phrases over
and over; other children compulsively pick at their skin.
Many children describe obsessions
about dirt or contamination, and children as well as adults describe handwashing
or showering rituals in which they wash their hands over 80 times a day or spend
hours attempting to shower themselves clean. Many children explain that they
don’t know why they do these rituals—they know they are senseless.
Still, they feel a sense of pressure, and the action partially relieves the
anxiety.
Demitri F. Papolos, M.D. and Steven
Tresker recently examined ratings on the Child Yale Brown Obsessive Compulsive
Scale (YBOCS) for 229 children diagnosed with bipolar disorder. They divided
the sample into groups stratified by frequency of symptoms and when they looked
at the group that had 14-or-more positively-endorsed symptoms, they found that
the most prevalent symptoms were hoarding obsessions, fears of contamination,
and fear of or attraction to violent or horrific images. In light of the fact
that one of the cardinal features of juvenile-onset bipolar disorder is difficulty
moderating aggressive impulses, specific fears and rituals associated with the
control of those aggressive impulses should not be surprising.
A mother from Oregon sent us an
email that sadly detailed her daughter’s anxiety about her aggressive
impulses:
Cally was very afraid to make
wishes when she was little. Blowing out candles on a birthday cake was horrible
for her because she was afraid that right at the last minute she would wish
for something bad to happen to someone and it would come true. She was/is
afraid to wish on stars in the sky for the same reason.
POSTTRAUMATIC STRESS DISORDER
Many children with bipolar disorder
have a pronounced sensory sensitivity. These children are easily aroused from
birth and overreact to environmental stimulation and their own internal body
intensities. They also seem susceptible to horrific night terrors or other arousal
disorders of sleep, which may possibly have a significant influence on their
perception and behavior and the development of social repertoire. One can’t
help wondering if the death, dismemberment and gory content of their dreams
and night terrors don’t traumatize these children also. These nighttime
agonies may make them extremely sensitive to any negative experiences witnessed
in life, and a vicious cycle may develop.
Because of this extreme sensitivity
to internal intrapsychic and bodily experience as well as environmental stimuli,
the impact of stressful events (whether they be a form of vivid, persistent
night terrors) or anger directed at them, or early loss, these children have
the potential to be easily traumatized, and therefore it should be no surprise
that both children and adults with a bipolar vulnerability often have symptoms
or diagnoses of posttraumatic stress disorder.
According to the DSM-IV, “The
essential feature of Posttraumatic Stress Disorder is the development of characteristic
symptoms following exposure to an extreme traumatic stressor involving direct
personal experience of an event that involves actual or threatened death or
serious injury, or other threat to one’s physical integrity; or witnessing
an event that involves actual death, injury, or a threat to the physical integrity
of another person.” The “D” criteria of PTSD reads:
Persistent symptoms of increased
arousal (not present before the trauma) as indicated by two or more of the following:
1) difficulty falling or staying
asleep.
2) irritability or outbursts of anger
3) difficulty concentrating
4) hypervigilance
5) exaggerated startle response
As one mother wrote about her 11-year-old
son:
My son’s anxiety is manifested
in always seeing the most negative outcome for any situation that begins to
turn even slightly in his disfavor. He is also fearful about being kidnapped
and becomes anxious in public when he thinks someone might be following us
or looks suspicious to him. I think he is still recovering from my being mugged
three years ago in broad daylight in his presence. But he was anxious before
that too. It is hard for him to fall asleep because negative thoughts pile
into his head at that time.
Dr. Janet Wozniak wrote and told
us of a study that she and her colleagues conducted focusing on PTSD using a
longitudinal sample of ADHD boys (about 20% of this sample had comorbid bipolar
disorder). They found that bipolar disorder generally pre-dated PTSD, when PTSD
occurred. “This is important because many clinicians erroneously attribute
the mood symptoms of bipolar disorder to having experienced a trauma, when in
fact the mood symptoms were present prior to the trauma,” says Dr. Wozniak.
This finding is also important because—as
we indicated earlier—it may be the case that children with bipolar disorder
are at particular risk for traumatic experience.
What Biological Underpinnings May
Explain the Association Between Bipolar Disorder and Anxiety Disorders?
It has long been recognized that
an excess of stressful life events is associated with the onset and relapse
of major depression and bipolar illness in adult patients. Prospective studies
of children at risk for the development of mood disorders suggest that they
are born with an enhanced genetic susceptibility to develop anxiety and depression.
These children appear to have a low threshold for anxiety and are over-reactive
to stressful events (real or perceived) such as deprivation, loss, rejection,
and humiliation. (This may be why these children so over-react to the simple
word “No,” which in its expression contains elements of deprivation,
loss, rejection, and humiliation.)
CRF and the Much-Talked-About
GRK3 Gene
CRF is the neuropeptide in the brain
that participates in the generation of the stress response. It also has important
influences on the systems that regulate arousal, sleep/wake transitions, appetite,
energy production, and the experience of pleasure and pain.
GRK3—a G-protein-coupled-receptor
kinase plays an important role in the regulation of CRF receptors by turning
them off at a certain point after they have been stimulated.
We spoke with Dr. Richard Hauger,
professor of psychiatry at the University of California San Diego and a leading
author of the recently reported study: “Evidence that a single nucleotide
polymorphism in the promoter of the G protein receptor kinase 3 gene is associated
with bipolar disorder,” and he explained:
We hypothesize that activation
of brain neural networks by CRF during stress may require rapid counterregulation
by the GRK3-mediated mechanism.
It has been established that exposure
to severe stress can induce a long-term sensitization to anxiety-inducing
stimuli. Therefore, a deficiency in GRK3 expression (caused by a different
sequence of nucleotides that makes the promotor gene less capable of promoting
transcription of the protein) may render brain CRF receptors incapable of
being turned off when chronically exposed to high levels of CRF. This excessive
degree of CRF receptor activation could contribute to the development of anxiety
and depression.
The Treatment of Children and Adolescents
With Anxiety Disorders
In some cases, the anxiety disorders,
whether they be generalized anxiety, panic disorder, or obsessive-compulsive
disorder, disappear with proper mood stabilization using lithium or one of the
anticonvulsants. Of particular interest, however, is a study published in the
March 2003 issue of the Journal of Clinical Psychiatry which looked at
318 adult bipolar patients in France and found that “Bipolar patients
with anxiety responded less well to anticonvulsant drugs than did bipolar subjects
without anxiety disorder, whereas the efficacy of lithium was similar in both
groups.” In other words, the patients who were bipolar and suffered with
anxiety disorders responded better to lithium than to the anticonvulsants.
This was the first study to show
that bipolar patients with anxiety disorders may have a poorer response to long-term
treatment, depending on the type of mood stabilizer given. However, this would
have to be replicated in a larger group of patients, with randomization, and
it would have to be specifically looked at in children and adolescents.
We asked Dr. Janet Wozniak from
the Harvard Medical School some questions about the treatment of bipolar disorder
and anxiety in youngsters and she replied:
In the cases of pediatric bipolar
disorder, our rule of thumb is to stabilize the manic mood prior to addressing
issues of comorbidity with depression, ADHD and anxiety. Sometimes when the
manic mood state is treated the anxiety symptoms also improve. Sometimes the
opposite is observed: after the mood is stabilized the anxiety “comes
front and center”. We have no way of predicting who will fall in which
category. But the idea that mood stabilizers "cause" anxiety may
be erroneous. It may be that the comorbid anxiety is more obvious when the
mood is stabilized, given that reports suggest anxiety occurs comorbidly with
bpd in many adults, children and adolescents.
There are no studies to inform
us which agents are best to use when we add an anti-anxiety agent for this
population. In practice, we make use of all the possible treatments including
Gabatril, Neurontin (which may be less likely to destabilize mood or in some
small number of cases might help mood), benzodiazepines (which unfortunately
could be sedating, cognitively clouding, or have a paradoxical effect), buspirone,
and antidepressants (which of course carry the risk of exacerbating mania).
Neurontin and Gabitril (two anticonvulsant
drugs) both increase the neurotransmitter GABA transynaptically, which is where
benzodiazepines such as Klonopin and Ativan work against anxiety.
New Medications in the Pipeline
New types of medications that target
the CRF receptors are looking good as anti-anxiety medications in early clinical
trials, and may be on the market in the next year or two. Dr. Hauger also told
us:
Clinical trials are currently
underway to test the efficacy of selective CRF1 receptor antagonists in the
treatment of major depression and anxiety disorders. Preliminary data revealed
that the small molecule CRF1 receptor antagonist R121919 (NBI30775) developed
by Neurocrine Biosciences Inc. significantly lowered anxiety and depression
scores in patients with major depression. The development of CRF1 receptor
antagonist pharmacotherapy rests on the assumption that presynaptic hypersecretion
of CRF is solely responsible for the hyper-stimulation of CRF systems observed
during episodes of major depression. However, it may also be important to
enhance GRK-mediated CRF1 receptor desensitization in patients with major
depression and anxiety disorders.
We have heard that other pharmaceutical
companies are also bringing a CRF receptor antagonist onto the market sometime
in the near future.
Although we know of no studies looking
specifically at anxiety disorders and bipolar disorder treated with cognitive
therapy, clinicians who have used it have told us that it does indeed help.
Some psychologists have suggested that the book, Brain Lock by UCLA psychiatrist,
Jeffrey Schwartz, is helpful with obsessive-compulsive symptoms. It’s
four-step method of Relabeling, Reattributing, Refocusing, and Revaluing may
make a difference for older children and adolescents.
In Conclusion
From all of the above, it is clear
that children with bipolar disorder are pre-disposed to and suffer unduly from
anxiety disorders (often more than one in their lifetime) and that this frequent
comorbidity should be taken into consideration when a diagnosis is made so that
the bipolar disorder is not missed and exacerbated by the wrong selection of
medication, and so that the child who is recognized as having bipolar disorder
is not left in an uncomfortable state as the mood becomes stabilized (if anxiety
should become an issue).
It is obvious that much needs to
be learned about the strong undisputable association between the anxiety disorders
and bipolar disorder and that clinicians and researchers need to devote time
and energy to this co-morbidity. The good news is that new discoveries in the
field of molecular genetics are certain to bring greater understanding and better
treatments.
* * * *
Despite the springtime weeks (and
weeks) of rain, we wish you sunny summer days, and balmy summer nights.
As always, we look forward to hearing
from you.
Janice Papolos and Demitri Papolos,
M.D.
In Loving Memory
of Beatrice Franz Cohen
(December 19, 1919 - May 23, 2003)
The authors wish to thank Cheryll Hart, Adrienne Robins, and Drs. Janet Wozniak, Ira Glovinsky,
and Richard Hauger
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www.bipolarchild.com
