The
Bipolar Child Newsletter
July 2003, Vol. 14
Anxiety
Symptoms in Children and Adolescents With Bipolar Disorder
--Janice
Papolos and Demitri F. Papolos, M.D.
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Anxiety
Symptoms in Children and Adolescents With Bipolar Disorder
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 Connor Langer, Cheryll Hart, Adrienne Robins, and Drs.
Janet Wozniak, Ira Glovinsky, and Richard Hauger
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