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

Bibliography:

American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th Edition). Washington, D.C: 1994.

Barrett, TB, Hauger, RL, et al. “Evidence that a single nucleotide polymorphism in the promotor of the G protein receptor kinase 3 gene is associated with bipolar disorder.” Molecular Psychiatry 2003; 8:546-557.

Biederman, J, Farrone, SV., et al. “Panic Disorder and agoraphobia in consecutively referred children and adolescents.” Journal of the American Academy of Child and Adolescent Psychiatry 1997;36: 214-223.

Birmaher, Boris, Kennah, Adam, Brent, David et al. “Is bipolar disorder specifically associated with panic disorder in youths?” Journal of Clinical Psychiatry 2002;63: 414-419.

Chen, Yian-Who, and Steven C. Dilsaver. “Comorbidity of panic disorder in bipolar illness: Evidence from the epidemiologic catchement area survey.” American Journal of Psychiatry 1995; 152:280-282.

Dautzenberg, Frank M., and Richard L. Hauger. “The CRF peptide family and their receptors: yet more partners discovered.” Trends in Pharmacological Sciences 2002;23: 71-77.

Duke, Patty. Call Me Anna. New York: Bantam Books, 1990.

Glovinsky, Ira. Personal communication June 12, 2003.

Gorman, Jack M. “New molecular targets for antianxiety interventions.” Journal of Clinical Psychiatry 2003; 64 (suppl 3): 28-35.

Hauger, Richard L. E-mail correspondence of June 16th and 21. Telephone conversation of June 21.

Henry, Chantel, Van den Bulke, Donatienne, Bellivier, Frank. “Anxiety disorders in 318 bipolar patients: prevalence and impact on illness severity and response to mood stabilizer.” Journal of Clinical Psychiatry 2003; 64: 331-335.

Lewinsohn, PM, Klein, DN, Seeley JR. “Bipolar disorder in community sample of older adolescents: prevalence, phenomenology, comorbidity and course.” Journal of the American Academy of Child and Adolescent Psychiatry 1995; 15: 219-226.

Johnson, JG, Cohen, P, and Brook JS. “Associations between bipolar disorder and other psychiatric disorders during adolescence and early adulthood: A community-based longitudinal investigation. American Journal of Psychiatry 2000; 157: 1679-1681.

Masi, Gabriele, Toni, Christina, Purugi, Guilio, et al. “Anxiety disorders in
children and adolescents: a neglected comorbidity.” Canadian
Journal of Psychiatry 2001; 46: 797-802.

Papolos, Demitri F., and Steven Tresker.”Assessment of obsessive-compulsive Behavior in childhood-onset bipolar disorder using the Yale-Brown Obsessive-compulsive scale.” (submitted)

Papolos, Demitri. “Bipolar disorder and comorbid disorders: The case for a dimensional nosology.” In Bipolar Disorder in Childhood and Early Adolescence by Barbara Geller and Melissa P. Delbello, editors. New York: Guilford Press, 2003.

Schwartz, Jeffrey M. with Beverly Beyette. Brain Lock: Free Yourself from Obsessive- Compulsive Behavior. New York: HarperCollins, 1997.

Wozniak, Janet, Biederman, Joseph, et al. “A pilot family study of childhood- onset mania. Journal of the American Academy of Child and Adolescent Psychiatry 1995;34: 1577-1583.

Wozniak, Janet, Joseph Biederman, et al. “Parsing the comorbidity between bipolar disorder and anxiety disorders: A familial risk analysis.” Journal of Child and Adolescent Psychopharmacology 2002;12: 101-111.

Wozniak, J, Crawford MH, Biederman J, Faraone SV, et al. Antecedents and complications of trauma in boys with ADHD: findings from a longitudinal study. Journal of the American Academy of Child and Adolescent Psychiaty 1999 Jan;38(1):48-55.

Wozniak, Janet. E-mail correspondence of June 20 and July 3, 2003.

2 Comments
  1. It is sad enough to hear about children with bi-polar disorder, but to hear of children and teens suffering from anxiety is heartbreaking. Anxiety attacks are hard enough for adults to deal with, let alone a small child. I do think that with separation anxiety, a small amount is good for children to learn some independence. But the other manifestations like, PTSD and OCD really need to be treated so the child will be comfortable and feel secure.

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