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Klein (1981) hypothesized in early studies on panic disorder that anxiety attacks represent a discrete alarm system built into the biologic hardware of the brain that is often evoked when an individual is threatened with separation from a significant other; some patients are more prone to these attacks, owing to an acquired or genetic vulnerability. Gittelman and Klein (1985) were able to demonstrate that patients with panic disorder had higher rates of pathologic separation anxiety and school phobia as children than did controls.
Weissman and colleagues (1984) reported that panic disorder in the parents, in contrast to other anxiety disorders, conferred a greater than threefold increase in separation anxiety in the children. Rosenbaum and colleagues (1988) found that 90 percent of children of patients with agoraphobia (most of whom had panic disorder), compared with 10 percent of children of controls, had "behavioral inhibition," defined as the tendency to manifest excessive withdrawal, inhibition, and physiologic responses to novel stimuli and mild cognitive challenge. The authors suggested that these were genetic traits that could lead to agoraphobia depending on the environmental input in childhood. Moreover, separation anxiety and school phobia respond to the same psychopharmacologic agent that Klein demonstrated was effective in panic disorder imipramine (Gittelman and Klein 1985).
Animal research has also supported Klein's hypothesis. Both infant dogs and rhesus monkeys respond with characteristic high-pitched distress, whines, and cries and apparent anxiety when separated from their mothers (Suomi 1984). Infant dogs and monkeys pretreated with imipramine did not emit these characteristic distress calls when separated from their mothers. This effect did not appear with any of several other pharmacologic agents.
In two recent uncontrolled studies, both Katon (1984) and Uhde and colleagues (1985a) reported significant separation events as frequent precipitants of panic disorder. Three controlled studies looked at stressful life events as precipitating factors in panic disorder. Finlay-Jones and Brown (1981) studied 164 young women attending a general practice clinic, using a structured psychiatric interview and a record of stressful life events. The raters of life events were blind to psychiatric diagnoses. Patients with anxiety neurosis, most of whom met DSM-III criteria for panic disorder, had a higher frequency of severe life events than controls, especially life events that connoted danger and threat. Patients with depression were more likely to report a severe loss, and patients suffering from both depression and anxiety neurosis reported both severe danger and severe loss before the onset of their psychiatric disorder. Roy Byrne, Geraci, and Uhde (1986) found that, when compared to controls, patients with panic disorder had significantly more stressful life events and had a higher proportion of events viewed as extremely uncontrollable, undesirable, and causing severe lowering of self-esteem. In the only other controlled study, Faravelli (1985) determined that patients with panic disorder had more events involving the death or severe illness of a friend or relative compared to controls.
One caveat is that many primary care patients minimize or deny stressful live events (Katon 1988). These patients often selectively focus on the somatic manifestations of anxiety and do not like to see themselves as distressed or needy in any way. Interviewing a spouse or family member of this type of patient is often helpful and can provide additional important data.
The following case describes the development of panic disorder in the context of a threatened separation from a spouse. The case also demonstrates the tendency of patients with panic disorder to somatize and how the developmental trauma can add to a patient's vulnerability.
Panic Disorder Associated With Stressful Life EventMrs. S was married physical therapist who presented to the primary care physician with complaints of dizziness, headaches, and paresthesias. She had had one hospitalization and two complete neurologic workups, both of which were negative, over a 3 – month period. She had a normal CAT scan, electromyelogram, electroencephalogram, and lumbar puncture, and a neurologic examination revealed no lateralizing or abnormal finding. Despite these negative workups, Mrs. S was very fearful that these attacks were the harbingers of an impending stroke. Further history revealed that she was the oldest of four children and that her father had died of a stroke when she was 14 years old. She had a poor relationship with her very critical, chronically depressed, distant mother, with whom she fought recurrently as an adolescent. Her mother accused her, at times, of causing her father’s death by raising his blood pressure with her rebellious behavior. Mrs. S revealed that she had been married for 6 months prior to the start of her symptoms, and that her relationship with her husband had deteriorated soon after the marriage began. She described her first attack as beginning after the marriage began. She described her first attack as beginning after a verbal battle with her husband in which he stated angrily, “You are going to kill me, too” and left the house precipitously. She described later in therapy that this statement brought up painful memories of losing her father as well as the fear that her husband was going to leave her. The patient described her attacks as not only including neurologic symptoms, such as headaches, dizziness, and paresthesias, but also tachycardia, shortness of breath, sweating, and a sense of impending doom. She had become increasingly fearful of going out alone since the attacks began, and she was much more dependent on her husband. The patient was diagnosed as meeting criteria for panic disorder and started on a daily dose of 25 mg of imipramine. This was increased to 100mg over 10 days, with the resolution of her panic attacks over a 2 –week period. The family physician and psychiatrist also worked with the patient with psychodynamic and marital therapy to help her stabilize her marriage and decrease may self-esteem vulnerabilities that she had had since childhood. |
Panic disorder is a familial disease. Several of the physicians who first described the syndrome recognized this familial tendency. Oppenheimer and Rothschild (1918) found a family history of nervousness in 45 percent of 100 World War I soldiers with Da Costa's Syndrome. Wood (1941) described a family history of "probable cardiac neurosis" in a quarter of his World War II soldiers with the syndrome. In the first two systematic investigations, Cohen and colleagues (1951) found that 22 percent of first-degree relatives of patients with "neurocirculatory asthenia" suffered from the same disorder, and Noyes and colleagues (1978) noted an 18-percent morbidity risk for anxiety neurosis in first degree relatives. The latter two studies both found females affected more frequently than males, with a ratio approaching 2:1, and found more alcoholism in the male relatives of anxiety neurotics than in control relatives.
Although these studies suggest a high morbidity risk in first-degree relatives of patients with panic disorder, the data were collected by the family history method (i.e., the patients were interviewed about a history of mental illness in all first degree relatives), which tends to produce a conservative estimate of morbidity (Andreason et al. 1977). By directly examining first-degree relatives of panic disorder patients with a structured psychiatric interview, Crowe and colleagues (1983) found a 41-percent morbidity risk of panic disorder among first-degree relatives compared to 4 percent among controls. Consistent with the prior studies, an increased rate of alcoholism (15 versus 4 percent) was found among male relatives.
The family history studies have all demonstrated a higher frequency of the disorder among first-degree relatives than would be expected, but these studies are not conclusive about the question of heredity (Torgerson 1983). The findings could be due to common environment as well as to common genetic vulnerability.
Twin studies offer an opportunity for resolving the question about the relative contribution of heredity and environment in the development of psychiatric disorders. Torgerson (1983) compared panic disorder rates in mono-zygotic (MZ) twins, who share the same genetic endowment, and dizygotic (DZ) twins, who are no more alike than the other siblings. Assuming that MZ and DZ twins are likely to have the same environment, then a finding of increased concordance for psychiatric illness in MZ compared to DZ twins is considered evidence for the importance of heredity in the development of the disorder. Torgerson found that 31 percent of MZ twins were concordant for panic disorder versus 0 percent of DZ twins, a highly significant finding. Overall, anxiety disorders with panic attacks were more than five times as frequent in MZ as in DZ twins.
Goldberg (1979) documented that 67 percent of patients with mental illness in primary care had mixed symptoms of anxiety and depression. Four studies of patients with panic disorder revealed that 50 to 88 percent of patients had a major depressive episode at some time in their lives (Breir et al. 1984; Cloninger et al. 1981; Raskin et al. 1982; Pariser et al. 1979). Taken from the opposite direction, 20 to 30 percent of patients identified as suffering from a major depression also have panic disorder (Leckman et al. 1983a). Thus, it is important to review the genetic studies of patients with panic disorder and major depression.
Leckman and colleagues (1983b) found that major depression plus panic disorder in probands was associated with a marked increase in risk in relatives for a number of psychiatric disorders. Relatives were more than twice as likely to have major depression, panic disorder, phobia, and/or alcoholism than the relatives of probands with major depression without any anxiety disorder. Weissman and colleagues (1984) also found that having parents with major depression and panic disorder conferred more than a threefold risk of separation anxiety in the children. Childhood separation anxiety is believed by some authors to be a precursor of panic disorder in adulthood (Gittelman and Klein 1985). Others believe it is a childhood precursor of neurotic illness in general (Berg et al. 1974).
The finding that only 31 percent of monozygotic twins of patients with panic disorder also suffer from this severe form of anxiety suggests environmental influences in the development of panic disorder. Patients with panic disorder retrospectively recall more childhood fears and being more anxious as children than do controls (Cowley and Roy-Byrne, 1988). Raskin and colleagues (1982) found a higher rate of grossly disturbed childhood environments in patients with panic disorder than controls with generalized anxiety.
Uncontrolled studies have suggested that parental over protectiveness (Solyom et al. 1976; Roth 1959; Bowlby 1973) and an excess of parental deprivation (Tucker 1956; Silove 1986) were more common in agoraphobic patients. However, recent controlled studies have found that agoraphobic patients recalled deficits in parental care and warmth during their early years, but only when they experienced, as a child, a sense of parental neglect and lack of care, either alone or with overprotection, did the risk of agoraphobia in adulthood appear to be increased (Silove 1986; Arrindel et al. 1983; Parker 1979).
It is unclear whether the lack of parental care experienced by agoraphobic patients (most of whom also had panic disorder) is also experienced by patients with panic disorder who do not have agoraphobia. Joyce et al. (in press) addressed this question and found that patients with panic disorder and moderate to severe phobic avoidance were more likely to have grown up in a family with parental conflict, were more likely to have had symptoms of a childhood conduct disorder, and tended to leave school at a younger age than did patients with panic disorder and no or mild phobic problems.
Taken together, the genetic, stressful life event, and developmental data suggest that panic disorder has both genetic and developmental antecedents and often begins in the context of stressful life events. Patients' developmental history, personality structure, and mechanisms of coping with stress are probably all important in determining whether an onset of panic attacks will lead to frequent and severe enough attacks to meet DSM-III-R criteria for panic disorder, as well as whether the patients will develop moderate to severe phobic behavior.