Case Study Panic Disorder in Children and Adolescents BRUCE BLACK, M.D.
AND
DO{JGLAS R. ROBBINS, M.D.
Abstract. Panic disorder is a common and well-known psychiatric disorder which commonly has its onset during adolescence. However, the disorder has only recently been described in children and adolescents. The clinical literature describing panic disorder in children and adolescents is reviewed, and six cases are presented. Future directions for research are suggested. J. Am. Acad. Child Adolesc. Psychiatry, 1990, 29, 1:36--44. Key Words: panic, anxiety disorders, separation anxiety disorder. Panic disorder (PD) and panic disorder with agoraphobia (PDAG) are common and well-known psychiatric disorders in adults that have only recently been described in children and adolescents. Despite significant advances in recent years in understanding the phenomenology of these disorders, their pathophysiology, inheritance, and treatment in adults, and the relationship to other psychiatric disorders of adults and children (Uhde and Nemiah, 1988), relatively little is known about the disorders in children and adolescents. This report will review what is known about PD in children and adolescents and will describe six cases of panic disorder presenting in childhood or adolescence, illustrating recurring issues in the diagnosis and treatment of PD in this age group. Finally, some important questions for further research will be highlighted.
lifetime prevalence estimate for panic disorder of 0.6%, with a prevalence estimate among girls of 0.7 % and among boys of 0.4%. Less than half of the cases they identified had received any treatment. A number of epidemiological studies have shown adolescence to. be the peak period of onset of the disorder. Although there are reports of patients with onset of PD prior to puberty, the disorder appears to be less common in this age group than in adolescence. In a group of 3,000 adults surveyed as part of the NIMH Epidemiologic Catchment Area Program, the peak age of onset was found to fall between 15 and 20 years of age (von Korff et al., 1985). Thyer et al. (1985), in a retrospective chart review of a group of 62 adults patients with PD without agoraphobia, found a mean age of onset of 26.6 years, with 39% of these patients reporting onset of symptoms before age 20 and 13% before 10. Among 95 patient with PDAG, they found a mean age of onset of 26.3 years, with 29% of these patients experiencing onset before age 20, and 4% before age 10. Among 100 patients with PDAG examined by Sheehan et al. (1981b), 30 reported their first panic attack as occurring before age 20, and 6 before age 10.
Prevalence and Age at Onset The lifetime prevalence of PD in the general adult population is about 1.5%, and 6-month prevalence is about 1% (Myers et al., 1984). In adults, the disorder is approximately two to three times more prevalent in females (Robins et al. , 1984). Many adult or adolescent patients retrospectively report the onset of their symptoms during childhood (Klein, 1981), andPD is not uncommonly encountered by psychiatristsworking with adolescents. However, only one recent study has directly examined the prevalence of disorder in young people. Whitaker et al. (in press) examined a nonclinical sample of 5, 108 high school students and found a
Case Reports A number of studies have directly assessed symptoms of PD in child or adolescent psychiatric populations. Moreau et al. (1989), in a study of 153 offspring of depressed parents, identified seven children and adolescents with panic symptoms; six met DSM-III criteria for PD. Four of the cases were prepubertal. Age of onset ranged from 5 to 18 years old, and all presented with symptoms patterns similar to that of adults with PD. Four of the seven had at least one parent with PD, four met diagnostic criteria for major depression, and four met those for separation anxiety disorder. Last and Strauss (1989) identified 17 cases of PD among 177 consecutive admissions to an outpatient child and adolescent anxiety clinic; all but one were postpubertal. They found a 2:1 female to male ratio, and a lifetime diagnosis of depressive disorder in 6 of 17. PD was diagnosed in 3 of 9 mothers of affected children. Alessi and Magen (1988) reported seven cases of PD among psychiatrically hospitalized children, ranging in age from 7 to 12 (four of the seven were 12 years old). Six of
Accepted August 7, 1989. Dr. Black is National Research Service Award Fellow, Section on Affective and Anxiety Disorders, Biological Psychiatry Branch, National Institute ofMental Health, Bethesda, MD, and Clinical Assistant Professor ofChild and Adolescent Psychiatry, University ofMaryland School of Medicine, Baltimore, MD. Dr. Robbins is Assistant Professor of Child and Adolescent Psychiatry, and Director, Affective Disorders Program, Emma Pendelton Bradley Hospital and Brown University Program in Medicine, Providence, RI. This work was supported in part by a National Research Service Award grant to Dr. Blackfrom the National Institute of Child Health and Human Development (HD07125-0l). Reprint requests to Dr. Black, Section on Affective and Anxiety Disorders, Biological Psychiatry Branch, National Institute of Mental Health, Building 10, Room 3S239, Bethesda, MD 20892. 0890-8567/9012901-O036$2.0010© 1990 by the American Academy of Child and Adolescent Psychiatry.
36
PANIC DISORDER IN CHILDREN AND ADOLESCENTS
the seven also had separation anxiety disorder, and four suffered from depressive disorders. Alessi et al. (1987) looked for the presence of panic attacks among 61 adolescents hospitalized on a psychiatric ward. Ten of these patients had definite panic attacks, with an average age of onset 13.9 years. Nine of the ten also were suffering from a mood disorder, five were diagnosed as having borderline personality disorder, and four had a past history of separation anxiety disorder of childhood. Fifteen more patients had possible panic attacks. None of the 61 patients had been given the diagnosis of PD at the time of admission to the hospital. Van Winter and Stickler (1984) reported six patients from 9 to 17 years of age seen at the Mayo Clinic with PD. One patient reported the onset of his disorder at age 8 years. By telephone interview, they diagnosed relatives from two previous generations of this patient's family as suffering from PD. Biederman (1987) has reported the cases of three children aged 8 to 11 with symptoms consistent with the diagnosis of PDAG. All three of these children also suffered from separation anxiety, and two had demonstrated school refusal. Two had mothers who also suffered from PDAG and had responded to pharmacological treatment. All three children showed rapid improvement in response to treatment with clonazepam. Ballenger et al. (1989) also reported three children aged 8 to 13 with PDAG, two of whom showed separation anxiety and school refusal. The mother of one child suffered from PDAG. All responded positively to treatment with imipramine or the combination of imipramine and alprazolam. Herman et al. (1981) conducted a retrospective review of records of 34 children seen over a 25-year period at the Mayo Clinic and given the diagnosis of "hyperventilation syndrome." Although they do not use the term "panic disorder, " it is clear from a review of the symptoms they report that many, if not most, of their patients were having panic attacks. Age of onset ranged from 6 to 18 years, with most occurring in early adolescence. Many had prominent somatic complaints. Although most of the children, after evaluation, were "simply reassured that they had a benign disorder," long-term follow-up by the investigators showed quite the opposite. Of 30 respondents to follow-up questionnaires, 12 were still reporting episodes of hyperventilation as adults. Over half reported chronic anxiety, and over one third complained of depression. Many also complained of a variety of somatic ailments. Four patients aged 9 to 16 years old with primarily neurological presentations of PD have also been reported (Herskowitz, 1986). One of these had previously been given the diagnosis of temporal lobe epilepsy and treated with phenytoin, and another had been given the diagnosis of pseudoseizures. Three of the four were also noted to be depressed. A number of studies have demonstrated that children with other psychiatric disorders, particularly depression, have very high rates of somatic complaints, far exceeding the rates for adults with similar diagnoses (Ryan et al., 1987; Mitchell et al., 1988). It seems likely that many children l.Am.Acad. Child Adolesc. Psychiatry, 29:1 ,lan.1990
and adolescents with PD are presenting to their pediatricians with primarily somatic complaints and that most of these cases of PD remain undetected.
Relationship to Separation Anxiety Disorder of Childhood A substantial body of evidence has now accumulated demonstrating important relationships among PD and separation anxiety disorder of childhood (SAD) and suggesting that for many patients these different clinical presentations may be the manifestations of a common underlying disorder (Klein, 1981). Symptomatically, panic attacks bear a striking resemblance to the reactions of children suffering from SAD to separation from parents (Klein and Fink, 1962). Furthermore, children, adolescents, and adults with PDAG commonly avoid being separated from attachment figures (for adults, these are more commonly spouses or friends, rather than parents). A high incidence of history of separation anxiety disorder in childhood in patients with PD has also been reported (Klein, 1964; Gittelman and Klein, 1985). Up to half of agoraphobics may have a history of separation anxiety in childhood, although the relationship seems much stronger for female than male agoraphobics (Gittelman and Klein, 1984). As with PD in adults, depression also commonly coexists with SAD in childhood (Klein and Gittelman-Klein, 1978). A recent study of 45 children and 50 adolescents with major depressive disorder found that 43% had coexisting separation anxiety disorder (Mitchell et al., 1988). In another study of 95 depressed prepubertal children, 58% had moderate to severe separation anxiety (Ryan et al., 1987). A strong familial overlap between PD, SAD, and depression had been demonstrated (Gittelman and Klein, 1984). Offspring of parents with PD have more than a threefold increased risk of SAD, while offspring of parents with PD plus major depression have more than a tenfold increased risk; over one-third of these offspring suffer from SAD (Weissmanet al., 1984; Leckman et al., 1985). Those agoraphobic women with an early history of SAD are more likely to have children with SAD than are agoraphobic women without a history of SAD. Furthermore, PD, SAD, and major depressive disorder all respond to the same pharmacological agents, namely tricyclic and monoamine oxidase inhibitor antidepressants (Klein and Gittelman-Klein, 1978), although there are also agents which appear to be effective against PD only or depression only (Charney et al., 1986). Donald Klein (1981), drawing heavily on the work of John Bowlby and on ethological studies of separation, has hypothesized that we all begin life with an innate biological mechanism regulating affective response to separation. Typically, the initial affective response which ensues when the threshold of this system is crossed is protest. If no relief occurs, protest turns to despair. In this model, protest is analogous to the behavior shown by children with separation anxiety or adults with panic disorder, and despair is anal-
37
BLACK AND ROBBINS
ogous to depression. Klein suggests that some individuals may have pathologically lowered thresholds in this system , and thus may respond to slight or even imagined or anticipated separation with any of these behavioral manifestations, separation anxiety, panic attacks, or depression. Other authors have suggested, that this control mechanism governs response not just to separation but to perception of danger in general (Cowley and Roy-Byrne, 1987). The hypothesis that a single control system governs all these different psy~ chiatric presentations may explain not only the high overlap of these disorders in particular individuals, but also the response of all three conditions to the same pharmacological agents and the observed high familial overlap of the disorders, presumably due to genetic influences on the threshold of the system. This conceptualization would predict an association between separation experiences and the onset of PD. In fact , several studies·have found an increased incidence of stressful life events preceding the onset of PD, particularly involving death or severe illness of a loved one or other separation experienced (Faravelli, 1985; Roy-Byrne et al. , 1986; Roy-Byrne and Uhde, 1988). One study found.an increased incidence of events involving the threat of "danger" for patients with anxiety disorders, while events involving the threat of "loss" were more common for patients with depression (Finlay-Jones and Brown, 1981). Similarly, major disruptions in attachment relationships have been reported to precede the onset of SAD in 80% of cases (Gittelman, 1985). In the authors' experience, adolescents with panic attacks have frequently suffered a recent major loss, such as .loss of a parent or rejection by a romantic partner, or anticipate such a loss. Animal models of the consequences of separation from family or peer relations have been developed in nonhuman primates and in rodents. Although it remains unclear to what extent these models correlate with human responses to separation or with human psychopathology, such as depression, panic, or anxiety, the models have afforded the opportunity to examine the physiological, neurochemical, and behavioral responses to social separation (Suomi , 1986; Hofer, 1987; Rosenblum and Paully , 1987). With regard to the present discussion , it is of interest that the characteristic behavioral responses to separation from peers seen in youn~ rhesus monkeys are blocked by treatment with imipramine and that the time course of this effect is similar to that seen in humans with either PD or depression (Suomi et al., 1978). Similarly, distress vocalizations in puppies precipitated by separation from littermates are blocked by imipramine (Scott et al., 1973). Isolation calls in adult squirrel monkeys are blocked by imipramine or clonidine (an
AND
DO{JGLAS R. ROBBINS, M.D.
Abstract. Panic disorder is a common and well-known psychiatric disorder which commonly has its onset during adolescence. However, the disorder has only recently been described in children and adolescents. The clinical literature describing panic disorder in children and adolescents is reviewed, and six cases are presented. Future directions for research are suggested. J. Am. Acad. Child Adolesc. Psychiatry, 1990, 29, 1:36--44. Key Words: panic, anxiety disorders, separation anxiety disorder. Panic disorder (PD) and panic disorder with agoraphobia (PDAG) are common and well-known psychiatric disorders in adults that have only recently been described in children and adolescents. Despite significant advances in recent years in understanding the phenomenology of these disorders, their pathophysiology, inheritance, and treatment in adults, and the relationship to other psychiatric disorders of adults and children (Uhde and Nemiah, 1988), relatively little is known about the disorders in children and adolescents. This report will review what is known about PD in children and adolescents and will describe six cases of panic disorder presenting in childhood or adolescence, illustrating recurring issues in the diagnosis and treatment of PD in this age group. Finally, some important questions for further research will be highlighted.
lifetime prevalence estimate for panic disorder of 0.6%, with a prevalence estimate among girls of 0.7 % and among boys of 0.4%. Less than half of the cases they identified had received any treatment. A number of epidemiological studies have shown adolescence to. be the peak period of onset of the disorder. Although there are reports of patients with onset of PD prior to puberty, the disorder appears to be less common in this age group than in adolescence. In a group of 3,000 adults surveyed as part of the NIMH Epidemiologic Catchment Area Program, the peak age of onset was found to fall between 15 and 20 years of age (von Korff et al., 1985). Thyer et al. (1985), in a retrospective chart review of a group of 62 adults patients with PD without agoraphobia, found a mean age of onset of 26.6 years, with 39% of these patients reporting onset of symptoms before age 20 and 13% before 10. Among 95 patient with PDAG, they found a mean age of onset of 26.3 years, with 29% of these patients experiencing onset before age 20, and 4% before age 10. Among 100 patients with PDAG examined by Sheehan et al. (1981b), 30 reported their first panic attack as occurring before age 20, and 6 before age 10.
Prevalence and Age at Onset The lifetime prevalence of PD in the general adult population is about 1.5%, and 6-month prevalence is about 1% (Myers et al., 1984). In adults, the disorder is approximately two to three times more prevalent in females (Robins et al. , 1984). Many adult or adolescent patients retrospectively report the onset of their symptoms during childhood (Klein, 1981), andPD is not uncommonly encountered by psychiatristsworking with adolescents. However, only one recent study has directly examined the prevalence of disorder in young people. Whitaker et al. (in press) examined a nonclinical sample of 5, 108 high school students and found a
Case Reports A number of studies have directly assessed symptoms of PD in child or adolescent psychiatric populations. Moreau et al. (1989), in a study of 153 offspring of depressed parents, identified seven children and adolescents with panic symptoms; six met DSM-III criteria for PD. Four of the cases were prepubertal. Age of onset ranged from 5 to 18 years old, and all presented with symptoms patterns similar to that of adults with PD. Four of the seven had at least one parent with PD, four met diagnostic criteria for major depression, and four met those for separation anxiety disorder. Last and Strauss (1989) identified 17 cases of PD among 177 consecutive admissions to an outpatient child and adolescent anxiety clinic; all but one were postpubertal. They found a 2:1 female to male ratio, and a lifetime diagnosis of depressive disorder in 6 of 17. PD was diagnosed in 3 of 9 mothers of affected children. Alessi and Magen (1988) reported seven cases of PD among psychiatrically hospitalized children, ranging in age from 7 to 12 (four of the seven were 12 years old). Six of
Accepted August 7, 1989. Dr. Black is National Research Service Award Fellow, Section on Affective and Anxiety Disorders, Biological Psychiatry Branch, National Institute ofMental Health, Bethesda, MD, and Clinical Assistant Professor ofChild and Adolescent Psychiatry, University ofMaryland School of Medicine, Baltimore, MD. Dr. Robbins is Assistant Professor of Child and Adolescent Psychiatry, and Director, Affective Disorders Program, Emma Pendelton Bradley Hospital and Brown University Program in Medicine, Providence, RI. This work was supported in part by a National Research Service Award grant to Dr. Blackfrom the National Institute of Child Health and Human Development (HD07125-0l). Reprint requests to Dr. Black, Section on Affective and Anxiety Disorders, Biological Psychiatry Branch, National Institute of Mental Health, Building 10, Room 3S239, Bethesda, MD 20892. 0890-8567/9012901-O036$2.0010© 1990 by the American Academy of Child and Adolescent Psychiatry.
36
PANIC DISORDER IN CHILDREN AND ADOLESCENTS
the seven also had separation anxiety disorder, and four suffered from depressive disorders. Alessi et al. (1987) looked for the presence of panic attacks among 61 adolescents hospitalized on a psychiatric ward. Ten of these patients had definite panic attacks, with an average age of onset 13.9 years. Nine of the ten also were suffering from a mood disorder, five were diagnosed as having borderline personality disorder, and four had a past history of separation anxiety disorder of childhood. Fifteen more patients had possible panic attacks. None of the 61 patients had been given the diagnosis of PD at the time of admission to the hospital. Van Winter and Stickler (1984) reported six patients from 9 to 17 years of age seen at the Mayo Clinic with PD. One patient reported the onset of his disorder at age 8 years. By telephone interview, they diagnosed relatives from two previous generations of this patient's family as suffering from PD. Biederman (1987) has reported the cases of three children aged 8 to 11 with symptoms consistent with the diagnosis of PDAG. All three of these children also suffered from separation anxiety, and two had demonstrated school refusal. Two had mothers who also suffered from PDAG and had responded to pharmacological treatment. All three children showed rapid improvement in response to treatment with clonazepam. Ballenger et al. (1989) also reported three children aged 8 to 13 with PDAG, two of whom showed separation anxiety and school refusal. The mother of one child suffered from PDAG. All responded positively to treatment with imipramine or the combination of imipramine and alprazolam. Herman et al. (1981) conducted a retrospective review of records of 34 children seen over a 25-year period at the Mayo Clinic and given the diagnosis of "hyperventilation syndrome." Although they do not use the term "panic disorder, " it is clear from a review of the symptoms they report that many, if not most, of their patients were having panic attacks. Age of onset ranged from 6 to 18 years, with most occurring in early adolescence. Many had prominent somatic complaints. Although most of the children, after evaluation, were "simply reassured that they had a benign disorder," long-term follow-up by the investigators showed quite the opposite. Of 30 respondents to follow-up questionnaires, 12 were still reporting episodes of hyperventilation as adults. Over half reported chronic anxiety, and over one third complained of depression. Many also complained of a variety of somatic ailments. Four patients aged 9 to 16 years old with primarily neurological presentations of PD have also been reported (Herskowitz, 1986). One of these had previously been given the diagnosis of temporal lobe epilepsy and treated with phenytoin, and another had been given the diagnosis of pseudoseizures. Three of the four were also noted to be depressed. A number of studies have demonstrated that children with other psychiatric disorders, particularly depression, have very high rates of somatic complaints, far exceeding the rates for adults with similar diagnoses (Ryan et al., 1987; Mitchell et al., 1988). It seems likely that many children l.Am.Acad. Child Adolesc. Psychiatry, 29:1 ,lan.1990
and adolescents with PD are presenting to their pediatricians with primarily somatic complaints and that most of these cases of PD remain undetected.
Relationship to Separation Anxiety Disorder of Childhood A substantial body of evidence has now accumulated demonstrating important relationships among PD and separation anxiety disorder of childhood (SAD) and suggesting that for many patients these different clinical presentations may be the manifestations of a common underlying disorder (Klein, 1981). Symptomatically, panic attacks bear a striking resemblance to the reactions of children suffering from SAD to separation from parents (Klein and Fink, 1962). Furthermore, children, adolescents, and adults with PDAG commonly avoid being separated from attachment figures (for adults, these are more commonly spouses or friends, rather than parents). A high incidence of history of separation anxiety disorder in childhood in patients with PD has also been reported (Klein, 1964; Gittelman and Klein, 1985). Up to half of agoraphobics may have a history of separation anxiety in childhood, although the relationship seems much stronger for female than male agoraphobics (Gittelman and Klein, 1984). As with PD in adults, depression also commonly coexists with SAD in childhood (Klein and Gittelman-Klein, 1978). A recent study of 45 children and 50 adolescents with major depressive disorder found that 43% had coexisting separation anxiety disorder (Mitchell et al., 1988). In another study of 95 depressed prepubertal children, 58% had moderate to severe separation anxiety (Ryan et al., 1987). A strong familial overlap between PD, SAD, and depression had been demonstrated (Gittelman and Klein, 1984). Offspring of parents with PD have more than a threefold increased risk of SAD, while offspring of parents with PD plus major depression have more than a tenfold increased risk; over one-third of these offspring suffer from SAD (Weissmanet al., 1984; Leckman et al., 1985). Those agoraphobic women with an early history of SAD are more likely to have children with SAD than are agoraphobic women without a history of SAD. Furthermore, PD, SAD, and major depressive disorder all respond to the same pharmacological agents, namely tricyclic and monoamine oxidase inhibitor antidepressants (Klein and Gittelman-Klein, 1978), although there are also agents which appear to be effective against PD only or depression only (Charney et al., 1986). Donald Klein (1981), drawing heavily on the work of John Bowlby and on ethological studies of separation, has hypothesized that we all begin life with an innate biological mechanism regulating affective response to separation. Typically, the initial affective response which ensues when the threshold of this system is crossed is protest. If no relief occurs, protest turns to despair. In this model, protest is analogous to the behavior shown by children with separation anxiety or adults with panic disorder, and despair is anal-
37
BLACK AND ROBBINS
ogous to depression. Klein suggests that some individuals may have pathologically lowered thresholds in this system , and thus may respond to slight or even imagined or anticipated separation with any of these behavioral manifestations, separation anxiety, panic attacks, or depression. Other authors have suggested, that this control mechanism governs response not just to separation but to perception of danger in general (Cowley and Roy-Byrne, 1987). The hypothesis that a single control system governs all these different psy~ chiatric presentations may explain not only the high overlap of these disorders in particular individuals, but also the response of all three conditions to the same pharmacological agents and the observed high familial overlap of the disorders, presumably due to genetic influences on the threshold of the system. This conceptualization would predict an association between separation experiences and the onset of PD. In fact , several studies·have found an increased incidence of stressful life events preceding the onset of PD, particularly involving death or severe illness of a loved one or other separation experienced (Faravelli, 1985; Roy-Byrne et al. , 1986; Roy-Byrne and Uhde, 1988). One study found.an increased incidence of events involving the threat of "danger" for patients with anxiety disorders, while events involving the threat of "loss" were more common for patients with depression (Finlay-Jones and Brown, 1981). Similarly, major disruptions in attachment relationships have been reported to precede the onset of SAD in 80% of cases (Gittelman, 1985). In the authors' experience, adolescents with panic attacks have frequently suffered a recent major loss, such as .loss of a parent or rejection by a romantic partner, or anticipate such a loss. Animal models of the consequences of separation from family or peer relations have been developed in nonhuman primates and in rodents. Although it remains unclear to what extent these models correlate with human responses to separation or with human psychopathology, such as depression, panic, or anxiety, the models have afforded the opportunity to examine the physiological, neurochemical, and behavioral responses to social separation (Suomi , 1986; Hofer, 1987; Rosenblum and Paully , 1987). With regard to the present discussion , it is of interest that the characteristic behavioral responses to separation from peers seen in youn~ rhesus monkeys are blocked by treatment with imipramine and that the time course of this effect is similar to that seen in humans with either PD or depression (Suomi et al., 1978). Similarly, distress vocalizations in puppies precipitated by separation from littermates are blocked by imipramine (Scott et al., 1973). Isolation calls in adult squirrel monkeys are blocked by imipramine or clonidine (an
