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Premorbid conditions and precipitating events in early-onset panic disorder
Premorbid Conditions and Precipitating Events in Early-Onset Panic Disorder Sara Venturello, Giulio Barzega, Giuseppe Maina, and Filippo Bogetto This study investigates differences in premorbid conditions and in the role of triggering events in the onset of early-onset versus adult-onset panic disorder (PD). Two hundred forty-one outpatients with a principal diagnosis of PD (DSM-IV) were evaluated using a semistructured interview to generate axis I and axis II diagnoses according to DSM-IV, and to collect family history of psychiatric disorders and life events. For statistical analysis the sample was subdivided in two groups according to age at onset (<18 years or >18 years). Early-onset and adult-onset patients with PD do not differ in the severity of the disorder and in the interference with their overall functioning. Early-on-
set patients have (1) higher familial loading for psychiatric disorders in general and for PD in particular; (2) higher frequency of preceding anxiety disorders, dysmorphophobia, and bulimia nervosa; and (3) higher comorbidity rates for personality disorders and particularly for disorders of the “anxious-fearful” cluster. The data we found on life stress indicate that the environmental factors play a major role in the development and/or in precipitating the onset of adultonset PD. Our findings suggest that the early-onset form of PD seems to be more characterized by endogenous components compared to the adult-onset form. Copyright © 2002 by W.B. Saunders Company
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PD with early-onset or with adult-onset. When examining premorbid clinical conditions with respect to the start of PD, the following features need to be considered: (1) familiarity for PD and/or familial comorbidity with other psychiatric disorders; (2) other axis I disorders whose onset preceded PD onset; and (3) premorbid personality disorders. Family studies on PD showed an increased risk (7.9% to 10.7%) among first-degree relatives of PD patients compared to relatives of healthy controls.19,20 Previous researches suggest a greater genetic loading for early-onset PD patients.12-15 Several studies have shown that PD is frequently preceded by another psychiatric condition, such as other anxiety disorders, mood disorders, and alcoholism.21-23 Concerning disorders usually first diagnosed in infancy, childhood, or adolescence, separation anxiety disorder has been frequently reported by adult PD patients, although the relationship between PD and separation anxiety disorder seems not to be specific since high comorbidity rates of separation anxiety in childhood have been found in most anxiety and/or mood disorders.24-26 Recently, Fones et al.27 found that attention deficit hyperactivity disorder may be an important clinical comorbidity in panic patients. Although different comorbidity patterns have been found in patient with early- versus late-onset PD, no study has focused on disorders with onset preceding PD onset. Several studies28-33 investigated the comorbidity between PD and personality disorders, evidencing wide ranges (between 35% and 95%). Although research on this topic has provided controversial
ANIC DISORDER (PD) is a common psychiatric condition with high lifetime prevalence rates in the general population (ranging from 1.4% to 3.8%) and with onset typically observed in late adolescence or early adulthood. Research examining the age of onset for PD have been consistent despite differing types of individuals being studied: both epidemiological1-6 and clinical7-9 investigations have reported the onset of PD in the midor late-20s in men and in women. Several recent studies10-15 also suggest that in a significant proportion of cases (10.2% to 28%) PD may begin in childhood or adolescence (early-onset PD). Some evidence exists that early-onset PD may represent a specific subtype of the disorder with respect to clinical presentation and premorbid clinical conditions. Clinical studies aimed to characterize an early-onset subtype of PD found a distinct phenomenology with higher rates of depersonalization symptoms,11,15-17 different pattern of comorbidity,10-11,13-15,18 more clinical severity,13 and higher suicide risk.10 The characterization of differences in premorbid clinical conditions and the role of triggering events in precipitating the onset of the disorder could further the hypothesis of two different subtypes of From the Department of Neurosciences, Psychiatry Section, University of Turin, Italy. Address reprint requests to Giuseppe Maina, M.D., Department of Neurosciences, Psychiatry Unit, University of Turin, Via Cherasco 11, 10126 Torino, Italy. Copyright © 2002 by W.B. Saunders Company 0010-440X/02/4301-0003$35.00/0 doi:10.1053/comp.2002.29844 28
Comprehensive Psychiatry, Vol. 43, No. 1 ( January/February), 2002: pp 28-36
EARLY-ONSET PANIC DISORDER
results, investigators generally agree that Cluster C personality disorders (dependent and avoidant) and Cluster B personality disorders (histrionic and borderline) were the most commonly diagnosed in PD patients. Concerning personality features in earlyonset PD patients, recently, Segui et al.15 observed a higher score in neuroticism on the Eysenck Personality Questionnaire-A (EPQ-A) among this group of patients, confirming previous reports.34 Considering the possible role of precipitating events in the onset of the PD, several studies referred that interpersonal conflicts, separation, and physical illness frequently occurred before the onset of PD.35-40 No study focused the attention on the differential role of triggering events in the onset of PD among early versus late-onset patients. The aim of the present study was to compare premorbid clinical conditions and the role of triggering events between patients with the early-onset form of the disorder and patients with the adultonset form. METHODS
Subjects Two hundred forty-one subjects were enrolled from patients consecutively referred to the Department of Neuroscience, Psychiatric Unit, University of Turin (Italy). All patients, aged over 18 years, had a principal diagnosis of PD according to DSM-IV diagnostic criteria. Exclusion criteria were current or previous diagnosis of schizophrenia or other psychotic disorders, and the presence of organic brain syndrome, mental retardation, and severe neurological or general medical conditions. In addition, to exclude patients with PD due to a general medical condition or associated with organic brain disorders, all subjects underwent thyroid tests, as well as an electrocardiogram, a chest x-ray, and a neurological examination. The average age of the sample was 37.2 years (⫾11.0 years), 61.4% were females, 62.2% were married, and the mean age at PD onset was 31.3 years (⫾11.0 years).
Interviews All patients gave their informed consent after the procedure had been fully explained. Axis I diagnoses of any current or longitudinal psychiatric disorder were assessed by using the Structured Clinical Interview for DSM-IV (SCID). The chronological relationship between PD and comorbid disorders was carefully explored: ages of onset of comorbid disorders were defined as the ages when all diagnostic criteria had been met and no attempt was made to establish chronological primacy when PD and a comorbid condition started in the same year: in such cases, the onset of both disorders was considered to be concomitant. When questions arose according to recall of historical information, patients were reapproached for further clarifications. Whenever possible, patient’s medical records were reviewed and information obtained from close family members and general practitioners.
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Axis II diagnoses were also assessed according to the specific section of the SCID. Assessment with the SCID was guided by items previously affirmed by patients on the SCID-PQ, a selfrated instrument to generate DSM-IV personality disorders diagnoses. Items not affirmed on the SCID-PQ were assumed to be true negatives. However, if an interviewer had any reason to believe these were false negatives, further items were assessed. This method is in accordance with instructions for using the SCID, and enabled personality disorder symptomatology to be based on clinical contact combined with a structured clinical interview. Other data were collected for each subject by a semistructured interview that was constructed to cover the following areas. (1) Sociodemographic data: gender, age, education, and marital and occupational status. (2) Onset of PD: the history of the onset of the disorder was explored collecting data regarding age at first panic attack and age at onset of the disorder. Patients were asked to identify when their first panic attack occurred and to describe its symptoms to ensure that it met full-blown DSM-IV criteria for panic attack. Patients were also asked about prior situational anxiety or agoraphobic avoidance in the day, week, and month before the first panic to ensure that they were recalling their first-ever panic attack and not merely the one most vividly remembered or the one that immediately preceded avoidance. In the same way, patients were asked about events immediately following the first panic attack to evaluate subsequent panics and avoidance. Onset of illness was dated within a 1-month period when patients first experienced unexpected recurrent panic attacks at least one of which was followed by at least 4 weeks of persistent concern about having additional attacks, or worry about the implications of the attack or its consequences, or a significant change in behavior related to the attacks (DSM-IV). An attempt was made to date onset of PD to a 4-week period, but if there was uncertainty, a close relative of the patient was interviewed and a range was plotted and its mid-point was used in the analysis. (3) Life events: patients were asked whether they had experienced a stressful life event within the year prior to the onset and the raters had to decide whether the event would fit any of the 61 items on the list by Paykel et al.41 Each life event reported was carefully investigated to determine the exact time of occurrence. To facilitate accurate dating, a calendar for the investigated years was constructed and the individuals were asked to show their geographical, work, and school positions throughout that year and to recall any circumstances that might serve as anchor points. The weighted score connected with each event, obtained through a calibration study, was considered for this investigation. Moreover, a subject was considered to have experienced a severe event when any of the top 20 events on the Paykel’s list had occurred. On the basis of this procedure it was possible to obtain several normative measures of stress (number of subjects with at least one life event, and number of subjects with at least on severe or highly distressing event). (4) Family history of psychiatric disorders: family history of psychiatric disorders was obtained from all patients and
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all first-degree relatives using the Family History Research Diagnostic Criteria interview (FH-RDC). A psychiatric diagnosis was assigned only if the identified family member had received treatment or had experienced symptoms sufficient to have met DSM-IV criteria for the disorder. Whenever possible, medical records were collected and examined. In addition, the following rating scales were included in the assessment of patients with PD: the Sheehan Clinician Rated Anxiety Scale (SCRAS),42 the Hamilton Anxiety Rating Scale (HAM-A),43 the 17-item Hamilton Depression Rating Scale (HAM-D),44 and the Global Assessment of Functioning Scale (GAF).
Interviewers and Raters All interviews were conducted in person by three investigators (G.M., G.B., and S.V.), each with at least 4 years of postgraduate clinical experience. They were also the original authors of the semistructured interview and devised the most appropriate interviewing techniques by discussing 10 cases of PD before the beginning of the study. Each patient was evaluated in two subsequent phases: (1) randomly by one of the three interviewers, by the SCID, and by a semistructured interview with a format that covered sociodemographic data, onset of PD, and family history. The same interviewer assessed the patient with the rating scales. (2) Randomly by one of the three interviewers (with the exclusion of the interviewer who had examined the subject previously) and blindly with respect to the first examination, by a semistructured interview to investigate the role of life events in the onset of the disorder. In conclusion, the same interviewer examined diagnosis, PD status, and demographic data and a different interviewer blindly examined life stress. Finally, data from the separate interviewers were reviewed with a senior psychiatrist (F.B.), and, if there were any events in proximity to PD onset, a final check with the respondents on the time order was made.
Inter-rater Reliability In the early phase of the study, inter-rater agreement between rater pairs on the diagnosis of PD and of comorbid psychiatric axis I and axis II disorders were ascertained; they were blindly conducted. For all evaluations, relevant clinical data were eventually submitted to the main investigator (F.B.) who, following an abbreviated face-to-face clinical interview, assigned consensus diagnoses. The inter-rater reliability of DSM-IV diagnoses was found to be good: the kappa coefficient was greater than 0.80 for the presence of any lifetime axis I disorder. To assess the reliability of axis II diagnoses, subjects were randomly selected to be reinterviewed with the SCID-II by an assessing clinician who previously had no contact with the patient and was blind to personality disorder diagnoses. Comparison of axis II diagnoses across raters showed good reliability. Test-retest reliability (n ⫽ 15) assessed by for the presence of any personality disorder was .75. Pearson’s correlation coefficient between rater pairs and intraclass coefficients demonstrated excellent agreement for the SCRAS of 10 PD patients assessed before the beginning of the study (P ⬍ .0001). In 10 depressed subjects, scores obtained by our raters of the HAM-D correlated above .90.
VENTURELLO ET AL
Statistical Analysis The PD sample was divided into two groups on the basis of age at PD onset: early-onset was fixed at 18 years of age or under, and adult-onset over 18 years. The choice of age 18 as a cut-off point was arbitrary, suggested by the threshold age of pediatric care in our country. The statistical tests used were Student’s t test for continuous variables, and chi-square test for categorical variables, applying Yates’correction or Fisher’s test where necessary. A P value less than .05 was considered statistically significant. The odds ratios (OR) were obtained by logistic regression, with a confidence interval of 95%. OR, which indicate the strength of association among comorbid psychiatric diagnoses in both groups, are statistically significant when the confidence intervals include 1.0.
RESULTS
Of the 241 patients with PD included in the data analysis, 44 (18.3%) displayed an early-onset disorder and 187 (81.7%) comprised the adult-onset group. Demographic and clinical characteristics of the PD sample according to age at onset are summarized in Table 1. Subjects with early-onset PD had also a lower index age with a higher single marital status and a lower rate of full-time employment. Considering the rating scales assessment, only the HAM-D was significantly different between the two subgroups of patients with the early-onset PD showing a higher mean total score. No particular difficulties were encountered in establishing age at onset of the disorder: only in eight patients (3.3%) was there uncertainty requiring that a close relative of the patient be interviewed. In these cases, a range was plotted and its mid-point was used in the analysis; the mean difference between the eight patients and their own relatives was 1.5 months with a maximum of 3 months. The uncertainty did not concern the 18year cut-off in any of these patients. Familial Comorbidity Family history for psychiatric disorders is reported in Table 2. Data were obtained from all 741 first-degree relatives: in 30.1% of cases, information was collected by direct interview of firstdegree relatives, while in the other 69.9% data were derived from patient interviews and medical records. There were no differences between the two groups in the number of first-degree relatives interviewed. More than one third of the whole sample (38.6%) had a first-degree relative with a
EARLY-ONSET PANIC DISORDER
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Table 1. Sociodemographic and Clinical Characteristics of the Sample: Comparison Between Early-Onset and Adult-Onset PD Patients
Female, N (%) Actual age (yr) Educational level (yr) Marital status, N (%) Single Married Vidowed Separated Employed full-time, N (%) PD ⫹ agoraphobia, N (%) Age at onset (yr) Age at first panic attack Illness duration (yr) GAS SCRAS HAM-A HAM-D
Early-Onset (N ⫽ 44)
Adult-Onset PD (N ⫽ 197)
28 (63.6%) 28.2 ⫾ 14.3 11.2 ⫾ 3.3
120 (60.9%) 39.2 ⫾ 9.2 11.7 ⫾ 3.8
32 (72.7%) 12 (27.3%) 0 (0.0%) 0 (0.0%) 17 (38.6%) 27 (61.4%) 16.9 ⫾ 1.4 14.4 ⫾ 2.7 12.6 ⫾ 9.8 51.8 ⫾ 7.4 47.7 ⫾ 6.4 24.0 ⫾ 4.0 14.0 ⫾ 2.3
40 (20.3%) 138 (70.1%) 4 (2.0%) 15 (7.6%) 128 (65.0%) 136 (69.0%) 34.5 ⫾ 9.5 30.9 ⫾ 10.8 5.4 ⫾ 6.6 53.6 ⫾ 6.1 48.7 ⫾ 6.1 23.4 ⫾ 3.2 12.0 ⫾ 3.2
P Value
NS .002 NS .0001
.001 NS .0001 .0001 .001 NS NS NS .03
Abbreviations: GAS, Global Functioning Assessment Scale; SCRAS, Sheehan Clinician-Rated Assessment Scale; HAM-A, Hamilton Scale for Anxiety; HAM-D, Hamilton Scale for Depression; NS, not significant.
der and no differences emerged between the two subgroups of patients. A past history of anxiety disorders was more common in the early-onset patients. In particular, early-onset PD patients were more frequently associated with separation anxiety disorder. No mood disorders were diagnosed prior the onset of PD in the group of early-onset patients: 17.3% of adult-onset patients had at least one mood disorder preceding the onset of PD (9.1% major depression, 5.6% dysthymia, and 2.5% cyclothymia). No statistical analyses were performed because of the small numbers of patients affected. A positive history of bulimia nervosa (11.4%) and dysmorphophobia (9.1%) was observed only among early-onset patients; conversely, only adult-
diagnosis of psychiatric disorder and the percentage was significantly higher in the early-onset group. Significantly more early-onset patients had at least one first-degree relative with PD. Considering anxiety disorders, another significant difference appeared for social phobia that was only represented in the family history of the early-onset group (9.1%). Among mood disorders, major depression was significantly more common in the early-onset group and bipolar disorder was observed only in the same group of patients. Axis I Disorders Preceding PD Onset Data concerning axis I disorders with onset preceding PD onset are summarized in Table 3. Of the entire sample, 82.6% had at least one axis I disor-
Table 2. Family History: Comparison Between Early-Onset and Adult-Onset PD Patients Early-Onset PD (N ⫽ 44)
Adult-Onset PD (N ⫽ 197)
Diagnosis
No.
%
No.
%
P
At least one Social phobia Panic disorder Major depression Bipolar disorder Substance disorders
29 4 17 20 6 5
65.9 9.1 38.6 45.5 13.6 11.4
61 0 24 27 0 13
31.0 0 12.2 13.7 0 6.6
.0001 .001* .0001 .0001 .0001* NS
*Chi-square with Fisher correction.
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Table 3. Axis I Disorders Preceding PD Onset: Comparison Between Early-Onset and Adult-Onset Patients Early-Onset PD (N ⫽ 44)
Adult-Onset PD (N ⫽ 197)
Statistics
Diagnosis
No.
%
No.
%
OR
CI
P
At least one Anxiety Separation anxiety Specific phobia Social phobia Obsessive-compulsive Generalized anxiety At least one
37
84.1
162
82.2
1.14
0.74-2.57
NS
25 27 1 9 3 31
56.8 61.4 2.3 20.5 6.8 70.5
23 64 16 19 30 120
11.7 32.5 8.1 9.6 15.2 60.9
9.95 3.3 0.26 2.41 0.40 1.5
1.32-11.2 0.84-3.4 0.07-4.34 0.61-3.48 0.21-2.22 0.59-2.44
⬍.01 NS NS NS NS NS
Abbreviations: OR, odds ratio; CI, confidence intervals.
onset patients had a positive history for substancerelated disorder (12.2%). Again, no statistical analyses were performed because of the small numbers of patients affected. Axis II Comorbid Disorders At least one axis II comorbid disorder was observed in 75.1% of the whole sample (Table 4) and the percentage of patients with at least one personality disorder was higher in the early-onset group. No significant differences were observed in patients with at least one Cluster A or B personality disorder. Cluster C significantly characterized the early-onset patients. Life Events Considering the role of stressful life events, the comparison between early-onset and adult-onset patients is summarized in Table 5. Patients in the adult-onset group reported a greater mean number of life events than patients in the early-onset group, and the number of patients who experienced at least one severe event was also higher. Moreover,
both the mean total score of all events and the single highest event mean score were higher in adult-onset patients; the adult-onset group was significantly associated with at least one severe event. Statistical analysis on the frequency of each event of Paykel’s list did not reveal any significant difference between the two subgroups of patients. DISCUSSION
The proportion of early-onset patients (18.3%) in our sample of PD subjects was in the range found in similar studies (10.2% to 28%). The width of the range may be explained by the differences in the age cut-off for early-onset selected (18, 20, 25 years).12-15 Segui et al.,15 with a similar age cut-off of 18 years, observed a lower proportion of earlyonset PD patients of 10.2%. Future research on this topic should refer to the same cut-off point to reduce the variability due to heterogeneous criteria of recruitment. Early-onset patients were more likely to be single, while adult-onset patients were more likely to be married and employed full-time; these findings
Table 4. Comorbidity With Personality Disorders: Comparison Between Early-Onset and Adult-Onset Patients Early-Onset PD (N ⫽ 44)
Adult-Onset PD (N ⫽ 197)
Statistics
Diagnosis
No.
%
No.
%
OR
CI
P
At least one Cluster A At least one Cluster B At least one Cluster C Avoidant Dependent Obsessive-compulsive At least one
40
90.9
141
71.6
3.97
0.60-5.33
NS
5
11.4
32
16.2
0.66
0.30-2.29
NS
7
15.9
60
30.5
0.43
0.29-1.67
NS
14 20 12 30
31.8 45.5 27.3 68.2
29 38 36 79
14.7 19.3 18.3 40.1
2.7 3.48 1.68 3.2
0.74-3.17 0.86-3.4 0.59-2.62 1.24-3.26
NS NS NS ⬍.01
EARLY-ONSET PANIC DISORDER
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Table 5. Life-Events Occurring in the Year Prior to the Onset of PD According to Paykel’s Interview for Recent Life Events: Comparison Between Patients With Early- or Adult-Onset PDL
Events (mean ⫾ SD) Events Total score (all events) Single highest event Patients with One event at least, N (%) One severe event, N (%)
EO-PD (N ⫽ 44)
AO-PD (N ⫽ 197)
0.7 ⫾ 0.6 6.7 ⫾ 6.1 4.3 ⫾ 5.1
1.8 ⫾ 1.1 15.7 ⫾ 11.7 10.6 ⫾ 6.9
24 (54.5%) 2 (4.5%)
149 (75.6%) 96 (48.7%)
Statistics OR
CI
P
.05* .03* .05*
2.58 7.4
0.77-2.94 1.11-7.53
NS ⬍.01
*Student’s t test.
probably reflect the younger age at observation in the early-onset group. In accordance with previous reports,13,15 early-onset PD patients did not display more severe panic symptomatology, higher comorbidity rates with agoraphobia, or worse social functioning. We found higher scores on the HAM-D scale among early-onset patients; the possibility that the longer illness duration of this subgroup of patients could have been a risk factor for the development of depressive symptoms should be considered. A significantly greater proportion of early-onset than adult-onset patients have a history of at least one psychiatric disorder in first-degree relatives. The finding is in accordance with previous literature studies.12-15 Our data also provided evidence of higher rates of other anxiety disorders and of mood disorders among first-degree relatives of early-onset panic patients. In particular, our findings indicate an association of the early-onset form with a positive family history for social phobia, major depression, and bipolar disorder. The high rate of familial comorbidity between PD and mood disorders is well known; recently, several authors focused on the association between PD and bipolar disorder.45-47 MacKinnon et al.,45 evaluating the familial comorbidity of a sample of bipolar patients, hypothesized that PD could be a specific marker for a familial subtype of bipolar disorder. Our investigation suggests that this co-occurrence is significantly more frequent in patients with the early-onset form. The finding of high percentages of PD chronologically secondary to other axis I disorders is in accordance with the literature,21-22 but some differences emerged between early-onset and adult-onset disorders. Concerning disorders usually first
diagnosed in infancy, childhood, or adolescence, separation anxiety disorder was significantly associated with early-onset PD, while we did not found any case of attention deficit hyperactivity disorder in our sample. Furthermore, preceding specific phobia, agoraphobia, and obsessive-compulsive disorder seem to characterize early-onset patients, but the association was not statistically significant. The literature on comorbidity with anxiety disorders is controversial: Segui et al.15 observed a higher frequency of social phobia among earlyonset patients and Goldstein et al.13 found a higher frequency of obsessive-compulsive disorder in the same group. Moreover, in accordance with published data, phobic disorders, in particular specific phobia and agoraphobia, usually have been described to be more frequently associated with early-onset PD,11,18 although in our sample the actual comorbidity with agoraphobia did not reveal any differences between the two groups. Comorbid mood disorders with onset preceding PD were observed only in the adult-onset group. The lower frequency of mood disorders preceding PD among early-onset patients may partly reflect the age cut-off: age at onset of mood disorders is commonly described in early adulthood rather than in adolescence. This finding is in accordance with Segui et al.,15 but contrasts with other reports11; the different age cut-offs may partly explain this controversy. Early-onset patients have also been found to be characterized by higher percentages of body dysmorphic disorder and bulimia nervosa. All patients with comorbid bulimia nervosa were females. Bulik et al.48 found high rates of comorbid anxiety disorder in women with eating disorders (anorexia nervosa or bulimia nervosa). In most cases, anxiety
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disorders preceded the current eating disorder, except for PD, which tends to develop after the onset of anorexia or bulimia. In contrast with the literature,10,15 our data on comorbid conditions with onset preceding PD onset showed more diagnoses of substance-related disorder among adult-onset patients. The high prevalence of personality disorders observed in our sample is in agreement with findings of several literature studies (range, 35% to 95%).28-33 Predictably, Cluster C personality disorders were the most prevalent in both goups of patients, followed by Cluster B personality disorders. Earlyonset PD patients had a significantly higher prevalence of at least one Cluster C personality disorder. Several authors15,34 have shown that early-onset PD is linked to higher levels of neuroticism. This suggests that PD shares a common underlying pathophysiology with the comorbid axis II disorders, which show greater prevalence in early-onset PD than in the late-onset PD, namely, Cluster C disorders. Segui et al.15 recently hypothesized that the early-onset form of the disorder derives from a common pathogenic factor rapresented by a temperamental dimension defined “behavioral inhibition.” This factor can lead to school phobia and overanxious disorder in childhood and to several anxiety disorders in adulthood, such as social phobia and PD. Among these children, several authors49-54 observed personality features (introversion, social inhibition, and response to novelty with silence and isolation and in adulthood little assertiveness, low self-esteem, and high interpersonal sensitivity) that are consistent with the characteristics of cluster C personality disorders (including avoidant, dependent, and obsessive-compulsive personality disorders) and that are frequently associated with anxiety disorders. Similarly, studies applying other assessment instruments, such as the EPQ-A, found that neuroticism, which is related to those personality characteristics as well as to anxiety, was higher in early-onset PD patients.15,34 Recently, Latas et al.46 observed in a sample of patients with panic disorder with agoraphobia that younger age at onset was associated with any Cluster B personality disorder, while the duration of the disorder was a significant predictor of any Cluster B and Cluster C personality disorder. This suggests
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that some of the Cluster B and Cluster C personality disorders may be a consequence of longlasting PD with agoraphobia. Since in our sample early-onset PD patients had a longer duration of the disorder, the possibility that higher rates of personality disorders may be a consequence of years of illness should to be considered. According to our data on life stress, the number of patients reporting at least one severe event, the mean number of events, and the mean weighted score were significantly higher among adult-onset patients. Our data have shown that the role of precipitating events in PD is significantly higher in the late-onset group; environmental factors are perhaps less relevant in the development of PD in early-onset patients. In conclusion, our data suggest that earlyonset and adult-onset patients with PD do not differ in the severity of the disorder or in the level of interference with their overall functioning. Some differences between the two subgroups of patients emerged when considering the premorbid clinical conditions. Early-onset patients have (1) higher familial rates of psychiatric disorders in general and for PD in particular; (2) a higher frequency of preceding separation anxiety disorder; and (3) higher comorbidity rates for the personality disorders of the “anxious-fearful” cluster. The presence of premorbid conditions for PD appears to increase the risk for an earlier onset of the disorder with a lower threshold for triggering events. The data that we found on life stress indicate that environmental factors play a minor role in the development and/or in precipitating the onset of early-onset PD that seems to be more characterized by “endogenous” components, referring to an anxious trait underlying and or predisposing to the disorder. Further psychobiological and genetic studies are needed to test this hypothesis. Our report had three major limitations. Our reliance on the retrospective recall of symptoms or events that occurred years before could be associated with under-reporting of the earlier symptoms or events or difficulty in precise recall of symptom onset or event occurrence. However, we collected corroborative histories from parents and medical records whenever possible. Second, one may question the accuracy of personality disorder diagnoses made on the basis of information derived from
EARLY-ONSET PANIC DISORDER
35
acutely anxious patients. Our raters were instructed to administer the SCID so that pathological behaviors would be assessed as present only when these behaviors were evident during periods of wellbeing. However, such subtle distinctions were not possible when patients were unable to think of a time when they were not anxious. Therefore, while we recognized that particular care must be exercised in assigning personality disorder diagnoses to
individuals currently affected by anxiety disorders, this study’s goal was to compare the prevalence of personality disorders in two acutely anxious groups of patients who showed equal symptoms of actual PD, but who differed in age at onset of their disorder. Third, our findings need to be replicated in larger samples that permit different statistical analyses.
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15. Seguı` J, Ma`rquez M, Garcı`a L, Canet J, Salvador-Carulla L, Ortiz M. Differential clinical features of early-onset panic disorder. J Affect Disord 1999;54:109-117. 16. Cassano GB, Petracca A, Perugi G, Toni C, Tundo A, Roth M. A clinical evaluation on 150 patients with panic disorder/agoraphobia. Compr Psychiatry 1989;30:5-12. 17. Toni C, Cassano GB, Perugi G, Murry L, Mancino M, Petracca A, et al. Psychosensorial and related phenomena in panic disorder and in temporal lobe epilepsy. Compr Psychiatry 1996;37:125-133. 18. Langs G., Quehenberger F, Fabisch K, Klug G, Fabisch H, Zapotoczky HG. The development of agoraphobia in panic disorder: a predictable process? J Affect Disord 2000;58:43-50. 19. Maier W, Lichtermann D, Minges J, Oehrlein A, Franke P. A controlled family study in panic disorder. J Psychiatr Res 1993;27(Suppl 1):23-33. 20. Goldstein RB, Weissman MM, Adams PB. Psychiatric disorders in relatives of probands with panic disorder and/or major depression. Arch Gen Psychiatry 1994;51:383-394. 21. Starcevic V, Uhlenhuth EH, Kellner R, Pathak D. Comorbidity in panic disorder: II. Chronology of appearance and pathogenic comorbidity. Psychiatry Res 1992;46:285-293. 22. Starcevic V, Uhlenhuth EH, Kellner R, Pathak D. Comparison of primary and secondary panic disorder: a preliminary report. J Affect Disord 1993;27:81-86. 23. Merikangas KR, Stevens DE, Fenton B, et al. Co-morbidity and familial aggregation of alcoholism and anxiety disorders. Psychol Med 1998;28:773-788. 24. Silove D, Manicavasagar V, Curtis J, Blaszczynski A. Is early separation anxiety a risk factor for adult panic disorder?: a critical review. Compr Psychiatry 1996;37:167-179. 25. Pollack MH, Otto MW, Sabatino S, et al. Relationship of childhood anxiety to adult panic disorder: correlates and influence on course. Am J Psychiatry 1996;153:376-381. 26. Fagiolini A, Shear K, Cassano GB, Frank E. Is lifetime separation anxiety a manifestation of panic spectrum? CNS Spectrums 1998;3:63-72. 27. Fones CSL, Pollack MH, Susswein L, Otto M. History of childhood attention deficit hyperactivity disorder (ADHD) features among adults with panic disorder. J Affect Disord 2000; 58:99-105. 28. Friedman CJ, Shear MK, Frances AF. DSM-III personality disorders in panic patients. J Pers Disord 1987;1:132-135. 29. Sanderson WC, Wetzler S, Beck AT, Betz F. Prevalence of personality disorders among patients with anxiety disorders. Psychatry Res 1993;51:167-174. 30. Hoffart A, Thornes K, Hedley LM, Strand J. DSM-III-R
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axis I and axis II disorders in agoraphobic patients with and without panic disorder. Acta Psychiatr Scand 1994;89:186-191. 31. Ampollini P, Marchesi C, Signifredi R, Maggini C. Temperament and personality features in panic disorder with or without comorbid mood disorders. Acta Psychiatr Scand 1997; 95:420-423. 32. Ampollini P, Marchesi C, Signifredi R, Ghinaglia E, Scardovi F, Codeluppi S, et al. Temperament and personality features in patients with major depression, panic disorder and mixed conditions. J Affect Disord 1999;52:203-207. 33. Langs G, Quehenberger F, Fabisch K, Klug G, Fabisch H, Zapotoczky HG. Prevalence, patterns and role of personality disorders in panic disorder patients with and without comorbid (lifetime) major depression. Acta Psychiatr Scand 1998;98:116123. 34. Kenardy J, Oei, TPS, Evans L. Neuroticism and age of onset for agoraphobia with panic attacks. J Behav Ther Exp Psychiatr 1990;21:193-197. 35. Faravelli C. Life events preceding the onset of panic disorder. J Affect Disord 1985;22:79-82. 36. Roy-Byrne PP, Geraci M, Uhde TW. Life events and the onset of panic disorder. Am J Psychiatry 1986;143:1424-1427. 37. Faravelli C, Pallanti S. Recent life events and panic disorder. Am J Psychiatry 1987;146:622-626. 38. Rapee RM, Litwin EM, Barlow DH. Impact of life events on subjects with panic disorder and on comparison subjects. Am J Psychiatry 1990;147:640-644. 39. Horesh N, Amir M, Kedem P, Goldberger Y, Kotler M. Life events in childhood, adolescence and adulthood and the relationship to panic disorder. Acta Psychiatr Scand 1997;96: 373-378. 40. Manfro GG, Otto MW, McArdle ET, Worthington III JJ, Rosenbaum JF, Pollack MH. Relationship of antecedent stressful life events to childhood and family history of anxiety and the course of panic disorder. J Affect Disord 1996;41:135-139. 41. Paykel E, Prusoff BA, Uhlenhuth EH. Scaling of life events. Arch Gen Psychiatry 1971;25:340-347. 42. Sheehan DV. The Anxiety Disease. New York, NY: Scribner, 1983.
VENTURELLO ET AL
43. Hamilton H. The assessment of anxiety states by rating. Br J Psychiatry 1959;32:50-55. 44. Hamilton H. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967;6:278-295. 45. MacKinnon DF, McMahon FJ, Simpson SG, McInnis MG, DePaulo JR. Panic disorder with familial bipolar disorder. Biol Psychiatry 1997;42:90-95. 46. Savino M, Perugi G, Simonini E, Soriani A, Cassano GB, Akiskal HS. Affective comorbidity in panic disorder: is there a bipolar connection? J Affect Disord 1993;28:155-163. 47. Perugi G, Akiskal HS, Lattanzi L, et al. The high prevalence of “soft” bipolar (II) features in atypical depression. Compr Psychiatry 1998;39:63-71. 48. Bulik CM, Sullivan PF, Fear JL, Joyce PR. Eating disorders and antecedent anxiety disorders: a controlled study. Acta Psychiatr Scand 1997;96:101-107. 49. Biederman J, Rosenbaum JFJ, Bolduc-Murphy EA, et al. A 3-year follow-up of children with and without behavioral inhibition. J Am Acad Child Adolesc Psychiatry 1993;32:814821. 50. Rosenbaum JF, Biederman J, Gersten M, et al. Behavioral inhibition in children of parents with panic disorder and agoraphobia. A controlled study. Arch Gen Psychiatry 1988;45: 463-470. 51. Rosenbaum JF, Biederman J, Hirshfeld DR, et al. Further evidence of an association between behavioral inhibition and anxiety disorders: results from a family study of children from a non-clinical sample. J Psychiatr Res 1991;25:49-65. 52. Rosenbaum JF, Biederman J, Hirshfeld DR, Bolduc EA, Chaloff J. Behavioral inhibition in children: a possible precursor of panic disorder or social phobia. J Clin Psychiatry 1991; 52:5-9. 53. Rosenbaum JF, Biederman J, Bolduc-Murphy EA, et al. Behavioral inhibition in childhood: a risk factor for anxiety disorders. Harv Rev Psychiatry 1993;1:2-16. 54. Rosenbaum JF, Biederman J, Pollock RA, Hirshfeld D. The etiology of social phobia. J Clin Psychiatry 1994; 55(Suppl):10-16.
set patients have (1) higher familial loading for psychiatric disorders in general and for PD in particular; (2) higher frequency of preceding anxiety disorders, dysmorphophobia, and bulimia nervosa; and (3) higher comorbidity rates for personality disorders and particularly for disorders of the “anxious-fearful” cluster. The data we found on life stress indicate that the environmental factors play a major role in the development and/or in precipitating the onset of adultonset PD. Our findings suggest that the early-onset form of PD seems to be more characterized by endogenous components compared to the adult-onset form. Copyright © 2002 by W.B. Saunders Company
P
PD with early-onset or with adult-onset. When examining premorbid clinical conditions with respect to the start of PD, the following features need to be considered: (1) familiarity for PD and/or familial comorbidity with other psychiatric disorders; (2) other axis I disorders whose onset preceded PD onset; and (3) premorbid personality disorders. Family studies on PD showed an increased risk (7.9% to 10.7%) among first-degree relatives of PD patients compared to relatives of healthy controls.19,20 Previous researches suggest a greater genetic loading for early-onset PD patients.12-15 Several studies have shown that PD is frequently preceded by another psychiatric condition, such as other anxiety disorders, mood disorders, and alcoholism.21-23 Concerning disorders usually first diagnosed in infancy, childhood, or adolescence, separation anxiety disorder has been frequently reported by adult PD patients, although the relationship between PD and separation anxiety disorder seems not to be specific since high comorbidity rates of separation anxiety in childhood have been found in most anxiety and/or mood disorders.24-26 Recently, Fones et al.27 found that attention deficit hyperactivity disorder may be an important clinical comorbidity in panic patients. Although different comorbidity patterns have been found in patient with early- versus late-onset PD, no study has focused on disorders with onset preceding PD onset. Several studies28-33 investigated the comorbidity between PD and personality disorders, evidencing wide ranges (between 35% and 95%). Although research on this topic has provided controversial
ANIC DISORDER (PD) is a common psychiatric condition with high lifetime prevalence rates in the general population (ranging from 1.4% to 3.8%) and with onset typically observed in late adolescence or early adulthood. Research examining the age of onset for PD have been consistent despite differing types of individuals being studied: both epidemiological1-6 and clinical7-9 investigations have reported the onset of PD in the midor late-20s in men and in women. Several recent studies10-15 also suggest that in a significant proportion of cases (10.2% to 28%) PD may begin in childhood or adolescence (early-onset PD). Some evidence exists that early-onset PD may represent a specific subtype of the disorder with respect to clinical presentation and premorbid clinical conditions. Clinical studies aimed to characterize an early-onset subtype of PD found a distinct phenomenology with higher rates of depersonalization symptoms,11,15-17 different pattern of comorbidity,10-11,13-15,18 more clinical severity,13 and higher suicide risk.10 The characterization of differences in premorbid clinical conditions and the role of triggering events in precipitating the onset of the disorder could further the hypothesis of two different subtypes of From the Department of Neurosciences, Psychiatry Section, University of Turin, Italy. Address reprint requests to Giuseppe Maina, M.D., Department of Neurosciences, Psychiatry Unit, University of Turin, Via Cherasco 11, 10126 Torino, Italy. Copyright © 2002 by W.B. Saunders Company 0010-440X/02/4301-0003$35.00/0 doi:10.1053/comp.2002.29844 28
Comprehensive Psychiatry, Vol. 43, No. 1 ( January/February), 2002: pp 28-36
EARLY-ONSET PANIC DISORDER
results, investigators generally agree that Cluster C personality disorders (dependent and avoidant) and Cluster B personality disorders (histrionic and borderline) were the most commonly diagnosed in PD patients. Concerning personality features in earlyonset PD patients, recently, Segui et al.15 observed a higher score in neuroticism on the Eysenck Personality Questionnaire-A (EPQ-A) among this group of patients, confirming previous reports.34 Considering the possible role of precipitating events in the onset of the PD, several studies referred that interpersonal conflicts, separation, and physical illness frequently occurred before the onset of PD.35-40 No study focused the attention on the differential role of triggering events in the onset of PD among early versus late-onset patients. The aim of the present study was to compare premorbid clinical conditions and the role of triggering events between patients with the early-onset form of the disorder and patients with the adultonset form. METHODS
Subjects Two hundred forty-one subjects were enrolled from patients consecutively referred to the Department of Neuroscience, Psychiatric Unit, University of Turin (Italy). All patients, aged over 18 years, had a principal diagnosis of PD according to DSM-IV diagnostic criteria. Exclusion criteria were current or previous diagnosis of schizophrenia or other psychotic disorders, and the presence of organic brain syndrome, mental retardation, and severe neurological or general medical conditions. In addition, to exclude patients with PD due to a general medical condition or associated with organic brain disorders, all subjects underwent thyroid tests, as well as an electrocardiogram, a chest x-ray, and a neurological examination. The average age of the sample was 37.2 years (⫾11.0 years), 61.4% were females, 62.2% were married, and the mean age at PD onset was 31.3 years (⫾11.0 years).
Interviews All patients gave their informed consent after the procedure had been fully explained. Axis I diagnoses of any current or longitudinal psychiatric disorder were assessed by using the Structured Clinical Interview for DSM-IV (SCID). The chronological relationship between PD and comorbid disorders was carefully explored: ages of onset of comorbid disorders were defined as the ages when all diagnostic criteria had been met and no attempt was made to establish chronological primacy when PD and a comorbid condition started in the same year: in such cases, the onset of both disorders was considered to be concomitant. When questions arose according to recall of historical information, patients were reapproached for further clarifications. Whenever possible, patient’s medical records were reviewed and information obtained from close family members and general practitioners.
29
Axis II diagnoses were also assessed according to the specific section of the SCID. Assessment with the SCID was guided by items previously affirmed by patients on the SCID-PQ, a selfrated instrument to generate DSM-IV personality disorders diagnoses. Items not affirmed on the SCID-PQ were assumed to be true negatives. However, if an interviewer had any reason to believe these were false negatives, further items were assessed. This method is in accordance with instructions for using the SCID, and enabled personality disorder symptomatology to be based on clinical contact combined with a structured clinical interview. Other data were collected for each subject by a semistructured interview that was constructed to cover the following areas. (1) Sociodemographic data: gender, age, education, and marital and occupational status. (2) Onset of PD: the history of the onset of the disorder was explored collecting data regarding age at first panic attack and age at onset of the disorder. Patients were asked to identify when their first panic attack occurred and to describe its symptoms to ensure that it met full-blown DSM-IV criteria for panic attack. Patients were also asked about prior situational anxiety or agoraphobic avoidance in the day, week, and month before the first panic to ensure that they were recalling their first-ever panic attack and not merely the one most vividly remembered or the one that immediately preceded avoidance. In the same way, patients were asked about events immediately following the first panic attack to evaluate subsequent panics and avoidance. Onset of illness was dated within a 1-month period when patients first experienced unexpected recurrent panic attacks at least one of which was followed by at least 4 weeks of persistent concern about having additional attacks, or worry about the implications of the attack or its consequences, or a significant change in behavior related to the attacks (DSM-IV). An attempt was made to date onset of PD to a 4-week period, but if there was uncertainty, a close relative of the patient was interviewed and a range was plotted and its mid-point was used in the analysis. (3) Life events: patients were asked whether they had experienced a stressful life event within the year prior to the onset and the raters had to decide whether the event would fit any of the 61 items on the list by Paykel et al.41 Each life event reported was carefully investigated to determine the exact time of occurrence. To facilitate accurate dating, a calendar for the investigated years was constructed and the individuals were asked to show their geographical, work, and school positions throughout that year and to recall any circumstances that might serve as anchor points. The weighted score connected with each event, obtained through a calibration study, was considered for this investigation. Moreover, a subject was considered to have experienced a severe event when any of the top 20 events on the Paykel’s list had occurred. On the basis of this procedure it was possible to obtain several normative measures of stress (number of subjects with at least one life event, and number of subjects with at least on severe or highly distressing event). (4) Family history of psychiatric disorders: family history of psychiatric disorders was obtained from all patients and
30
all first-degree relatives using the Family History Research Diagnostic Criteria interview (FH-RDC). A psychiatric diagnosis was assigned only if the identified family member had received treatment or had experienced symptoms sufficient to have met DSM-IV criteria for the disorder. Whenever possible, medical records were collected and examined. In addition, the following rating scales were included in the assessment of patients with PD: the Sheehan Clinician Rated Anxiety Scale (SCRAS),42 the Hamilton Anxiety Rating Scale (HAM-A),43 the 17-item Hamilton Depression Rating Scale (HAM-D),44 and the Global Assessment of Functioning Scale (GAF).
Interviewers and Raters All interviews were conducted in person by three investigators (G.M., G.B., and S.V.), each with at least 4 years of postgraduate clinical experience. They were also the original authors of the semistructured interview and devised the most appropriate interviewing techniques by discussing 10 cases of PD before the beginning of the study. Each patient was evaluated in two subsequent phases: (1) randomly by one of the three interviewers, by the SCID, and by a semistructured interview with a format that covered sociodemographic data, onset of PD, and family history. The same interviewer assessed the patient with the rating scales. (2) Randomly by one of the three interviewers (with the exclusion of the interviewer who had examined the subject previously) and blindly with respect to the first examination, by a semistructured interview to investigate the role of life events in the onset of the disorder. In conclusion, the same interviewer examined diagnosis, PD status, and demographic data and a different interviewer blindly examined life stress. Finally, data from the separate interviewers were reviewed with a senior psychiatrist (F.B.), and, if there were any events in proximity to PD onset, a final check with the respondents on the time order was made.
Inter-rater Reliability In the early phase of the study, inter-rater agreement between rater pairs on the diagnosis of PD and of comorbid psychiatric axis I and axis II disorders were ascertained; they were blindly conducted. For all evaluations, relevant clinical data were eventually submitted to the main investigator (F.B.) who, following an abbreviated face-to-face clinical interview, assigned consensus diagnoses. The inter-rater reliability of DSM-IV diagnoses was found to be good: the kappa coefficient was greater than 0.80 for the presence of any lifetime axis I disorder. To assess the reliability of axis II diagnoses, subjects were randomly selected to be reinterviewed with the SCID-II by an assessing clinician who previously had no contact with the patient and was blind to personality disorder diagnoses. Comparison of axis II diagnoses across raters showed good reliability. Test-retest reliability (n ⫽ 15) assessed by for the presence of any personality disorder was .75. Pearson’s correlation coefficient between rater pairs and intraclass coefficients demonstrated excellent agreement for the SCRAS of 10 PD patients assessed before the beginning of the study (P ⬍ .0001). In 10 depressed subjects, scores obtained by our raters of the HAM-D correlated above .90.
VENTURELLO ET AL
Statistical Analysis The PD sample was divided into two groups on the basis of age at PD onset: early-onset was fixed at 18 years of age or under, and adult-onset over 18 years. The choice of age 18 as a cut-off point was arbitrary, suggested by the threshold age of pediatric care in our country. The statistical tests used were Student’s t test for continuous variables, and chi-square test for categorical variables, applying Yates’correction or Fisher’s test where necessary. A P value less than .05 was considered statistically significant. The odds ratios (OR) were obtained by logistic regression, with a confidence interval of 95%. OR, which indicate the strength of association among comorbid psychiatric diagnoses in both groups, are statistically significant when the confidence intervals include 1.0.
RESULTS
Of the 241 patients with PD included in the data analysis, 44 (18.3%) displayed an early-onset disorder and 187 (81.7%) comprised the adult-onset group. Demographic and clinical characteristics of the PD sample according to age at onset are summarized in Table 1. Subjects with early-onset PD had also a lower index age with a higher single marital status and a lower rate of full-time employment. Considering the rating scales assessment, only the HAM-D was significantly different between the two subgroups of patients with the early-onset PD showing a higher mean total score. No particular difficulties were encountered in establishing age at onset of the disorder: only in eight patients (3.3%) was there uncertainty requiring that a close relative of the patient be interviewed. In these cases, a range was plotted and its mid-point was used in the analysis; the mean difference between the eight patients and their own relatives was 1.5 months with a maximum of 3 months. The uncertainty did not concern the 18year cut-off in any of these patients. Familial Comorbidity Family history for psychiatric disorders is reported in Table 2. Data were obtained from all 741 first-degree relatives: in 30.1% of cases, information was collected by direct interview of firstdegree relatives, while in the other 69.9% data were derived from patient interviews and medical records. There were no differences between the two groups in the number of first-degree relatives interviewed. More than one third of the whole sample (38.6%) had a first-degree relative with a
EARLY-ONSET PANIC DISORDER
31
Table 1. Sociodemographic and Clinical Characteristics of the Sample: Comparison Between Early-Onset and Adult-Onset PD Patients
Female, N (%) Actual age (yr) Educational level (yr) Marital status, N (%) Single Married Vidowed Separated Employed full-time, N (%) PD ⫹ agoraphobia, N (%) Age at onset (yr) Age at first panic attack Illness duration (yr) GAS SCRAS HAM-A HAM-D
Early-Onset (N ⫽ 44)
Adult-Onset PD (N ⫽ 197)
28 (63.6%) 28.2 ⫾ 14.3 11.2 ⫾ 3.3
120 (60.9%) 39.2 ⫾ 9.2 11.7 ⫾ 3.8
32 (72.7%) 12 (27.3%) 0 (0.0%) 0 (0.0%) 17 (38.6%) 27 (61.4%) 16.9 ⫾ 1.4 14.4 ⫾ 2.7 12.6 ⫾ 9.8 51.8 ⫾ 7.4 47.7 ⫾ 6.4 24.0 ⫾ 4.0 14.0 ⫾ 2.3
40 (20.3%) 138 (70.1%) 4 (2.0%) 15 (7.6%) 128 (65.0%) 136 (69.0%) 34.5 ⫾ 9.5 30.9 ⫾ 10.8 5.4 ⫾ 6.6 53.6 ⫾ 6.1 48.7 ⫾ 6.1 23.4 ⫾ 3.2 12.0 ⫾ 3.2
P Value
NS .002 NS .0001
.001 NS .0001 .0001 .001 NS NS NS .03
Abbreviations: GAS, Global Functioning Assessment Scale; SCRAS, Sheehan Clinician-Rated Assessment Scale; HAM-A, Hamilton Scale for Anxiety; HAM-D, Hamilton Scale for Depression; NS, not significant.
der and no differences emerged between the two subgroups of patients. A past history of anxiety disorders was more common in the early-onset patients. In particular, early-onset PD patients were more frequently associated with separation anxiety disorder. No mood disorders were diagnosed prior the onset of PD in the group of early-onset patients: 17.3% of adult-onset patients had at least one mood disorder preceding the onset of PD (9.1% major depression, 5.6% dysthymia, and 2.5% cyclothymia). No statistical analyses were performed because of the small numbers of patients affected. A positive history of bulimia nervosa (11.4%) and dysmorphophobia (9.1%) was observed only among early-onset patients; conversely, only adult-
diagnosis of psychiatric disorder and the percentage was significantly higher in the early-onset group. Significantly more early-onset patients had at least one first-degree relative with PD. Considering anxiety disorders, another significant difference appeared for social phobia that was only represented in the family history of the early-onset group (9.1%). Among mood disorders, major depression was significantly more common in the early-onset group and bipolar disorder was observed only in the same group of patients. Axis I Disorders Preceding PD Onset Data concerning axis I disorders with onset preceding PD onset are summarized in Table 3. Of the entire sample, 82.6% had at least one axis I disor-
Table 2. Family History: Comparison Between Early-Onset and Adult-Onset PD Patients Early-Onset PD (N ⫽ 44)
Adult-Onset PD (N ⫽ 197)
Diagnosis
No.
%
No.
%
P
At least one Social phobia Panic disorder Major depression Bipolar disorder Substance disorders
29 4 17 20 6 5
65.9 9.1 38.6 45.5 13.6 11.4
61 0 24 27 0 13
31.0 0 12.2 13.7 0 6.6
.0001 .001* .0001 .0001 .0001* NS
*Chi-square with Fisher correction.
32
VENTURELLO ET AL
Table 3. Axis I Disorders Preceding PD Onset: Comparison Between Early-Onset and Adult-Onset Patients Early-Onset PD (N ⫽ 44)
Adult-Onset PD (N ⫽ 197)
Statistics
Diagnosis
No.
%
No.
%
OR
CI
P
At least one Anxiety Separation anxiety Specific phobia Social phobia Obsessive-compulsive Generalized anxiety At least one
37
84.1
162
82.2
1.14
0.74-2.57
NS
25 27 1 9 3 31
56.8 61.4 2.3 20.5 6.8 70.5
23 64 16 19 30 120
11.7 32.5 8.1 9.6 15.2 60.9
9.95 3.3 0.26 2.41 0.40 1.5
1.32-11.2 0.84-3.4 0.07-4.34 0.61-3.48 0.21-2.22 0.59-2.44
⬍.01 NS NS NS NS NS
Abbreviations: OR, odds ratio; CI, confidence intervals.
onset patients had a positive history for substancerelated disorder (12.2%). Again, no statistical analyses were performed because of the small numbers of patients affected. Axis II Comorbid Disorders At least one axis II comorbid disorder was observed in 75.1% of the whole sample (Table 4) and the percentage of patients with at least one personality disorder was higher in the early-onset group. No significant differences were observed in patients with at least one Cluster A or B personality disorder. Cluster C significantly characterized the early-onset patients. Life Events Considering the role of stressful life events, the comparison between early-onset and adult-onset patients is summarized in Table 5. Patients in the adult-onset group reported a greater mean number of life events than patients in the early-onset group, and the number of patients who experienced at least one severe event was also higher. Moreover,
both the mean total score of all events and the single highest event mean score were higher in adult-onset patients; the adult-onset group was significantly associated with at least one severe event. Statistical analysis on the frequency of each event of Paykel’s list did not reveal any significant difference between the two subgroups of patients. DISCUSSION
The proportion of early-onset patients (18.3%) in our sample of PD subjects was in the range found in similar studies (10.2% to 28%). The width of the range may be explained by the differences in the age cut-off for early-onset selected (18, 20, 25 years).12-15 Segui et al.,15 with a similar age cut-off of 18 years, observed a lower proportion of earlyonset PD patients of 10.2%. Future research on this topic should refer to the same cut-off point to reduce the variability due to heterogeneous criteria of recruitment. Early-onset patients were more likely to be single, while adult-onset patients were more likely to be married and employed full-time; these findings
Table 4. Comorbidity With Personality Disorders: Comparison Between Early-Onset and Adult-Onset Patients Early-Onset PD (N ⫽ 44)
Adult-Onset PD (N ⫽ 197)
Statistics
Diagnosis
No.
%
No.
%
OR
CI
P
At least one Cluster A At least one Cluster B At least one Cluster C Avoidant Dependent Obsessive-compulsive At least one
40
90.9
141
71.6
3.97
0.60-5.33
NS
5
11.4
32
16.2
0.66
0.30-2.29
NS
7
15.9
60
30.5
0.43
0.29-1.67
NS
14 20 12 30
31.8 45.5 27.3 68.2
29 38 36 79
14.7 19.3 18.3 40.1
2.7 3.48 1.68 3.2
0.74-3.17 0.86-3.4 0.59-2.62 1.24-3.26
NS NS NS ⬍.01
EARLY-ONSET PANIC DISORDER
33
Table 5. Life-Events Occurring in the Year Prior to the Onset of PD According to Paykel’s Interview for Recent Life Events: Comparison Between Patients With Early- or Adult-Onset PDL
Events (mean ⫾ SD) Events Total score (all events) Single highest event Patients with One event at least, N (%) One severe event, N (%)
EO-PD (N ⫽ 44)
AO-PD (N ⫽ 197)
0.7 ⫾ 0.6 6.7 ⫾ 6.1 4.3 ⫾ 5.1
1.8 ⫾ 1.1 15.7 ⫾ 11.7 10.6 ⫾ 6.9
24 (54.5%) 2 (4.5%)
149 (75.6%) 96 (48.7%)
Statistics OR
CI
P
.05* .03* .05*
2.58 7.4
0.77-2.94 1.11-7.53
NS ⬍.01
*Student’s t test.
probably reflect the younger age at observation in the early-onset group. In accordance with previous reports,13,15 early-onset PD patients did not display more severe panic symptomatology, higher comorbidity rates with agoraphobia, or worse social functioning. We found higher scores on the HAM-D scale among early-onset patients; the possibility that the longer illness duration of this subgroup of patients could have been a risk factor for the development of depressive symptoms should be considered. A significantly greater proportion of early-onset than adult-onset patients have a history of at least one psychiatric disorder in first-degree relatives. The finding is in accordance with previous literature studies.12-15 Our data also provided evidence of higher rates of other anxiety disorders and of mood disorders among first-degree relatives of early-onset panic patients. In particular, our findings indicate an association of the early-onset form with a positive family history for social phobia, major depression, and bipolar disorder. The high rate of familial comorbidity between PD and mood disorders is well known; recently, several authors focused on the association between PD and bipolar disorder.45-47 MacKinnon et al.,45 evaluating the familial comorbidity of a sample of bipolar patients, hypothesized that PD could be a specific marker for a familial subtype of bipolar disorder. Our investigation suggests that this co-occurrence is significantly more frequent in patients with the early-onset form. The finding of high percentages of PD chronologically secondary to other axis I disorders is in accordance with the literature,21-22 but some differences emerged between early-onset and adult-onset disorders. Concerning disorders usually first
diagnosed in infancy, childhood, or adolescence, separation anxiety disorder was significantly associated with early-onset PD, while we did not found any case of attention deficit hyperactivity disorder in our sample. Furthermore, preceding specific phobia, agoraphobia, and obsessive-compulsive disorder seem to characterize early-onset patients, but the association was not statistically significant. The literature on comorbidity with anxiety disorders is controversial: Segui et al.15 observed a higher frequency of social phobia among earlyonset patients and Goldstein et al.13 found a higher frequency of obsessive-compulsive disorder in the same group. Moreover, in accordance with published data, phobic disorders, in particular specific phobia and agoraphobia, usually have been described to be more frequently associated with early-onset PD,11,18 although in our sample the actual comorbidity with agoraphobia did not reveal any differences between the two groups. Comorbid mood disorders with onset preceding PD were observed only in the adult-onset group. The lower frequency of mood disorders preceding PD among early-onset patients may partly reflect the age cut-off: age at onset of mood disorders is commonly described in early adulthood rather than in adolescence. This finding is in accordance with Segui et al.,15 but contrasts with other reports11; the different age cut-offs may partly explain this controversy. Early-onset patients have also been found to be characterized by higher percentages of body dysmorphic disorder and bulimia nervosa. All patients with comorbid bulimia nervosa were females. Bulik et al.48 found high rates of comorbid anxiety disorder in women with eating disorders (anorexia nervosa or bulimia nervosa). In most cases, anxiety
34
disorders preceded the current eating disorder, except for PD, which tends to develop after the onset of anorexia or bulimia. In contrast with the literature,10,15 our data on comorbid conditions with onset preceding PD onset showed more diagnoses of substance-related disorder among adult-onset patients. The high prevalence of personality disorders observed in our sample is in agreement with findings of several literature studies (range, 35% to 95%).28-33 Predictably, Cluster C personality disorders were the most prevalent in both goups of patients, followed by Cluster B personality disorders. Earlyonset PD patients had a significantly higher prevalence of at least one Cluster C personality disorder. Several authors15,34 have shown that early-onset PD is linked to higher levels of neuroticism. This suggests that PD shares a common underlying pathophysiology with the comorbid axis II disorders, which show greater prevalence in early-onset PD than in the late-onset PD, namely, Cluster C disorders. Segui et al.15 recently hypothesized that the early-onset form of the disorder derives from a common pathogenic factor rapresented by a temperamental dimension defined “behavioral inhibition.” This factor can lead to school phobia and overanxious disorder in childhood and to several anxiety disorders in adulthood, such as social phobia and PD. Among these children, several authors49-54 observed personality features (introversion, social inhibition, and response to novelty with silence and isolation and in adulthood little assertiveness, low self-esteem, and high interpersonal sensitivity) that are consistent with the characteristics of cluster C personality disorders (including avoidant, dependent, and obsessive-compulsive personality disorders) and that are frequently associated with anxiety disorders. Similarly, studies applying other assessment instruments, such as the EPQ-A, found that neuroticism, which is related to those personality characteristics as well as to anxiety, was higher in early-onset PD patients.15,34 Recently, Latas et al.46 observed in a sample of patients with panic disorder with agoraphobia that younger age at onset was associated with any Cluster B personality disorder, while the duration of the disorder was a significant predictor of any Cluster B and Cluster C personality disorder. This suggests
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that some of the Cluster B and Cluster C personality disorders may be a consequence of longlasting PD with agoraphobia. Since in our sample early-onset PD patients had a longer duration of the disorder, the possibility that higher rates of personality disorders may be a consequence of years of illness should to be considered. According to our data on life stress, the number of patients reporting at least one severe event, the mean number of events, and the mean weighted score were significantly higher among adult-onset patients. Our data have shown that the role of precipitating events in PD is significantly higher in the late-onset group; environmental factors are perhaps less relevant in the development of PD in early-onset patients. In conclusion, our data suggest that earlyonset and adult-onset patients with PD do not differ in the severity of the disorder or in the level of interference with their overall functioning. Some differences between the two subgroups of patients emerged when considering the premorbid clinical conditions. Early-onset patients have (1) higher familial rates of psychiatric disorders in general and for PD in particular; (2) a higher frequency of preceding separation anxiety disorder; and (3) higher comorbidity rates for the personality disorders of the “anxious-fearful” cluster. The presence of premorbid conditions for PD appears to increase the risk for an earlier onset of the disorder with a lower threshold for triggering events. The data that we found on life stress indicate that environmental factors play a minor role in the development and/or in precipitating the onset of early-onset PD that seems to be more characterized by “endogenous” components, referring to an anxious trait underlying and or predisposing to the disorder. Further psychobiological and genetic studies are needed to test this hypothesis. Our report had three major limitations. Our reliance on the retrospective recall of symptoms or events that occurred years before could be associated with under-reporting of the earlier symptoms or events or difficulty in precise recall of symptom onset or event occurrence. However, we collected corroborative histories from parents and medical records whenever possible. Second, one may question the accuracy of personality disorder diagnoses made on the basis of information derived from
EARLY-ONSET PANIC DISORDER
35
acutely anxious patients. Our raters were instructed to administer the SCID so that pathological behaviors would be assessed as present only when these behaviors were evident during periods of wellbeing. However, such subtle distinctions were not possible when patients were unable to think of a time when they were not anxious. Therefore, while we recognized that particular care must be exercised in assigning personality disorder diagnoses to
individuals currently affected by anxiety disorders, this study’s goal was to compare the prevalence of personality disorders in two acutely anxious groups of patients who showed equal symptoms of actual PD, but who differed in age at onset of their disorder. Third, our findings need to be replicated in larger samples that permit different statistical analyses.
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