Association Study between 5-HT1A Receptor Gene C(-1019)G Polymorphism and Panic Disorder in a Korean Population

Objective

Serotonergic dysfunction is quite evident in panic disorder. We investigated whether the C(-1019)G polymorphism of 5-HT1A receptor gene may play a role in the pathogenesis of panic disorder in a Korean population.

Methods

The 5-HT1A receptor genotype for the single nucleotide polymorphism (SNP) C(-1019)G was analyzed in 94 patients and 111 healthy controls. The severity of the patients'' symptoms was examined using the Spielberger State-Trait Anxiety Inventory (STAI), Panic Disorder Severity Scale (PDSS), Anxiety sensitivity index (ASI), Acute Panic Inventory (API) and Hamilton''s Rating Scale for Anxiety (HAM-A).

Results

The distribution of the genotypes of the C/G polymorphism did not differ significantly from those predicted by Hardy-Weinberg equilibrium in patients as well as the controls. No association between the C(-1019)G polymorphism and panic disorder was detected in either the allele frequency or genotype distribution. There was no significant association with genotype distribution in the panic disorder with agoraphobia. However, there was a significant difference of symptom severity between C/C, C/G, and G/G genotype or between C and G allele in panic disorder patients without agoraphobia. PDSS scores were significantly higher in subjects with the G/G genotype or with G allele in patients without agoraphobia, not in total patients or patients with agoraphobia.

Conclusion

Although there were no significant differences in the genotype and allele distributions, we found a significant association between panic symptom severity and the serotonin 1A receptor gene. This result suggests that the serotonin 1A receptor and serotonin may play a role in the pathogenesis of panic disorder.     

Panic Disorder Severity Scale: reliability and validity of the Turkish version

We assessed the reliability and validity of the Turkish version of the seven-item Panic Disorder Severity Scale (PDSS). We recruited 174 subjects, including 104 with current DSM-IV panic disorder with (n=76) or without(n=28)agoraphobia, 14 with a major depressive episode, 24 with a non-panic anxiety disorder, and 32 healthy controls. Assessment instruments were Panic Disorder Severity Scale, Panic and Agoraphobia Scale, both the observer-rated (P&Ao) and self-rating (P& Asr); Clinical Global Impression Scale (CGI); Hamilton Anxiety Scale, and Beck Depression Inventory. We repeated the measures for a group of panic disorder patients (n = 51) after 4 weeks to assess test-retest reliability. The internal consistency (Cronbach's alpha) of the PDSS was .92-94. The inter-rater correlation coefficient was .79. The test-retest correlation coefficient after 4 weeks was .63. In discriminant validity analyses, the highest correlation for PDSS was with P&Ao, P&Asr (r=.87 and.87, respectively) and CGI (r=.76) and the lowest with Beck Depression Inventory (r=.29). The cut-off point was six/seven, associated with high sensitivity (99%) and specificity (98%). This study confirmed the objectivity, reliability and validity of the Turkish version of the PDSS.     

Cross-cultural evaluation of the Panic Disorder Severity Scale in Japan

The Panic Disorder Severity Scale (PDSS) [Shear et al., 1997] is rapidly gaining world-wide acceptance as a standard global severity measure of panic disorder, however, its cross-cultural validity and reliability have not been reported yet. We developed the Japanese version of the PDSS and examined its factor structure, internal consistency and inter-rater reliability and concurrent validity among Japanese patients with panic disorder with or without agoraphobia. We also established rules of thumb for interpreting PDSS total scores, taking the Clinical Global Impression severity scale as the anchoring criterion. The identical one-factor structure of the PDSS was confirmed among the Japanese patients as among the United States patients. Both internal and inter-rater reliability was excellent (Cronbach's alpha was 0.86, and ANOVA ICCs were all above 0.90). Concurrent validity of the PDSS items with self-report questionnaires tapping similar or overlapping domains was satisfactory (Pearson correlation coefficients were mostly above 0.5). Using the anchor-based approach, the following interpretative guides are suggested: among those with established panic disorder diagnosis, PDSS total scores up to 10 correspond with "mild," those between 11 and 15 with "moderate," and those at or above 16 correspond with "severe" panic disorder. The present findings support the cross-cultural generalizability of panic disorder symptomatology and of the PDSS, in particular.     

Evidence‐based guidelines for interpretation of the Panic Disorder Severity Scale

Background: The Panic Disorder Severity Scale (PDSS) is promising to be a standard global rating scale for panic disorder. In order for a clinical scale to be useful, we need a guideline for interpreting its scores and their changes, and for defining clinical change points such as response and remission. Methods: We used individual patient data from two large randomized controlled trials of panic disorder (total n=568). Study participants were administered the PDSS and the Clinical Global Impression (CGI)—Severity and —Improvement. We applied equipercentile linking technique to draw correspondences between PDSS and CGI‐Severity, numeric changes in PDSS and CGI‐Improvement, and percent changes in PDSS and CGI‐Improvement. Results: The interpretation of the PDSS total score differed according to the presence or absence of agoraphobia. When the patients were not agoraphobic, score ranges 0–1 corresponded with “Normal,” 2–5 with “Borderline,” 6–9 with “Slightly ill,” 10–13 with “Moderately ill,” and 14 and above with “Markedly ill.” When the patients were agoraphobic, score ranges 3–7 meant “Borderline ill,” 8–10 “Slightly ill,” 11–15 “Moderately ill,” and 16 and above “Markedly ill.” The relationship between PDSS change and CGI‐Improvement was more linear when measured as percentile change than as numeric changes, and was indistinguishable for those with or without agoraphobia. The decrease by 75–100% was considered “Very much improved,” that by 40–74% “Much improved,” and that by 10–39% “Minimally improved.” Conclusion: We propose that “remission” of panic disorder be defined by PDSS scores of five or less and its “response” by 40% or greater reduction. Depression and Anxiety, 2009. © 2008 Wiley‐Liss, Inc.     

The Burden of Agoraphobia in Worsening Quality of Life in a Community Survey in Italy

ObjectiveCurrent nosology redefined agoraphobia as an autonomous diagnosis distinct from panic disorder. We investigated the lifetime prevalence of agoraphobia, its association with other mental disorders, and its impact on the health-related quality of life (HR-QoL). MethodsCommunity survey in 2,338 randomly selected adult subjects. Participants were interviewed with the Advanced Neuropsychiatric Tools and Assessment Schedule (ANTAS), administered by clinicians. The diagnoses were based on the ICD-10 criteria. The Short-Form Health Survey (SF-12) was used to quantify HR-QoL. ResultsIn the sample, 35 subjects met the criteria for agoraphobia (1.5%), with greater prevalence among women (2.0%) than men (0.9%): odds ratio (OR) 2.23; 95% CI: 1.0-5–2. Agoraphobia was more often seen among those with (n=26; 1.1%) than without (n=9; 0.4%) panic disorder: OR=8.3; 2.9–24.4. Co-morbidity with other mental disorders was substantial. The mean score of SF-12 in people with agoraphobia was 35.2±7.8, with similar levels of HR-QoL in people with (35.3±7.9) or without (34.8±7.3) panic disorder: ANOVA: F(1;33)=0.0; p=1.00. ConclusionOne out of seventy people may suffer from agoraphobia in their lifetime. The attributable burden in terms of HR-QoL is substantial and comparable to the one observed for chronic mental disorders such as major depression, post-traumatic stress disorder, or obsessive-compulsive disorder.     

Relationship between panic disorder and agoraphobia. A family study

A family study of patients with agoraphobia (n = 40), panic disorder (n = 40), and nonanxious controls (n = 20) showed that the morbidity risk for panic disorder was increased among the relatives of agoraphobics (8.3%) and the relatives of patients with panic disorder (17.3%). The morbidity risk for agoraphobia was also increased among the relatives of agoraphobics (11.6%) but not the relatives of panic disorder patients (1.9%). Male relatives of agoraphobics were shown to be at higher risk for alcohol disorders (30.8%). No greater risk for primary affective disorders was found among the relatives of agoraphobic or panic disorder patients or among the relatives of probands with secondary depression compared with relatives of probands without secondary depression. Probands and relatives with agoraphobia reported an earlier onset of illness, more persistent and disabling symptoms, more frequent complications, and a less favorable outcome than probands and relatives with panic disorder. The findings suggest that agoraphobia is a more severe variant of panic disorder. They also lend support to the separation between anxiety disorders and affective disorders.     

Psychiatric disorders in asthmatic outpatients

It has been reported that the lifetime prevalence of panic disorder in patients with pulmonary disease is higher than epidemiologic estimates of population prevalence. We evaluated the frequency of anxiety disorders in 86 subjects from the Outpatient Asthma Clinic. Psychiatric diagnoses were assessed with the Mini-International Neuropsychiatric Interview 4.4 Version (MINI). Forty-five asthmatic patients (52.3%) reported at least one current anxiety disorder. The frequency of panic disorder with or without agoraphobia was 13.9% (n=12) and that of agoraphobia without panic disorder was 26.8% (n=23). Social anxiety and generalized anxiety disorders occurred in 9.3% (n=8) and 24.4% (n=21) of the sample, respectively. Twenty-nine patients (33.7%) reported a major depressive episode. The psychiatric morbidity of the sample was 61.6% (n=53). Our results tend to support the high morbidity of anxiety disorders, particularly panic/agoraphobic spectrum disorders, in asthmatic outpatients.     

Heightened embarrassability discriminates between panic disorder patients with and without agoraphobia

Embarrassability refers to an individual's general susceptibility to becoming embarrassed and is closely linked to another personality characteristic known as fear of negative evaluation. To find out if panic disorder patients with and without agoraphobia differ in terms of embarrassability and fear of negative evaluation 100 patients with a DSM-III-R diagnosis of panic disorder with agoraphobia, 30 patients with a DSM-III-R diagnosis of uncomplicated panic disorder and 80 controls were administered the Embarrassability Scale and the 12-item version of the Fear of Negative Evaluation Scale. Depressive mood in the clinical group was assessed with the help of the Beck Depression Inventory. Comparisons between these three groups, between patients with mild, moderate, and severe phobic avoidance and between male and female subjects were carried out. Patients with agoraphobic avoidance showed significantly higher scores on both scales than patients with uncomplicated panic disorder and controls and women generally showed higher embarrassability scores than men. We conclude that heightened embarrassability is an important characteristic of patients suffering from panic disorder with agoraphobia.     

Thyroid hormones in panic disorder, panic disorder with agoraphobia, and generalized anxiety disorder

Fifty-two patients with generalized anxiety disorder who had symptoms persisting for at least 6 months, 41 patients suffering from either panic disorder (32 patients) or panic disorder with agoraphobia (9 patients), and 14 control subjects were screened for thyroid disease. Total serum thyroxine (TT4), serum-free thyroxine index (FT4I), and triiodothyronine resin uptake (T3RU), were examined for the entire sample, using a one-way analysis of variance (ANOVA). No significant differences were found in TT4 (p = .24), FT4I (p = .24), and T3RU (p = .19). Thyroid-stimulating hormone (TSH) was examined in a subsample of 10 patients with generalized anxiety disorder, 11 with panic disorder or panic disorder with agoraphobia, and 10 controls. One-way ANOVA again showed no significant differences, although there was a trend (p = .07). This is the first report that compares generalized anxiety disorder patients, panic disorder patients, and patients with panic disorder and agoraphobia with controls on measures of thyroid function. It is also the first to report normal values in the thyroid indices of generalized anxiety disorder patients.     

Onset of panic disorder.

The situations in which the first panic attack occurred were investigated in 44 patients affected by panic disorder. Although the first panic attack was reported to be unexpected and no avoidance was present before it, 75.8% of patients (N = 22) with panic disorder with agoraphobia had their first panic attack in phobogenic situations, compared with 20% of patients (N = 3) with panic disorder without agoraphobia.     

DSM-III-R Axis I and II disorders in agoraphobic patients with and without panic disorder

Patients attending an inpatient phobia treatment program were diagnosed for DSM-III-R Axis I and II disorders, using the Structured Clinical Interview for DSM-III-R Disorders, and completed a set of self-report instruments. They were divided into 3 groups: (a) those who met the criteria for panic disorder with agoraphobia (n= 57), (b) those who met the criteria for agoraphobia without a history of panic disorder (n= 21), and (c) those who met criteria for other anxiety disorders, but not for panic/agoraphobia (n= 14). On Axis I, more of the panic with agoraphobia than of the agoraphobia without panic patients had obsessive-compulsive disorder. On Axis II, no significant differences between the agoraphobic patients with and without panic occurred. However, the number of hysterical traits was related to the presence of panic disorder among the agoraphobic patients. Avoidant and dependent traits were related to symptom severity.     

Open‐Label Support for Duloxetine for the Treatment of Panic Disorder

Panic disorder with or without agoraphobia is a common, often chronic and refractory anxiety disorder. Although a number of pharmacotherapies are now indicated for panic disorder, many patients do not respond to available interventions. We hypothesized that duloxetine, a serotonin‐norepinephrine reuptake inhibitor (SNRI) that has greater initial noradrenergic effects than venlafaxine, would have broad efficacy for individuals with panic disorder. Fifteen individuals with panic disorder with or without agoraphobia received 8 weeks of open label duloxetine flexibly dosed from 60 to 120 mg per day. Duloxetine treatment resulted in significant anxiolysis as measured by the primary outcome measure, the Panic Disorder Severity Scale (PDSS) (paired t(df) = 4.02(14), P= 0.0013), as well as measures of generalized anxiety, depression and quality of life (all P < 0.05). Although definitive conclusions are limited due to its small open‐label nature, this first prospective study provides preliminary support for the efficacy of duloxetine for panic disorder and suggests larger randomized controlled study is warranted.     

Personality traits in early phases of panic disorder: implications on the presence of agoraphobia, clinical severity and short-term outcome

OBJECTIVE: To explore the relations between personality traits using the Big Five model and presence of agoraphobia, clinical severity and short-term outcome in an unbiased clinical sample of never-treated panic disorder patients. METHOD: Panic disorder (PD) patients (n = 103) in the first stages of their illness were evaluated using the Neuroticism-Extraversion-Openness Five Factor Inventory of Personality (NEO-FFI) and were compared with a sample of healthy subjects. Severity was assessed by the Panic Disorder Severity Scale and the Clinical Global Impression Scales. Patients were evaluated after 8 weeks of naturalistic pharmacologic treatment with Selective Serotonin Reuptake Inhibitors. RESULTS: Panic disorder patients show more neuroticism than healthy subjects. Patients suffering from agoraphobia are more introverted than controls. Extraversion, in addition to gender and distress, during panic attacks allows to correctly classifying 72% of the cases of agoraphobia. CONCLUSION: Low scores in extraversion contribute to explain the presence of agoraphobia in panic disorder. Personality traits are neither related to clinical severity nor to short-term response to pharmacological treatment.     

Correlates of DSM-III personality disorder in panic disorder and agoraphobia

One hundred eighty-seven patients meeting DSM-III criteria for panic disorder (n = 26) or agoraphobia with panic (n = 161) were assessed with the Personality Diagnostic Questionnaire (PDQ), a self-rating scale designed to assess Axis II personality disorders and traits. Results replicated our earlier findings of a preponderance of dependent, avoidant, and histrionic features and the finding that patients exhibiting a greater number of personality traits were also significantly more symptomatic. Patients with the diagnosis of panic disorder did not differ on any personality disorder variables from patients with the diagnosis of agoraphobia with panic. Furthermore, none of the specific symptom dimensions, i.e., panic, anxiety, or agoraphobia, was selected as a unique predictor of any personality variables in the regression analyses. Rather, the most important correlates of personality disorder in these patients consisted of general factors such as dysphoric mood, social phobia, or interpersonal sensitivity, and Eysenck's neuroticism dimension. The results are discussed in light of recent findings suggesting a nonspecific link between panic disorder or agoraphobia and personality disorder.     

Moderating effects of major depression on patterns of comorbidity in patients with panic disorder

Given the high rate of co-occurring major depression in patients with panic disorder, it is unclear whether patterns of comorbidity in individuals with panic disorder reported in the literature are associated with panic disorder or with the presence of major depression. Subjects were 231 adult subjects with panic disorder and major depression (n=102), panic disorder without comorbid major depression (n=29), major depression without comorbid panic disorder (n=39), and neither panic disorder nor major depression (n=61). Subjects were comprehensively assessed with structured diagnostic interviews that examined psychopathology across the life cycle. Panic disorder, independently of comorbidity with major depression, was significantly associated with comorbid separation anxiety disorder, simple phobia, obsessive-compulsive disorder, generalized anxiety disorder, and agoraphobia. Major depression, independently of comorbidity with panic disorder, was significantly associated with comorbidity with psychoactive substance use disorders and childhood disruptive behavior disorders. Overanxious disorder was associated with both panic disorder and major depression. Major depression has important moderating effects on patterns of comorbidity of panic disorder in referred adults.     

Platelet [3H]imipramine binding in generalized anxiety disorder, panic disorder, and agoraphobia with panic attacks

The density of platelet [3H]imipramine binding sites is reported to be decreased in unipolar depression and, hence, is a putative biological marker. There is considerable evidence for a phenomenological and biological relationship of panic disorder with affective disorder. We studied platelet [3H]imipramine binding site density in unmedicated subjects with generalized anxiety disorder (GAD; n = 55), panic disorder (PD) with and without agoraphobia (n = 52), and normal controls (n = 26) in order to determine whether or not patients with panic disorder differed from controls in this biological assay. We found no differences in binding site density (Bmax) or affinity (Kd) among the PD, PD with agoraphobia, GAD, and control groups. Nor did we find a relationship between Bmax or Kd and the severity of depressive symptoms or the presence of a family history of affective disorder. In view of two conflicting prior studies, the use of [3H]imipramine binding in panic disorder remains problematic.     

Comparing panic disorder uncomplicated and panic disorder with agoraphobia in cardiology patients with atypical or nonanginal chest pain

Thirty-eight cardiology patients with either atypical or nonanginal chest pain and current panic disorder were divided into two groups, those with agoraphobia (N = 8) and those without agoraphobia (N = 30). The agoraphobia group reported marginally longer duration of panic disorder (17.0 ± 21.1 years vs. 3.0 ± 3.2 years) and significantly more panic symptoms (10.6 ± 3 vs. 7.3 ± 2.2) during the last major attack. The agoraphobia group also scored significantly higher on measures of anxiety, depression, phobic avoidance, somatization, interpersonal sensitivity, and psychoticism and also scored higher on three of three global measures of distress. This agoraphobia group differed from previously reported agoraphobics with panic attacks in that they all had current panic disorder, while previously reported groups were categorized according to DSM-III, which required only a history of panic attacks. These findings suggest that patients who have current panic disorder and agoraphobia are more symptomatic. Of interest is the low proportion of agoraphobics compared to nonagoraphobics found in this panic disorder population.     

Panic disorder with and without agoraphobia: comorbidity within a half-year of the onset of panic disorder

The present study was performed to compare the clinical features of patients with panic disorder with and without agoraphobia. The subjects were 233 outpatients with panic disorder (99 males and 134 females) diagnosed according to DSM-IV criteria. Sixty-three patients met the criteria for panic disorder without agoraphobia, and 170 met the criteria for panic disorder with agoraphobia. Patients with agoraphobia showed a significantly longer duration of panic disorder and higher prevalence of generalized anxiety disorder. However, there were no significant differences in prevalence of major depressive episodes, in current severity of panic attacks, or in gender ratio between the two groups. The second aim of the present study was to investigate the effects of onset age and sex differences on the development of agoraphobia within a half-year. The subjects were divided into two groups according to their self-report: patients who did or did not develop agoraphobia within 24 weeks of onset of panic disorder. A total of 40.6% of the patients developed agoraphobia within 24 weeks of the onset of panic disorder, and onset age and sex differences had no robust effect on the development of agoraphobia within 24 weeks.     

Long-term treatment of panic disorder with agoraphobia in private practice

The author followed 67 patients with panic disorder with agoraphobia (PDA) for a minimum of 5 years in a private practice setting. They were treated with a combination of pharmacotherapy (antidepressants or benzodiazepines) and cognitive-behavioral psychotherapy. The author examines outcomes for three groups: A) 11 male patients, 10 of whom had comorbid conditions; B) 21 female patients with comorbid conditions; and C) 35 female patients without comorbid conditions. Symptom severity was assessed using the Panic Disorder Severity Scale (PDSS). Patients in all groups showed marked improvement in all the domains measured by the PDSS, with the greatest improvement in PDSS scores occurring during the first year in all three groups. Patients in groups A and B tended to plateau after 5 years of treatment and show no additional improvement thereafter, whereas patients in group C (women with "pure PDA") continued to improve, although at a gradually slower rate. However, after an average of 11 years of treatment, the majority of patients remained symptomatic. The presence of comorbid alcohol abuse or depression was associated with poorer outcomes. The results in this effectiveness study are generally not as good as the outcomes of published PDA follow-up efficacy studies, but appear to be superior to outcomes in cohorts of chronically anxious patients treated decades ago.     

The relationships among separation anxiety disorder,adult attachment style and agoraphobia in patients with panic disorder

Epidemiological studies indicate that separation anxiety disorder occurs more frequently in adults than children. It is unclear whether the presence of adult separation anxiety disorder (ASAD) is a manifestation of anxious attachment, or a form of agoraphobia, or a specific condition with clinically significant consequences. We conducted a study to examine these questions. A sample of 141 adult outpatients with panic disorder participated in the study. Participants completed standardized measures of separation anxiety, attachment style, agoraphobia, panic disorder severity and quality of life. Patients with ASAD (49.5% of our sample) had greater panic symptom severity and more impairment in quality of life than those without separation anxiety. We found a greater rate of symptoms suggestive of anxious attachment among panic patients with ASAD compared to those without ASAD. However, the relationship between ASAD and attachment style is not strong, and adult ASAD occurs in some patients who report secure attachment style. Similarly, there is little evidence for the idea that separation anxiety disorder is a form of agoraphobia. Factor analysis shows clear differentiation of agoraphobic and separation anxiety symptoms. Our data corroborate the notion that ASAD is a distinct condition associated with impairment in quality of life and needs to be better recognized and treated in patients with panic disorder.