Avoidance behaviour: A predictor of the efficacy of pharmacotherapy in panic disorder?

Summary The impact of the avoidance behaviour on the psychopharmacological treatment of panic disorder was explored in the Cross National Collaborative Panic Study (n=1134 patients); in this double blind randomized trial alprazolam, imipramine and placebo were compared during an 8-week treatment period. Patients with extensive avoidance behaviour (agoraphobia) had the most profit from the active drugs. Counter expectancy these specific drug effects were most pronounced in avoidance behaviour. Active drugs (in particular imipramine) were especially more effective than placebo if the patients presented with associated avoidance behaviour. The results suggest that agoraphobia defines more a particular type of anxiety disorder overlapping with panic disorder than merely a severe state of panic disorder.     

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.     

Major depression and agoraphobia in patients with angiographically normal coronary arteries and panic disorder

Patients with panic disorder and/or agoraphobia appearing in psychiatric settings report rates for lifetime major depression between 24% and 91%. Between 40% and 90% of patients with panic disorder in psychiatric populations report concomitant agoraphobia. A recent study of panic disorder subjects appearing in an outpatient cardiology clinic confirmed the strong link between panic and depression but found only a weak association between panic disorder and agoraphobia. In order to test the reliability of these outpatient cardiology findings, the authors studied major depression and agoraphobia in patients with angiographically normal coronary arteries and panic disorder. Twelve of the 32 (37.5%) panic disorder subjects reported a lifetime history of major depression (nine current, three past only). Only two of the 32 (six percent) reported any phobic avoidance. This study confirms the previous findings which suggest that major depression is common in cardiology populations with panic disorder and that phobic avoidance is uncommon in this group.     

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.     

Differential drug response of panic and agoraphobic avoidance in a case of panic disorder

A case is presented of a patient with severe panic disorder and agoraphobia in whom initial treatment with clomipramine resulted in complete elimination of panic attacks, with no improvement in agoraphobic avoidance. The addition of phenelzine to the pre-existing clomipramine treatment resulted in rapid and complete disappearance of the agoraphobic avoidance. The possible implications of this case for our understanding of the neurobiological relationship between panic attacks and agoraphobia are discussed.     

An examination of syndromal validity and diagnostic subtypes in social phobia and panic disorder.

BACKGROUND: We investigated whether patients with DSM-III-R panic disorder and patients with social phobia could be distinguished on the basis of selected demographic variables and by several commonly used anxiety and phobia rating scales. METHOD: Sixty-six patients with social phobia and 60 patients with panic disorder (42 with and 18 without agoraphobia) were studied. Subjects completed a battery of self-report measures that assessed phobic fears, avoidance, and related problems. RESULTS: Social phobic patients showed an earlier age at onset than the panic disorder group, and there was a trend for more social phobics to have never married. Social phobics reported significantly greater levels of social phobic avoidance and distress, fear of negative evaluation, and avoidance of social situations than the panic disorder patients who reported more overall anxiety and rated themselves as significantly more avoidant of situations involving exposure to public places and to blood or injury. Discriminant function analyses showed that social phobic and panic disorder patients can be reliably discriminated on these scales. CONCLUSION: The results of this study lend further support for the validity of the DSM-III-R nosologic distinctions between social phobia and panic disorder. Furthermore, generalized social phobia appears to be remarkably different from discrete social phobia on these measures. This study provides less support for considering panic disorder with agoraphobia to be distinct from panic disorder without agoraphobia.     

Cortisol and sodium lactate-induced panic

Sodium lactate infusions induce panic attacks in patients with panic disorder, but not in normal controls, by an unknown mechanism. We studied the plasma cortisol response to infusion of 0.5 mol/L of sodium lactate in 103 patients with panic disorder or agoraphobia with panic attacks, and 32 normal controls. Baseline cortisol levels did not distinguish early panickers from non-panickers and controls, but late panickers had significantly elevated baseline cortisol levels. In addition, a higher percentage of late panickers manifested an increase in cortisol during the baseline period compared with the other groups. Despite the fact that late panickers manifested elevated baseline cortisol levels, early panickers had significantly greater somatic distress as measured by the Acute Panic inventory. There was no increase in cortisol with lactate-induced panic, and cortisol levels fell significantly during the lactate infusion in all groups. Cortisol elevation occurred with moderate anxiety but not with severe panic anxiety. These results suggest different pathophysiologic mechanisms of early and late panic, and differences between anticipatory anxiety and panic anxiety.     

Alprazolam plasma concentrations and treatment response in panic disorder and agoraphobia.

OBJECTIVE: The authors' goal was to evaluate the relationship between plasma concentrations of alprazolam and both treatment response and side effects in patients with panic disorder and agoraphobia. METHOD: Ninety-six patients with panic disorder and agoraphobia were treated at three sites in a 6-week, fixed-dose, double-blind, placebo-controlled, dose-response study of 2 mg/day or 6 mg/day of alprazolam. Assessments were made of panic attacks, avoidance behavior, generalized anxiety, and global response. Blood samples were collected throughout the study and analyzed for alprazolam and other benzodiazepines. RESULTS: Patient compliance with the protocol was judged to be good on the basis of plasma concentrations. According to logistic regression analysis, the relationships between plasma alprazolam concentration and response, as reflected by number of panic attacks reported, phobia ratings, physicians' and patients' ratings of global improvement, and the emergence of side effects, were significant. However, there was no significant relationship between plasma alprazolam concentration and the degree of generalized anxiety symptoms. CONCLUSIONS: The authors conclude that plasma concentration of alprazolam is related to treatment response, particularly in panic attacks. The alprazolam concentration associated with treatment response or with emergence of a given side effect varied widely among individuals, highlighting the necessity for individualized dose adjustment to obtain optimal treatment response while minimizing side effects.     

Assessing the clinical utility of agoraphobia in the context of panic disorder

In the DSM-IV, a panic disorder (PD) diagnosis includes specification of agoraphobia, which is primarily an index of situational avoidance due to fear of panic. No other anxiety diagnosis requires specification of level of avoidance. This raises the question as to whether agoraphobia provides unique information beyond the core features of PD (i.e., panic attacks and panic-related worry). The incremental validity of agoraphobia, defined using DSM-IV specifiers versus level of situational avoidance, was examined in relation to the expression and treatment of PD (N=146). Analyses indicate that agoraphobia status adds uniquely to the prediction of PD symptoms, impairment, and response to treatment. However, level of situational avoidance, defined either as a continuous or dichotomous variable, appears to have greater utility compared to the DSM-IV method of classifying agoraphobia. In summary, the agoraphobia specifier seems to have clinical utility but this could be improved by focusing on a dimensional assessment of situational avoidance.     

Examining determinants of early and late age at onset in panic disorder: An admixture analysis

Past research demonstrated that age at onset might account for different clinical and etiological characteristics in panic disorder (PD). However, prior research relied on arbitrary choices of age cut-offs. Using a data-driven validated method, this study aimed to examine differences between early and late onset PD in various determinants. Admixture analysis was used to determine the best fitting model of age at onset distribution in PD. Data was collected from 511 individuals (ages 18–65) with PD diagnoses, who participated in the Netherlands Study of Depression and Anxiety (NESDA). DSM-IV comorbidities and various measures of childhood adversities, suicidal behavior, anxiety and depressive symptoms were assessed. The best fitting cut-off score between early and late age at onset groups was 27 years (early age at onset ≤ 27 years). Univariate tests showed that participants with early onset PD were younger and more likely to be female. Early onset PD was associated with agoraphobia, higher frequency of childhood trauma and life events, and higher rates of suicide attempts as compared to late onset PD. Multivariate logistic regression analysis demonstrated that only current age, childhood trauma and agoraphobia remained significantly associated with early onset PD. Findings suggest that 27 years marks two onset groups in PD, which are slightly distinct. Early onset PD is independently associated with exposure to childhood trauma and increased avoidance. This highlights the importance of subtyping age of onset in PD. Clinical implications are further discussed.     

Age at onset, precipitating events, sex distribution, and co-occurrence of anxiety disorders.

178 outpatients were administered to a structured interview evaluating diagnostic, illness history, and sociodemographic data of DSM-III-R anxiety disorders. Patients with panic disorder with agoraphobia were a more severely ill subgroup than patients with panic disorder without agoraphobia. Simple and social phobia had the earliest age at onset, panic disorder the latest age at onset. Conjugal stress was the most frequent event preceding the onset of the anxiety disorders. Female patients showed more severe impairment suffering more frequently from concomitant phobic avoidance, generalized anxiety, and depression compared to male patients.     

Relationship and chronology of depression, agoraphobia, and panic disorder in the general population

The comorbidity of disorders and chronology of first symptoms of depression, agoraphobia, and panic disorder were investigated. The Diagnostic Interview Schedule was administered to 3258 household residents. Strong associations were shown among all three disorders. However, the comorbidity of agoraphobia and panic disorder seemed to be accounted for by the relationship of both disorders with depression. The mean age at appearance of first symptoms was earlier for agoraphobia (low teens) than for depression or panic disorder (both about age 20). The results do not support the view that panic disorder is an integral component of agoraphobia, but rather that it is more closely associated with depression. The fact that agoraphobia precedes depression casts doubt on the thesis that depression is primary to anxiety disorders. Interpretation should, however, be viewed with caution because of the retrospective nature of the diagnostic instrument.     

Frequency of panic as an outcome measure in agoraphobia research: Latent effects of exposure on panic

The frequency of panic attacks during treatment of patients with panic disorder and agoraphobia was studied with an event sampling method. Treatment comprised panic management techniques followed by exposure in vivo. Results revealed that the frequency of panic attacks varied considerably across patients. There was a group of patients that responded to treatment with a decrease in both panic attacks and avoidance. Another group of patients, however, experienced little panic in the initial phase of treatment, but during the exposure phase they evidenced an increase in the frequency of panic attacks along with a decrease in avoidance. Consequently, merely focusing on panic frequency could lead to considering some patients as treatment failures, while in fact they did respond to the treatment. Recommendations for the use of panic attack frequency as an outcome measure in the evaluation of treatment for panic disorder with agoraphobia are discussed.     

A cluster analysis of early onset in common anxiety disorders

Early onset is regarded as an important characteristic of anxiety disorders, associated with higher severity. However, previous findings diverge, as definitions of early onset vary and are often unsubstantiated. We objectively defined early onset in social phobia, panic disorder, agoraphobia, and generalised anxiety disorder, using cluster analysis with data gathered in the general population. Resulting cut-off ages for early onset were ≤22 (social phobia), ≤31 (panic disorder), ≤21 (agoraphobia), and ≤27 (generalised anxiety disorder). Comparison of psychiatric comorbidity and general wellbeing between subjects with early and late onset in the general population and an outpatient cohort, demonstrated that among outpatients anxiety comorbidity was more common in early onset agoraphobia, but also that anxiety- as well as mood comorbidity were more common in late onset social phobia. A major limitation was the retrospective assessment of onset. Our results encourage future studies into correlates of early onset of psychiatric disorders.     

Dsm-iv panic attacks and panic disorder in a community sample of adolescents and young adults: how specific are panic attacks?

The study investigates the lifetime and 12-month prevalence, symptoms, age of onset and comorbidity patterns of DSM-IV panic attacks and panic disorder in a community sample of 3021 adolescents and young adults aged 14–24 years. Findings are based on DSM-IV symptoms and diagnoses assessed by interviews using a computerised, extended version of the Munich Composite International Diagnostic Interview (M-CIDI). Lifetime prevalence of DSM-IV panic disorder among 14–24 year-olds was 1.6% (0.8% with and 0.8% without agoraphobia). Panic symptoms were found to be quite frequent (13.1%) in the community, with lifetime prevalence of DSM-IV panic attack at 4.3% (12-month prevalence, 2.7%), with first onset rarely before puberty. Women were considerably more likely to have panic disorder and to have an earlier age of onset than males. Occurrence of DSM-IV panic attacks was strongly related to the subsequent development of various forms of mental disorders—not only panic disorder and agoraphobia. The conditional probability in those with panic attacks to develop other forms of mental disorders was 63% in males and 40% in females. Particularly late onset panic attacks (after the age of 18 years) are associated strongly with the development of multimorbidity of mental disorders. This suggests that panic attacks are generally highly indicative for more severe psychopathology and not only for panic disorder and agoraphobia.     

The diagnosis and management of panic disorder

The diagnosis of panic disorder without agoraphobia can very often be quite difficult because of the similarity with physical disorders particularly in the cardiac, gastrointestinal or neurological systems. The distinction must be made between panic attacks appearing as medical problems and medical problems appearing as panic attacks. Sometimes the diagnosis of panic attacks is made only after the medical diagnoses have been excluded. Panic disorder with agoraphobia however is much easier to detect if one carefully traces the historical development of agoraphobia and carefully distinguishes between the anxiety produced by agoraphobia and the panic attacks related to panic disorder. Panic disorder must also be distinguished from other anxiety disorders since the treatment for panic disorder still is quite specific. Once diagnosed however, the treatment of panic disorder without agoraphobia is rather simple. It involves the use of a benzodiazepine, either alprazolam or clonazopam, and perhaps the concomitant use of either imipramine or phenelzine sulfate for the rapid control of anxiety symptoms and continued treatment of the disorder. It is also very helpful to have the patient in psychotherapy either using a supportive or cognitive approach. If the patient has a panic disorder with agoraphobia, the pharmacological approach is the same, with the initiation of treatment using either alprazolam or clonazopam, but the psychotherapeutic approach is somewhat different in that behavioral therapy is emphasized rather than purely supportive or cognitive approaches. Given the fact that 1%-2% of the population is at risk for panic disorder, it is important that the condition be rapidly recognized and treated effectively since the currently available modalities of treatment result in almost total resolution of symptoms. Some individuals will remain on medication for several years while others will find it possible to decrease and/or discontinue their medications after only a few months or a few years. There is little excuse at this point for this disorder to be ineffectively diagnosed or treated.     

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.     

Subtyping panic disorder by major depression and avoidance behaviour and the response to active treatment

Summary In order to establish the clinical validity of currently used ways of subtyping panic disorder the predictive power of associated current avoidance behaviour and (secondary) major depression for the response to active treatment (alprazolam, imipramine) was tested. The analysis was based on the data from the Cross-National-Collaborative-Panic-Study. Limited support for validity evidenced by predicting drug response was found for grading panic disorder by the severity of avoidance behaviour: patients with panic attacks and agoraphobia are more responsive to imipramine (compared with alprazolam) when using the reduction of the total number of panic attacks (or of spontaneous panic attacks) as the outcome criterion; patients without any avoidance behaviour did better with alprazolam (compared with imipramine).     

Early improvement predicts endpoint remission status in sertraline and placebo treatments of panic disorder

The early identification of likely remitters and non-remitters to pharmacotherapy for panic disorder may have important implications for clinical treatment decisions. To address this question, combined data from two fixed-dose and two flexible dose placebo-controlled studies of sertraline treatment of panic disorder were examined. Patients (N=544) diagnosed with panic disorder, with or without agoraphobia, were treated with 50 mg of sertraline, 100 mg of sertraline, flexible dosages of sertraline, or placebo. Measures of early improvement included panic attack frequency (full + limited symptom attacks), anticipatory anxiety, the Hamilton Anxiety Rating Scale (HAM-A), and the Clinical Global Impression Improvement (CGI-I) Scale. Improvement as reflected in CGI-I ratings and change from baseline in the HAM-A at weeks 1, 2, and 3 significantly (P<0.0001) predicted endpoint clinical remission (defined at endpoint as no full panic attacks and a CGI-Severity rating of 1 or 2). Improvements in panic attack frequency and anticipatory anxiety were not consistent predictors in multivariate predictive models. Receiver-Operator Curve analyses revealed good specificity (0.83) for change in CGI-I at week 2, and good sensitivity (0.82) for change in HAM-A at week 3. Predictive success for HAM-A and CGI-I was not significantly different for fixed vs. flexible dose sertraline treatment, nor for sertraline vs. placebo treatment. The use of ROC analyses for examination of early response as a predictor of final remission holds promise for aiding clinicians in decision making regarding the need for alternative or supplemental treatment approaches during the course of pharmacotherapy for panic disorder.     

Prodromal symptoms in panic disorder with agoraphobia

Of 20 patients suffering from panic disorder with agoraphobia, 18 reported experiencing agoraphobic avoidance, generalized anxiety, and/or hypochondriacal fears and beliefs before the first panic attack. The prevalence of these symptoms in the patients was significantly higher than the prevalence in 20 healthy control subjects. The results indicate that phobic avoidance in panic disorder with agoraphobia may not be secondary to the panic attacks, a finding that runs counter to the current DSM-III-R classification of anxiety disorders.