The Longitudinal Course and Outcome of Panic Disorder

ANXIETY DISORDERS: LONGITUDINAL COURSE AND TREATMENT

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THE LONGITUDINAL COURSE AND OUTCOME OF PANIC DISORDER Mark H. Pollack, MD, and Jordan W. Smoller, MD

During the last two decades, there has been burgeoning interest in longitudinal aspects of panic disorder. Information about the long-term course and treatment outcome of panic disorder is of critical clinical and research importance. Patients and clinicians need to understand the possible course of illness including likely acute and long-term response to treatment, and the expected likelihood of sustained recovery or relapse during treatment and with treatment discontinuation. Information about the longitudinal course of illness is also helpful in defining patients at risk for acute and long-term difficulties, in examining differential response of patient subtypes to therapeutic interventions, and in determining whether treatment confers added benefit or adversely affects normative recovery. A DEVELOPMENTAL MODEL OF PANIC DISORDER

Converging lines of evidence suggest that panic and other anxiety disorders in adulthood may represent one manifestation of an underlying constitutional vulnerability or diathesis for anxiety that is familial and probably genetic, and variably expressed over the life-cycle. The assertion that many of the anxiety disorders are familial and likely have a genetic basis is supported by family and twin studies of panic disorder,19• 90 generalized anxiety disorder,34 and social and simple

From the Anxiety Disorders Program, Massachusetts General Hospital; and Harvard Medical School, Boston, Massachusetts

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phobia. 24 • 35 Further evidence comes from studies demonstrating elevated rates of anxiety disorders in the children of adult patients with anxiety disorders 8• 95 and the parents of children with anxiety disorders,2 6• 37 which are consistent with the notion of a relationship between childhood and adult illness. Whether the familial transmission is for a specific disorder or a general predisposition to pathologic anxiety remains an unresolved issue. Temperament and the Development of Pathologic Anxiety

Primate models offer a unique opportunity to explore the relative and interactive contributions of genetics and environmental factors on the development and persistence of pathologic anxiety. Suomi87 identified a temperamentally fearful and hyper-reactive subgroup of Rhesus monkeys who produce similarly affected offspring, suggesting a heritable vulnerability to anxiety. Primates reared under conditions of relative separation and insecurity manifest persistent anxiety 17• 81 ; adverse developmental experience during infancy may have long-term effects on central noradrenergic and serotonergic systems and may determine subsequent susceptibility to anxiety and affective disorders and pharmacologic responsivity. 82 These animal models support the idea that both genetic factors and early experience influence the development of anxiety disorders. A parallel line of investigation has examined the presentation and course of behaviorally inhibited temperament in children, including a population at risk, the offspring of adult anxiety patients. 28 • 80 Behavioral inhibition (BI) to the unfamiliar is a laboratory-based temperamental construct characterized by irritability and colic in infancy followed by shyness, fearfulness, and the tendency to constrict behavior in novel or unfamiliar situations during childhood. 29 Inhibited children have higher rates of anxiety disorders, and these rates increase with age, suggesting an underlying anxiety diathesis with progressively increasing expression through time.11 Children with BI also have higher rates of nonanxiety disorders than do children without BI.79 Children of parents with anxiety disorders are more likely to manifest behavioral inhibition. 8° Conversely, the parents of BI children have increased rates of childhood and adult anxiety disorders (particularly panic disorder and social phobia), providing further evidence that BI in children is linked to a familial predisposition to anxiety disorder. 79 Not all BI children remain behaviorally inhibited through time, 27 however, and 70% of BI children are free of anxiety disorders, 12 suggesting that other factors may influence the emergence of pathologic anxiety through time. The primate work cited earlier17• 81 • 87 points to the potential importance of early developmental experiences in shaping neural substrates and presentation of symptomatology through time in individuals genetically predisposed to anxiety. BI may, thus, reflect a general predisposi-

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tion to anxiety, whereas a number of genetic, familial, psychosocial, and psychological factors determine whether an individual will go on to develop pathologic anxiety. Retrospective Reports of Childhood Anxiety by Adult Panic Patients

Retrospective reports by adult anxiety patients also support a link between childhood and adult psychopathologic conditions. Between 20% and 40% of patients with panic disorder experience their first panic attack before the age of 20 years 13• 88 • 94 and 7% to 11% before the age of 10 years.ss. 94 Early reports that suggested a specific link between separation anxiety in childhood and adult panic disorder 36 have been broadened to include a more general link between pathologic anxiety during child and adulthood. 2 • 8• 9 • 64 There is relatively limited information on how a childhood history of anxiety may affect the course of anxiety disorders in adults. Berg8 observed that agoraphobic women with a childhood history of school phobia had an earlier age of onset of agoraphobia, had more severe symptoms, and had more school-phobic children than those mothers without school phobia. Perugi et al67 and Ayuso et al4 also reported that panic disorder and phobic avoidance occurred at an earlier age in adults with a history of childhood separation anxiety or school phobia. In the ongoing Massachusetts General Hospital Longitudinal Study of Panic Disorder, Pollack et aF2• 73 reported that about 54% of adult panic patients reported at least one anxiety disorder during childhood. A history of separation anxiety, overanxious disorder, social phobia, or avoidant disorder during childhood was associated with increased rates of comorbid adult anxiety disorders, apparent Axis II pathologic conditions, and anxiety sensitivity. All of these factors were associated with a more chronic course of panic disorder in adulthood. Sixty-eight percent of patients with a comorbid anxiety disorder had a history of childhood anxiety. For many of these patients, the adult disorders appeared to be manifestations of persistent childhood difficulties: 61 % of patients with childhood social phobia were socially phobic as adults; overanxious disorder in childhood was associated with elevated rates of generalized anxiety disorder (35%) and social phobia (58%) in the adult patients. 64 Patients with childhood anxiety were more agoraphobic as adults, suggesting that early anxiety experiences may contribute to patterns of avoidance maintained through adulthood. Preliminary results from this study examining the longitudinal course of naturalistically treated panic patients suggest that a history of childhood anxiety disorders does not exert independently a significant negative effect on the likelihood of or duration of remission. Childhood pathologic anxiety, however, does appear linked with increased agoraphobic avoidance and comorbidity, which are critical determinants of chronicity.74 One implication of this link is that early intervention efforts

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in anxiety-disordered children directed at the reduction of avoidance and prevention of comorbidity may improve the course of anxiety in adulthood. Overall then, evidence is growing for the hypothesis that some individuals with panic disorder have an underlying anxiety diathesis, which often is first expressed in childhood. Of adult patients with panic disorder, these individuals may be at greatest risk for comorbid disorders, phobic avoidance, and a chronic and severe course of illness during adulthood. FOLLOW-UP STUDIES OF PHARMACOTHERAPY FOR PANIC DISORDER If panic disorder is a manifestation of a lifelong anxiety diathesis, then we would expect to see continued symptomatology in many patients treated through time, and high rates of relapse when treatment is discontinued. Studies addressing the long-term outcome of patients treated with pharmacotherapy support this hypothesis.68 Despite the advances in the pharmacologic treatment of panic disorder during the past three decades, studies suggest that many patients, although improved, remain symptomatic despite treatment. A comprehensive review of studies on the long-term outcome of panic disorder recently was completed by Roy-Byrne and Cowley.84 In these studies, the efficacy of interventions for panic disorder depended on the outcome measure being assessed. For example, reported panicfree rates for patients 6 months to 7 years after treatment initiation range from 30% to 80%.*. Response rates fall, however, when other outcome domains are assessed, including phobic anxiety and avoidance, generalized anxiety, functional impairment, and global status. Resolution of phobic avoidance occurs in 18% to 64% of patients, with lower rates reported when remission in both phobic anxiety and avoidance is assessed. Remission in functional impairment was reported in 33% to 61 % of patients. Follow-up studies of pharmacotherapy with antidepressants or high-potency benzodiazepines (HPBs) are consistent with the notion that panic disorder is a chronic illness. Noyes and colleagues60 reported on 107 patients with panic disorder treated with tricyclic antidepressants (TCAs) and followed up at a mean of 2.5 years (range 1-4 years). Almost two thirds of patients were on medication at follow-up at a mean dose of 109 mg/ d of imipramine or its equivalent. Although three-quarters of patients reported at least moderate improvement, only 14% were free of symptoms. Although discontinuation-related difficulties more typically have been associated with benzodiazepine therapy, more than half of patients who experienced at least moderate improvement during TCA treatment and who attempted to discontinue treatment relapsed, *References l, 7, 18, 21, 33, 39, 42, 44, 54-57, 61, 76, 93.

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usually within the first 2 months following discontinuation. Only a quarter of patients discontinuing antidepressant treatment sustained remission for 2 years or longer. Rickels et al,77 reporting on patients in naturalistic follow-up after participation in an 8-month, placebo-controlled trial of alprazolam and imipramine for panic disorder, noted that about half the patients continued to receive pharmacotherapy. Initial treatment assignment to alprazolam, imipramine, or placebo did not differentially predict the likelihood of receiving medication almost 2 years later. After 1 year of naturalistic treatment, approximately 70% of patients from the three groups were panic free but other residual symptoms were not assessed. Katschnig et al3° reported on a 2- to 6-year follow-up (mean 4 years) of 367 patients participating in the Cross National collaborative panic study of alprazolam and imipramine. At follow-up, 61 % continued to experience occasional panic attacks, 40% had phobic avoidance, and 50% were still taking medication. Patients experienced a variable course and outcome during the follow-up period: 31 % recovered and stayed well; 19% had a severe, chronic course; and 50% had an intermediate course characterized by recurrent or mild symptomatology. Again, the type of medication received during the initial trial did not predict outcome on the follow-up variables. These findings are consistent with other reports of patients followed up after participating in clinical trials. For instance, 78% of patients who had entered a placebo-controlled trial of alprazolam and clonazepam remained on medication at 1.5-year follow-up, and 40% remained symptomatic. Patients treated with benzodiazepine alone experienced a small decrement in their global clinical status during the follow-up period (during which benzodiazepine doses were either stable or had declined), although they remained significantly better than prior to initiation of treatment.76 Seventy percent of treated patients receiving an initial 4month trial of alprazolam and behavioral therapy remained on medication 2 to 3 years later,55 as did 50% of those patients similarly treated with imipramine and behavior therapy. 54 Forty-three percent of the alprazolam-treated patients and 61 % of the imipramine-treated patients were in remission at follow-up. Doses of alprazolam were reduced during the follow-up period, allaying concerns about potential dose escalation. As in the study by Pollack et al,76 however, benzodiazepine doses often were decreased despite the fact that patients remained symptomatic. The mean dose of imipramine (74 mg/ d) at the end of the follow-up period was significantly less than at the end of the acute treatment period, consistent with another report that acute robust responders to imipramine maintain benefit at lower doses. 46 Whether or not those who remained symptomatic in both the alprazolam and imipramine studies may have benefited from a dose increase remains unknown, however. Consistent with the report by Noyes et al,60 more than half the patients attempting imipramine discontinuation reported increased anxiety during or after imipramine taper and more than half of these patients could not discontinue the medication.54 Discontinuation

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rates in this study were not substantially different than those in the parallel study that used alprazolam. 55 The authors note that the contribution of patients' expectations in discontinuation-related difficulties cannot be estimated because patients were not blind to their medication taper status. Reports of significant symptoms emerging during sham benzodiazepine withdrawal and during placebo discontinuation ("pseudowithdrawal")59• 91 suggest that cognitive factors may contribute to discontinuation difficulties and may explain the success of cognitivebehavioral strategies in facilitating benzodiazepine discontinuation. 63• 86 Despite the relatively high rate of chronicity and relapse seen in follow-up studies, some patients do appear to achieve sustained benefit after an acute treatment trial. This may explain the finding in some studies that degree of symptomatology at follow-up is not related to whether patients remain on medication. 54• 55• 77 For example, in the studies by Nagy and associates,54• 55 improvements in panic attack frequency and other measures of symptoms severity following a 4-month trial of imipramine or alprazolam were maintained at 1- to 5-year follow-up, whether or not patients remained on the medication at follow-up. Patients whose natural course of illness is characterized by time-limited episodes and enduring remissions may remain panic-free off medication following a successful acute treatment trial. Those with a more relapsing, chronic form of the illness may sustain similar improvement but only if they remain on medication at follow-up . In light of the developmental model discussed earlier, it would be of interest to know if those patients with apparent chronic conditions who require ongoing treatment or remain treatment resistant can be distinguished by a history suggesting an underlying anxiety diathesis (e.g., a family history or childhood history of BI or anxiety disorder). Preliminary data from our study74 suggest childhood history of anxiety may be associated with factors such as comorbidity and phobic avoidance that promote relapse in treated patients. There is some evidence that long-term course is improved for some patients by acute treatment with cognitive-behavioral therapy. For example, Clark and colleagues15 compared imipramine (mean dose 233 mg/ d) with cognitive therapy and applied relaxation. Patients were seen weekly for the first 3 months. Imipramine was tapered off after the 6month assessment. At the end of 6 months, cognitive therapy and imipramine were similarly superior to applied relaxation, but at 15month follow-up, fewer patients who had received cognitive therapy had relapsed. Follow-up studies of cognitive-behavioral therapy have reported that at 15- to 24-month follow-up, about 85% of patients remain panic free but 30% to 50% continue to have other symptoms and functional impairments such as agoraphobic avoidance.15 • 18• 62 Finally, a small study49 suggests that patients who relapse after imipramine discontinuation can be retreated successfully, although the time to remission may be increased. Seven patients with panic disorder and agoraphobia who had responded robustly to imipramine and who relapsed several months after discontinuation of the drug were retreated

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with the same dose of imipramine. All achieved full remission again when retreated but the response to retreatment was slower than during initial treatment.

Discontinuation of Pharmacotherapy for Panic Disorder

As noted previously, discontinuation of either antidepressant or benzodiazepine therapy for panic disorder is associated with discontinuation-related symptomatology and relapse, 58 and most patients starting treatment remain on medication at follow-up. Greater acute difficulties, however, are associated with benzodiazepine withdrawal, with rates of panic attack recurrence of up to 74% to 89%. 20 • 23 • 59 In a study by Noyes et al, 59 64% of patients on alprazolam were unsuccessful in discontinuing their medication, and 60% reported that discontinuation led to anxiety symptoms as bad or worse than those experienced prior to the initiation of treatment. Although slow taper strategies and use of long- half-life agents tend to reduce discontinuation-associated difficulties in clinical practice, 51 · 66· 68 a study by Schweizer et al 85 that compared gradual versus abrupt discontinuation in patients receiving long or short halflife benzodiazepines demonstrated that 32% of the patients treated with long half-life benzodiazepines and 42% of those treated with short halflife benzodiazepine were unable to complete discontinuation despite a gradual tapering of medication. Patients with greater pretreatment panic attack frequency and duration of illness appear to have more difficulty with henzodiazepine taper than those patients who did not. 77 A number of strategies, including adjunctive antidepressants, buspirone, beta-blockers, and anticonvulsants, have met with variable and generally limited success in reducing the acute distress associated with benzodiazepine discontinuation in panic patients. 83 None of these strategies has been shown to prevent recurrence of disorder when medication was discontinued. Recently, cognitive-behavioral techniques aimed at reducing withdrawal symptoms have demonstrated efficacy in reducing distress during acute withdrawal and, more importantly, may offer some protection against relapse after medication discontinuation.65, s6

LONGITUDINAL STUDIES OF PANIC DISORDER

There is a relative paucity of data available from systematic, prospective studies of the course of panic disorder, although at least two such studies currently are under way. 32• 72 Keller et al reported that patients with panic disorder followed naturalistically had a 39% probability of achieving remission (at least 8 weeks essentially symptom free) by 1 year; those with panic disorder and agoraphobia had a 17% likeli-

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hood of remission. 33 Rates of relapse within 1 year of remission were high for both groups (31% to 35%). Forty percent of more than 250 patients followed in the Massachusetts General Hospital Longitudinal Study of Panic Disorder met criteria for remission (2 2 months essentially symptom free), and close to 60% of these patients experienced a relapse during a 2-year period.75 Predictors of relapse for those patients achieving remission included frequency of panic attacks, phobic avoidance, global severity of illness, and anxiety sensitivity. The duration of illness prior to intake in both studies was greater than 10 years, and these reports suggest that the typical course of panic disorder is characterized by prolonged periods of illness interspersed with relatively brief periods of remission. As noted by Roy-Byrne and Cowley,84 however, follow-up studies of naturalistic treatment have not assessed the adequacy of treatments given to patients during the study period. FACTORS CONTRIBUTING TO CHRONICITY

A number of patient-related and pharmacologic factors may contribute to a patient's remaining symptomatic despite pharmacotherapy. Patient-Related Factors Comorbid Psychiatric Disorders

Comorbid depression,1· 38• 42• 55· 56· 61 agoraphobia,21· 42• 57· 61· 76 social phobia,76 substance abuse,1° personality disorders,61 and family dysfunction61 all may interfere with response to treatment for panic. Recognition of comorbid conditions may permit tailoring of interventions to maximize response. Panic patients with significant comorbid depression may respond better to an antidepressant than to a benzodiazepine; those patients with comorbid social phobia or atypical depression respond better to treatment with a monoamine oxidase inhibitor (MAOI), an HPB, or a selective serotonin reuptake inhibitor (SSRI) than to a TCA. Significant personality dysfunction or psychosocial (e.g., family) disturbance may contribute to ongoing symptoms unless specifically add ressed during treatment. Untreated Cognitive Factors and Anxiety Sensitivity

Consistent with findings from studies of panic disorder that examined factors associated with chronicity and recurrence,2· 30• 33• 42• 72• 93 persistent symptomatology may be associated with untreated phobic fear, avoidance, and sensitivity to anxiety. Clark et al1 5 found that misinterpretations of bodily sensations at the end of treatment with imipramine,

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cognitive therapy, or applied relaxation predicted persistent symptoms and relapse after 6 months. In many patients who experience substantial reduction in panic attacks with treatment, anticipatory and phobic fear and avoidance may be overlooked and remain resistant to treatment. Phobic avoidant behaviors may persist as long as the fear of anxiety symptoms and propensity to avoid are incompletely treated. The predictors of poor outcome in a number of follow-up studies of treated patients,61• 76 including greater agoraphobic avoidance and comorbid social phobia, are consistent with the hypothesis that phobic symptoms may limit response to pharmacotherapy. Whereas increased agoraphobia and anxiety sensitivity are also negative predictors of response to cognitive-behavioral therapy, the addition of cognitive-behavioral therapy to medication refractory panic patients may result in significant gains. In one study, 40% of medication-refractory patients entered remission after addition of cognitive-behavioral therapy. 70 Thus, combined pharmacologic and cognitive-behavioral therapy may offer substantial benefit in reducing the chronicity associated with untreated manifestations of anxiety pathology. Comorbid Medical Conditions

Although the issue has not been subjected to systematic study, the presence of comorbid medical conditions may contribute to chronicity. The treatment of patients with medical illness may be complicated by a number of factors including the direct anxiogenic effects of certain medical conditions such as chronic obstructive pulmonary disease or medications used to treat them (e.g., bronchodilators). 78 Some conditions (e.g., coronary artery disease with accompanying chest pain) may provoke anxiety by their potentially ominous significance or by mimicking anxiety symptoms making diagnostic evaluation and targeted treatment difficult. Medically ill patients may be more sensitive to medication side effects and unable to tolerate therapeutic levels of antianxiety agents. The development of better-tolerated pharmacotherapeutic agents, increased availability of cognitive-behavioral therapies, attention to pertinent psychosocial factors, and treatment of underlying medical factors may facilitate therapeutic response in panic patients with comorbid medical conditions. Pharmacologic Factors Dosing

Antidepressants. Some reports suggest better responses associated with higher doses and blood levels of TCAs. 45 Desipramine responders in one study of panic patients all had therapeutic blood levels greater than 125 ng/ mL, and nonresponders converted to responders once their dose was increased to obtain levels greater than 125 ng/mL. 40 Ballenger

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and colleagues,6 however, reported that some agoraphobic patients responded better to imipramine blood levels in the range of 100 to 150 ng/mL compared with those in the range of 200 to 250 ng/ mL, suggesting that lower levels of imipramine plus desipramine were sufficient for good response. In an elegant study, Mavissakalian and Perel48 reported that optimal dosing of imipramine for panic is in the range of 2.25 mg/kg/d (100- 200 mg/d for most patients) achieving a plasma level (imipramine + desipramine) of 110 to 140 ng/mL. Thus, patients who remain symptomatic with TCA plasma levels outside this range may benefit from dosage adjustment aimed at bringing the plasma levels within the target parameters. These authors also examined the issue of maintenance treatment with TCAs for panic disorder, reporting that a group of patients who remitted during a 6-month trial of imipramine (mean dose 168 mg/ d) remained well during a 1-year maintenance phase during which doses were reduced by 50%. 46 This study suggests that lower-dose TCA therapy may be adequate to maintain remission in patients responding robustly to acute full-dose therapy, although it is important to emphasize that patients in this study met strict criteria for remission prior to the dose reduction. There are no clear guidelines as to what constitutes an adequate dose of the newer antidepressants, including the SSRis, for panic disorder, although in the absence of definitive data, most clinicians aim for typical levels used to treat depression. Treatment should be initiated at low doses, however, to minimize early excessive medication-related activation that may contribute to treatment noncompliance. High-Potency Benzodiazepines. Inadequate dosing with benzodiazepines over time may contribute to continued symptomatology and chronicity. Decreases in dose during maintenance treatment is one potential explanation for the persistence of symptoms and diminution of acute treatment effects in follow-up studies of HPB-treated patients.ss, 76 Maintenance treatment with subtherapeutic doses of HPBs was associated with increased relapse in remitted panic patients assessed longitudinally.7s The decrease in HPB dose during the maintenance period despite continued symptomatology may be due to patients' desire to minimize the use of medications to treat anxiety symptoms (particularly benzodiazepines), concerns about withdrawal-associated difficulties, and clinician fears about dose escalation and abuse despite the reassuring data on this issue in anxiety disorder patients.3, 16, so Side effects of benzodiazepines, when present, usually occur early in treatment and are generally not problematic over time, suggesting that this is an unlikely cause of dose reduction for most patients. In naturalistic treatment, however, early dramatic response may result in failure to consider further upward dose adjustment despite residual symptomatology. Target doses of HPBs for the treatment of panic disorder are 4 to 10 mg/ d for alprazolam and 2 to 5 mg/ d for clonazepam although some patients may experience substantial benefit from lower doses. In the Cross National Collaborative Panic Study, panic attacks remitted for many patients at around 2 to 3 mg/ d of alprazolam, w hereas 6 mg/ d

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was necessary in many patients to resolve phobic avoidant behaviors. 5 This finding is consistent with that of other reports that demonstrated greater improvement and fewer dropouts among patients treated with higher doses of alprazolam. 92 Interpretation of a fixed-dose study of alprazolam for panic disorder that reported no significant differences in efficacy between patients treated with 2 and 6 mg/ d of alprazolam is complicated by the high proportion of patients in the low-dose group surreptitiously using other benzodiazepines.41 Continued symptomatology and residual distress may require dose escalation beyond the level needed to achieve an acute therapeutic response in HPB-treated patients. The data from the follow-up and longitudinal studies referenced previously suggest that maintaining patients on the HPB dose necessary to achieve full remission may decrease relapse and improve long-term outcome, although this critical question warrants additional systematic study. Interdose rebound anxiety, more common with shorter half-life HPBs such as alprazolam, may contribute to ongoing symptomatology in panic patients, focus attention on somatic sensations associated with benzodiazepine withdrawal, increase sensitivity to anxiety, and foster a sense of dependence on the medication to control symptoms. 63 In addition, short half-life agents may " wear off" over night, leading to nocturnal panic and early morning anticipatory anxiety. Regular and frequent dosing with shorter-acting agents or use of longer-acting agents (e.g., clonazepam) can reduce interdose rebound anxiety. Duration of Treatment

Adequate duration of treatment also may be a critical variable to consider in maximizing the response to pharmacotherapy. Muskin and Fyer53 reported that 3 to 9 months were necessary for a group of patients on TCAs to become panic free, and as long as 14 to 26 months to become free of anticipatory anxiety. In a placebo-controlled study of imipramine and alprazolam in patients with panic disorder and comorbid depression,71 the degree of phobic avoidance was a negative predictor of response at 4 weeks but not at 16 weeks, suggesting phobic avoidance may require months to respond fully to treatment. In one study, more than 80% of patients who remitted during 6 months of treatment with imipramine (mean dose, 146 mg/d) relapsed within 6 months of discontinuing drug therapy, whereas none maintained at half that dose experienced worsening of panic or phobic symptoms during the next year with continued treatment; only 25% of these relapsed in the 6 months after discontinuing medication. 47 Thus, longer periods of maintenance therapy, even with lower doses of TCAs, were associated with lower rates of relapse. Resolution of anticipatory and phobic anxiety and avoidance only may occur over time as patients test the protective antipanic effects of medication while exposing themselves to feared situations. Consistent with this hypothesis are reports that cognitive-behavioral therapy and

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progressive self-directed exposure enhance the effects of antidepressant pharmacotherapy for panic. 43, 70 Compliance

Treatment-emergent adverse effects may limit the patients willingness or ability to receive an adequate trial of pharmacotherapy. More than half the panic patients who stopped TCA therapy during a 2.5-year follow-up period did so because of medication side effects, including increased anxiety early in the course of treatment and weight gain over the long term. 57 Side effects limited dose increases in close to half of the patients who failed to respond. Aggressive management of treatmentemergent side effects,69 as well as the development of newer agents with favorable side-effect profiles, may facilitate compliance and improve outcome in long-term pharmacotherapy of panic disorder. Although benzodiazepines generally are well tolerated, the achievement of adequate dosing may be hampered by patient and clinician ambivalence toward their use. Patient and clinician education about the longitudinal course of the disorder is critical; if panic disorder is recognized as a chronic condition for many patients, then concerns about physical dependence and acute withdrawal difficulties may be viewed in perspective. Poor compliance with adequate intensity and frequency of dosing may result in continued symptomatology and, paradoxically, may increase psychological dependence on medication by focusing on the association between acute anxiolytic relief and pill taking. Educating patients about the reassuring date regarding lack of dose escalation or misuse of benzodiazepines through time in those without risk factors for substance abuse, and discussion of potential management strategies for discontinuation (e.g., gradual downward dose titration, cognitivebehavioral strategies) may improve compliance with HPB treatment. ADJUNCTIVE STRATEGIES FOR THE REFRACTORY PANIC DISORDER PATIENT

The management of panic disorder patients who remain symptomatic despite an adequate trial of treatment has not been well studied. Combined treatment with different classes of medication (e.g., an antidepressant plus a benzodiazepine) or within classes (e.g., an SSRI plus a TCA),89 switching among agents within a class (e.g., from a TCA to an SSRI), use of alternative agents (e.g., clomipramine,52 MAOis,14 valproic acid31), and augmentation of an antidepressant or HPB (e.g., with lithium,22 buspirone,25 a low-potency benzodiazepine, or a beta-blocker) all have been useful strategies for select patients, but none have yet been subjected to rigorous systematic inquiry. Combined treatment with pharmacologic and cognitive-behavioral strategies also may improve acute and long-term outcome for patients with panic disorder,43 , 62, 70 and may be used at treatment onset, during

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maintenance therapy, or at medication discontinuation. Although, the "prescription" of cognitive-behavioral therapy may be limited by the availability of clinicians experienced in these treatments, patient-directed situational exposure can be included as part of a time-efficient pharmacologic management of panic disorder, and has been demonstrated to facilitate maintenance of acute therapeutic gains at long-term followup.44

SUMMARY

Converging lines of evidence from a variety of methods of inquiry support a developmental model for panic disorder that includes a constitutional predisposition for anxiety influenced by genetic, familial, cognitive-behavioral and psychosocial factors, early expression during childhood, and variable manifestations during the life-cycle. Studies of patients followed up after acute pharmacotherapy trials and those treated naturalistically are consistent with this model and portray panic disorder as a generally chronic condition with a longitudinal course marked by relatively brief intervals of remission and high rates of recurrence and relapse. Longitudinal and follow-up studies suggest that panic attack frequency responds more readily and rapidly to pharmacotherapy than do other aspects of panic disorder such as agoraphobia and generalized anxiety. In general, the presence of agoraphobia is associated with more severe symptoms, greater chronicity, and more limited response to treatment. Other variables associated with chronicity and treatment resistance include patient-related factors (psychiatric and medical comorbidity, anxiety sensitivity) and pharmacologic factors (adequacy of dose, duration, and compliance). Although it is currently difficult to predict the duration of treatment needed for an individual patient, available evidence suggests that a substantial proportion of patients may require chronic treatment for panic disorder.

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sion: A 2-year prospective follow-up study. Am J Psychiatry 150:1878-1880, 1993 2. Aronson T, Logue C: On the longitudinal course of panic disorder: Developmental history and predictors of phobic complications. Compr Psychiatry 28:344-355, 1987 3. Association AP: Benzodiazepine Dependence, Toxicity, and Abuse. Washington, American Psychiatric Association, 1990 4. Ayuso JL, Alfonso S, Rivera A: Childhood separation anxiety and panic disorder: A comparative study. Prog Neuropsychopharmacol Biol Psychiatry 13:665-671, 1989 5. Ballenger J, Burrows G, DuPont R, et al: Alprazolam in panic disorder and agoraphobia: Results from a multicenter trial, I: Efficacy in short-term treatment. Arch Gen Psychiatry 45:413-422, 1988 6. Ballenger JC, Peterson GA, Laraia M, et al: A study of plasma catecholamines in agoraphobia and the relationship of serum tricyclic levels to treatment response.

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