Early detection of relapse in panic disorder.

OBJECTIVE: To explore predictive models of relapsing based on change in symptoms at a time when panic disorder patients are still in remission following discontinuation of antidepressants. METHOD: Forty-seven subjects, who were randomized to double-blind placebo and who had valid data at four time points: pretreatment, randomization to placebo substitution, an assessment on placebo prior to the last assessment or relapse and their last assessment (relapsers n = 15, non-relapsers n = 32) were studied using descriptive, growth curve analysis and logistic regression methodologies. RESULTS: Measures of generalized anxiety, fearfulness and disability at work and at home were better predictors of relapse than measures of panic and anxiety sensitivity. Logistic regression models using any one of these four general variables and its linear change correctly predicted relapse for 78.7-84.4% of the study subjects. CONCLUSION: It is possible to gauge, with a fair degree of accuracy, the probability of relapsing in panic disorder patients who have discontinued serotonergic antidepressants 2 months prior to the return of panic.

2nd year maintenance and discontinuation of imipramine in panic disorder with agoraphobia.

BACKGROUND: The results from our 1 year placebo-controlled maintenance/discontinuation study in remitted panic disorder with agoraphobia patients confirmed the significant prophylactic effectiveness of imipramine maintenance treatment but suggested that this may be necessary in only 37% of the patients who relapse following discontinuation of 6 months acute imipramine treatment. This paper presents pilot data from a second year extension of the above-mentioned study with the aim of exploring the putative protective effects of maintenance imipramine therapy beyond the 1st year. METHOD: Eighteen patients from the 30 who survived, in stable remission, the first 12 months of the maintenance/discontinuation study gave written consent to participate in a double-blind 2nd year extension phase with the knowledge that those on placebo will continue on the same condition (N = 7, PBO-PBO) and those on imipramine (N = 11) will be rerandomized to 2nd year maintenance (N = 4, IMI-IMI) or placebo substitution (N = 7, IMI-PBO). The procedures continued unchanged from that of the 1st year of the study and patients were followed with planned assessments every 2 months over the second 12-month experimental period of the study. RESULTS: None of the IMI-IMI patients relapsed, two (28.5%) of the IMI-PBO patients relapsed, and two (28.5%) of PBO-PBO patients relapsed. The mean estimated time without relapse was 10 months and 9 months for IMI-PBO and PBO-PBO, respectively. The estimated probability of not relapsing was .64 for IMI-PBO and .60 for PBO-PBO (Mantel-cox test chi2 =.84, p = .77). CONCLUSION: These interlocking controlled observations tentatively suggest that a substantial degree of prophylactic efficacy continues and that a substantial need for continued prophylaxis exists beyond the 1st year of maintenance imipramine treatment in panic disorder with agoraphobia patients.

The side effects burden of extended imipramine treatment of panic disorder.

In a recent study, the authors gauged the net effectiveness of imipramine to be 53%; that is, of 110 patients having panic disorder with agoraphobia who started a course of imipramine at a fixed, targeted, weight-adjusted dose of 2.25 mg x kg(-1) x day(-1), 59 adhered to the regimen and showed a marked and stable response. The present study investigated in detail the side effects burden of imipramine treatment in the same sample using hierarchical linear modeling in a short-term perspective, based on data at baseline (N = 110) and at weeks 1, 2, 4, 6, and 8 (N = 77) of treatment, and a long-term perspective, based on data at baseline and at weeks 8, 16 (N = 66), and 24 (N = 59). Deviations from the general pattern were explored by considering only severe side effects or only completers of treatment to better gauge the clinical significance of the findings. The results revealed that of 15 complaints systematically elicited using a side effects inventory, only 3--dry mouth, sweating, and constipation--continued as a substantial burden at the end of 6 months of treatment. On most other items, the initial increase was followed by a decrease to lower than baseline at the end of treatment. In the case of nausea, vomiting, increased energy, headache, and sexual disorders, the complaints were at their worst before treatment started and improved over the course of treatment. A sustained heart rate elevation between 10 and 15 beats per minute was found, but there were no significant effects on blood pressure or weight. The discussion underscores the need for more methodologically improved comparative studies with selective serotonin reuptake inhibitors in the treatment of panic disorder.

Generalized anxiety disorder versus panic disorder: participation in controlled efficacy trials.

Seventy-one patients with panic disorder (PD) and 46 patients with generalized anxiety disorder (GAD) were studied in relation to their behavior before, during, and after participation in two contemporaneous and procedurally similar double-blind drug efficacy trials. The two groups were administered a battery of assessments aimed at comparing them on the nature and intensity of various symptom domains, social and work-related disability, personality, life events, and previous treatments. The results yielded few significant differences that were not due to definitional factors, most notably a more prevalent history of depression and treatment for depression in the GAD group and a higher rate of pharmacological treatment in the PD group. On the other hand, the two groups behaved in a comparable way in the screening, experimental, and postexperimental phases of the trials. The findings are in support of more similarities than differences between the groups. In addition, the comparable behavior of the two groups throughout the three phases of the trial suggests that differential pretreatment attrition and compliance with placebo-controlled trials may not present major confounding problems in comparative treatment effectiveness studies between GAD and PD diagnostic groups.

Cost effectiveness of acute imipramine therapy versus two imipramine maintenance treatment regimens for panic disorder.

OBJECTIVE: To examine the medical costs and effectiveness of acute treatment with imipramine versus acute treatment plus 2 different maintenance therapies for panic disorder. METHODS: A clinical decision model was constructed to estimate 18-month costs and outcomes associated with these treatment scenarios based on the medical literature and clinician judgment. The clinical parameters and outcomes for the model were derived from a series of systematic clinical trials with imipramine utilising uniform dosage procedures and validated response criteria. Costs were calculated based on standardised treatment regimens. The outcome measures were 18-month medical costs, quality-adjusted life years (QALYs) and costs per QALY gained. A sensitivity analysis was performed to explore the impact of treatment withdrawals on outcomes. STUDY PERSPECTIVE: US mental healthcare system. RESULTS: Over 18 months, the total costs (1997 values) and QALYs associated with half-dose maintenance therapy (imipramine 1.1 mg/kg/day) [$US3377; QALYs = 0.991] and full-dose maintenance therapy (imipramine 2.25 mg/kg/ day) [$US3361; QALYs = 0.991] were almost identical; both were cost saving compared with acute imipramine therapy (2.25 mg/kg/day) with no maintenance treatment ($US3691; QALYs = 0.979). Whether patients withdrawing from treatment were considered to have continued to respond to treatment or to have relapsed, the half-dose and full-dose maintenance treatments were still cost saving compared with acute treatment alone. CONCLUSIONS: The results indicate that imipramine maintenance treatment is cost effective compared with acute imipramine treatment for patients with panic disorder. The basic findings and conclusions are not affected after modifying model assumptions for clinical response in patients withdrawing from treatment.

Long-term maintenance and discontinuation of imipramine therapy in panic disorder with agoraphobia.

BACKGROUND: There has been little systematic work done regarding the long-term treatment of panic disorders. The aim of the present study was to assess the 12-month cumulative risk of relapse specifically due to discontinuation of imipramine and to test the hypothesis that maintenance treatment with imipramine protects patients with panic disorder and agoraphobia from such reversals. METHOD: Following an acute-phase open trial with imipramine (2.25 mg/kg per day) involving 110 patients for 6 months, the 56 patients who were in stable remission, did not require additional treatment, and consented to be randomly assigned to double-blind maintenance (n = 29) or discontinuation (n = 27) conditions were followed up with planned assessments every 2 months during a 1-year period. There were no behaviorally oriented interventions or instructions at any time during the 18 months of the study. RESULTS: Maintenance treatment (1 relapse) and discontinuation (10 relapses) conditions had significantly different survival curves (Mantel-Cox statistic chi(2)1 = 10.47, P = .001). None of the additional 10 variables from demographic, clinical, and open-treatment domains considered in the proportional hazard model disrupted the significant relationship between experimental drug condition and relapse; other things being equal, a patient receiving imipramine maintenance was 92.5% lower in the hazard rate of relapse than a patient receiving placebo. CONCLUSION: The results confirm the very high degree of prophylactic effectiveness of maintenance imipramine treatment and demonstrate that relapse, although substantial, occurs in a minority of patients with panic disorder and agoraphobia who are in stable remission prior to treatment discontinuation.

Gauging the effectiveness of extended imipramine treatment for panic disorder with agoraphobia.

BACKGROUND: Imipramine has proven efficacy for panic disorder. This study assesses the net effectiveness of systematic, open imipramine treatment in a homogenous sample of panic disorder patients with agoraphobia. METHODS: One hundred and ten consecutive patients with DSM-III-R moderate to severe panic disorder with agoraphobia were treated with a fixed regimen of imipramine 2.25 mg/kg/day for 24 weeks. No instructions or encouragement for self-directed exposure to phobic situations or other coping strategies with panic or fear were given. Assessments were conducted at the end of the 2-week placebo run-in and at weeks 8, 16, and 24 of treatment. RESULTS: Overall, 53% had a marked and stable response. Most measures revealed that substantial improvement continued beyond week 8 of treatment. Treatment success was accompanied with significant improvements in anxiety sensitivity, dysphoric mood, and functional well-being. CONCLUSIONS: These results provide a clinically relevant reference with which to compare the effectiveness of alternative treatments in providing nearly complete symptom remission in patients with primary panic disorder with agoraphobia.

Rational treatment of panic disorder with antidepressants.

Rational treatment of panic disorders with antidepressants rests on decisions of drug choice, dosage, and duration of treatment. In this paper, we selectively review the author's research with the standard antidepressant, imipramine, in the treatment of panic disorder with agoraphobia as it relates to practical issues. We develop general guidelines for treatment, suggest researchable ways of increasing the net effectiveness of treatment with this class of drugs, and discuss limited generalizations to the extant literature on selective serotonin reuptake inhibitors in panic disorders.

Life events and panic disorder/agoraphobia: a comparison at two time periods.

Semistructured interviews of 187 patients with a DSM-III diagnosis of panic disorder or agoraphobia with panic attacks were conducted an average of 12 years after onset of the disorder. Interviews solicited life events that occurred in the year before onset and in the year preceding index evaluation. The number and type of life events were found to be similar at onset and at the later evaluation. However, the results showed that a tendency for increased reporting of life events before onset in a subgroup of patients was counterbalanced by a tendency for decreased reporting in another subgroup. Attention to individual differences rather than group means may be more important in future prospective studies.

Phenomenology of panic attacks: responsiveness of individual symptoms to imipramine.

A number of studies have demonstrated that individual panic symptoms are not equivalent vis-a-vis their clinical salience. This study investigated the proposition that individual panic symptoms may also differ in their specific responsiveness to treatment in 63 patients with panic disorder with agoraphobia who had completed an 8-week placebo-controlled dose-ranging study with imipramine. The results revealed that fear, unreality, and respiratory symptoms, most strongly dyspnea and choking, displayed the highest degree of early differentiation between effective and ineffective doses of the drug, whereas palpitations, tingling, and sweating had the most pronounced effects between weeks 4 and 8 of treatment. On the other hand, the symptom of hot and cold flashes did not differ between adequate and inadequate treatment. The evidence presented reinforces the notion that individual panic symptoms are not functionally equivalent and suggests that some symptoms, in particular fear, derealization, and the respiratory symptoms, may be more central than others to the therapeutic process just as some of them have been found to be more important for diagnostic considerations. The results are briefly discussed from the methodologic and phenomenologic perspectives.

The relationship of plasma imipramine and N-desmethylimipramine to response in panic disorder.

This report is a descriptive summary of the relationship between response and plasma tricyclic concentrations found in our previously reported dose-ranging study of imipramine (IMI) in panic disorder (Mavissakalian & Perel 1995). In addition, we explore the relative strength with which plasma levels of the parent compound (IMI) and N-desmethylimipramine predict the probability of response in the total plasma range for which there was continued improving response. The results, which indicated that IMI was the better predictor, are briefly discussed from a neurobiochemical perspective. Specifically, it is suggested that imipramine's effects are mediated predominantly through its serotonergic action and that the increased noradrenergicity of the drug with increasing total plasma concentrations reduces its potency, in particular its antiphobic effects, in panic disorder with agoraphobia.

Imipramine treatment of panic disorder with agoraphobia: dose ranging and plasma level-response relationships.

OBJECTIVE: The aim of this study was to characterize the specific effects of imipramine in the treatment of panic disorder with agoraphobia and to delineate dose-response and possibly plasma level-response relationships. METHOD: Eighty patients with panic disorder with agoraphobia were randomly assigned, for an 8-week, double-blind dose-ranging trial, to placebo or to a weight-adjusted dose of imipramine: (low) 0.5 mg/kg per day, (medium) 1.5 mg/kg per day, or (high) 3.0 mg/kg per day. Plasma levels of imipramine and N-methylimipramine, patients' and clinicians' ratings of panic and phobic symptoms, and response to treatment according to operationalized criteria were ascertained after 4 and 8 weeks. RESULTS: Rates of dropouts due to drug side effects were 6%, 15%, and 36% in the low-, medium-, and high-dose groups, respectively; 63 patients completed the study. Compliance with the drug regimen was high. There was a positive dose-response relationship, with significant group differences involving primarily the high- and medium-dose groups versus the placebo group. There were no significant differences between the placebo and low-dose groups or the medium- and high-dose groups. For phobias, the best total drug plasma level was in the range of 110-140 ng/ml; higher levels had a detrimental effect. For panic, the probability of response increased quickly with greater plasma levels and then tapered off, with no improvement at levels beyond 140 ng/ml. CONCLUSIONS: The results provide strong evidence that imipramine has specific, clinically significant effects in this disorder, with practical implications for target doses and optimal plasma concentrations, and suggest that different mechanisms underlie the drug's antipanic and antiphobic effects.

Life events and panic disorder/agoraphobia.

A patient-rated checklist adapted from the Psychiatric Epidemiology Research Interview was used to assess frequency and desirability of life events in the 12 months preceding an index evaluation of a large sample of patients with a DSM-III diagnosis of panic disorder or agoraphobia with panic, on average 12 years after onset of illness. A total of 1,360 events were reported; 25% were considered most undesirable, whereas 22% were estimated to be most desirable. Negative life events were predominantly health-related issues and interpersonal conflicts. Making new friends, having significant success at work, and taking up a new activity were examples of positive events. Correlations of life events with clinical and demographic variables and with symptom rating scales were also analyzed. Negative life events were associated with greater psychopathology and neuroticism scores. Positive life events were associated with greater extraversion scores, more years of education, better employment status, and less functional impairment due to symptoms. This exploratory study does not allow interpretation from an etiologic perspective. It begins to shed light on the possible role of life events in the course of the disorder.

Blood pressure and heart rate response of panic disorder patients receiving imipramine in a dose-response treatment paradigm.

This article reports the effects of imipramine on heart rate and blood pressure in panic disorder patients who participated in an 8-week double-blind dosage response treatment protocol. At the end of a placebo baseline, patients were randomly assigned to placebo or one of three weight-adjusted imipramine dosages: low (0.5 mg/kg per day), medium (1.5 mg/kg per day), or high (3.0 mg/kg per day). It was demonstrated that imipramine had no significant effect on sitting or standing diastolic or systolic blood pressure. Although there was a trend toward a systolic blood pressure drop with positional change, it did not reach statistical significance. There were no significant changes in diastolic blood pressure with postural change. Imipramine did increase sitting and standing heart rate without revealing a clear dosage correlation. In contrast to the pretreated state, the reflex heart rate response to postural change was significantly increased in the posttreatment state, also in a dosage-independent manner. Within the high-dose imipramine group, the baseline sitting to standing heart rate increase was significantly higher in those who dropped out because of drug side effects compared with those who remained. Evidence from this study suggests that imipramine has a dosage-independent effect on resting and reflex heart rate. Future studies should consider postural heart rate reactivity as a potential measure of intolerance to the side effects of high doses of imipramine.

Patterns of obsessive compulsive symptoms in Tourette subjects are independent of severity.

Studies have examined the expression of obsessive compulsive (OC) symptoms in obsessive compulsive disorder (OCD), OCD with co-occurring Tourette's Syndrome (TS) or chronic motor tic disorder (CMT) and TS alone. In adult samples, there appears to be a relatively consistent OC symptom thematic content that characterizes OCD alone and OCD in conjunction with tics or TS. Previous studies have controlled for the severity of OC symptoms in OCD and TS groups. In the current study, it was our objective to determine whether patterns of OC symptoms in TS are independent of OC symptom severity. The current exploratory study examined OC symptom expression in a nonclinically based TS sample with a broad range of OC symptoms and severity and a selected clinical OCD sample without TS/tics. Univariate and multivariate statistical analysis explored patterns of OC symptom expression between the two groups. Similar to previous reports examining OC symptoms in OCD and OCD with TS/tics, subjects with OCD alone were characterized by contamination obsessions and cleaning compulsions. In contrast, TS subjects had more somatic, sexual and symmetry obsessions and more checking, counting and touching/blinking compulsions, independent of OC symptom and tic severity. A discriminant function using obsessive items alone correctly grouped 91.4% of cases. The current study replicates patterns of OC symptom expression unique to OCD alone. Patterns of OC symptoms, in particular obsessive symptoms, can robustly predict membership in OCD or TS groups, even with a substantial variation in OC symptom severity as measured by the Y-BOCS score.

Dose-response characterization of the antipanic effects of imipramine.

This article presents panic diary results of a dose-response study with imipramine hydrochloride in panic disorder with agoraphobia patients. Analysis of variance revealed significant time effects on panic frequency and severity measures, but group x time interaction effects were present for the severity measures only. Results also provided evidence for a positive dose-response relationship with 20 percent of patients in the placebo group, 31 percent in the low-dose group (0.5 mg/kg/day), 54 percent in the medium-dose group (1.5 mg/kg/day), and 70 percent in the high-dose (3 mg/kg/day) group being free of recurrent or severe panic attacks at posttreatment. Further stratified and logistic regression analyses revealed a direct linear relationship between total plasma tricyclic concentration and response. These findings affirm the dose-dependent nature and the specificity of imipramine's antipanic effects.

DSM-III personality disorders in generalized anxiety, panic/agoraphobia, and obsessive-compulsive disorders.

In an earlier report, we stated that personality profiles of patients with panic disorder/agoraphobia (n = 187) and obsessive-compulsive disorder ([ODC] n = 51) were similar, albeit more pronounced in OCD, suggesting that the link between panic disorder/agoraphobia and DSM-III personality disorders (PDs) or traits may be nonspecific. The present report extends the comparative study of DSM-III PDs/traits, as assessed by the Personality Diagnostic Questionnaire (PDQ), by adding a third diagnostic group of 39 patients with generalized anxiety disorder (GAD). The personality assessment of panic disorder/agoraphobia and GAD patients yielded virtually identical results on the PDQ and Eysenck Personality Inventory (EPI). Because GAD lacks the prominent panic, phobic, and obsessive-compulsive symptoms of other anxiety disorders, the present findings provide strong support for a nonspecific link between panic disorder/agoraphobia and DSM-III PDs/traits and for the presence of common personality characteristics in anxiety disorders.

Imipramine treatment of panic disorder with agoraphobia: the second time around.

The purpose of the present study was to assess and compare the therapeutic effects of imipramine during the initial treatment and retreatment of panic disorder with agoraphobia patients. Seven women with panic disorder with agoraphobia who had shown a marked and stable response to imipramine (121.4 +/- 41.8 mg/day) during their initial treatment of 24 weeks were retreated with the same dose (125 +/- 40.8 mg/day) of imipramine when they relapsed, on average 3 months following discontinuation of the drug. Assessments included operationalized criteria for response and relapse and plasma drug concentrations to verify treatment compliance. Data on phobic, panic, anxiety and depression measures were analyzed for 6 assessment times common to all patients; pretreatment, week 8 and 24 weeks follow-up of initial treatment, relapse which was also the beginning of retreatment, week 8 and 16-24 weeks follow-up of retreatment. At the end of retreatment all patients were marked responders and there was no significant difference on any outcome measure between the end of initial and retreatment assessment periods. However, overall therapeutic response to retreatment was slower than during initial treatment, in particular on phobic and patient rated panic measures. Although the full restoration of remission is clinically reassuring, the results caution that relapse may have sensitizing effects which delay, and if repeated could impede the response of panic disorder with agoraphobia patients to imipramine.

Clomipramine in obsessive-compulsive disorder: clinical response and plasma levels.

Two related data sets are presented that point to a specific pharmacological effect and support a predominantly serotonergic mediation of clomipramine's antiobsessional effect. A significant placebo versus clomipramine contrast from both the between- and within-group perspectives was found in 25 patients with moderate to severe obsessive-compulsive disorder of at least 2 years' duration and no evidence of depression who completed a double-blind, placebo-controlled, 10-week study. There was no significant improvement in the placebo group, six of whom subsequently improved with clomipramine. Analysis of the clinical significance of pharmacotherapy and the relationship between outcome and plasma drug concentrations in 33 obsessive-compulsive disorder patients treated with clomipramine (239.4 +/- 57.0 mg/day) revealed that 47% of the patients were rated in the subclinical range with one third of the sample being virtually symptom-free. Plasma levels of clomipramine, but not N-desmethylclomipramine, correlated significantly with posttreatment outcome measures, with responders having significantly higher clomipramine levels and a trend toward lower desmethylclomipramine ratios.