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Gauging the Effectiveness of Extended Imipramine Treatment for Panic Disorder with Agoraphobia
Gauging the Effectiveness of Extended Imipramine Treatment for Panic Disorder with Agoraphobia Matig R. Mavissakalian, James M. Perel, Marlene Talbott-Green, and Claudia Sloan 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. Biol Psychiatry 1998;43:848–854 © 1998 Society of Biological Psychiatry Key Words: Efficacy, effectiveness, imipramine, panic disorder, agoraphobia, remission, health status
Introduction
I
mipramine is the most extensively studied pharmacologic treatment of panic disorder. Large placebo controlled studies (Cross-National 1992) have firmly established the efficacy of imipramine in panic disorder in general and panic disorder with agoraphobia in particular (Maier et al 1991). A recent dose-ranging study (Mavissakalian and Perel 1995) in panic disorder with agoraphobia has provided incontrovertible evidence for imipra-
From the Department of Psychiatry, the Ohio State University College of Medicine, Columbus, Ohio; and the Clinical Pharmacology Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania . Address requests to Matig R. Mavissakalian, M.D., Department of Psychiatry, Case Western Reserve University, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106. Received September 20, 1996; revised March 22, 1997; revised June 25, 1997; accepted July 9, 1997.
© 1998 Society of Biological Psychiatry
mine’s specific antipanic and antiphobic effects in this more fully developed and usually more severe syndromal form of the disorder. Further evidence suggests that imipramine’s effects become consolidated over 6 months of treatment (Zitrin et al 1980; Telch et al 1985; Clark et al 1994; Schweizer et al 1993) and that continued treatment maintains treatment gains over extended periods of time (Mavissaklian and Perel 1992). The aim of the present paper was to determine the net effectiveness of systematic, open imipramine treatment in panic disorder with agoraphobia patients and to characterize the 6-month treatment outcome in salient symptom and quality of life domains. Because this protocol aimed to transfer optimal pharmacologic treatment in terms of dosing and duration into this large sample, the present results provide a useful reference with which to gauge the effectiveness of newer, primarily nonbenzodiazepine, pharmacologic agents in panic disorder with agoraphobia.
Methods and Materials Subjects Subjects included the first 110 consecutive patients with a diagnosis of panic disorder with agoraphobia who gave informed consent and who started the active open imipramine treatment planned for 24-weeks overall. This protocol preceded an ongoing placebo-controlled, 12-month maintenance phase trial. Subjects, aged 18 – 65 years, contacted the Phobia and Anxiety Disorders Clinic either through clinical referrals or in response to media coverage or advertisement. In addition to meeting DSM-III-R diagnostic criteria for panic disorder with agoraphobia of moderate severity and of at least 3 months’ duration, patients must have been experiencing active recurrent panic attacks at the time of initial evaluation and the fear of panicking or losing control must have been an essential motivation for their escape or avoidance behaviors. Exclusion criteria included evidence of organic mental disorders, psychotic, bipolar, and obsessive-compulsive disorders, primary or current major depression with melancholia, suicidal intention, or a score of $18 on the 17-item Hamilton Depression Rating Scale (HDRS) (Hamilton 1960). Other exclusionary disorders included posttraumatic stress disorder (PTSD), somatization disorder, severe personality (borderline, schizotypal) disorders, and substance abuse disorder current or in remission 0006-3223/98/$19.00 PII S0006-3223(97)00376-4
Effectiveness of Imipramine in Panic Disorder
for less than 6 months. In addition, patients had to be in good general health, have no contraindications for use of imipramine, and be compliant during an initial 2-week single blind placebo run-in. Finally, although the general expectation was to have patients be free of all psychotropic drugs for 14 days before treatment began, an exception was made in the case of patients who were unable to stop benzodiazepines initially, with the proviso that benzodiazepines would be tapered off gradually starting at week 1 of imipramine treatment and completely discontinued by week 16 assessment in order to qualify for randomization to the maintenance study. The sample had a mean age of 36.5 6 9.9 years with a mean age at onset of 26.7 6 9.4 years and a mean duration of illness of 9.7 6 9.2 years. The sample had 14.1 6 2.2 years of education on average, 75 (68%) of them were women, 61 (56%) were married, and 80 (73%) were gainfully employed. One subject met criteria of current major depression, 16 (14.5%) had a history of past depression, 15 (13.6%) had a history of past alcohol abuse, and 17 (15.5%) had a history of abuse for other substances. Thirty-five (31.7%) patients met criteria for one or two concurrent anxiety disorders: 14 (12.7%) had simple phobia, 12 (10.9%) had generalized anxiety disorder, four (3.6%) had social phobia, and five (4.5%) had both generalized anxiety disorder and social phobia. Five (4.5%) patients were on stable thyroid medication in a euthyroid state and 17 (15.5%) of the patients started treatment while on benzodiazepines.
Treatment Following a 2-week, single blind, placebo run-in imipramine was begun. Patients were given consecutively dated packets prepared by the hospital pharmacist, each containing four identical looking tablets composed of placebo or 10, 25, 50, or 75 mg of imipramine hydrochloride to be taken at bedtime. The target dose was 2.25 mg/kg/day of imipramine based on the findings of our recent dose-ranging study (Mavissakalian and Perel 1995). Dose escalation followed a fixed regimen with initial dosing being one-sixth of the target dose for 3 days with equivalent increments every third day such that stable assigned dose was achieved on the 16th day of treatment. At each visit (weekly up until week 4 of treatment, twice a month from week 4 – 8, and monthly thereafter) patients were seen for monitoring of vital signs and side effects, collection of old packets, and provision of new packets of pills for the next period. At the 8-, 16- and 24-week assessments, 12 hours after the preceding dose, blood samples were collected into plasticizer-free evacuated tubes containing eidetic acid powder (Becton Dickinson) and promptly centrifuged. The plasma samples were stored at 220°C for later determination of imipramine and N-desmethylimipramine concentrations by modifications of high-performance-liquid-chromatographic techniques (Mavissakalian and Perel 1995; Westenberg et al 1977; Foglia et al 1991). No additional treatments, in particular, no encouragement or instructions for self-directed exposure to phobic situations or other coping strategies, were given during the trial. For patients on benzodiazepines, a flexible taper was initiated at week 4 usually to be completed by week 8 with the proviso that only
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patients who were successful at stopping benzodiazepines completely for 1 month prior to week 16 assessment would be considered candidates for randomization in the double-blind maintenance study. Patients identified as nonresponders at week 16 were dropped from the study and offered alternative clinically appropriate treatment. The treatment was free.
Assessments The same clinical psychologist (MTG) administered all diagnostic and clinical assessments. Diagnoses were based on the Structured Clinical Interview DSM-III-R, patient version (Spitzer et al 1988) and an independent confirmatory clinical interview by the first author. The assessment battery included the same outcome measures that were validated in our dose-ranging study (Mavissakalian and Perel 1995). The severity of each patient’s condition was assessed by the 5-point Global Assessment of Severity Scale and a 9-point scale of Self-Rating of Severity of Phobia. Clinical measures of agoraphobic fears included the Agoraphobia subscale of the Fear Questionnaire (Marks and Mathews 1979) and a more individualized clinical measure of phobic anxiety and avoidance, consisting of the mean rating of each patient’s five most feared situations on a ninepoint scale. Patients also were asked to take a behavioral assessment test to obtain a functional in vivo measure of phobic anxiety ranging from 0 – 8. Panic attacks were assessed with self-rated and clinician-rated questionnaires using the DSM-III criteria for panic disorder (American Psychiatric Association 1980) definition of panic attacks as “discrete episodes of intense fear or apprehension of sudden onset, not associated with physical exertion. Do not consider fear to be a panic attack if it lasts most of the day or is limited to a specific event or object.” Patients were asked to consider frequency and severity of individual panic attacks of the previous 2 weeks to determine an overall severity rating of panic, using a 0 – 8 point scale (0, none; 2, mild; 4, moderate; 6, severe; and 8, very severe). Similarly, the clinician rated the overall severity of panic attacks on a scale from 0 – 4, ranging from none to very severe. These seven outcome measures, as described in detail elsewhere, were used to assess a composite index of end-state functioning (ESF); range: 0 –7, which has been validated in our dose-ranging study (Mavissakalian and Perel 1992; Mavissakalian 1996). Patients who met response criteria (i.e., either $50% improvement from pretreatment scores or a cutoff score signifying mild to absent symptomatology) simultaneously on six or all of these measures (ESF score $6) were identified as overall syndromal responders, and those who met four or fewer of these criteria (ESF score #4) were identified as nonresponders. Patients were given diary forms and asked to keep a record of the number and severity of their panic attacks for four 2-week periods during the study (i.e., placebo baseline, weeks 7– 8, weeks 15–16, and weeks 23–24). Panic attacks were defined according to DSM-III (American Psychiatric Association 1980). Four variables were derived from the diaries: (1) number of panic attacks; (2) number of days with panic attacks; (3) severity of panic attacks, and (4) peak severity of panic, that is, the most
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Table 1. Stratification of Treatment Response by Endstate Functioning (ESF) Category at Weeks 8, 16, and 24 Treatment times
ESF $ 6 response
ESF 5 5
ESF # 4 nonresponse
Week 8 (n 5 77) Week 16 (n 5 66) Week 24 (n 5 59)
46 (60%) 55 (83%) 58 (98%)a
12 (15%) 5 (8%) 1 (2%)b
19 (25%) 6 (9%) 0
a
One subject still on benzodiazepines. This subject has an ESF of 6 at Week 16.
(100%), and ESF $ 6: 38/46 (83%). The results were significant overall (X2[2] 5 13.659, p 5 .001) and when only the two extreme categories were considered (X2[1] 5 8.339, p 5 .004). Finally, the probability of achieving stable remission in the benzodiazepine (7/17 5 41%) and the nonbenzodiazepine subgroups (52/93 5 56%) was not statistically significant even when the one patient still on benzodiazepine was counted as a nonresponder.
b
Time to Achieve 50% Improvement severe rating given to a panic attack during a given assessment period, based on a 0 – 8 scale (0: none, 2: mild, 4: moderate, 6: severe, and 8: very severe). As described previously in the context of the dose-ranging study, a panic index was developed (range: 0 – 4) by assigning a score of 1 to each of the following panic diary descriptors: at least one panic attack reported, three or more panic attacks, 2 or more days with panic, and peak panic severity $3. A score of #1 on the panic index, signifying no recurrent or severe panic attacks during the 2-week assessment period, was used to identify clinically significant response. Other measures of interest reported in the present study were the Anxiety Sensitivity Index (Peterson and Reiss 1987) to assess the fear of anxiety symptoms that characterize panic disorder, and the Beck Depression Inventory (BDI) (Beck et al 1961) to assess depression and dysphoric mood. Finally, the Medical Outcomes Study Short Form Health Survey (SF-36) (Stewart 1989) was administered at pretreatment and at week 16 of treatment. The SF-36 is a standard measure of quality of life that includes eight subscales, each scored from 0 –100, with 100 representing optimal health status; physical functioning, social functioning, limitations in daily activities caused by physical health (role-physical) or emotional problems (role-emotional), mental health, energy, pain, and general health perceptions.
Results Net Effectiveness of Treatment Of the 110 patients started on imipramine, 77 completed week 8, 66 completed week 16, and 59 went on to week 24 in stable remission, yielding a net effectiveness of 53%. Table 1 presents the proportion of patients meeting three categories of response based on the ESF scale at weeks 8, 16, and 24 of treatment, respectively. Three analyses of interest were applied to these data. First, Bowker’s test of symmetry showed that between weeks 8 and 16 responder status was more likely to improve than to worsen (X2[3] 5 15.4, p 5 .002). Indeed, of the 27 patients who had an ESF score of #5 at week 8, 18 (66%) had improved their response category by week 16 and all but one had achieved an ESF score of $6. Second, we formally tested whether the probability of completing the protocol in stable remission was different in the three response categories at week 8; ESF # 4: 9/19 (47%), ESF 5 5: 12/12
Figure 1 illustrates the change in group means observed on the seven measures constituting the ESF scale in the 59 protocol completers. As a simple summary measure of the rate of improvement, we focused on the time at which subjects achieved 50% improvement. This was defined as follows. On each scale the total improvement was first computed for each subject as the week 24 score minus the pretreatment score. Then, the time at which the subject achieved 50% of their total improvement was computed by fitting a smooth curve (cubic spline) to the subject’s score over time and then estimating the time to 50% improvement from this curve. The median of those times (the time at which one-half the subjects had reached 50% improvement) is marked with arrows in Figure 1. For most measures, this time occurred after approximately 4 weeks of imipramine treatment. A second summary of interest was the percent of subjects whose estimated time to 50% improvement occurred within 8 weeks: Global Assessment of Severity, 61%; Self-Rating of Severity, 86%; Phobic Anxiety and Avoidance, 86%; Fear Questionnaire Agoraphobia, 76%; Behavioral Assessment Test, 81%; Panic Severity (patient), 83%; and Panic Severity (clinician), 80%. Finally, the time at which all of the subjects had reached 50% improvement was estimated to be 12.8 weeks for Global Assessment of Severity, 16 weeks for Self-Rating of Severity, 18.4 weeks for Phobic Anxiety and Avoidance, 22.9 weeks for Fear Questionnaire Agoraphobia, 14.1 weeks for Behavioral Assessment Test, 12 weeks for patient rated Panic Severity, and 12.5 weeks for clinical rated Panic Severity.
Characterization of Treatment Response Panic activity: Table 2 presents the available diary data of the entire sample, e.g., the number and severity of attacks and two response categories at various stages of treatment, Panic Index #1, and panic free status. These data demonstrate continuing improvement over time. Even when completers were considered (week 8, N 5 49; week 16, N 5 51; and week 24, N 5 50), the increase in the percentage of panic free patients from 36.7%–58.8% from weeks 8 –16 and from weeks 16 –24, (80%) was statisti-
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Figure 1. Mean scores in 59 completers at pretreatment (22), start of imipramine treatment (0), and weeks of imipramine 2.25 mg/kg/day protocol. The arrows mark the time at which one-half of the subjects reached 50% of total improvement on the respective measures. Confidence intervals for the means are given in brackets: Global Assessment of Severity: 5.8 [4.8, 6.4]; Self-Rating of Severity: 4 [2.5, 4.5]; Phobic Anxiety and Avoidance: 4 [2.5, 4.5]; Fear Questionnaire, Agoraphobia: 4.8 [4.0, 6.8]; Behavioral Assessment Test: 4.3 [2.9, 5.2]; Panic Severity, patient: 2.7 [2.2, 4.1] and Panic Severity, clinician: 4.5 [4.5, 6.0].
cally significant (McNamar Test, p 5 .0037 and p 5 .005, respectively).
Depression/Dysphoria Changes in the BDI from week 0 of imipramine treatment were highly significant both from an intent to treat perspective in all 110 subjects (week 0 5 11.3 6 8.2 to last observation carried forward: 5.5 6 6.1, t(107) 5 8.7, p , .0001) and within only the 59 completers (week 0 5 11.6 6 8.1 to week 24 5 2.4 6 2.8, t(56) 5 11.2, p , .0001). In the latter, the times at which 50% improvement was reached by 50% and 100% of the patients were estimated at 1.1 and 18.9 weeks, respectively. Analysis using the 17 item HDRS yielded identical results.
Anxiety Sensitivity Index The significant improvement in Anxiety Sensitivity Index scores from week 0 to imipramine treatment are illustrated in Figure 2 both from an intent to treat perspective and within only the 59 completers. In the latter, the times at which 50% improvement was received by 50% and 100% of the patients were estimated at 2.6 and 20.6 weeks, respectively.
Table 2. Frequency and Severity of Panic Attacks and Response at Baseline and Weeks 8, 26, and 24 Sample means (SD)
Treatment times Baseline (n 5 97) Week 8 (n 5 68) Week 16 (n 5 58) Week 24 (n 5 50)
% of patients
Number of attacks
Severity of attacks
Panic free
Panic index #1
5.7 (4.1) 1.7 (1.9) 1.0 (1.4) 0.2 (0.5)
5.3 (1.5) 2.3 (2.2) 1.4 (1.9) 0.6 (1.5)
0% 29% 55% 80%
0% 47% 69% 90%
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Treatment Integrity
Figure 2. Changes in mean Anxiety Sensitivity Index Score in the 59 completers (Week 0 5 33.6 6 12.0 to Week 24 5 12.5 6 9.2; t(57) 5 13.6, p , .0001) and in all 110 subjects (Week 0 5 29.5 6 11.9 to last observation carried forward 18.1, t(108) 5 10.5, p # .0001) over the course of imipramine 2.25 mg/kg/day protocol.
Quality of Life Figure 3 shows the significant improvement on all SF-36 scales from pretreatment to week 16 of treatment in the protocol completers.
Figure 3. Improvement on SF-36 subscales from pretreatment (shaded bar) to 16 weeks. Protocol completers. The mean changes (6 SD) are all significant at p # .001; physical functioning 5 9.02 (615.1), t[55] 5 4.5; social functioning 5 30.7 (627.2), t[56] 5 8.5; role physical 5 27.1 (642.2), t[56] 5 4.8; role emotional 5 45.4 (642.1), t[56] 5 8.14; mental health 5 30.7 (620.7), t[56] 5 11.2; energy 5 32.2 (625.3), t[56] 5 9.6; pain 5 21.95 (628.5, t[56] 5 5.8, and health perception 5 15.2 (617.25), t[54] 5 6.5.
The mean administered weight adjusted dose of imipramine was 2.18 6 0.05 mg/kg/day yielding an average actual dose of 165.3 6 42.5 mg/day for the total sample. The total (imipramine 1 desipramine) plasma concentrations (6 SD) available at weeks 8 (n 5 74), 16 (n 5 60), and 24 (n 5 54) were 175.13 6 132.71 ng/ml, 177.79 6 124.45 ng/ml, and 191.84 6 142.06 ng/ml, respectively. As a general measure of adherence to the fixed dose protocol, the plasma level to actual imipramine dose (LD) ratio was calculated for protocol completers on available data. The mean (6 SE) LD ratios for week 8 (n 5 57, 1.15 6 .10), week 16 (n 5 53, 1.13 6 .09), and week 24 (n 5 54, 1.19 6 .10) were not significantly different, [analysis of variance (ANOVA): F[2, 1.3] 5 .81, p 5 .447]. Similarly, a multivariate repeated measures analysis based on the 47 subjects with complete plasma data across all three assessments failed to show a significant time effect (F[2, 45] 5 7.29, p 5 .488). The constancy of LD ratios during the 24-week period indicates a high degree of pharmacotherapeutic adherence and renders validity to the analyses of treatment outcomes.
Net Failure of Treatment Of the 110 patients, 51 failed to complete the protocol in stable remission, a net failure rate of 47%. Of these, 33 patients dropped out before week 8, six due to noncompliance and 27 due to typical imipramine side effects (with 22 [89.5%] of these occurring before week 3 of treatment). A further 18 patients dropped out after week 8, three patients for drug side effects, six for noncompliance and nine patients for failure to show good response by week 16 of treatment. Baseline comparisons between treatment success (n 5 59) versus treatment failure (n 5 51) were done on four data bases: (1) demographic, comorbidity, and clinical variables including actual imipramine dosage and whether or not on benzodiazepine at the beginning of treatment; (2) outcome measures constituting the ESF scale, Anxiety Sensitivity Index, and Depression Scales; (3) Panic Diary Measures; and (4) SF-36 variables. Analyses did not show significant differences on demographic, comorbidity, clinical, treatment, or diary variables. On the symptom scales only phobic anxiety and avoidance (completers: 5.9 6 1.5 versus noncompleters: 6.5 6 1.3; t[108] 5 2.01, p 5 .047) showed a difference although this would not achieve statistical significance at the .05 level with a Bonferroni correction. As for SF-36, only pain was significantly different, even with a Bonferroni correction, between completers (59.7 6 24.5) and noncompleters (76.4 6 22.5), t[104] 5 3.63, p , .001. Thus, very few differences emerged between completers and noncompleters, strongly suggesting that the 59 patients who
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achieved stable remission were representative of the entire treatment sample.
Discussion With the advent of newer antidepressants (Preskorn 1994) that share common active mechanisms with imipramine and have more favorable side effect profiles, treatment selection may shift from efficacy-based considerations to practical emphasis on effectiveness (i.e., the likelihood that patients started on a given treatment can take it without adversity and have a successful outcome). This study indicates a net effectiveness of 53% for imipramine in the treatment of panic disorder with agoraphobia. The results obtained under the conditions specified in the present paper should not be interpreted as the effectiveness of imipramine in clinical practice. Rather, they provide a clinically relevant standard reference with which to compare the effectiveness of alternative treatment in providing virtually complete symptom remission in these patients. Although the present results are essentially descriptive and straightforward, the synchronized improvement of different core syndromal components is noteworthy. Secondly, substantial improvement continued past the 8 weeks of treatment to the point that nearly one-half of the patients who were nonresponders at week 8 met full response criteria with continued treatment. These observations strongly suggest that future studies of effectiveness and perhaps even of efficacy of antidepressant drugs should be of at least 16 –24 weeks duration. It is also interesting to note the significant improvement in anxiety sensitivity from levels that are typically found in untreated panic disorder samples down to levels that are characteristic of normal control samples (Peterson & Reiss 1992). The demonstration that imipramine alone reduces anxiety sensitivity challenges the view that “normalization” of the fear or the catastrophic misinterpretation of anxiety symptoms may be selectively mediated through specific cognitive/behavioral treatments (Clark et al 1994; McNally and Lorenz 1987; Peterson and Reiss 1992; Telch et al 1993). Finally, the magnitude of change on the SF-36 dimensions was, in general, commensurate with the difference found on the corresponding dimensions in a study comparing primary care patients with untreated anxiety and those without anxiety (Fifer et al 1994). In terms of calibration of results, note that a nine-point difference in the physical functioning score is equivalent to the effect of having arthritis or back problems, controlling for other medical conditions (Stewart et al 1989). Similarly, a difference of 13 points on the Measure of General Health Perceptions has been reported to be equivalent to the effect on a healthy person of developing diabetes or congestive
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heart failure (Kravitz et al 1992). The present results, for the first time to our knowledge, demonstrate clinically meaningful improvement in functional well-being of the successfully treated patients and show the feasibility of conducting pharmacoeconomic analyses of imipramine and other drug treatments of panic disorder with agoraphobia patients based on quality of life measurements.
Supported by National Institute of Mental Health Grant MH42730 and National Institute of Mental Health Clinical Research Center Grant MH30915. We acknowledge the assistance of Michael Fligner, Ph.D., for the statistical analysis and of Nicholas Votolato, R.Ph., in pharmacy support, and of Dev Pathak, Ph.D., for his helpful suggestions regarding the pharmacoeconomic assessments.
References American Psychiatric Association (1980): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. Washington, DC: American Psychiatric Press. Beck AT, War CH, Medelson M, et al (1961): An inventory for measuring depression. Arch Gen Psychiatry 4:53– 64. Clark DM, Salkovskis PM, Hackmann A, et al (1994): A comparison of cognitive therapy, applied relaxation and imipramine in the treatment of panic disorder. Br J Psychiatry 164:759 –769. Cross-National Collaborative Panic Study, Second Phase Investigators (1992): Drug treatment of panic disorder: Comparative efficacy of alprazolam, imipramine, and placebo. Br J Psychiatry 160:191–202. Fifer SK, Mathis SD, Patrick DL, et al (1994): Untreated anxiety among adult primary care patients in a health maintenance organization. Arch Gen Psychiatry 51:740 –750. Foglia JP, Sorisio D, Perel JM (1991): Determination of imipramine, desipramine and their hydroxy metabolites by reverse phase chromatography with ultraviolet and coulometric detection. J Chromatogr 572:247–258. Hamilton M (1960): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56 – 62. Kravitz RL, Greenfield S, Rogers W, et al (1992): Differences in the mix of patients among medical specialties and systems of care: Results from the Medical Outcome Study. J Am Med Assoc 267:1617–1623. Maier W, Roth M, Argyle N, et al (1991): Avoidance behaviour: A predictor of the efficacy of pharmacotherapy in panic disorder? Eur Arch Psychiatry Clin Neurosci 241:151–158. Marks IM, Mathews AM (1979): Brief standard self-rating for phobic patients. Behav Res Ther 17:263–367. Mavissakalian MR (1996): Antidepressant medications for panic disorder. In: Mavissakalian MR, Prien R, editors. Long-Term Treatments of Anxiety Disorders. Washington DC: American Psychiatric Press. Mavissakalian M, Perel JM (1992): Clinical experiments in maintenance and discontinuation of imipramine in panic disorder with agoraphobia. Arch Gen Psychiatry 49:318 –323. Mavissakalian MR, Perel JM (1994): Dose-response character-
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istics of antipanic effects of imipramine. Psychopharmacol Bull 30:171–174. Mavissakalian MR, Perel JM (1995). Imipramine treatment of panic disorder with agoraphobia: dose-ranging and plasma level-response relationships. Am J Psychiatry 152:673– 682. McNally RJ, Lorenz M (1987). Anxiety sensitivity in agoraphobia. J Behav Ther Exp Psychiatry 18:3–11. Peterson RA, Reiss S (1987): Anxiety Sensitivity Index Manual. Palos Heights: International Diagnostics Systems. Peterson RA, Reiss S (1992): Anxiety Sensitivity Index Revised Test Manual. Worthington OH: International Diagnostics Services. Preskorn SH (1994): Antidepressant drug selection: Criteria and options. J Clin Psychiatry 55(Suppl A):6 –22. Schweizer E, Rickels K, Weiss S, et al (1993): Maintenance drug treatment of panic disorder: Results of a prospective, placebocontrolled comparison of alprazolam and imipramine. Arch Gen Psychiatry 50:51– 60. Spitzer RI, Williams JBW, Gibbon M, et al (1988): Structured
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Clinical Interview for DSM-III-R Patient Version (SCID-P). New York: New York State Psychiatric Institute, Biometrics Research. Stewart A, Greenfield S, Hays RD, et al (1989): Functional status and well-being of patients with chronic conditions: Results from the Medical Outcome Study. J Am Med Assoc 262:907– 913. Telch MJ, Agras WS, Taylor CB, et al (1985): Combined pharmacological and behavioral treatment for agoraphobia. Behav Res Ther 23:325–335. Telch MJ, Lucus JA, Schmidt NB, et al (1993): Group cognitivebehavioral treatment of panic disorder. Behav Res Ther 31:279 –287. Westenberg HG, Drenth BG, DeZeeuw RA, et al (1977): Determination of clomipramine and desmethylclomipramine in plasma by liquid chromatography. J Chromatogr 142:725– 733. Zitrin CM, Klein DF, Woerner MG (1980): Treatment of agoraphobia with group exposure in vivo and imipramine. Arch Gen Psychiatry 37:63–72.
Introduction
I
mipramine is the most extensively studied pharmacologic treatment of panic disorder. Large placebo controlled studies (Cross-National 1992) have firmly established the efficacy of imipramine in panic disorder in general and panic disorder with agoraphobia in particular (Maier et al 1991). A recent dose-ranging study (Mavissakalian and Perel 1995) in panic disorder with agoraphobia has provided incontrovertible evidence for imipra-
From the Department of Psychiatry, the Ohio State University College of Medicine, Columbus, Ohio; and the Clinical Pharmacology Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania . Address requests to Matig R. Mavissakalian, M.D., Department of Psychiatry, Case Western Reserve University, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106. Received September 20, 1996; revised March 22, 1997; revised June 25, 1997; accepted July 9, 1997.
© 1998 Society of Biological Psychiatry
mine’s specific antipanic and antiphobic effects in this more fully developed and usually more severe syndromal form of the disorder. Further evidence suggests that imipramine’s effects become consolidated over 6 months of treatment (Zitrin et al 1980; Telch et al 1985; Clark et al 1994; Schweizer et al 1993) and that continued treatment maintains treatment gains over extended periods of time (Mavissaklian and Perel 1992). The aim of the present paper was to determine the net effectiveness of systematic, open imipramine treatment in panic disorder with agoraphobia patients and to characterize the 6-month treatment outcome in salient symptom and quality of life domains. Because this protocol aimed to transfer optimal pharmacologic treatment in terms of dosing and duration into this large sample, the present results provide a useful reference with which to gauge the effectiveness of newer, primarily nonbenzodiazepine, pharmacologic agents in panic disorder with agoraphobia.
Methods and Materials Subjects Subjects included the first 110 consecutive patients with a diagnosis of panic disorder with agoraphobia who gave informed consent and who started the active open imipramine treatment planned for 24-weeks overall. This protocol preceded an ongoing placebo-controlled, 12-month maintenance phase trial. Subjects, aged 18 – 65 years, contacted the Phobia and Anxiety Disorders Clinic either through clinical referrals or in response to media coverage or advertisement. In addition to meeting DSM-III-R diagnostic criteria for panic disorder with agoraphobia of moderate severity and of at least 3 months’ duration, patients must have been experiencing active recurrent panic attacks at the time of initial evaluation and the fear of panicking or losing control must have been an essential motivation for their escape or avoidance behaviors. Exclusion criteria included evidence of organic mental disorders, psychotic, bipolar, and obsessive-compulsive disorders, primary or current major depression with melancholia, suicidal intention, or a score of $18 on the 17-item Hamilton Depression Rating Scale (HDRS) (Hamilton 1960). Other exclusionary disorders included posttraumatic stress disorder (PTSD), somatization disorder, severe personality (borderline, schizotypal) disorders, and substance abuse disorder current or in remission 0006-3223/98/$19.00 PII S0006-3223(97)00376-4
Effectiveness of Imipramine in Panic Disorder
for less than 6 months. In addition, patients had to be in good general health, have no contraindications for use of imipramine, and be compliant during an initial 2-week single blind placebo run-in. Finally, although the general expectation was to have patients be free of all psychotropic drugs for 14 days before treatment began, an exception was made in the case of patients who were unable to stop benzodiazepines initially, with the proviso that benzodiazepines would be tapered off gradually starting at week 1 of imipramine treatment and completely discontinued by week 16 assessment in order to qualify for randomization to the maintenance study. The sample had a mean age of 36.5 6 9.9 years with a mean age at onset of 26.7 6 9.4 years and a mean duration of illness of 9.7 6 9.2 years. The sample had 14.1 6 2.2 years of education on average, 75 (68%) of them were women, 61 (56%) were married, and 80 (73%) were gainfully employed. One subject met criteria of current major depression, 16 (14.5%) had a history of past depression, 15 (13.6%) had a history of past alcohol abuse, and 17 (15.5%) had a history of abuse for other substances. Thirty-five (31.7%) patients met criteria for one or two concurrent anxiety disorders: 14 (12.7%) had simple phobia, 12 (10.9%) had generalized anxiety disorder, four (3.6%) had social phobia, and five (4.5%) had both generalized anxiety disorder and social phobia. Five (4.5%) patients were on stable thyroid medication in a euthyroid state and 17 (15.5%) of the patients started treatment while on benzodiazepines.
Treatment Following a 2-week, single blind, placebo run-in imipramine was begun. Patients were given consecutively dated packets prepared by the hospital pharmacist, each containing four identical looking tablets composed of placebo or 10, 25, 50, or 75 mg of imipramine hydrochloride to be taken at bedtime. The target dose was 2.25 mg/kg/day of imipramine based on the findings of our recent dose-ranging study (Mavissakalian and Perel 1995). Dose escalation followed a fixed regimen with initial dosing being one-sixth of the target dose for 3 days with equivalent increments every third day such that stable assigned dose was achieved on the 16th day of treatment. At each visit (weekly up until week 4 of treatment, twice a month from week 4 – 8, and monthly thereafter) patients were seen for monitoring of vital signs and side effects, collection of old packets, and provision of new packets of pills for the next period. At the 8-, 16- and 24-week assessments, 12 hours after the preceding dose, blood samples were collected into plasticizer-free evacuated tubes containing eidetic acid powder (Becton Dickinson) and promptly centrifuged. The plasma samples were stored at 220°C for later determination of imipramine and N-desmethylimipramine concentrations by modifications of high-performance-liquid-chromatographic techniques (Mavissakalian and Perel 1995; Westenberg et al 1977; Foglia et al 1991). No additional treatments, in particular, no encouragement or instructions for self-directed exposure to phobic situations or other coping strategies, were given during the trial. For patients on benzodiazepines, a flexible taper was initiated at week 4 usually to be completed by week 8 with the proviso that only
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patients who were successful at stopping benzodiazepines completely for 1 month prior to week 16 assessment would be considered candidates for randomization in the double-blind maintenance study. Patients identified as nonresponders at week 16 were dropped from the study and offered alternative clinically appropriate treatment. The treatment was free.
Assessments The same clinical psychologist (MTG) administered all diagnostic and clinical assessments. Diagnoses were based on the Structured Clinical Interview DSM-III-R, patient version (Spitzer et al 1988) and an independent confirmatory clinical interview by the first author. The assessment battery included the same outcome measures that were validated in our dose-ranging study (Mavissakalian and Perel 1995). The severity of each patient’s condition was assessed by the 5-point Global Assessment of Severity Scale and a 9-point scale of Self-Rating of Severity of Phobia. Clinical measures of agoraphobic fears included the Agoraphobia subscale of the Fear Questionnaire (Marks and Mathews 1979) and a more individualized clinical measure of phobic anxiety and avoidance, consisting of the mean rating of each patient’s five most feared situations on a ninepoint scale. Patients also were asked to take a behavioral assessment test to obtain a functional in vivo measure of phobic anxiety ranging from 0 – 8. Panic attacks were assessed with self-rated and clinician-rated questionnaires using the DSM-III criteria for panic disorder (American Psychiatric Association 1980) definition of panic attacks as “discrete episodes of intense fear or apprehension of sudden onset, not associated with physical exertion. Do not consider fear to be a panic attack if it lasts most of the day or is limited to a specific event or object.” Patients were asked to consider frequency and severity of individual panic attacks of the previous 2 weeks to determine an overall severity rating of panic, using a 0 – 8 point scale (0, none; 2, mild; 4, moderate; 6, severe; and 8, very severe). Similarly, the clinician rated the overall severity of panic attacks on a scale from 0 – 4, ranging from none to very severe. These seven outcome measures, as described in detail elsewhere, were used to assess a composite index of end-state functioning (ESF); range: 0 –7, which has been validated in our dose-ranging study (Mavissakalian and Perel 1992; Mavissakalian 1996). Patients who met response criteria (i.e., either $50% improvement from pretreatment scores or a cutoff score signifying mild to absent symptomatology) simultaneously on six or all of these measures (ESF score $6) were identified as overall syndromal responders, and those who met four or fewer of these criteria (ESF score #4) were identified as nonresponders. Patients were given diary forms and asked to keep a record of the number and severity of their panic attacks for four 2-week periods during the study (i.e., placebo baseline, weeks 7– 8, weeks 15–16, and weeks 23–24). Panic attacks were defined according to DSM-III (American Psychiatric Association 1980). Four variables were derived from the diaries: (1) number of panic attacks; (2) number of days with panic attacks; (3) severity of panic attacks, and (4) peak severity of panic, that is, the most
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Table 1. Stratification of Treatment Response by Endstate Functioning (ESF) Category at Weeks 8, 16, and 24 Treatment times
ESF $ 6 response
ESF 5 5
ESF # 4 nonresponse
Week 8 (n 5 77) Week 16 (n 5 66) Week 24 (n 5 59)
46 (60%) 55 (83%) 58 (98%)a
12 (15%) 5 (8%) 1 (2%)b
19 (25%) 6 (9%) 0
a
One subject still on benzodiazepines. This subject has an ESF of 6 at Week 16.
(100%), and ESF $ 6: 38/46 (83%). The results were significant overall (X2[2] 5 13.659, p 5 .001) and when only the two extreme categories were considered (X2[1] 5 8.339, p 5 .004). Finally, the probability of achieving stable remission in the benzodiazepine (7/17 5 41%) and the nonbenzodiazepine subgroups (52/93 5 56%) was not statistically significant even when the one patient still on benzodiazepine was counted as a nonresponder.
b
Time to Achieve 50% Improvement severe rating given to a panic attack during a given assessment period, based on a 0 – 8 scale (0: none, 2: mild, 4: moderate, 6: severe, and 8: very severe). As described previously in the context of the dose-ranging study, a panic index was developed (range: 0 – 4) by assigning a score of 1 to each of the following panic diary descriptors: at least one panic attack reported, three or more panic attacks, 2 or more days with panic, and peak panic severity $3. A score of #1 on the panic index, signifying no recurrent or severe panic attacks during the 2-week assessment period, was used to identify clinically significant response. Other measures of interest reported in the present study were the Anxiety Sensitivity Index (Peterson and Reiss 1987) to assess the fear of anxiety symptoms that characterize panic disorder, and the Beck Depression Inventory (BDI) (Beck et al 1961) to assess depression and dysphoric mood. Finally, the Medical Outcomes Study Short Form Health Survey (SF-36) (Stewart 1989) was administered at pretreatment and at week 16 of treatment. The SF-36 is a standard measure of quality of life that includes eight subscales, each scored from 0 –100, with 100 representing optimal health status; physical functioning, social functioning, limitations in daily activities caused by physical health (role-physical) or emotional problems (role-emotional), mental health, energy, pain, and general health perceptions.
Results Net Effectiveness of Treatment Of the 110 patients started on imipramine, 77 completed week 8, 66 completed week 16, and 59 went on to week 24 in stable remission, yielding a net effectiveness of 53%. Table 1 presents the proportion of patients meeting three categories of response based on the ESF scale at weeks 8, 16, and 24 of treatment, respectively. Three analyses of interest were applied to these data. First, Bowker’s test of symmetry showed that between weeks 8 and 16 responder status was more likely to improve than to worsen (X2[3] 5 15.4, p 5 .002). Indeed, of the 27 patients who had an ESF score of #5 at week 8, 18 (66%) had improved their response category by week 16 and all but one had achieved an ESF score of $6. Second, we formally tested whether the probability of completing the protocol in stable remission was different in the three response categories at week 8; ESF # 4: 9/19 (47%), ESF 5 5: 12/12
Figure 1 illustrates the change in group means observed on the seven measures constituting the ESF scale in the 59 protocol completers. As a simple summary measure of the rate of improvement, we focused on the time at which subjects achieved 50% improvement. This was defined as follows. On each scale the total improvement was first computed for each subject as the week 24 score minus the pretreatment score. Then, the time at which the subject achieved 50% of their total improvement was computed by fitting a smooth curve (cubic spline) to the subject’s score over time and then estimating the time to 50% improvement from this curve. The median of those times (the time at which one-half the subjects had reached 50% improvement) is marked with arrows in Figure 1. For most measures, this time occurred after approximately 4 weeks of imipramine treatment. A second summary of interest was the percent of subjects whose estimated time to 50% improvement occurred within 8 weeks: Global Assessment of Severity, 61%; Self-Rating of Severity, 86%; Phobic Anxiety and Avoidance, 86%; Fear Questionnaire Agoraphobia, 76%; Behavioral Assessment Test, 81%; Panic Severity (patient), 83%; and Panic Severity (clinician), 80%. Finally, the time at which all of the subjects had reached 50% improvement was estimated to be 12.8 weeks for Global Assessment of Severity, 16 weeks for Self-Rating of Severity, 18.4 weeks for Phobic Anxiety and Avoidance, 22.9 weeks for Fear Questionnaire Agoraphobia, 14.1 weeks for Behavioral Assessment Test, 12 weeks for patient rated Panic Severity, and 12.5 weeks for clinical rated Panic Severity.
Characterization of Treatment Response Panic activity: Table 2 presents the available diary data of the entire sample, e.g., the number and severity of attacks and two response categories at various stages of treatment, Panic Index #1, and panic free status. These data demonstrate continuing improvement over time. Even when completers were considered (week 8, N 5 49; week 16, N 5 51; and week 24, N 5 50), the increase in the percentage of panic free patients from 36.7%–58.8% from weeks 8 –16 and from weeks 16 –24, (80%) was statisti-
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Figure 1. Mean scores in 59 completers at pretreatment (22), start of imipramine treatment (0), and weeks of imipramine 2.25 mg/kg/day protocol. The arrows mark the time at which one-half of the subjects reached 50% of total improvement on the respective measures. Confidence intervals for the means are given in brackets: Global Assessment of Severity: 5.8 [4.8, 6.4]; Self-Rating of Severity: 4 [2.5, 4.5]; Phobic Anxiety and Avoidance: 4 [2.5, 4.5]; Fear Questionnaire, Agoraphobia: 4.8 [4.0, 6.8]; Behavioral Assessment Test: 4.3 [2.9, 5.2]; Panic Severity, patient: 2.7 [2.2, 4.1] and Panic Severity, clinician: 4.5 [4.5, 6.0].
cally significant (McNamar Test, p 5 .0037 and p 5 .005, respectively).
Depression/Dysphoria Changes in the BDI from week 0 of imipramine treatment were highly significant both from an intent to treat perspective in all 110 subjects (week 0 5 11.3 6 8.2 to last observation carried forward: 5.5 6 6.1, t(107) 5 8.7, p , .0001) and within only the 59 completers (week 0 5 11.6 6 8.1 to week 24 5 2.4 6 2.8, t(56) 5 11.2, p , .0001). In the latter, the times at which 50% improvement was reached by 50% and 100% of the patients were estimated at 1.1 and 18.9 weeks, respectively. Analysis using the 17 item HDRS yielded identical results.
Anxiety Sensitivity Index The significant improvement in Anxiety Sensitivity Index scores from week 0 to imipramine treatment are illustrated in Figure 2 both from an intent to treat perspective and within only the 59 completers. In the latter, the times at which 50% improvement was received by 50% and 100% of the patients were estimated at 2.6 and 20.6 weeks, respectively.
Table 2. Frequency and Severity of Panic Attacks and Response at Baseline and Weeks 8, 26, and 24 Sample means (SD)
Treatment times Baseline (n 5 97) Week 8 (n 5 68) Week 16 (n 5 58) Week 24 (n 5 50)
% of patients
Number of attacks
Severity of attacks
Panic free
Panic index #1
5.7 (4.1) 1.7 (1.9) 1.0 (1.4) 0.2 (0.5)
5.3 (1.5) 2.3 (2.2) 1.4 (1.9) 0.6 (1.5)
0% 29% 55% 80%
0% 47% 69% 90%
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Treatment Integrity
Figure 2. Changes in mean Anxiety Sensitivity Index Score in the 59 completers (Week 0 5 33.6 6 12.0 to Week 24 5 12.5 6 9.2; t(57) 5 13.6, p , .0001) and in all 110 subjects (Week 0 5 29.5 6 11.9 to last observation carried forward 18.1, t(108) 5 10.5, p # .0001) over the course of imipramine 2.25 mg/kg/day protocol.
Quality of Life Figure 3 shows the significant improvement on all SF-36 scales from pretreatment to week 16 of treatment in the protocol completers.
Figure 3. Improvement on SF-36 subscales from pretreatment (shaded bar) to 16 weeks. Protocol completers. The mean changes (6 SD) are all significant at p # .001; physical functioning 5 9.02 (615.1), t[55] 5 4.5; social functioning 5 30.7 (627.2), t[56] 5 8.5; role physical 5 27.1 (642.2), t[56] 5 4.8; role emotional 5 45.4 (642.1), t[56] 5 8.14; mental health 5 30.7 (620.7), t[56] 5 11.2; energy 5 32.2 (625.3), t[56] 5 9.6; pain 5 21.95 (628.5, t[56] 5 5.8, and health perception 5 15.2 (617.25), t[54] 5 6.5.
The mean administered weight adjusted dose of imipramine was 2.18 6 0.05 mg/kg/day yielding an average actual dose of 165.3 6 42.5 mg/day for the total sample. The total (imipramine 1 desipramine) plasma concentrations (6 SD) available at weeks 8 (n 5 74), 16 (n 5 60), and 24 (n 5 54) were 175.13 6 132.71 ng/ml, 177.79 6 124.45 ng/ml, and 191.84 6 142.06 ng/ml, respectively. As a general measure of adherence to the fixed dose protocol, the plasma level to actual imipramine dose (LD) ratio was calculated for protocol completers on available data. The mean (6 SE) LD ratios for week 8 (n 5 57, 1.15 6 .10), week 16 (n 5 53, 1.13 6 .09), and week 24 (n 5 54, 1.19 6 .10) were not significantly different, [analysis of variance (ANOVA): F[2, 1.3] 5 .81, p 5 .447]. Similarly, a multivariate repeated measures analysis based on the 47 subjects with complete plasma data across all three assessments failed to show a significant time effect (F[2, 45] 5 7.29, p 5 .488). The constancy of LD ratios during the 24-week period indicates a high degree of pharmacotherapeutic adherence and renders validity to the analyses of treatment outcomes.
Net Failure of Treatment Of the 110 patients, 51 failed to complete the protocol in stable remission, a net failure rate of 47%. Of these, 33 patients dropped out before week 8, six due to noncompliance and 27 due to typical imipramine side effects (with 22 [89.5%] of these occurring before week 3 of treatment). A further 18 patients dropped out after week 8, three patients for drug side effects, six for noncompliance and nine patients for failure to show good response by week 16 of treatment. Baseline comparisons between treatment success (n 5 59) versus treatment failure (n 5 51) were done on four data bases: (1) demographic, comorbidity, and clinical variables including actual imipramine dosage and whether or not on benzodiazepine at the beginning of treatment; (2) outcome measures constituting the ESF scale, Anxiety Sensitivity Index, and Depression Scales; (3) Panic Diary Measures; and (4) SF-36 variables. Analyses did not show significant differences on demographic, comorbidity, clinical, treatment, or diary variables. On the symptom scales only phobic anxiety and avoidance (completers: 5.9 6 1.5 versus noncompleters: 6.5 6 1.3; t[108] 5 2.01, p 5 .047) showed a difference although this would not achieve statistical significance at the .05 level with a Bonferroni correction. As for SF-36, only pain was significantly different, even with a Bonferroni correction, between completers (59.7 6 24.5) and noncompleters (76.4 6 22.5), t[104] 5 3.63, p , .001. Thus, very few differences emerged between completers and noncompleters, strongly suggesting that the 59 patients who
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achieved stable remission were representative of the entire treatment sample.
Discussion With the advent of newer antidepressants (Preskorn 1994) that share common active mechanisms with imipramine and have more favorable side effect profiles, treatment selection may shift from efficacy-based considerations to practical emphasis on effectiveness (i.e., the likelihood that patients started on a given treatment can take it without adversity and have a successful outcome). This study indicates a net effectiveness of 53% for imipramine in the treatment of panic disorder with agoraphobia. The results obtained under the conditions specified in the present paper should not be interpreted as the effectiveness of imipramine in clinical practice. Rather, they provide a clinically relevant standard reference with which to compare the effectiveness of alternative treatment in providing virtually complete symptom remission in these patients. Although the present results are essentially descriptive and straightforward, the synchronized improvement of different core syndromal components is noteworthy. Secondly, substantial improvement continued past the 8 weeks of treatment to the point that nearly one-half of the patients who were nonresponders at week 8 met full response criteria with continued treatment. These observations strongly suggest that future studies of effectiveness and perhaps even of efficacy of antidepressant drugs should be of at least 16 –24 weeks duration. It is also interesting to note the significant improvement in anxiety sensitivity from levels that are typically found in untreated panic disorder samples down to levels that are characteristic of normal control samples (Peterson & Reiss 1992). The demonstration that imipramine alone reduces anxiety sensitivity challenges the view that “normalization” of the fear or the catastrophic misinterpretation of anxiety symptoms may be selectively mediated through specific cognitive/behavioral treatments (Clark et al 1994; McNally and Lorenz 1987; Peterson and Reiss 1992; Telch et al 1993). Finally, the magnitude of change on the SF-36 dimensions was, in general, commensurate with the difference found on the corresponding dimensions in a study comparing primary care patients with untreated anxiety and those without anxiety (Fifer et al 1994). In terms of calibration of results, note that a nine-point difference in the physical functioning score is equivalent to the effect of having arthritis or back problems, controlling for other medical conditions (Stewart et al 1989). Similarly, a difference of 13 points on the Measure of General Health Perceptions has been reported to be equivalent to the effect on a healthy person of developing diabetes or congestive
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heart failure (Kravitz et al 1992). The present results, for the first time to our knowledge, demonstrate clinically meaningful improvement in functional well-being of the successfully treated patients and show the feasibility of conducting pharmacoeconomic analyses of imipramine and other drug treatments of panic disorder with agoraphobia patients based on quality of life measurements.
Supported by National Institute of Mental Health Grant MH42730 and National Institute of Mental Health Clinical Research Center Grant MH30915. We acknowledge the assistance of Michael Fligner, Ph.D., for the statistical analysis and of Nicholas Votolato, R.Ph., in pharmacy support, and of Dev Pathak, Ph.D., for his helpful suggestions regarding the pharmacoeconomic assessments.
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