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An Open Trial of Fluvoxamine for Hypochondriasis
An Open Trial of Fluvoxamine for Hypochondriasis BRIAN A. FALLON, M.D., M.P.H, ALTAMASH I. QURESHI, M.D. FRANKLIN R. SCHNEIER, M.D., ARTURO SANCHEZ-LACAY, M.D. DONNA VERMES, R.N., ROBERT FEINSTEIN, M.D. JOSEPH CONNELLY, M.D., MICHAEL R. LIEBOWITZ, M.D.
The authors conducted a 12-week, open-label trial of fluvoxamine among 18 patients with DSMIV hypochondriasis. Response was defined as a physician-rated CGI improvement rating of at least “much improved.” Four patients discontinued during the 2-week placebo run-in phase. Among 14 patients given fluvoxamine, the response rate was 72.7% (N⳱8 of 11) for those completing at least 6 weeks of the trial (minimum-treatment analysis) and 57.1% (N⳱8 of 14) for the intent-to-treat analysis; these are comparable to rates reported previously for fluoxetine. Significant improvement was also noted on each of the self-report and physician-administered hypochondriasis measures. Fluvoxamine was also well tolerated. A controlled trial is needed. (Psychosomatics 2003; 44:298–303)
H
ypochondriasis is a distressing or disabling disorder characterized by the fear or belief that one has a severe illness on the basis of signs and symptoms. Before the 1990s, this condition was regarded as refractory to most treatments. Because the prevalence of hypochondriasis ranges from 4.2% to 7.7% among medical outpatients,1,2 the care of these patients represents a significant cost to the healthcare system.3–5 Recent reports have suggested that cognitive behavior therapy and selective serotonin reuptake inhibitors (SSRIs) may be particularly beneficial;6,7 these reports offer the promise of relief to patients and a decreased socioeconomic burden to society. Striking phenomenological similarities exist between hypochondriasis and obsessive-compulsive disorder (OCD),8,9 particularly when one considers pathologic doubt and the need to check. Patients with hypochondriasis
may experience pathological doubt about the thoroughness with which symptoms are communicated or examinations and tests conducted, and they may seek to relieve their anxiety by compulsions to check their body for signs of disease or to check with others for reassurance that they are not ill. A family study of OCD10 identified a higher frequency of hypochondriasis among the first-degree relatives of OCD patients relative to those of comparison subjects, providing support for the notion that hypochondriasis may fall within the OCD spectrum. Fluvoxamine, having been shown in numerous studies to be effective for OCD,11 was also reported in a case study to be effective for hypochondriasis.12 Similarities between OCD and hypochondriasis led to the following study examining the effectiveness of fluvoxamine. METHOD
Received Dec. 14, 2001; revision received Sept. 27, 2002; accepted Oct. 18, 2002. From the New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia University; and the Division of Family Medicine, St. Joseph Medical Center, Stamford, Conn. Address reprint requests to Dr. Fallon, New York State Psychiatric Institute, 1051 Riverside Dr., Unit 69, New York, NY 10032. Copyright 䉷 2003 The Academy of Psychosomatic Medicine.
298
Study Design All patients signed informed consent approved by the Institutional Review Board of the New York State Psychiatric Institute and by the Department of Medicine of the Psychosomatics 44:4, July-August 2003
Fallon et al. St. Joseph Medical Center in Stamford, Conn. Recruitment for patients occurred through physician referrals, media advertisements, and direct screening of patients at the St. Joseph Medical Center Family Medicine Clinic. Patients 18 years of age and older underwent comprehensive evaluation by a psychiatrist, who assigned a DSMIV diagnosis.13 Particular attention was paid to reviewing the medical record to ensure that the patient in fact had received an adequate medical workup to exclude other medical conditions that might explain the patient’s symptoms. Patients were then examined by either a study internist or a family medicine physician to confirm that the patient’s illness fears and somatic symptoms did not have an identifiable medical cause. A routine blood workup, ECG, and urinalysis were also conducted. Patients with a medical illness were allowed to enter the study only if 1) the medical illness was clearly stable for the prior year; and 2) the somatic symptoms of concern could not possibly be related to the underlying medical condition. Patients were then interviewed by raters trained in the use of the Structured Clinical Interview for DSM-IV (SCID) to confirm the psychiatrist’s diagnosis and to make sure another diagnosis was not present that could better explain the patient’s concerns (e.g., panic disorder). To enter the study, patients had to have a hypochondriasis rating of at least moderate on the Heightened Illness Concern Severity Scale,7 as rated by the psychiatrist. Patients were excluded from participation if any of the following criteria were met: 1) concurrent major mental disorder (schizophrenia, schizoaffective disorder, bipolar disorder, substance abuse/dependence, major depression with psychotic features, mental disorders due to a general medical condition, or a severe personality disorder that might interfere with treatment compliance); 2) active suicidal ideation; or 3) concurrent use of drugs that could interact in a potentially harmful way with fluvoxamine, such as terfenadine, astemizole, ketoconazole, theophylline, warfarin, and certain antibiotics such as erythromycin, azithromycin, or clarithromycin. Patients with concurrent major depression or dysthymia were allowed to enter the study only if this episode of hypochondriasis started before the onset of the mood disorder. Women who were pregnant, lactating, or not using effective methods of birth control were excluded from the study. Prior to starting the study, patients had to have discontinued all psychoactive medication for at least 2 weeks and fluoxetine for at least 5 weeks, with the single exception of occasional benzodiazepine use for sleep (three or fewer doses per week). The Psychosomatics 44:4, July-August 2003
same restrictions on psychoactive medication use were maintained during the study. To minimize the effects of placebo response and of early dropout for this small, open-label trial, we used a 2week placebo run-in phase before initiating fluvoxamine. The sequence of when the placebo was given was singleblind, i.e., known to the investigator but not the patient. Patients received one placebo pill daily for 2 weeks. Noncompliant patients or patients whose illness concerns were no longer problematic at the end of the placebo run-in phase were dropped from the study. To continue into active treatment, patients had to have a Heightened Illness Concern Severity rating of at least moderate. The Heightened Illness Concern Severity Scale7 is a clinician-rated scale with scores ranging from 1 (no heightened illness concern) to 7 (extreme heightened illness concern). Accompanying the scale is a detailed legend that provides anchors specific to hypochondriasis for each severity level. For example, for a score of 4 or “heightened illness concern of moderate severity,” the legend states the following: “Illness concerns may be occasional (fewer than three episodes per week) and moderately distressing—or— more frequent and mildly distressing. Patient may spend more than 1 hour worrying per episode. Patient may have a moderate urge to check with friends, family, or health professionals for reassurance—or—to avoid illness-related situations.” The clinician-rated Columbia Heightened Illness Concern Obsessive Compulsive Scale represents a slight modification of the Yale-Brown Obsessive Compulsive Scale14—the well-validated and reliable gold standard scale for the rating of change and severity in OCD. Two modifications were made to the original Yale-Brown Obsessive Compulsive Scale. First, the questions and examples all focus on illness thoughts or illness behaviors. Second, items 11 and 12 were added which address illness insight and avoidance; similar to the Yale-Brown Obsessive Compulsive Scale, only the first 10 items are included in the total score. A copy of this scale is available upon request from the authors. The major evaluations at baseline, week 6, and week 10 included patient-rated measures (Whiteley Index, ordinal version;15 Illness Attitude Scale;16 Beck Depression Inventory;17 and the Medical Outcomes Study 36-item ShortForm Health Survey18) and physician-rated measures (Clinical Global Impression [CGI];19 the Heightened Illness Concern Severity Scale;7 Hamilton Depression Rating Scale;20 Hamilton Anxiety Rating Scale;21 and the Columbia Heightened Illness Concern Obsessive Compulsive Scale). The primary outcome measure was the clinician299
Fluvoxamine Treatment of Hypochondriasis rated hypochondriasis change score; response required a rating of “much improved” or “very much improved.” During the 10 weeks of active treatment, the psychiatrist met weekly with the patient. During each visit, the psychiatrist reviewed the patient’s illness-related worries and behaviors of the past week with a particular focus on clarifying the degree of distress, the duration of worry, the amount of social or vocational interference caused by the illness concern, the effort by the patient to resist an illness compulsion, and the degree of control over fears and illness behaviors. During each 30-minute session, the psychiatrist also asked about any treatment-related adverse events and provided encouragement to the patient to continue taking the study medication, since an adequate trial might take up to 12 weeks. More specific forms of therapy (e.g., behavioral, cognitive-educational) were not allowed. The administration of fluvoxamine was based on a fixed/flexible schedule, starting at 50 mg and increasing every 7 days to a maximum dose of 300 mg by the beginning of the 6th week of treatment. Dosage was given on a twice-a-day schedule. In the event of improvement at a lower dose or troubling side effects, the dose was not increased. Response was defined by a physician-rated CGI improvement rating of at least much improved (rating of 2) or very much improved (rating of 1). Minimum treatment to qualify the patient for inclusion in our outcome analysis required at least 6 weeks of fluvoxamine therapy. Statistical Analysis Scores on the various measures were compared statistically at baseline and at week 10 by using a paired-sample t test. All p values ⱕ0.05 were considered statistically significant.
RESULTS Eighteen patients entered this study. Four patients discontinued or dropped out during the placebo run-in phase. Of these four patients, one developed a tooth abscess and chose not to return to the study, one felt his physical symptoms were too severe to continue participation in the study, and two did not return for subsequent evaluations for unknown reasons. Of the 14 patients given fluvoxamine, there were six men and eight women, and the mean age was 37.2 years (SD⳱12.5). Six were Caucasian, one patient was Asian, 300
six were Hispanic, and one was African American. The SCID interviews revealed that three of the 14 treated patients had hypochondriasis unaccompanied by any other axis I disorder, nine had hypochondriasis with a depressive disorder (major depression or dysthymia), and seven had hypochondriasis with an anxiety disorder. Of the 11 patients with comorbid current diagnoses, seven had major depression, three had panic disorder, three had generalized anxiety disorder, two had dysthymia, one had simple phobia, and one had OCD. The median baseline score on the Beck Depression Inventory was 17 (range⳱3–48), while on the 24-item Hamilton depression scale the median score was 16.5 (range⳱7–38). Three of the 14 patients given active drug discontinued before week 6, leaving 11 patients for the minimumtreatment analysis, which required at least 6 weeks of fluvoxamine therapy. Of the three dropouts before week 6, one discontinued after week 1 when he felt reassured after an independently obtained magnetic resonance imaging scan of the brain indicated that there was no brain tumor. The second one dropped out after week 1 because he felt worse and believed he was more likely to get help by active engagement in his religious community. The investigators discontinued the study for the third patient, who was noncompliant with study visits because of travel abroad. Of the 11 patients who completed at least 6 weeks of treatment, one who did not respond discontinued after the week 6 evaluation because an underlying medical illness was uncovered as the cause of the multisystemic symptoms. Two patients who did not respond discontinued at week 8 because of adverse events (tremors in one and decreased sexual responsiveness in the other). The patient with a previously unidentified medical illness had Lyme disease, which was confirmed by the patient’s history and by the presence of immunoglobulin G as determined from a Western blot analysis. The physical and hypochondriacal symptoms resolved after antibiotic therapy. Patients with hypochondriasis showed a significant decrease in their symptom severity between baseline and week 10 as analyzed by various rating scales (Table 1). From a dimensional perspective, statistically significant improvement was noted in hypochondriasis (Whiteley Index, Columbia Heightened Illness Concern Obsessive Compulsive Scale, the Heightened Illness Concern Severity Scale, and selected subscales of the Illness Attitude Scale), in self-reported and clinician-rated depression (Beck Depression Inventory, Hamilton depression scale), and in anxiety (Hamilton anxiety scale). Degree of insight at baseline was not associated with response among those Psychosomatics 44:4, July-August 2003
Fallon et al. who completed at least 6 weeks of the trial: improvement was noted among four of six minimal treatment completers with poor insight and four of five patients with good insight. Similarly, degree of avoidance at baseline was not associated with response: improvement was noted among six of seven patients with significant avoidance of illness situations versus two of four patients with little to no avoidance. From a categorical perspective, of 11 patients given active medication who completed at least 6 weeks, eight (72.7%) responded to treatment. For an intent-to-treat analysis, of all 14 patients who were given active medication, 57.1% responded. On the measures of general health and well-being (36item Short-Form Health Survey), significant improvement was noted at week 10 on the scales measuring physical functioning, role-emotional, and pain. Fluvoxamine was also well tolerated. Of 14 given fluvoxamine, only three discontinued medication because of adverse effects that may have been due to fluvoxamine.
TABLE 1.
DISCUSSION This single-blind study suggests that fluvoxamine may be a beneficial treatment for patients with hypochondriasis. This study is the third report of a series of patients with welldiagnosed hypochondriasis to suggest that pharmacologic treatment with a selective serotonin reuptake inhibitor is helpful. To our knowledge, this is the first trial of fluvoxamine for the treatment of hypochondriasis. The first published open-label series of an SSRI (fluoxetine) reported a 71.4% response rate among 14 patients who completed 12 weeks.22 In a preliminary analysis of a double-blind study of fluoxetine for hypochondriasis, the response rate at 10 weeks was 80% for the 10 fluoxetine-treated patients and 50% for the six patients given placebo.12 The results of the current study indicate a response rate of 72.7% among patients who completed at least 6 weeks of treatment and 57.1% for all 14 patients who entered the 10-week active medication phase. This compares favorably
Baseline and Endpoint Ratings of Hypochondriasis, Depression, and Anxiety Among 11 Patients Who Completed at Least 6 Weeks of Fluvoxamine Treatment Score Week 0 (baseline)
Clinical Scale Heightened Illness Concern Severity Scale Whiteley Index Total Body preoccupation Disease phobia Disease conviction Columbia Heightened Illness Concern Obsessive Compulsive Scale Illness obsessions (1–5) Illness compulsions (6–10) Total (1–10) Insight (item 11) Avoidance (item 12) Illness Attitude Scale Worry about illness Concern about pain Health habits Hypochondriacal beliefs Thanatophobia Disease phobia Bodily preoccupation Treatment experience Effects of symptoms Hamilton Anxiety Rating Scale Beck Depression Inventory Hamilton Depression Rating Scale 21 item 24 item
Psychosomatics 44:4, July-August 2003
Mean
Week 10 (or last rating)
Analysis
SD
Mean
SD
t (dfⴔ10)
p
5.00
0.77
3.64
1.57
4.89
0.001
50.45 12.55 15.36 9.73
10.22 2.02 4.27 3.07
40.91 10.18 12.09 7.45
16.51 4.09 4.11 3.59
2.55 2.32 2.56 3.02
0.03 0.05 0.03 0.02
10.64 7.64 18.27 1.73 1.64
3.70 4.80 7.76 1.01 1.2
6.65 4.00 10.45 1.0 1.09
5.05 4.41 8.87 1.07 1.22
4.27 3.50 4.57 3.07 1.20
0.002 0.006 0.001 0.02 0.26
9.64 909 7.82 6.00 7.18 6.91 8.09 8.27 7.00 19.45 20.27
2.73 2.98 3.49 3.63 4.69 3.11 3.08 2.83 3.46 9.18 13.70
7.82 7.82 6.18 4.82 5.73 5.18 6.36 7.91 5.64 12.64 13.00
3.49 3.25 3.85 3.76 3.95 3.49 3.83 2.55 3.53 7.83 12.25
3.03 2.22 2.28 1.09 1.79 2.16 2.08 1.08 1.87 3.43 2.85
0.02 0.051 0.05 0.31 0.11 0.06 0.07 0.31 0.10 0.006 0.02
16.73 18.00
7.85 9.46
9.91 10.36
7.62 8.61
3.60 3.14
0.005 0.02
301
Fluvoxamine Treatment of Hypochondriasis with previously reported response rates for fluoxetine of 71% and 80%.7,12 As has been demonstrated to be true for the treatment of OCD, failure to respond to one SSRI does not preclude response to another. In a case report,12 a woman with profoundly distressing fears of breast cancer and compulsive ritualistic checking of her body and reassurance seeking with multiple physicians had failed to benefit from a 12-week trial of fluoxetine up to 80 mg/day but did experience marked improvement after 8 weeks of treatment with fluvoxamine, 300 mg/day. On the clinicianrated Columbia Heightened Illness Concern Obsessive Compulsive Scale, significant improvement was noted on the insight item but not on the avoidance item, suggesting that insight into the irrationality of one’s fears is more readily modified by pharmacotherapy than change in illness avoidance behaviors. Further, in this small study group, neither poor insight nor significant avoidance at baseline were associated with poor response. Because the majority of treated subjects had some degree of comorbid affective illness, we cannot be certain that the improvement in hypochondriasis was not merely a reflection of the improvement in depression. Given the small group size, the effect of depression could not be removed as a confounder in the analysis. An independent antihypochondriasis effect is suggested by the observation that in the intent-to-treat group, nearly twice as many patients without comorbid depressive disorders at baseline responded well to therapy (80.0% [N⳱4 of 5]) compared with patients with depressive comorbidity (44.4% [N⳱4 of 9]). Two additional aspects of this study are worthy of note. First, patients with hypochondriasis were able to tolerate fluvoxamine treatment well, with only three of the 14 patients dropping out from adverse effects that might have been drug-related. Second, one patient in the study with the highest level of hypochondriacal anxiety of all patients in our study had persistent symptoms that were not responding to fluvoxamine. At 6 weeks, he presented with a round, red rash with central clearing on his chest. Since this rash looked identical to an erythema migrans rash seen in Lyme disease and this man gardened in a Lyme endemic area, his blood was tested by means of enzyme-linked immunosorbent assay (ELISA) and Western blot, the results of which confirmed the presence of Lyme disease. The blood tests provided evidence of exposure to the spirochete as well as confirmation that this rash was most likely a satellite lesion from past infection. This man was withdrawn from fluvoxamine and instead given oral antibiotics for the Lyme disease. Not only did this man’s physical symptoms resolve by the 6th week of antibiotic therapy but 302
his severe hypochondriasis completely resolved as well. This case highlights the fact that patients with a predisposition to hypochondriacal reactions (this man had a prior episode of hypochondriasis several years earlier) will experience an exacerbation of their hypochondriacal anxiety when faced with physical symptoms due to other medical conditions. Despite efforts to screen carefully for medical illnesses (and this man did have a negative ELISA screening result before our study), there will be patients who have been labeled as having hypochondriasis who in fact may have an as yet undetected medical illness. The signal in this particular patient was that he had failed to respond to fluvoxamine and he had also failed to respond to electroconvulsive therapy 6 months earlier, a treatment that had worked for him in the past. Failure to respond to previously effective treatments should raise the question of another disorder being present. Does this study support the hypothesis that hypochondriasis is a variant of OCD? Only one patient had comorbid OCD, and no patients had comorbid body dysmorphic disorder or an eating disorder; these latter two disorders have strong evidence to support their links to an OCD spectrum. Three patients however did have comorbid generalized anxiety disorder, which in its intrusive worry would be a disorder that shares many obsessional features with disorders in the OCD spectrum. These observations about comorbidity therefore do not provide strong evidence either in favor or against the notion that hypochondriasis should be included within the OCD spectrum. Nor does the favorable response to treatment help in this regard, since fluvoxamine is an agent that is effective for a variety of disorders, including OCD and depression. Trials have been conducted among patients with OCD during which the effectiveness of a more serotonergic agent is compared with that of a more noradrenergic agent. Such a trial would be valuable among patients with hypochondriasis, since it would help to clarify whether hypochondriasis is more like OCD than depression in its response to these agents. The limitations of this study need comment. First, because this was an exploratory rather than a confirmatory study, correction for multiple comparisons on the secondary outcome measures was not conducted. While this approach has the benefit of providing the reader with all significant findings, the disadvantage is that the likelihood of a type I error is increased. Second, the small study group size precludes broad generalizations from these results. Third, although patients were unaware during the trial when the 2 weeks of placebo were administered, the raters were not blind and hence this study should be considered Psychosomatics 44:4, July-August 2003
Fallon et al. an uncontrolled open trial requiring confirmation in a double-blinded placebo-controlled study. The results of this trial suggest that fluvoxamine should be considered when treating a patient with hypochondriasis. These preliminary findings require confirmation in a double-blind, placebo-controlled study.
This study was presented by Dr. Qureshi as a New Research poster presentation at the 153rd annual meeting of the American Psychiatric Association, Chicago, May 13–18, 2000. Funding for this study was provided by Solvay Pharmaceuticals.
References
1. Barsky AJ, Wyshak G, Klerman GL, Latham KS: The prevalence of hypochondriasis in medical outpatients. Soc Psychiatry Psychiatr Epidemiol 1990; 25:90–94 2. Kirmayer LJ, Robbins JM: Three forms of somatization in primary care: prevalence, co-occurrence, and sociodemographic characteristics. J Nerv Ment Dis 1991; 179:647–655 3. Noyes R, Kathol RG, Fisher MM, Phillips BM, Suelzer MT, Woodman CL: One-year follow-up of medical outpatients with hypochondriasis. Psychosomatics 1994; 35:533–545 4. Palsson N: Functional somatic symptoms and hypochondriasis among general practice patients: a pilot study. Acta Psychiatr Scand 1998; 78:191–197 5. Pilowsky I, Smith QP, Katsikitits M: Illness behaviour and general practice utilisation: a prospective study. J Psychosom Res 1987; 31:177–183 6. Warwick HM, Salkovskis PM: Cognitive-behavioral treatment of hypochondriasis, in Hypochondriasis: Modern Perspectives on an Ancient Malady. Edited by Starcevic V, Lipsitt DR. New York, Oxford University Press, 2001, pp 314–328 7. Fallon BA: Pharmacologic strategies for hypochondriasis. Ibid, pp 329–351 8. Fallon BA, Javitch JA, Hollander E, Liebowitz MR: Hypochondriasis and obsessive compulsive disorder: overlaps in diagnosis and treatment. J Clin Psychiatry 1991; 52:457–560 9. Barsky AJ: Hypochondriasis and obsessive compulsive disorder. Psychiatr Clin North Am 1992; 15:791–801 10. Bienvenu OJ, Samuels JF, Riddle MA, Hoehn-Saric R, Liang KY, Cullen BA, Grados MA, Nestadt G: The relationship of obsessivecompulsive disorder to possible spectrum disorders: results from a family study. Biol Psychiatry 2000; 48:287–293 11. Goodman WK, Kozak MJ, Liebowitz M, White KL: Treatment of obsessive-compulsive disorder with fluvoxamine: a multicentre,
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double-blind, placebo-controlled trial. Int Clin Psychopharmacol 1996; 11:21–29 12. Fallon BA, Schneier FR, Marshall R, Campeas R, Vermes D, Goetz D, Liebowitz MR: The pharmacotherapy of hypochondriasis. Psychopharmacol Bull 1996; 32:607–611 13. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, APA, 1994 14. Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, Heninger GR, Charney DS: The Yale-Brown Obsessive Compulsive Scale, I: development, use, and reliability. Arch Gen Psychiatry 1989; 46:1006–1011 15. Pilowsky I: Dimensions of hypochondriasis. Br J Psychiatry 1967; 113:89–93 16. Kellner R: Abridged Manual of the Illness Attitude Scales. Albuquerque, University of New Mexico School of Medicine, Department of Psychiatry, 1987 17. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J: An inventory for measuring depression. Arch Gen Psychiatry 1961; 4:561– 571 18. Ware JE Jr, Sherbourne CD: The MOS 36-Item Short-Form Health Survey (SF-36), I: conceptual framework and item selection. Med Care 1992; 30:473–483 19. Guy W (ed): ECDEU Assessment Manual for Psychopharmacology: Publication ADM 76-338. Washington, DC, US Department of Health, Education, and Welfare, 1976, pp 218–222 20. Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56–62 21. Hamilton M: The assessment of anxiety states by rating. Br J Med Psychol 1959; 32:50–55 22. Fallon BA, Liebowitz MR, Salman S, Schneier FR, Jusino C, Hollander E, Klein DF: Fluoxetine for hypochondriacal patients without major depression. J Clin Psychopharmacol 1993; 13:438–441
303
The authors conducted a 12-week, open-label trial of fluvoxamine among 18 patients with DSMIV hypochondriasis. Response was defined as a physician-rated CGI improvement rating of at least “much improved.” Four patients discontinued during the 2-week placebo run-in phase. Among 14 patients given fluvoxamine, the response rate was 72.7% (N⳱8 of 11) for those completing at least 6 weeks of the trial (minimum-treatment analysis) and 57.1% (N⳱8 of 14) for the intent-to-treat analysis; these are comparable to rates reported previously for fluoxetine. Significant improvement was also noted on each of the self-report and physician-administered hypochondriasis measures. Fluvoxamine was also well tolerated. A controlled trial is needed. (Psychosomatics 2003; 44:298–303)
H
ypochondriasis is a distressing or disabling disorder characterized by the fear or belief that one has a severe illness on the basis of signs and symptoms. Before the 1990s, this condition was regarded as refractory to most treatments. Because the prevalence of hypochondriasis ranges from 4.2% to 7.7% among medical outpatients,1,2 the care of these patients represents a significant cost to the healthcare system.3–5 Recent reports have suggested that cognitive behavior therapy and selective serotonin reuptake inhibitors (SSRIs) may be particularly beneficial;6,7 these reports offer the promise of relief to patients and a decreased socioeconomic burden to society. Striking phenomenological similarities exist between hypochondriasis and obsessive-compulsive disorder (OCD),8,9 particularly when one considers pathologic doubt and the need to check. Patients with hypochondriasis
may experience pathological doubt about the thoroughness with which symptoms are communicated or examinations and tests conducted, and they may seek to relieve their anxiety by compulsions to check their body for signs of disease or to check with others for reassurance that they are not ill. A family study of OCD10 identified a higher frequency of hypochondriasis among the first-degree relatives of OCD patients relative to those of comparison subjects, providing support for the notion that hypochondriasis may fall within the OCD spectrum. Fluvoxamine, having been shown in numerous studies to be effective for OCD,11 was also reported in a case study to be effective for hypochondriasis.12 Similarities between OCD and hypochondriasis led to the following study examining the effectiveness of fluvoxamine. METHOD
Received Dec. 14, 2001; revision received Sept. 27, 2002; accepted Oct. 18, 2002. From the New York State Psychiatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia University; and the Division of Family Medicine, St. Joseph Medical Center, Stamford, Conn. Address reprint requests to Dr. Fallon, New York State Psychiatric Institute, 1051 Riverside Dr., Unit 69, New York, NY 10032. Copyright 䉷 2003 The Academy of Psychosomatic Medicine.
298
Study Design All patients signed informed consent approved by the Institutional Review Board of the New York State Psychiatric Institute and by the Department of Medicine of the Psychosomatics 44:4, July-August 2003
Fallon et al. St. Joseph Medical Center in Stamford, Conn. Recruitment for patients occurred through physician referrals, media advertisements, and direct screening of patients at the St. Joseph Medical Center Family Medicine Clinic. Patients 18 years of age and older underwent comprehensive evaluation by a psychiatrist, who assigned a DSMIV diagnosis.13 Particular attention was paid to reviewing the medical record to ensure that the patient in fact had received an adequate medical workup to exclude other medical conditions that might explain the patient’s symptoms. Patients were then examined by either a study internist or a family medicine physician to confirm that the patient’s illness fears and somatic symptoms did not have an identifiable medical cause. A routine blood workup, ECG, and urinalysis were also conducted. Patients with a medical illness were allowed to enter the study only if 1) the medical illness was clearly stable for the prior year; and 2) the somatic symptoms of concern could not possibly be related to the underlying medical condition. Patients were then interviewed by raters trained in the use of the Structured Clinical Interview for DSM-IV (SCID) to confirm the psychiatrist’s diagnosis and to make sure another diagnosis was not present that could better explain the patient’s concerns (e.g., panic disorder). To enter the study, patients had to have a hypochondriasis rating of at least moderate on the Heightened Illness Concern Severity Scale,7 as rated by the psychiatrist. Patients were excluded from participation if any of the following criteria were met: 1) concurrent major mental disorder (schizophrenia, schizoaffective disorder, bipolar disorder, substance abuse/dependence, major depression with psychotic features, mental disorders due to a general medical condition, or a severe personality disorder that might interfere with treatment compliance); 2) active suicidal ideation; or 3) concurrent use of drugs that could interact in a potentially harmful way with fluvoxamine, such as terfenadine, astemizole, ketoconazole, theophylline, warfarin, and certain antibiotics such as erythromycin, azithromycin, or clarithromycin. Patients with concurrent major depression or dysthymia were allowed to enter the study only if this episode of hypochondriasis started before the onset of the mood disorder. Women who were pregnant, lactating, or not using effective methods of birth control were excluded from the study. Prior to starting the study, patients had to have discontinued all psychoactive medication for at least 2 weeks and fluoxetine for at least 5 weeks, with the single exception of occasional benzodiazepine use for sleep (three or fewer doses per week). The Psychosomatics 44:4, July-August 2003
same restrictions on psychoactive medication use were maintained during the study. To minimize the effects of placebo response and of early dropout for this small, open-label trial, we used a 2week placebo run-in phase before initiating fluvoxamine. The sequence of when the placebo was given was singleblind, i.e., known to the investigator but not the patient. Patients received one placebo pill daily for 2 weeks. Noncompliant patients or patients whose illness concerns were no longer problematic at the end of the placebo run-in phase were dropped from the study. To continue into active treatment, patients had to have a Heightened Illness Concern Severity rating of at least moderate. The Heightened Illness Concern Severity Scale7 is a clinician-rated scale with scores ranging from 1 (no heightened illness concern) to 7 (extreme heightened illness concern). Accompanying the scale is a detailed legend that provides anchors specific to hypochondriasis for each severity level. For example, for a score of 4 or “heightened illness concern of moderate severity,” the legend states the following: “Illness concerns may be occasional (fewer than three episodes per week) and moderately distressing—or— more frequent and mildly distressing. Patient may spend more than 1 hour worrying per episode. Patient may have a moderate urge to check with friends, family, or health professionals for reassurance—or—to avoid illness-related situations.” The clinician-rated Columbia Heightened Illness Concern Obsessive Compulsive Scale represents a slight modification of the Yale-Brown Obsessive Compulsive Scale14—the well-validated and reliable gold standard scale for the rating of change and severity in OCD. Two modifications were made to the original Yale-Brown Obsessive Compulsive Scale. First, the questions and examples all focus on illness thoughts or illness behaviors. Second, items 11 and 12 were added which address illness insight and avoidance; similar to the Yale-Brown Obsessive Compulsive Scale, only the first 10 items are included in the total score. A copy of this scale is available upon request from the authors. The major evaluations at baseline, week 6, and week 10 included patient-rated measures (Whiteley Index, ordinal version;15 Illness Attitude Scale;16 Beck Depression Inventory;17 and the Medical Outcomes Study 36-item ShortForm Health Survey18) and physician-rated measures (Clinical Global Impression [CGI];19 the Heightened Illness Concern Severity Scale;7 Hamilton Depression Rating Scale;20 Hamilton Anxiety Rating Scale;21 and the Columbia Heightened Illness Concern Obsessive Compulsive Scale). The primary outcome measure was the clinician299
Fluvoxamine Treatment of Hypochondriasis rated hypochondriasis change score; response required a rating of “much improved” or “very much improved.” During the 10 weeks of active treatment, the psychiatrist met weekly with the patient. During each visit, the psychiatrist reviewed the patient’s illness-related worries and behaviors of the past week with a particular focus on clarifying the degree of distress, the duration of worry, the amount of social or vocational interference caused by the illness concern, the effort by the patient to resist an illness compulsion, and the degree of control over fears and illness behaviors. During each 30-minute session, the psychiatrist also asked about any treatment-related adverse events and provided encouragement to the patient to continue taking the study medication, since an adequate trial might take up to 12 weeks. More specific forms of therapy (e.g., behavioral, cognitive-educational) were not allowed. The administration of fluvoxamine was based on a fixed/flexible schedule, starting at 50 mg and increasing every 7 days to a maximum dose of 300 mg by the beginning of the 6th week of treatment. Dosage was given on a twice-a-day schedule. In the event of improvement at a lower dose or troubling side effects, the dose was not increased. Response was defined by a physician-rated CGI improvement rating of at least much improved (rating of 2) or very much improved (rating of 1). Minimum treatment to qualify the patient for inclusion in our outcome analysis required at least 6 weeks of fluvoxamine therapy. Statistical Analysis Scores on the various measures were compared statistically at baseline and at week 10 by using a paired-sample t test. All p values ⱕ0.05 were considered statistically significant.
RESULTS Eighteen patients entered this study. Four patients discontinued or dropped out during the placebo run-in phase. Of these four patients, one developed a tooth abscess and chose not to return to the study, one felt his physical symptoms were too severe to continue participation in the study, and two did not return for subsequent evaluations for unknown reasons. Of the 14 patients given fluvoxamine, there were six men and eight women, and the mean age was 37.2 years (SD⳱12.5). Six were Caucasian, one patient was Asian, 300
six were Hispanic, and one was African American. The SCID interviews revealed that three of the 14 treated patients had hypochondriasis unaccompanied by any other axis I disorder, nine had hypochondriasis with a depressive disorder (major depression or dysthymia), and seven had hypochondriasis with an anxiety disorder. Of the 11 patients with comorbid current diagnoses, seven had major depression, three had panic disorder, three had generalized anxiety disorder, two had dysthymia, one had simple phobia, and one had OCD. The median baseline score on the Beck Depression Inventory was 17 (range⳱3–48), while on the 24-item Hamilton depression scale the median score was 16.5 (range⳱7–38). Three of the 14 patients given active drug discontinued before week 6, leaving 11 patients for the minimumtreatment analysis, which required at least 6 weeks of fluvoxamine therapy. Of the three dropouts before week 6, one discontinued after week 1 when he felt reassured after an independently obtained magnetic resonance imaging scan of the brain indicated that there was no brain tumor. The second one dropped out after week 1 because he felt worse and believed he was more likely to get help by active engagement in his religious community. The investigators discontinued the study for the third patient, who was noncompliant with study visits because of travel abroad. Of the 11 patients who completed at least 6 weeks of treatment, one who did not respond discontinued after the week 6 evaluation because an underlying medical illness was uncovered as the cause of the multisystemic symptoms. Two patients who did not respond discontinued at week 8 because of adverse events (tremors in one and decreased sexual responsiveness in the other). The patient with a previously unidentified medical illness had Lyme disease, which was confirmed by the patient’s history and by the presence of immunoglobulin G as determined from a Western blot analysis. The physical and hypochondriacal symptoms resolved after antibiotic therapy. Patients with hypochondriasis showed a significant decrease in their symptom severity between baseline and week 10 as analyzed by various rating scales (Table 1). From a dimensional perspective, statistically significant improvement was noted in hypochondriasis (Whiteley Index, Columbia Heightened Illness Concern Obsessive Compulsive Scale, the Heightened Illness Concern Severity Scale, and selected subscales of the Illness Attitude Scale), in self-reported and clinician-rated depression (Beck Depression Inventory, Hamilton depression scale), and in anxiety (Hamilton anxiety scale). Degree of insight at baseline was not associated with response among those Psychosomatics 44:4, July-August 2003
Fallon et al. who completed at least 6 weeks of the trial: improvement was noted among four of six minimal treatment completers with poor insight and four of five patients with good insight. Similarly, degree of avoidance at baseline was not associated with response: improvement was noted among six of seven patients with significant avoidance of illness situations versus two of four patients with little to no avoidance. From a categorical perspective, of 11 patients given active medication who completed at least 6 weeks, eight (72.7%) responded to treatment. For an intent-to-treat analysis, of all 14 patients who were given active medication, 57.1% responded. On the measures of general health and well-being (36item Short-Form Health Survey), significant improvement was noted at week 10 on the scales measuring physical functioning, role-emotional, and pain. Fluvoxamine was also well tolerated. Of 14 given fluvoxamine, only three discontinued medication because of adverse effects that may have been due to fluvoxamine.
TABLE 1.
DISCUSSION This single-blind study suggests that fluvoxamine may be a beneficial treatment for patients with hypochondriasis. This study is the third report of a series of patients with welldiagnosed hypochondriasis to suggest that pharmacologic treatment with a selective serotonin reuptake inhibitor is helpful. To our knowledge, this is the first trial of fluvoxamine for the treatment of hypochondriasis. The first published open-label series of an SSRI (fluoxetine) reported a 71.4% response rate among 14 patients who completed 12 weeks.22 In a preliminary analysis of a double-blind study of fluoxetine for hypochondriasis, the response rate at 10 weeks was 80% for the 10 fluoxetine-treated patients and 50% for the six patients given placebo.12 The results of the current study indicate a response rate of 72.7% among patients who completed at least 6 weeks of treatment and 57.1% for all 14 patients who entered the 10-week active medication phase. This compares favorably
Baseline and Endpoint Ratings of Hypochondriasis, Depression, and Anxiety Among 11 Patients Who Completed at Least 6 Weeks of Fluvoxamine Treatment Score Week 0 (baseline)
Clinical Scale Heightened Illness Concern Severity Scale Whiteley Index Total Body preoccupation Disease phobia Disease conviction Columbia Heightened Illness Concern Obsessive Compulsive Scale Illness obsessions (1–5) Illness compulsions (6–10) Total (1–10) Insight (item 11) Avoidance (item 12) Illness Attitude Scale Worry about illness Concern about pain Health habits Hypochondriacal beliefs Thanatophobia Disease phobia Bodily preoccupation Treatment experience Effects of symptoms Hamilton Anxiety Rating Scale Beck Depression Inventory Hamilton Depression Rating Scale 21 item 24 item
Psychosomatics 44:4, July-August 2003
Mean
Week 10 (or last rating)
Analysis
SD
Mean
SD
t (dfⴔ10)
p
5.00
0.77
3.64
1.57
4.89
0.001
50.45 12.55 15.36 9.73
10.22 2.02 4.27 3.07
40.91 10.18 12.09 7.45
16.51 4.09 4.11 3.59
2.55 2.32 2.56 3.02
0.03 0.05 0.03 0.02
10.64 7.64 18.27 1.73 1.64
3.70 4.80 7.76 1.01 1.2
6.65 4.00 10.45 1.0 1.09
5.05 4.41 8.87 1.07 1.22
4.27 3.50 4.57 3.07 1.20
0.002 0.006 0.001 0.02 0.26
9.64 909 7.82 6.00 7.18 6.91 8.09 8.27 7.00 19.45 20.27
2.73 2.98 3.49 3.63 4.69 3.11 3.08 2.83 3.46 9.18 13.70
7.82 7.82 6.18 4.82 5.73 5.18 6.36 7.91 5.64 12.64 13.00
3.49 3.25 3.85 3.76 3.95 3.49 3.83 2.55 3.53 7.83 12.25
3.03 2.22 2.28 1.09 1.79 2.16 2.08 1.08 1.87 3.43 2.85
0.02 0.051 0.05 0.31 0.11 0.06 0.07 0.31 0.10 0.006 0.02
16.73 18.00
7.85 9.46
9.91 10.36
7.62 8.61
3.60 3.14
0.005 0.02
301
Fluvoxamine Treatment of Hypochondriasis with previously reported response rates for fluoxetine of 71% and 80%.7,12 As has been demonstrated to be true for the treatment of OCD, failure to respond to one SSRI does not preclude response to another. In a case report,12 a woman with profoundly distressing fears of breast cancer and compulsive ritualistic checking of her body and reassurance seeking with multiple physicians had failed to benefit from a 12-week trial of fluoxetine up to 80 mg/day but did experience marked improvement after 8 weeks of treatment with fluvoxamine, 300 mg/day. On the clinicianrated Columbia Heightened Illness Concern Obsessive Compulsive Scale, significant improvement was noted on the insight item but not on the avoidance item, suggesting that insight into the irrationality of one’s fears is more readily modified by pharmacotherapy than change in illness avoidance behaviors. Further, in this small study group, neither poor insight nor significant avoidance at baseline were associated with poor response. Because the majority of treated subjects had some degree of comorbid affective illness, we cannot be certain that the improvement in hypochondriasis was not merely a reflection of the improvement in depression. Given the small group size, the effect of depression could not be removed as a confounder in the analysis. An independent antihypochondriasis effect is suggested by the observation that in the intent-to-treat group, nearly twice as many patients without comorbid depressive disorders at baseline responded well to therapy (80.0% [N⳱4 of 5]) compared with patients with depressive comorbidity (44.4% [N⳱4 of 9]). Two additional aspects of this study are worthy of note. First, patients with hypochondriasis were able to tolerate fluvoxamine treatment well, with only three of the 14 patients dropping out from adverse effects that might have been drug-related. Second, one patient in the study with the highest level of hypochondriacal anxiety of all patients in our study had persistent symptoms that were not responding to fluvoxamine. At 6 weeks, he presented with a round, red rash with central clearing on his chest. Since this rash looked identical to an erythema migrans rash seen in Lyme disease and this man gardened in a Lyme endemic area, his blood was tested by means of enzyme-linked immunosorbent assay (ELISA) and Western blot, the results of which confirmed the presence of Lyme disease. The blood tests provided evidence of exposure to the spirochete as well as confirmation that this rash was most likely a satellite lesion from past infection. This man was withdrawn from fluvoxamine and instead given oral antibiotics for the Lyme disease. Not only did this man’s physical symptoms resolve by the 6th week of antibiotic therapy but 302
his severe hypochondriasis completely resolved as well. This case highlights the fact that patients with a predisposition to hypochondriacal reactions (this man had a prior episode of hypochondriasis several years earlier) will experience an exacerbation of their hypochondriacal anxiety when faced with physical symptoms due to other medical conditions. Despite efforts to screen carefully for medical illnesses (and this man did have a negative ELISA screening result before our study), there will be patients who have been labeled as having hypochondriasis who in fact may have an as yet undetected medical illness. The signal in this particular patient was that he had failed to respond to fluvoxamine and he had also failed to respond to electroconvulsive therapy 6 months earlier, a treatment that had worked for him in the past. Failure to respond to previously effective treatments should raise the question of another disorder being present. Does this study support the hypothesis that hypochondriasis is a variant of OCD? Only one patient had comorbid OCD, and no patients had comorbid body dysmorphic disorder or an eating disorder; these latter two disorders have strong evidence to support their links to an OCD spectrum. Three patients however did have comorbid generalized anxiety disorder, which in its intrusive worry would be a disorder that shares many obsessional features with disorders in the OCD spectrum. These observations about comorbidity therefore do not provide strong evidence either in favor or against the notion that hypochondriasis should be included within the OCD spectrum. Nor does the favorable response to treatment help in this regard, since fluvoxamine is an agent that is effective for a variety of disorders, including OCD and depression. Trials have been conducted among patients with OCD during which the effectiveness of a more serotonergic agent is compared with that of a more noradrenergic agent. Such a trial would be valuable among patients with hypochondriasis, since it would help to clarify whether hypochondriasis is more like OCD than depression in its response to these agents. The limitations of this study need comment. First, because this was an exploratory rather than a confirmatory study, correction for multiple comparisons on the secondary outcome measures was not conducted. While this approach has the benefit of providing the reader with all significant findings, the disadvantage is that the likelihood of a type I error is increased. Second, the small study group size precludes broad generalizations from these results. Third, although patients were unaware during the trial when the 2 weeks of placebo were administered, the raters were not blind and hence this study should be considered Psychosomatics 44:4, July-August 2003
Fallon et al. an uncontrolled open trial requiring confirmation in a double-blinded placebo-controlled study. The results of this trial suggest that fluvoxamine should be considered when treating a patient with hypochondriasis. These preliminary findings require confirmation in a double-blind, placebo-controlled study.
This study was presented by Dr. Qureshi as a New Research poster presentation at the 153rd annual meeting of the American Psychiatric Association, Chicago, May 13–18, 2000. Funding for this study was provided by Solvay Pharmaceuticals.
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