Psychosomatics 43:290-294, August 2002
© 2002 The Academy of Psychosomatic Medicine
An Open-Label Clinical Trial of Nefazodone in Hypochondriasis
Kevin D. Kjernisted, M.D.,
Murray W. Enns, M.D., and
Mark Lander, M.D.
Received September 6, 2001; revised December 31, 2001; accepted January 17, 2002. From the Department of Psychiatry, University of Manitoba, Winnipeg, Manitoba, Canada. Address correspondence and reprint requests to Dr. Enns, Department of Psychiatry, PZ430 771 Bannatyne Avenue, Winnipeg, Manitoba R3E 3N4, Canada; menns{at}cc.umanitoba.ca (e-mail).
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ABSTRACT
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Hypochondriasis is a common and challenging problem in general medical practice, but little research is available on pharmacotherapeutic treatment approaches. The purpose of the present study was to evaluate the use of nefazodone in the treatment of hypochondriasis in an open-label trial. Eleven patients with a primary diagnosis of DSM-IV hypochondriasis received an 8-week trial of nefazodone with a maximum dose of 600 mg/day and a mean dose of 432 mg. Clinician and self-ratings were completed at each of six visits. Nine of the 11 patients who started the trial completed 8 weeks of treatment. Five of the nine patients completing the trial were rated as much or very much improved on the clinician-rated global improvement scale. Self-ratings indicated statistically significant improvement on the Illness Attitudes Scales—Total Score (P < .01) and the Beck Depression Inventory (P < .04), and there was a trend toward improvement on the Whiteley Index (P < .06). The results of this study suggest that nefazodone is a promising treatment for hypochondriasis. More extensive evaluation in longer open-label trials and double-blind, placebo-controlled trials would be warranted.
Key Words: Nefazodone • Clinical Trial
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INTRODUCTION
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DSM-IV defines hypochondriasis as a preoccupation with fears of having, or the idea that one has, a serious disease based on a person's misinterpretation of bodily symptoms. It persists despite medical reassurance and causes significant distress or impairment. Hypochondriasis is a problem that frequently leads to excessive use of medical resources. Physicians frequently find these patients very frustrating to assess and treat. Despite an estimated prevalence of hypochondriasis of 3%–9% in general medical practice,1–3 relatively little research has been done on possible pharmacotherapeutic treatment approaches.
Hypochondriasis has been found to have frequent comorbidity. Mood, anxiety, somatoform, and substance abuse disorders are all common. There is a 40%–50% rate of comorbid mood disorders, up to a 70% rate of comorbid anxiety disorders, and a 20% rate of comorbid substance abuse disorders.4,5
As recently as 1985, a major psychiatric textbook, Kaplan and Sadock's Comprehensive Textbook of Psychiatry,6 stated that "unless hypochondriasis is part of a depressive disorder with an overt affective disturbance, medications and ECT are without effect." More recently, there have been a number of published case studies of a variety of antidepressant agents (including clomipramine7 and fluoxetine8) that suggest more encouraging prospects for treatment of hypochondriasis. To date, there have been only two reports of open-label trials. In 1991, Wesner and Noyes9 described a study of 10 patients with "illness phobia" subtype of hypochondriasis (who also met the criteria for DSM-III-R hypochondriasis) treated using 125–150 mg of imipramine per day for an 8-week trial. All of the eight who received at least 4 weeks of treatment achieved moderate or greater improvement. Fallon and his colleagues10 described an open-label trial of 12 weeks of fluoxetine (20–80 mg/day) in patients with hypochondriasis without major depression. Ten of 16 patients were much or very much improved.
To date, only a single randomized placebo-controlled trial for hypochondriasis has been reported.11 Unfortunately, only a midstudy report has been published by Fallon and his colleagues in 1996.11 Eight of 12 patients who received fluoxetine were responders as compared to four of eight on placebo over a 12-week trial.
The fact that serotonergic agents have been the most frequently evaluated may relate to the similarities in symptoms of hypochondriasis and obsessive-compulsive disorder.12 A number of authors have commented that these patients tend to be exquisitely sensitive to early side effects.9,13 Nefazodone is a serotonergic antidepressant that has a favorable side-effect profile, causing little sexual dysfunction and improving sleep.14–17 For these reasons, we felt it would be a reasonable choice for this patient group.
To evaluate the efficacy of nefazodone in the treatment of DSM-IV hypochondriasis, we conducted an open-label pilot study with patients recruited specifically for this trial.
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METHODS
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Patients for the study were recruited with the use of a newspaper advertisement that described a study of the treatment of "Intense Illness Worries." The advertisement asked questions that parallel the DSM-IV criteria for hypochondriasis (e.g., Do you fear that you have a serious medical illness, such as cancer or heart disease, that doctors have missed? Do others say you worry about your health too much?). Individuals who appeared to be suitable during a telephone screening interview had a clinical evaluation including the Structured Clinical Interview for DSM-IV Patient Version.18 Inclusion criteria for the study were a primary DSM-IV diagnosis of hypochondriasis, medical examination and tests that were normal or that indicate abnormalities that were not related to the diagnosis of hypochondriasis and the worries experienced by the patient, negative urinary screen for psychiatric medications and drugs of abuse, and, in the case of female participants, using a reliable method of birth control. Exclusion criteria were history of bipolar disorder or psychotic disorder, psychoactive substance abuse disorder (within the last 6 months), and any medical or psychiatric condition that would contraindicate participation in the study. To increase our confidence that observed improvement during nefazodone treatment was related to the study drug, patients did not receive psychiatric treatment of any other kind during the study period (psychotropic medications were not allowed within the previous 2 weeks). Comorbid diagnoses were allowed provided that hypochondriasis was the most clinically important disorder. Fifteen patients with hypochondriasis were formally screened, and 11 individuals met the entry criteria for the study and provided written informed consent after the procedures and potential side effects were fully explained.
Nefazodone was initially started at 50 mg twice a day and increased by 100 mg/day in weekly increments until the total dosage reached 300 mg/day. Further dosage increases of 50–100 mg/day were allowed according to clinical response and adverse events. The maximum dose was 600 mg/day, and the mean dose was 432 mg (SD = 98). Patients were seen at weeks 0, 1, 2, 3, 5, and 8 for a total of six visits. Visits included self and observer ratings and medication management but no other therapy.
Clinician ratings with the Clinical Global Impression (CGI) Scale (Severity at the first visit, Improvement and Severity at the last visit),19 the Hamilton Anxiety Scale,20 and the Hamilton Depression Scale (HamD)21 were completed on the first and the last study visits. The patients also completed self-report symptom ratings: the Illness Attitudes Scale (IAS)22 and the Beck Depression Inventory23 at every visit and the Whiteley Index24 at the first and last visits. The IAS consists of 21 items rated on a five-point scale. Eight subscales were considered: Illness Worry, Concern About Pain, Health Habits, Hypochondriacal Beliefs, Disease Phobia, Body Preoccupation, Thanatophobia, and Symptom Effect. The Treatment Experience subscale (which describes use of health services) was not used because the time frame of the scale is longer than the period of the study. In addition to subscale scores, the present study used a total score on the IAS as an overall indicator of hypochondriasis symptoms. Although the IAS was not originally designed to yield a total score, there is psychometric evidence that the IAS subscales are related to a single higher-order factor,25 and total scores on the IAS have proven sensitive to change during treatment for hypochondriasis.26
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RESULTS
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Nine of the 11 patients who started the trial completed 8 weeks of acute treatment. A summary of patient characteristics and overall response to treatment is presented in Table 1. Patient 10 withdrew consent after 3 weeks of treatment with minimal improvement. Patient 11 dropped out because of lack of response.
Treatment with nefazodone at moderate doses (300–600 mg/day) was well tolerated. Side effects were generally mild to moderate and diminished with increasing length of treatment. The most commonly observed side effects included dry mouth (N = 3), lightheadedness (N = 3), nausea (N = 2), and headaches (N = 2). The response rate based on a CGI score of one or two (very much or much improved) was five of nine for patients completing 8 weeks of treatment and five of 11 for patients beginning the trial.
Paired-sample t tests were conducted to compare baseline versus week 8 scores on the secondary outcome measures for the nine completers. The results are presented in Table 2. All scales showed significant improvement except two subscales of the IAS (Thanatophobia and Symptom Effect) and the Whiteley Index (which showed a nonsignificant trend toward improvement).
Table 3 presents the longitudinal course of change in illness worry (IAS-total) and self-reported distress (BDI) over the 8-week course of treatment.
Change in hypochondriasis symptoms was associated with change in depression symptoms. The correlation between change scores on the IAS and change scores on the HamD was r = 0.588 (P = 0.096).
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DISCUSSION
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It is desirable to have a range of treatments available for common and challenging clinical problems. This is particularly true for hypochondriasis because of the wide range of comorbid conditions that occur along with it. While there have been several controlled trials of cognitive-behavioral treatments for hypochondriasis with promising results,27–29 there has been very limited research on pharmacological treatment of hypochondriasis. To our knowledge, this is the first report of the use of nefazodone in this population. Given the difficulty of this clinical problem, the results were promising, with clinical global improvement ratings of "much improved" or "very much improved" for five of nine for patients completing 8 weeks of treatment and five of 11 for patients beginning the trial. Further, the treatment was well tolerated, which is noteworthy given the sensitivity to side effects commonly noted in this population.9,10 For the completers, improvements over time were seen in self-report measures specifically assessing symptoms of hypochondriasis, including most of the subscales of the IAS and a trend toward improvement in the Whiteley Index. The original version of the Whiteley Index, which uses a yes/no response format, was used in the present study. A newer version of the Whiteley Index30 that uses a five-point response format may have been a more sensitive measure of change. Meaningful changes were also seen in broader measures of anxiety and depression. These findings were considered encouraging, given the small sample size and the limited power of the statistical tests. However, given the open-label design of the study, it is not possible to determine how much of the observed improvement may reflect patients' and clinicians' positive expectations (i.e., expectancy effects).
In the limited number of published studies on the treatment of primary hypochondriasis, there has been a lack of consistency in the measures of hypochondriasis that have been used. Many of the studies have reported measures used only by that research group. For now, it may be best to include a range of measures in each study to allow comparisons among studies. The IAS used in the present study is becoming one of the more widely used and researched measures.
An association between change in depression symptoms (HamD) and change in hypochondriasis symptoms (IAS) was observed in the present study; r = 0.588, P = 0.096 (see also Table 3). This raises an important question about the mechanism of improvement of hypochondriasis symptoms. To what extent does nefazodone have an effect on hypochondriasis independent of its known antidepressant effects? Some degree of association between change in hypochondriasis and change in depression symptoms is to be expected since measures of "depression" capture general subjective distress (not exclusively symptoms due to major depressive disorder), and improvement in one's primary disorder should be accompanied by a reduction of general distress. However, two of the patients rated as "much improved" by clinicians (patients 2 and 4) were not suffering from any comorbid Axis I disorders, suggesting that at least some patients may experience benefit in the absence of diagnosable depressive illness.
Clearly, it would be helpful to have more and longer open-label trials and placebo-controlled trials of pharmacological treatments for primary hypochondriasis to provide more direction to the clinician in treating this challenging population. The results of this and other open-label trials are encouraging but should be interpreted with caution until a wider range of placebo-controlled trials are available.
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ACKNOWLEDGMENTS
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This study was supported in part by an unrestricted grant from Bristol-Meyers Squibb Canada. Thanks to Drs. Trish Furer, Norah Vincent, and John Walker for their assistance in carrying out this study.
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REFERENCES
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[Abstract]
[Full Text]
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ABSTRACT
INTRODUCTION
