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Psychosomatics 47:348-352, August 2006
doi: 10.1176/appi.psy.47.4.348
© 2006 Academy of Psychosomatic Medicine
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Somatic Symptoms in Outpatients With Major Depressive Disorder Treated With Fluoxetine

John W. Denninger, M.D., Ph.D., George I. Papakostas, M.D., Yasmin Mahal, B.A., Wendelien Merens, M.A., Jonathan E. Alpert, M.D., Ph.D., Andrew A. Nierenberg, M.D., Albert Yeung, M.D., and Maurizio Fava, M.D.

Received October 5, 2005; accepted October 7, 2005. From the Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA. Address correspondence and reprint requests to Dr. Denninger, Massachusetts General Hospital, Depression Clinical and Research Program, Dept. of Psychiatry, 50 Staniford St., Suite 401, Boston, MA 02114-2541. e-mail: jdenninger{at}partners.org


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 
Among patients with major depressive disorder (MDD), physical and somatic symptoms are associated with a high degree of disability and healthcare utilization. However, little is known regarding the treatment of these symptoms with standard pharmacotherapy. To measure somatic symptoms of depression, the authors administered The Symptom Questionnaire (Kellner) before and after 8 weeks of open-label treatment with fluoxetine, 20 mg/day, in 170 MDD outpatients (mean age: 40.4 years). Somatic symptom scores decreased significantly after fluoxetine treatment. The degree of reduction in somatic symptoms was significantly and positively correlated with the degree of improvement in depressive symptoms as measured by the 17-item Hamilton Rating Scale for Depression (Ham-D). Somatic symptom scores at baseline did not predict the degree of reduction in Ham-D scores during treatment. However, fluoxetine-remitters had significantly lower somatic symptom scores at end-point than responders who did not remit. Taken together, these findings suggest that developing treatment strategies that successfully target somatic symptoms of depression may further improve the ability to treat depression to remission.


  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 
Increasingly, somatic symptoms have been recognized to play a greater role in major depressive disorder (MDD) than is reflected in the current nosology.1 In fact, physical and somatic symptoms are highly prevalent in MDD and present in rates that are comparable to those of the most common psychological symptoms.2 As many as 76% of patients suffering from MDD reported somatic symptoms, including various types of pain, such as headaches, stomach pain, back pain, and poorly localized pain.3,4 Physical symptoms such as back pain, musculoskeletal complaints, and chest pain have been shown to be associated with greater depression severity,5 and somatic complaints have been shown to predict subsequent depressive symptoms, at least in women.6 Furthermore, among patients suffering with MDD, physical and somatic symptoms are associated with a high degree of disability and healthcare utilization.7–9

In studies addressing the effect of antidepressant treatment on somatic symptoms of depression, there is evidence that somatic symptoms improve with such treatment. For example, in a study of MDD patients who had not responded to selective serotonin reuptake inhibitors (SSRIs), we reported a significant reduction in somatic symptoms of depression, as measured by a symptom questionnaire,10 after treatment with open-label mirtazapine.11 Duloxetine, a dual serotonin and norepinephrine reuptake inhibitor, also appears to be effective in the treatment of somatic symptoms of depression, such as pain.12,13 Also, our group found a greater number of somatic symptoms at baseline to predict poorer response to nortriptyline among MDD patients who had failed to experience significant improvement to a number of antidepressant trials of adequate dosage and duration.14 Despite these findings, however, the impact of somatic symptoms on the treatment of depression with SSRIs, the most commonly selected first-line pharmacotherapy for depression,15 has been inadequately studied.16 In the present work, we evaluated 1) the relationship between the severity of somatic symptoms of depression at baseline and clinical response; and 2) the impact of the treatment of MDD on somatic symptoms of depression in MDD outpatients enrolled in an 8-week, fixed-dose, open-label trial of 20 mg of fluoxetine.


  METHOD

 
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 ABSTRACT
 INTRODUCTION
 METHOD
RESULTS
 DISCUSSION
 REFERENCES
 
Outpatients, ages 18–65 years, who met criteria for a current major depressive episode according to the Structured Clinical Interview for DSM-III-R17 and were medication-free for at least 2 weeks, with a baseline 17-item Hamilton Rating Scale for Depression (Ham-D)18 score ≥16, were eligible to enroll in an 8-week, fixed-dose, open-label trial of 20 mg fluoxetine conducted at the Massachusetts General Hospital Depression Clinical and Research Program. Patients were recruited through radio advertisements, newspaper advertisements, or colleague referrals.

Exclusion criteria included pregnancy and being a woman of childbearing age who was not using a medically-accepted means of contraception; being a woman of childbearing age taking a birth control pill or lactating; having serious suicidal risk or serious, unstable medical illness, a history of seizure disorder, a DSM-III-R diagnosis of organic mental disorder, substance use disorder—including alcohol—active within the last year, schizophrenia, delusional disorder, psychotic disorders not elsewhere classified, bipolar disorder, or antisocial personality disorder; a history of multiple adverse drug reactions or allergy to the study drugs; having mood-congruent or mood-incongruent psychotic features; currently using other psychotropic drugs; clinical or laboratory evidence of hypothyroidism; having depression that had failed to respond in the past to a trial of fluoxetine, or to the combination of fluoxetine and desipramine, or the combination of fluoxetine and lithium; and failing to respond during the course of their current major depressive episode to at least one adequate antidepressant trial, defined as 6 weeks or more of treatment with either >150 mg of imipramine (or its tricyclic equivalent) or >60 of phenelzine (or its monoamine oxidase inhibitor equivalent).

During the screening visit, all enrolled patients signed an Institutional Review Board-approved written informed consent form. A medical and psychiatric history, physical examination, serum chemistries, hematological measures, ECG, and urine pregnancy test were then performed. The 31-item version of the Ham-D,18 which allows the scoring of the 17-item version, was also administered during the screening visit and during all subsequent visits. The screening visit was conducted by experienced psychologists or psychiatrists extensively trained in the use of the 31-item Ham-D scale through didactic sessions and periodic reviews of videotaped interviews. The interrater reliability for the use of the SCID–P Mood module for the psychologists or psychiatrists involved in the study was estimated as {kappa}=0.80.19 At the conclusion of the screening visit, all enrolled patients were asked to return 1 week later for the baseline visit. Patients who returned for their baseline visit (N=384) were started on a 20-mg, fixed-dose regimen of fluoxetine. Subsequent to the baseline visit, patients returned every other week for a total of 8 weeks. The Ham-D was administered during all study visits.

Assessment of Somatic Symptoms of Depression
The presence and number of somatic symptoms was assessed during the baseline visit by use of Kellner's Symptom Questionnaire. Because this scale was introduced later in the study, it was administered to a subset (N=170) of subjects enrolled. The Symptom Questionnaire (SQ) is a 92-item, self-rated questionnaire that includes four scales (Anxiety, Depression, Somatic Symptoms, and Anger/Hostility). It has been widely used in clinical studies and has shown excellent sensitivity to detect change in somatic symptoms after treatment.10,11 The 23-item Somatic scale is composed of items that include both negative (17 items) and positive (6 items) somatic symptoms. (To clarify: we will refer to scores on the 23-item scale, both positive and negative, as "Somatic Symptom scores.") The 17 negative somatic symptoms are as follows: feeling of not having enough air, heavy arms or legs, appetite poor, tight head and neck, choking feeling, feeling of pressure in head or body, weak arms or legs, breathing difficult, parts of the body feel numb or tingling, heart beating fast or pounding, pressure on head, nauseated/sick to stomach, upset bowels or stomach, muscles pains, headaches, cramps, head pains. The six positive somatic symptoms are as follows: feeling healthy, feeling fit, no pains anywhere, arms and legs feel strong, no aches anywhere, no unpleasant feelings in head or body.

Definition of Outcome Measures and Statistical Analyses
Treatment response was defined as a ≥50% decrease in score on the Ham-D from baseline to endpoint. An intent-to-treat analysis with the last observation carried forward was used to define the severity of depression at endpoint; for patients who prematurely discontinued the study, the last recorded Ham-D score was used as the endpoint score.

Simple linear regression was used to assess the relationship between somatic symptom score at baseline and either degree of baseline depression severity or degree of clinical improvement. The same method was used to assess the relationship between Somatic Symptom score at endpoint and degree of depression severity at endpoint. We defined Responders as those patients with a ≥50% reduction in Ham-D scores from baseline to endpoint,20 Remitters as those patients with scores ≤5, and Responders Without Remission as those Responders with scores ≥6. We have defined remission as Ham-D score ≤5 because previous, less restrictive definitions of remission, such as scores ≤7, have been shown to be associated with significant residual symptoms.21 Analysis of variance (ANOVA) was used to compare Somatic Symptom scores between Remitters and Responders Without Remission.


  RESULTS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
DISCUSSION
 REFERENCES
 
In summary, a total of 324 (84.4%) of the 384 patients in the study completed the open trial; there were 60 dropouts (15.6%). Of the 384 patients, 193 (50.3%) responded, and 148 (38.5%) had acute remission, with final Ham-D scores of 5 or lower. There were no statistically significant differences between patients who did (N=170) and did not (N=214) have baseline Somatic Symptom scores in terms of gender ratio (female subjects: 58.2% [N=99] and 51.8% [N=111], respectively), age (40.4 [SD=11.2] and 39.4 [SD=10.1] years), baseline Ham-D scores (19.7 [SD=3.3] and 19.7 [SD=3.6]), duration of the current major depressive episode (3.2 [SD=5.2] and 3.4 [SD=6.1] years), or the age at onset of MDD (25.4 [SD=13.0] and 25.8 [SD=12.9] years). Of the 170 patients who had baseline Somatic Symptom scores, there were 155 Completers (91.2%), 15 dropouts (8.8%), 95 Responders (55.9%), and 50 Remitters (29.4%).

Among the 170 outpatients with MDD who completed the Symptom Questionnaire at baseline, the Somatic Symptom scores decreased significantly after treatment, from a mean of 9.6 (SD=5.6) to 6.1 (SD=5.3; paired t=7.2; p<0.0001). Also, Somatic Symptom scores at baseline were significantly related to baseline depression severity (r=0.47; p<0.0001) but were not significantly related to the degree of improvement in depressive symptoms (as measured by the change in Ham-D score in the intent-to-treat group) after fluoxetine treatment. However, the degree of reduction in Somatic Symptoms was significantly correlated with the degree of change in Ham-D scores (r=0.34; p<0.0001). Among Responders (N=95), the 50 who achieved remission had significantly lower Somatic Symptom scores at endpoint (mean: 3.4; SD: 3.4) than did the 45 Nonremitters (mean: 5.2, SD: 4.2; F=5.3; p<0.03).


  DISCUSSION

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
REFERENCES
 
To our knowledge, this is the first study to report on the effect of treatment with SSRIs on somatic symptoms in MDD. We found both a significant decrease in somatic symptoms during treatment with fluoxetine and a positive correlation between the change in somatic symptoms and the change in overall depression severity. Also, although—as found by Small et al.16—a greater severity of somatic symptoms at baseline did not predict poorer response to fluoxetine, fluoxetine-remitters had significantly fewer somatic symptoms at endpoint than responders who did not go on to experience full remission of symptoms.

This association between incomplete response and somatic symptoms may be viewed in different ways. Somatic symptoms may simply represent a depression symptom that is incompletely treated in responders to fluoxetine treatment who do not remit. In this case, somatic symptoms may be state-markers of depression that do not require independent treatment and are likely to improve with treatment in parallel with other depressive symptoms. In support of this view, the change in somatic symptoms reported by patients was significantly related to the change in overall depression severity. Alternatively, given that our data demonstrate only a moderate correlation between change in somatic symptoms and change in Ham-D scores with fluoxetine treatment, it is possible that antidepressant treatment of somatic symptoms proceeds by a different mechanism, as well (e.g., a direct effect on pain), given the importance, as pointed out in a review by Fava,22 of both the serotonin and norepinephrine neurotransmitter systems in mediating physical symptoms of MDD. One may therefore postulate that changes in somatic symptoms occurring with antidepressant treatment reflect both the general improvement in depressive symptoms and the specific effects of the antidepressant treatment on physical symptoms such as pain. This latter hypothesis is supported by a recent study showing that treatment with the serotonin–norepinephrine reuptake-inhibitor (SNRI) duloxetine significantly reduced pain compared with placebo in depressed outpatients and that the improvements in pain severity were attributable equally to the direct effect of duloxetine and to associated changes in depression severity.23

The literature on antidepressant treatment of pain and somatic syndromes provides some insight into this question: Perhaps because of their ability to inhibit the reuptake of both serotonin and norepinephrine, as well as their ability to block sodium channels, the tricyclic antidepressants appear to be more effective in treating neuropathic pain than do the SSRIs.24 In fact, the results of a separate metaanalysis reveal the tricyclic antidepressants to be superior to the SSRIs in the treatment of a number of somatic/pain disorders often diagnosed in patients with chronic depression, including headaches, fibromyalgia, irritable bowel disorder, idiopathic pain, tinnitus, and chronic fatigue.25 In parallel, although the monoamine oxidase inhibitors (MAOIs) also seem to be effective in the treatment of fatigue in fibromyalgia or chronic fatigue syndrome,26–30 SSRIs had no effect on fatigue in four out of five studies.31–35 Also, dual-acting antidepressants, such as most tricyclic antidepressants,36 mirtazapine,11 and duloxetine,12,13,23 may be particularly effective in treating somatic symptoms of depression. Studies comparing SSRIs with dual-acting antidepressants for MDD patients with prominent somatic complaints could help clarify whether antidepressants acting on the noradrenergic system, in addition to the serotonergic system, are more effective than serotonergic-specific agents in treating depression in this population. In light of our finding of significantly more somatic symptoms in responders who do not completely remit, it is possible that failing to adequately treat somatic symptoms may make it more difficult to treat depression to remission.

One limitation of the present study is the absence of placebo treatment, which would help clarify any potential impact of somatic symptoms on true drug response versus placebo response. Second, because of the relatively strict inclusion and exclusion criteria involved for participation in this trial, it may be difficult to generalize our results to the general population of outpatients with MDD. The exclusion of patients with severe comorbid medical illness similarly limits the ability to generalize these results to a population with a presumably high rate of somatic complaints. Third, this study does little to address causality in the changes in somatic symptoms with fluoxetine treatment. For example, medication side effects may have increased somatic symptom scores even as the desired effect of the medication may have been decreasing them. Future studies addressing these limitations are necessary to shed light on the relationship between somatic symptoms and MDD. Nevertheless, our findings are notable in demonstrating that, in a sample of outpatients with MDD, whereas treatment with fluoxetine results in significant decreases in somatic symptoms in general, remitters had significantly fewer somatic symptoms than responders who did not go on to experience full remission of depression symptoms.


  ACKNOWLEDGMENTS

 
John W. Denninger, M.D., Ph.D., has received research support from Aspect Medical Systems, Merck and Co., Inc., and Pfizer, Inc. Jonathan E. Alpert, M.D., Ph.D., has received research support from Aspect Medical Systems, Eli Lilly and Co., Forest Pharmaceuticals, and Pfizer, Inc. He has received research support and honoraria from Organon, Inc., and has received research support and consulting fees from Pharmavite LLC and Pamlab LLC.

This study was supported by NIMH Grant #R01-MH-48-483-05 (MF).


  REFERENCES

 
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 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 

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This Article
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* Articles by Denninger, J. W.
* Articles by Fava, M.
Related Collections
* Depression
* Somatoform Disorders

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