A Prospective Trial of Sertraline for Chronic Subjective Dizziness

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The Laryngoscope Lippincott Williams & Wilkins, Inc. © 2004 The American Laryngological, Rhinological and Otological Society, Inc.

A Prospective Trial of Sertraline for Chronic Subjective Dizziness Jeffrey P. Staab, MD, MS; Michael J. Ruckenstein, MD; Jay D. Amsterdam, MD

Objectives/Hypothesis: The authors previously reported that selective serotonin reuptake inhibitors (SSRIs) reduce chronic subjective dizziness in patients with and without psychiatric illnesses. To extend those preliminary findings and test the hypothesis that SSRIs may offer a novel treatment for chronic subjective dizziness, the authors conducted a prospective study of sertraline in patients with dizziness for more than 6 months, in the absence of active physical neurotologic illness. Study Design: Sixteenweek, prospective, open-label, flexible-dose clinical trial. Methods: Twenty-four patients with subjective dizziness for more than 6 months and no active physical neurotologic illness were studied. Eighteen patients had major anxiety disorders. Six had minor frustration or worry that did not warrant a psychiatric diagnosis. Sertraline was administered at a daily dose of 25 mg, which was increased to a maximum daily dose of 200 mg. Dizziness, functional impairment, and psychological distress were measured using the Dizziness Handicap Inventory (DHI) and Brief Symptom Inventory-53 (BSI-53). Treatment outcomes were analyzed using repeated-measures multivariate analyses of variance, with last observations carried forward. Results: Three patients were excluded from data analysis for disqualifying medical conditions, one for protocol violations. Fifteen (75%) patients completed treatment. Five (25%) withdrew for adverse effects or lack of efficacy. The median daily dose of sertraline was 100 mg. Sertraline significantly reduced scores on all three DHI subscales and the BSI53. Eleven of 15 (73%) patients who completed treatment had a positive response, including 8 of 11 (73%) with major anxiety disorders and 3 of 4 (75%) with no Presented in part at the 156th Annual Meeting of the American Psychiatric Association, San Francisco, CA, May 20, 2003, and the 50th Annual Meeting of the Academy of Psychosomatic Medicine, Coronado, CA, November 20, 2003. From the Departments of Psychiatry (J.P.S., J.A.) and Otorhinolaryngology—Head and Neck Surgery (J.P.S., M.J.R.), Balance Center (J.P.S., M.J.R.), and Depression Research Unit (J.D.A.), University of Pennsylvania Health System, Philadelphia, Pennsylvania, U.S.A. Supported by an unrestricted grant from Pfizer, Inc. Editor’s Note: This Manuscript was accepted for publication February 19, 2004. Send Correspondence to Jeffrey P. Staab, MD, MS, Departments of Psychiatry and Otorhinolaryngology—Head and Neck Surgery, Hospital of the University of Pennsylvania, 3400 Spruce Street, Founders Pavilion F11.015, Philadelphia, PA 19104, U.S.A. E-mail: jeffrey.staab@uphs. upenn.edu

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psychopathological conditions. Six patients enjoyed a full remission of symptoms. Conclusion: Sertraline significantly reduced chronic subjective dizziness in patients without active physical neurotologic illness, including those with and without psychiatric comorbidity. Key Words: Dizziness, psychiatric disorder, sertraline, serotonin, serotonin uptake inhibitor. Laryngoscope, 114:1637–1641, 2004

INTRODUCTION Among patients evaluated for dizziness, a subgroup of individuals has vague, nonspecific symptoms that do not correspond to an active physical illness. These patients have chronic lightheadedness or fullness in the head, subjective imbalance, sensations of detachment from the environment, and hypersensitivity to motion stimuli, rather than true rotary vertigo, objective imbalance, or ataxia. This common clinical syndrome is present in a least 10% of dizzy patients referred to neurotology practices worldwide.1,2 Recent clinical data3 have suggested that it may be triggered by transient neurotologic illnesses, other medical conditions, or psychiatric disorders. Several terms have been applied to this condition, including psychogenic dizziness, phobic postural vertigo, space-motion discomfort, and space phobia.4 Despite the psychological implications of these labels, approximately 25% of patients do not have major psychiatric illnesses.4 Therefore, we use the descriptive term “chronic subjective dizziness” for this clinical syndrome. Chronic subjective dizziness has no established treatment. Antivertigo therapies such as meclizine or benzodiazepines are ineffective.4 We previously found that selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), and citalopram (Celexa), reduced the symptoms of chronic subjective dizziness in a case series of 60 patients, 19 of whom had no major psychiatric diagnosis.4 Response rates did not differ between patients with and without psychiatric disorders. Neurophysiologic studies support the use of serotonergic agents for chronic subjective dizziness. Serotonin alters the response patterns of motion-sensitive neurons in the vestibular nuclei,5 inferior olive,6 and midline cerebellar nuclei.6 Serotonin also modulates neural activity in the central nucleus of the amygdala, which is reciproStaab et al.: Sertraline for Chronic Dizziness

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cally connected to the central vestibular nuclei and autonomic centers in the brainstem.7 In the present study, we conducted a prospective, 16-week, open trial of sertraline in patients with chronic subjective dizziness and no active physical neurotologic illnesses. We hypothesized that sertraline would reduce the symptoms of chronic subjective dizziness in patients with and without psychiatric disorders by affecting the central vestibular and amygdala pathways that play crucial roles in the processing of motion stimuli.

PATIENTS AND METHODS Patient Selection Study patients were recruited from an urban, universitybased, neurotology referral center. All patients underwent a standardized neurotologic examination, balance function tests, and neuroimaging. They also had a semi-structured psychiatric evaluation adapted from the patient edition of the Structured Clinical Interview for Axis I DSM-IV Disorders.8 Men and women were included in the study if they were 18 years of age or older, had a chief complaint of chronic subjective dizziness (i.e., lightheadedness, fullness in the head, subjective imbalance, sensations of detachment from the environment, or hypersensitivity to motion stimuli) for more than 6 months, and their neurotologic evaluation revealed no currently active, physical cause of dizziness. Patients with previous bouts of dizziness were eligible if their past symptoms had resolved completely. Individuals with recurrent physical illnesses, such as Meniere’s disease or vestibular migraine, were excluded, even if their conditions were quiescent at the time of evaluation. Women who were pregnant or breast-feeding and patients with a history of adverse reactions to sertraline were ineligible. Patients were recruited into the study regardless of coexisting anxiety or depressive symptoms. However, individuals with psychosis, bipolar disorder, substance abuse, conversion or factitious disorders, malingering, and suicidal or homicidal ideation were excluded. Twenty-four of 29 (83%) consecutively eligible patients agreed to participate. All patients provided written, informed consent before undergoing any study procedures. The Institutional Review Board of the University of Pennsylvania School of Medicine (Philadelphia, PA) approved the present study.

Sertraline (Zoloft) Treatment Protocol All patients underwent a screening evaluation that included a detailed review of their medical and psychiatric records to ensure protocol compliance. They also received a general physical examination, electrocardiogram, and laboratory testing (serum chemistry studies, urine drug screen, thyroid stimulating hormone test). Patients taking vestibular suppressants, antiemetics, sedating antihistamines, psychotropic agents, narcotics, barbiturates, antiepileptic drugs, or diuretics were tapered completely off these medications before taking any study drug. Patients who required these drugs for treatment of conditions other than dizziness were excluded from the study. After the screening procedures were completed and nonstudy medications were discontinued, patients began open-label treatment with sertraline. Clinic visits were scheduled at baseline and at weeks 2, 4, 8, 12, and 16 of treatment. Additional appointments were available as needed. Sertraline was dispensed at a dose of 25 mg daily for the first 2 weeks. Thereafter, it was titrated to optimal clinical benefit in a flexible dose design. The allowable dose range was 12.5 to 200 mg daily. Patients unable to tolerate a minimum daily dose of 12.5 mg were withdrawn from the study. Patients received no other treatment interventions during the sertraline trial. The U.S.

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Food and Drug Administration approved our use of sertraline as an investigational new drug for dizziness.

Outcome Measures The primary outcome measures were the Dizziness Handicap Inventory (DHI),9 a validated, 25-item, self-report with three subscales to measure physical and emotional symptoms and functional impairment attributable to dizziness and the Brief Symptom Inventory-53 (BSI-53),10 a validated, 53-item, self-report of overall psychological distress. Secondary outcome measures were widely used, well-validated, patient and investigator ratings of anxiety and depression. The State-Trait Anxiety Index (STAI, state version)11 is a 20-item self-report of general anxiety symptoms. The Centers for Epidemiological Studies–Depression (CES-D) scale12 is a 20-item self-report of depressive symptoms. The 20-item Hamilton Anxiety Rating Scale (HAM-A)13 and 17item Hamilton Depression Rating Scale (HAM-D)14 are investigator-rated instruments for assessing anxiety and depressive symptoms, respectively. The Clinical Global Impressions– Improvement (CGI-I)15 scale is an investigator rating of overall clinical change with scores ranging from 1 (very much improved) to 7 (very much worse). Patients completed the DHI and BSI-53 at screening and baseline visits and at treatment weeks 2, 4, 8, 12, and 16. Investigators completed the HAM-A, HAM-D, and CGI-I at each of these visits. Patients also completed the STAI and CES-D at screening, baseline, and treatment weeks 4, 8, and 16. Adverse events were recorded at each treatment visit. Drug doses and medication compliance were verified by pill counts.

Statistical Analysis Three patients were found to have exclusionary medical conditions after study enrollment (hyperthyroidism, dysautonomia, middle ear dysfunction). A fourth patient was disqualified at baseline for protocol noncompliance. Two of these patients had anxiety disorders; two had no psychiatric diagnosis. Data from the remaining 20 patients were analyzed with the SAS System for Windows, release 8.2 (SAS Institute, Inc., Cary, NC). As a first step, two analyses were performed to test the validity of the diagnostic assessments and the reliability of the outcome measures for the study population. First, the severity of pretreatment physical and psychiatric symptoms and functional impairment was determined from the mean values of the primary and secondary outcome measures at the screening visit. These results were compared between patients with and without psychiatric disorders using the Student t test to verify pretreatment diagnostic assessments. Second, Pearson correlation coefficients were calculated between primary and secondary outcome measures using screening visit data to assess the reliability of the rating scales for this study population. Correlation coefficients between instruments measuring similar symptoms (eg, patient and investigator ratings of anxiety) were examined for evidence of consistent ratings. After the outcome measures were validated, the effects of sertraline treatment on dizziness and psychiatric symptoms were analyzed using dimensional (parametric) and categorical (nonparametric) methods. First, overall treatment effects on dizziness and psychological distress were examined with repeatedmeasures multivariate analysis of variance (MANOVA) on the primary outcome measures (DHI and BSI-53). Last observations carried forward (LOCF) were used for patients who did not complete the 16-week trial. Second, within-subject treatment effects on dizziness and psychological symptoms were investigated with repeated-measures univariate analyses of variance (ANOVA) on each of the three subscales of the DHI and the Global Severity Index of the BSI-53. Separate analyses were performed on the intent-to-treat cohort (N ⫽ 20, LOCF) and study completers (n ⫽

Staab et al.: Sertraline for Chronic Dizziness

15, observed data only). Third, within-subject treatment effects on anxiety and depression were examined with repeatedmeasures ANOVA of the secondary outcome measures (STAI, CES-D, HAM-A, HAM-D). Intent-to-treat and completer cohorts were analyzed separately. Fourth, categorical rates of response and remission were calculated from a priori definitions of full remission (end-point total DHI score ⬍5 and CGI-I score ⫽ 1), partial response (end-point total DHI score ⱕ50% of baseline and CGI-I score ⫽ 2), and no response (end-point total DHI score ⬎50% of baseline and CGI-I score ⬎2). Response rates were calculated for all patients and for study completers.

RESULTS Table I lists the demographic profile of the study cohort, which reflects the age, sex, and racial characteristics of patients referred to the Balance Center at the University of Pennsylvania (Philadelphia, PA) during the last 5 years. The 83% study enrollment rate from consecutively eligible patients negates the possibility of a selection bias. Among the 20 patients included in the data analysis, 16 had major anxiety disorders (panic disorder [n ⫽ 8], generalized anxiety disorder [n ⫽ 6], obsessive compulsive disorder [n ⫽ 2]), with varying degrees of depression. The other four patients had only minor psychological symptoms that did not warrant a psychiatric diagnosis (eg, mild frustration, demoralization, or worry related to their dizziness). Patients with and without major psychiatric disorders had similar ratings for physical symptoms of dizziness (DHI-Physical subscale) and functional impairment (DHI-Functional subscale) on entry into the study (Table I). Patients with coexisting psychiatric illnesses had the added burden of clinically significant levels of anxiety (STAI, HAM-A), depression (CES-D, HAM-D), and overall psychological distress (BSI-53 Global Severity Index). The mean scores on all five psychiatric rating scales were in the normal range for patients with no psychiatric diagnosis but were above clinically significant cutoff values for patients with major

anxiety disorders (Table I). These group differences did not reach statistical significance on all measures because of the small sample size. In summary, patients enrolled in the present study represented the larger population of individuals referred to our tertiary care center for evaluation of chronic dizziness. Their physical symptoms of dizziness and functional impairment were moderately severe. Their emotional symptoms ranged from minimal distress to major anxiety disorders accompanied by depression. The DHI-Physical and DHI-Functional subscales correlated strongly with each other (Pearson correlation coefficient [r] ⫽ .83 [P ⬍ .0001]) and moderately with the DHI-Emotional subscale (r ⫽ .56 [P ⬍ .05] and r ⫽ .61 [P ⬍ .01], respectively), but not with any of the psychiatric measures. In contrast, the DHI-Emotional subscale correlated significantly with self-rated anxiety (STAI, r ⫽ .76 [P ⬍ .0001]), depression (CES-D, r ⫽ .85 [P ⬍ .0001]), and psychological distress (BSI-53 Global Severity Index, r ⫽ 0.82 [P ⬍ .0001]). As expected, the rating scales for anxiety and depression correlated significantly with each other (STAI and HAM-A, r ⫽ .56 [P ⬍ .05]; CES-D and HAM-D, r ⫽ .62 [P ⬍ .01]). These results support the validity of the outcome measures used in the present study. In particular, they indicate that the DHI was able to measure dizziness and functional impairment independently of psychological distress in patients with varying degrees of psychiatric symptoms. Fifteen of 20 (75%) patients completed the 16-week sertraline trial. Four patients (20%) withdrew because of adverse events (increased anxiety or sedation). One (5%) withdrew at 2 weeks for lack of efficacy, although she responded well to sertraline plus lorazepam after leaving the study. All five dropouts had major anxiety disorders. The median daily dose of sertraline for study completers was 100 mg (mean dose, 120 ⫾ 52.4 mg/d; range, 50 –200 mg/d).

TABLE I. Patient Demographics and Ratings of Presenting Symptoms.

Demographics Age (y) Sex (M/F) Race (white/nonwhite) Presenting symptoms DHI Physical Functional Emotional BSI: Global Severity (normal, ⬍63) STAI (anxiety) (normal, ⬍20) CES-D (depression) (normal, ⬍16) HAM-A (anxiety) (normal, ⬍10) HAM-D (depression) (normal, ⬍8)

All Patients (n ⫽ 20)

Patients With No Psychiatric Diagnosis (n ⫽ 4)

Patients with Anxiety With or Without Depression (n ⫽ 16)

Patients With vs. Without Psychiatric Diagnosis

43.2 ⫾ 13.7 9/11 17/3

44.2 ⫾ 9.0 1/3 4/0

43.0 ⫾ 15.0 8/8 13/3

NS NS NS

7.2 ⫾ 3.0 8.4 ⫾ 4.6 8.0 ⫾ 4.3 65.6 ⫾ 10.8 22.4 ⫾ 17.8 18.7 ⫾ 14.4 13.8 ⫾ 7.5 12.8 ⫾ 7.2

8.0 ⫾ 3.6 9.8 ⫾ 6.3 5.5 ⫾ 2.4 56.2 ⫾ 8.2 5.2 ⫾ 5.7 5.0 ⫾ 4.4 8.5 ⫾ 6.9 8.0 ⫾ 6.8

7.0 ⫾ 2.9 8.1 ⫾ 4.3 8.6 ⫾ 4.6 67.9 ⫾ 9.8 26.8 ⫾ 17.2 22.1 ⫾ 14.0 15.1 ⫾ 7.2 14.1 ⫾ 7.0

NS NS P ⬍ .10 P ⬍ .06 P ⬍ .001 P ⬍ .001 NS NS

NS, not significant; DHI ⫽ Dizziness Handicap Inventory; BSI ⫽ Brief Symptom Inventory; STAI ⫽ State-Trait Anxiety Index; CES-D ⫽ Centers for Epidemiological Studies–Depression scale; HAM-A and HAM-D ⫽ Hamilton Anxiety and Depression rating scales, respectively.

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Figure 1 shows that sertraline produced significant reductions in mean DHI scores for all patients (repeatedmeasures MANOVA, F ⫽ 3.73; degrees of freedom [df] ⫽ 5,15 [P ⬍ .05]). Within-subjects treatment effects were significant for all three subscales (repeated-measures ANOVA using LOCF: DHI-Physical, F ⫽ 9.95, df ⫽ 5 [P ⬍ .0001]; DHI-Functional, F ⫽ 8.21, df ⫽ 5 [P ⬍ .0001]; DHI-Emotional, F ⫽ 11.9, df ⫽ 5 [P ⬍ .0001]). Among the 15 patients who completed treatment, mean scores on all DHI subscales improved significantly by week 8 (repeated-measures ANOVA: DHI-Physical, F ⫽ 3.75, df ⫽ 3 [P ⬍ .05]; DHI-Functional, F ⫽ 3.41, df ⫽ 3 [P ⬍ .05]; DHI-Emotional, F ⫽ 4.39, df ⫽ 3 [P ⬍ .01]) and continued to improve through the end of the study. Figures 2 and 3 illustrate the improvements in psychiatric symptoms. Sertraline reduced psychological distress, anxiety, and depression by the eighth week of treatment, although these improvements did not achieve statistical significance on all measures until week 12 or 16 (repeated-measures ANOVA, P ⬍ .01 for all five psychiatric rating scales at week 16). Figure 4 shows the categorical outcomes for all patients and for those with and without major anxiety disorders. Eleven patients responded positively to sertraline, including six who enjoyed a complete remission, giving response rates of 55% (11 of 20) for the intent-to-treat cohort and 73% (11 of 15) for study completers. Patients with and without a major psychiatric illness had roughly equivalent response rates: 73% (8 of 11) for those with a psychiatric diagnosis and 75% (3 of 4) for those without. The dropout rate for all subjects was 25% (5 of 20).

DISCUSSION The present prospective study demonstrates the efficacy of sertraline for patients with chronic subjective diz-

Fig. 1. Sertraline treatment response for dizziness-related physical and emotional symptoms and functional impairment as measured by the Dizziness Handicap Inventory (DHI). Last observations carried forward (LOCF) is the rating (mean ⫾ SEM) for all 20 patients, with the last observation carried forward to 16 weeks. Other time points are ratings (mean ⫾ SEM) for study completers. Statistical significance: *P ⬍ .05 and **P ⬍ .01.

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Fig. 2. Sertraline treatment response for overall psychological distress as measured by the Global Severity Index of the Brief Symptom Inventory-53 (BSI-53). A score of 63 or higher strongly suggests the presence of a major psychiatric illness. Individual time points and last observations carried forward (LOCF) are depicted as in Figure 1. Statistical significance: **P ⬍ .01.

ziness, a condition for which there currently is no established therapy. More than half of the intent-to-treat cohort and nearly three-fourths of those who completed sertraline treatment achieved a substantial reduction in symptoms. Most patients in the present study had coexisting anxiety or depressive symptoms, as is usually the case in clinical practice. However, pretreatment symptoms on the physical and functional scales of the DHI did not correlate with psychiatric symptoms and treatment response did not depend on the presence or absence of psychopathological conditions. Furthermore, physical symptoms and functional impairment improved significantly by week 8, which was earlier than reductions in anxiety and depres-

Fig. 3. Sertraline treatment response for anxiety and depressive symptoms as measured by two patient and two clinician rating scales (see “Patients and Methods” section for a description of each instrument). Time points and last observations carried forward (LOCF) are depicted as in Figure 1. Statistical significance : *P ⬍ .05 and **P ⬍ .01.

Staab et al.: Sertraline for Chronic Dizziness

Eleven patients had their symptoms reduced by more than half as measured by the DHI, yielding a positive response rate of 55% for the entire cohort and of 73% for those who completed treatment. Six responders enjoyed a complete remission of their dizziness. Outcomes were not dependent on the presence of psychiatric comorbidity; patients with and without major anxiety disorders responded equally well to treatment. Future placebocontrolled clinical trials are needed to confirm these observations and elucidate the mechanism of action of sertraline for patients with chronic subjective dizziness.

BIBLIOGRAPHY

Fig. 4. Categorical response to sertraline treatment for all 20 patients as measured by the total Dizziness Handicap Inventory (DHI) score. Responses are shown for the 16 patients with major anxiety disorders and 4 patients without psychiatric illnesses. A positive response was a reduction in total DHI score of more than 50%.

sion. These results are entirely consistent with the findings of our previous case series.4 The results of the present study suggest that the benefits of sertraline for chronic subjective dizziness may involve serotonin-dependent systems in the brain that are independent of the ones that control mood and anxiety. Neurophysiologic investigations have identified possible sites of serotonergic activity in central vestibular pathways from the vestibular nuclei through the inferior olive to the midline cerebellum.5,6 Serotonin is not the primary neurotransmitter in any of these pathways. However, manipulations of serotonergic tone in the vestibular nuclei affect the responsiveness of more than 85% of secondary vestibular neurons to physiologically relevant stimuli.5,6 Future studies will have to determine whether SSRIs exert their therapeutic effect through any of these pathways. The primary limitations of the present exploratory study were its small size and uncontrolled design. The sample size was large enough to analyze the main effects of sertraline treatment on chronic subjective dizziness and psychological distress but not to investigate interactions between dizziness and psychiatric symptoms. The uncontrolled design cannot eliminate nonspecific therapeutic factors. On the other hand, the high enrollment rate indicates that the study cohort is representative of the larger population of tertiary care patients with chronic subjective dizziness.

CONCLUSION The present prospective clinical trial found sertraline to be efficacious in reducing chronic subjective dizziness in 20 patients without active, physical neurotologic illness.

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