Trimipramine

Abstract

Depression is often coincident with chronic tinnitus, and several studies have suggested that antidepressant medications may play a role in relieving tinnitus as well as depression. We conducted a retrospective study of the use of selective serotonin reuptake inhibitors (SSRIs) by patients at a large tinnitus clinic to assess the effects of these antidepressants on tinnitus severity. We focused on a subgroup of 30 patients with depression who had begun taking SSRI medication after the onset of their tinnitus; these patients had also been treated with psychotherapy by a mental health clinician. At a mean follow-up of 20.6 months, only 10 of the 30 patients reported that they were still experiencing major depression. Moreover, this group as a whole demonstrated a statistically significant improvement in tinnitus symptoms as reflected by a reduction in their Tinnitus Severity Index scores. We conclude that SSRIs represent one category of tools that can be used to help patients with severe tinnitus and depression. Like all antidepressant medications, SSRIs should be used in conjunction with psychotherapy to facilitate patient improvement.

Introduction

Because depression is often coincident with chronic tinnitus, (1-3) several studies have investigated the effectiveness of antidepressant medications in patients with tinnitus. Some success was reported with the tricyclic antidepressants amitriptyline (4) and nortriptyline, (5,6) but Mihail et al (7) found that trimipramine was not superior to placebo. In a 1999 review of tinnitus treatments, Dobie suggested that future studies should explore the use of the newer antidepressant drugs, such as the selective serotonin reuptake inhibitors (SSRIs). (8) SSRIs increase the availability of serotonin in the brain, which often leads to the desired effects of improving patients' mood and reducing anxiety and obsessive-compulsive tendencies. This class of medications includes citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine.

There have been few published reports of clinicians using SSRIs to treat tinnitus patients. Shemen claimed that "a trial with low-dose fluoxetine (10 mg every day) completely abolished the tinnitus in all three patients within one week." (9) He went on to write, "Perhaps a double-blind study with fluoxetine should be undertaken in a center with a large number of patients with this symptom, given the encouraging result of this anecdotal report."

Christensen reported the case of a woman who switched antidepressant medications from imipramine to paroxetine. (10) "Within 8 weeks, this individual had a significant improvement in her mood disorder and a pronounced diminishment of panic attacks," he wrote. "Moreover, her tinnitus completely resolved after the 8 weeks of treatment of paroxetine at the maintenance dose of 30 mg [per] day."

Although reports of chronic tinnitus completely resolving after treatment with various medications are encouraging, such occurrences are rare. Consider two facts:

* Millions of people worldwide experience chronic tinnitus.

* Millions of people worldwide take SSRI medication daily.

Given these facts (and the relatively high prevalence of depression among tinnitus sufferers), it is logical to assume that thousands of tinnitus patients have taken SSRI medication. Yet few of these patients have reported that taking an SSRI stopped their perception of tinnitus. It is therefore unlikely that current SSRI medications represent a potential "cure" for most patients with chronic tinnitus. However, some patients do benefit from taking these medications, which can contribute to improvements in their overall condition.

In this article, we describe a retrospective study that we undertook for two reasons: (1) to obtain information on a large clinic population of tinnitus patients who took SSRIs and (2) to assess the effects of SSRIs on tinnitus severity.

Patients and methods

We reviewed the records of 957 consecutive patients who had been evaluated and treated in the Tinnitus Clinic at Oregon Health and Science University (OHSU) between 1996 and 2002. Detailed questionnaires had been mailed to all patients prior to their initial appointment. These questionnaires solicited information about each patient's medical, hearing, and tinnitus history. (11) Included were 12 questions that constitute the Tinnitus Severity Index, which is an efficient indicator of the negative impact that tinnitus has on patients (appendix). (12) Patients rated the loudness of their usual tinnitus on a scale of 1 (very quiet) to 10 (very loud). Patients were also asked if they had ever experienced depression or were currently experiencing depression. Information from these questionnaires was entered into a database known as the Oregon Tinnitus Data Registry. (13)

The initial Tinnitus Clinic visit had been conducted according to the following format:

* Members of the Tinnitus Management Team--an otolaryngologist, a neurophysiologist, and an audiologist--reviewed each patient's questionnaire and medical records prior to each patient encounter.

* Patients met with all management team members for an in-depth interview and review of their medical, hearing, tinnitus, and psychosocial histories and conditions. Patients were educated as to the possible causes of their tinnitus, and they received reassurance and counseling regarding factors that could exacerbate or improve their condition.

* Patients underwent otolaryngologic and neurologic examinations.

* Patients underwent audiologic evaluations, including tympanometry and measurements of pure-tone air and bone conduction thresholds, speech perception in quiet and noise, and most comfortable and uncomfortable loudness levels.

* Patients underwent tinnitus evaluations, which included matching their tinnitus to sounds played through headphones, a determination of minimum masking levels, and measurements of residual inhibition (see Johnson (11) for a description of these procedures).

* Based on each patient's audiologic evaluation, the audiologist described and demonstrated various devices to evaluate the effectiveness of acoustic therapies. These devices included hearing aids, in-the-ear sound generators, tinnitus instruments (combinations of hearing aids and sound generators), table-top sound generation machines, sound pillows, cassette tapes, and compact disks that emitted sounds of water or other masking sounds.

* The Tinnitus Management Team reviewed the results of these evaluations and explained them to each patient.

* The team then formulated its recommendations and explained them to each patient. The team also provided referral and contact information regarding physical or psychiatric evaluations, psychologic counseling, and other recommended services and products.

* Patients were encouraged to contact the clinic any time they had questions and to inform the team of their progress. Patients were contacted by telephone 1 and 3 months after their initial visit.

We mailed follow-up questionnaires to 37 patients who had started taking an SSRI following the onset of their tinnitus. We then analyzed the responses and tabulated data relating to patient demographics and their self-ratings of tinnitus loudness and severity. Mean values were calculated and compared using analyses of variance and paired t tests (two-tailed p values).

These protocols were reviewed and approved by the Institutional Review Board at OHSU. Informed consent was obtained in writing from all patients prior to their participation in this study.

Results

Of the 957 patients in our original sample, 323 (33.8%)--204 men and 119 women (mean age: 50.6 [+ or -] 12.7 yr)--reported a history of depression. A total of 253 patients (26.4%)--160 men and 93 women--reported that they had experienced depression at the time of their initial visit to the Tinnitus Clinic.

Of the 957 patients, 105 (11.0%) had already been taking an SSRI at the time of their initial appointment (table 1). Some 37 of these patients had started taking an SSRI after the onset of their tinnitus and prior to their initial clinic visit. All 37 patients had been diagnosed with major depression and all bad received psychotherapy in addition to an SSRI.

Of the 37 patients who had started taking an SSRI after the onset of tinnitus, 30--18 men and 12 women, aged 26 to 73 years (mean: 52.3)--returned follow-up questionnaires (mean time between the initial clinic visit and the return of the follow-up questionnaire: 20.6 [+ or -] 12.3 mo). All 30 patients reported that they had experienced depression at the time of their initial Tinnitus Clinic visit. At the time of the follow-up questionnaire, only 10 of these patients reported that they were experiencing depression. We calculated the means and standard deviations of their self-rated tinnitus loudness according to both their initial and follow-up questionnaire responses (table 2). We found that no significant difference in self-rated tinnitus loudness had occurred between the time of the two questionnaires.

We also calculated the means and standard deviations of the 30 patients' responses to the 12 Tinnitus Severity Index questions and found that a significant improvement was reflected in the responses to nine of the 12 questions; a significant difference (p<0.005) was also reflected in the group's total Tinnitus Severity Index score (table 2). Overall, 23 of the 30 patients had a lower Tinnitus Severity Index score on follow-up, 4 had a higher score, and 3 showed no change.

Discussion

The prevalence of both current (26.4%) and lifetime (33.8%) depression was much greater in our study population than in the general population. Dobie and Sullivan estimated that the prevalence of current major depression in the general adult population is 5% and the lifetime prevalence of major depression (one or more bouts) is 15%--10% among males and 20% among females. [14] Goldberg reported that the prevalence of depression is high in groups of patients afflicted with various chronic medical conditions (table 3). (15)

Because patients in our study were evaluated and treated at a specialized clinic, we can assume that most of them perceived their tinnitus to be a significant and sometimes debilitating problem. It is therefore not surprising that the prevalence of depression in our study population was high and similar to that observed in other groups of patients who experienced chronic medical conditions. Erlandsson et al reported that the prevalence of current depression among a population of tinnitus clinic patients in Sweden was between 25 and 30%. (16)

Studies conducted by Sullivan et al, (1) Folmer et al, (2,3) and others demonstrated that tinnitus severity is positively correlated with the presence and severity of depression. Sullivan et al wrote, "treatment of the concurrent affective illness may reduce disability due to tinnitus." (1) Folmer et al came to a similar conclusion: "successful treatment of depression with medication and/or psychotherapy can reduce the severity of tinnitus for many of these patients." (2) Folmer recently reported the results of a long-term follow-up study of patients who completed the OHSU Tinnitus Management Program. (17) In that study, 190 patients--133 men and 57 women (mean age: 57 yr)--returned follow-up questionnaires 6 to 36 months (mean: 22) after their initial visit to the OHSU Tinnitus Clinic. Overall, this group of patients reported significant reductions in self-rated tinnitus loudness, Tinnitus Severity Index scores, tinnitus-related anxiety, and the prevalence of current depression. Patients who improved their sleep patterns or Beck Depression Inventory (18) scores exhibited greater reductions in tinnitus severity scores than did patients who continued to experience insomnia and depression at follow-up (table 4).

Therefore, it is imperative to identify depression when it is present in patients who seek treatment for tinnitus. A question such as Do you feel depressed? in written or oral form will identify most of these patients. However, some patients do not readily admit the presence or severity of their own depression. An instrument such as the Beck Depression Inventory (19) or the shorter version of this questionnaire (18) is useful for identifying and assessing the severity of patients' depression.

SSRIs reduce the frequency and severity of depressive episodes in many patients. However, the United States Agency for Health Care Policy and Research reported that "newer [SSRI] antidepressants have similar efficacy and total dropout rates compared to older antidepressants [such as tricyclic antidepressants]. Because of similar efficacy, both newer and older antidepressants should be considered when making treatment decisions." (20)

Christensen warned that "tinnitus can sometimes be a side-effect to tricyclic antidepressants. There have been numerous reports of tinnitus developing after the initiation of imipramine, amitriptyline, and doxepin." (10) In fact, most psychotropic substances, including the SSRIs, have the potential to trigger tinnitus in a small percentage of patients. (21) However, like tinnitus caused by large doses of aspirin, most cases of tinnitus attributable to antidepressants or anxiolyties are reversible after patients stop taking these medications. Fear of an unlikely side effect such as tinnitus should not keep patients from trying a medication that has a good chance of improving their condition. Similarly, patients who already have chronic tinnitus should not resist trying physician-recommended medications because of unfounded fears that their tinnitus might become louder. In most cases, it is difficult to predict how a particular medication will affect a patient or his or her tinnitus.

Matthew Rudorfer, MD, of the National Institute of Mental Health, has said, "It's clear that in the effective treatment of depression, one has many options, all of which work. What can make the difference, therefore, is how well matched a given individual with depression is with a given treatment." (22)

Patients with depression and chronic tinnitus have a better chance of experiencing improvement in both conditions when they are assessed and managed within a multimodal program. A statement written by Goodhill could apply to both conditions: "Any management which is based upon a single panacea for the treatment of a symptom and not a disease will result in failure." (23) Other clinicians agree that a combination of tinnitus management strategies is more effective than one form of remediation used in isolation. (24-28)

The 30 patients in our study who returned follow-up questionnaires experienced significant long-term improvement in tinnitus severity and a significant reduction in the prevalence of current depression. SSRI antidepressants facilitated some of this improvement, but these medications were not the only treatments that had been prescribed or used. All of these patients had attended a series of psychotherapy sessions conducted by a psychologist or psychiatrist. Moreover, all received counseling, education, and reassurance in a specialized tinnitus management program, Finally, these patients followed specific individualized recommendations with respect to acoustic therapy, lifestyle changes, and strategies to improve sleep patterns, increase relaxation, and decrease anxiety (see Folmer (17) for more detailed descriptions of these recommendations). The long-term improvements in sleep patterns and tinnitus severity experienced by these 30 patients were similar to those observed in larger groups of patients who were evaluated and treated in our clinic. (17,29)

Because tinnitus that has been present for 1 year or longer is likely to persist indefinitely, we should help patients learn how to live with this symptom so it does not detract from their enjoyment of life. This can be a very time-consuming process. When necessary, we refer patients to a mental health professional for evaluation and psychotherapy. Psychotherapy or counseling can reduce the severity of tinnitus and depression. A series of effective counseling sessions is required to identify and begin to change counterproductive thoughts and behaviors exhibited by some patients. In fact, psychotherapy should be given priority over medication in the treatment of depression, anxiety, and obsessive-compulsive disorders. For complex problems such as these, medication alone is not sufficient. (30)

References

(1.) Sullivan MD, Katon W, Dobie R, et al. Disabling tinnitus. Association with affective disorder. Gen Hosp Psychiatry 1988; 10:285-91.

(2.) Folmer RL, Griest SE, Meikle MB, Martin WH. Tinnitus severity, loudness, and depression. Otolaryngol Head Neck Surg 1999; 121:48-51.

(3.) Folmer RL, Griest SE, Martin WH. Chronic tinnitus as phantom auditory pain. Otolaryngol Head Neck Surg 2001;124:394-400.

(4.) Koshes RJ. Use of amitriptyline in a patient with tinnitus. Psychosomatics 1992;33:341-3.

(5.) Dobie RA, Sakai CS, Sullivan MD, et al. Antidepressant treatment of tinnitus patients: Report of a randomized clinical trial and clinical prediction of benefit. Am J Otol 1993; 14:18-23.

(6.) Sullivan M, Katon W, Russo J, et al. A randomized trial of nortriptyline for severe chronic tinnitus. Effects on depression, disability, and tinnitus symptoms. Arch Intern Med 1993;153: 2251-9.

(7.) Mihail RC, Crowley JM, Walden BE, et al. The tricyclic trimipramine in the treatment of subjective tinnitus. Ann Otol Rhinol Laryngol 1988;97:120-3.

(8.) Dobie RA. A review of randomized clinical trials in tinnitus. Laryngoscope 1999;109:1202-11.

(9.) Shemen L. Fluoxetine for treatment of tinnitus [letter]. Otolaryngol Head Neck Surg 1998;118:421.

(10.) Christensen RC. Paroxetine in the treatment of tinnitus. Otolaryngol Head Neck Surg 2001;125:436-8.

(11). Johnson RM. The masking of tinnitus. In: Vernon JA, ed. Tinnitus: Treatment and Relief. Boston: Allyn and Bacon, 1998:164 86.

(12). Meikle MB, Griest SE, Stewart BJ, Press LS. Measuring the negative impact of tinnitus: A brief severity index. Abstr Assoc Res Otolaryngol 1995:167.

(13). Meikle MB. Electronic access to tinnitus data: The Oregon Tinnitus Data Archive. Otolaryngol Head Neck Surg 1997;117: 698-700.

(14). Dobie RA, Sullivan MD. Antidepressant drugs and tinnitus. In: Vernon JA, ed. Tinnitus: Treatment and Relief. Boston: Allyn and Bacon. 1998:43-51.

(15). Goldberg RJ. Depression in medical patients. R I Med 1993;76: 391-6.

(16). Erlandsson SI, Rubinstein B, Axelsson A, Carlsson SG. Psychological dimensions in patients with disabling tinnitus and craniomandibular disorders. Br J Audiol 1991;25:15-24.

(17.) Folmer RL. Long-term reductions in tinnitus severity. BMC Ear Nose Throat Disord 2002;2:3.

(18). Beck AT, Beck RW. Screening depressed patients in family practice. A rapid technic. Postgrad Med 1972;52(6):81-5.

(19.) Beck AT, Steer RA. Beck Depression Inventory Manual. San Antonio, Tex.: Psychological Corp., 1987.

(20.) Treatment of Depression--NewerPharmacotherapies. Summary. Evidence Report/Technology Assessment No. 7. Rockville, Md.: Agency for Health Care Policy and Research, March 1999. www.ahcpr.gov/clinic/epcsums/deprsumm.htm

(21.) Physicians' Desk Reference. Montvale, N.J.: Medical Economics, 2003.

(22) Goode E. New and old depression drugs are found equal. New York Times, March 19, 1999.

(23.) Goodhill V. The management of tinnitus. Laryngoscope 1950; 60:442-50.

(24.) Jakes SC, Hallam RS, Chambers C, Hinchcliffe R. Group cognitive therapy for medical patients: An application to tinnitus. Cog Therapy Res 1992;16:67-82.

(25.) Jastreboff PJ, Hazell JW. A neurophysiological approach to tinnitus: Clinical implications. Br J Audiol 1993;27:7-17.

(26.) Sullivan M, Katon W, Russo J, et al. Coping and marital support as correlates of tinnitus disability. Gen Hosp Psychiatry 1994; 16:259-66.

(27.) Dineen R, Doyle J, Bench J. Managing tinnitus: A comparison of different approaches to tinnitus management training. Br J Audiol 1997;31:331-44.

(28.) Hamill-Ruth RJ, Ruth RA, Chastain DC, Cook A. Management of tinnitus and hyperacusis using a multidisciplinary pain model. American Pain Society Bulletin 2000;10(5). www.ampainsoc.org/ pub/bulletin/sep00/article1.htm

(29.) Folmer RL, Griest SE. Improvements in tinnitus severity: A follow-up study. In: Hazell J, ed. Proceedings of the Sixth International Tinnitus Seminar. London: The Tinnitus and Hyperacusis Centre, 1999:546-9.

(30.) Folmer RL. Reply to: Paroxetine in the treatment of tinnitus. Otolaryngol Head Neck Surg 2001;125:437-8.

From the OHSU Tinnitus Clinic, Oregon Hearing Research Center, Department of Otolaryngology, Oregon Health and Science University, Portland.

Reprint requests: Robert L. Folmer, PhD, OHSU Tinnitus Clinic, Mail Code NRC04, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97239. Phone: (503) 494-7954; fax: (503) 494-5656; e-mail: folmerr@ohsu.edu

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