OTOLOGY

Medium-term results of combined treatment with transcranialmagnetic stimulation and antidepressant drug for chronic tinnitus

Suat Bilici • Ozgur Yigit • Umit Taskin •

Ayse Pelin Gor • Enver Demirel Yilmaz

Received: 10 February 2013 / Accepted: 30 November 2013

� Springer-Verlag Berlin Heidelberg 2013

Abstract We compared the effects of repetitive trans-

cranial magnetic stimulation (rTMS) and paroxetine [a

selective serotonin reuptake inhibitor (SSRI)] on tinnitus in

terms of effectiveness and medium-term results. This is a

randomised, double-blind, placebo-controlled study. Sev-

enty-five patients with moderate tinnitus were divided into

five equal groups. Each group was treated for 1 month as

follows: group 1 received rTMS alone at 1 Hz frequency;

group 2 received rTMS alone at 10 Hz frequency; group 3

received rTMS at 1 Hz frequency combined with paroxe-

tine; group 4 received paroxetine alone; and group 5

received a placebo (sham rTMS). Participants were tested

using the Tinnitus Handicap Inventory (THI), Tinnitus

Severity Index (TSI), the Beck Anxiety Scoring (BAS), and

Psychiatric Sign Screening (PSS) tests. THI, TSI, BAS, and

PSS were measured prior to treatment, and at the first and

sixth month post-treatment. The THI and TSI scores

improved after treatment in all groups, except the placebo

group. The THI scores in groups 1 and 2 showed a statis-

tically significant improvement after the first and sixth

month compared to pretreatment scores, whereas a signif-

icant improvement in THI scores occurred only after the

sixth month in groups 3 and 4. The TSI scores in group 3

showed a significant improvement at the first and sixth

month marks after treatment. The rTMS and SSRI play

potential roles in the reduction of tinnitus severity, but

without cumulative or synergistic effects when a combi-

nation of treatment regimens is applied. These positive

effects might be due to the relationship between the audi-

tory cortex areas related to emotions and tinnitus.

Keywords Repetitive transcranial magnetic stimulation

(rTMS) � Tinnitus � Selective serotonin reuptake

inhibitor � Clinical trial

Introduction

Tinnitus is the perception of sound without any objective

sound source [1]. Vascular lesions as well as neurological,

physiological, and psychological disorders may cause tin-

nitus, but most cases are idiopathic [2]. The severity of

tinnitus impairs the daily lives of almost 1–2 % of patients

[3]. A range of different treatment modalities have been

tried involving anticonvulsants, tricyclic antidepressants

(TCAs), lidocaine, spasmolytics, and vasodilators [4], but

no given protocol is completely effective. Psychological

therapies, musical therapy, acupuncture, hyperbaric oxygen

treatment, and electrical stimulation of the auditory cortex

have also been applied. Currently, repetitive transcranial

magnetic stimulation (rTMS), which is indicated to

improve focal dystonia, focal epileptic discharge,

Electronic supplementary material The online version of thisarticle (doi:10.1007/s00405-013-2851-z) contains supplementarymaterial, which is available to authorized users.

S. Bilici (&) � O. Yigit

Department of Otorhinolaryngology, Istanbul Research

and Training Hospital, Istanbul, Turkey

e-mail: suatbilici@yahoo.com

U. Taskin

Department of Otorhinolaryngology, Bagcilar Research

and Training Hospital, Istanbul, Turkey

A. P. Gor

Division of Otorhinolaryngology, Catalca State Hospital,

Istanbul, Turkey

E. D. Yilmaz

Division of Psychiatry, Istanbul Research and Training Hospital,

Istanbul, Turkey

123

Eur Arch Otorhinolaryngol

DOI 10.1007/s00405-013-2851-z

Parkinson’s disease recovery from stroke, chronic pain,

depression, mania, schizophrenia, obsessive–compulsive

disorder, panic and post-traumatic stress disorders, is being

used as a tinnitus treatment, with mixed reports [5–7]. The

mechanism of rTMS is thought to involve stabilisation of

the overstimulated neurons that underlie the emergence of

tinnitus.

Physiological and psychological problems are associ-

ated with moderate-to-severe tinnitus. Chronic severe tin-

nitus is accompanied by major depression in 48–60 % of

patients [4] and the severity of chronic tinnitus may be

correlated with the severity of accompanying insomnia,

anxiety, and depression, thereby leading to relationships

similar to those seen in many patients with chronic pain

[8]. These patients focus on their tinnitus, therefore their

signs of anxiety and depression may worsen [9]. Antide-

pressant drugs may be effective both due to improvement

of anxiety and depression, and due to effect on the auditory

cortical dysfunction. The auditory cortex has direct pro-

jections to the limbic system and is rich in serotonin

receptors, which explains why selective serotonin reuptake

inhibitors (SSRIs) might be helpful [3].

Among antidepressants, SSRIs are generally better tol-

erated than TCAs and are a first-line treatment option for

major depressive disorder, dysthymia or minor depression.

Paroxetine is the only SSRI currently approved for the

treatment of social anxiety disorder, which makes it the

only drug of its class indicated for all anxiety disorders in

addition to major depressive disorder [4]. In the literature,

many studies have reported the efficiency of antidepres-

sants and rTMS as therapy for tinnitus. However, few

studies have examined antidepressants and rTMS as com-

bination therapy. In our study, our aim was to compare the

efficiency of rTMS and the SSRI paroxetine, supplied

singly and in combination, as a treatment for tinnitus.

Methods

The Local Ethics Committee of the Istanbul Research and

Training Hospital approved this study (26/05/2009 date and

number 27) and the informed consent of patients was

obtained. Patients with chronic tinnitus were included in

this randomised, double-blind, placebo-controlled study.

All participants underwent otologic examinations and any

patients with middle ear disease were excluded from the

study. Cranial magnetic resonance imaging (MRI) was also

performed in all participants to exclude anyone with

intracranial lesions from the study. Inclusion criteria were:

unilateral or bilateral moderate-to-severe tinnitus contin-

uing for at least 1 year, a Tinnitus Handicap Inventory

(THI) total score above 38 (Level 3, 4, 5), a Tinnitus

Severity Index (TSI) total score above 36, normal hearing

level, no previous rTMS treatment history, no antidepres-

sant or tinnitus drugs usage for the past year. Exclusion

criteria were: middle ear disease, presence of an intracra-

nial lesion, hearing loss, presence of systemic illness, any

contraindication to rTMS exposure, patient rTMS refusal,

communication problems, cardiac pacemaker, electronic

implants, gestation or lactation, epilepsy or syncope his-

tory, chronic alcohol consumption, or any drug usage

compromising cognitive functions. The patients whose

Beck Anxiety Scoring (BAS) and Psychiatric Sign

Screening (PSS) test scores were abnormal were excluded

from the study; therefore, no included patient had anxiety

syndrome or depression.

The severity of tinnitus was evaluated using the THI and

TSI; a THI score above 38 was considered as moderate-to-

severe tinnitus, and a TSI score of 36 or higher indicated

severe tinnitus. The BAS test and PSS test were adminis-

tered to the patients to evaluate any presence of psycho-

pathological disorder and depression. All forms, including

the THI, TSI, BAS, and PSS, were filled in by the patients

before treatment and at the first and sixth month mark post-

treatment. A neuro-MS magnetic stimulator with a large

circular coil (trade name Neurosoft) was used for rTMS

(Supplemental Fig. 1). For each 15 min session of 1 Hz

rTMS, 900 stimuli were applied at an intensity of 110 %

resting motor threshold. For 10 Hz rTMS session, 600

stimuli were applied as 20 trains of 30 stimuli (inter-train

interval of 25 s) at an intensity of 110 % resting motor

threshold. Patients received stimulation on ten subsequent

days. Stimulation was applied via a coil placed close to the

left temporoparietal region, independent of the side of the

tinnitus, as described by Khedr et al. [10]. Placebo stimu-

lation was performed with a sham coil system that mim-

icked the sound of active stimulation, without producing a

magnetic field. Paroxetine treatment began with a 10 mg/

day dosage during the first week, 20 mg/day during the

second week, 30 mg/day during the third week, and 40 mg/

day during the fourth week.

Patients were divided into five groups of fifteen subjects

each: group 1 received rTMS alone at 1 Hz frequency;

group 2 received rTMS alone at 10 Hz frequency; group 3

received a combination of rTMS at 1 Hz frequency and

paroxetine; group 4 received paroxetine only; and group 5

received a placebo (sham rTMS). All rTMS treatment

regimens were applied daily (five sessions each week) for

2 weeks and paroxetine treatment was administered over a

4-week period.

Statistical analysis

Statistical data analysis was performed with SPSS 21.0

(SPSS Inc., Chicago, IL). The descriptive analysis included

the use of mean, standard deviation, frequency, and ratio.

Eur Arch Otorhinolaryngol

123

Distribution of variables was evaluated using the Kol-

mogorov–Smirnov test and all variables were parametric.

Independent groups were evaluated by ANOVA and Tu-

key’s tests. Proportional analysis was conducted using the

v2 test. Where the v2 test was not sufficient, the Fisher

Exact test was used. The paired samples t test was used for

repeated measurement analysis of the tinnitus tests scores.

We correlated THI, TSI, BAS, and PSS scores in active

study groups through Pearson correlation analysis.

p \ 0.05 were considered statistically significant, without

correction for multiple comparisons. Tests were conducted

with a 95 % CI.

Results

Seventy-five patients (42 female, 33 male) were included in

the study. The mean age was 40 ± 13.2 (range 20–62)

(Supplemental table 1). No significant difference was

found in either bilaterality or unilaterality of tinnitus, or

right or left sidedness among the five groups (p = 0.746)

(Supplemental table 2).

The THI and TSI scores decreased after treatment in all

groups except the placebo group. The THI scores showed a

statistically significant difference after the first and sixth

month when compared to the pretreatment scores in groups

1 and 2. However, no significant difference was noted in

groups 3 and 4 after the first month of treatment, whereas a

significant improvement in the THI scores occurred after

sixth month of treatment (Table 1; Fig. 1). The TSI scores

showed no significant difference at the first and sixth

month after treatment in groups 1 and 4. However, a sig-

nificant difference in TSI scores was noted at the first and

sixth months after treatment in group 3. A significant

decrease appeared in group 2, but only after the sixth

month (Table 2; Fig. 2). Although BAS and PSS scores

were improved after sixth month of treatment in all groups,

the differences were not statistically significant in intra-

group comparisons (Tables 3, 4).

The Pearson correlation analysis indicated a significant

correlation between THI, TSI, BAS, and PSS scores in

some of active study groups, as shown in Table 5.

None of the patients complained of any increase in the

severity of their tinnitus. None of the rTMS-treated patients

experienced any side effects requiring cessation of the

treatment. No epileptic attacks occurred in any patient.

However, in the 10 Hz TMS treatment group, two patients

complained of neck and shoulder stiffness, which disap-

peared in 2 days without any medical treatment; two

patients had jaw fasciculation, which continued for 1 h;

and one patient had a headache for 1 day. One patient in

the 1 Hz rTMS group had mild jaw pain for 2 days. All

patients in the paroxetine-treated group were asked to

report possible side effects of the drug. Among those, three

had cephalalgia, two had gastrointestinal disorders, and one

had sexual dysfunction; all these side effects were mild-to-

moderate in intensity and did not delay the therapy.

Discussion

Chronic tinnitus is a very common disabling disorder, but it

lacks an exact treatment modality [11]. Brain imaging

studies of patients with tinnitus indicate that asymmetric

cortical arousal is often localised to the first and second

auditory cortex (Brodmann areas 40, 41, 22, and 39) [12].

Several functional imaging studies have indicated activa-

tion of the temporoparietal cortex specifically during tin-

nitus perception [13, 14]. rTMS which decreases cortical

excitations, as shown by positron emission tomography

Table 1 THI scores: intragroup comparisons and intergroup comparisons

Group 1

(1 Hz rTMS)

Mean ± SD

Group 2

(10 Hz rTMS)

Mean ± SD

Group 3

(1 Hz rTMS ? SSRI)

Mean ± SD

Group 4

(SSRI)

Mean ± SD

Group 5

(Placebo)

Mean ± SD

p

THI

Beginning 58.7 ± 24.7 42.7 ± 18.9 44.5 ± 26.8 42.4 ± 30.0 42.4 ± 21.4 0.306

1st month 40.7 ± 24.3 33.6 ± 17.7 38.3 ± 26.5 36.6 ± 26.5 43.1 ± 20.4 0.832

6th month 40.9 ± 26.7 27.5 ± 16.3 34.3 ± 25.7 34.4 ± 30.1 43.1 ± 20.7 0.434

Change from beginning

1st month -18.0 ± 21.0 -9.1 ± 8.8 -6.3 ± 14.9 -5.8 ± 10.7 0.7 ± 5.0 0.006

p 0.005 0.001 0.126 0.054 0.613

6th month -17.7 ± 22.4 -15.2 ± 11.7 -10.3 ± 14.9 -8.0 ± 13.6 0.7 ± 5.0 0.010

p 0.008 0.000 0.018 0.040 0.615

ANOVA (Tukey test)/paired samples t test p \ 0.05 difference with placebo group

THI tinnitus handicap inventory, rTMS repetitive transcranial magnetic stimulation, SSRI selective serotonin reuptake inhibitor

Eur Arch Otorhinolaryngol

123

(PET) is one of the new treatment modality in tinnitus [15].

In the literature, a long-term stimulation protocol was

shown to be more effective than a short-term stimulation

protocol for treating depression, but this strategy has not

been applied to tinnitus and no definitive protocol has been

established [16].

On the other hand, a variety of psychological and psy-

chosomatic (self-assessment of vertigo and headache and

the perceived severity of tinnitus) factors are recognised in

patients with tinnitus, including a high prevalence of

depressive disorders [17–19]. Zoger et al. [20] have shown

that the severity of tinnitus is associated with anxiety and

depression, so that the daily activities of patients with

severe tinnitus are affected, resulting in greater stress and

depression. The severity of tinnitus may also tend to wor-

sen in patients with underlying psychological disorders [4].

An association between the increase in the severity of

tinnitus and a depressive state has been reported [3];

Fig. 1 Differences between

pre- and post-treatment scores

of THI. THI tinnitus handicap

inventory

Table 2 TSI scores: intragroup comparisons and intergroup comparisons

Group 1

(1 Hz rTMS)

Mean ± SD

Group 2

(10 Hz rTMS)

Mean ± SD

Group 3

(1 Hz rTMS ? SSRI)

Mean ± SD

Group 4

(SSRI)

Mean ± SD

Group 5

(Placebo)

Mean ± SD

p

TSI

Beginning 36.5 ± 10.3 31.2 ± 9.0 32.5 ± 11.0 31.6 ± 15.4 34.1 ± 11.6 0.726

1st month 32.2 ± 9.5 29.1 ± 9.2 29.6 ± 11.7 29.4 ± 13.4 33.5 ± 11.5 0.753

6th month 32.7 ± 11.4 24.5 ± 6.5 27.9 ± 11.0 28.3 ± 16.1 35.2 ± 11.5 0.113

Change from the beginning

1st month -4.3 ± 6.7 -2.1 ± 5.1 -2.9 ± 4.9 -2.2 ± 7.4 -0.6 ± 4.9 0.552

p 0.057 0.129 0.038 0.269 0.642

6th month -3.7 ± 11.4 -6.7 ± 5.9 -4.6 ± 6.2 -3.3 ± 7.7 1.1 ± 6.3 0.105

p 0.226 0.001 0.013 0.121 0.523

ANOVA (Tukey test)/paired samples t test/p \ 0.05 difference with placebo group

TSI Tinnitus Severity Index, rTMS repetitive transcranial magnetic stimulation, SSRI selective serotonin reuptake inhibitor

Fig. 2 Differences between

pre- and post-treatment scores

of TSI. TSI Tinnitus Severity

Index

Eur Arch Otorhinolaryngol

123

therefore, interventions for the treatment of tinnitus in

cases where an underlying depressive disorder is present

may fail or may need further correction in the long term.

Oishi et al. [21] demonstrated that paroxetine was

effective in treating patients with chronic tinnitus, depres-

sion, and anxiety, by reducing tinnitus severity as well as

depression and anxiety. In contrast, a study by Robinson

reported no effect of paroxetine in tinnitus patients [4].

Baldo et al. [22] analysed six trials involving 610 patients

receiving antidepressant drugs versus placebo for the

treatment of tinnitus; four trials were performed using

TCAs, one used an SSRI and the last trial used trazodone.

These authors found that tinnitus was slightly improved,

but the difference was not statistically significant in all

trials. In our study, tinnitus was improved in some patients.

Another study reported a significant improvement in tin-

nitus scores in patients treated with nortriptyline [23].

The available literature contains few studies that eval-

uate the efficiency of combination therapy consisting of

rTMS and an antidepressant. The main purpose of our

study was to investigate and compare the effectiveness of

combination therapy on tinnitus patients who had no psy-

chosomatic disorders such as anxiety, depression, etc., as

determined by BAS and PSS tests. We found that a 10-day

rTMS treatment period was partially effective at both 1 and

10 Hz treatment regimens, in agreement with other studies

in the recent literature [24]. Temporary suppression of

tinnitus was observed after applying high-frequency rTMS

(10 Hz) to the temporal and temporoparietal cortex [25,

26]. Chen et al. [27] demonstrated that low-frequency

rTMS (1 Hz) reduced neural activity in excitable brain

regions. We obtained nearly similar results at both fre-

quencies. All patients showed positive responses to active

rTMS treatment, and the lack of side effects was quite

gratifying.

The psychometric tests results for our study groups

supported the efficiency of antidepressant drugs even in

patients without anxiety disorder. The BAS and PSS

Table 3 The changes of BAS scores (pre- and post-treatment, intragroup and intergroup comparisons)

Group 1

(1 Hz rTMS)

Mean ± SD

Group 2

(10 Hz rTMS)

Mean ± SD

Group 3

(1 Hz rTMS ? SSRI)

Mean ± SD

Group 4

(SSRI)

Mean ± SD

Group 5

(Placebo)

Mean ± SD

p

BAS

Beginning 12.1 ± 11.1 15.9 ± 9.4 13.3 ± 10.1 19.6 ± 11.7 13.0 ± 9.6 0.288

1st month 10.5 ± 9.0 15.3 ± 8.7 12.2 ± 9.1 18.5 ± 10.7 13.0 ± 9.5 0.172

6th month 10.3 ± 8.3 15.0 ± 7.9 11.8 ± 8.9 16.9 ± 10.5 14.1 ± 10.2 0.308

Change from beginning

1st month -1.7 ± 2.5 -0.7 ± 1.9 -1.1 ± 1.4 -1.1 ± 1.5 0.0 ± 1.1 0.127

p 0.022 0.199 0.010 0.015 1.000

6th month -1.9 ± 3.4� -0.9 ± 1.9 -1.5 ± 1.6� -2.7 ± 2.2�1.1 ± 1.9 0.001

p 0.050 0.084 0.003 0.000 0.044

ANOVA (Tukey test)/paired samples t test p \ 0.05 difference with placebo group

BAS beck anxiety scoring, rTMS repetitive transcranial magnetic stimulation, SSRI selective serotonin reuptake inhibitor

Table 4 The changes of PSS scores (pre- and post-treatment, intragroup and intergroup comparisons)

Group 1

(1 Hz rTMS)

Mean ± SD

Group 2

(10 Hz rTMS)

Mean ± SD

Group 3

(1 Hz rTMS ? SSRI)

Mean ± SD

Group 4

(SSRI)

Mean ± SD

Group 5

(Placebo)

Mean ± SD

p

PSS

Beginning 0.5 ± 0.3 0.7 ± 0.4 0.7 ± 0.5 0.8 ± 0.5 0.8 ± 0.4 0.221

1st month 0.6 ± 0.3 0.7 ± 0.4 0.7 ± 0.5 0.8 ± 0.5 0.8 ± 0.4 0.496

6th month 0.5 ± 0.3 0.7 ± 0.4 0.7 ± 0.5 0.8 ± 0.5 0.8 ± 0.4 0.258

Change from beginning

1st month -0.03 ± 0.16 -0.03 ± 0.05 -0.03 ± 0.03 -0.01 ± 0.02 0.00 ± 0.01 0.693

p 0.313 0.036 0.006 0.017 0.457

6th month -0.10 ± 0.16 -0.04 ± 0.06� -0.04 ± 0.04 -0.02 ± 0.03 0.01 ± 0.02 0.008

p 0.865 0.026 0.005 0.006 0.194

ANOVA (Tukey test)/paired samples t test p \ 0.05 difference with placebo group

PSS psychiatric sign screening, rTMS repetitive transcranial magnetic stimulation, SSRI selective serotonin reuptake inhibitor

Eur Arch Otorhinolaryngol

123

scores, even when in normal ranges, were significantly

decreased in patients who received combined therapy or

who received only antidepressant treatment. A positive

correlation between THI and TSI scores with BAS and PSS

scores was also determined in all active groups, which

shows that tinnitus alone can affect the psychology of the

patient. On the other hand, contrary to expectations, the use

of antidepressant medication combined with rTMS did not

cause any additional reduction in the severity of tinnitus.

After treatment, all groups that had undergone active

treatment had a statistically significant improvement

compared to the placebo, but no statistically significant

difference was noted between these active groups. Simi-

larly, Kleinjung et al. [28] demonstrated that administration

of bupropion (a dopamine and noradrenaline reuptake

inhibitor) did not enhance the clinical effects of 1 Hz rTMS

treatment in tinnitus patients. Positive results were similar

in all active groups in our study, but combination therapy

revealed no evidence of any synergistic effect.

This study showed that rTMS and SSRIs have poten-

tially useful roles in the treatment of tinnitus. However,

three weakness of this study limit generalised conclusions

about the method: the use of a single type placebo, the

limited number of rTMS pulses (600 or 900 pulses per

session) and the use of a circular coil (less spatially accu-

rate than a figure-eight coil).

Conclusions

The main result of our study is that treatment regimens that

include either 1 or 10 Hz rTMS or an SSRI have positive

effects on the reduction of tinnitus severity. However, no

cumulative and synergistic effect was seen when the

treatment regimens were combined. The positive effects

that were observed might reflect a relationship between

tinnitus and auditory cortex areas related to emotions.

Further investigation is required to determine an adequate

protocol and to evaluate the long-term therapeutic effect of

treating tinnitus patients using these methods.

Conflict of interest None of the authors has any financial disclo-

sures or commercial associations that might pose or create a conflict

of interest with the information presented in this article.

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6th month, change from

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Pearson correlation

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