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Psychopathological dimensions of tinnitus and psychopharmacologic approaches in its treatment
Available online at www.sciencedirect.com
General Hospital Psychiatry 34 (2012) 282 – 289
Psychopathological dimensions of tinnitus and psychopharmacologic approaches in its treatment☆,☆☆ Hasan Belli, M.D. a,⁎, Seyda Belli, M.D. b , Mehmet Faruk Oktay, M.D. b , Cenk Ural, M.D. a b
a Bagcilar Education And Research Hospital Department of Psychiatry, 34400 Istanbul, Turkey Bagcilar Education And Research Hospital Department of Otorhinolaryngology, 34400 Istanbul, Turkey Received 20 August 2011; accepted 20 December 2011
Abstract Background: The aim of this review to investigate presence of psychopathological states and efficacy of psychopharmacological drugs in the treatment of tinnitus. Materials and Methods: An extensive Internet search has been performed for this aim through PubMed by using related key words in English. Results: Higher anxiety and depression levels and somatoform disorder clusters are defined in patients with tinnitus. Additionally, impulsivity, hostility, demanding, physical discomfort, anxiety for health, emotionality and suicidal tendency are also defined in these people. Personality characteristics in these patients are depression, hysteria and hypochondriac features. Besides these symptom clusters, more severe psychopathologies like personality disorders may be encountered in these patients. Sertraline, paroxetine and nortriptyline can be considered as the first-line antidepressants in the psychopharmacological treatment of tinnitus. There are studies which have reported the efficacy of sulpiride. Carbamazepine, valproate and gabapentin can be effective as mood stabilizers. Short-acting benzodiazepines like alprazolam and midazolam are effective in signs of anxiety. Clonazepam and diazepam can be evaluated as other options. However, some glutamate receptor antagonists also can be used in the treatment of tinnitus. Disturbed sleep is frequently associated with tinnitus. Sleep disturbance can disrupt the quality of life in the patients with tinnitus. These patients might benefit from cognitive–behavioral therapy, which offers the promise of relief from tinnitus-related distress and insomnia. Conclusion: When pathophysiologic reasons are excluded, it should be at least considered that tinnitus is exaggerated by psychopathological symptoms. Life quality of patients can be increased by treating these symptoms. © 2012 Elsevier Inc. All rights reserved. Keywords: Tinnitus; Psychopathology; Psychopharmacology
1. Introduction Tinnitus is perceived in one or both ears and sometimes in the head. Although it is defined as a ringing sound, some patients may define it as buzzing, whistling, pipe sounds or ‘tic tac’ sound, clicking, roaring, a song or a horn [1,2]. Psychological reasons of tinnitus are not known precisely. Tinnitus symptoms compose big problems for both patients and physicians [3]. There are subjective and objective forms. ☆
Conflicts of interest: There are no conflicts of interest. Role of funding source: None of the authors have received funding for this article. ⁎ Corresponding author. Bağcılar Eğitim ve Araştırma Hastanesi, 34400 Istanbul, Turkey. Tel.: +90 212 440 40 00; fax: +90 212 440 40 02. E-mail address: [email protected] (H. Belli). ☆☆
0163-8343/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.genhosppsych.2011.12.006
While objective tinnitus results from sounds in the body, subjective tinnitus results from abnormal neural activities, which are not formed by sounds. The objective form, which is rare, refers to a condition in which a real sound is generated by an internal biological activity, such as vascular turbulence or pulsations or spasm of the muscles in the middle ear, eustachian tube or soft palate [4]. Subjective or idiopathic tinnitus is observed in approximately 10%–14% of the general population. The severity grade of 1%–2% of this rate causes a prominent disruption in daily life activities [5,6]. As with most disorders, the prevalence of tinnitus increases with age and peaks at around 60–70 years [7]. Tinnitus may result from very different pathological states. Tinnitus itself is not a disease, and most frequent reasons of tinnitus are otologic diseases, which may be
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underlying ear infections, foreign body in the ear, cerumen and noise damages. Apart from these, drug intakes which lower serotonin levels, and hearing loss related with exposures to high and severe sounds cause tinnitus frequently. Ototoxic drugs can cause tinnitus secondary to hearing loss or without hearing loss [8,9]. Although tinnitus has negative effects on daily lives in some patients, it does not disturb daily activities, but in some patients, it affects the working performance, social relations and sleep severely [3]. Since pathophysiology of tinnitus is not known clearly, its treatment is mainly focused on symptom relief. Treatments have very different methods. Idiopathic tinnitus is a commonly encountered symptom in adults [3]. Although patients have a detailed otologic examination, only a small number of patients can be specifically treated, and diseases like otosclerosis and Ménière disease can be detected. Sensorineural hearing loss, exposure to noise and head injuries can be detected in the majority of subjective tinnitus in patients [10]. Psychological factors may increase severity of tinnitus symptoms. Generally, ‘a tinnitus personality’ may be defined from the patient history. Majority of patients cannot tolerate the complaints. The severity of patient's complaints is beyond the clinical picture. Therefore, symptoms may be resistant to the treatment [11]. Tinnitus is frequently accepted to be originated from an organic background of unknown origin. The definition of psychopathological components has revealed that psychological symptoms have an important role in a patient's perception of tinnitus. These factors help for appropriate diagnosis and structuring the therapeutic approaches. Psychopathological characteristics are not evaluated as the reasons of tinnitus. However, they appear as serious components of symptoms [12]. Patients with complaints of severe tinnitus have been reported to have a higher psychosocial overload when compared with patients with less severe tinnitus complaints [13]. Tinnitus symptoms have been related to psychological and psychosomatic problems [14,15]. Major depression has been diagnosed at 48%–60% in patients with chronic tinnitus [16,17]. Besides, anxiety disorders have been reported at 45% [18]. Psychopharmacological and psychiatric approaches have an important role in the treatment and management of patients with tinnitus and psychiatric comorbidity. However, no single specialty can cover all the aspects of therapy for tinnitus so in some cases may be necessary a collaboration with the audiologist for the sound therapy and tinnitus retraining therapy, phase-out treatment with the psychotherapist for the cognitive–behavioral therapy [19]. However, it has been reported that some psychopharmacological approaches might be effective in tinnitus treatment. Antidepressant drugs have been reported to have serious contributions in tinnitus treatment [20,21]. There are also studies indicating that antipsychotics, mood stabilizers, sedative-hypnotics and some glutamate receptor antagonists are effective apart from antidepressants [22].
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2. Aims and methods The aim of this review is to investigate the presence of psychopathological states and efficacy of psychopharmacological drugs in its treatment. An extensive Internet search has been performed for this aim through PubMed by using related key words in English, like “Tinnitus AND psychiatric comorbidities,” “Tinnitus AND Psychopathology,” “Tinnitus AND antidepressants,” “Tinnitus AND antipsychotics,” “Tinnitus AND mood stabilizers” and “Tinnitus AND sedative-hypnotics.” Original research, meta-analysis and review articles were evaluated as a priority. Although time interval is not taken in consideration during the Internet search, recent studies are mainly emphasized.
3. Psychopathological dimensions of tinnitus In many trials, high rates of psychopathological disorders and anxiety/depression scores have been reported in patients with tinnitus [2,23,24]. Marciano et al. [12] enrolled the first 75 applicants in their trial, and they applied a half-structured Mini International Neuropsychiatric Interview (MINI) test to their patients. This test was a diagnostic scale compliant with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Additionally, the Minnesota Multiphasic Personality Inventory (MMPI) test was performed to understand personality characteristics of patients. Fiftyeight patients (77%) met the diagnosis of psychiatric disorder. The most frequently encountered disorders were affect and somatoform disorders in Axis I, and various personality disorders in Axis II. High rates of depression, hysteria and hypochondriasis characteristics were determined in the MMPI test. Langguth et al. [25] included 72 patients with chronic tinnitus complaints in their trial and investigated five large personality features in compliance with affective components. These personality features included components like neuroticism, extraversion, clarity, compromise and being conscientious. While compromisable aspects of patients were lower, neuroticism, which was a characteristic feature of anxiety, was high and compliant with depressive symptoms. Anxiety and depression states and lower compliance levels were related to the severity of tinnitus. Adogga et al. [26] conducted a study including 104 patients. The Hospital Anxiety and Depression Scale (HAMDS) was performed on patients in this study. Depression incidence was 17.4% among patients; this rate was higher in females than males. The prevalence of general anxiety was 22.8%. With these rates, males were diagnosed more frequently with anxiety than females. Only three patients were diagnosed with both depression and anxiety. Weber et al. [27] followed up 121 patients with tinnitus for 22 months. Personality characteristics, depression symptoms, demographic profiles and levels of tinnitus
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related to stress were investigated. For this, Tinnitus-Practice (TN), a single test containing three scales, was performed. There were correlations between stress-related tinnitus severity and depression symptoms and demographic profiles. Also, prominent rates of impulsivity, hostility, demanding, physical irritation, anxiety for health and emotional characteristics were detected. A study performed by Belli et al. [28] was designed more comprehensively and with a control group. A total of 90 patients with subjective tinnitus signs were included in this study, and 90 individuals with matched age and gender were included as a control group. Psychiatric diagnostic investigations in Axis I and II were performed in all patients. Therefore, structured clinical interview scales for DSM-III-R were applied to all individuals. Structured Clinical Interview for DSM-III-R (SCID-I and SCID-II) scales were applied for diagnosis of both Axis I and Axis II. Additionally, Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) and Symptom Check List-90-Revised (SCL-90-R) tests were applied for the screening of psychiatric symptoms. While 24 out of the tinnitus patients (26.7%) had at least one psychiatric diagnosis, five participants (5.6%) in the control group had at least one psychiatric diagnosis. Anxiety and somatoform group disorders were significantly high when compared to the control group. Among these disorder groups, anxiety disorder and social phobia diagnoses were the most frequently encountered in the anxiety group. Among the somatoform disorders, the most frequent diagnoses were undifferentiated somatoform disorder and somatization disorder. Among mood disorders, major depressive and dysthymic disorders were frequently diagnosed. All subscales in the SCL-90-R test were higher than those of the control group. Additionally, psychoticism findings were the symptom with the strongest relationship with tinnitus. Point scores in the BDI and BAI tests were significantly higher than those in the control group. Three individuals had personality disorder in the tinnitus group. In this context, Schaaf et al. [29] compared tinnitus patients with psoriasis patients; they included 89 tinnitus and 105 psoriasis patients into the study. They applied SCL-90-R and HAMDS tests, and tinnitus patients were determined to have a more tendency for suicide, depression and anxiety levels. Langguth et al. [30] reported in their review that depression signs were very prominent in patients with tinnitus. They emphasized concomitant appearances of tinnitus and depression and reported that depression prominently has increased the severity of tinnitus. Also, they reported that both situations could appear with the same mechanisms, going through the same pathophysiologic process, and affect each other. Again, in this review, changes in the hypothalamic–pituitary–adrenal axis in depression and tinnitus were shown. Hyperactivity was detected at the dorsal cochlear nucleus in tinnitus. This region has also responded attention and emotional stimuli through projections from locus coeruleus, reticular formation and nucleus raphe. This region was affected at both situations.
Some candidate genes in charge of both situations were also defined, and they have been proposed to cause tendencies to both tinnitus and depression. 3.1. Sleep disturbance in tinnitus A survey administered to a large random sample of 6103 elderly people in Sweden confirmed a higher prevalence of sleep disturbance in individuals with than without tinnitus [31]. However, some studies have found significant correlations between sleep disturbance and depression [32] and between sleep difficulties and tinnitus severity [33]. Sleep difficulties have in turn been regarded as a risk factor [34], correlate, characteristic [35] and predictor [36] of tinnitus-related distress. It is likely that insomnia is linked to the anomalies in the physiological stress response previously found in tinnitus groups [37,38]. Crönlein and colleagues compared retrospectively the polysomnographic sleep of patients referred to their sleep clinic for complaints of insomnia and suffering or not from tinnitus [39]. They found no significant differences in objective or subjective sleep variables between the two patient groups with insomnia complaints, with the exception of longer sleep latency in the group with tinnitus. Sleep disturbance can disrupt the quality of life in the patients with tinnitus. Therefore, both tinnitus and sleep disturbance should be treated early. On the other hand, these patients might benefit from cognitive–behavioral therapy, which offers the promise of relief from tinnitus-related distress and insomnia [40]. 3.2. Psychopharmacological treatment of tinnitus A patient's emotional or psychological response to tinnitus can vary from one individual to the next, even among patients whose tinnitus is similar. Consequently, it is important to determine how a drug affects a person's social or emotional response to tinnitus, as well as its perceptual qualities. Frequently used questionnaires for assessing a patient's reaction to tinnitus are the Tinnitus Handicap Inventory (THI), Tinnitus Handicap Questionnaire (THQ) and Tinnitus Reaction Questionnaire (TRQ) [41–43]. These questionnaires focus on issues related to the degree of handicap, sleep, social interactions, emotion, concentration, depression and annoyance of tinnitus. Drugs used to treat tinnitus should either reduce the tinnitus perception or the emotional response, and ideally both. Many psychopharmacological agents are employed in the treatment of tinnitus (Table 1). 3.3. Antidepressants In their meta-analysis study, Baldo et al. investigated the efficacy of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) in tinnitus treatment. They defined the efficacy of these two groups of antidepressants. However, methodological insufficiencies or single case presentations have decreased the study value [44].
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Table 1 Psychopharmacological agents for tinnitus Groups
Drugs
Evidence
TCAs SSRIs Antipsychotics
Nortriptyline Sertraline Sulpiride
Mood stabilizers
Carbamazepine
Superior to placebo, reduced depression and tinnitus loudness More effective than placebo, reduced depression and tinnitus symptoms Superior to placebo in a single-blind, placebo-controlled study. Sulpiride reported to decrease the perception of tinnitus. Some success in case report and trials. It is the recommended drug to be used alone or combination with lidocaine, salicylate or steroids. Effective in a single case study Superior to placebo, effective in reducing subjective or objective tinnitus Superior to placebo in the treatment of severe tinnitus and high levels of anxiety It was evaluated in double-blind, triple-crossover trials; effective in reducing tinnitus Effective for pulsatile tinnitus when associated with beta-blockers Superior to placebo Not yet investigated in humans for tinnitus treatment Potentially effective for tinnitus and Ménière disease Superior than placebo; effective for tinnitus
Sedative-hypnotics/BZDs
Glutamate receptor antagonists
Valproate Gabapentin Alprazolam Diazepam Clonazepam Midazolam Memantine Caroverine Acamprosate
The analysis written by Robinson has covered better designed trials. In that trial, TCAs and SSRIs have been emphasized to be effective in tinnitus patients with symptoms of depression, anxiety and insomnia [45]. TCAs especially like nortriptyline have been reported to be effective. In a small, single-blind, placebo-washout study involving patients with severe tinnitus and major depression, nortriptyline significantly reduced depression and tinnitus loudness. In a double-blind, placebo-controlled, follow-up study involving subjects with severe tinnitus and severe depression or depressive symptoms, nortriptyline significantly reduced depression scores, tinnitus disability scores and tinnitus loudness [46]. Some antidepressants, especially non-TCAs (lower doses of heterocyclic drugs) like trazodone and mianserin, were proposed to be related to the initiation of tinnitus [47,48]. Moreover, these drugs have been reported to be effective in some publications [49–51]. Although tinnitus was reported to initiate after the cessation of sertraline [52], it was found to be more effective than placebo in severe and resistant tinnitus cases. In a randomized, double-blind, placebo-controlled study in patients without severe hearing loss but with depression, anxiety and a high risk for developing severe tinnitus, sertraline was shown to be significantly more effective than placebo in reducing tinnitus loudness and tinnitus severity [53]. However, in a double-blind, placebo-controlled study involving chronic tinnitus patients, few of whom suffered from depression, the paroxetine group showed little difference from placebo on tinnitus loudness matching, THQ scores and other measures; however, the paroxetine group showed a significant improvement in tinnitus aggravation compared with the control group. Although SSRIs are widely used to treat tinnitus, the authors suggested that antidepressants should not be used to treat nondepressed tinnitus patients. However, in a case study, paroxetine significantly reduced tinnitus and improved mood in a patient with severe depression, anxiety and tinnitus [54].
Although new antidepressants have not been investigated as much as TCAs and SSRIs, there were few study results about their efficacies. There were few findings related to serotonin–noradrenaline reuptake inhibitors. Additionally, it was reported that, rarely, cessation of venlafaxine and duloxetine could cause appearance of tinnitus signs [55–57]. 3.4. Antipsychotics Sometimes, it may be hard to differentiate tinnitus from psychotic symptoms. Schizophrenic patients with increased rates of tinnitus like perceptions, hallucinations and who were taking antipsychotics were reported [58]. Until now, sulpiride is the most accurately investigated antipsychotic drug in tinnitus treatment. In the prospective, randomized, single-blind, placebo-controlled, hydroxyzine comparative study, which was designed by Lopez-Gonzalez et al., sulpiride was reported to decrease the perception of tinnitus. Sulpiride was used at lower doses in this study [59]. 3.5. Mood stabilizers Although names of many mood stabilizer drugs have been discussed in the tinnitus treatment, there was no compromise because all of the available data were not from systematic studies [22]. Among other drugs, only carbamazepine is the recommended drug to be used alone [60] or in combination with lidocaine [61], salicylate [62] or steroids [63] in the treatment of subjective tinnitus. Valproate is another popular mood stabilizer drug investigated in tinnitus treatment [64,65]. Lamotrigine was found to be ineffective in tinnitus treatment [66]. Gabapentin is a well-investigated drug in tinnitus treatment. Bauer and Brozoski reported in their placebo-controlled study that it was effective in the treatment of objective and subjective tinnitus. It was also found to be effective especially in individuals with acoustic trauma [67]. Recent placebo-controlled studies (in one study, 1800 mg/day; in
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another, 900–3600 mg/day) revealed that high-dose gabapentin was effective [68,69]. 3.6. Sedative-hypnotics Daftary et al. reported that benzodiazepines (BZD) and other sedative-hypnotics were world-widely used drugs in tinnitus treatment [70]. Although there were no systematic studies, majority of results, especially in cases with dense anxiety signs, showed that they were effective in the treatment. BDZs with shorter half-lives like alprazolam [71], midazolam [72] and clonazepam [73] have been shown to be effective in placebo-controlled trials. However, complications associated with alprazolam include drug dependency and difficulty of discontinuing use. In a prospective, double-blind, placebocontrolled study, alprazolam was administered to patients with tinnitus; the dose was increased until it caused side effects or had an effect on tinnitus. Alprazolam reduced tinnitus loudness, measured with a tinnitus synthesizer and visual analog scale, in 76% of subjects, whereas only 5% showed a reduction in tinnitus loudness in the control group. Although the positive effects of alprazolam observed in this study are encouraging, the study design has been criticized because of the small sample size, drug dosing method, failure to assess emotional effect and the need for replication [74]. Diazepam was evaluated in a double-blind, triplecrossover trial involving 21 tinnitus patients. The drug had no effect on tinnitus loudness, a result which is surprising considering that its mechanisms of action are similar to those of alprazolam. One possible explanation for the discrepancy is that the dose of alprazolam, but not diazepam, was adjusted for each patient to maximize its effects on tinnitus [75]. Complications associated with diazepam include drug dependency and difficulty of discontinuing use [76]. There is information about the efficacy of clonazepam in pulsatile tinnitus when used with beta blockers [77]. 3.7. Glutamate receptor antagonists N-methyl-D-aspartate (NMDA) glutamate receptor is most likely involved in tinnitus, as it is involved in many forms of central neuropathic pain [78]. It has been shown that acetylsalicylic acid activates cochlear NMDA receptors and that the use of NMDA antagonists at the round window abolishes tinnitus [79], while NMDA receptor agonists may induce tinnitus-like behaviors [80]. Memantine, used to treat neuropathic pain and mild to moderate forms of Alzheimer's disease [81], blocks NMDA transmission in hair cells also modulating the cholinergic transmission [82]. The efficacy of memantine is only based on some observations in the treatment of tinnitus. There are no systematic human studies on the efficacy of this drug. Caroverine acts as a glutamate antagonist. Denk et al. [83] reported variable results in patients with tinnitus treated with caroverine. Ehrenberger et al. [84] investigated the effects of caroverine on tinnitus patients for several years.
Initially, they had success in 63% of participants using an intravenous infusion of caroverine; subsequently, they reported a success in 50% of patients with Ménière disease and sudden hearing loss. Acamprosate has been recently used like a glutamate antagonist. A small clinical trial of acamprosate conducted on 25 tinnitus patients showed that 87% had some degree of relief and nearly 48% had a reduction of more than 50%. Many side effects were described (depression, diarrhea, anxiety), and the drowsiness caused by acamprosate itself may have contributed to improvement as many tinnitus patients have trouble sleeping [85].
4. Conclusion Tinnitus is a frequently encountered situation in the population. For clinicians, tinnitus is a cluster of symptoms with very complex aspects [16]. Apart from this, it may ensue as a result of many pathological situations. Despite this, very little is known about the pathogenesis of tinnitus [8,9]. Tinnitus can severely deteriorate the working life, social relationships and sleep order. Especially when nothing pathological is defined in otoneurological examinations of patients, high concomitance of psychiatric diagnosis and symptoms can be detected [28]. According to our identifications in patients with tinnitus, high anxiety, depression levels and somatoform disorder clusters can be detected. Additionally, impulsivity, hostility, demanding, physical irritation, anxiety in health and emotionality, and tendency for suicide features have been detected. As characteristics of personality, depression, hysteria and hypochondriasis have been detected. In addition to these symptom clusters, personality disorders with more severe psychopathologies can be detected. These kinds of personality disorders are difficult to diagnose and are infrequent situations. In order to define types and severity of symptoms in patients, clinically applicable tests like HAMDS, SCL-90-R, BDI and BAI can easily be employed, and as a result of these, psychopharmacological treatment can be initiated. Drugs used to treat tinnitus should either reduce the tinnitus perception or the emotional response, and ideally both. For this, THI, THQ and TRQ tests can also be employed in clinical practice. However, information about history and descriptive characteristics of the patient's tinnitus or tinnitus-related conditions could be obtained by the Tinnitus Sample Case History Questionnaire (TSCHQ) [86] (Table 2). If a complicated psychopathology is suspected, patients can consult a psychiatrist. Sertraline, paroxetine and nortriptyline can be considered as the first-line antidepressants in the psychopharmacological treatment of tinnitus. There are studies which have reported the efficacy of sulpiride. Carbamazepine, valproate and gabapentin can be effective as mood stabilizers. Shortacting BZDs like alprazolam and midazolam are effective in signs of anxiety. Clonazepam and diazepam can be evaluated
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Table 2 Scales used in tinnitus Scales
The meaning of the test
The purpose of using
MINI MMPI HAMDS TN BDI BAI SCL-90-R THI, THQ, TRQ
Mini International Neuropsychiatric Interview Minnesota Multiphasic Personality Inventory Hospital Anxiety and Depression Scale Tinnitus-Practice Beck Depression Inventory Beck Anxiety Inventory Symptom Check List-90-Revised Tinnitus Handicap Inventory, Tinnitus Handicap Questionnaire, Tinnitus Reaction Questionnaire
TSCHQ
Tinnitus Sample Case History Questionnaire
This test is a diagnostic scale compliant with DSM-IV criteria Used for understanding personality characteristics of patients Used to measure the level of anxiety and depression Used to measure the stress-related tinnitus severity and depression Used to measure the level of depression Used to measure the level of anxiety Used for the screening of psychiatric symptoms These questionnaires that focus on issues related to the degree of handicap, sleep, social interaction, emotion, concentration, depression and annoyance of tinnitus Information about history and descriptive characteristics of the patient's tinnitus or tinnitus-related conditions
as other options. Additionally, addiction potentials of BZDs should not be missed. High doses and long durations of their use should be avoided. However, some glutamate receptor antagonists such as memantine, caroverine and acamprosate can be effective. Disturbed sleep is frequently associated with tinnitus. Sleep disturbance can disrupt the quality of life in the patients with tinnitus. Therefore, both tinnitus and sleep disturbance should be treated early. If pathophysiologic reasons are excluded, it should at least be considered that tinnitus deteriorates with psychopathological symptoms. It should be known that if these symptoms are treated, life qualities of patients can be increased. References [1] Heller AJ. Classification and epidemiology of tinnitus. Otolaryngol Clin North Am 2003;36:239–48. [2] Holgers KM, Zöger S, Svedlund J, Erlandsson SI. Psychiatric profile of tinnitus patients referred to an audiology clinic. In: Hazell J, editor. Proceedings of the Sixth International Tinnitus Seminar. Cambridge, UK: The Tinnitus and Hyperacusis Centre; 1999, pp. 283–5. [3] Laurikainen E, Johansson R, Akaan-Penttila E, Haapaniemi J. Treatment of severe tinnitus. Acta Otolaryngol Suppl 2000;543:77–8. [4] Moller AR. Neural plasticity in tinnitus. Prog Brain Res 2006;157: 365–72. [5] Axelsson A, Ringdahl A. Tinnitus: a study of its prevalence and characteristics. Br J Audiol 1989;23:53–62. [6] Davis AC. Hearing in adults. London, UK: Whurr; 1995, pp. 122–5. [7] Axelsson A, Ringdahl A. Tinnitus — a study of its prevalence and characteristics. Br J Audiol 1989;23:53–62. [8] Brown RD, Penny JE, Henley CM, Hodges KB, Kupetz SA, Glenn DW, et al. Ototoxic drugs and noise. Ciba Found Symp 1981;85: 151–71. [9] Nicolas-Puel C, Akbaraly T, Lloyd R, Berr C, Uziel A, Rebillard G, et al. Characteristics of tinnitus in a population of 555 patients: specificities of tinnitus induced by noise trauma. Int Tinnitus J 2006; 12:64–70. [10] Dobie RA. A review of randomized clinical trials in tinnitus. Laryngoscope 1999;109:1202–11. [11] Schleuning AJ. Management of the patient with tinnitus. Med Clin North Am 1991;75:1225–37. [12] Marciano E, Carrabba L, Giannini P, Sementina C, Verde P, Bruno C, et al. Psychiatric comorbidity in a population of outpatients affected by tinnitus. Int J Audiology 2003;42:4–9.
[13] Holgers KM, Zöger S, Svedlund J. Predictive factors for severe tinnitus suffering: further characterisation. Int J Audiology 2005; 44:584–92. [14] Erlandsson S, Hallberg L, Axelsson A. Psychological and audiological correlates of perceived tinnitus severity. Audiology 1992;31:168–79. [15] Collet L, Moussu MF, Disant F, Ahami T, Morgon A. Minnesota Multiphasic Personality Inventory in tinnitus disorders. Audiology 1990;28:101–6. [16] Harrop-Griffiths J, Katon W, Dobie R, Sakai C, Russo J. Chronic tinnitus: association with psychiatric diagnosis. J Psychosom Res 1987;31:613–21. [17] Sullivan MD, Katon W, Dobie R, Sakai C, Russo J. Disabling tinnitus: association with affective disorder. Gen Hosp Psychiatry 1988; 10:285–91. [18] Zöger S, Svedlund J, Holgers KM. Psychiatric disorders in tinnitus patients without severe hearing impairment: 24-month follow-up of patients at an audiological clinic. Audiology 2001;40:133–40. [19] Fioretti A, Eibenstein A, Fusetti M. New trends in tinnitus management. Open Neurol J 2011;22:12–7. [20] Dobie RA. Depression and tinnitus. Otolaryngol Clin N Am 2003;36: 383–8. [21] Sullivan MD, Dobie RA, Sakai CS, Katon WJ. Treatment of depressed tinnitus patients with nortriptyline. Ann Otol Rhinol Laryngol 1989; 98:867–72. [22] Fornaro M, Martino M. Tinnitus psychopharmacology: a comprehensive review of its pathomechanisms and management. Neuropsychiatr Dis Treat 2010;6:209–18. [23] Andersson G, McKenna L. Tinnitus masking and depression. Audiology 1998;37:174–82. [24] Anderson G, Carlbring P, Kaldo V, Ström L. Screening of psychiatric disorders via the Internet. A pilot study with tinnitus patients. Nord J Psychiatry 2004;58:287–91. [25] Langguth B, Kleinjung T, Fischer B, Hajak G, Eichhammer P, Sand PG. Tinnitus severity, depression, and the big five personality traits. Prog Brain Res 2007;166:221–5. [26] Adoga AA, Adoga AS, Obindo JT. Tinnitus and the prevalence of comorbid psychological stress. Niger J Med 2008;17:95–7. [27] Weber JH, Jagsch R, Hallas B. The relationship between tinnitus, personality, and depression. Z Psychosom Med Psychother 2008; 54:227–40. [28] Belli S, Belli H, Bahcebasi T, Ozcetin A, Alpay E, Ertem U. Assessment of psychopathological aspects and psychiatric comorbidities in patients affected by tinnitus. Eur Arch Otorhinolaryngol 2008; 265:279–85. [29] Schaaf H, Eipp C, Deubner R, Vasa R, Gieler U. Psychosocial aspects of coping with tinnitus and psoriasis patients. A comparative study of suicidal tendencies, anxiety and depression. HNO 2009;57:57–63. [30] Langguth B, Landgrebe M, Kleinjung T, Sand GP, Hajak G. Tinnitus and depression. World J Biol Psychiatry 2011;12:489–500.
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[31] Asplund R. Sleepiness and sleep in elderly persons with tinnitus. Arch Gerontol Geriatr 2003;37:139–45. [32] Alster J, Shemesh Z, Ornan M, Attias J. Sleep disturbance associated with chronic tinnitus. Biol Psychiatry 1993;34:84–90. [33] Folmer RL, Griest SE. Tinnitus and insomnia. Am J Otolaryngol 2000; 21:287–93. [34] Holgers KM, Erlandsson SI, Barrenäs ML. Predictive factors for the severity of tinnitus. Audiology 2000;39:284–91. [35] Nondahl DM, Cruickshanks KJ, Wiley TL, Klein R, Klein BE, Tweed TS. Prevalence and 5-year incidence of tinnitus among older adults: the epidemiology of hearing loss study. J Am Acad Audiol 2002;13: 323–31. [36] Langenbach M, Olderog M, Michel O, Albus C, Köhle K. Psychosocial and personality predictors of tinnitus-related distress. Gen Hosp Psychiatry 2005;27:73–7. [37] Hébert S, Paiement P, Lupien SJ. A physiological correlate for the intolerance to both internal and external sounds. Hear Res 2004;190: 1–9. [38] Hébert S, Lupien SJ. The sound of stress: blunted cortisol reactivity to psychosocial stress in tinnitus sufferers. Neurosci Lett 2007;411: 138–42. [39] Crönlein T, Langguth B, Geisler P, Hajak G. Tinnitus and insomnia. Prog Brain Res 2007;166:227–33. [40] Andersson G, Porsaeus D, Wiklund M, Kaldo V, Larsen HC. Treatment of tinnitus in the elderly: a controlled trial of cognitive behavior therapy. Int J Audiol 2005;44:671–5. [41] Newman CW, Jacobson GP, Spitzer JB. Development of the Tinnitus Handicap Inventory. Arch Otolaryngol Head Neck Surg 1996;122: 143–8. [42] Wilson PH, Henry J, Bowen M, Haralambous G. Tinnitus reaction questionnaire: psychometric properties of a measure of distress associated with tinnitus. J Speech Hear Res 1991;34:197–201. [43] Kuk FK, Tyler RS, Russell D, Jordan H. The psychometric properties of a tinnitus handicap questionnaire. Ear Hear 1990;11:434–45. [44] Baldo P, Doree C, Lazzarini R, Molin P, McFerran DJ. Antidepressants for patients with tinnitus. Cochrane Database Syst Rev 2006(4): CD003853. [45] Robinson S. Antidepressants for treatment of tinnitus. Prog Brain Res 2007;166:263–71. [46] Dobie RA, Sullivan MD, Katon WJ, Sakai CS, Russo J. Antidepressant treatment of tinnitus patients. Interim report of a randomized clinical trial. Acta Otolaryngol 1992;112:242–7. [47] Mendis D, Johnston M. An unusual case of prolonged tinnitus following low-dose amitriptyline. J Psychopharmacol 2008;22:574–5. [48] Podoshin L, Ben-David Y, Fradis M, Malatskey S, Hafner H. Idiopathic subjective tinnitus treated by amitriptyline hydrochloride/ biofeedback. Int Tinnitus J 1995;1:54–60. [49] Bayar N, Böke B, Turan E, Belgin E. Efficacy of amitriptyline in the treatment of subjective tinnitus. J Otolaryngol 2001;30:300–3. [50] Dib GC, Kasse CA, Alves de Andrade T, Gurgel Testa JR, Cruz OL. Tinnitus treatment with trazodone. Braz J Otorhinolaryngol 2007;73: 390–7. [51] Marais J. Cochleotoxicity due to mianserin hydrochloride. J Laryngol Otol 1991;105:475–6. [52] Leiter FL, Nierenberg AA, Sanders KM, Stern TA. Discontinuation reactions following sertraline. Biol Psychiatry 1995;38:694–5. [53] Zoger S, Svedlund J, Holgers KM. The effects of sertraline on severe tinnitus suffering — a randomized double-blind placebo-controlled study. J Clin Psychopharmacol 2006;26(1):32–9. [54] Salvi R, Lobarinas E, Sun W. Pharmacological treatments for tinnitus: new and old. Drugs Future 2009;34:381–400. [55] Pondrom MF, Brahm NC. Venlafaxine-associated tinnitus. Am J Health Syst Pharm 2009;66:1606–8. [56] Ahmad S. Venlafaxine and severe tinnitus. Am Fam Physician 1995; 51:1830. [57] De Marinis M, Santilli V. Tinnitus in postherpetic neuralgia. J Headache Pain 2010;11:83–4.
[58] D'Amelio R, Delb W. Comorbidity of schizophrenic psychosis and tinnitus. A hitherto neglected theme in research and therapy. HNO 2008;56:670–2. [59] Lopez-Gonzalez MA, Moliner-Peiro F, Alfaro-Garcia J, EstebanOrtega F. Sulpiride plus hydroxyzine decrease tinnitus perception. Auris Nasus Larynx 2007;34:23–7. [60] Hulshof JH, Vermeij P. The value of carbamazepine in the treatment of tinnitus. ORL J Otorhinolaryngol Relat Spec 1985;47:262–6. [61] Sanchez TG, Balbani AP, Bittar RS, Bento RF, Câmara J. Lidocaine test in patients with tinnitus: rationale of accomplishment and relation to the treatment with carbamazepine. Auris Nasus Larynx 1999;26: 411–7. [62] Zheng Y, Hooton K, Smith PF, Darlington C. Carbamazepine reduces the behavioural manifestations of tinnitus following salicylate treatment in rats. Acta Otolaryngol 2008;128:48–52. [63] She W, Dai Y, Du X, Ding X, Cui X. Treatment of subjective tinnitus: a comparative clinical study of intratympanic steroid injection vs. oral carbamazepine. Med Sci Monit 2009;15:135–9. [64] Mansbach AL, Freyens P. Tinnitus: current data and treatment with sodium valproate. Acta Otorhinolaryngol Belg 1983;37:697–705. [65] Menkes DB, Larson PM. Sodium valproate for tinnitus. J Neurol Neurosurg Psychiatry 1998;65:803. [66] Simpson JJ, Gilbert AM, Weiner GM, Davies WE. The assessment of lamotrigine an antiepileptic drug in the treatment of tinnitus. Am J Otol 1999;20:627–31. [67] Bauer CA, Brozoski TJ. Effect of gabapentin on the sensation and impact of tinnitus. Laryngoscope 2006;116:675–81. [68] Witsell DL, Hannley MT, Stinnet S, Tucci DL. Treatment of tinnitus with gabapentin: a pilot study. Otol Neurotol 2007;28:11–5. [69] Piccirillo JF, Finnell J, Vlahiotis A, Chole RA, Spitznagel Jr E. Relief of idiopathic subjective tinnitus: is gabapentin effective? Arch Otolaryngol Head Neck Surg 2007;133:390–7. [70] Daftary A, Shulman A, Strashun A Gottschalk C, Zoghbi SS, Seibyl JP. Benzodiazepine receptor distribution in severe intractable tinnitus. Int Tinnitus J 2004;10:17–23. [71] Jalali MM, Kousha A, Naghavi SE, Soleimani R, Banan R. The effects of alprazolam on tinnitus: a cross-over randomized clinical trial. Med Sci Monit 2009;15:I55–60. [72] Panford-Walsh R, Singer W, Rüttiger L, Hadjab S, Tan J, Geisler HS, et al. Midazolam reverses salicylate-induced changes in brain-derived neurotrophic factor and Arg3.1 expression: implications for tinnitus perception and auditory plasticity. Mol Pharmacol 2008;74:595–604. [73] Ganança MM, Caovilla HH, Ganança FF, Ganança CF, Munhoz MS, da Silva ML, et al. Clonazepam in the pharmacological treatment of vertigo and tinnitus. Int Tinnitus J 2002;8:50–3. [74] Johnson RM, Brummett R, Schleuning A. Use of alprazolam for relief of tinnitus. A double-blind study. Arch Otolaryngol Head Neck Surg 1993;119:842–54. [75] Busto U, Fornazzari L, Naranjo CA. Protracted tinnitus after discontinuation of long-term therapeutic use of benzodiazepines. J Clin Psychopharmacol 1988;8:359. [76] Busto U, Sellers EM, Naranjo CA, Cappell H, Sanchez-Craig M, Sykora K. Withdrawal reaction after long-term therapeutic use of benzodiazepines. New Engl J Med 1986;315:854. [77] Albertino S, Assuncao AR, Souza JA. Pulsatile tinnitus: treatment with clonazepam and propranolol. Braz J Otorhinolaryngol 2005;71: 111–3. [78] Puel JL. Cochlear NMDA receptor blockade prevents salicylateinduced tinnitus. B-ENT 2007;3(Suppl 7):19–22. [79] Guitton MJ, Caston J, Ruel J, Johnson RM, Pujol R, Puel JL. Salicylate induces tinnitus through activation of cochlear NMDA receptors. J Neurosci 2003;23:3944–52. [80] Guitton MJ, Dudai Y. Blockade of cochlear NMDA receptors prevents long-term tinnitus during a brief consolidation window after acoustic trauma. Neural Plast 2007;2007:80904. [81] Pomara N, Ott BR, Peskind E, Resnick EM. Memantine treatment of cognitive symptoms in mild to moderate Alzheimer disease: secondary
H. Belli et al. / General Hospital Psychiatry 34 (2012) 282–289 analyses from a placebo-controlled randomized trial. Alzheimer Dis Assoc Disord 2007;21:60–4. [82] Oliver D, Ludwig J, Reisinger E, Zoellner W, Ruppersberg JP, Fakler B. Memantine inhibits efferent cholinergic transmission in the cochlea by blocking nicotinic acetylcholine receptors of outer hair cells. Mol Pharmacol 2001;60:183–9. [83] Denk DM, Heinzl H, Franz P, Ehrenberger K. Caroverine in tinnitus treatment. A placebo-controlled blind study. Acta Otolaryngol 1997; 117:825–30.
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[84] Ehrenberger K. Topical administration of caroverine in somatic tinnitus treatment: proof-of-concept study. Int Tinnitus J 2005;11:34–7. [85] Azevedo AA, Figuerido RR. Tinnitus treatment with acamprosate: double-blind study. Braz J Otorhinolaryngol 2005;71:618–23. [86] Langguth B, Goodey R, Azevedo A, et al. Consensus for tinnitus patient assessment and treatment outcome measurement. In: Langguth B, Hajak G, Kleinjung T, Cacace AT, & Møller AR, editors. Tinnitus: pathophysiology and treatment. Amsterdam: Elsevier; 2007, pp. 529–31.
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Psychopathological dimensions of tinnitus and psychopharmacologic approaches in its treatment☆,☆☆ Hasan Belli, M.D. a,⁎, Seyda Belli, M.D. b , Mehmet Faruk Oktay, M.D. b , Cenk Ural, M.D. a b
a Bagcilar Education And Research Hospital Department of Psychiatry, 34400 Istanbul, Turkey Bagcilar Education And Research Hospital Department of Otorhinolaryngology, 34400 Istanbul, Turkey Received 20 August 2011; accepted 20 December 2011
Abstract Background: The aim of this review to investigate presence of psychopathological states and efficacy of psychopharmacological drugs in the treatment of tinnitus. Materials and Methods: An extensive Internet search has been performed for this aim through PubMed by using related key words in English. Results: Higher anxiety and depression levels and somatoform disorder clusters are defined in patients with tinnitus. Additionally, impulsivity, hostility, demanding, physical discomfort, anxiety for health, emotionality and suicidal tendency are also defined in these people. Personality characteristics in these patients are depression, hysteria and hypochondriac features. Besides these symptom clusters, more severe psychopathologies like personality disorders may be encountered in these patients. Sertraline, paroxetine and nortriptyline can be considered as the first-line antidepressants in the psychopharmacological treatment of tinnitus. There are studies which have reported the efficacy of sulpiride. Carbamazepine, valproate and gabapentin can be effective as mood stabilizers. Short-acting benzodiazepines like alprazolam and midazolam are effective in signs of anxiety. Clonazepam and diazepam can be evaluated as other options. However, some glutamate receptor antagonists also can be used in the treatment of tinnitus. Disturbed sleep is frequently associated with tinnitus. Sleep disturbance can disrupt the quality of life in the patients with tinnitus. These patients might benefit from cognitive–behavioral therapy, which offers the promise of relief from tinnitus-related distress and insomnia. Conclusion: When pathophysiologic reasons are excluded, it should be at least considered that tinnitus is exaggerated by psychopathological symptoms. Life quality of patients can be increased by treating these symptoms. © 2012 Elsevier Inc. All rights reserved. Keywords: Tinnitus; Psychopathology; Psychopharmacology
1. Introduction Tinnitus is perceived in one or both ears and sometimes in the head. Although it is defined as a ringing sound, some patients may define it as buzzing, whistling, pipe sounds or ‘tic tac’ sound, clicking, roaring, a song or a horn [1,2]. Psychological reasons of tinnitus are not known precisely. Tinnitus symptoms compose big problems for both patients and physicians [3]. There are subjective and objective forms. ☆
Conflicts of interest: There are no conflicts of interest. Role of funding source: None of the authors have received funding for this article. ⁎ Corresponding author. Bağcılar Eğitim ve Araştırma Hastanesi, 34400 Istanbul, Turkey. Tel.: +90 212 440 40 00; fax: +90 212 440 40 02. E-mail address: [email protected] (H. Belli). ☆☆
0163-8343/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.genhosppsych.2011.12.006
While objective tinnitus results from sounds in the body, subjective tinnitus results from abnormal neural activities, which are not formed by sounds. The objective form, which is rare, refers to a condition in which a real sound is generated by an internal biological activity, such as vascular turbulence or pulsations or spasm of the muscles in the middle ear, eustachian tube or soft palate [4]. Subjective or idiopathic tinnitus is observed in approximately 10%–14% of the general population. The severity grade of 1%–2% of this rate causes a prominent disruption in daily life activities [5,6]. As with most disorders, the prevalence of tinnitus increases with age and peaks at around 60–70 years [7]. Tinnitus may result from very different pathological states. Tinnitus itself is not a disease, and most frequent reasons of tinnitus are otologic diseases, which may be
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underlying ear infections, foreign body in the ear, cerumen and noise damages. Apart from these, drug intakes which lower serotonin levels, and hearing loss related with exposures to high and severe sounds cause tinnitus frequently. Ototoxic drugs can cause tinnitus secondary to hearing loss or without hearing loss [8,9]. Although tinnitus has negative effects on daily lives in some patients, it does not disturb daily activities, but in some patients, it affects the working performance, social relations and sleep severely [3]. Since pathophysiology of tinnitus is not known clearly, its treatment is mainly focused on symptom relief. Treatments have very different methods. Idiopathic tinnitus is a commonly encountered symptom in adults [3]. Although patients have a detailed otologic examination, only a small number of patients can be specifically treated, and diseases like otosclerosis and Ménière disease can be detected. Sensorineural hearing loss, exposure to noise and head injuries can be detected in the majority of subjective tinnitus in patients [10]. Psychological factors may increase severity of tinnitus symptoms. Generally, ‘a tinnitus personality’ may be defined from the patient history. Majority of patients cannot tolerate the complaints. The severity of patient's complaints is beyond the clinical picture. Therefore, symptoms may be resistant to the treatment [11]. Tinnitus is frequently accepted to be originated from an organic background of unknown origin. The definition of psychopathological components has revealed that psychological symptoms have an important role in a patient's perception of tinnitus. These factors help for appropriate diagnosis and structuring the therapeutic approaches. Psychopathological characteristics are not evaluated as the reasons of tinnitus. However, they appear as serious components of symptoms [12]. Patients with complaints of severe tinnitus have been reported to have a higher psychosocial overload when compared with patients with less severe tinnitus complaints [13]. Tinnitus symptoms have been related to psychological and psychosomatic problems [14,15]. Major depression has been diagnosed at 48%–60% in patients with chronic tinnitus [16,17]. Besides, anxiety disorders have been reported at 45% [18]. Psychopharmacological and psychiatric approaches have an important role in the treatment and management of patients with tinnitus and psychiatric comorbidity. However, no single specialty can cover all the aspects of therapy for tinnitus so in some cases may be necessary a collaboration with the audiologist for the sound therapy and tinnitus retraining therapy, phase-out treatment with the psychotherapist for the cognitive–behavioral therapy [19]. However, it has been reported that some psychopharmacological approaches might be effective in tinnitus treatment. Antidepressant drugs have been reported to have serious contributions in tinnitus treatment [20,21]. There are also studies indicating that antipsychotics, mood stabilizers, sedative-hypnotics and some glutamate receptor antagonists are effective apart from antidepressants [22].
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2. Aims and methods The aim of this review is to investigate the presence of psychopathological states and efficacy of psychopharmacological drugs in its treatment. An extensive Internet search has been performed for this aim through PubMed by using related key words in English, like “Tinnitus AND psychiatric comorbidities,” “Tinnitus AND Psychopathology,” “Tinnitus AND antidepressants,” “Tinnitus AND antipsychotics,” “Tinnitus AND mood stabilizers” and “Tinnitus AND sedative-hypnotics.” Original research, meta-analysis and review articles were evaluated as a priority. Although time interval is not taken in consideration during the Internet search, recent studies are mainly emphasized.
3. Psychopathological dimensions of tinnitus In many trials, high rates of psychopathological disorders and anxiety/depression scores have been reported in patients with tinnitus [2,23,24]. Marciano et al. [12] enrolled the first 75 applicants in their trial, and they applied a half-structured Mini International Neuropsychiatric Interview (MINI) test to their patients. This test was a diagnostic scale compliant with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Additionally, the Minnesota Multiphasic Personality Inventory (MMPI) test was performed to understand personality characteristics of patients. Fiftyeight patients (77%) met the diagnosis of psychiatric disorder. The most frequently encountered disorders were affect and somatoform disorders in Axis I, and various personality disorders in Axis II. High rates of depression, hysteria and hypochondriasis characteristics were determined in the MMPI test. Langguth et al. [25] included 72 patients with chronic tinnitus complaints in their trial and investigated five large personality features in compliance with affective components. These personality features included components like neuroticism, extraversion, clarity, compromise and being conscientious. While compromisable aspects of patients were lower, neuroticism, which was a characteristic feature of anxiety, was high and compliant with depressive symptoms. Anxiety and depression states and lower compliance levels were related to the severity of tinnitus. Adogga et al. [26] conducted a study including 104 patients. The Hospital Anxiety and Depression Scale (HAMDS) was performed on patients in this study. Depression incidence was 17.4% among patients; this rate was higher in females than males. The prevalence of general anxiety was 22.8%. With these rates, males were diagnosed more frequently with anxiety than females. Only three patients were diagnosed with both depression and anxiety. Weber et al. [27] followed up 121 patients with tinnitus for 22 months. Personality characteristics, depression symptoms, demographic profiles and levels of tinnitus
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related to stress were investigated. For this, Tinnitus-Practice (TN), a single test containing three scales, was performed. There were correlations between stress-related tinnitus severity and depression symptoms and demographic profiles. Also, prominent rates of impulsivity, hostility, demanding, physical irritation, anxiety for health and emotional characteristics were detected. A study performed by Belli et al. [28] was designed more comprehensively and with a control group. A total of 90 patients with subjective tinnitus signs were included in this study, and 90 individuals with matched age and gender were included as a control group. Psychiatric diagnostic investigations in Axis I and II were performed in all patients. Therefore, structured clinical interview scales for DSM-III-R were applied to all individuals. Structured Clinical Interview for DSM-III-R (SCID-I and SCID-II) scales were applied for diagnosis of both Axis I and Axis II. Additionally, Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) and Symptom Check List-90-Revised (SCL-90-R) tests were applied for the screening of psychiatric symptoms. While 24 out of the tinnitus patients (26.7%) had at least one psychiatric diagnosis, five participants (5.6%) in the control group had at least one psychiatric diagnosis. Anxiety and somatoform group disorders were significantly high when compared to the control group. Among these disorder groups, anxiety disorder and social phobia diagnoses were the most frequently encountered in the anxiety group. Among the somatoform disorders, the most frequent diagnoses were undifferentiated somatoform disorder and somatization disorder. Among mood disorders, major depressive and dysthymic disorders were frequently diagnosed. All subscales in the SCL-90-R test were higher than those of the control group. Additionally, psychoticism findings were the symptom with the strongest relationship with tinnitus. Point scores in the BDI and BAI tests were significantly higher than those in the control group. Three individuals had personality disorder in the tinnitus group. In this context, Schaaf et al. [29] compared tinnitus patients with psoriasis patients; they included 89 tinnitus and 105 psoriasis patients into the study. They applied SCL-90-R and HAMDS tests, and tinnitus patients were determined to have a more tendency for suicide, depression and anxiety levels. Langguth et al. [30] reported in their review that depression signs were very prominent in patients with tinnitus. They emphasized concomitant appearances of tinnitus and depression and reported that depression prominently has increased the severity of tinnitus. Also, they reported that both situations could appear with the same mechanisms, going through the same pathophysiologic process, and affect each other. Again, in this review, changes in the hypothalamic–pituitary–adrenal axis in depression and tinnitus were shown. Hyperactivity was detected at the dorsal cochlear nucleus in tinnitus. This region has also responded attention and emotional stimuli through projections from locus coeruleus, reticular formation and nucleus raphe. This region was affected at both situations.
Some candidate genes in charge of both situations were also defined, and they have been proposed to cause tendencies to both tinnitus and depression. 3.1. Sleep disturbance in tinnitus A survey administered to a large random sample of 6103 elderly people in Sweden confirmed a higher prevalence of sleep disturbance in individuals with than without tinnitus [31]. However, some studies have found significant correlations between sleep disturbance and depression [32] and between sleep difficulties and tinnitus severity [33]. Sleep difficulties have in turn been regarded as a risk factor [34], correlate, characteristic [35] and predictor [36] of tinnitus-related distress. It is likely that insomnia is linked to the anomalies in the physiological stress response previously found in tinnitus groups [37,38]. Crönlein and colleagues compared retrospectively the polysomnographic sleep of patients referred to their sleep clinic for complaints of insomnia and suffering or not from tinnitus [39]. They found no significant differences in objective or subjective sleep variables between the two patient groups with insomnia complaints, with the exception of longer sleep latency in the group with tinnitus. Sleep disturbance can disrupt the quality of life in the patients with tinnitus. Therefore, both tinnitus and sleep disturbance should be treated early. On the other hand, these patients might benefit from cognitive–behavioral therapy, which offers the promise of relief from tinnitus-related distress and insomnia [40]. 3.2. Psychopharmacological treatment of tinnitus A patient's emotional or psychological response to tinnitus can vary from one individual to the next, even among patients whose tinnitus is similar. Consequently, it is important to determine how a drug affects a person's social or emotional response to tinnitus, as well as its perceptual qualities. Frequently used questionnaires for assessing a patient's reaction to tinnitus are the Tinnitus Handicap Inventory (THI), Tinnitus Handicap Questionnaire (THQ) and Tinnitus Reaction Questionnaire (TRQ) [41–43]. These questionnaires focus on issues related to the degree of handicap, sleep, social interactions, emotion, concentration, depression and annoyance of tinnitus. Drugs used to treat tinnitus should either reduce the tinnitus perception or the emotional response, and ideally both. Many psychopharmacological agents are employed in the treatment of tinnitus (Table 1). 3.3. Antidepressants In their meta-analysis study, Baldo et al. investigated the efficacy of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) in tinnitus treatment. They defined the efficacy of these two groups of antidepressants. However, methodological insufficiencies or single case presentations have decreased the study value [44].
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Table 1 Psychopharmacological agents for tinnitus Groups
Drugs
Evidence
TCAs SSRIs Antipsychotics
Nortriptyline Sertraline Sulpiride
Mood stabilizers
Carbamazepine
Superior to placebo, reduced depression and tinnitus loudness More effective than placebo, reduced depression and tinnitus symptoms Superior to placebo in a single-blind, placebo-controlled study. Sulpiride reported to decrease the perception of tinnitus. Some success in case report and trials. It is the recommended drug to be used alone or combination with lidocaine, salicylate or steroids. Effective in a single case study Superior to placebo, effective in reducing subjective or objective tinnitus Superior to placebo in the treatment of severe tinnitus and high levels of anxiety It was evaluated in double-blind, triple-crossover trials; effective in reducing tinnitus Effective for pulsatile tinnitus when associated with beta-blockers Superior to placebo Not yet investigated in humans for tinnitus treatment Potentially effective for tinnitus and Ménière disease Superior than placebo; effective for tinnitus
Sedative-hypnotics/BZDs
Glutamate receptor antagonists
Valproate Gabapentin Alprazolam Diazepam Clonazepam Midazolam Memantine Caroverine Acamprosate
The analysis written by Robinson has covered better designed trials. In that trial, TCAs and SSRIs have been emphasized to be effective in tinnitus patients with symptoms of depression, anxiety and insomnia [45]. TCAs especially like nortriptyline have been reported to be effective. In a small, single-blind, placebo-washout study involving patients with severe tinnitus and major depression, nortriptyline significantly reduced depression and tinnitus loudness. In a double-blind, placebo-controlled, follow-up study involving subjects with severe tinnitus and severe depression or depressive symptoms, nortriptyline significantly reduced depression scores, tinnitus disability scores and tinnitus loudness [46]. Some antidepressants, especially non-TCAs (lower doses of heterocyclic drugs) like trazodone and mianserin, were proposed to be related to the initiation of tinnitus [47,48]. Moreover, these drugs have been reported to be effective in some publications [49–51]. Although tinnitus was reported to initiate after the cessation of sertraline [52], it was found to be more effective than placebo in severe and resistant tinnitus cases. In a randomized, double-blind, placebo-controlled study in patients without severe hearing loss but with depression, anxiety and a high risk for developing severe tinnitus, sertraline was shown to be significantly more effective than placebo in reducing tinnitus loudness and tinnitus severity [53]. However, in a double-blind, placebo-controlled study involving chronic tinnitus patients, few of whom suffered from depression, the paroxetine group showed little difference from placebo on tinnitus loudness matching, THQ scores and other measures; however, the paroxetine group showed a significant improvement in tinnitus aggravation compared with the control group. Although SSRIs are widely used to treat tinnitus, the authors suggested that antidepressants should not be used to treat nondepressed tinnitus patients. However, in a case study, paroxetine significantly reduced tinnitus and improved mood in a patient with severe depression, anxiety and tinnitus [54].
Although new antidepressants have not been investigated as much as TCAs and SSRIs, there were few study results about their efficacies. There were few findings related to serotonin–noradrenaline reuptake inhibitors. Additionally, it was reported that, rarely, cessation of venlafaxine and duloxetine could cause appearance of tinnitus signs [55–57]. 3.4. Antipsychotics Sometimes, it may be hard to differentiate tinnitus from psychotic symptoms. Schizophrenic patients with increased rates of tinnitus like perceptions, hallucinations and who were taking antipsychotics were reported [58]. Until now, sulpiride is the most accurately investigated antipsychotic drug in tinnitus treatment. In the prospective, randomized, single-blind, placebo-controlled, hydroxyzine comparative study, which was designed by Lopez-Gonzalez et al., sulpiride was reported to decrease the perception of tinnitus. Sulpiride was used at lower doses in this study [59]. 3.5. Mood stabilizers Although names of many mood stabilizer drugs have been discussed in the tinnitus treatment, there was no compromise because all of the available data were not from systematic studies [22]. Among other drugs, only carbamazepine is the recommended drug to be used alone [60] or in combination with lidocaine [61], salicylate [62] or steroids [63] in the treatment of subjective tinnitus. Valproate is another popular mood stabilizer drug investigated in tinnitus treatment [64,65]. Lamotrigine was found to be ineffective in tinnitus treatment [66]. Gabapentin is a well-investigated drug in tinnitus treatment. Bauer and Brozoski reported in their placebo-controlled study that it was effective in the treatment of objective and subjective tinnitus. It was also found to be effective especially in individuals with acoustic trauma [67]. Recent placebo-controlled studies (in one study, 1800 mg/day; in
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another, 900–3600 mg/day) revealed that high-dose gabapentin was effective [68,69]. 3.6. Sedative-hypnotics Daftary et al. reported that benzodiazepines (BZD) and other sedative-hypnotics were world-widely used drugs in tinnitus treatment [70]. Although there were no systematic studies, majority of results, especially in cases with dense anxiety signs, showed that they were effective in the treatment. BDZs with shorter half-lives like alprazolam [71], midazolam [72] and clonazepam [73] have been shown to be effective in placebo-controlled trials. However, complications associated with alprazolam include drug dependency and difficulty of discontinuing use. In a prospective, double-blind, placebocontrolled study, alprazolam was administered to patients with tinnitus; the dose was increased until it caused side effects or had an effect on tinnitus. Alprazolam reduced tinnitus loudness, measured with a tinnitus synthesizer and visual analog scale, in 76% of subjects, whereas only 5% showed a reduction in tinnitus loudness in the control group. Although the positive effects of alprazolam observed in this study are encouraging, the study design has been criticized because of the small sample size, drug dosing method, failure to assess emotional effect and the need for replication [74]. Diazepam was evaluated in a double-blind, triplecrossover trial involving 21 tinnitus patients. The drug had no effect on tinnitus loudness, a result which is surprising considering that its mechanisms of action are similar to those of alprazolam. One possible explanation for the discrepancy is that the dose of alprazolam, but not diazepam, was adjusted for each patient to maximize its effects on tinnitus [75]. Complications associated with diazepam include drug dependency and difficulty of discontinuing use [76]. There is information about the efficacy of clonazepam in pulsatile tinnitus when used with beta blockers [77]. 3.7. Glutamate receptor antagonists N-methyl-D-aspartate (NMDA) glutamate receptor is most likely involved in tinnitus, as it is involved in many forms of central neuropathic pain [78]. It has been shown that acetylsalicylic acid activates cochlear NMDA receptors and that the use of NMDA antagonists at the round window abolishes tinnitus [79], while NMDA receptor agonists may induce tinnitus-like behaviors [80]. Memantine, used to treat neuropathic pain and mild to moderate forms of Alzheimer's disease [81], blocks NMDA transmission in hair cells also modulating the cholinergic transmission [82]. The efficacy of memantine is only based on some observations in the treatment of tinnitus. There are no systematic human studies on the efficacy of this drug. Caroverine acts as a glutamate antagonist. Denk et al. [83] reported variable results in patients with tinnitus treated with caroverine. Ehrenberger et al. [84] investigated the effects of caroverine on tinnitus patients for several years.
Initially, they had success in 63% of participants using an intravenous infusion of caroverine; subsequently, they reported a success in 50% of patients with Ménière disease and sudden hearing loss. Acamprosate has been recently used like a glutamate antagonist. A small clinical trial of acamprosate conducted on 25 tinnitus patients showed that 87% had some degree of relief and nearly 48% had a reduction of more than 50%. Many side effects were described (depression, diarrhea, anxiety), and the drowsiness caused by acamprosate itself may have contributed to improvement as many tinnitus patients have trouble sleeping [85].
4. Conclusion Tinnitus is a frequently encountered situation in the population. For clinicians, tinnitus is a cluster of symptoms with very complex aspects [16]. Apart from this, it may ensue as a result of many pathological situations. Despite this, very little is known about the pathogenesis of tinnitus [8,9]. Tinnitus can severely deteriorate the working life, social relationships and sleep order. Especially when nothing pathological is defined in otoneurological examinations of patients, high concomitance of psychiatric diagnosis and symptoms can be detected [28]. According to our identifications in patients with tinnitus, high anxiety, depression levels and somatoform disorder clusters can be detected. Additionally, impulsivity, hostility, demanding, physical irritation, anxiety in health and emotionality, and tendency for suicide features have been detected. As characteristics of personality, depression, hysteria and hypochondriasis have been detected. In addition to these symptom clusters, personality disorders with more severe psychopathologies can be detected. These kinds of personality disorders are difficult to diagnose and are infrequent situations. In order to define types and severity of symptoms in patients, clinically applicable tests like HAMDS, SCL-90-R, BDI and BAI can easily be employed, and as a result of these, psychopharmacological treatment can be initiated. Drugs used to treat tinnitus should either reduce the tinnitus perception or the emotional response, and ideally both. For this, THI, THQ and TRQ tests can also be employed in clinical practice. However, information about history and descriptive characteristics of the patient's tinnitus or tinnitus-related conditions could be obtained by the Tinnitus Sample Case History Questionnaire (TSCHQ) [86] (Table 2). If a complicated psychopathology is suspected, patients can consult a psychiatrist. Sertraline, paroxetine and nortriptyline can be considered as the first-line antidepressants in the psychopharmacological treatment of tinnitus. There are studies which have reported the efficacy of sulpiride. Carbamazepine, valproate and gabapentin can be effective as mood stabilizers. Shortacting BZDs like alprazolam and midazolam are effective in signs of anxiety. Clonazepam and diazepam can be evaluated
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Table 2 Scales used in tinnitus Scales
The meaning of the test
The purpose of using
MINI MMPI HAMDS TN BDI BAI SCL-90-R THI, THQ, TRQ
Mini International Neuropsychiatric Interview Minnesota Multiphasic Personality Inventory Hospital Anxiety and Depression Scale Tinnitus-Practice Beck Depression Inventory Beck Anxiety Inventory Symptom Check List-90-Revised Tinnitus Handicap Inventory, Tinnitus Handicap Questionnaire, Tinnitus Reaction Questionnaire
TSCHQ
Tinnitus Sample Case History Questionnaire
This test is a diagnostic scale compliant with DSM-IV criteria Used for understanding personality characteristics of patients Used to measure the level of anxiety and depression Used to measure the stress-related tinnitus severity and depression Used to measure the level of depression Used to measure the level of anxiety Used for the screening of psychiatric symptoms These questionnaires that focus on issues related to the degree of handicap, sleep, social interaction, emotion, concentration, depression and annoyance of tinnitus Information about history and descriptive characteristics of the patient's tinnitus or tinnitus-related conditions
as other options. Additionally, addiction potentials of BZDs should not be missed. High doses and long durations of their use should be avoided. However, some glutamate receptor antagonists such as memantine, caroverine and acamprosate can be effective. Disturbed sleep is frequently associated with tinnitus. Sleep disturbance can disrupt the quality of life in the patients with tinnitus. Therefore, both tinnitus and sleep disturbance should be treated early. If pathophysiologic reasons are excluded, it should at least be considered that tinnitus deteriorates with psychopathological symptoms. It should be known that if these symptoms are treated, life qualities of patients can be increased. References [1] Heller AJ. Classification and epidemiology of tinnitus. Otolaryngol Clin North Am 2003;36:239–48. [2] Holgers KM, Zöger S, Svedlund J, Erlandsson SI. Psychiatric profile of tinnitus patients referred to an audiology clinic. In: Hazell J, editor. Proceedings of the Sixth International Tinnitus Seminar. Cambridge, UK: The Tinnitus and Hyperacusis Centre; 1999, pp. 283–5. [3] Laurikainen E, Johansson R, Akaan-Penttila E, Haapaniemi J. Treatment of severe tinnitus. Acta Otolaryngol Suppl 2000;543:77–8. [4] Moller AR. Neural plasticity in tinnitus. Prog Brain Res 2006;157: 365–72. [5] Axelsson A, Ringdahl A. Tinnitus: a study of its prevalence and characteristics. Br J Audiol 1989;23:53–62. [6] Davis AC. Hearing in adults. London, UK: Whurr; 1995, pp. 122–5. [7] Axelsson A, Ringdahl A. Tinnitus — a study of its prevalence and characteristics. Br J Audiol 1989;23:53–62. [8] Brown RD, Penny JE, Henley CM, Hodges KB, Kupetz SA, Glenn DW, et al. Ototoxic drugs and noise. Ciba Found Symp 1981;85: 151–71. [9] Nicolas-Puel C, Akbaraly T, Lloyd R, Berr C, Uziel A, Rebillard G, et al. Characteristics of tinnitus in a population of 555 patients: specificities of tinnitus induced by noise trauma. Int Tinnitus J 2006; 12:64–70. [10] Dobie RA. A review of randomized clinical trials in tinnitus. Laryngoscope 1999;109:1202–11. [11] Schleuning AJ. Management of the patient with tinnitus. Med Clin North Am 1991;75:1225–37. [12] Marciano E, Carrabba L, Giannini P, Sementina C, Verde P, Bruno C, et al. Psychiatric comorbidity in a population of outpatients affected by tinnitus. Int J Audiology 2003;42:4–9.
[13] Holgers KM, Zöger S, Svedlund J. Predictive factors for severe tinnitus suffering: further characterisation. Int J Audiology 2005; 44:584–92. [14] Erlandsson S, Hallberg L, Axelsson A. Psychological and audiological correlates of perceived tinnitus severity. Audiology 1992;31:168–79. [15] Collet L, Moussu MF, Disant F, Ahami T, Morgon A. Minnesota Multiphasic Personality Inventory in tinnitus disorders. Audiology 1990;28:101–6. [16] Harrop-Griffiths J, Katon W, Dobie R, Sakai C, Russo J. Chronic tinnitus: association with psychiatric diagnosis. J Psychosom Res 1987;31:613–21. [17] Sullivan MD, Katon W, Dobie R, Sakai C, Russo J. Disabling tinnitus: association with affective disorder. Gen Hosp Psychiatry 1988; 10:285–91. [18] Zöger S, Svedlund J, Holgers KM. Psychiatric disorders in tinnitus patients without severe hearing impairment: 24-month follow-up of patients at an audiological clinic. Audiology 2001;40:133–40. [19] Fioretti A, Eibenstein A, Fusetti M. New trends in tinnitus management. Open Neurol J 2011;22:12–7. [20] Dobie RA. Depression and tinnitus. Otolaryngol Clin N Am 2003;36: 383–8. [21] Sullivan MD, Dobie RA, Sakai CS, Katon WJ. Treatment of depressed tinnitus patients with nortriptyline. Ann Otol Rhinol Laryngol 1989; 98:867–72. [22] Fornaro M, Martino M. Tinnitus psychopharmacology: a comprehensive review of its pathomechanisms and management. Neuropsychiatr Dis Treat 2010;6:209–18. [23] Andersson G, McKenna L. Tinnitus masking and depression. Audiology 1998;37:174–82. [24] Anderson G, Carlbring P, Kaldo V, Ström L. Screening of psychiatric disorders via the Internet. A pilot study with tinnitus patients. Nord J Psychiatry 2004;58:287–91. [25] Langguth B, Kleinjung T, Fischer B, Hajak G, Eichhammer P, Sand PG. Tinnitus severity, depression, and the big five personality traits. Prog Brain Res 2007;166:221–5. [26] Adoga AA, Adoga AS, Obindo JT. Tinnitus and the prevalence of comorbid psychological stress. Niger J Med 2008;17:95–7. [27] Weber JH, Jagsch R, Hallas B. The relationship between tinnitus, personality, and depression. Z Psychosom Med Psychother 2008; 54:227–40. [28] Belli S, Belli H, Bahcebasi T, Ozcetin A, Alpay E, Ertem U. Assessment of psychopathological aspects and psychiatric comorbidities in patients affected by tinnitus. Eur Arch Otorhinolaryngol 2008; 265:279–85. [29] Schaaf H, Eipp C, Deubner R, Vasa R, Gieler U. Psychosocial aspects of coping with tinnitus and psoriasis patients. A comparative study of suicidal tendencies, anxiety and depression. HNO 2009;57:57–63. [30] Langguth B, Landgrebe M, Kleinjung T, Sand GP, Hajak G. Tinnitus and depression. World J Biol Psychiatry 2011;12:489–500.
288
H. Belli et al. / General Hospital Psychiatry 34 (2012) 282–289
[31] Asplund R. Sleepiness and sleep in elderly persons with tinnitus. Arch Gerontol Geriatr 2003;37:139–45. [32] Alster J, Shemesh Z, Ornan M, Attias J. Sleep disturbance associated with chronic tinnitus. Biol Psychiatry 1993;34:84–90. [33] Folmer RL, Griest SE. Tinnitus and insomnia. Am J Otolaryngol 2000; 21:287–93. [34] Holgers KM, Erlandsson SI, Barrenäs ML. Predictive factors for the severity of tinnitus. Audiology 2000;39:284–91. [35] Nondahl DM, Cruickshanks KJ, Wiley TL, Klein R, Klein BE, Tweed TS. Prevalence and 5-year incidence of tinnitus among older adults: the epidemiology of hearing loss study. J Am Acad Audiol 2002;13: 323–31. [36] Langenbach M, Olderog M, Michel O, Albus C, Köhle K. Psychosocial and personality predictors of tinnitus-related distress. Gen Hosp Psychiatry 2005;27:73–7. [37] Hébert S, Paiement P, Lupien SJ. A physiological correlate for the intolerance to both internal and external sounds. Hear Res 2004;190: 1–9. [38] Hébert S, Lupien SJ. The sound of stress: blunted cortisol reactivity to psychosocial stress in tinnitus sufferers. Neurosci Lett 2007;411: 138–42. [39] Crönlein T, Langguth B, Geisler P, Hajak G. Tinnitus and insomnia. Prog Brain Res 2007;166:227–33. [40] Andersson G, Porsaeus D, Wiklund M, Kaldo V, Larsen HC. Treatment of tinnitus in the elderly: a controlled trial of cognitive behavior therapy. Int J Audiol 2005;44:671–5. [41] Newman CW, Jacobson GP, Spitzer JB. Development of the Tinnitus Handicap Inventory. Arch Otolaryngol Head Neck Surg 1996;122: 143–8. [42] Wilson PH, Henry J, Bowen M, Haralambous G. Tinnitus reaction questionnaire: psychometric properties of a measure of distress associated with tinnitus. J Speech Hear Res 1991;34:197–201. [43] Kuk FK, Tyler RS, Russell D, Jordan H. The psychometric properties of a tinnitus handicap questionnaire. Ear Hear 1990;11:434–45. [44] Baldo P, Doree C, Lazzarini R, Molin P, McFerran DJ. Antidepressants for patients with tinnitus. Cochrane Database Syst Rev 2006(4): CD003853. [45] Robinson S. Antidepressants for treatment of tinnitus. Prog Brain Res 2007;166:263–71. [46] Dobie RA, Sullivan MD, Katon WJ, Sakai CS, Russo J. Antidepressant treatment of tinnitus patients. Interim report of a randomized clinical trial. Acta Otolaryngol 1992;112:242–7. [47] Mendis D, Johnston M. An unusual case of prolonged tinnitus following low-dose amitriptyline. J Psychopharmacol 2008;22:574–5. [48] Podoshin L, Ben-David Y, Fradis M, Malatskey S, Hafner H. Idiopathic subjective tinnitus treated by amitriptyline hydrochloride/ biofeedback. Int Tinnitus J 1995;1:54–60. [49] Bayar N, Böke B, Turan E, Belgin E. Efficacy of amitriptyline in the treatment of subjective tinnitus. J Otolaryngol 2001;30:300–3. [50] Dib GC, Kasse CA, Alves de Andrade T, Gurgel Testa JR, Cruz OL. Tinnitus treatment with trazodone. Braz J Otorhinolaryngol 2007;73: 390–7. [51] Marais J. Cochleotoxicity due to mianserin hydrochloride. J Laryngol Otol 1991;105:475–6. [52] Leiter FL, Nierenberg AA, Sanders KM, Stern TA. Discontinuation reactions following sertraline. Biol Psychiatry 1995;38:694–5. [53] Zoger S, Svedlund J, Holgers KM. The effects of sertraline on severe tinnitus suffering — a randomized double-blind placebo-controlled study. J Clin Psychopharmacol 2006;26(1):32–9. [54] Salvi R, Lobarinas E, Sun W. Pharmacological treatments for tinnitus: new and old. Drugs Future 2009;34:381–400. [55] Pondrom MF, Brahm NC. Venlafaxine-associated tinnitus. Am J Health Syst Pharm 2009;66:1606–8. [56] Ahmad S. Venlafaxine and severe tinnitus. Am Fam Physician 1995; 51:1830. [57] De Marinis M, Santilli V. Tinnitus in postherpetic neuralgia. J Headache Pain 2010;11:83–4.
[58] D'Amelio R, Delb W. Comorbidity of schizophrenic psychosis and tinnitus. A hitherto neglected theme in research and therapy. HNO 2008;56:670–2. [59] Lopez-Gonzalez MA, Moliner-Peiro F, Alfaro-Garcia J, EstebanOrtega F. Sulpiride plus hydroxyzine decrease tinnitus perception. Auris Nasus Larynx 2007;34:23–7. [60] Hulshof JH, Vermeij P. The value of carbamazepine in the treatment of tinnitus. ORL J Otorhinolaryngol Relat Spec 1985;47:262–6. [61] Sanchez TG, Balbani AP, Bittar RS, Bento RF, Câmara J. Lidocaine test in patients with tinnitus: rationale of accomplishment and relation to the treatment with carbamazepine. Auris Nasus Larynx 1999;26: 411–7. [62] Zheng Y, Hooton K, Smith PF, Darlington C. Carbamazepine reduces the behavioural manifestations of tinnitus following salicylate treatment in rats. Acta Otolaryngol 2008;128:48–52. [63] She W, Dai Y, Du X, Ding X, Cui X. Treatment of subjective tinnitus: a comparative clinical study of intratympanic steroid injection vs. oral carbamazepine. Med Sci Monit 2009;15:135–9. [64] Mansbach AL, Freyens P. Tinnitus: current data and treatment with sodium valproate. Acta Otorhinolaryngol Belg 1983;37:697–705. [65] Menkes DB, Larson PM. Sodium valproate for tinnitus. J Neurol Neurosurg Psychiatry 1998;65:803. [66] Simpson JJ, Gilbert AM, Weiner GM, Davies WE. The assessment of lamotrigine an antiepileptic drug in the treatment of tinnitus. Am J Otol 1999;20:627–31. [67] Bauer CA, Brozoski TJ. Effect of gabapentin on the sensation and impact of tinnitus. Laryngoscope 2006;116:675–81. [68] Witsell DL, Hannley MT, Stinnet S, Tucci DL. Treatment of tinnitus with gabapentin: a pilot study. Otol Neurotol 2007;28:11–5. [69] Piccirillo JF, Finnell J, Vlahiotis A, Chole RA, Spitznagel Jr E. Relief of idiopathic subjective tinnitus: is gabapentin effective? Arch Otolaryngol Head Neck Surg 2007;133:390–7. [70] Daftary A, Shulman A, Strashun A Gottschalk C, Zoghbi SS, Seibyl JP. Benzodiazepine receptor distribution in severe intractable tinnitus. Int Tinnitus J 2004;10:17–23. [71] Jalali MM, Kousha A, Naghavi SE, Soleimani R, Banan R. The effects of alprazolam on tinnitus: a cross-over randomized clinical trial. Med Sci Monit 2009;15:I55–60. [72] Panford-Walsh R, Singer W, Rüttiger L, Hadjab S, Tan J, Geisler HS, et al. Midazolam reverses salicylate-induced changes in brain-derived neurotrophic factor and Arg3.1 expression: implications for tinnitus perception and auditory plasticity. Mol Pharmacol 2008;74:595–604. [73] Ganança MM, Caovilla HH, Ganança FF, Ganança CF, Munhoz MS, da Silva ML, et al. Clonazepam in the pharmacological treatment of vertigo and tinnitus. Int Tinnitus J 2002;8:50–3. [74] Johnson RM, Brummett R, Schleuning A. Use of alprazolam for relief of tinnitus. A double-blind study. Arch Otolaryngol Head Neck Surg 1993;119:842–54. [75] Busto U, Fornazzari L, Naranjo CA. Protracted tinnitus after discontinuation of long-term therapeutic use of benzodiazepines. J Clin Psychopharmacol 1988;8:359. [76] Busto U, Sellers EM, Naranjo CA, Cappell H, Sanchez-Craig M, Sykora K. Withdrawal reaction after long-term therapeutic use of benzodiazepines. New Engl J Med 1986;315:854. [77] Albertino S, Assuncao AR, Souza JA. Pulsatile tinnitus: treatment with clonazepam and propranolol. Braz J Otorhinolaryngol 2005;71: 111–3. [78] Puel JL. Cochlear NMDA receptor blockade prevents salicylateinduced tinnitus. B-ENT 2007;3(Suppl 7):19–22. [79] Guitton MJ, Caston J, Ruel J, Johnson RM, Pujol R, Puel JL. Salicylate induces tinnitus through activation of cochlear NMDA receptors. J Neurosci 2003;23:3944–52. [80] Guitton MJ, Dudai Y. Blockade of cochlear NMDA receptors prevents long-term tinnitus during a brief consolidation window after acoustic trauma. Neural Plast 2007;2007:80904. [81] Pomara N, Ott BR, Peskind E, Resnick EM. Memantine treatment of cognitive symptoms in mild to moderate Alzheimer disease: secondary
H. Belli et al. / General Hospital Psychiatry 34 (2012) 282–289 analyses from a placebo-controlled randomized trial. Alzheimer Dis Assoc Disord 2007;21:60–4. [82] Oliver D, Ludwig J, Reisinger E, Zoellner W, Ruppersberg JP, Fakler B. Memantine inhibits efferent cholinergic transmission in the cochlea by blocking nicotinic acetylcholine receptors of outer hair cells. Mol Pharmacol 2001;60:183–9. [83] Denk DM, Heinzl H, Franz P, Ehrenberger K. Caroverine in tinnitus treatment. A placebo-controlled blind study. Acta Otolaryngol 1997; 117:825–30.
289
[84] Ehrenberger K. Topical administration of caroverine in somatic tinnitus treatment: proof-of-concept study. Int Tinnitus J 2005;11:34–7. [85] Azevedo AA, Figuerido RR. Tinnitus treatment with acamprosate: double-blind study. Braz J Otorhinolaryngol 2005;71:618–23. [86] Langguth B, Goodey R, Azevedo A, et al. Consensus for tinnitus patient assessment and treatment outcome measurement. In: Langguth B, Hajak G, Kleinjung T, Cacace AT, & Møller AR, editors. Tinnitus: pathophysiology and treatment. Amsterdam: Elsevier; 2007, pp. 529–31.