Psychiatric comorbidities and use of milnacipran in patients with chronic dizziness

Abstract

BACKGROUND: Psychiatric comorbidities are an important issue in the treatment of chronic dizziness patients.

OBJECTIVE: To test the correlation between psychiatric status and subjective handicaps and to examine the effects of milnacipran on handicaps.

METHODS: Hospital anxiety and depression scale (HADS) and handicaps were assessed by a questionnaire before and eight weeks after milnacipran treatment (50 mg/day) in 29 consecutive patients with chronic dizziness. Effects of milnaciplan were compared with fluvoxamine (200 mg/day).

RESULTS: A significant correlation was found between anxious and depressive scale scores and also between HADS and handicaps. Duration of symptoms was longer in the anxious/depressive group (HADS≧13) than in the non-anxious/depressive group. Handicaps and HADS were significantly decreased after treatment only in the anxious/depressive group. There were no overall differences in drug effects between milnaciplan and fluvoxamine. However, the rate of patients with a post/pre ratio of handicaps <80% was higher in milnaciplan group compared with the fluvoxamine group.

CONCLUSIONS: Not only anxiety disorders but also depression should be considered as comorbid psychiatric disorders in patients with chronic dizziness. Dizzy patients with psychiatric comorbidities have a longer duration of symptoms and more handicaps than those without psychiatric disorders. Milnacipran may be chosen as a treatment for patients with chronic dizziness with comorbid psychiatric disorders in case of and insufficient response to SSRIs.

Keywords

Chronic dizziness SNRI milnacipran anxiety depression

1 Introduction

In clinical settings, it is well known that dizzy patients sometimes have comorbid psychiatric disorders such as anxiety disorders, depression, and somatoform disorders [5 , 11]. Among these psychiatric disorders, anxiety disorders are thought to be the most relevant that cause vestibular symptoms [1 , 26] and, therefore, minor tranquilizers have been often used. In turn, psychiatric diseases including depression and anxiety also develop secondary to or coexist with peripheral vestibular disorders such as Meniere’s disease [19]. In the former case, psychiatric disease is the primary cause of vestibular symptoms and in the latter case it exacerbates the primary vestibular disorder. In both cases, treatment of psychiatric disease is important for the recovery of subjective symptoms of dizziness [6, 7].

Recently, selective serotonin reuptake inhibitors (SSRIs) that also exert anti-anxiety effects were reported to be effective for subjective handicaps of dizzy patients [7 , 21]. Serotonin noradrenaline reuptake inhibitors (SNRIs) have almost the same anti-depressive effects as the tricycle antidepressants and SSRIs but with better tolerance [2 , 24]. Milnacipran, one of SNRIs, has unique pharmacokinetic and pharmacodynamic characteristics that distinguish it from the other marketed SNRIs, venlafaxine, desvenlafaxine, and duloxetine such as equipotent serotonin and norepinephrine reuptake inhibition and a linear dose-concentration trend at therapeutic doses [14]. Moreover, evidence suggests that milnacipran is effective and tolerable in the treatment of fibromyalgia and may have usefulness for fatigue and anxiety symptoms [14]. Also, milnacipran was effective for depressive symptoms in patients with Parknson’s disease who showed insufficient response to SSRIs [23]. Therefore, SNRIs would be expected to have different or stronger effects on vestibular symptoms in dizzy patients compared with SSRIs. In the present study, we aimed to first test the correlation between the psychiatric status and subjective handicaps in chronic dizziness patients and second to compare the effects of milnacipran on subjective handicaps due to dizziness with those of fluvoxamine. Psychiatric status and subjective handicaps due to dizziness were assessed by the hospital anxiety and depression scale (HADS) and by a validated questionnaire [7, 8], respectively.

2 Methods

This study was approved by the IRB of Osaka University Hospital (#0526). Written informed consent to participate in the study was obtained from all patients. Twenty-nine consecutive patients with a complaint of chronic dizziness were enrolled into the study. Patients whose symptoms were expected to disappear in a short time, i.e, BPPV, sudden deafness with vertigo, and the acute stage of Meniere’s disease, were excluded from the study. Vestibular tests including nystagmus observation using an infrared Frenzel camera for spontaneous, positional, positioning and head shake nystagmus, the head impulse test, and ENG recordings of bithermal caloric irrigation and an eye tracking test was performed. Based on these vestibular tests, a careful history regarding migraine and traumatic brain injury, and radiological examinations, 29 patients were diagnosed as follows: five patients with Meniere’s disease, one with delayed endolymphatic hydrops, one with vestibular neuritis, 12 with chronic subjective dizziness [22], and 10 with chronic dizziness due to vestibular dysfunction. Chronic dizziness due to vestibular dysfunction was diagnosed if the patients did not meet the diagnostic criteria for Meniere’s disease, delayed endolymphatic hydrops, vestibular neuritis, BPPV or other dizziness of known vestibular origin but had more than 20% canal paresis. Anxious and depressive status was assessed by the hospital anxiety and depression scale (HADS) before and eight weeks after treatment. Subjective handicaps due to dizziness were also evaluated before and eight weeks after treatment using a validated questionnaire [7, 8]. All patients were prescribed 50 mg/day of milnaciplan for eight weeks. If patients were already being treated for their organic diseases, their medication including betahistine, diphenidol, isosorbide and vitamin B12 were continued. No patients had been treated previously with anti-depressants or minor tranquilizers. Before treatment, the correlation between anxious state and depressive state of all patients was tested. Correlation between HADS and subjective handicaps of all patients before treatment was also tested. Then, patients were divided into two groups by their psychiatric status. Group I consisted of 12 patients with HADS less than 13, whereas Group II consisted of 17 patients with HADS equal to or more than 13. The patients’ profiles are shown in Table 1. Data were mean ± S.E. There were no differences in age, gender, hearing level, canal paresis, and diseases. However, duration of the symptoms was significantly longer in Group II patients than those in Group I (p < 0.01). Subjective handicaps and HADS were compared between pre- and post-treatment using the Mann-Whitney U-test. The effects of milnaciplan on subjective handicaps due to dizziness and HADS were compared with those of fluvoxamine (200 mg/day) obtained by our previous study in which the same methods with regard to patient selection criteria and evaluation, i.e., HADS and handicaps questionnaires, were used [8]. The ratio of subjective handicaps at post-/pre-treatment were calculated and used as an index of drug effects. For Group II patients (HADS≧13), drug effect for subjective handicaps were compared between the present milnaciplan study and our previous fluvoxamine study [8]. The rate of patients whose post/pre ratio of subjective handicaps was <80% was compared between the milnaciplan study and the fluvoxamine study using the Chi square test. P < 0.05 was considered statistically significant.

3 Results

HADS in all patients before treatment was 14.1 ± 1.3 (mean ± S.E.). Figure 1A) shows the anxiety scale and the depressive scale for all patients before treatment. There was a significant correlation between anxiety and depressive scale in dizzy patients (p < 0.0001, r = 0.751). Figure 1B) shows the HADS and subjective handicaps before treatment. There was a significant correlation between HADS and subjective handicaps (p < 0.0001, r = 0.69). Subjective handicaps were more severe in Group II (HADS≧13) patients than Group I (HADS <13) before treatment (p < 0.01) (Fig. 2). As shown in Table 1, the duration of symptoms was significantly longer in Group II (HADS≧13) patients compared with those in Group I (HADS <13) patients (p < 0.01).

In Group I (HADS <13) patients, there were no differences in HADS and subjective handicaps between pre- and post-treatment (Fig. 3). However, in Group II patients (HADS≧13), subjective handicaps as well as HADS at post-treatment were significantly lower compared with pre-treatment level (p < 0.05) (Fig. 4).

There were no differences in drug effects between milnaciplan and fluvoxamine (Fig. 5). However, the rate of patients whose post / pre ratio of subjective handicaps was <80% was significantly higher in the milnaciplan group as compared with the fluvoxamine group (p < 0.01) (63.6% vs. 40.9%).

4 Discussion

According to the investigations of the screening efficacy of the HADS to diagnose psychiatric disorders, the sensitivity and specificity to predict the existence of psychiatric comorbidities in ENT patients was 92% and 90% when the HADS (anxiety plus depressive scales) was more than 12 [9]. In the present study, the HADS score of chronic dizziness patients was 14.1 ± 1.3 (mean ± S.E.) at pre-treatment, suggesting a high comorbidity of psychiatric disorders in chronic dizziness patients. In previous studies, anxiety disorders were thought to be the most relevant psychiatric disorders relating to vestibular symptoms [1 , 26]. However, as shown by Fig. 1A), there was a good correlation between the anxiety and depression scales in dizzy patients, suggesting that not only anxiety disorders but also depression should be considered as part of the psychiatric background of chronic dizziness patients. Chronic dizziness patients had more severe psychiatric comorbidities with a longer duration of symptoms (Table 1). Moreover, the HADS correlated with subjective handicaps (Fig. 1B) and subjective handicaps were more severe in patients with a higher HADS score (Fig. 2), suggesting that the treatment of psychiatric diseases may have an important role in a recovery of subjective handicaps in chronic dizziness patients. These results are consistent with previous studies [4 , 25]

As shown in Fig. 4, milnaciplan was effectivefor subjective handicaps due to dizziness as well as anxiety and depression in dizzy patients (Group II). However, it was not effective for non-anxious/depression patients (Group I) as shown in Fig. 3. It is suggested that milnaciplan exerts its anti-dizziness effects through its anti-anxious/depression mechanisms rather than the vestibular pathway-mediated mechanisms. These results are in accordance with our previous studies using paroxetine [7] and suggest that milnaciplan is recommended for a treatment of chronic dizziness especially for patients with comorbid anxiety disorders and depression.

Regarding the comparison of efficacy of milnaciplan and fluvoxamine, there were no overall differences in post/pre ratio of subjective handicaps. However, the rate of patients whose post/pre ratio of subjective handicaps was <80% was significantly higher in the milnaciplan group than the fluvoxamine group (Fig. 5). Milnaciplan was reported to be effective for depressive symptoms in patients with Parknson’s disease who showed an insufficient response to SSRIs [23]. Moreover, in overall comparison, grouping the terms intolerance, serious adverse events and concurrent illnesses, the total incidence of drop-outs during treatment was 7.6% with milnacipran and 14.2% with SSRIs [27].Therefore, milnaciplan may be chosen for chronic dizziness patients with psychiatric comorbidities, if SSRIs are not effective.

SSRIs were reported to be effective for subjective dizziness in patients with or without psychiatric illness [18, 20]. Different results in our study may be accounted for by differences in the medical treatment used (SSRIs vs. milnacipran) and the background of patients (chronic subjective dizziness (CSD) in previous studies vs. CSD plus other neurotologic diseases in the current study). Due to the limited number of CSD patients in our study, it is difficult to compare the outcome only in CSD patients between Group I and Group II. Effects of SSRIs or SNRIs should be re-examined only for CSD patients in futurestudies.

In conclusions, not only anxiety disorders but also depression should be considered as comorbid psychiatric disorders in chronic dizziness patients. Chronic dizziness patients with psychiatric comorbidities have a longer duration of symptoms and more subjective handicaps due to dizziness than those without psychiatric disorders. Milnacipran may be chosen for chronic dizziness patients with comorbid psychiatric disorders who show an insufficient response to SSRIs.

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