A Case Report of Onset of Tinnitus Following Discontinuation of Antidepressant and a Review of the Literature

A Case Report of Onset of Tinnitus Following Discontinuation of Antidepressant and a Review of the Literature

Jane Clewes, MA

It is well established that discontinuation symptoms of most antidepressants are common.1-6 It could be suggested that, for patients who have taken antidepressant medication for several years or more, a regimen of graded reduction of dosage toward discontinuation might be made over a period of months/years rather than weeks in order to mitigate against discontinuation syndrome including rebound anxiety and relapse difficulties. In this report, the case of a patient who experienced tinnitus following discontinuation of venlafaxine is presented. Also, a review of the literature on antidepressant discontinuation syndrome is provided.

CASE REPORT

Ms A, a 46-year-old woman with a history of a severe depressive episode (ICD-10 code F33) 10 years prior, had been treated with various antidepressants (paroxetine 40 mg, lofepramine 280 mg) for 2 years and then was started on venlafaxine 150 mg (first, she was started on 75 mg twice a day, and she was later switched to extended-release 150 mg). The treatment was successful, and Ms A reported a good initial recovery and gradual improvement in function over the years.

Ms A had been maintained on venlafaxine 150 mg for 8 years and was functioning well, including her usual activities of full-time work and socializing. Feeling stable, Ms A decided it was time to discontinue the medication and was given a tapered reduction program by her general practitioner, with the dose to be cut by a 37.5-mg daily reduction on a weekly basis. Table 1 provides details on dates and doses used during the discontinuation period. Within 1 day, the lowered dose produced symptoms that were typical of discontinuation syndrome. Table 2 provides details of the symptoms described by Ms A and the dates on which they were reported.

One of the symptoms that Ms A experienced was tinnitus, and this symptom was still persistent over 2 years later and at the same intensity even after reinstatement of the venlafaxine. It is possible that the tinnitus may have been caused by the discontinuation of venlafaxine, as its onset was concurrent with the discontinuation. The tinnitus was described as a continuous buzzing in the head rather than a ringing in the ears, although Ms A did experience occasional ringing in the ears as well. The ringing and buzzing were slightly worse on the right side.

The general practitioner checked for other possible causes of the tinnitus. A course of ear spray eliminated the possibility of an ear infection. A referral was made to the ear, nose, and throat clinic, and a hearing test noted slight but insignificant hearing loss in the right ear; the pure tone audiometry was essentially normal. On examination, the lympanic membranes were normal. A diagnosis of minor tinnitus in both ears was made.

• Antidepressant therapy is often associated with a side effect of tinnitus.
• Withdrawal from antidepressants should be tapered over a longer period (such as 6 to 24 months or more) when they have been taken for the longer term (a few years or more) in order to avoid withdrawal syndrome.
• Rebound panic/anxiety occurring 2 or 3 months following antidepressant withdrawal might be effectively treated by returning to the same antidepressant at the same dose.

Two months after discontinuation of the antidepressant, Ms A experienced onset of persistent and worsening anxiety symptoms. Ms A was referred for consultation with a psychiatrist at the local community mental health center, and a diagnosis of episodic depression (ICD-10 code F33) was made. Reinstatement of the venlafaxine (titrated over 2 weeks to the original dose of 150 mg) produced complete remittance of the anxiety symptoms. The anxiety symptoms did not recur during 12 months of follow-up. However, the tinnitus has been the same and continuous (same level 24 hours/day) and persists 2 years later at the time of writing.

Review of the Literature

Method

The databases AMED, BNI, CINAHL, EMBASE, MEDLINE, and PsychINFO were searched with no date limit using English language only and the keywords antidepressant, discontinuation, withdrawal, and tinnitus. Articles cited in reference lists from retrieved articles were also included.

Antidepressant Discontinuation

Several descriptions and lists of the various key symptoms that are characteristic of a discontinuation syndrome have been compiled (Table 3). Ms A suffered from symptoms in all of the categories described.

According to Haddad, “‘ ¦ the severity of discontinuation reactions varies across a spectrum; some patients manifest an isolated symptom, others a cluster of symptoms, and symptoms vary from mild to severely disabling. This raises a ‘ threshold’ issue for defining a discontinuation syndrome.”3(p185) Some researchers have found that the use of the Discontinuation Emergent Signs and Symptoms Scale (DESS) checklist is helpful.16-18 For example, Fava et al19 classified patients as experiencing a discontinuation syndrome “if the number of DESS checklist events increased by 4 or more during the interruption period.”(p836)

Symptoms can be mild to severe20-22 and usually abate within a few weeks.13,23-27 To avoid these symptoms, antidepressant discontinuation should be tapered.2,7,28,29 Most of the recommended time periods for tapered discontinuation are over several weeks (eg, 7-4 days,12 a 4-week period,7,23 and 4 weeks or more29).

Those who are considered to be perhaps most at risk for encountering more severe discontinuation symptoms include the following:

1. Females30

2. Those with underlying anxiety and dysthymic disorders30

3. Those with earlier age at onset of dysthymia30

4. Those taking higher doses of antidepressants21

5. Those who have been on longer courses of treatment2,3,7,19,21,22,30,31

6. Those reducing treatment more abruptly than more gradually2,12,18,32-34

7. Those discontinuing from particular antidepressants, including medications with a shorter half-life such as paroxetine and venlafaxine7,35-40

8. Those who have a history of difficulties in discontinuation or dose reduction3,7

9. The elderly.9

For these patients, it may be advisable to use a very slow, long taper of over 6 months’ duration.29

In the case presented here, Ms A had a number of the factors that placed her at risk for experiencing more severe symptoms of discontinuation. She was female, with underlying early onset dysthymia, and she had been taking venlafaxine for the long-term. Ms A experienced a reaction similar to that of the patient in the case report by Bhanji et al,30 who had a relapse and onset of panic a few months after the commencement of discontinuation. Thus, on reflection, a very slow taper over more than 6 months or more would have been advisable for Ms A.

On occasion, individuals encounter longer-term discontinuation problems and/or relapse symptoms. For example, in the case reported by Bhanji et al,30 the female patient described a 4-week history of persistent and worsening anxiety symptoms that began 1 month following abrupt paroxetine discontinuation. The patient’s presenting symptoms of panic and anxiety were distinguished by a crescendo-like occurrence in the absence of any obvious triggers, unlike the underlying panic, anxiety, and depressive disorders that she had previously experienced, and waves of anxiety and tension led to further anticipatory anxiety.30 Rebound panic symptoms included shortness of breath, palpitations, nausea, feelings of depersonalization and derealization, and initial and middle insomnia. The patient denied other somatic complaints such as paresthesias, dizziness, or autonomic symptoms, and there were no depressive symptoms. Rebound symptoms were not abating and were becoming worse despite an 8-week period since stopping paroxetine.30

Discontinuation symptoms can be severe and chronic and can seriously impact the patient’s lifestyle.20 Symptoms can on occasion last for months.41 Fava et al19 found that patients who had discontinuation syndrome also had a relapse of panic disorder. Baldessarini et al42 and Freedman43 noted the likelihood of relapse particularly when discontinuation was abrupt and with the shorter half-life antidepressants.

For those who experience severe discontinuation syndrome, alleviation can be found (as was the case of Ms A) by reintroducing the original antidepressant2,3,13,15,21,29,32,44 at the same dose as before discontinuation.1,7 Other medications have been found to be ineffective for discontinuation syndrome (eg, benzodiazepines45 and switching to a different antidepressant in some cases).19,46 One strategy to avoid discontinuation symptoms when reducing antidepressants with a shorter half-life is to switch to a medication that has a longer half-life during the tapering phase.7

Antidepressants and Tinnitus

The literature has produced evidence to associate the use of antidepressants with the onset of tinnitus. These reports indicate a causal relationship between antidepressant use and onset of tinnitus. Paradoxically, antidepressants are one line of treatment for tinnitus47-49 though studies have not yet established an understanding of their efficacy for treating this condition.50,51 Case reports (Table 4) indicate that the onset of tinnitus coincides with the taking of rather than the discontinuation of antidepressants (except in 1 case51). These results are different from the case of Ms A, who experienced the onset of tinnitus when discontinuing the antidepressant and continued to experience tinnitus after the reinstatement of the antidepressant 3 months after the start of the discontinuation regimen.

There are studies that conclude that the perception of tinnitus is the result of neural activity in the brain and/or auditory system.59-64 Given that, in the present case, Ms A had been taking venlafaxine for a long time (8 years) it is quite possible that some changes in the patterns of neural activity and/or concentrations of neural transmitters and receptors within her brain would have taken place over that time. The discontinuation of the antidepressant may have caused biochemical reactions affecting Ms A’s brain, including the auditory regions.

Possible mechanisms have been discussed, and serotonin (5-HT) neurotransmitters appear to be involved. It could be that with longer-term administration of an antidepressant, the 5-HT receptors down-regulate, and the abrupt cessation may result in stores of 5-HT having insufficient amounts for neuronal signaling, initiating the onset of withdrawal symptoms,30 or it may be that the neurotransmitter receptors undergo changes in their sensitivity during antidepressant treatment.4 Serotonin is considered to play a role in subjective tinnitus, such as tinnitus caused by the effect of some drugs such as antidepressants.60,61,64

COMPARIson of THe CASE of Ms A WITH THE LITERATURE

Ms A experienced the usual immediate onset of withdrawal symptoms as reported in the literature4,42 despite tapering. The British National Formulary has been updated in recent years from stating that the withdrawal symptoms are “avoidable” if the discontinuation is “tapered over a few weeks”65(p206) to “‘ ¦the dose should be tapered over a few weeks to avoid these effects. For some patients, it may be necessary to withdraw treatment over a longer period; consider obtaining specialist advice if symptoms persist.”28(p232) The British National Formulary65 included some of the usual symptoms from each of the categories, such as disequilibrium, gastrointestinal symptoms, flu-like symptoms, sensory disturbances, and psychological symptoms. These symptoms continued through the 4 weeks of tapered discontinuation from 150 mg venlafaxine to none in the case of Ms A.

After the antidepressant was out of Ms A’s system, some symptoms continued that impacted her functioning in daily life (see Table 4). This experience is not always mentioned in the literature that covers antidepressant discontinuation. At the 3-month point following commencement of the reduction regimen, Ms A experienced rebound anxiety and a number of additional symptoms on top of those that had continued, which could be considered a relapse. This experience is, perhaps, underreported in the literature and was described by Ms A as almost identical to the report of the patient of Bhanji et al.30

The tinnitus onset in the case of Ms A was concurrent with the discontinuation of antidepressants. This onset contrasts with what has been reported in the literature, wherein the tinnitus onset has been associated with the commencement of an antidepressant and cessation of the antidepressant has been followed by cessation of the tinnitus (except for the authors of 1 article who found that tinnitus was associated with withdrawal of antidepressants [venlafaxine and sertraline]51). In the case of Ms A, the antidepressant was reintroduced and the tinnitus continued.

CONCLUSION

Antidepressant withdrawal symptoms are not always mild, transitory, and tolerable so that patients can successfully cease antidepressant therapy. In increasing numbers of field cases and reports, it has been shown that withdrawal effects do not necessarily disappear spontaneously or in the short-term and can be so disabling that patients have to return to taking the antidepressant that enables withdrawal symptoms to disappear (otherwise they can last for years and can worsen).

This single case study reflects many of the findings of recent research into antidepressant discontinuation syndrome: the case was of a severe and long-term treated depression and the original depression was associated with anxiety. This indicated that a much slower (months or years rather than weeks) discontinuation would have been preferred to the standard few weeks of tapered discontinuation that was undertaken. Even with long-term gradual tapering of dose, the withdrawal syndrome can still occur.6,19 The discontinuation may be a cause of the concurrent onset of long-term tinnitus experienced in this case.

Drug names: citalopram (Celexa and others), mirtazapine (Remeron and others), paroxetine (Paxil, Pexeva, and others), protriptyline (Vivactil and others), trimipramine (Surmontil and others), venlafaxine (Effexor and others).

Author affiliation: North Staffordshire Combined Healthcare NHS Trust, Central Therapies Mental Health, Harplands Hospital, Stoke-on-Trent, Staffordshire, United Kingdom.

Potential conflicts of interest: None reported.

Funding/support: None reported.

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