Tinnitus Associated With Bupropion: The Importance of Dosage Adjustment

Tinnitus, the perception of sound in the absence of an external acoustic source, is a rare but potentially distressing adverse effect of bupropion. Although bupropion is generally well tolerated, reports of auditory adverse effects remain uncommon and underdiscussed in clinical settings. This case illustrates a reversible instance of bupropion-induced tinnitus that improved with dose reduction, offering a practical approach for management.

Case Presentation

A 39-year-old woman with a psychiatric history of major depressive disorder (MDD) and unspecified anxiety disorder and no significant medical history presented to her outpatient psychiatrist for debilitating sadness. On examination, she appeared melancholic and reported suffering from poor sleep, low energy throughout the day, decreased interest in pleasurable activities, guilty ruminations about not being a good enough mother, poor concentration, and occasional suicidal ideation. She had tried bupropion 4 years prior and desired a retrial, as she previously had had a good response for MDD and had discontinued the medication only due to nausea during pregnancy.

She was started on bupropion extended release 150 mg daily. The dose was further increased to 300 mg daily on day 42. At her follow-up visit on day 80, she reported the resolution of previously functionally impairing MDD symptoms, so a decision was made to maintain her dosage at 300 mg daily. At her follow-up visit on day 116, she reported a recurrence of her MDD symptoms, so the dosage was increased to 450 mg daily.

A few days after the latest dosage increase, the patient began experiencing a constant, loud, bilateral ringing sound that was particularly distressing in quiet environments, such as when trying to sleep. She denied any changes to her daily routine prior to the constant ringing, and had not been taking any other medications or supplements throughout her treatment course. On day 132, she informed her psychiatrist of the new-onset ringing, so the decision was made to decrease the dosage to 300 mg daily and schedule a follow-up visit 2 weeks later.

At the follow-up visit on day 146, she reported a 30% reduction in the loudness of the ringing. She was informed that further reduction or cessation could lead to resolution of the ringing, and that other medications for depression could be trialed, but she wanted to continue bupropion at the same dosage, given the historical benefit for her MDD. At her follow-up visit on day 164, she reported that the ringing was now occasional and not persistent.

On day 202, she met with her primary care physician (PCP), to whom she also described the ringing as now intermittent and only noticeable when her environment was quiet, such as when driving. On exam, her bilateral hearing, tympanic membranes, ear canals, and external ears all appeared normal, and the PCP confirmed a diagnosis of bupropion-induced tinnitus. She completed an audiologic evaluation on day 292, which found normal hearing sensitivity bilaterally. A virtual consult with an ear, nose, and throat (ENT) clinician on day 304 supported the diagnosis of secondary tinnitus due to bupropion, and the clinician recommended switching to a different medication. The patient again declined, preferring to continue taking bupropion.

Discussion

Bupropion is a norepinephrine and dopamine reuptake inhibitor antidepressant. It was first introduced in the United States in 1989 as an immediate-release (IR) formulation, later followed by sustained-release (SR) and extended-release (XL) preparations to improve dosing convenience and tolerability. It is FDA approved for the treatment of MDD, seasonal affective disorder, and for smoking cessation. Bupropion’s mechanism of action is primarily attributed to its inhibition of neuronal reuptake of norepinephrine and dopamine, with minimal effect on serotonin reuptake.¹ Psychiatrists often choose bupropion for several reasons: It can be as effective as selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants for MDD, but is associated with a lower risk of sexual dysfunction, weight gain, and sedation.² It is also favored in patients with comorbid nicotine dependence, those experiencing SSRI-induced sexual dysfunction, and/or those with fatigue and hypersomnia. Although bupropion has a range of common adverse effects (Table), its ability to cause tinnitus is less well described.³

Tinnitus is the perception of sound, such as ringing, buzzing, hissing, or roaring, in the ears or head without an external sound source. It is a symptom, not a specific disease, and can be either subjective (common; heard only by the patient) or objective (rare; audible to an examiner, often due to vascular or muscular causes).⁴

The bupropion package insert notes that tinnitus occurred in 3% of patients receiving bupropion XL 150 mg or 300 mg daily across 3 placebo-controlled trials for seasonal affective disorder (mean dose range, 257-280 mg per day), compared with less than 1% in patients receiving placebo. The insert also indicates that tinnitus occurred in 6% of patients taking bupropion SR 300 mg daily and 6% of patients taking bupropion SR 400 mg daily, as compared with 2% of patients taking the placebo in placebo-controlled trials for MDD.³

As in our case, Settle reported 2 cases of bilateral tinnitus developing after 3 weeks of treatment with bupropion 300 mg to 450 mg XL per day.⁵ In the first case, the patient’s tinnitus resolved spontaneously after 9 months of continued treatment with bupropion. Interestingly, the resolution of tinnitus was accompanied by a return of the patient’s depressive symptoms despite patient adherence with the medication. The medication was temporarily discontinued due to a presumed treatment failure, and when retrialed later, the patient again reported tinnitus. In the second case, the tinnitus worsened with dose escalation and resolved with medication cessation. Humma and Swims also reported a case of tinnitus with bupropion IR 100 mg 3 times daily used for smoking cessation in a 67-year-old male.⁶ The tinnitus resolved with medication cessation.

The mechanism by which bupropion causes tinnitus is unknown, though Fornaro and Mattino highlighted that both tinnitus perception and dopamine neurotransmission act through prefrontal, primary temporal, and temporoparietal associative areas, as well as in the limbic system.^7,8 Tinnitus perception and the dopaminergic pathway share the same neuroanatomic structures, which control attention, stress, emotions, learning, memory, and motivated behavior. Distress from tinnitus emanates from these same cerebral functions and could therefore potentially be modulated by bupropion, which enhances dopaminergic transmission as a norepinephrine/dopamine reuptake inhibitor.

Regarding clinical significance, clinicians should be mindful that bupropion can cause tinnitus that appears to be dose dependent and reversible with dosage reduction and/or cessation of the medication. If tinnitus develops, it is important to discuss with the patient the risks of ongoing tinnitus vs the benefits of treating MDD. In this case, the patient strongly preferred to continue bupropion at the lower dosage, as the tinnitus had become tolerable and the medication continued to adequately treat the MDD. Despite being informed that complete cessation of the medication could likely lead to tinnitus resolution and that other medications for MDD could be trialed, our patient preferred continuing bupropion given the benefit it had provided for her previously severe MDD.

Not all patients with tinnitus will prefer to continue taking bupropion. Tinnitus itself is associated with an increased risk of depression, anxiety, stress, insomnia, and even suicidality.⁹ These effects have been seen both in patients with severe, bothersome tinnitus and in those with milder forms, though the impact is greater with higher severity and interference in daily life.¹⁰ Data from meta-analyses demonstrate that patients with tinnitus have higher odds of depressive symptoms (OR, 1.5-2), anxiety (OR, 1.6-1.8), stress, and sleep disturbances (OR, 3 for insomnia) than those without tinnitus. The risk of suicide is also elevated (OR, 5).^9,11 Thus, the impact of bupropion-induced tinnitus on a patient’s mental health must be regularly monitored and discussed throughout the course of treatment, not just at symptom onset.

The evidence-based approach to managing bupropion‑induced tinnitus appears to involve decreasing the dosage or complete cessation, then managing any bothersome residual tinnitus per tinnitus treatment guidelines. The American Academy of Otolaryngology-Head and Neck Surgery recommends an initial evaluation to determine whether the tinnitus is bothersome, review the otologic and medical history, and assess for contributing factors such as ototoxic medications.⁴ Neuroimaging is not recommended unless tinnitus is unilateral, pulsatile, or associated with asymmetric hearing loss or focal neurologic deficits. For bothersome tinnitus, clinicians should offer cognitive behavioral therapy as first-line treatment, with optional sound therapy as an adjunct. Audiology evaluation should be pursued if there is additional concern for hearing loss, though this does not always accompany tinnitus.⁴ In this case, the patient did not have any residual bothersome tinnitus, so further management as indicated above was not pursued. The patient also completed an audiology evaluation, which found her hearing to be normal.

Some literature suggests that certain antidepressants may be helpful for treating subjective tinnitus, but the American Academy of Otolaryngology-Head and Neck Surgery recommends against pharmacotherapy, including antidepressants, anticonvulsants, anxiolytics, intratympanic drugs, or supplements, as none have been definitively shown to be effective.^4,12 It is important to note that psychiatric disorders often occur in association with bothersome tinnitus and to offer treatment for these comorbid psychiatric illnesses when clinically indicated.

Data are still emerging on the use of repetitive transcranial magnetic stimulation (rTMS) as a nonpharmacological treatment modality for tinnitus. rTMS is a noninvasive method of brain stimulation that alters the activity of specific brain circuits by repeatedly applying electromagnetic stimulation to targeted brain regions.¹³ Marder et al demonstrated a significant decrease (average, 21.7%) in symptoms on the Tinnitus Functional Index with a sequential protocol involving stimulation of the dorsolateral prefrontal cortex followed by the auditory cortex in 10 patients, but they ultimately highlighted the need for further investigation to determine optimal sequential rTMS protocols for addressing tinnitus.¹³

Concluding Thoughts

Psychiatrists should be aware of the potential for patients to develop tinnitus while taking bupropion. Though it typically appears reversible with the de-escalation of therapy, this approach may not always be desired by either patient or clinician if bupropion is effective for treating MDD. Though not currently recommended, routine screening for tinnitus at baseline and throughout the treatment course may be prudent, as tinnitus itself is a significant risk factor for worsening psychiatric symptoms. Psychiatrists should promptly involve other clinicians, including primary care, audiology, and ENT, to address distressing tinnitus when it persists despite de-escalation of bupropion therapy or when the benefits of continuing bupropion outweigh the risks.

Dr Khan is a fourth-year psychiatry resident at UC Davis Health in Sacramento, California.

Dr Bourgeois is vice chair of hospital psychiatry services at UC Davis Health in Sacramento, California.

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13. Marder KG, Cho J, Chincanchan R, et al. Sequential prefrontal and temporoparietal repetitive transcranial magnetic stimulation (rTMS) for treatment of tinnitus with and without comorbid depression: a case series and systematic review. Front Neurol. 2022;13:831832.