Hypomanic Switch Induced by Dextromethorphan–Bupropion Combination: A Case Report

Dear Editor,

The dextromethorphan–bupropion (45 mg/105 mg) is a recently approved drug for major depressive disorder (MDD). ¹ Bupropion exerts its antidepressant effect through norepinephrine– dopamine reuptake inhibition and carries a comparatively lower risk of inducing hypomania than other antidepressants.^1,2 Nevertheless, several cases of bupropion-induced hypomania or mania have been reported, including mania following its use for smoking cessation and manic switches in patients with bipolar disorder.^3,4 Similarly, dextromethorphan, which at therapeutic doses acts as an antidepressant through N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist with mild serotonin–norepinephrine reuptake inhibition.^1,5 It is generally not associated with hypomania or mania at therapeutic dosages. However, at supratherapeutic or recreational doses, dextromethorphan has been associated with an acute mania-like state. ⁶ In a rare case, a transient manic-like episode occurred even at a low dose of dextromethorphan. ⁷

Given this background, we report a novel case of hypomanic switch temporally associated with the dextromethorphan–bupropion combination. To the best of our knowledge, no such case has been reported in the literature. The patient provided written informed consent.

Case Report

Mr X, a 41-year-old married man from a middle-class nuclear family, educated to 12th grade, had no past or family history of psychiatric illnesses. He presented with four years of chronic depressive symptoms (low mood, anhedonia, low energy, and negative thoughts), consistent with symptoms of a moderate depressive episode. The depressive symptoms were continuous, with no symptom-free interval clearly reported by the patient. No clear psychosocial stressor could be elicited that might have precipitated or perpetuated the symptoms. The patient also reported episodic abnormal lower-limb movements, characterized by purposeless, non-rhythmic shaking of the legs. These movements were suppressible and were more commonly associated with stressful situations. Baseline laboratory investigations (blood counts, renal and liver function tests, thyroid profile, fasting glucose, and electrolytes) were all within normal limits. An Magnetic Resonance Imaging (MRI) of the brain was performed one year earlier for evaluation of dissociative motor symptoms and showed no significant abnormalities. As there were no new neurological signs at presentation, a repeat MRI was not considered. Neurological examination was normal. A diagnosis of MDD, with dissociative (conversion) motor symptoms, was considered.

Due to inadequate response to conventional antidepressants (fluoxetine, sertraline, escitalopram, and venlafaxine), a fixed dose combination of dextromethorphan and bupropion was initiated, considering emerging evidence of its efficacy in refractory depression. ⁵ Dextromethorphan–bupropion was started once daily, increased to twice daily after five days, and continued for 10 days. Initially, the patient noted improved energy and reduced leg movements. However, after the second week, his family noted behavioral changes, including an elevated mood, increased energy, decreased need for sleep, overfamiliarity with even strangers, and excessive social media posting. Family could appreciate these changes more than his usual self. No delusions, hallucinations, aggression, or risk-taking behavior were reported. Importantly, his dissociative movements have completely resolved.

The clinical picture met criteria for hypomania, likely antidepressant induced. Other causes of hypomania were excluded (e.g., concomitant use of different medications, medical conditions), and there was no history of concurrent substance use. Naranjo’s adverse drug reaction probability score (eight) indicated a “probable” relationship with the dextromethorphan–bupropion. ⁸ Although chronic depression may later manifest as bipolar II depression independent of antidepressant exposure, the temporal association with dextromethorphan–bupropion and the Naranjo score suggests a probable drug-related switch in this case. The drug was immediately discontinued, and within one week of stopping it, the patient’s mood and behavior gradually normalized. He was subsequently started on divalproex sodium, considering a revised diagnosis of bipolar II disorder.

Discussion

This first published case of hypomania with dextromethorphan–bupropion highlights that even agents considered “low-switch” risk individually can precipitate hypomania when combined. ²

A recent systematic review of bipolar depression treatments reports that bupropion carries a lower switch risk than tricyclics. ² Nonetheless, case reports of bupropion-induced hypomania exist.^2,3 Dextromethorphan’s unique NMDA receptor antagonism and sigma-1 agonism may underlie its rapid antidepressant effects. However, dextromethorphan, at high doses or recreational misuse, can produce neuropsychiatric excitation or a “manic-toxidrome.”^5,6 Even at a low therapeutic dose, dextromethorphan has been associated with rare, short-lived manic episodes. ⁷ Therefore, a manic switch with dextromethorphan is pharmacologically plausible.

In the dextromethorphan–bupropion combination, bupropion enhances dopaminergic and noradrenergic, while dextromethorphan reduces glutamatergic activity, enhances sigma-1 signaling, and at higher levels adds serotonin– norepinephrine reuptake inhibition. ⁴ The bupropion–dextromethorphan combination may synergistically induce a catecholaminergic surge with enhanced neuroplastic and neuro-stimulatory effects, potentially shifting the neurochemical balance toward hypomania in susceptible individuals. ⁴ In our patient, this mechanism likely precipitated the switch with concurrent resolution of dissociative motor symptoms, possibly due to the surge in monoamines.

Pharmacokinetically, bupropion strongly inhibits Cytochrome P450 2D6 (CYP2D6); thus, it can markedly increase dextromethorphan plasma levels and prolong its half-life (approximately 22 hours). ⁹ Furthermore, CYP2D6 poor metabolizers may experience around threefold higher exposure to dextromethorphan compared to extensive metabolizers.^9,10 In this case, elevated dextromethorphan combined with bupropion’s psychoactive effects likely precipitated hypomania, suggesting that both pharmacokinetic interaction and individual susceptibility contributed to this switch.

Conclusions

This case demonstrates that even an “atypical” antidepressant combination, such as dextromethorphan–bupropion, can precipitate a hypomanic switch. Clinicians should remain vigilant and adhere to bipolar screening recommendations when prescribing antidepressants. While dextromethorphan–bupropion holds promise for treatment-resistant depression, the potential for adverse effects of mood switch should not be disregarded. This case highlights the need for systematic research, vigilant post-marketing surveillance, and adverse drug reaction reporting systems to track the risk of hypomania or mania with this combination.

Supplemental Material

Supplemental material for this article is available online.

Supplemental Material

Supplemental material for this article is available online.