Apathy is a noticeable lack of emotion, motivation, and volition and absence of interest, initiation, or effort to learn new things or complete a task.¹ It could be the primary condition or secondary to a wide range of psychiatric, medical, or neurological illnesses.¹ These illnesses might include depression, bipolar disorder, schizophrenia, various personality and eating disorders, neurocognitive degeneration, posttraumatic stress disorder, attention-deficit/ hyperactivity disorder, and substance abuse.¹ Apathy may occur secondary to a medication like selective serotonin reuptake inhibitor (SSRI) antidepressants.¹ It is commonly seen in older adults and in up to three-fourths of Alzheimer dementia patients.^1,2 Despite being a common, complex, multidisciplinary, and disabling condition, it is rarely reported by patients or screened for by health care providers.² Apathy is classically observed in patients with depressive symptoms in the “learned helplessness” phenomenon.³ The characteristic response frequently seen in animals includes amotivation, nonreactiveness, and decreased motor reactivity to aversive stimuli, clinically mirroring apathy.³ The European Alzheimer’s Disease 2008 apathy guidelines comprise diminished motivation for 4 weeks, associated with 2 of the following 3 criteria: (1) reduced goal-directed behavior, (2) reduced goal-directed cognitive activity, and (3) reduced emotions,⁴ along with functional impairment due to apathy.⁴ There are no similar guidelines for adult or nondementia elderly patients. Despite various pharmacologic trial attempts that include cholinergic agents like the cholinesterase inhibitor donepezil and dopaminergic psychostimulants like methylphenidate, bupropion, and modafinil,^2,4 currently, there is no US Food and Drug Administration (FDA)–approved treatment for apathy.^2,4

N-methyl-D-aspartate (NMDA) receptor–related glutamate block represents a new fast approach to treat severe, resistant depressive symptoms and might be a new hope for treatment of apathy.^5,6 Dextromethorphan is an σ-1 receptor agonist and a serotonin-norepinephrine reuptake inhibitor, primarily acting through the glutamate system, as well as an uncompetitive antagonist of NMDA.⁶ Dextromethorphan plays a vital regulatory role in limiting emotional lability and affects dysregulation in pseudobulbar palsy patients.⁷ We report the case of a patient with depression and apathy, whose mood improved with antidepressants such as sertraline (an SSRI) and bupropion (a dopamine-norepinephrine reuptake inhibitor), but whose apathy responded only to a combination of dextromethorphan-bupropion.

Case Report

A 44-year-old white man with major depressive disorder and apathetic symptoms presented to the outpatient psychiatric clinic seeking treatment of low mood and apathy, which had lasted for almost a year. He reported marked reduction in his interest, initiative, and motivation to learn or start new things, including socializing with friends, his significant other, and family members. His baseline evaluation included the following: Montgomery-Asberg Depression Rating Scale (MADRS) score of 32,⁸ Hamilton Depression Rating Scale (HDRS) score of 24,⁹ and Apathy Evaluation Scale (AES) score of 40.¹⁰ He tried a therapeutic dose and adequate duration of 2 SSRIs and bupropion extended release with significant improvement in his mood (MADRS score=10). However, he was still struggling with apathy, and his AES score continued to be above 40. He was given a trial of combination dextromethorphan-bupropion with a starting dose of 105-45 mg twice daily. He reported significant improvement in his mood and apathy symptoms after 4 weeks. He displayed more motivation and enthusiasm to start new things and hobbies, became interested in establishing new relationships, and began looking for jobs and attending social events. The apathy and depression scale scores (AES=10, MADRS=12, HDRS=8) also reflected these changes. Improvement in mood and apathy persisted at the 3-month and 6-month follow-up visits. No safety adverse effects, including dissociative, sexual, or manic/hypomanic symptoms, were reported. The patient denied any active medical condition, use of illegal recreational substances or alcohol use, psychosis, or family history of psychiatric conditions. All other investigations, including brain magnetic resonance imaging, urine drug screen, and laboratory values, were within normal limits.

Discussion

This case shows potential benefits of medication that activates the glutamate system in addressing clinically challenging apathy in adult patients with depression. Dextromethorphan exemplifies uncompetitive antagonism of the NMDA receptor, primarily acting through the glutamate system.^6,7 When combined with bupropion, it has a dual pharmacologic effect, serving as a cytochrome P450 2D6 inhibitor, which increases dextromethorphan plasma bioavailability, and providing a dopaminergic-norepinephrine boost effect.⁶ Apathy is a complex, treatment-resistant multidisciplinary syndrome associated with limited motivation, reaction, emotional detachment, goal-directed thinking, and behavior.^11,12 Dopamine and norepinephrine were the primary therapeutic target neurotransmitters for motivation and executive functioning improvement in the last 2 decades,^11,12 even though the glutamate neurotransmitter is the most abundant excitatory chemical messenger in the brain for learning, motivation, and cognitive function. There are limited trials utilizing the glutamate neurotransmitter as a key factor in apathy treatment.¹² The glutamate system plays a key role in the stress response with respect to helplessness behaviors.¹¹ Activation of the NMDA receptor in animal models, along with the use of NMDA receptor antagonists such as dextromethorphan, memantine, and ketamine, appears to prevent amotivational and helpless behavior syndromes.¹¹ Monoamine pathway theory, through modulation of the serotonergic, dopaminergic, or noradrenergic system, has its own limitations due to delayed onset and treatment resistance compared to the glutamate neurotransmitter.^13,14 In contrast, a combination of glutamate and monoamine-based medication shows a promising fast response, like a combination of dextromethorphan-bupropion or adjunct intranasal esketamine (noncompetitive, nonselective NMDA receptor blocker) with an SSRI or SNRI antidepressant for treatment-resistant depression or suicidality.^13,14 Dextromethorphan has mild agonist effects on μ-opioid receptors, without severe opioid toxicity.¹⁵ There are inconsistent findings regarding NMDA receptor blockers in the management of apathy secondary to negative or cognitive schizophrenia symptoms.¹⁶ Multiple dopaminergic and cholinergic pharmaceutical medication clinical trials for Alzheimer disease–associated apathy have demonstrated limited benefits, including cholinesterase donepezil, bupropion, modafinil, and methylphenidate.^17–20 Memantine (a low-affinity uncompetitive NMDA receptor blocker) monotherapy or adjunct to citalopram was shown to be promising for apathy in Alzheimer dementia in a 12-week randomized controlled trial (N = 40 memantine vs N = 40 memantine + citalopram).²⁰ Dextromethorphan, in combination with quinidine, is FDA approved for the emotional regulation of pseudobulbar affect disturbance secondary to stroke, amyotrophic lateral sclerosis, traumatic brain injury, and multiple sclerosis.⁷ Currently, there is no large clinical randomized study utilizing NMDA receptor blockers for apathy in adult or elderly patients. In conclusion, NMDA receptor blockers like dextromethorphan could have a potential therapeutic role in the treatment of apathy.

Article Information

Published Online: April 2, 2026. https://doi.org/10.4088/PCC.25cr04112
© 2026 Physicians Postgraduate Press, Inc.
Prim Care Companion CNS Disord 2026;28(2):25cr04112
Submitted: October 16, 2025; accepted December 18, 2025.
To Cite: Al Jumaili W, Al Gburi N, Jain S, et al. Bupropion- dextromethorphan is a potential treatment combination for clinically challenging apathy. Prim Care Companion CNS Disord 2026;28(2):25cr04112.
Author Affiliations: Northwest Clinical Research Center, Bellevue, Washington (Wisam Al Jumaili, Al Gburi, Khan); Providence Regional Medical Center, Everett, Washington (Wisam Al Jumaili); Department of Psychiatry, Texas Tech University, Permian Basin, Texas (Jain); Bellevue Digital Academy, Bellevue, Washington (Lian Al Jumaili).
Corresponding Author: Wisam Al Jumaili, MD, 1951 152nd Place NE Ste 200, Bellevue, WA 98007 ([email protected]).
Financial Disclosure: None.
Funding/Support: None.
Patient Consent: Consent was received from the patient to publish the case report, and information has been de-identified to protect patient anonymity.