Rapid Mood Improvement and Transient Hypomania After Low-Dose Oral OTC Glutamatergic Augmentation in Post-TBI Bipolar Disorder

Background: Bipolar disorder secondary to traumatic brain injury (TBI) is common, mechanistically distinct, and notoriously treatment-resistant. Rapid-acting glutamatergic antidepressants such as ketamine are effective in bipolar depression but remain inaccessible to most patients.Case presentation: We describe a woman in her mid-thirties with documented right frontal atrophy after a severe violence-related subdural hematoma in 2009, subsequent onset of cyclothymic-to-bipolar illness, and recent severe depressive relapse with insomnia, auditory hallucinations, PHQ-9 = 22 and GAD-7 = 14. Conventional treatment (valproate, low-dose risperidone, lemborexant, and Deanxit [flupentixol 0.5 mg + melitracen 15 mg]) produced minimal benefit. On 5 November 2025, low-dose dextromethorphan 30 mg nightly and piracetam 600 mg nightly were added. Melitracen, a moderate CYP2D6 inhibitor, inadvertently prolonged dextromethorphan exposure, effectively replicating the pharmacokinetic principle of Auvelity® while piracetam supplied AMPA positive allosteric modulation.Results: Within four weeks the patient reported marked mood stabilization and reduced ruminations. Transient mild hypomania with moria-like inappropriate laughter emerged, prompting spontaneous reduction of dextromethorphan to 22.5 mg nightly and upward titration of piracetam to 1 200 mg, after which euthymia was restored and maintained. No dissociation or worsening psychosis occurred.Conclusions: This case provides the first clinical illustration that an ultra-low-cost, fully oral glutamatergic oral regimen (dextromethorphan + unintended CYP2D6 inhibition + piracetam) can produce ketamine-class speed and magnitude of response in secondary bipolar depression after TBI, even at dextromethorphan doses far below those in licensed combinations. The narrow therapeutic window and hypomanic overshoot highlight the heightened glutamatergic sensitivity of the post-TBI brain.