Background: Extended-release (XL) bupropion hydrochloride (HCl) received FDA approval for Major Depressive Disorder (MDD) in 2003 and for Seasonal Affective Disorder (SAD) in 2006. XL bupropion hydrobromide (HBr) (Aplenzin®) received FDA approval in 2008 for both MDD and SAD following demonstration of pharmacokinetic bioequivalence to XL bupropion HCl. However, no human clinical efficacy trials of XL bupropion HBr have been completed and none comparing it to XL bupropion HCl. We wanted to compare equivalent FDA-approved dosing of XL bupropion HBr to generic XL bupropion HCl in patients with Treatment-Resistant Depression (TRD). There is only one FDA-approved oral TRD combination medication, fluoxetine-olanzapine, that carries cardiometabolic side effects and sedation, and one approved adjunctive nasal spray, esketamine, that requires 2-hour in-office monitoring limiting access. 
Methods: We obtained informed consent from each patient prior to conducting a de-identified retrospective chart review of 30 adults with TRD (18 females, 12 males) who directly switched from their maximally tolerated dose of generic XL bupropion HCl, due to inadequate response and/or side effects, to an equivalent dose of XL bupropion HBr. PHQ-9 scales were administered by a blinded rater. 
Results: Patients had a mean age of 38.7 +/- 14.7 years, failed a mean of 4 +/- 2 antidepressants, and had a mean baseline PHQ-9 score of 20.9 +/- 4.3 prior to taking a mean XL bupropion HCl dose of 300 mg/day (range 150‒450 mg/day) for a mean duration of 88.8 weeks (range 4‒480 weeks). After 2 weeks on a mean XL bupropion HBr dose of 348 mg/day (range 174‒522 mg/day), these patients demonstrated improvement in PHQ-9 scores from a mean of 15.3 +/- 5.3 on XL bupropion HCl to a mean of 6.4 +/- 5.0 on XL bupropion HBr (t = −8.63, p < 0.00001). The most commonly encountered side effects with generic XL bupropion HCl were insomnia (21 patients), anxiety (19 patients), and gastrointestinal upset (2 patients), which resolved on XL bupropion HBr except for residual insomnia (3 patients). 96.7% of patients (29 of 30) chose to continue on XL bupropion HBr rather than change back to generic XL bupropion HCl.
Conclusion: Adult patients suffering from TRD experience rapid and significant improvement in mood with greater tolerability when switching from generic XL bupropion HCl to an equivalent dose of XL bupropion HBr. A further double-blind study could enable the first FDA-approved oral monotherapy for TRD.

Extended-Release Bupropion Hydrobromide for Treatment-Resistant Depression

Background: Since the FDA has mandated a boxed warning on all psychostimulants due to risks for misuse and death, coupled with nationwide shortages, clinicians have utilized non-stimulants, such as alpha-2-agonists for hyperactivity/impulsivity and the norepinephrine reuptake inhibitor atomoxetine for inattention, as safer alternatives. However, these agents lack comparable efficacy with delayed onset compared to psychostimulants. Insurers require generic atomoxetine prior to covering Viloxazine ER (VER), a novel 5-HT2B antagonist, 5-HT2C partial agonist, and 5-HT7 antagonist. We wanted to know whether patients taking atomoxetine would experience improvement in ADHD symptoms after switching to VER.
Methods: 50 patients (35 children) received mean doses of atomoxetine 60 mg (25-100 mg once daily) followed by VER 300 mg (100-600 mg once daily) after 5-day atomoxetine washout. Both atomoxetine and VER were flexibly titrated according to FDA guidelines. The pediatric ADHD-Rating Scale-5 (ADHD-RS-5) and the Adult Investigator Symptom Rating Scale (AISRS) were completed prior to starting atomoxetine; 4 weeks after treatment with atomoxetine or upon earlier response or discontinuation due to side effects, whichever occurred first; same protocol after treatment with VER. We conducted a retrospective chart review of these 50 patients. Statistical analysis was performed using a within-subject, 2-tailed t-test with significance level of p < 0.05.
Results: From baseline total ADHD-RS-5 mean score (40.3+10.3), improvements were greater on VER (13.9+10.2) than atomoxetine (33.1+12.1) (t = -10.12, p < 0.00001), in Inattention (t = -8.57, p < 0.00001) and in Hyperactivity/Impulsivity (t = -9.87, p < 0.00001). From baseline total AISRS mean score (37.3+11.8), improvements were greater on VER (11.9+9.4) than atomoxetine (28.8+14.9) (t = -4.18, p = 0.0009), in Inattention (t = -3.50, p < 0.004) and in Hyperactivity/Impulsivity (t = -3.90, p < 0.002). 86% of patients on VER reported positive response by 2 weeks versus 14% on atomoxetine. 36% discontinued atomoxetine for side effects, including GI upset (6 patients), irritability (6), fatigue (5), insomnia (1) versus 4% who discontinued VER due to fatigue. 96% preferred VER over atomoxetine with 85% (22/26) able to taper psychostimulants following stabilization on VER. 
Conclusion: Pediatric and adult ADHD patients, who have experienced less than optimal response to atomoxetine, demonstrate rapid improvement in inattention and in hyperactivity/impulsivity with greater tolerability on viloxazine extended-release, which deserves consideration as a new first-line ADHD treatment option

Maxwell Price

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