Is Contrave (bupropion and naltrexone) effective for treating Premenstrual Dysphoric Disorder (PMDD)?

Contrave for PMDD: Not Recommended

Contrave (naltrexone-bupropion) is not an effective treatment for PMDD and should not be used for this indication. Selective serotonin reuptake inhibitors (SSRIs) remain the established first-line pharmacologic treatment for PMDD, with specific evidence demonstrating that bupropion (a component of Contrave) is inferior to SSRIs for this condition. 1, 2, 3

Evidence Against Bupropion for PMDD

The only direct comparative trial evaluating bupropion for PMDD demonstrated clear inferiority to serotonergic antidepressants:

• Fluoxetine was significantly superior to bupropion in a randomized controlled trial of 34 women with PMDD, with fluoxetine showing superior efficacy on Clinical Global Impressions ratings compared to both bupropion and placebo 3
• Bupropion showed only intermediate improvement between fluoxetine and placebo, with no statistically significant difference from placebo on Hamilton Depression Rating Scale and Global Assessment Scale scores 3
• Patient satisfaction was far greater with fluoxetine than bupropion, despite both medications being well-tolerated 3

Established First-Line Treatment

SSRIs are the evidence-based first-line treatment for PMDD:

• Sertraline (50-150 mg/day), fluoxetine (10-20 mg/day), escitalopram (10-20 mg/day), and paroxetine (12.5-25 mg/day) are recommended as first-line treatments 1
• SSRIs can be dosed continuously or during the luteal phase only, with both regimens showing efficacy 2
• The serotonergic mechanism directly addresses the pathophysiology of PMDD, which involves luteal phase abnormalities in serotonergic activity 4

Alternative Evidence-Based Options

If SSRIs are contraindicated or ineffective:

• Combined hormonal contraceptives with drospirenone (specifically 20 mcg ethinyl estradiol/3 mg drospirenone in a 24/4 extended cycle) have demonstrated significant improvement in emotional and physical PMDD symptoms 1, 4
• Cognitive behavioral therapy (CBT) shows positive results in reducing functional impairment, depressed mood, anxiety, mood swings, and symptom severity 1
• Other psychiatric medications with evidence include venlafaxine, duloxetine, alprazolam, and buspirone 2

Why Contrave Is Not Appropriate

While Contrave is FDA-approved for obesity management and may help with food cravings through its effects on dopamine/norepinephrine reuptake and opioid receptor antagonism 5, 6, this mechanism does not address the core serotonergic and neuroactive steroid pathophysiology of PMDD 4. The naltrexone component alone showed some benefit in a small 1988 study of premenstrual syndrome 7, but this does not translate to efficacy for the combination product in PMDD, particularly given bupropion's demonstrated inferiority to SSRIs 3.

Clinical Algorithm for PMDD Treatment

1. Start with an SSRI (sertraline, fluoxetine, escitalopram, or paroxetine) at standard doses, either continuously or luteal phase only 1, 2
2. If SSRIs fail or are contraindicated, consider drospirenone-containing combined hormonal contraceptives in extended cycle regimen 1, 4
3. Add or substitute CBT for patients preferring non-pharmacologic approaches or as adjunctive therapy 1
4. Avoid progestin-only contraceptives (progestin-only pills, levonorgestrel IUD, etonorgestrel implant, DMPA) as these may worsen mood symptoms in PMDD 4