Can Hormone Replacement Therapy (HRT) cause an increase in depressive symptoms?

Hormone Replacement Therapy and Depression Risk

Hormone replacement therapy (HRT) can increase the risk of depression, particularly when administered systemically during perimenopause, with the highest risk occurring in the first year after initiation. 1

Evidence on HRT and Depression Risk

• Systemically administered HRT (oral or transdermal) is associated with a higher risk of subsequent depression diagnosis, especially when initiated before age 50 (hazard ratio 1.50) 1
• The risk of depression is particularly elevated in the first year after initiating either estrogen alone (HR 2.03) or estrogen combined with progestin (HR 2.01) 1
• Self-controlled analysis shows users of systemically administered HRT had higher rates of depression in the years following initiation compared to pre-treatment (incidence rate ratio 1.66 in the first year) 1
• Locally administered HRT (intravaginal or intrauterine) was not associated with increased depression risk and may actually lower depression risk when initiated after age 54 1

Factors Affecting Depression Risk with HRT

• The timing of HRT initiation significantly impacts depression risk:
  • Higher risk when started before or during menopause 1
  • Potentially lower risk when started after age 54 with local administration 1
• Type of administration matters:
  • Systemic administration (oral/transdermal) carries higher depression risk 1
  • Local administration (vaginal/intrauterine) does not increase risk and may be protective in older women 1

Potential Benefits of HRT on Mood

Despite the risk of depression with systemic HRT, some evidence suggests potential benefits:

• A meta-analysis found that HRT was effective in reducing depressed mood among menopausal women (effect size 0.68) 2
• Estrogen-androgen replacement therapy may reduce psychiatric disorders in women following bilateral oophorectomy 3
• For women with existing depression, discontinuation of hormone therapy has been associated with rapid recurrence of depression 4

Clinical Approach to HRT and Depression Risk

• For women considering HRT for menopausal symptoms:
  • Screen for history of depression before initiating systemic HRT 1
  • Monitor closely for depressive symptoms during the first year of treatment, when risk is highest 1
  • Consider locally administered HRT for women over 54 years of age, which may have a protective effect against depression 1
• For women with a history of depression:
  • Be aware that discontinuing HRT may trigger depression recurrence within weeks 4
  • Consider that some women with depression may benefit from combined approaches (HRT plus antidepressants) 5

Important Caveats and Considerations

• HRT is not recommended for primary prevention of chronic conditions in postmenopausal women 6, 7
• If HRT is used for menopausal symptom management, use the lowest effective dose for the shortest possible time 6
• Women should be informed of all potential risks of HRT, including increased risk for venous thromboembolism, stroke, cardiovascular events, breast cancer, gallbladder disease, and urinary incontinence 6
• For transgender individuals receiving gender-affirming hormone therapy, studies have shown decreased depression and anxiety levels following hormone treatment 8

Depression Risk Algorithm for HRT Decision-Making

1. Assess baseline depression risk:

   • History of depression (higher risk) 1, 4
   • Age (higher risk if <50 years) 1
   • Surgical vs. natural menopause (surgical carries higher risk) 3

2. Select administration route based on risk profile:

   • Higher depression risk: Consider local administration 1
   • Lower depression risk: Either administration may be appropriate 1

3. Implement monitoring protocol:

   • Most intensive monitoring during first year of treatment 1
   • Regular depression screening at follow-up visits 1
   • Patient education about early warning signs 1