Stopping Estradiol After Perimenopausal Depression: What the Withdrawal Trial Shows

A review of hormone therapy can include a question about mood: “My depression improved during treatment. What should we watch for if we change it?” Write down that history before the appointment, including what was happening with your periods when the depression began.

Our perimenopausal depression guide covers the wider risk studies and treatment options.

The trial selected women with a particular history

A 2015 NIH trial randomized 56 postmenopausal women aged 45–65: 26 had past perimenopausal depression that responded to hormone therapy, and 30 had no lifetime depression. All were without clinically significant mood symptoms.¹

Everyone first used estradiol patches delivering 100 micrograms daily for three weeks. They then continued estradiol or switched to matching placebo patches for three more weeks, with weekly assessment.¹

A symptom threshold was crossed by some participants

Among 14 women with past depression switched to placebo, five reached at least 16 on the CES-D symptom questionnaire. No other group reached that threshold.¹

That screening result does not mean all 14 developed a new episode of major depression.¹

NICE’s² adult-depression guidance calls for an assessment of severity, duration, history and effects on functioning, beyond a symptom count alone.²

The experiment did not compare tapering methods

The trial tested abrupt withdrawal, so it cannot establish whether gradual reduction prevents mood recurrence or give an individual woman’s relapse risk.¹

NICE³ guidance for England, updated in April 2026, offers a choice of gradually reducing or immediately stopping HRT. It says gradual reduction may limit returning symptoms in the short term, while the approaches make no difference to symptoms in the longer term. That general stopping advice does not supply a proven depression-prevention schedule for this selected trial population.³

Put mood in the follow-up plan

NICE³ distinguishes depressive symptoms below a depression diagnosis from suspected or diagnosed depression. For the latter, it advises using menopause guidance alongside its adult-depression guideline. It recommends reviewing menopause treatments at 3 months and annually afterward, with earlier review when clinically indicated.³

Before a planned hormone change, ask who will review your mood, what would prompt earlier contact and how to reach that person. Record the agreed change date and preparation alongside sleep, interest in usual activities and effects on work or relationships. Bring your previous treatment history if mood symptoms return. These are details a depression assessment should consider.²

You could say: “My earlier depression began during irregular periods and improved with treatment. Can we agree how to monitor mood during this change, and what to do if symptoms return?”

The Visit Brief in My Body Changed. Now What? includes your stage, symptom impact, previous treatments, health history and appointment questions. Its Nights, Moods and Lost Words chapter explains why an earlier episode of depression belongs in that history.