What could be causing a 20-year-old female patient with a history of depression and anxiety, taking Lexapro (escitalopram), to experience symptoms of sadness 1 week before her Depo (medroxyprogesterone acetate) shots are due?

Hormonal Withdrawal-Induced Mood Symptoms from Depo-Provera

This patient is experiencing premenstrual-like depressive symptoms triggered by declining medroxyprogesterone acetate (DMPA) levels as the injection wears off, representing a hormone withdrawal phenomenon that should be managed by shortening the injection interval to 10-11 weeks rather than the standard 12-13 weeks.

Understanding the Mechanism

The sadness occurring 1 week before shots are due represents a predictable pattern of hormone withdrawal-induced mood destabilization. This occurs because:

• Mood disturbances are specifically associated with sudden withdrawal after sustained elevation, rapid fluctuations, and sustained deficiencies of reproductive hormones—not the absolute hormone levels themselves 1, 2
• DMPA provides sustained progestin elevation for approximately 11-12 weeks, after which levels decline rapidly, creating the exact withdrawal pattern known to trigger mood symptoms in vulnerable individuals 1
• Women show differential sensitivity to these hormonal changes, with vulnerability determined by history of depression or reproductive-related mood disorders 1, 2
• This patient's existing depression/anxiety history (requiring Lexapro) marks her as particularly vulnerable to hormone fluctuation-induced mood destabilization 2

Evidence on DMPA and Depression

The relationship between DMPA and depression shows mixed but concerning signals:

• A randomized controlled trial found statistically significant higher depression scores at 1 month (EPDS, p=0.04) and 3 months (BDI-II, p=0.002) in DMPA users compared to IUD users, with more major depression cases at 3 months (8 vs 2, p=0.05) 3
• A prospective population-based study found increased likelihood of depressive symptoms among continuous DMPA users (OR=1.44,95% CI 1.00-2.07) and discontinuers (OR=1.60,95% CI 1.03-2.48) compared to non-users 4
• Women who discontinued DMPA had elevated depressive symptoms prior to discontinuation (OR=2.30) and immediately following (OR=2.46), which subsided at subsequent visits 4
• However, one older study found no evidence of increasing depression with long-term DMPA use and no short-term dose-related mood effects 5

Primary Management Strategy

Shorten the injection interval to prevent hormone withdrawal:

• Administer DMPA injections every 10-11 weeks instead of waiting the full 12-13 weeks 6
• This maintains more stable progestin levels and prevents the precipitous decline that triggers withdrawal symptoms 1, 2
• DMPA remains safe and effective when given at shorter intervals within the contraceptive range 6

Alternative Contraceptive Options

If shortening the interval proves insufficient or impractical:

• Switch to a progestin IUD (preferred) or copper IUD, both of which provide stable hormone delivery without cyclical withdrawal 6
• Progestin IUDs are safe in all women with depression/anxiety and may decrease menstrual bleeding 6
• IUDs have <1% failure rates and eliminate the cyclical hormone fluctuation pattern 6
• A progestin implant provides another highly effective option with stable hormone delivery, though limited data exist 6

Avoid combined estrogen-progestin contraceptives in this patient, as the hormone-free intervals would perpetuate the withdrawal pattern triggering her symptoms 6, 1

Optimizing Antidepressant Management

Regarding her Lexapro (escitalopram) therapy:

• Escitalopram is the most selective SSRI with minimal drug interactions and is at least as effective as other SSRIs for depression and anxiety 7
• The best-fitting model for SSRI response shows clinically significant improvement by week 6 and maximal improvement by week 12 or later 6
• If her current dose is inadequate to cover the hormone withdrawal period, consider dose optimization rather than adding medications 6
• Monitor closely for behavioral activation, suicidal ideation (especially in patients under age 24), and sexual dysfunction 6, 8

Critical Clinical Pitfalls

Do not attribute her symptoms solely to inadequate antidepressant treatment without addressing the hormonal trigger—the temporal relationship to injection timing is diagnostic 1, 2

Do not discontinue DMPA abruptly if switching methods, as this may worsen withdrawal symptoms; overlap with the new contraceptive method 4

Do not assume this represents treatment-resistant depression requiring aggressive medication escalation when the underlying cause is iatrogenic hormone withdrawal 1, 2

Monitoring Plan

• Document mood symptoms daily for 2-4 weeks using a simple mood diary to confirm the temporal relationship to injection timing 1
• After implementing shortened injection intervals, reassess mood symptoms at 1 month and 3 months 3
• If symptoms persist despite stable hormone delivery, this suggests the depression/anxiety requires independent optimization of psychopharmacologic treatment 6
• Screen for other contributors including thyroid dysfunction, which can overlap with these symptoms 9