Should I initiate a selective serotonin reuptake inhibitor or testosterone replacement therapy for my low free testosterone and depressive symptoms?

Should You Start an Antidepressant or Fix Your Low Free Testosterone?

Fix your low free testosterone first—if you have confirmed biochemical hypogonadism (two morning testosterone measurements <300 ng/dL) and sexual symptoms (diminished libido or erectile dysfunction), testosterone replacement is your primary treatment, not an SSRI. 1

Diagnostic Confirmation Required Before Any Treatment

You cannot make this decision without proper testing:

• Obtain two separate fasting morning total testosterone measurements (8–10 AM) on different days—a single value is insufficient due to diurnal variation and assay variability 1
• Measure free testosterone by equilibrium dialysis (the gold standard) or calculate the free androgen index, especially since you mention low free testosterone 1
• Check LH and FSH levels to distinguish primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism—this distinction is critical for treatment selection and fertility counseling 1
• Measure sex hormone-binding globulin (SHBG) because elevated SHBG can create a discrepancy between total testosterone (appearing normal) and free testosterone (actually low) 1

The Evidence Hierarchy: Testosterone vs. Antidepressants for Your Symptoms

If You Have Sexual Symptoms (Low Libido, Erectile Dysfunction)

Testosterone replacement is the evidence-based choice:

• Testosterone produces a small but statistically significant improvement in sexual function and libido (standardized mean difference 0.35) in men with confirmed hypogonadism 1
• Decreased spontaneous or morning erections respond reliably to testosterone replacement 1
• SSRIs like sertraline are notorious for worsening sexual dysfunction—they commonly cause delayed ejaculation, anorgasmia, and decreased libido 2

If Your Primary Complaints Are Fatigue, Low Energy, or Mood

The evidence is sobering—neither option works well:

• Testosterone therapy produces little to no clinically meaningful effect on energy, vitality, physical functioning, or cognition even in confirmed hypogonadism 1
• The improvement in fatigue/energy with testosterone is negligible (standardized mean difference 0.17)—well below the threshold for clinical significance 1
• For depressive symptoms, testosterone shows only a "less-than-small improvement" (standardized mean difference -0.19) 1
• Approximately 20-30% of men over 60 have testosterone in the low-normal range—this does not constitute a disease requiring treatment 1

When Testosterone Replacement May Help Depression

There is a specific subpopulation where testosterone can improve mood:

• Men with HIV/AIDS and depression 3
• Men with mild depression (not severe major depressive disorder) 3
• Men with more severe testosterone deficiency (not borderline-low levels) 3
• Men using transdermal testosterone (not intramuscular injections) 3
• Men not responding to SSRIs after an adequate trial 3, 4

One high-quality study showed dramatic results: Five men with SSRI-refractory depression and low testosterone (mean 277 ng/dL) had their Hamilton Depression Rating Scale scores drop from 19.2 to 4.0 within 8 weeks of testosterone augmentation 4. However, three of four patients began to relapse when testosterone was discontinued under single-blind placebo conditions 4.

Another randomized controlled trial of 100 men with major depression on serotonergic antidepressants and low/low-normal testosterone showed that testosterone gel significantly improved sexual function (mean difference 16.8 points on IIEF; p=0.001), with benefits seen even in men with higher baseline testosterone levels 5.

A 2019 meta-analysis of 27 RCTs (1,890 men) found testosterone treatment associated with significant reduction in depressive symptoms (Hedges g=0.21; 95% CI 0.10-0.32), with efficacy OR 2.30 (95% CI 1.30-4.06), particularly when higher dosages (>0.5 g/week) were used 6.

The Critical Decision Algorithm

Step 1: Confirm True Hypogonadism

• If both morning testosterone values are <300 ng/dL AND you have diminished libido or erectile dysfunction → proceed to testosterone replacement 1
• If testosterone is 231-346 ng/dL (gray zone) → calculate free androgen index (total testosterone ÷ SHBG × 100); if FAI <30, you have functional hypogonadism despite borderline total testosterone 1
• If testosterone is >350 ng/dL → testosterone replacement is not indicated regardless of symptoms 1

Step 2: Rule Out Reversible Causes

Before starting testosterone, address:

• Obesity-associated hypogonadism—weight loss of 5-10% can significantly increase endogenous testosterone; attempt hypocaloric diet (500-750 kcal/day deficit) and structured exercise (≥150 min/week moderate-intensity aerobic + resistance training 2-3×/week) for 3-6 months first 1
• Elevated SHBG from liver disease, hyperthyroidism, or medications (anticonvulsants, estrogens) 1
• Hyperprolactinemia—measure prolactin; if >1.5× upper limit of normal, order pituitary MRI 1
• Chronic systemic illnesses (diabetes, HIV, chronic kidney/liver disease) 1

Step 3: Consider Fertility

• If you desire fertility preservation now or in the future, testosterone replacement is absolutely contraindicated—it causes prolonged, potentially irreversible azoospermia 1
• For secondary hypogonadism with fertility concerns, use gonadotropin therapy (hCG + FSH) instead, which restores both testosterone and sperm production 1

Step 4: Choose Your Treatment Path

Path A: Confirmed Hypogonadism + Sexual Symptoms → Testosterone Replacement

First-line formulation:

• Transdermal testosterone gel 1.62% at 40.5 mg daily (applied to shoulders/upper arms)—provides stable day-to-day levels and lower erythrocytosis risk (15.4%) compared to injectables (43.8%) 1, 7

Alternative if cost is a concern:

• Testosterone cypionate 100-200 mg intramuscular every 2 weeks (annual cost $156 vs. $2,135 for transdermal)—but higher erythrocytosis risk 1
• Target mid-normal testosterone levels (500-600 ng/dL) measured midway between injections 1

Monitoring requirements:

• Testosterone levels at 2-3 months, then every 6-12 months once stable 1
• Hematocrit at every visit—withhold treatment if >54% and consider phlebotomy 1
• PSA in men >40 years—refer to urology if PSA rises >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 1
• Reassess symptoms at 12 months—discontinue if no improvement in sexual function 1

Path B: Depression Without Confirmed Hypogonadism → SSRI

• If testosterone is >300 ng/dL on repeat testing, your depressive symptoms are not due to testosterone deficiency 1
• Start sertraline (typical SSRI) with standard psychiatric monitoring 2
• Be aware that SSRIs commonly cause sexual side effects (delayed ejaculation, anorgasmia, decreased libido) 2

Path C: SSRI-Refractory Depression + Confirmed Hypogonadism → Testosterone Augmentation

• If you've had an adequate SSRI trial (≥8 weeks at therapeutic dose) without response AND have confirmed low testosterone (<300 ng/dL), consider testosterone as augmentation therapy 3, 4
• This approach showed dramatic improvement in a small study: HAM-D scores dropped from 19.2 to 4.0 within 8 weeks 4
• Use transdermal testosterone rather than intramuscular—better outcomes for depression 3
• Continue the SSRI while adding testosterone; one study showed men on SSRIs experienced further improvement in depressive symptoms after initiating testosterone 3

Common Pitfalls to Avoid

• Do not diagnose hypogonadism on a single testosterone measurement or symptoms alone—require two morning values <300 ng/dL plus specific sexual symptoms 1
• Do not start testosterone for "low energy" or "brain fog" without sexual symptoms—the evidence shows no meaningful benefit for these complaints 1
• Do not ignore the fertility question—approximately 25-30% of men on testosterone therapy do not meet diagnostic criteria for hypogonadism initially, and many are started without fertility counseling 1
• Do not expect testosterone to cure depression—even in confirmed hypogonadism, the effect on mood is minimal (SMD -0.19) 1
• Do not combine testosterone with an SSRI as first-line therapy—fix the testosterone deficiency first if confirmed, then reassess mood symptoms 1

The Bottom Line

If you have two morning testosterone measurements <300 ng/dL AND diminished libido or erectile dysfunction, start testosterone replacement—not an SSRI.** 1 The sexual symptoms will improve (small but significant effect), and you may see modest mood benefits as a secondary effect 1, 6. **If your testosterone is normal (>300 ng/dL) and your primary complaint is depression without sexual symptoms, an SSRI is the appropriate choice. 1 If you've failed an adequate SSRI trial and have confirmed low testosterone, testosterone augmentation is a reasonable next step. 4, 5

The key is proper diagnostic confirmation before making any treatment decision—get those two morning testosterone measurements, free testosterone, LH, FSH, and SHBG levels checked first 1.