Updated October 2025

Primary Care | Psychiatry

Major Depressive Disorder: Diagnosis and First‑Line Pharmacotherapy

Concise, evidence-informed guide to diagnosing MDD and initiating first-line pharmacotherapy. Emphasizes DSM-5/operational criteria, risk stratification, shared decision-making, SSRI/SNRI selection, dosing, titration, monitoring, and when to combine with psychotherapy.

Clinical question

How should clinicians diagnose major depressive disorder and select first-line pharmacotherapy in adults?

DepressionPrimary CarePsychiatryPharmacotherapyGuidelines

Key points

Confirm the diagnosis

Use operational DSM criteria: ≥5 symptoms for ≥2 weeks with functional impairment and rule out bipolar, substances, and medical mimics ^[1].

Stratify severity and suicide risk

Assess severity, comorbidity, and acute suicide risk to determine outpatient vs higher level of care and urgency of pharmacotherapy ^[2].

Select first‑line therapy

Start with an SSRI based on tolerability and safety; escitalopram supported as a suitable first‑line option in moderate–severe MDD ^[4], with alternatives per patient factors ^[2], ^[3].

Combine with psychotherapy when feasible

Evidence‑based psychotherapies (CBT, IPT, BA) are as effective as medication for many, and combination improves outcomes in moderate–severe or chronic MDD ^[5].

Plan for measurement‑based care

Set a follow‑up schedule, use standardized scales, titrate every 2–4 weeks, and adjust if <20–25% improvement by 4–6 weeks ^[2].

Evidence highlights

≥5 symptoms for ≥2 weeks incl. depressed mood or anhedonia ^[1]

Diagnostic threshold

SSRIs favored for tolerability; SNRIs, others reasonable alternatives ^[2], ^[3]

First‑line meds

Escitalopram suitable first‑line in moderate–severe MDD ^[4]

Effectiveness

EBT psychotherapy comparable to meds for many patients ^[5]

Nonpharmacologic

Diagnosis

Operational Diagnostic Approach

Define MDD using DSM-style operational criteria and exclude differentials before initiating therapy.

Apply DSM operational criteria

Require ≥5 depressive symptoms for ≥2 weeks, including depressed mood or anhedonia, with distress/impairment; exclude bereavement-only presentations, mania/hypomania, and psychosis ^[1].

Screen and stage severity

Use PHQ‑9 or similar to quantify baseline severity and to facilitate measurement‑based care; document functional impairment and episode specifiers (anxious distress, melancholic, peripartum, seasonal) ^[2].

Rule out medical and substance causes

Targeted history, medications/substances review, and selective labs (TSH, CBC, CMP, B12/folate as indicated). Evaluate for bipolar spectrum to avoid antidepressant‑induced mania ^[2].

Initial Treatment

First‑Line Pharmacotherapy Selection

SSRIs are generally preferred for tolerability; choose agent and dose by patient profile, prior response, comorbidities, and drug–drug interactions.

Start with an SSRI for most

Guidance and reviews favor SSRIs as first‑line due to higher tolerability and safety in overdose compared with older classes ^[2], while acknowledging no single class is universally superior in efficacy ^[3].

Consider escitalopram as a default option

Network/meta-analytic data support escitalopram as a suitable first‑line for moderate–severe MDD, with favorable acceptability; reported outcomes favor response and remission vs several comparators ^[4].

Individualize alternatives

SNRIs (e.g., venlafaxine, duloxetine) for comorbid pain or prior SSRI nonresponse; bupropion for low energy and sexual side effects avoidance; mirtazapine for insomnia/weight loss. Balance benefits with patient risks and preferences ^[2], ^[3].

Combine with psychotherapy as indicated

For mild–moderate MDD, psychotherapy alone may be comparable to meds; for moderate–severe or chronic MDD, combination improves outcomes and adherence ^[5].

Practical Dosing

Starting Doses, Titration, and Monitoring

Initiate low, titrate based on tolerability and symptom change, and monitor systematically.

SSRI starting and typical ranges

Escitalopram: start 5–10 mg daily; typical 10–20 mg ^[4], ^[2]

Sertraline: start 25–50 mg; typical 50–200 mg ^[2]

Fluoxetine: start 10–20 mg; typical 20–60 mg ^[2]

Citalopram: start 10–20 mg; typical 20–40 mg (QT caution at higher doses) ^[2]

SNRIs and other options

Venlafaxine XR: start 37.5–75 mg; typical 75–225 mg ^[2]

Duloxetine: start 30 mg; typical 60–120 mg ^[2]

Bupropion SR/XL: start 100–150 mg; typical 300–450 mg/day (avoid in seizure/eating disorders) ^[2]

Mirtazapine: start 7.5–15 mg; typical 15–45 mg (sedating, weight gain) ^[2]

Follow‑up cadence

Reassess at 2 weeks for tolerability; 4–6 weeks for early efficacy ^[2]

If <20–25% improvement by 4–6 weeks: optimize dose or switch ^[2]

Aim for remission (PHQ‑9 ≤4) rather than partial response ^[2]

Safety monitoring

Suicidality, especially early in treatment and in younger adults ^[2]

Activation/anxiety, GI effects, sexual dysfunction (SSRIs/SNRIs) ^[2]

Blood pressure (SNRIs), QT risk (citalopram), hyponatremia in older adults ^[2]

Special populations and cautions

Pregnancy/lactation: weigh risks/benefits; sertraline commonly used ^[2]

Bipolar risk: screen before starting antidepressants ^[2]

Recent MI/arrhythmia: prefer sertraline; avoid high‑dose citalopram (QT) ^[2]

If inadequate response

Confirm adherence, diagnosis, dose, and comorbidities ^[2]

Switch within class or to SNRI/bupropion/mirtazapine ^[2], ^[3]

Augment with psychotherapy; pharmacologic augmentation per guidance and FDA trial principles in treatment‑resistant settings ^[6], ^[2]

Trial Design Insight

Regulatory Guidance Touchpoints (for interpretation of evidence)

Understanding FDA guidance helps contextualize endpoints and response definitions in antidepressant trials.

Primary endpoints and timing

Trials typically evaluate change in validated depression scales (e.g., MADRS, HAM‑D) over 6–8 weeks; response is often ≥50% reduction and remission based on scale thresholds ^[6].

Populations and designs

Guidance supports monotherapy, adjunctive, and combination designs, with attention to placebo control, enrichment strategies, and safety signal detection for suicidality and activation ^[6].

References

Source material

Primary literature that informs this article.