What is an appropriate first‑line medication for an adult with severe anxiety and depressive symptoms?

First-Line Medication for High Anxiety and Depression

Start sertraline 50 mg once daily as the preferred first-line medication for an adult with severe anxiety and depressive symptoms. 1, 2, 3

Why Sertraline Is the Optimal Choice

Sertraline offers the best balance of efficacy, safety, and tolerability among all antidepressants for treating comorbid anxiety and depression. 1, 2, 3 It demonstrates:

• Equivalent efficacy to all other SSRIs and SNRIs for both depression and anxiety, with a number needed to treat (NNT) of 7-8 4, 2
• Superior tolerability profile compared to other antidepressants, with lower discontinuation rates due to adverse effects 3, 5
• Minimal drug interaction risk because it does not potently inhibit cytochrome P450 enzymes, unlike fluoxetine, fluvoxamine, and paroxetine 2, 3
• Lower cardiac risk than citalopram or escitalopram, which carry dose-dependent QTc prolongation warnings 2
• Low lethality in overdose, making it safer for patients with suicidal ideation 2

Practical Dosing Strategy

• Start with 50 mg once daily for most patients 1, 2
• For highly anxious or agitated patients, begin with 25 mg daily for the first week as a "test dose" to minimize initial activation symptoms, then increase to 50 mg 1, 2
• Titrate in 50 mg increments every 1-2 weeks if response is inadequate, up to a maximum of 200 mg daily 1, 2
• Allow 6-8 weeks for an adequate trial, including at least 2 weeks at the maximum tolerated dose before considering a medication switch 1, 2

Expected Timeline and Response

• Statistically significant improvement begins at week 2, with clinically meaningful benefits typically evident by week 4 1
• Maximal therapeutic benefit is achieved by week 12 or later 1, 2
• Approximately 62% of patients achieve treatment response within 6-12 weeks, though 38% may require dose optimization or medication switching 4, 2

Critical Safety Monitoring

Monitor closely for treatment-emergent suicidality, especially during the first 1-2 weeks after starting or adjusting the dose. 1, 2 All SSRIs carry FDA black box warnings for increased suicidal thinking, with an absolute risk increase of 0.7% (number needed to harm = 143) 2

Initial adverse effects such as nausea, headache, insomnia, or mild anxiety/agitation typically emerge within the first 2-4 weeks and resolve with continued treatment 1, 2

Schedule follow-up within 1-2 weeks after initiating treatment to assess for adverse effects and initial response, then at 4 and 8 weeks to evaluate symptom relief using standardized measures 1, 2

Treatment Duration

Continue sertraline for a minimum of 4-9 months after achieving satisfactory response for a first episode of depression or anxiety 4, 1, 2

For recurrent episodes, consider longer duration (≥1 year or indefinite maintenance therapy) because relapse risk increases substantially with each episode: 50% after one episode, 70% after two episodes, and 90% after three episodes 2

Combination Treatment Strategy

Adding cognitive-behavioral therapy (CBT) to sertraline provides superior outcomes compared to either treatment alone, particularly for moderate to severe anxiety and depression 1, 2 This combination should be offered preferentially when available.

Alternative First-Line Options

If sertraline is contraindicated or not tolerated:

• Escitalopram 10-20 mg daily has the most selective serotonin reuptake profile and minimal drug interactions 1, 6, 7
• Venlafaxine extended-release 75-225 mg daily (an SNRI) may have slightly better response rates specifically for depression with prominent anxiety symptoms, though it carries higher rates of nausea and discontinuation due to adverse effects 4, 1, 8

When to Switch Medications

If inadequate response after 6-8 weeks at therapeutic doses (100-200 mg sertraline), switch to another first-line SSRI (escitalopram, fluoxetine) or venlafaxine extended-release 4, 2 One in four patients becomes symptom-free after switching medications 4

Medications to Avoid

Do not use benzodiazepines beyond short-term crisis management due to risks of dependence, tolerance, and withdrawal 1

Avoid bupropion as it is activating and can exacerbate anxiety symptoms 1

Never combine sertraline with MAOIs due to serotonin syndrome risk; allow at least 2 weeks washout when switching between these drug classes 2

Common Pitfalls to Avoid

• Do not discontinue prematurely—partial response at 4 weeks warrants continued treatment and possible dose increase, not switching 1, 2
• Do not abruptly stop sertraline—taper gradually when discontinuing to avoid withdrawal symptoms including dizziness, nausea, and sensory disturbances 1, 2
• Do not exceed 40 mg daily of citalopram or 20 mg daily of escitalopram in older adults (>60 years) due to QTc prolongation risk 2