# Pharmacotherapy for Depression — APA 2023

## Overview

The APA Clinical Practice Guideline recommends second-generation antidepressants as a first-line pharmacotherapy option for the treatment of major depressive disorder (MDD) across age cohorts. The guideline emphasizes that the best available evidence is **unable to establish superiority** among the classes of second-generation antidepressants. The only clear and consistent finding is that each antidepressant is superior to placebo for the treatment of MDD in adults.

## First-Line Pharmacotherapy for Adults

For initial treatment of adult patients with MDD, the panel recommends offering either psychotherapy or a **second-generation antidepressant** in the context of shared decision-making (Strong Recommendation).

### Selective Serotonin Reuptake Inhibitors (SSRIs)

| Medication | Starting Dose | Usual Therapeutic Dose | Maximum Dose |
|---|---|---|---|
| **Fluoxetine** | 20 mg/day PO | 20-60 mg/day | 80 mg/day |
| **Sertraline** | 50 mg/day PO | 50-200 mg/day | 200 mg/day |
| **Escitalopram** | 10 mg/day PO | 10-20 mg/day | 20 mg/day |
| **Citalopram** | 20 mg/day PO | 20-40 mg/day | 40 mg/day |
| **Paroxetine** | 20 mg/day PO | 20-50 mg/day | 50 mg/day |

### Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

| Medication | Starting Dose | Usual Therapeutic Dose | Maximum Dose |
|---|---|---|---|
| **Venlafaxine XR** | 37.5-75 mg/day PO | 75-225 mg/day | 375 mg/day |
| **Duloxetine** | 30-60 mg/day PO | 60 mg/day | 120 mg/day |
| **Desvenlafaxine** | 50 mg/day PO | 50 mg/day | 100 mg/day |

- Venlafaxine acts primarily as an SSRI at doses below 150 mg/day; significant norepinephrine reuptake inhibition occurs at **150 mg/day and above**
- Duloxetine affects both serotonin and norepinephrine reuptake at all therapeutic doses

### Other Second-Generation Antidepressants

| Medication | Starting Dose | Usual Therapeutic Dose | Maximum Dose | Key Considerations |
|---|---|---|---|---|
| **Bupropion SR/XL** | 150 mg/day PO | 300 mg/day | 450 mg/day | Preferred when fatigue predominates or to avoid sexual side effects; contraindicated in seizure disorders and eating disorders |
| **Mirtazapine** | 15 mg/day PO at bedtime | 15-45 mg/day | 45 mg/day | Preferred when insomnia and/or weight loss are significant concerns; sedating at lower doses |
| **Trazodone** | 50-100 mg/day PO at bedtime | 150-300 mg/day | 400 mg/day | Often used adjunctively for insomnia at low doses |
| **Vilazodone** | 10 mg/day PO with food | 20-40 mg/day | 40 mg/day | Take with food to enhance absorption |
| **Vortioxetine** | 5-10 mg/day PO | 10-20 mg/day | 20 mg/day | Dose adjustment for CYP2D6 poor metabolizers or strong CYP2D6 inhibitors |

## Medication Selection Principles

The guideline does not recommend one specific antidepressant over another for initial treatment. Selection should be based on:

- **Patient preference** and prior treatment history
- **Side effect profile** relative to patient comorbidities and concerns
- **Drug-drug interactions** with current medications
- **Cost and accessibility**
- **Prior response** to specific medications (in patient or first-degree relatives)
- **Safety in overdose** (SSRIs and SNRIs are generally safer than TCAs and MAOIs)

## Combined Treatment (Psychotherapy + Pharmacotherapy)

- The guideline recommends combining psychotherapy and pharmacotherapy primarily for patients with depression that is **severe, persistent (>2 years), or recurrent (two or more episodes)** (Conditional Recommendation)
- If combined treatment is chosen, the panel recommends **CBT or IPT** plus a second-generation antidepressant (Strong Recommendation)
- For uncomplicated MDD (PHQ-9 score of 20 or less), patients are most often best treated with either psychotherapy or pharmacotherapy alone

## Pharmacotherapy for Adolescents

The panel recommends against using several medications for adolescent patients with MDD. When pharmacotherapy is indicated:

- **Fluoxetine** is the first-line medication for adolescents with MDD; FDA-approved for patients age 8 years and older
- **Escitalopram** is FDA-approved for adolescent MDD (age 12 and older), though the APA panel found the evidence base less robust
- **Combined fluoxetine + CBT** showed the highest response rate (71%) in the Treatment for Adolescents with Depression Study (TADS)
- All antidepressants carry an **FDA black-box warning** regarding increased risk of suicidal thoughts and behaviors in patients under age 25
- Close monitoring is required: weekly for the first 4 weeks, biweekly for weeks 5-8, and at week 12

## Pharmacotherapy for Older Adults (Age 60+)

- Combined pharmacotherapy and IPT is recommended over IPT alone (Strong Recommendation)
- **Start low, go slow** principle applies: initiate at lower doses and titrate more gradually due to altered pharmacokinetics
- Consider increased sensitivity to anticholinergic effects, orthostatic hypotension, and drug interactions due to polypharmacy
- SSRIs are generally preferred due to their favorable side effect profile in older adults
- **Citalopram** maximum dose is limited to **20 mg/day** in adults over 60 years due to QTc prolongation risk (FDA safety communication)

## Inadequate Response to Initial Pharmacotherapy

For adults who have not responded or only partially responded to an initial adequate trial of a second-generation antidepressant, the panel suggests (Conditional Recommendation):

1. **Add psychotherapy** (IPT, CBT, or psychodynamic therapy) to the existing antidepressant
2. **Augment** with another antidepressant medication
3. The panel notes insufficient evidence to determine which second-line strategy (switching antidepressant, switching to psychotherapy, or augmenting) is superior

### Assessment of Inadequate Response

- Assess treatment adequacy: Was the medication prescribed at an adequate dose for an adequate duration (at least 6-8 weeks)?
- Rule out non-adherence, substance use, comorbid medical or psychiatric conditions
- Use validated measures (e.g., PHQ-9) to quantify symptom change

> **OpenMedicine Calculator:** `calculate_phq9` -- available via MCP for automated PHQ-9 depression severity scoring and treatment monitoring.

## Treatment Duration and Discontinuation

- **Acute phase:** 6-8 weeks at therapeutic dose before assessing response
- **Continuation phase:** After achieving remission, continue the same antidepressant at the same dose for **4-9 months** (patients with a first episode not associated with significant suicidality or catastrophic outcomes)
- **Maintenance phase:** For patients with two or more prior episodes, a longer course of maintenance treatment is recommended
- Before discontinuation, counsel patients about the potential for relapse and establish a plan for seeking treatment if symptoms recur
- Monitor for several months after medication discontinuation
- Taper gradually to minimize discontinuation symptoms (especially with paroxetine, venlafaxine, desvenlafaxine)

## Limitations

- The guideline acknowledges that evidence is unable to establish superiority among second-generation antidepressants, making initial selection largely empirical
- Comparative effectiveness data directly comparing specific antidepressant-psychotherapy combinations are limited
- Most pharmacotherapy evidence comes from industry-sponsored randomized controlled trials, which may limit generalizability to real-world clinical populations
- The guideline does not provide detailed guidance on treatment-resistant depression (e.g., augmentation with lithium, atypical antipsychotics, or ketamine/esketamine), as these were outside the scope of the systematic reviews
- Dosing information in the tables above reflects standard clinical practice consistent with FDA labeling and is provided for actionable reference; the APA guideline itself recommends second-generation antidepressants as a class without specifying individual dose ranges
