In the treatment of TRD in adolescents, the first line drugs are Prozac or Lexapro, what’s the next choice in augmentation? (ChatGPT, 2025-5-16)

 Yes, you’re right: Prozac (fluoxetine) and Lexapro (escitalopram) are the two SSRIs with the strongest evidence and FDA approval for treating major depressive disorder (MDD) in adolescents. In treatment-resistant depression (TRD)—defined typically as non-response to two adequate trials—augmentation becomes a reasonable next step.

Here’s an overview of evidence-based next-line augmentation strategies for adolescents with TRD after SSRI failure:

I. Psychotherapy Augmentation (First Preferred Step)

• Cognitive Behavioral Therapy (CBT) or Interpersonal Therapy (IPT) is strongly recommended in combination with pharmacotherapy.
• Studies (e.g., the TORDIA trial) show that adding CBT to a second antidepressant trial yields better outcomes than medication alone in adolescents with SSRI-resistant depression.

II. Pharmacologic Augmentation Options

1. 

Switching to or augmenting with another SSRI/SNRI

• Sertraline (Zoloft) or Venlafaxine (Effexor XR) may be considered in cases where fluoxetine or escitalopram fail.
• TORDIA trial found switching to another SSRI or to venlafaxine with added CBT improved remission rates.

2. 

Atypical Antipsychotics (used cautiously)

• Aripiprazole or quetiapine may be used off-label as augmentation for severe, resistant cases, especially with suicidality, psychotic features, or agitation.
• Risks include metabolic syndrome, sedation, weight gain, and extrapyramidal symptoms, so must be closely monitored.

3. 

Lithium (limited but historic evidence)

• Lithium augmentation has some support from adult TRD studies and limited pediatric data.
• May be considered in specialized settings, particularly for adolescents with suicidality.
• Requires regular monitoring (serum levels, kidney, thyroid).

4. 

Bupropion (Wellbutrin)

• Off-label in adolescents, but sometimes used as augmentation for anergic, apathetic, or executive-dysfunction presentations.
• Avoid in patients with seizure risk or eating disorders.

5. 

Buspirone

 or 

Omega-3 Fatty Acids

• Weak evidence; sometimes used as add-on options for anxiety-related features or mild symptoms.

III. Experimental and Under-Research Options (Use with Caution)

• Ketamine/esketamine: Under investigation for adolescent TRD; not approved for pediatric use.
• Vortioxetine or agomelatine: Limited evidence in adolescents; promising in adults but off-label and not first-line.

Recommended Stepwise Augmentation Algorithm in Adolescent TRD

1. Ensure adequate dose and duration (at least 6–8 weeks)
2. Combine with CBT if not already done
3. Switch to a different SSRI or SNRI + CBT
4. Augment with atypical antipsychotic or lithium (case-by-case)
5. Consult child and adolescent psychiatry specialist for complex augmentation (e.g., bupropion, vortioxetine)

Summary Table:

Augmentation Option	Evidence in Adolescents	Notes
CBT + SSRI/SNRI	Strong	First-line combination
Switch to another SSRI	Moderate (TORDIA)	Try sertraline, fluoxetine, etc.
Switch to venlafaxine	Moderate (TORDIA)	More side effects
Atypical antipsychotics	Limited, cautious use	Consider aripiprazole, quetiapine
Lithium	Limited, specialist use	Monitor labs, suicidality focus
Bupropion	Limited, off-label	Avoid in seizure risk
Omega-3, buspirone	Weak	Adjunctive only
Agomelatine, vortioxetine	Experimental	Not routine

Would you like a PDF clinical algorithm or decision-tree version of this overview?