What is the right medication to try for Major Depressive Disorder (MDD), Generalized Anxiety Disorder (GAD), and Post-Traumatic Stress Disorder (PTSD) if amitriptyline is not effective?

Medication Options After Amitriptyline Failure for MDD, GAD, and PTSD

For patients with Major Depressive Disorder (MDD), Generalized Anxiety Disorder (GAD), and Post-Traumatic Stress Disorder (PTSD) who have not responded to amitriptyline, a selective serotonin reuptake inhibitor (SSRI) such as sertraline should be the next medication tried, with venlafaxine or bupropion as alternatives depending on symptom profile.

First-Line Options After TCA Failure

• Sertraline is recommended as a first-line alternative after amitriptyline failure due to its established efficacy in treating MDD, GAD, and PTSD with a favorable side effect profile 1
• Sertraline has shown consistent efficacy across multiple trials and is FDA-approved for PTSD, making it particularly suitable for patients with comorbid PTSD 1
• Escitalopram is another excellent first-line option with superior efficacy compared to other second-generation antidepressants according to meta-analyses 2

Medication Selection Algorithm

1. For patients with prominent anxiety symptoms:

   • Start with sertraline (50-200 mg/day) due to its proven efficacy in anxiety disorders and PTSD 1
   • Alternative: Venlafaxine (75-225 mg/day) has shown statistically significantly better response and remission rates for patients with MDD and anxiety symptoms 3

2. For patients with prominent pain symptoms:

   • Consider duloxetine (60 mg/day) which has shown efficacy in both depression and pain conditions 3, 4

3. For patients concerned about sexual side effects:

   • Bupropion (300-450 mg/day) is associated with lower rates of sexual adverse events compared to SSRIs 5

4. For patients needing rapid response:

   • Mirtazapine has demonstrated a statistically significantly faster onset of action than citalopram, fluoxetine, paroxetine, or sertraline 3

Evidence for Specific Medications

SSRIs (Sertraline, Escitalopram)

• The STAR*D study showed that 1 in 4 patients became symptom-free after switching to alternative medications including sertraline 3
• Sertraline has fewer drug interactions compared to many antidepressants, with less prominent inhibitory effect on CYP2D6 than others in its class 6
• Sertraline has shown better efficacy for managing melancholia and psychomotor agitation compared to fluoxetine 3

SNRIs (Venlafaxine, Duloxetine)

• Venlafaxine has shown efficacy in painful diabetic neuropathy and painful polyneuropathies, which may benefit patients with comorbid pain conditions 3
• Duloxetine (60 mg once daily) has shown consistent efficacy in treating MDD and GAD with simple dosing 3
• Caution: Venlafaxine overdoses are more frequently fatal than SSRI overdoses, and it can cause dose-dependent blood pressure elevation 7

Bupropion

• Bupropion has comparable efficacy to other second-generation antidepressants with the advantage of minimal sexual side effects 5
• Particularly beneficial for patients with depression and comorbid conditions such as ADHD or nicotine dependence 5
• Common side effects include insomnia, dry mouth, headache, and tremor 5

Monitoring and Follow-up

• Evaluate response after 4-6 weeks of adequate dosing 3
• If partial response (average symptoms reduced but still significant), consider adding another first-line medication 3
• If no response (<30% reduction in symptoms), switch to an alternative first-line medication 3
• Continue treatment for 4-9 months after satisfactory response for first episode; longer for recurrent depression 5

Important Considerations and Precautions

• Avoid combining any of these medications with MAOIs due to risk of serotonin syndrome 6, 4
• Monitor blood pressure regularly with venlafaxine and duloxetine, particularly at higher doses 4, 7
• Consider cardiac status before prescribing certain antidepressants; venlafaxine, citalopram, and escitalopram have higher risk of cardiovascular adverse effects 7
• Be aware that approximately 38% of patients do not achieve treatment response during 6-12 weeks of treatment with second-generation antidepressants and 54% do not achieve remission 3