What alternative treatment options are available for a patient with treatment-resistant depression and anxiety, who has a history of IV drug use and THC use, and has not responded to citalopram, Lexapro, and Wellbutrin?

Treatment Options for Treatment-Resistant Depression with Comorbid Anxiety

For a patient who has failed citalopram, escitalopram (Lexapro), and bupropion (Wellbutrin), the most evidence-based next step is augmentation with aripiprazole, as it is the only FDA-approved augmentation agent for treatment-resistant depression and was one of only six augmentation strategies whose confidence intervals did not overlap with placebo in American College of Physicians guidelines. 1, 2

Defining Treatment Resistance

• Your patient meets criteria for treatment-resistant depression (TRD) after failing three adequate antidepressant trials from different classes: two SSRIs (citalopram, escitalopram) and one NDRI (bupropion) 3, 4
• After two treatment failures, remission rates decrease significantly with each subsequent trial, making aggressive intervention critical 4, 5

First-Line Augmentation Strategy: Aripiprazole

Aripiprazole augmentation should be the primary recommendation because:

• It achieved 55.4% remission rates in clinical trials, significantly higher than bupropion augmentation (34.0%; P = 0.031) 1
• It is FDA-approved specifically for treatment-resistant depression 2
• The American College of Physicians identified it as having the strongest evidence among augmentation agents 1

Dosing Protocol

• Start aripiprazole at 2-5 mg daily added to the current antidepressant 2
• Titrate to 5-15 mg daily based on response and tolerability 2
• Monitor for akathisia, weight gain, and metabolic effects as primary adverse events 1

Alternative Augmentation Options

Buspirone Augmentation

• Consider if aripiprazole is not tolerated or patient prefers to avoid antipsychotics 1, 6
• Significantly lower discontinuation rates due to adverse events (12.5%) compared to other augmentation strategies (20.6%; P < 0.001) 1, 6
• Start at 5 mg twice daily, titrate to maximum 20 mg three times daily 6
• Critical caveat: Takes 2-4 weeks to reach full therapeutic effect, unlike benzodiazepines 6
• Monitor intensively for serotonin syndrome in first 24-48 hours after initiation, watching for the triad: mental status changes, neuromuscular hyperactivity, and autonomic hyperactivity 6

Lithium Augmentation

• Well-studied traditional augmentation strategy with established efficacy 7, 2, 8
• Requires therapeutic drug monitoring (target 0.6-1.0 mEq/L) and monitoring of thyroid/renal function 2
• Consider in patients with family history of bipolar disorder or those with treatment-resistant features 8

Lamotrigine Augmentation

• Effective augmentation option, particularly for patients with bipolar depression features 2, 8
• Requires slow titration (25 mg every 2 weeks) to minimize risk of Stevens-Johnson syndrome 2

Switching Strategies

If augmentation fails or is not tolerated, the American College of Physicians found no significant differences in efficacy when switching between second-generation antidepressants 3:

Switch to Venlafaxine or Duloxetine (SNRIs)

• Moderate-quality evidence shows similar efficacy to other switches 3, 9
• Dual mechanism (serotonin and norepinephrine) may benefit patients who failed SSRIs 9
• Start venlafaxine XR at 37.5 mg daily for 4-7 days, increase to 75 mg after first week, target 150-225 mg daily 9
• Duloxetine 60 mg once daily (start at 30 mg for one week) 10

Mirtazapine

• Different mechanism (alpha-2 antagonist, 5-HT2/5-HT3 antagonist) than prior failed medications 2
• May address insomnia and appetite issues common in depression 2

Combination Antidepressant Strategies

If partial response was achieved with any prior medication, consider combination rather than switching 3, 7:

• Combining bupropion with an SSRI/SNRI addresses different neurotransmitter systems and may reduce sexual dysfunction 9, 7
• Mirtazapine combined with SSRI/SNRI ("California rocket fuel") has demonstrated efficacy in case reports 2
• Warning: Avoid combining SSRIs with MAOIs (14-day washout required) and monitor for serotonin syndrome with any combination 6, 10

Cognitive Behavioral Therapy Augmentation

• The American College of Physicians emphasizes that adding CBT has similar efficacy to medication augmentation with potentially fewer adverse events 1, 6
• CBT augmentation showed numerically lower discontinuation rates (9.2%) compared to medication augmentation (18.8%; P = 0.086) 1
• Should be discussed as alternative or adjunctive to pharmacologic augmentation 1

Special Considerations for Substance Use History

• History of IV drug use requires careful monitoring for medication diversion and adherence [@general medicine knowledge@]
• THC use may complicate assessment of treatment response and should be addressed as part of comprehensive treatment [@general medicine knowledge@]
• Bupropion should be used cautiously if history of stimulant abuse due to dopaminergic effects [@general medicine knowledge@]
• Avoid benzodiazepines given addiction risk; buspirone is safer alternative for anxiety 6

Emerging Treatments for Severe TRD

If multiple augmentation strategies fail:

• Ketamine/esketamine appear effective for TRD with rapid onset of action 2
• Requires specialized administration and monitoring 2
• Consider referral to psychiatry for evaluation if not already involved [@general medicine knowledge@]

Timeline and Monitoring

• Assess response at 6-8 weeks after initiating augmentation strategy 1
• Monitor for suicidal ideation increases during first 1-2 months of any medication change 1
• Continue successful combination therapy for 4-9 months after achieving response, potentially longer with multiple prior episodes 1

Common Pitfalls to Avoid

• Inadequate trial duration: Ensure each medication trial was adequate dose for adequate duration (8-12 weeks) before declaring failure 3, 5
• Expecting immediate results from buspirone: Unlike benzodiazepines, requires 2-4 weeks for efficacy 6
• Missing comorbid conditions: Ensure accurate diagnosis and screen for bipolar disorder, anxiety disorders, substance use disorders, and medical conditions that may contribute to treatment resistance 5
• Abrupt discontinuation: Taper antidepressants gradually to avoid discontinuation syndrome, particularly with SSRIs and SNRIs 6, 10
• Ignoring psychotherapy: Medication alone is often insufficient; combined treatment typically superior 3, 1