What can be prescribed to a 30-year-old female patient with a history of IV drug use and THC use, and treatment-resistant depression and anxiety, currently taking [MEDICATION] 25 mg and propranolol 10 mg three times a day?

Treatment Options for Treatment-Resistant Depression with Anxiety

This patient meets criteria for treatment-resistant depression and should be started on augmentation therapy with an atypical antipsychotic, specifically aripiprazole 2-5 mg daily or quetiapine 150-300 mg daily at bedtime, as these have the strongest FDA approval and evidence base for TRD. 1, 2

Confirming Treatment-Resistant Depression Diagnosis

Your patient clearly meets TRD criteria based on documented failure of multiple adequate antidepressant trials:

• Failed SSRIs: mirtazapine, fluoxetine (Prozac), escitalopram (Lexapro) 3, 1
• Each trial must have been at minimum effective dosage for ≥4 weeks to count as a treatment failure 3, 1
• TRD is defined as failure of at least 2 adequate antidepressant trials with different mechanisms of action 3, 1, 2

The propranolol 10 mg three times daily is addressing somatic anxiety symptoms but is NOT an adequate treatment for generalized anxiety disorder or panic disorder, and should not be relied upon as primary anxiolytic therapy 4, 5. Beta-blockers may actually induce or worsen depression, which is particularly concerning in this patient 4, 6.

Primary Recommendation: Atypical Antipsychotic Augmentation

Augmentation with atypical antipsychotics is the primary first-line FDA-approved strategy and has the most extensive and rigorous evidence base of all pharmacological approaches in TRD. 1, 2

Specific Options:

Option 1: Aripiprazole (Preferred)

• Start 2 mg daily, can increase to 5-15 mg daily based on response 1, 2
• FDA-approved specifically as adjunctive therapy for TRD 2
• Lower metabolic side effect profile compared to other atypicals 2
• Continue current antidepressant regimen while adding aripiprazole 1, 2

Option 2: Quetiapine

• Start 50 mg at bedtime, increase to 150-300 mg for depression (FDA-approved for bipolar depression) 7, 8
• Day 1: 50 mg at bedtime, Day 2: 100 mg, Day 3: 200 mg, Day 4: 300 mg 7
• Has additional benefit for anxiety and insomnia 8
• Maximum dose 300 mg/day for depression indication 7

Option 3: Olanzapine-Fluoxetine Combination

• FDA-approved specifically for TRD 2
• Start 5 mg olanzapine with 20 mg fluoxetine once daily in evening 2
• Dose range: olanzapine 5-20 mg with fluoxetine 20-50 mg 2
• Major caveat: Significant metabolic side effects (weight gain, diabetes risk) limit use 2, 8
• Requires metabolic monitoring (weight, glucose, lipids) 2

Alternative Augmentation Strategies

If atypical antipsychotics are not tolerated or contraindicated:

Lithium augmentation:

• Strong evidence for TRD 2, 8
• Requires therapeutic drug monitoring and renal/thyroid function tests 8

Bupropion combination:

• Add bupropion SR 150 mg daily, increase to 300-400 mg daily 2, 8
• Lower sexual side effects compared to SSRIs 2
• Beneficial for comorbid substance use history 2
• Caution: Seizure risk with history of IV drug use if active withdrawal 2

Lamotrigine augmentation:

• Effective augmentation strategy 2, 8
• Requires slow titration due to Stevens-Johnson syndrome risk 8

Addressing Anxiety Component

The propranolol regimen is inadequate for treating generalized anxiety disorder and should be reconsidered. 4, 5

• Propranolol is NOT effective for generalized anxiety disorder or panic disorder as monotherapy 4
• May provide symptomatic relief for somatic symptoms (palpitations, tremor) but does not address core anxiety 4, 5
• Beta-blockers can induce or worsen depression, which is particularly problematic in TRD 4, 6

For anxiety management:

• Quetiapine (if chosen as augmentation agent) provides dual benefit for depression AND anxiety 8
• Hydroxyzine and trazodone can be continued for PRN anxiety and sleep 1
• Avoid chronic benzodiazepines given history of IV drug use and substance abuse risk 9
• If acute anxiety management needed: low-dose clonazepam 0.25-0.5 mg PRN (maximum 2 mg daily, not more than 2-3 times weekly) with clear time-limited parameters 9, 10

Highly Refractory Cases

If the patient fails augmentation with atypical antipsychotics:

Esketamine nasal spray or IV ketamine:

• Reserved for highly refractory TRD 1, 2, 8
• Rapid onset of action 8
• May reduce suicidal ideation 2
• Requires specialized clinic setting and monitoring 2

Transcranial Magnetic Stimulation (TMS):

• Consider for patients who have failed multiple medication trials 1

Critical Implementation Points

• Do NOT increase antidepressant doses beyond minimum effective dosage - most studies show no benefit with increased side effects 2
• Continue current mood stabilizer (not specified in question but mentioned patient is on one) 1
• Mandatory: Implement cognitive behavioral therapy (CBT) in conjunction with pharmacotherapy - combination treatment is superior to either alone 1, 9
• Weekly visits for first month to assess tolerability and response, then monthly once stable 9
• Continue combination therapy for at least 12-24 months after achieving stability 9

What NOT to Do

• Do not count treatment discontinuation before 4 weeks as treatment failure unless clear evidence of non-response 3, 1
• Do not use propranolol as primary treatment for generalized anxiety disorder 4, 5
• Do not prescribe chronic benzodiazepines given substance use history 9
• Do not exclude this patient from treatment trials based on number of prior failures or substance use history 1, 2