What alternative medications can be prescribed for a patient with treatment-resistant depression and anxiety, who is intolerant to hydroxyzine, trazodone, and Abilify (aripiprazole), and has a history of IV drug use and THC use?

Alternative Medications for Treatment-Resistant Depression and Anxiety with Intolerance to Hydroxyzine, Trazodone, and Aripiprazole

Primary Recommendation: SSRI or SNRI Monotherapy

Start with escitalopram 10 mg daily (titrating to 20 mg after 1 week) or venlafaxine extended-release 37.5-225 mg daily as first-line pharmacotherapy, as these agents address both depression and anxiety simultaneously, have robust efficacy data, and lack abuse potential—critical for patients with substance use history. 1

Rationale for SSRI/SNRI Selection

• Escitalopram has the most favorable drug interaction profile among SSRIs, with minimal effect on CYP450 isoenzymes, making it safer for patients with complex medication histories or potential future polypharmacy 1
• SNRIs (venlafaxine, duloxetine) demonstrate statistically significantly better response and remission rates than SSRIs in treatment-resistant depression, with dual action on serotonin and norepinephrine providing greater efficacy for both depression and anxiety symptoms 1
• Response rates of 50-70% are expected in controlled trials for anxiety disorders including GAD, panic disorder, and social anxiety disorder with SSRI therapy 1

Dosing and Titration Strategy

• Start escitalopram at a subtherapeutic "test" dose (5-10 mg) to minimize initial anxiety or agitation, then titrate gradually every 2-4 weeks 1
• Maximum dose of escitalopram is 20 mg daily due to QT prolongation risk at higher doses 1
• For venlafaxine, start at 37.5 mg and titrate to 75-225 mg daily based on response and tolerability 1
• Allow 8-12 weeks at therapeutic dose before declaring treatment failure, as full antidepressant response requires adequate trial duration 1

Secondary Option: Tricyclic Antidepressants (TCAs)

If SSRIs/SNRIs fail or are not tolerated, consider secondary amine TCAs such as desipramine or nortriptyline starting at 10 mg at bedtime, titrated gradually to minimize anticholinergic effects. 1

TCA Considerations

• Secondary amine TCAs (desipramine, nortriptyline) have lower anticholinergic effects than tertiary amines, making them more tolerable 1
• Start at low doses (10 mg at bedtime) and titrate gradually to minimize side effects including dry mouth, sedation, and constipation 1
• TCAs have multiple beneficial actions including reduction of anxiety symptoms independent of effects on depression, though effects may take several weeks to manifest 1
• Imipramine has demonstrated efficacy in double-blind, placebo-controlled studies for GAD and may be considered as an alternative 2

Augmentation Strategy if Monotherapy Partially Effective

If partial response occurs with SSRI/SNRI monotherapy after 8-12 weeks, add bupropion SR 150-400 mg daily rather than switching, as combination therapy achieves remission rates of approximately 50% compared to 30% with monotherapy alone. 1

Augmentation Rationale

• Bupropion augmentation has significantly lower discontinuation rates due to adverse events (12.5%) compared to buspirone augmentation (20.6%, p<0.001) 1
• Bupropion has the additional advantage of lower sexual dysfunction rates compared to continuing SSRI monotherapy, a common reason for treatment discontinuation 1
• The STAR*D trial demonstrated similar efficacy between bupropion and buspirone augmentation of citalopram (closely related to escitalopram) 1

Alternative Augmentation Options

Pregabalin or Valproate

Pregabalin and valproate have demonstrated efficacy in double-blind, placebo-controlled studies for GAD and may be considered as augmentation agents. 2

• Pregabalin was among the most effective agents in controlled trials for GAD, though it is a controlled substance requiring careful monitoring in patients with substance use history 2
• Valproate also showed efficacy in controlled trials and may be considered, particularly if mood instability is present 2

Atypical Antipsychotics (Alternative to Aripiprazole)

If atypical antipsychotic augmentation is necessary despite aripiprazole intolerance, consider risperidone or olanzapine, though these carry significant metabolic risks. 3, 2

• Risperidone and olanzapine have evidence of efficacy in double-blind, placebo-controlled trials for treatment-resistant anxiety disorders 2
• Antipsychotic augmentation of SSRIs has a smaller effect size than SSRIs alone, with only one-third of SSRI-resistant patients showing clinically meaningful response 3
• Ongoing monitoring of risk-benefit ratio is essential with particular attention to weight gain and metabolic dysregulation 3
• Ziprasidone may have a more favorable metabolic profile than risperidone or olanzapine if antipsychotic augmentation is required 2

Sleep Management Without Trazodone

For insomnia comorbid with depression and anxiety, prescribe ramelteon 8 mg at bedtime as first-line non-controlled sleep medication, or consider mirtazapine 7.5-15 mg at bedtime as a sedating antidepressant alternative. 4

Sleep Medication Options

• Ramelteon is the only non-controlled, FDA-approved sleep medication specifically recommended for insomnia without short-term usage restrictions, making it ideal for patients with substance use concerns 4
• Mirtazapine offers dual benefits of sleep promotion and appetite stimulation, which may be valuable if weight loss or poor appetite from depression is present 4
• Avoid benzodiazepines and Z-drugs due to abuse potential and dependence risk in patients with substance use history 4
• Do not use antihistamines or melatonin supplements as they lack evidence for chronic insomnia 4

Critical Monitoring Requirements

Monitor for suicidal ideation during the first 1-2 months after any medication change, as suicide risk is greatest during this period, and assess treatment response every 2-4 weeks using standardized rating scales. 1

• Use standardized depression (PHQ-9, HAM-D) and anxiety rating scales to objectively track symptoms 1
• Monitor for behavioral activation syndrome within 24-48 hours of dose adjustments, manifesting as increased agitation, anxiety, or confusion 1
• Assess for discontinuation syndrome if switching medications, characterized by dizziness, anxiety, irritability, and sensory disturbances 1
• Baseline ECG monitoring may be warranted if combining medications that prolong QTc interval or in patients with cardiac risk factors 1

Common Pitfalls to Avoid

• Do not switch medications before allowing adequate trial duration (8-12 weeks at therapeutic dose), as premature switching leads to missed opportunities for response 1
• Do not combine multiple serotonergic agents without careful monitoring for serotonin syndrome risk 1
• Do not prescribe benzodiazepines given the patient's history of IV drug use and THC use, as these carry high abuse potential 4
• Do not exceed escitalopram 20 mg daily without cardiac monitoring due to QT prolongation risk 1
• Do not use low-dose antidepressants expecting full antidepressant effects—ensure therapeutic dosing is achieved 1

Duration of Continuation Therapy

Continue treatment for 4-9 months after satisfactory response in patients with a first episode, and for recurrent depression (2+ episodes), consider years to lifelong maintenance therapy. 1