What alternative treatment options are recommended for treatment-resistant depression and anxiety in a client who has tried multiple antidepressants with no relief and has a positive response to Ativan (lorazepam)?

Treatment Recommendations for Treatment-Resistant Depression and Anxiety

For this client who has failed multiple antidepressants and responds positively to benzodiazepines, consider augmentation with an atypical antipsychotic (aripiprazole, quetiapine, or brexpiprazole) added to the current antidepressant, or switch to mirtazapine for faster onset, while addressing the concerning benzodiazepine preference through careful risk assessment and structured tapering.

Critical Safety Concern: Benzodiazepine Use

The client's preference for Ativan (lorazepam) raises significant red flags that must be addressed immediately:

• Benzodiazepines carry substantial risks of abuse, misuse, and addiction, which can lead to overdose or death 1
• Lorazepam is not recommended for primary depressive disorders and can worsen pre-existing depression 1
• Physical dependence develops with continued use, and abrupt discontinuation can cause life-threatening withdrawal reactions including seizures 1
• The FDA explicitly warns that benzodiazepines should be prescribed at the lowest effective dosage with careful monitoring for signs of abuse, misuse, and addiction 1

Before proceeding with any antidepressant strategy, assess this client's risk for substance use disorder using a standardized screening tool 1. If substance use disorder is suspected, refer for early treatment 1.

First-Line Treatment Options for Treatment-Resistant Depression

Option 1: Augmentation with Atypical Antipsychotics (Preferred for Partial Responders)

Atypical antipsychotics are the most widely studied and FDA-approved augmentation agents for treatment-resistant depression 2, 3:

• Aripiprazole, brexpiprazole, cariprazine, quetiapine extended-release, and olanzapine-fluoxetine combination are all FDA-approved for depression 2
• Augmentation builds upon any partial improvements already achieved, avoiding the loss of response that occurs with switching 4, 5
• This strategy is particularly appropriate since the client has tried multiple antidepressants, suggesting they may be a partial responder 5

Practical considerations:

• Quetiapine or aripiprazole augmentation is preferred over switching to antidepressant monotherapy based on efficacy data 3
• Monitor carefully for metabolic side effects (weight gain), akathisia, and tardive dyskinesia 2
• The olanzapine-fluoxetine combination, while effective, has more concerning metabolic side effects 3

Option 2: Switch to Mirtazapine (For Rapid Symptom Relief)

Mirtazapine demonstrates statistically significantly faster onset of action compared to SSRIs (citalopram, fluoxetine, paroxetine, sertraline) 6:

• Response rates become similar after 4 weeks, but the faster initial response may be clinically meaningful 6, 7
• Particularly beneficial for clients with comorbid anxiety and insomnia due to sedating properties 7
• Avoids polypharmacy and reduces the range of potential adverse events 4

Caveat: The STAR*D study showed that only 1 in 4 patients became symptom-free after switching medications, with no significant differences between bupropion, sertraline, and venlafaxine 6. This suggests switching alone has limited effectiveness 4.

Option 3: Switch to Venlafaxine (For Prominent Anxiety)

Venlafaxine has shown superior efficacy compared to fluoxetine for treating anxiety symptoms 6, 7:

• One fair-quality trial demonstrated statistically significantly better response and remission rates for venlafaxine versus fluoxetine in patients with depression and anxiety 6
• Since the client has already tried Effexor (venlafaxine), this option is only viable if the previous trial was inadequate in dose or duration 6

Per consensus guidelines, an adequate trial requires minimum licensed dosage for at least 4 weeks 6.

Option 4: Augmentation with Bupropion

Adding bupropion to an existing SSRI/SNRI decreases depression severity more than augmentation with buspirone 6, 7:

• The STAR*D study showed no difference in response or remission between bupropion augmentation and buspirone augmentation, but bupropion had superior effects on depression severity 6
• Bupropion augmentation had lower discontinuation rates due to adverse events compared to buspirone 6
• This strategy is appropriate when switching hasn't been effective 7

Alternative Augmentation Strategies

Lithium Augmentation

• Lithium augmentation is one of the best-documented treatments for TRD but among the least utilized 8
• Effective based on multiple studies, though requires careful monitoring of blood levels and thyroid/renal function 3, 5

Liothyronine (T3) Augmentation

• Thyroid hormone augmentation with T3 is effective and well-studied 3, 5
• Simpler to manage than lithium with fewer monitoring requirements 5

Lamotrigine Augmentation

• Effective augmentation strategy for treatment-resistant depression 3
• Requires slow titration to minimize risk of serious rash 3

Treatment Algorithm

Step 1: Assess for substance use disorder given benzodiazepine preference 1

Step 2: Determine if the client had any partial response to previous antidepressants:

• If partial response: Augment with atypical antipsychotic (aripiprazole or quetiapine preferred) 2, 3
• If no response: Switch to mirtazapine for faster onset 6, 7

Step 3: If anxiety symptoms are prominent and mirtazapine is chosen, this addresses both depression and anxiety with sedating properties beneficial for sleep 7

Step 4: If Step 2 fails, consider:

• Lithium augmentation (best-documented but requires monitoring) 8, 3
• Liothyronine (T3) augmentation (simpler than lithium) 3, 5
• Lamotrigine augmentation 3

Step 5: If multiple augmentation strategies fail, consider non-pharmacological options including cognitive behavioral therapy, electroconvulsive therapy, or newer treatments like ketamine/esketamine 3

Critical Pitfalls to Avoid

Do not prescribe benzodiazepines long-term for depression or anxiety in this client:

• The client's stated preference for how Ativan "feels" suggests potential for misuse 1
• Benzodiazepines worsen depression and are contraindicated as primary treatment 1
• If currently on benzodiazepines, implement a gradual taper using a patient-specific plan to avoid life-threatening withdrawal 1

Do not switch antidepressants without considering augmentation first:

• After failing 5 antidepressants, the likelihood of response to another monotherapy switch is low (only 25% achieve symptom-free status) 6
• Augmentation strategies are generally more effective at this stage 4, 5

Do not assume all previous trials were adequate:

• Verify each antidepressant was given at minimum licensed dosage for at least 4 weeks 6
• Inadequate trials should not count toward treatment resistance 6