What is the best course of treatment for a patient with Major Depressive Disorder (MDD) and anxiety who was previously misdiagnosed with bipolar disorder and treated with lithium (lithium) 900mg and Vraylar (cariprazine) 1.5mg, but has shown improvement after discontinuing Vraylar?

Recommended Treatment Plan for MDD with Anxiety After Lithium/Vraylar Discontinuation

Immediate Next Steps: Taper and Discontinue Lithium

Gradually taper and discontinue lithium since it was prescribed for a misdiagnosis of bipolar disorder and the patient actually has MDD with anxiety. 1 Lithium is not indicated for MDD without bipolar disorder, and continuing it exposes the patient to unnecessary long-term monitoring requirements and side effects. 1

• Taper lithium slowly over 2-4 weeks to avoid rebound worsening of mood symptoms, even though the patient doesn't have bipolar disorder. 1
• Monitor for withdrawal symptoms during the taper, though the patient may continue to feel improvement as the medication is removed. 1
• The patient's report of feeling "lighter, more expressive, smiling more" after discontinuing Vraylar suggests the antipsychotic was causing emotional blunting, which is common with these agents. 2

First-Line Pharmacologic Treatment: Switch to Mirtazapine

Switch to mirtazapine 15-45mg at bedtime as the preferred first-line treatment for this patient with MDD and prominent anxiety. 3 This is the strongest evidence-based option for treatment-resistant depression with comorbid anxiety.

• Mirtazapine provides statistically significantly faster symptom relief compared to SSRIs and addresses both anxiety and likely sleep disturbance simultaneously through its sedating properties. 3
• Start at 15mg at bedtime and titrate to 30-45mg based on response over 2-4 weeks. 3
• The patient should show some response by 2 weeks, but allow a minimum of 4 weeks at therapeutic dose before declaring treatment failure. 4

Alternative First-Line Option: Switch to Venlafaxine

If anxiety symptoms are particularly prominent without significant insomnia, switch to venlafaxine extended-release 75-225mg daily instead of mirtazapine. 3, 4

• Venlafaxine demonstrates superior efficacy compared to fluoxetine specifically for treating anxiety symptoms in patients with depression and anxiety. 3, 4
• The STAR*D trial showed that switching to venlafaxine achieved symptom-free status in 25% of patients after first-line treatment failure, with high-quality evidence. 4
• Start at 75mg daily and titrate to 150-225mg based on response and tolerability. 4

If Partial Response Occurs: Augmentation Strategy

If the patient achieves partial but incomplete response to either mirtazapine or venlafaxine, augment with bupropion 150-300mg daily. 3

• Bupropion augmentation decreases depression severity more than buspirone and has lower discontinuation rates due to adverse events. 3
• This strategy is supported by moderate-quality evidence from the STAR*D trial showing similar efficacy between different augmentation approaches. 1
• Start bupropion at 150mg daily and increase to 300mg if needed after 1-2 weeks. 3

Essential Concurrent Treatment: Cognitive Behavioral Therapy

Initiate cognitive behavioral therapy (CBT) immediately alongside medication changes. 1, 3

• Low-quality evidence shows no difference between switching to another antidepressant versus switching to cognitive therapy, indicating CBT should be offered regardless of medication choice. 3
• The STAR*D trial demonstrated similar efficacy when augmenting with cognitive therapy versus medication augmentation. 1
• CBT is particularly important for addressing the anxiety component of this patient's presentation. 1

Monitoring Plan

Establish a structured monitoring schedule to assess response and detect any return of symptoms:

• Assess depressive and anxiety symptoms every 2 weeks for the first 8 weeks using standardized measures like PHQ-9. 5, 6
• Monitor for activation, agitation, or suicidal ideation, particularly in the first 2-4 weeks after medication changes. 4, 5
• Continue treatment for at least 16-24 weeks after achieving remission to prevent recurrence. 5

If Multiple Strategies Fail: Third-Line Options

If the patient fails to respond to both switching and augmentation strategies, consider atypical antipsychotic augmentation only as a last resort before non-pharmacological options. 3

• Aripiprazole 2-15mg or quetiapine 150-300mg can be considered for augmentation, though this should be reserved after trying other strategies first given the patient's negative experience with Vraylar (cariprazine). 3
• Given the emotional blunting experienced with cariprazine, carefully discuss risks and benefits of any antipsychotic augmentation. 2
• Consider electroconvulsive therapy or referral to psychiatry if pharmacological approaches continue to fail. 3, 5

Critical Pitfalls to Avoid

• Do not restart Vraylar or any antipsychotic as first-line treatment since the patient clearly experienced emotional blunting and the diagnosis is MDD, not bipolar disorder. 2
• Do not use benzodiazepines for long-term anxiety management in this patient; they play only a very limited short-term role in depression treatment. 7
• Do not declare treatment failure prematurely; ensure each medication trial lasts at least 4 weeks at therapeutic dose. 4
• Do not continue lithium as it requires ongoing monitoring and provides no benefit for MDD without bipolar disorder. 1