What is the recommended augmentation treatment with atypical antipsychotics (AAPs) for patients with anxious depression who have not responded to initial treatment with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)?

Atypical Antipsychotic Augmentation for Anxious Depression

Risperidone and aripiprazole are the most effective atypical antipsychotic augmentation options for patients with anxious depression who have not responded to initial treatment with SSRIs or SNRIs, with approximately one-third of treatment-resistant patients showing clinically meaningful response. 1

First-Line Treatments and Treatment Resistance

Before considering augmentation strategies, it's important to understand the initial treatment approach:

• SSRIs and SNRIs are the first-line pharmacological treatments for depression, including anxious depression 1
• Approximately 40-70% of patients treated with SSRIs/SNRIs do not achieve remission with initial treatment 1
• For patients with inadequate response to first-line treatments, second-step treatments including augmentation strategies are necessary 1

Atypical Antipsychotic Augmentation

When patients with anxious depression fail to respond adequately to SSRIs or SNRIs, atypical antipsychotic augmentation is a well-established strategy:

• Augmentation with atypical antipsychotics is one of the most commonly used pharmacological strategies for SSRI-resistant patients 1
• Meta-analyses provide evidence of efficacy specifically for risperidone and aripiprazole augmentation 1
• Approximately one-third of patients with SSRI-resistant depression show clinically meaningful response to atypical antipsychotic augmentation 1
• Low doses of atypical antipsychotics that are ineffective for schizophrenia are typically used for depression augmentation 2

Specific Atypical Antipsychotics

Aripiprazole

• FDA-approved for adjunctive therapy in treatment-resistant depression 3
• Demonstrated significant antidepressant responses and remissions in three large placebo-controlled studies 2
• 59% of patients with depression and anxiety disorders showed significant improvement with aripiprazole augmentation of SSRIs 4
• Effective dose range: 15-30 mg/day, though gradual titration is recommended to minimize side effects 4, 2
• Common adverse effects include akathisia and restlessness; weight gain is typically minimal 2

Risperidone

• Effective at low doses (acting primarily as a 5-HT2 antagonist) 5
• Can produce remission within one week of addition to ongoing SSRI treatment 5
• May have beneficial effects on sleep disturbance and sexual dysfunction 5

Quetiapine

• FDA-approved for adjunctive therapy in treatment-resistant depression 3
• Increases extracellular levels of dopamine and noradrenaline when combined with SSRIs 6

Mechanism of Action

The effectiveness of atypical antipsychotics as augmentation agents is attributed to:

• 5-HT2A receptor antagonism, which can reverse SSRI-induced suppression of norepinephrine neuron firing 2, 6
• Enhanced dopamine and noradrenaline release in the prefrontal cortex when combined with SSRIs 6
• Involvement of serotonin 5-HT1A, 5-HT2A, and adrenergic α2 receptors 6

Monitoring and Precautions

• Ongoing monitoring of the risk-benefit ratio is essential due to potential adverse effects 1
• Particular attention should be paid to weight gain and metabolic dysregulation 1
• Start with low doses and titrate gradually to minimize side effects, especially akathisia 2
• Consider discontinuation if no response is observed after an adequate trial period 1

Alternative Augmentation Strategies

If atypical antipsychotics are not effective or poorly tolerated, other evidence-based augmentation strategies include:

• Augmentation with CBT (larger effect sizes compared to risperidone augmentation in some studies) 1
• Switching to a different SSRI or using higher doses of the current SSRI 1
• Trial of an SNRI if not already attempted 1
• Augmentation with other agents such as bupropion or buspirone 1