What can a patient with inadequate response to sertraline (Selective Serotonin Reuptake Inhibitor - SSRI) for anxiety augment with?

Augmentation Strategies for Sertraline in Anxiety Disorders

The most effective augmentation strategy for inadequate response to sertraline for anxiety is adding cognitive behavioral therapy (CBT), which has demonstrated superior outcomes compared to medication alone or antipsychotic augmentation. 1, 2

First-Line Augmentation: Add CBT

Combination treatment with CBT and sertraline should be offered preferentially over medication adjustments alone. 1

• The American Academy of Child and Adolescent Psychiatry suggests that combination treatment (CBT and an SSRI) could be offered preferentially over monotherapy for patients with social anxiety, generalized anxiety, separation anxiety, or panic disorder 1
• CBT should be structured with approximately 14 individual sessions over 4 months, with each session lasting 60-90 minutes 2
• Effect sizes are larger with SSRI augmentation using CBT compared to augmentation with antipsychotics like risperidone 1
• If face-to-face CBT is not feasible, self-help with support based on CBT principles is an alternative 2

Before Adding Medications: Optimize Sertraline Dose

Ensure sertraline has been optimized before adding augmentation agents. 1, 2

• Increase sertraline dose gradually in the smallest available increments at approximately 1-2 week intervals until the benefit-to-harm ratio is optimized 1
• Higher doses of SSRIs within the therapeutic range are associated with greater treatment benefit, with a number needed to treat (NNT) of 4.70 2
• Allow adequate trial duration: clinically significant improvement typically occurs by week 6, with maximal improvement by week 12 or later 2
• Confirm medication adherence before considering augmentation 1

Pharmacological Augmentation Options

Second-Line: Switch to Different SSRI or SNRI

If sertraline optimization plus CBT fails, switching to a different medication class is preferred over adding augmentation agents. 1, 2

• Venlafaxine (SNRI) at doses of 75-225 mg/day is an effective second-line option for generalized anxiety disorder, panic disorder, and social anxiety disorder, with an NNT of 4.94 2
• Escitalopram is recommended as a first-line alternative with potentially fewer drug interactions than other SSRIs 2
• SNRIs may be more effective than SSRIs for patients who have failed an initial SSRI trial 2

Third-Line: Medication Augmentation

If switching medications is unsuccessful, consider the following augmentation agents, though evidence is primarily from OCD studies: 1, 3

Buspirone

• Buspirone is an option for relatively healthy older adults, particularly if avoiding sexual side effects is a priority 4
• Evidence shows it can be used to augment SSRIs in anxiety disorders 3

Antipsychotics (Use with Caution)

• Antipsychotic augmentation (risperidone, aripiprazole, quetiapine) has evidence primarily in SSRI-resistant OCD 1
• Only one-third of patients with SSRI-resistant OCD show clinically meaningful response to antipsychotic augmentation 1
• Requires ongoing monitoring of risk-benefit ratio with particular attention to weight gain and metabolic dysregulation 1
• Quetiapine may be considered as a later option if other strategies fail 4

Glutamatergic Agents

• N-acetylcysteine has the largest evidence base, with three out of five randomized controlled trials demonstrating superiority to placebo in reducing OCD symptoms 1
• Memantine augmentation can be considered, as several trials have demonstrated efficacy in SSRI augmentation for treatment-resistant OCD 1

Other Options

• Pregabalin/gabapentin may be considered as third-line options 4
• Buspirone augmentation of citalopram showed no difference compared to bupropion augmentation in one trial 1

Critical Safety Considerations

Avoid Serotonin Syndrome

Exercise extreme caution when combining serotonergic agents. 1

• Concomitant administration of any SSRIs with MAOIs is absolutely contraindicated due to risk of serotonin syndrome 1, 2
• When combining two or more non-MAOI serotonergic drugs, start the second agent at a low dose, increase slowly, and monitor closely for symptoms, especially in the first 24-48 hours after dosage changes 1
• Serotonin syndrome symptoms include mental status changes (confusion, agitation), neuromuscular hyperactivity (tremors, clonus, hyperreflexia), and autonomic hyperactivity (hypertension, tachycardia, diaphoresis) 1

Monitor for Suicidality

• All SSRIs have a boxed warning for suicidal thinking and behavior through age 24 years 1
• Close monitoring is recommended, especially in the first months of treatment and following dosage adjustments 1

Discontinuation Syndrome Risk

• Sertraline has been associated with discontinuation syndrome characterized by dizziness, fatigue, headaches, nausea, insomnia, and anxiety 1, 2
• Taper gradually when discontinuing or switching medications 1

Common Pitfalls to Avoid

• Do not add augmentation agents before optimizing sertraline dose and ensuring adequate trial duration (at least 12 weeks) 1, 2
• Do not overlook CBT as first-line augmentation—it has superior evidence compared to medication augmentation 1
• Avoid combining multiple serotonergic agents without careful dose titration and monitoring 1
• Do not use benzodiazepines for acute treatment in older adults due to safety concerns 4