What non‑sedating, weight‑neutral anxiolytic is appropriate for a 35‑year‑old woman with generalized anxiety disorder whose anxiety has worsened despite escitalopram (Lexapro) 20 mg daily?

Buspirone Augmentation Is the Best Non-Sedating, Weight-Neutral Option

Add buspirone 5 mg twice daily to the existing escitalopram 20 mg regimen, titrating to 20 mg three times daily over 2–4 weeks. 1 This combination provides the most favorable profile for avoiding both sedation and weight gain while addressing breakthrough anxiety symptoms in a patient already on an optimized SSRI dose.

Rationale for Buspirone Augmentation

• Buspirone has no sedative properties and does not cause weight gain, making it ideal for patients prioritizing these concerns. 1, 2
• The therapeutic effect requires 2–4 weeks to manifest, so patients should be counseled about delayed onset rather than expecting immediate relief. 1, 2
• Buspirone augmentation of SSRIs has demonstrated efficacy in the STAR*D trial, achieving remission rates comparable to other augmentation strategies (~30%). 1
• Escitalopram has minimal CYP450 interactions, reducing the risk of pharmacokinetic drug-drug interactions when combined with buspirone. 1

Critical Safety Monitoring

• Do not combine escitalopram with other serotonergic agents beyond buspirone due to serotonin syndrome risk; warning signs include mental status changes, neuromuscular hyperactivity (tremor, clonus, hyperreflexia), and autonomic instability (tachycardia, diaphoresis, fever). 1
• Monitor treatment response every 2–4 weeks using standardized anxiety scales (GAD-7 is validated for primary care). 3, 1
• Do not exceed escitalopram 20 mg daily, as higher doses increase QT prolongation risk without additional benefit. 1, 4

Alternative If Buspirone Fails After 8–12 Weeks

• Switch to an SNRI (venlafaxine 75–225 mg daily or duloxetine 40–120 mg daily) rather than adding another medication, as SNRIs demonstrate statistically superior response and remission rates compared to SSRIs in treatment-resistant anxiety. 1, 2
• Venlafaxine carries a dose-dependent risk of treatment-emergent hypertension, requiring blood pressure monitoring at baseline and with each dose increase. 4
• Discontinuation rates due to adverse events are significantly higher with venlafaxine (13%) compared to escitalopram (7%), primarily due to nausea. 5

Why Not Other Options

• Benzodiazepines must be avoided despite their rapid anxiolytic effect, as they cause cognitive impairment, dependence, and paradoxical agitation in approximately 10% of patients, with no role in long-term GAD management. 4, 2
• Hydroxyzine causes sedation and anticholinergic effects, directly contradicting the patient's requirement for a non-sedating agent. 1, 4
• Mirtazapine causes significant weight gain and sedation, making it inappropriate for this patient's priorities. 4
• Switching to another SSRI (sertraline, paroxetine) is not recommended after adequate escitalopram trial, as head-to-head trials show no clinically meaningful efficacy differences between SSRIs. 1, 6

Adjunctive Cognitive-Behavioral Therapy

• Adding CBT to escitalopram demonstrates superior efficacy compared to medication alone for anxiety disorders and should be initiated immediately while optimizing pharmacotherapy. 1
• Individual CBT following evidence-based protocols (Clark-and-Wells or Heimberg models) is preferred over group therapy due to superior clinical effectiveness. 4
• CBT can be started without waiting for medication optimization, providing synergistic benefit. 1

Treatment Timeline and Expectations

• Allow 8–12 weeks at the optimized buspirone dose (20 mg three times daily) before declaring treatment failure, as full anxiolytic response may require this duration. 1, 2
• Approximately 50% of patients who ultimately achieve remission do so between weeks 6 and 14 of combined treatment. 1
• After achieving satisfactory response, continue treatment for at least 6 months for a first episode of GAD; for recurrent anxiety, longer-term or indefinite treatment may be beneficial. 4, 7

Common Pitfalls to Avoid

• Do not make medication changes before completing an adequate trial (8–12 weeks at therapeutic doses), as premature switching delays recovery and misses opportunities for response. 1
• Do not add multiple serotonergic agents simultaneously; the cumulative serotonin syndrome risk increases dramatically with polypharmacy. 1
• Do not discontinue escitalopram abruptly if switching medications; taper gradually over 10–14 days to avoid discontinuation syndrome (dizziness, anxiety, irritability, sensory disturbances). 1, 4