Best Evidence-Based Treatment for Generalized Anxiety Disorder (GAD)
For adults with GAD, first-line pharmacological treatment should be SSRIs (escitalopram, paroxetine, or sertraline) or SNRIs (venlafaxine or duloxetine), with cognitive behavioral therapy (CBT) as an equally effective alternative or combination approach for more severe presentations. 1, 2, 3, 4
Pharmacological Treatment
First-Line Agents
SSRIs are the primary pharmacological recommendation with high-certainty evidence showing a 41% greater treatment response compared to placebo (NNTB = 7). 4 Specifically recommended agents include:
Escitalopram: Demonstrated efficacy in three 8-week placebo-controlled trials with doses of 10-20 mg/day showing statistically significant improvement on the Hamilton Anxiety Scale (HAM-A). 2 This agent has a favorable safety profile with low drug interaction potential, making it particularly suitable for elderly patients. 5
Paroxetine and Sertraline: Both have established efficacy in GAD treatment with comparable effectiveness. 1, 6, 3
Second-Line Agents
SNRIs, particularly venlafaxine extended-release and duloxetine, are equally effective alternatives to SSRIs. 1, 6, 3 Venlafaxine is specifically suggested with weak recommendation strength but demonstrated efficacy. 1
Dosing Strategy
Start with a subtherapeutic "test" dose to minimize initial anxiety or agitation, which is a common early adverse effect of SSRIs. 1 For shorter half-life SSRIs (sertraline, escitalopram), increase doses at 1-2 week intervals; for longer half-life SSRIs (fluoxetine), increase at 3-4 week intervals. 1 Titrate within the therapeutic range until the benefit-to-harm ratio is optimized and remission is achieved. 1
Psychotherapy
Individual CBT specifically developed for GAD (Clark and Wells model or Heimberg model) delivered by a skilled therapist is recommended as first-line psychotherapy. 1 Structure treatment with approximately 14 sessions over 4 months, with each session lasting 60-90 minutes. 5 Individual therapy is prioritized over group therapy due to superior clinical and economic effectiveness. 1
For patients who decline face-to-face CBT, self-help with support based on CBT principles is an acceptable alternative. 1
Combination Therapy
For moderate to severe GAD presentations, combination treatment (CBT plus SSRI) demonstrates superior outcomes compared to monotherapy. 1 The Child-Adolescent Anxiety Multimodal Study (CAMS) showed that combination CBT plus sertraline improved primary anxiety symptoms, global function, treatment response, and remission rates compared to either treatment alone (moderate strength of evidence). 1
However, for adults with social anxiety disorder (which often overlaps with GAD), there is no formal recommendation for combination therapy over monotherapy. 1 The decision should be guided by symptom severity and initial treatment response.
Treatment Duration
Continue treatment for at least 4-12 months after symptom remission for first episodes. 5 For recurrent GAD, longer-term or indefinite treatment may be necessary given the chronic, waxing-and-waning nature of the disorder. 5, 7 Long-term use of buspirone for up to 1 year has been shown to be safe without ill effects. 8
Alternative Agents
Buspirone is indicated for GAD management and significantly reduces symptoms with less sexual dysfunction than SSRIs and less sedation than benzodiazepines. 8, 7 It is appropriate for patients who cannot tolerate SSRIs/SNRIs or as an alternative first-line agent. 8
Pregabalin and quetiapine have demonstrated efficacy but are not considered first-line treatments. 3
Acceptability and Tolerability
Antidepressants have similar overall dropout rates compared to placebo (no significant difference in acceptability). 4 However, fewer participants drop out due to lack of efficacy (NNTB = 27), while more drop out due to adverse effects (NNTH = 17) compared to placebo. 4 This high-certainty evidence indicates that while antidepressants are effective, adverse effects are a significant consideration.
Common Pitfalls to Avoid
Do not start with full therapeutic doses of SSRIs, as initial anxiety or agitation is a common early adverse effect. 1 Begin with subtherapeutic doses and titrate gradually.
Avoid abrupt discontinuation of shorter-acting SSRIs (particularly paroxetine, but also fluvoxamine and sertraline), as this causes withdrawal symptoms including vertigo, sensory disturbances, paresthesias, anxiety, irritability, and agitation. 1
Do not assume higher doses provide greater efficacy—dose is not clearly related to magnitude of response, and higher doses are associated with more adverse effects. 1
Special Populations
Elderly Patients
Escitalopram and sertraline are preferred due to favorable safety profiles and lower drug interaction potential. 5 No differences in efficacy exist between elderly and younger patients. 1
Children and Adolescents (6-18 years)
Combination treatment (CBT plus SSRI, specifically sertraline) is suggested preferentially over monotherapy. 1 Parental oversight of medication regimens is paramount. 1 SNRIs are also suggested as treatment options for this age group. 1
Patients with Comorbid Depression
Antidepressants are particularly advantageous given the high comorbidity of GAD with major depressive disorder (62%) and dysthymia (37%). 9 SSRIs and SNRIs effectively treat both conditions simultaneously. 9, 6