What is the optimal treatment for generalized anxiety disorder (GAD) in a patient intolerant to Selective Serotonin Reuptake Inhibitors (SSRIs) or hydroxyzine with frequent severe anxiety and/or panic attacks?

From the Guidelines

For a patient with generalized anxiety disorder who cannot tolerate SSRIs or hydroxyzine, I strongly recommend initiating cognitive behavioral therapy (CBT) as the first-line treatment, given its strong evidence base and minimal risk of adverse effects, as supported by the 2023 guideline update from the Journal of Clinical Oncology 1. This approach prioritizes the patient's quality of life and minimizes the risk of medication side effects. The guideline suggests offering individual or group therapy with CBT, behavioral activation (BA), structured physical activity and exercise, or psychosocial interventions with empirically supported components, such as relaxation and problem-solving, for patients with moderate symptoms of anxiety. Given the patient's severe anxiety and/or panic attacks, it is crucial to address these symptoms promptly while initiating CBT. In addition to CBT, lifestyle modifications including regular exercise, sleep hygiene practices, and mindfulness meditation can provide significant benefits. While pharmacotherapy may be considered, it is essential to weigh the benefits and harms of each treatment option, taking into account the patient's values and preferences, as emphasized in the Japanese Society of Anxiety and Related Disorders/Japanese Society of Neuropsychopharmacology clinical practice guideline for social anxiety disorder 1. Ultimately, the treatment plan should be tailored to the patient's unique needs and circumstances, prioritizing their quality of life, morbidity, and mortality. Key considerations include:

• Initiating CBT as the first-line treatment
• Incorporating lifestyle modifications, such as regular exercise and mindfulness meditation
• Weighing the benefits and harms of pharmacotherapy options, if necessary
• Prioritizing the patient's values and preferences in the treatment plan.

From the FDA Drug Label

Buspirone hydrochloride tablets are indicated for the management of anxiety disorder or the short-term relief of the symptoms of anxiety. The efficacy of buspirone hydrochloride tablets has been demonstrated in controlled clinical trials of outpatients whose diagnosis roughly corresponds to Generalized Anxiety Disorder (GAD).

The optimal treatment for generalized anxiety disorder (GAD) in a patient intolerant to Selective Serotonin Reuptake Inhibitors (SSRIs) or hydroxyzine with frequent severe anxiety and/or panic attacks is buspirone.

• Buspirone has been demonstrated to be effective in controlled clinical trials for the management of GAD.
• It is also effective in relieving anxiety in the presence of coexisting depressive symptoms. However, the effectiveness of buspirone in long-term use (more than 3 to 4 weeks) has not been demonstrated in controlled trials 2.

From the Research

Treatment Options for Generalized Anxiety Disorder (GAD)

In patients intolerant to Selective Serotonin Reuptake Inhibitors (SSRIs) or hydroxyzine with frequent severe anxiety and/or panic attacks, several alternative treatment options can be considered:

• Benzodiazepines, although they are not recommended for long-term treatment due to associated risks such as tolerance, psychomotor impairment, and physical dependence 3
• Buspirone, which has demonstrated anxiolytic benefits but may not be effective in treating comorbid depression 4, 5
• Antidepressants such as venlafaxine and paroxetine, which have shown efficacy in treating GAD and comorbid depression 4, 5, 3
• Alternative medications such as older antidepressants, antipsychotics, anticonvulsants, and β-blockers, which may be effective in reducing symptoms of GAD 6
• Cognitive-behavioral therapy (CBT), which has shown significant benefits in treating GAD patients and may be maintained for up to 1 year 3

Pharmacologic Alternatives

Some pharmacologic alternatives to newer antidepressants and benzodiazepines that may be effective in treating GAD include:

• Imipramine, which has been shown to be effective in reducing symptoms of GAD 6
• Hydroxyzine, which has been found to be more effective than placebo in alleviating symptoms of GAD, although its use is limited due to a high risk of bias in included studies 7
• Valproate and pregabalin, which have demonstrated efficacy in reducing symptoms of GAD 6
• Risperidone, olanzapine, ziprasidone, and aripiprazole, which may also reduce symptoms of GAD, although more research is needed to confirm their effectiveness 6

Considerations for Treatment

When individualizing treatment for GAD, it is essential to consider the patient's comorbid conditions, drug dose ranges, and side effect profiles 5. Treatment should be tailored to the individual patient's needs, and doses may need to be adjusted based on factors such as age, medical illness, or concomitant medications.