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 and is experiencing severe anxiety or panic attacks, I recommend initiating a longer-term treatment with either an SNRI like venlafaxine or pregabalin, alongside cognitive behavioral therapy (CBT), as the optimal treatment approach. This recommendation is based on the most recent and highest quality evidence available, which suggests that SNRIs and pregabalin are effective in managing generalized anxiety disorder 1.

Treatment Options

• Venlafaxine, an SNRI, can be started at 37.5mg daily and gradually increased to 75-225mg daily, as it has shown efficacy in treating generalized anxiety disorder 1.
• Pregabalin, a calcium channel modulator, can be initiated at 75mg twice daily and increased to 300-600mg daily in divided doses, as it has also demonstrated effectiveness in reducing anxiety symptoms 1.
• Cognitive behavioral therapy (CBT) should be implemented concurrently, with sessions once or twice weekly for 12-16 weeks, as it is a recommended treatment option for anxiety disorders 1.

Lifestyle Modifications

• Regular exercise, sleep hygiene, and mindfulness practices should complement pharmacological treatment to enhance overall well-being and reduce anxiety symptoms.
• Regular monitoring for side effects and therapeutic response is essential, with follow-up every 2-4 weeks initially, to ensure the treatment plan is effective and safe.

Benzodiazepines

• While benzodiazepines like lorazepam or clonazepam can provide immediate relief for severe anxiety or panic attacks, their use should be limited to 2-4 weeks due to the risk of dependence 1.
• Benzodiazepines can be considered for short-term relief, but they should not be the primary treatment approach due to their potential for abuse and dependence.

Evidence-Based Recommendations

The recommendation to use SNRIs, pregabalin, and CBT is based on the evidence from 1, which suggests that these treatments are effective in managing anxiety disorders, and 1, which provides guidance on the pharmacological management of neuropathic pain and anxiety disorders. The most recent and highest quality study 1 supports the use of SNRIs and pregabalin as first-line treatments for generalized anxiety disorder.

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, which are effective as short-term anxiolytics, but their use is compromised by a poor adverse event profile 3
• Buspirone, which lacks the antidepressant efficacy important for addressing the comorbid depression experienced by many patients with GAD 3
• Antihistamines, such as hydroxyzine, which has been shown to be more effective than placebo for GAD, but with a high risk of bias in the included studies 4
• Atypical antipsychotics, such as quetiapine, which has similar efficacy to SSRIs in low dosages, but with lower overall tolerability 5
• Anticonvulsants, such as pregabalin, which rapidly reduces anxiety, has a safe side effect profile, and presents a low potential for abuse 5

Non-Antidepressant Treatments

Non-antidepressant treatments, such as:

• Pregabalin, which is the anticonvulsant with the most robust level of evidence in GAD 5
• Quetiapine, which is the atypical antipsychic of choice in GAD, with similar efficacy to SSRIs in low dosages 5
• Benzodiazepines, which are FDA approved for GAD, but with a poor adverse event profile 6, 5
• Buspirone, which is FDA approved for GAD, but with limited efficacy 6, 5
• Hydroxyzine, which is FDA approved for GAD, but with a high risk of bias in the included studies 4, 6

Considerations for Treatment

When individualizing treatment, drug dose ranges and side effect profiles need to be considered, as well as the patient's comorbid conditions 6. Doses may need to be reduced for elderly or medically ill patients or those taking other medications. Doses may need to be increased for refractory cases. Common comorbid conditions with GAD include depression, alcohol or drug abuse, social anxiety disorder, and panic disorder. In patients with significant depression, an antidepressant is more likely to succeed than a benzodiazepine 6.