Treatment guidelines recommend using selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) as first-line options for the treatment of GAD, which are drugs that were originally developed as antidepressants. These are well-known drugs and have been around for a long time.
The problem with SSRIs and SNRIs is that they aren’t very effective for treating anxiety. They can take up to 12 weeks to have an anxiolytic effect in a patient, and often, that's too long to wait. Another problem is that many patients who are taking SSRIs experience sexual dysfunction. Whether due to lack of efficacy or tolerability, many patients do not experience adequate response.
After SSRIs or SNRIs, guidelines recommend adding or switching to benzodiazepines, which are gamma-aminobutyric acid (GABA) modulators initially discovered in the 1950s. GABA is the most important inhibitory neurotransmitter in the brain and plays a central role in regulating anxiety. Modulation of the GABAA receptor is a well-validated approach for controlling GAD symptoms. In fact, over 30 drugs have been approved that target the GABAA channels inspired by the benzodiazepines, representing one of the most successful drug classes in pharmaceutical history.
Benzodiazepines are highly effective, and they act very quickly; even with the first dose of a benzodiazepine, the patient can have an anxiolytic effect. The problem with benzodiazepines is that they are limited to short-term use due to their abuse liability and significant side effects, including withdrawal effects, cognitive and motor impairment, and sedation.