____________________________________________________________________________ Anxiety Disorders
subjectively rated as improved with both active treatments. Pregabalin effects on sleep and sleep architecture were distinct from benzodiazepines. Enhancement of slow-wave sleep was relevant to frequent reports of reductions in slow-wave sleep in patients with fibromyalgia or GAD [271]. Clinical trials have reported euphoria, which emphasizes the need for careful and continuing evaluation of any potential for abuse. Reports of pregabalin abuse have appeared, usually involving individuals with a history of psychotropic medication abuse [243]. Discontinuation symptoms were reported after abruptly stopping pregabalin and were more prominent with higher daily doses. However, significantly fewer withdrawal symptoms were found after stopping pregabalin compared with lorazepam, and when tapered over one week, pregabalin withdrawal symptoms are minimal. Tentative evidence suggests pregabalin may be beneficial in withdrawal from benzodiaz- epines and related compounds [243]. Agomelatine Agomelatine studies have mostly investigated its efficacy in GAD. Three randomized controlled trials have been performed. One trial with an escitalopram arm found that agomelatine led to comparable efficacy in GAD and signifi- cantly improved sleep restoration with fewer side effects and no discontinuation symptoms compared with escitalopram [202]. The low discontinuation rate reflected good tolerability, and laboratory results showed a low incidence of transient eleva- tions in liver enzymes. Another trial that measured therapeutic response as 50% or greater reduction in HAM-A score found response rates of 66.7% with agomelatine, compared with 46.6% with placebo. Agomelatine was noted to improve sleep quality, with a lack of sexual side effects or discontinuation syndrome. Dizziness (8%) and nausea (5%) were more frequent than placebo [202; 272]. Agomelatine was superior to placebo in symptom reduction beginning at six weeks and in relapse prevention at six-month follow-up [203]. Second-Line Options When treatment with SSRIs/SNRIs proves to be ineffective or intolerable, alternative choices with demonstrable efficacy include TCAs (e.g., imipramine) or a second-generation anti- psychotic agent (quetiapine or pregabalin). Pregabalin is also effective for augmenting other first- and second-line agents in patients showing partial response. Internationally, pregabalin is regarded as a first-line option for GAD, but U.S. guidelines have not yet integrated this agent into the first-line tier [185]. Several options as second-line agents have efficacy in GAD comparable to first-line agents but possess potential side effects or other risks that preclude first-line use [120]. Benzodiazepines would be considered first in most cases, except where there is a risk of substance abuse, while bupropion XL would likely be reserved for later. Quetiapine XR remains a good choice in terms of efficacy, but given the metabolic concerns associ- ated with this atypical antipsychotic, it should be reserved for patients who lack response or cannot tolerate antidepressants
or benzodiazepines [120]. It is important to note that drugs such as beta-blockers (e.g., propranolol) prescribed to address the physical symptoms of anxiety are ineffective in the treat- ment of GAD [243]. Quetiapine In three 10-week randomized controlled trials of patients with GAD, quetiapine monotherapy showed clinically and statistically significant improvements in anxiety reduction and remission rates versus placebo [185]. Meaningful separation from placebo in anxiety reduction began as early as four to seven days after initiation of treatment. Somnolence, dizziness, and fatigue were more frequent with quetiapine, and sexual function improved slightly in quetiapine groups. Quetiapine has shown decreased symptom recurrence and improved sleep quality during maintenance treatment. However, quetiapine is not recommended for patients with nonresponding GAD because efficacy is inconsistent [185]. One literature review included three studies that evaluated the use of quetiapine extended-release (XR) as monotherapy for acute GAD treat- ment, one study that evaluated quetiapine XR monotherapy for maintenance treatment of GAD, and five studies that evaluated quetiapine (2 XR, 3 immediate release) as adjunct therapy for acute GAD treatment [273]. Quetiapine displayed both efficacy and tolerability in all monotherapy trials evaluating its use for acute and long-term treatment of GAD. Despite limitations to and heterogeneity among the five adjunct therapy studies, three studies showed that quetiapine resulted in statistically significant changes in the HAM-A scores [273]. Imipramine While TCA use has become disfavored because of tolerability and safety issues, compelling support of imipramine efficacy for GAD came from a landmark study comparing the anxiolytic effects of imipramine, trazodone, diazepam, and placebo in non-depressed patients with GAD. Imipramine resulted in moderate-to-marked improvement between weeks 2 and 8 of therapy in 73% of patients, compared with 69% for trazodone, 66% for diazepam, and 44% for placebo [274]. Vortioxetine Multiple randomized controlled trials involving patients with GAD found clinical improvement and symptom reduction with vortioxetine marginally greater or similar to placebo. With vortioxetine, discontinuation from side effects was modestly greater than placebo, with incidence of sexual dysfunction comparable. Patients with severe baseline GAD did show significantly greater benefit from vortioxetine [186; 275; 276]. Comorbid Major Depression With a few caveats, treatment of GAD is generally the same whether comorbid major depression is present or absent. Use of buspirone and pregabalin is not recommended, while duloxetine has shown efficacy in comorbid anxiety disorder and major depressive disorder [277]. Patients with comorbid major depression and GAD prescribed benzodiazepines, sedating
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