Anxiety Disorders ____________________________________________________________________________
Pregabalin Two randomized, placebo- and active comparator-controlled, double-blind studies evaluated the efficacy of pregabalin versus lorazepam for the treatment of GAD. The pregabalin and lorazepam groups experienced greater reductions in Hamilton Anxiety Rating Scale (HAM-A) score by week 4 compared with placebo, with no observed statistically significant differ- ences among the active-treatment groups. Relative to placebo, pregabalin 600 mg significantly reduced psychic and somatic anxiety, while lorazepam significantly reduced somatic anxiety symptoms only. Anxiety reduction with pregabalin and loraz- epam was evident within one week [185]. A four-week trial randomized 451 patients with GAD to alprazolam 1.5 mg/day; pregabalin 300, 450, or 600 mg/day; or placebo. As measured by HAM-A scores, psychic anxiety symptoms were significantly reduced (vs. placebo) with all pregabalin doses and alprazolam by weeks 1 and 4. Somatic anxiety symptoms were significantly reduced by 300 and 600 mg pregabalin, but not by 450 mg pregabalin or 1.5 mg alprazolam (vs. placebo). Pregabalin produced an early onset (≤1 week) of clinically relevant anxiety reduction comparable to alprazolam and anxiety reduction over a broader range of GAD symptoms than alprazolam by four weeks [269]. Data was combined from six placebo-controlled trials of patients with GAD randomized to pregabalin 150 mg, 300–450 mg, or 600 mg; lorazepam 6 mg/day; alprazolam 1.5 mg/day; or placebo. Pregabalin 300–600 mg significantly improved HAM-A psychic and somatic anxiety factor scores, but prega- balin 150 mg showed significance in psychic anxiety only. Of the 14 HAM-A items, significant improvement was shown on 13 with pregabalin 300–450 mg, 10 with pregabalin 600 mg, and 5 with benzodiazepines. A dose-response effect was evident for pregabalin [270]. Along with SSRIs/SNRIs, pregabalin is considered a first-line agent for long-term GAD treatment by the World Federation of Societies of Biological Psychiatry. Head-to-head studies with SSRIs/SNRIs are lacking, but pregabalin augmentation of SSRI/SNRI therapy has been found more effective than SSRI/SNRI alone [205]. Sleep dynamics were evaluated in healthy volunteers random- ized to pregabalin (150 mg three times per day), alprazolam (1 mg three times per day), or placebo for three days. Pregabalin and alprazolam modestly but significantly reduced sleep-onset latency (compared with placebo). Pregabalin significantly increased the proportion of slow-wave sleep to total sleep period, and the slow-wave sleep duration of stage 4 sleep. Alprazolam significantly reduced slow-wave sleep. Rapid eye movement (REM) sleep latency with pregabalin did not differ from placebo and was significantly shorter than with alpra- zolam. Pregabalin and alprazolam similarly reduced the REM sleep proportion to total sleep (vs. placebo), while pregabalin significantly reduced the number of awakenings longer than one minute. Ease in getting to sleep and sleep quality were
Short- and long-term psychodynamic psychotherapy has a degree of efficacy and may be useful when CBT/cognitive therapy is unavailable. Specific psychotherapy targets in GAD include intolerance of uncertainty, poor problem-solving confidence, and positive and negative metacognitive beliefs concerning the value or utility of worry [263]. Adjunctive Approaches Additional modalities can be added to psychotherapy and/ or drug therapy. Exercise is not widely studied in GAD, but available data have shown reduction in anxiety symptoms [264]. Meditation training is an option for patients unable or unwilling to receive psychotherapy [265]. Applied relaxation is effective as adjunctive therapy and uses relaxation techniques that are self-monitoring without the use of in-depth psycho- therapy [266]. In addition, physical activity has been noted as a cost-effective treatment for GAD [121]. Sleep disturbances are highly prevalent in patients with GAD. Sleep hygiene education can be a useful tool in primary care, used with CBT in GAD to ensure the best possible sleep efficiency and quality. Patients can be counseled to improve sleep hygiene by going to bed and waking up at the same time each day, eliminating alcohol after 6 p.m., avoiding caffeine after 3 p.m., and getting out of bed if unable to fall asleep to avoid development of negative associations with the bed environment [267; 268]. Long-term follow-up data from a meta-analysis and randomized controlled trials suggest that benefits of psychologic treatments are maintained one to three years following treatment [120]. PHARMACOTHERAPY In addition to demonstrated efficacy, the selection of initial drug therapy for GAD is based on illness severity (degree of distress and disability), medical and psychiatric comorbidities, substance abuse profile, patient preference, and side effect profile. In general, an SSRI or SNRI is preferred for initial pharmacological treatment. These agents have been shown to be moderately effective in multiple controlled clinical trials, and no single agent has proved more effective than others. The choice of an SNRI or SNRI over an older antidepressant (e.g., TCA) is due more to increased tolerability (side effects and toxicity) than to difference in efficacy [54]. First-Line Options The ADAC and the Anxiety and Depression Association of America (ADAA) have created guidelines for the selection of appropriate pharmacotherapy in the treatment of GAD with differing recommendations regarding first- and second-line medications [120; 261]. The ADAC recommends agomela- tine, pregabalin, venlafaxine XR, duloxetine, escitalopram, paroxetine, or sertraline as first-line options, while the ADAA suggests venlafaxine XR, duloxetine, paroxetine, escitalopram, sertraline, or fluoxetine [120; 261].
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