Anxiety Disorders ____________________________________________________________________________
Atypical Antipsychotics Olanzapine, risperidone, aripiprazole, and quetiapine are dopamine D2 receptor antagonists, as with all antipsychotic drugs, but differ from typical (first-generation) antipsychotics by also acting as 5-HT2A receptor antagonists (minimizing development of extrapyramidal effects), 5-HT1A receptor partial agonists (producing anxiolytic effects), and histamine receptor antagonists (further augmenting sedative and anxio- lytic effects) [185]. Quetiapine Quetiapine (Seroquel) is the most-studied atypical in anxiety disorder treatment and has greatest efficacy in GAD. A review of quetiapine in GAD found efficacy and tolerability in all acute and long-term monotherapy trials and statistically sig- nificant changes in anxiety and symptom severity in three of five adjunct therapy studies. Quetiapine is a treatment option for patients unresponsive to first-line therapy, and potential benefits may outweigh risks with appropriate monitoring and side effect management [212]. While the unique efficacy of quetiapine monotherapy in GAD is supported by a Cochrane review, quetiapine was denied FDA approval for GAD, likely due to its tendency for inducing lipid abnormalities, weight gain, and glucose intolerance, and concerns over widespread use in primary care without careful consideration of alterna- tives or monitoring adverse metabolic effects during follow-up
The relative efficacy and early onset of effect of pregabalin versus benzodiazepines may represent a new therapeutic intervention for GAD as mono- and augmentation therapy. Pregabalin has a low risk of drug interactions, lacks withdrawal or physical dependence risk, is associated with minimal adverse effects (e.g., dizziness, weight gain, insomnia), and is safe and well tolerated. A potential role for pregabalin in patients with GAD tapering off long-term benzodiazepine therapy has been suggested [185]. Benzodiazepines have been the only anxiolytic agents that rapidly reduce anxiety, but trials conducted in the last decade have also found this effect with pregabalin. In 89 patients with moderate-to-severe dental anxiety (without anxiety disorder diagnosis) given single-dose pregabalin 150 mg, alprazolam 0.5 mg, or placebo four hours before a dental procedure, the onset of anxiolytic effects began within three to four hours after pregabalin and within two hours after alprazolam. The magnitude of anxiety reduction and tolerability were equiva- lent between pregabalin and alprazolam [206]. Common GAD comorbidities of insomnia, gastrointestinal symptoms, and depression do not impair efficacy and are specifically improved by pregabalin. Pregabalin is generally well tolerated; the adverse event profile includes dizziness, somnolence, incoordination, dry mouth, headache, and weight gain. Risk of withdrawal symptoms is low when tapered over one week [205]. Levetiracetam (Keppra) is an analog of the nootropic drug piracetam and structurally unrelated to other anti-epileptic drugs. It has a novel mechanism of action that involves bind- ing to synaptic vesicle protein SV2A, a protein that modulates neurotransmitter release including GABA. Metabolism has no effect on the cytochrome P450 enzyme system. The most common side effects include somnolence, dizziness, and weakness [207]. In one study, adjunctive levetiracetam (mean: 1,969 mg/day for 9.3 weeks) in highly symptomatic patients with treatment-refractory anxiety disorders led to clinically and statistically significant improvement in illness severity [208]. Further research involving patients with panic disorder with or without agoraphobia given levetiracetam for 12 weeks showed significant improvement in panic attack frequency, anxiety, and global severity ratings. Clinical benefits were apparent by one to two weeks for most patients, and side effects were minimal [209]. Patients with SAD initially administered levetiracetam 250 mg/day and flexibly titrated up to 3,000 mg/day over eight weeks showed significant improvements on measures of social anxiety, overall anxiety, and illness severity [210]. In contrast to the anti-epileptic agents zonisamide and topiramate, levetiracetam has not shown decrements in neuropsychologic performance on tests of cognitive impairment in patients with seizure disorder [211].
[136; 213]. Buspirone
Introduced in 1986, buspirone (BuSpar) was the first anxiety- specific medication unrelated to benzodiazepines or barbitu- rates in pharmacology, effect, and abuse potential. The 5-HT1A receptor partial agonism mediates the anxiolytic effects. Buspirone acts as a weak presynaptic dopamine D2, D3, and D4 receptor antagonist and alpha-1 agonist [214]. Buspirone is primarily used in the treatment of GAD and to augment antidepressants for improved response. Hydroxyzine Hydroxyzine (Vistaril) acts mechanistically as a potent H1 receptor inverse agonist, and as a 5-HT2A, D2, and alpha- 1-adrenergic receptor antagonist. The serotonergic activity of hydroxyzine is more potent than its dopaminergic and adrener- gic activity and likely accounts for its anxiolytic efficacy, as other antihistamines lacking this property have not been effective in the treatment of anxiety [178; 216]. Hydroxyzine efficacy in anxiety disorders is limited to GAD, for which anxiety-reducing efficacy is demonstrated [217; 218; 219]. Benzodiazepines Since their introduction in the early 1960s, benzodiazepines have been the most prescribed drugs for anxiety over the majority of the past half-century. Although SSRI/SNRI agents have replaced benzodiazepines as the top-prescribed anxiolyt- ics, benzodiazepine prescribing remains common. In 2020,
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