Anxiety Disorders ____________________________________________________________________________
Brain imaging cannabidiol trials in patients with GAD or SAD consistently showed changes in functional activity in limbic and paralimbic cortical areas implicated in anxiety pathophysiology, with effects in the left para-hippocampal gyrus, the hippocampus, and the right posterior cingulate gyrus. Cannabidiol was found safe and tolerable, with few side effects and without major side effects during acute treat- ment. Cannabidiol administered chronically in oral doses of 10–1,280 mg/day to healthy volunteers and patients with schizophrenia, bipolar affective disorder, Parkinson disease, or Huntington disease did not find significant side effects or induction of any new neurologic, psychiatric, or general clinical conditions [136; 327]. Overall, evidence indicates cannabidiol has considerable potential as a treatment for several anxiety disorders, with further study of chronic and therapeutic effects in relevant clinical populations needed [325; 328]. Etifoxine Etifoxine (also known as etafenoxine) is a non-benzodiazepine anxiolytic and anticonvulsant not yet approved in the United States. Clinical effects are mediated by GABA-A α 2 receptors, similar to benzodiazepines, and etifoxine appears to produce anxiolytic effects directly by binding to β 2 or β 3 subunits of the GABA-A receptor complex. The effects of etifoxine are not completely reversed by the benzodiazepine antagonist flumaze- nil. Etifoxine also stimulates neurosteroid production, which contributes to anxiolytic and neuroprotective effects. Several randomized controlled trials comparing etifoxine to lorazepam found vigilance, psychomotor performance, and free recall significantly impaired by lorazepam but not etifoxine. Superior anxiolytic effect and memory recall were noted with etifoxine, with fewer withdrawal symptoms than with lorazepam. Etifox- ine appears promising as a non-benzodiazepine anxiolytic agent that lacks many shortcomings with benzodiazepines and SSRIs, although acute liver toxicity has been reported [329; 330]. Asenapine Asenapine is a newer atypical antipsychotic drug. Its domi- nant mechanism of action is mediated through 5HT2A and D2 receptor antagonism and also by antagonism of 5HT2B, 5HT2C, 5HT6, and 5HT7 serotoninergic; α 1A, α 2A, α 2B and α 2C adrenergic; and D3/D4 dopaminergic receptors [178]. Clinical efficacy in anxiety and mood disorders is predicted by its serotoninergic profile. This agent lacks affinity for mus- carinic receptors and induces fewer anticholinergic side effects than other second-generation antipsychotics [331]. Asenapine is FDA-approved for schizophrenia and bipolar disorder; its use for anxiety disorders is off-label [178]. Tandospirone Closely related to buspirone, tandospirone (also known as metanopirone) is a 5-HT1A receptor partial agonist used in China and Japan. Its efficacy was compared to sertraline in an eight-week randomized controlled trial in adolescents with SAD. Both drugs significantly improved anxiety scores from baseline, showed similar overall response and anxiety symptom-
specific response rates (≥50% reduction), and resulted in signifi- cant and comparable improvements in social phobia symptoms. Tandospirone appeared non-inferior to sertraline treatment of SAD in adolescents. The drug is not FDA-approved [332].
COMPLEMENTARY/ALTERNATIVE THERAPIES HERBAL PRODUCTS AND SUPPLEMENTS Myo-Inositol
Myo-inositol is a glucose isomer and essential component of the phosphatidylinositol second messenger system critically linked to several CNS receptor-signaling systems [333]. Myo-inositol anxiolytic and antidepressant activity is mediated by a sero- toninergic 5-HT2A/5-HT2C receptor-signaling pathway [334]. Several randomized controlled trials have been conducted using placebo or active controls. In 21 patients with panic disorder with or without agoraphobia given inositol 12 g/day or placebo for four weeks, significant decreases were found in the frequency and severity of panic attacks and agorapho- bia severity with inositol relative to placebo [335]. Another randomized controlled trial compared myo-inositol 18 g/day with fluvoxamine 150 mg/day in patients with panic disorder with or without agoraphobia. Both drugs led to significant but comparable improvements in anxiety symptoms/severity, agoraphobia symptoms/severity, and global impression. In the first month, reduction in the number of panic attacks per week was significantly greater with inositol than fluvoxamine (4.0 vs. 2.4). Nausea and fatigue were significantly more common with fluvoxamine [336]. Other randomized controlled trials found that myo-inositol 12 g/day in 28 patients with major depression significantly reduced Hamilton Depression Rating Scale scores (vs. placebo) after four weeks; and 18 g/day given to patients with OCD for six weeks led to significant reductions in OCD symptom scores (vs. placebo) [335]. A review of supplements and herbal thera- pies with purported anxiolytic efficacy concluded myo-inositol was one of very few with demonstrated effectiveness [337]. The published research needs larger trials but is intriguing in light of a study in which patients with severe depression receiving treatment with rTMS showed significantly elevated prefrontal cortex myo-inositol levels, and this elevation correlated with extent of clinical improvement [338]. A meta-analysis of inosi- tol for depression and anxiety disorders found that the agent may be particularly beneficial for treatment of depression [339]. The effective dose is 12–18 g per day, and inositol is free of side effects other than loose stools and drowsiness [335]. A drawback is the large amount required for therapeutic benefit, necessary to compensate for poor blood-brain barrier penetra- tion. An Italian pharmaceutical company has developed a more concentrated myo-inositol formulation, with dose comparabil- ity to standard myo-inositol at 25% the dose level [338].
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