exercise caution when considering pregabalin therapy in patients with a history of substance use disorder, particularly opioid use disorder. If treatment with pregabalin is discontinued, provide patients with a taper schedule to avoid withdrawal. Like pregabalin, gabapentin’s mechanism of action is modulation of neurotransmitter release via activity at voltage-gated calcium channels. Despite a lack of evidence supporting this use, it may be prescribed off-label for treating anxiety disorders. One small place-controlled trial found gabapentin effective for treating SAD (Garakani et al., 2020). Another small study evaluating its use in PD found it superior to placebo, but only for treating PD patients with severe panic symptoms. Adverse effects with gabapentin include constipation, dry mouth, edema, sedation, and weight gain (Garakani et al., 2020). Like pregabalin, it carries risk for dependence and abuse but is not considered a scheduled substance by the DEA. However, certain states in the United States have classified gabapentin as a controlled substance. Exercise caution when considering gabapentin use in a patient with a substance use disorder. Because of the risk for withdrawal upon discontinuation, counsel patients on the importance of tapering the dose over time. Chlordiazepoxide (Librium) is a long-acting benzodiazepine with FDA indications for, among other conditions, managing anxiety disorders and short-term relief of anxiety symptoms. It may be useful as an augmenting agent used alongside a SSRI or SNRI for managing anxiety disorders (Ahwazi & Abdijadid, 2021). Common adverse effects include ataxia, confusion, dizziness, fatigue, forgetfulness, slurred speech, sedation, and weakness. More serious ADRs can include mania, hypotension, blood dyscrasias, hepatic dysfunction, and renal dysfunction. Respiratory depression is also possible when chlordiazepoxide is taken with other CNS depressants at large doses (Ahwazi & Abdijadid, 2021). See Table 6. Several new and emerging therapies with potential for treating anxiety disorders are discussed in more detail in the following sections. Cannabinoids Technically, cannabinoids are neither new nor emerging; the cannabis plant has been consumed by humans for numerous purposes, both recreational and medicinal, for thousands of years (Bridgeman & Abazia, 2017). However, the Controlled Substances Act of 1970 moved cannabis into Schedule I category, which is reserved for substances with “no accepted medicinal use, high abuse potential, concerns for dependence, and lack of accepted safety for use under medical supervision.” (Bridgeman & Abazia, 2017). This created significant hurdles for scientific and academic research into potential uses of cannabis, including for treatment of anxiety disorders. Recent trends in legalization and liberalization of cannabis prohibition laws have led to a resurgence in academic research into potential medicinal uses for cannabis. Cannabinoids refer to naturally occurring compounds in the Cannabis sativa plant. Well-known cannabinoids include tetrahydrocannabinol (THC) and cannabidiol (CBD), but more than 100 cannabinoids have been identified, many of which are not well understood (Bridgeman & Abazia, 2017). Currently, scientific literature does not support the use of cannabinoids for treating anxiety disorders or for improving anxiety symptoms (Garakani et al., 2020). There is also a lack of evidence backing the safety of cannabinoids and cannabis use in persons with anxiety disorders (Garakani et al., 2020). Research on cannabis for use in managing anxiety disorders is hampered by numerous limitations, including small sample sizes, lack of active controls, and a lack of research into efficacy in persons with primary anxiety disorders rather than anxiety secondary to another condition such as multiple sclerosis (Garakani et al., 2020).
Table 6: FDA-Approved and Off-Label Use of GABAergic Medications for Treating Anxiety Disorders
FDA- approved Anxiety Disorders
Off-Label Uses
Therapeutic Dose Range
Medication
Alprazolam (Xanax)
GAD, PD Anxiety
1-4 mg/day
Chlordiazepoxide (Librium)
Anxiety GAD, PD, SAD
20-100 mg/day
Clonazepam (Klonopin)
PD
Anxiety, GAD, PD, SAD GAD, PD, SAD
1-2 mg/day
Gabapentin (Neurontin) Lorazepam (Ativan)
None
600-2,400 mg/ day
Anxiety GAD, PD, SAD
2-6 mg/day
Oxazepam Anxiety GAD, PD, SAD
30-60 mg/day
Pregabalin (Lyrica)
None
GAD, SAD 150-600 mg/ day
NEW AND EMERGING THERAPIES
Cannabinoids act on cannabinoid type 1 (CB1) receptors, serotonergic type 1A (5HT1A) receptors, and the transient receptor potential vanilloid type 1 (TRPV1) receptors. CB1 receptor agonists exhibit an anxiolytic effect at low doses, with increasing anxiogenic properties as the dose increases. This is because low-dose CB1 receptor activation has inhibitory neuronal effects; as doses increase, activation at TRPV1 receptors is increased, which has an anxiogenic effect (Garakani et al., 2020). CBD is currently the most-studied cannabinoid with respect to treating and managing anxiety disorders. One study found a single 600-mg dose administered prior to a public speaking test was effective for improving anxiety symptoms in persons with SAD (Garakani et al., 2020). A randomized, double-blind, placebo-controlled trial (NCT03549819) is currently underway and is evaluating the effectiveness of CBD oil capsules versus placebo for treating GAD, SAD, PD, and agoraphobia in adults (Garakani et al., 2020). In contrast to CBD, THC is known to have anxiogenic effects (Garakani et al., 2020). Low doses can have an anxiolytic effect, but THC is known to induce anxiety and panic attacks at higher doses (Garakani et al., 2020). While more research is needed, current evidence suggests that THC and THC/CBD combinations are ineffective for managing anxiety disorders and may be harmful in persons with these conditions (Garakani et al., 2020). Ketamine Ketamine is a glutamate modulator, originally developed as an anesthetic. Recent randomized controlled trials have shown efficacy for treatment-resistant depression (TRD). An intranasal form of S-ketamine, Spravato, was approved by the FDA in 2019 for treating adults with MDD specifically classified as TRD (Garakani, et al., 2020). Spravato is a Schedule III controlled substance.
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