____________________________________________________________________________ Anxiety Disorders
Moclobemide is a reversible inhibitor of monoamine oxidase type A (RIMA). With reversibility, MAO enzyme detach- ment and/or displacement readily occur, greatly improving safety. Compared to tranylcypromine, it takes eight times the tyramine level (8 mg vs. 63 mg) with moclobemide to induce a 30 mm Hg rise in diastolic blood pressure; dietary and co- medication concerns are greatly reduced. No washout period is required for switching anti-depressants. Moclobemide is safe in overdose, and 20,000 mg has been ingested without fatal- ity. Common side effects include nausea, insomnia, tremor, and lightheadedness. Orthostatic hypotension is uncommon, even in the elderly [176]. Moclobemide lacks the cholinergic and histaminergic side effects of TCAs and the sexual side effects of SSRI/SNRIs. Depressive patients more commonly reported improved libido, erection/ejaculation, and orgasm with moclobemide. Weight gain or lowered seizure threshold are not side effects [177]. Moclobemide was slated for intro- duction in the United States in 1992. It was withdrawn from the application process because SSRI popularity cast doubts on its profit potential. This drug is available in Canada and throughout Europe and Asia [176; 178]. MAOIs and RIMAs are effective for panic disorder and SAD and are thought by some to be superior options for severe, treatment-resistant anxiety disorders. As noted, MAOIs have a substantial side effect profile and impose the greatest safety burden of all antidepressants. Therefore, they are usually reserved as the last treatment option after other drug thera- pies have failed to achieve remission [179]. Clinicians do not routinely prescribe MAOIs for anxiety disorders, although they are probably not considered often enough in treatment- resistant patients [136]. SSRIs SSRIs are considered first-line therapy for GAD and panic disorder [121; 172]. SSRI mechanism is thought to involve serotonin transporter (SERT) inhibition at the presynaptic axon terminal of 5-HT neurons. SERT inhibition also occurs at the somatodendritic end of the neuron, where the increase in 5-HT causes 5-HT1A autoreceptors to downregulate, desen- sitize, and over time lose the ability to inhibit 5-HT release. The resultant increase in synaptic 5-HT level mediates the therapeutic action. SSRIs were termed “selective” because, unlike TCAs, they were believed to have little-to-no interac- tion with non-serotonin receptors and transporters [136; 180]. It is now recognized that SSRIs differ in pharmacologic effect, including activity beyond SERT inhibition [179; 180]: • Fluoxetine: Antagonist at 5-HT2C receptors, which enhances norepinephrine and dopamine release. Therapeutic effects may emerge more slowly than other SSRIs. • Sertraline (Zoloft): A weak dopamine transporter inhibitor, sigma-1 receptor activity. Along with fluoxetine, increases cortex monoamine levels to possibly explain patient reports of improved energy,
motivation, and concentration. • Paroxetine (Paxil): A weak norepinephrine transporter inhibitor, which contributes to antidepressant effects. Muscarinic cholinergic receptor activity may underlie some sedative and anxiolytic effects. • Fluvoxamine (Luvox): Along with sertraline, has sigma-1 receptor activity that possibly contributes to the anxiolytic effects of both agents. • Citalopram (Celexa): Mild antihistamine properties not observed with escitalopram. • Escitalopram (Lexapro): Is considered the only SSRI without pharmacologic activity beyond SERT inhibition. The atypical SSRIs vilazodone (Viibryd) and vortioxetine (Brintellix) display expanded serotonergic and other monoami- nergic activity beyond those of standard SSRIs. Vilazodone and vortioxetine are likely to be treatment options for patients who do not respond to or cannot tolerate typical SSRIs/SNRIs. Side effects associated with SSRI treatment include gastrointes- tinal upset (nausea, vomiting, diarrhea), activation/insomnia (restlessness, agitation, anxiety, akathisia, sleep disturbances), sexual dysfunction (loss of erectile or ejaculatory function in men, loss of libido and anorgasmia in both sexes), headache, fatigue, and weight gain. Many side effects dissipate over time. Sertraline is particularly associated with diarrhea, and parox- etine with weight gain. Discontinuation syndrome from par- oxetine is more severe and protracted than other SSRIs [181]. To avoid relapse, medication should be continued for at least 12 months after symptom improvement before tapering [121]. Vilazodone Approved by the FDA in 2011, vilazodone primarily acts as a serotonin reuptake inhibitor and 5-HT1A receptor partial agonist, with modest action as a dopamine and norepinephrine reuptake inhibitor, with 5-HT4 receptor activity [173]. This profile resembles the combination of SSRI and buspirone, and GAD efficacy of both agents suggests a potential role for vilazodone in anxiety disorder treatment. Two eight-week randomized controlled trials of vilazodone treatment of GAD have been published. One using a flexible-dose design found nominal clinical improvement with vilazodone compared with placebo, while the other study using a fixed-dose design found statistically significant reduction in anxiety scores (vs. placebo) with vilazodone 40 mg but not 20 mg [182; 183]. Vilazodone does not appear to improve efficacy over drugs already in use, but it does have advantages of earlier onset of clinical response (beginning by two weeks) and little evidence of sexual dysfunc- tion or weight gain. Vilazodone should be taken with food, which increases its absorption and bioavailability by 72% [184]. Vortioxetine Approved by the FDA in 2013, vortioxetine is a multimodal antidepressant and potential anxiolytic with activity as an antagonist in 5-HT1D/3A/7 receptors, a 5-HT1A receptor
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