Anxiety Disorders ____________________________________________________________________________
agonist, 5-HT1B partial agonist, serotonin transporter inhibi- tor, and weak norepinephrine transporter inhibitor. This mul- tiple receptor activity modulates serotonergic, noradrenergic, dopaminergic, and histaminic systems to produce clinical effect [185]. Results from four randomized controlled trials suggest vortioxetine may have potential efficacy in the treatment of severe GAD, but effects in patients with more moderate GAD were minimally improved compared with placebo. Nausea, the most common side effect, was dose dependent [186]. Sexual dysfunction rates were similar to placebo across the 5–20 mg/ day dose range, and vortioxetine can be taken without regard for meals [187]. SNRIs Venlafaxine, the first SNRI approved in the United States, was introduced as immediate release (IR) in 1993 and extended release (XR) in 1997. This was followed by the introduction of duloxetine in 2004, desvenlafaxine in 2008, milnacipran in 2009, and levomilnacipran in 2013. SNRIs increase synaptic concentrations of 5-HT and norepinephrine by blocking reup- take of these neurotransmitters by their respective transport- ers. SNRIs lack significant affinity for adrenergic, cholinergic, histaminergic, opioid, glutamate, or GABA receptors and transporters [136; 188]. SNRIs differ in proportion of 5-HT/norepinephrine reuptake inhibition. Venlafaxine is the most serotonergic SNRI, followed by duloxetine and desvenlafaxine. Milnacipran shows relatively equal influence on 5-HT and norepinephrine reuptake inhibi- tion, and levomilnacipran is a greater norepinephrine than 5-HT reuptake inhibitor. Such differences suggest that SNRIs are dissimilar from one another. Venlafaxine and duloxetine exhibit dose-related sequential effects on reuptake inhibition, while desvenlafaxine, milnacipran, and levomilnacipran act simultaneously on 5-HT and norepinephrine reuptake inhibi- tion with proportionality intact with dose escalation [189]. Side effects from SNRIs overlap with SSRIs but can also include adrenergic effects of increased pulse rate and blood pressure, dilated pupils, dry mouth, and excessive sweating. Venlafaxine has a greater incidence of nausea and vomiting than SSRIs and may be associated with an increased risk for cardiovascular events [181]. Sexual side effects associated with SNRIs include decreased response to sexual stimuli, loss of interest in sex, anorgasmia, and much less frequently, genital anesthesia. Discontinuation syndrome from venlafaxine is markedly worse than other SNRIs and SSRIs [188]. Relative to SSRIs and TCAs, the SNRIs have relatively short half-lives, and few or no active metabolites for simpler overall pharmacology. In contrast to venlafaxine and duloxetine, des- venlafaxine, milnacipran, and levomilnacipran largely bypass the hepatic cytochrome P450 isoenzyme system, making drug interactions less likely. Of the five available SNRIs, only venla- faxine has an active metabolite (desvenlafaxine). Dosing with venlafaxine IR and milnacipran is twice daily; the remaining SNRIs are dosed once daily [184].
The impairing effects from synaptic plasticity induced by con- ditioned psychologic stress were found reversed by SNRI treat- ment. Long-term venlafaxine and milnacipran use suppressed long-term potentiation in hippocampal CA1 via 5-HT1A receptor and a1-adrenoceptor activity, contributing to reversal in synaptic plasticity-related impairment induced by condi- tioned fear stress. Increased responsiveness of a1-adrenergic and dopaminergic D3 systems, decreased responsiveness of 5-HT2 systems, and development of adaptive changes occurred despite lack of SNRI affinity for these neurotransmitter recep- tors [188; 190; 191]. Venlafaxine Venlafaxine IR was introduced in 1993 but from the outset was plagued with side effects, leading to the 1997 introduction of venlafaxine XR. The XR formulation has become a widely prescribed agent with established efficacy in several anxiety disorders. In addition to the dose-related reuptake inhibition of 5-HT and norepinephrine mentioned, weak dopamine reuptake inhibition may appear at dosages greater than 300 mg/day. This sequential activity is mirrored by the initial pre- dominant serotonergic side effects (headache, nausea, fatigue, sexual dysfunction), with noradrenergic effects at higher doses (activation effects, dry mouth, night sweats) [184]. Desvenlafaxine Desvenlafaxine (Pristiq) shows a 10-fold higher selectivity for serotonin over norepinephrine reuptake inhibition at 50 mg/day, with selectivity unchanged by dose increase to 100 mg/day [184]. A primary advantage of desvenlafaxine over venlafaxine involves metabolic pathways and drug interac- tions. Venlafaxine is extensively metabolized by the hepatic CYP2D6 isoenzyme to desvenlafaxine, while desvenlafaxine is metabolized primarily via glucuronidation and minimally through CYP3A4 [178]. Venlafaxine, but not desvenlafaxine, clearance in patients with polymorphic 2D6 can be accelerated or delayed, resulting in non-efficacy or greater side effects/ toxicity. This makes desvenlafaxine preferable to venlafaxine for these patients. The desvenlafaxine metabolic pathway also eliminates adverse drug interactions with 2D6 substrates that require consideration with venlafaxine prescribing [188; 192]. However, few trials have evaluated desvenlafaxine in anxiety disorder treatment [184]. A comparison of the efficacy and safety of desvenlafaxine and escitalopram for treatment of depression with anxiety found that both drugs reported simi- lar efficacy, but escitalopram was better tolerated with fewer adverse effects [193]. Duloxetine Duloxetine (Cymbalta) has greater potency in 5-HT reuptake inhibition than fluoxetine. It has an elimination half-life of roughly 12.5 hours, steady-state is usually achieved after three days, and metabolism occurs mainly through hepatic CYP 2D6 and 1A2 [178; 194]. Common adverse effects of duloxetine include nausea, headache, and weight loss. Certain adverse effects, including xerostomia, drowsiness, and fatigue, are dose related [178].
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