SSRIs block the neuronal reuptake of serotonin (5-hydroxytryptamine [5-HT]), a monoamine neurotransmitter, which works in depression symptoms by increasing serotonin activity (Rosenthal, & Burchum, 2021). The use of SSRI in GAD without depression is also effective. Hou et al. (2019) accounted for biological mechanisms of cytokine imbalance that can alter the hypothalamic-pituitary-adrenal axis (HPA) via stimulant effects on the expression and release of corticotropin-releasing hormone, adreno-corticotropic hormone, and cortisol causing the continued release of chronic fear and anxiety. Thus, SSRIs demonstrated an increased pro-inflammatory response to the HPA, correcting this and promoting anxiolytic effects.
Rosenthal and Burchum (2021) presented SSRIs, Paroxetine (Paxil), and Escitalopram (Lexapro) as FDA-approved SSRIs for GAD. Chu and Wadwa (2022) described its availability in oral form, only permitting administration with or without food. Because it does little or no effect on dopamine, norepinephrine, histamine, or acetylcholine — it has fewer side effects of xerostomia, sedation, constipation, urinary retention, and cognitive impairment. This accounts for its being the first-line option, but this group still has risks, especially in accompanying conditions of depression with acute suicide risks. Common side effects are sexual dysfunction, sleep disturbances, weight changes, anxiety, dizziness, headache, and gastrointestinal disturbance. In addition, it affects the cytochrome P450 by inhibiting CYP3D6.
It is also essential to note that Citalopram can cause longer QT intervals, leading to fatal arrhythmias, torsade de pointes. In addition, a life-threatening condition similar to Neuroleptic Malignant Syndrome called Serotonin Syndrome can occur resulting from overdosing on SSRIs or combining medications that increase serotonin levels. Only supportive measures in the ICU, discontinuation of the SSRI, and BZs for agitation can address this, although there is some success on Cyproheptadine.
In pediatrics, it is available in syrup form. Therefore, an algorithmic approach to addressing this age group with GAD is encouraged (Strawn, Geracioti, Rajdev, Clemenza, & Levine, 2018).
In adolescents, the impact of variants in HTR2A and serotonin transporter (SLC6A4) genes and cytochrome P450 2C19 (CYP2C19) phenotypes on response as well as CYP2C19 phenotype on escitalopram pharmacokinetics have been seen to alter drug levels (Strewn et al., 2020).
Rosenthal and Burchum (2021) presented SNRIs, Venlafaxine (Effexor XR), and duloxetine (Cymbalta) as FDA-approved SNRIs for GAD. These drugs block the reuptake of both serotonin (5-HT) and norepinephrine with differing selectivity (Nelson, 2020). Venlafaxine has a 30-fold higher affinity for reuptake of serotonin compared to norepinephrine. Duloxetine has 10-fold selectivity to serotonin. This may be why the FDA has more approved indications among the SNRIs. The dual action of serotonin and norepinephrine appear to present more advantages than SSRI. This means weighing the benefits over the risks as therapy and pseudo-anticholinergic side effects (constipation, dry mouth, and urinary retention) despite the lack of direct effect on cholinergic receptors.
The pharmacokinetics of SNRI is affected by food, but not the degree of absorption. Nausea, being pronounced in Venlafexine, may be relieved by food, although symptom diminishes over time (Rosenthal and Burchum, 2021). Duloxetine is highly protein-bound, with clearance being primarily hepatic. The kidneys excrete the drug unchanged in the urine. This required patients with hepatic and kidney diseases to reduce the dose.
Nelson (2020) cautioned not to abruptly withdraw SNRI, common in Venlafaxine, to prevent chills, dizziness, dysphoria, fatigue, gastrointestinal distress, and myalgias. In addition, regular blood pressure checks for the first two weeks up to six months should be done. Hypertension is related to the potency of norepinephrine effects. Low dosing is observed for this reason.
Like SSRI, combining Venlafaxine with a monoamine oxidase inhibitor (MAOI) can lead to cardiotoxicity.
Busipirone (Buspar), a class of drug from Azapirones, is primarily prescribed for GAD as a second-line agent after SSRIs.
Rosenthal and Burchum (2021) presented buspirone providing anxiolytic efficacy that, in contrast with BZs, does not cause abuse potential and does not heighten CNS depressants. Wilson and Tripp (2021) emphasized that it has little efficacy on acute anxiolytic needs as it typically takes 2 to 4 weeks to peak. However, it is as effective as benzodiazepines for GAD.
The mechanism of action of Buspirone is by being a partial agonist to serotonin 5HT1a receptor and on a weaker degree,
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