NURS 6521 Discussion: Comparing and Contrasting Pharmacologic Options for the Treatment of Generalized Anxiety Disorder

Generalized Anxiety Disorder and Pharmacotherapies

Life situations typically face us with a level of anxiety, and we cope despite the stress. Our recent experience with the Covid19 pandemic exposed us to fear, uncertainty, and some loss of control. We remembered being in a long Costco line and hoarding food and toilet paper, which gave us some sense of control. As the pandemic worsened, we found ourselves more anxious at work from call lights and code blues, and the added chaos at home from children we needed to home-school. No matter what we did to survive those trying moments, indeed, we experienced temporary anxiety. This pandemic left us with some unwanted memories, to an extent. In time, our anxieties resolved because we coped. Unfortunately, for some of us, the similar anxiety did not leave to the point of becoming pathological.

Rosenthal and Burchum (2021) described GAD as a chronic condition manifested by uncontrollable worrying, and a diagnosis is made if it persists for six months and more. It can exist with another psychiatric disorder, commonly depression. In addition, physical symptoms of restlessness, easy fatiguability, difficulty concentrating, irritability, muscle tension, or sleep disturbance affect the individual with GAD (Terlizzi & Villaroel, 2020). It is more common among women and highest among 18-29 years, decreasing with age. De Martini, Patel, and Fancher (2019) reported that most patients could be diagnosed and managed by primary care providers; otherwise, this can increase the risk for suicide and cardiovascular-related events and death.

Cassano, Rossi, and Pini (2022) emphasized the revolutionized approach to the treatment of a spectrum of anxiety disorders, generalized anxiety disorder (GAD), along with obsessive-compulsive disorder (OCD), panic disorder (PD), phobias, and post-traumatic disorder PTSD). This meant replacing the chronic use of benzodiazepines (BZs). For this reason—focusing on GAD management meant pharmacotherapeutic strategies with serotonergic reuptake inhibitors (SRIs) through selective serotonergic-reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs); and a nonbenzodiazepine-nonbarbiturate drug (azapirones).

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Selective-Serotonin Reuptake Inhibitors (SSRIs)

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).

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

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.

Azapirones

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, with serotonin 5HT2 receptor affecting the brain’s anxiety and fear circuitry, and as a weak antagonist on dopamine D2 autoreceptors. There is no GABA effect.

Absorption is reduced with food intake, while concomitant food intake also reduces the drug’s first-pass metabolism, increasing bioavailability. Therefore, providers may instruct patients to take food or on an empty stomach as long as the dosage pattern is consistent. There is a known fourteenfold increase in hepatic impairment due to its effect on cytochrome P450 and twofold among those with renal insufficiency.

The most common side effect among 10% of the patients is dizziness. A sidenote is a relief from sexual adverse effects among SSRIs if co-administered. In addition, patients should be observed for symptoms of CNS depression, akathisia from central dopamine antagonism, and serotonin syndrome.

Personal Plan of Care

BZs, medications used for GAD are alprazolam, chlordiazepoxide, and lorazepam — on acute presentation of GAD may still benefit the patient and are recommended (Rosanthal and Burchum, 2021). Warning the patients of side effects and safety risks from sedation and psychomotor slowing should be added to the instructions. History taking on substance and alcohol abuse should be considered to assess abuse potential. Monitoring the patient’s need for more frequent refills should be noted. This way, including a multi-disciplinary approach with cognitive behavior therapy with psychotherapists and social workers, should be considered.

The knowledge of the pharmacological differences of various GAD therapies is necessary for appropriate decisions on the relevance and niche depending on the situation and conditions of the patient. Understanding the possible and more serious side effects based on the drug choices will be included in the instructions, surveillance, diet (avoidance of grapefruit and alcohol), and periodic follow-up appointments. Verifying level of understanding of patients and families should also be added.

If suicide risk is noted, involving the team and family is imperative (Hou et al., 2019). In addition, instructions on the 2 to 4 weeks of initiation of therapy should alert for safety and rid the patient of an environment where he can carry out his dark plan.

Conclusion

As benzodiazepines become notorious for dependency and abuse, the pharmacotherapies above offer a promising approach to managing GAD alongside cognitive behavior therapy. These drug therapies are helpful; however, the risks of side effects should be considered and prevented.

GAD is a concerning psychiatric condition as it is a chronic and unremitting disorder. We witnessed how these patients have become frequent flyers in our health practice, presenting recurrent problems and somatic symptoms. Therefore, GAD pharmacotherapies with reinforcement for healthy coping mechanisms are essential and should prolong the intervals of remissions if we cannot wholly assist in overcoming this in our future nurse practice.

References:

Cassano, G. B., Rossi, N. B., & Pini, S. (2022). Psychopharmacology of anxiety disorders. Dialogues in clinical neuroscience.

Chu,A.,& Wadhwa,R. [Updated 2022 Jan 11]. Selective Serotonin Reuptake Inhibitors. Retrieved from: https://www.ncbi.nlm.nih.gov/books/NBK554406/

DeMartini, J., Patel, G., & Fancher, T. L. (2019). Generalized anxiety disorder. Annals of internal medicine, 170(7), ITC49-ITC64.

Hou, R., Ye, G., Liu, Y., Chen, X., Pan, M., Zhu, F., & Tang, Z. (2019). Effects of SSRIs on peripheral inflammatory cytokines in patients with Generalized Anxiety Disorder. Brain, behavior, and immunity, 81, 105-110.

Nelson, C. (2020). Serotonin-norepinephrine reuptake inhibitors (SNRIs): pharmacology, administration, and side effects.

Rosenthal, L., & Burchum, J. (2021). Lehne’s Pharmacotherapeutics for Advanced Practice Nurses and Physician Assistants-E-Book. Elsevier Health Sciences, 215-218, 243-247.

Strawn, J. R., Geracioti, L., Rajdev, N., Clemenza, K., & Levine, A. (2018). Pharmacotherapy for generalized anxiety disorder in adult and pediatric patients: an evidence-based treatment review. Expert opinion on pharmacotherapy, 19(10), 1057-1070.

Strawn, J. R., Mills, J. A., Schroeder, H., Mossman, S. A., Varney, S. T., Ramsey, L. B., … & DelBello, M. P. (2020). Escitalopram in adolescents with generalized anxiety disorder: a double-blind, randomized, placebo-controlled study. The Journal of clinical psychiatry, 81(5), 6584.

Terlizzi, E. P., & Villarroel, M. A. (2020). Symptoms of generalized anxiety disorder among adults: United States, 2019 (p. 8). US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics.

Wilson, T.,& Tripp J. [Updated 2021, Aug 12].  Buspirone. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK531477/