Generalized anxiety disorder (GAD) is the most prevalent anxiety disorder seen in primary care, affecting about 4%-7% of US adults (DeMartini et al., 2019). This condition is linked to a lower health-related quality of life and reduced global life satisfaction. GAD affects patients physically and psychologically, negatively impacting their relationships, work, and other commitments. It is, therefore, crucial for advanced nurse practitioners to correctly diagnose and, importantly, treat GAD to prevent the complications associated with GAD and ensure the patient’s overall well-being. When considering pharmacokinetic (PK) and pharmacodynamic (PD) factors for a patient, it is important to note that factors like genetics (including pharmacogenetics), gender, age, behavior, ethnicity, and pathophysiological changes due to disease can significantly affect the drug’s efficacy and safety as they influence how a patient metabolizes and responds to the medication.
Last year, my team and I saw a 67-year-old female of Asian descent with generalized anxiety disorder. She reported experiencing persistent worry, restlessness, difficulty concentrating, and sleep disturbances for the past eight months. She has been treated for GAD but has had several relapses due to non-compliance with her medications, as she said they were not producing the “relaxing effect” she was hoping to achieve. She also cited a significant alcohol use that she says helps her cope with anxiety. She mentioned that she had been on Zoloft (sertraline) with no significant side effects.
This patient’s age, ethnicity, and concurrent alcohol use have a substantial influence on PK and PD. Elderly patients are prone to alterations in drug metabolism and excretion due to age-related physiological changes. Additionally, her descent as an Asian American may impact drug metabolism, specifically regarding cytochrome P450 enzymes (Guttman et al., 2019). The patient’s comorbid alcohol use further complicates this situation, given alcohol’s effects on liver function and, hence, drug metabolism. These factors need to be carefully considered because they affect drug efficacy and toxicity.
The patient had been on sertraline, a selective serotonin reuptake inhibitor (SSRI). This drug works to reduce anxiety symptoms; however, in a non-compliant case with concomitant alcohol use, suboptimal or even unpredictable responses may be witnessed, possibly due to fluctuating enzyme activity and altered serotonin pathways (Garakani et al., 2020).
Compared to the general population, several factors alter her PK and PD, especially her age, ethnicity, and alcohol use. This patient has an advanced age, which means she mostly has reduced hepatic and renal function that can slow down drug metabolism and excretion. Nevertheless, studies indicate that anxiolytics such as SSRIs and SNRIs are generally well tolerated in the elderly population (Fagan & Baldwin, 2023). In turn, this can lead to higher systemic drug concentrations. On the other hand, her ethnicity is a crucial consideration as there are genetic polymorphisms common in Asian populations that may affect drug metabolism enzymes, altering drug efficacy and side-effect profiles (Guttman et al., 2019). Moreover, chronic alcohol consumption can induce or inhibit certain cytochrome P450 enzymes, affecting drug metabolism and possibly inducing serotonin syndrome. Suzuki and Otani (2019) suggest that alcohol’s PD interaction with SSRIs can result in reduced clearance of extracellular serotonin in the brain, leading to serotonin syndrome.
There are various drugs with FDA approval for treating GAD, including selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), benzodiazepines, and buspirone (DeGeorge et al., 2022). SSRIs like sertraline, paroxetine, and escitalopram and SNRIs like venlafaxine and duloxetine are generally first-line due to efficacy and safety profile (DeMartini et al., 2019). Common side effects for SSRIs and SNRIs include gastrointestinal abnormalities like diarrhea and nausea, weight gain, insomnia, sweating, and dizziness. Venlafaxine is associated with increased blood pressure and should be avoided or used judiciously in hypertensive patients (Fagan & Baldwin, 2023). Benzodiazepines such as alprazolam and diazepam are recommended for quick relief of anxiety symptoms but are not ideal for long-term use, especially in older adults due to risks of dependence, cognitive impairment, and interaction with alcohol (DeGeorge et al., 2022). Buspirone, an azapirone, is not associated with dependence or sedation and it is beneficial for patients with history of substance abuse but may be less effective than other options. Buspirone is mostly used for augmentation of the other treatment options (DeMartini et al., 2019).
In this case, SSRIs or SNRIs are the most effective treatment options given their documented safety and efficacy profile in the elderly population, nevertheless, it is crucial to ensure careful monitoring due to altered metabolism (DeMartini et al., 2019). Benzodiazepines have a high risk of dependency and interaction with alcohol, making them less favorable for this patient. Buspirone, due to its non-addictive nature, could be safer but may require dose adjustments for efficacy.
Given the patient’s age, ethnicity, and alcohol use, my team and I careful balanced between efficacy and safety. Since the patient had a suboptimal response to sertraline, we tapered her off the medication and titrated her on escitalopram 10mg PO QD . DeMartini says that inadequate response to one SSRI or SNRI does not predict the failure for a second drug in the same class in treating GAD. Thus, healthcare providers should consider changing to another agent in these classes before trying another medications. We also initiated her on buspirone 15 mg per day PO BID as an adjunct, given the patient’s history of suboptimal response. Moreover, we referred her for cognitive behavioral therapy (CBT) and connected her to a social-worker to ensure her timely follow-up.
In conclusion, this case called for prioritizing medications with a lower risk of side effects and interactions, considering the patient’s age, ethnicity, and concurrent alcohol use. SSRIs and SNRIs are preferred, but their dosing should be carefully adjusted in case of any adverse reactions. For patients with suboptimal responses, switching to another agent within the same first line class and adding buspirone as an adjunct is recommended. It is crucial for advanced nurse practitioners to understand the various factors that affect a patient’s PK and PD as well as the need for regular follow-up and monitoring for both efficacy and side effects to optimize patient treatment outcomes.
References
DeGeorge, K. C., Grover, M., & Streeter, G. S. (2022). Generalized Anxiety Disorder and Panic Disorder in Adults. American family physician, 106(2), 157–164. https://pubmed.ncbi.nlm.nih.gov/35977134/
DeMartini, J., Patel, G., & Fancher, T. L. (2019). Generalized Anxiety Disorder. Annals of internal medicine, 170(7), ITC49–ITC64. https://doi.org/10.7326/AITC201904020
Fagan, H. A., & Baldwin, D. S. (2023). Pharmacological Treatment of Generalized Anxiety Disorder: Current Practice and Future Directions. Expert review of neurotherapeutics, 23(6), 535–548. https://doi.org/10.1080/14737175.2023.2211767
Garakani, A., Murrough, J. W., Freire, R. C., Thom, R. P., Larkin, K., Buono, F. D., & Iosifescu, D. V. (2020). Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options. Frontiers in psychiatry, 11, 595584. https://doi.org/10.3389/fpsyt.2020.595584
Guttman, Y., Nudel, A., & Kerem, Z. (2019). Polymorphism in Cytochrome P450 3A4 Is Ethnicity Related. Frontiers in genetics, 10, 224. https://doi.org/10.3389/fgene.2019.00224
Suzuki, A., & Otani, K. (2019). Serotonin Syndrome After an Alcohol Intake in a Patient Treated with Escitalopram and Clomipramine. Clinical neuropharmacology, 42(3), 103–104. https://doi.org/10.1097/WNF.0000000000000331
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