Evidence-Based Reviews

Generalized anxiety disorder: 8 studies of biological interventions

Current Psychiatry. 2022 July;21(7):10-12,20,22-27 | doi: 10.12788/cp.0264

Sy Atezaz Saeed, MD, MS

Daniel John Majarwitz, MD

FIRST OF 2 PARTS

Evidence suggests several medications and rTMS may offer benefit.

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References

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2. Walkup JT, Albano AM, Piacentini J, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med. 2008;359(26):2753-2766. doi:10.1056/NEJMoa0804633
3. Strawn JR, Sakolsky DJ, Rynn MA. Psychopharmacologic treatment of children and adolescents with anxiety disorders. Child Adolesc Psychiatr Clin N Am. 2012;21(3):527-539. doi:10.1016/j.chc.2012.05.003
4. Beidel DC, Turner SM, Sallee FR, et al. SET-C versus fluoxetine in the treatment of childhood social phobia. J Am Acad Child Adolesc Psychiatry. 2007;46(12):1622-1632. doi:10.1097/chi.0b013e318154bb57
5. Wetherell JL, Petkus AJ, White KS, et al. Antidepressant medication augmented with cognitive-behavioral therapy for generalized anxiety disorder in older adults. Am J Psychiatry. 2013;170(7):782-789. doi:10.1176/app.ajp.2013.12081104
6. Stein DJ. Evidence-based pharmacotherapy of generalised anxiety disorder: focus on agomelatine. Adv Ther. 2021;38(Suppl 2):52-60. doi:10.1007/s12325-021-01860-1
7. Andrews G, Bell C, Boyce P, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of panic disorder, social anxiety disorder and generalised anxiety disorder. Aust N Z J Psychiatry. 2018;52(12):1109-1172. doi:10.1177/0004867418799453
8. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol. 2014;28(5):403-439. doi:10.1177/0269881114525674
9. Bandelow B, Sher L, Bunevicius R, et al. Guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder and posttraumatic stress disorder in primary care. Int J Psychiatry Clin Pract. 2012;16(2):77-84. doi:10.3109/13651501.2012.667114
10. Katzman MA, Bleau P, Blier P, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14 Suppl 1(Suppl 1):S1. doi:10.1186/1471-244X-14-S1-S1
11. Generalised anxiety disorder and panic disorder in adults: management. National Institute for Health and Care Excellence. January 26, 2011. Updated June 15, 2020. Accessed April 27, 2022. https://www.nice.org.uk/guidance/cg113
12. Strawn JR, Mills JA, Schroeder H, et al. Escitalopram in adolescents with generalized anxiety disorder: a double-blind, randomized, placebo-controlled study. J Clin Psychiatry. 2020;81(5):20m13396. doi:10.4088/JCP.20m13396
13. Christensen MC, Loft H, Florea I, et al. Efficacy of vortioxetine in working patients with generalized anxiety disorder. CNS Spectr. 2019;24(2):249-257. doi:10.1017/S1092852917000761
14. Xie ZJ, Han N, Law S, et al. The efficacy of group cognitive-behavioural therapy plus duloxetine for generalised anxiety disorder versus duloxetine alone. Acta Neuropsychiatr. 2019;31(6):316-324. doi:10.1017/neu.2019.32
15. Huang Z, Li Y, Bianchi MT, et al. Repetitive transcranial magnetic stimulation of the right parietal cortex for comorbid generalized anxiety disorder and insomnia: a randomized, double-blind, sham-controlled pilot study. Brain Stimul. 2018;11(5):1103-1109. doi:10.1016/j.brs.2018.05.016
16. Amsterdam JD, Li QS, Xie SX, et al. Putative antidepressant effect of chamomile (Matricaria chamomilla L.) oral extract in subjects with comorbid generalized anxiety disorder and depression. J Altern Complement Med. 2020;26(9):813-819. doi:10.1089/acm.2019.0252
17. Dilkov D, Hawken ER, Kaludiev E, et al. Repetitive transcranial magnetic stimulation of the right dorsal lateral prefrontal cortex in the treatment of generalized anxiety disorder: a randomized, double-blind sham controlled clinical trial. Prog Neuropsychopharmacol Biol Psychiatry. 2017;78:61-65. doi:10.1016/j.pnpbp.2017.05.018
18. Keefe JR, Guo W, Li QS, et al. An exploratory study of salivary cortisol changes during chamomile extract therapy of moderate to severe generalized anxiety disorder. J Psychiatr Res. 2018;96:189-195. doi:10.1016/j.jpsychires.2017.10.011
19. Stein DJ, Khoo J, Ahokas A, et al. 12-week double-blind randomized multicenter study of efficacy and safety of agomelatine (25-50 mg/day) versus escitalopram (10-20 mg/day) in out-patients with severe generalized anxiety disorder. Eur Neuropsychopharmacol. 2018;28(8):970-979. doi:10.1016/j.euroneuro.2018.05.006
20. Amsterdam JD, Li Y, Soeller I, et al. A randomized, double-blind, placebo-controlled trial of oral Matricaria recutita (chamomile) extract therapy for generalized anxiety disorder. J Clin Psychopharmacol. 2009;29(4):378-382. doi:10.1097/JCP.0b013e3181ac935c
21. Amsterdam JD, Shults J, Soeller I, et al. Chamomile (Matricaria recutita) may provide antidepressant activity in anxious, depressed humans: an exploratory study. Altern Ther Health Med. 2012;18(5):44-49.
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26. Stein DJ, Ahokas A, Jarema M, et al. Efficacy and safety of agomelatine (10 or 25 mg/day) in non-depressed out-patients with generalized anxiety disorder: a 12-week, double-blind, placebo-controlled study. Eur Neuropsychopharmacol. 2017;27(5):526-537. doi:10.1016/j.euroneuro.2017.02.007

Generalized anxiety disorder (GAD) typically begins in early adulthood and persists throughout life. Many individuals with GAD report they have felt anxious their entire lives. The essential symptom of GAD is excessive anxiety and worry about numerous events or activities. The intensity, duration, and/or frequency of the anxiety and worry are out of proportion to the actual likelihood or impact of the anticipated event. The individual finds it difficult to control their worry and prevent worrisome thoughts from interfering with attention to everyday tasks.¹

Treatment of GAD typically consists of psychotherapy and pharmacotherapy. Several studies have suggested that concurrent psychotherapy amplifies the benefits of pharmacotherapy.^2-5 Additionally, combined treatment may differentially target specific symptoms (eg, cognitive vs somatic). The addition of psychotherapy may also increase treatment adherence and decrease potential adverse effects of pharmacotherapy.

Multiple classes of medications are available for treating GAD. Current guidelines and evidence suggest that selective serotonin reuptake inhibitors (SSRIs) should be considered a first-line intervention, followed by serotonin-norepinephrine reuptake inhibitors.^6-11While the evidence supporting pharmacotherapy for GAD continues to expand, many patients with GAD do not respond to first-line treatment. There is limited data regarding second-line or augmentation strategies for treating these patients. Because current treatment options for GAD are commonly associated with suboptimal treatment outcomes, researchers are investigating the use of nonpharmacologic biological interventions, such as repetitive transcranial magnetic stimulation (rTMS), which was first cleared by the FDA to treat major depressive disorder (MDD) in 2008.

In Part 1 of this 2-part article, we review 8 randomized controlled trials (RCTs) of biological interventions for GAD that have been published within the last 5 years (Table^12-19).

1. Strawn JR, Mills JA, Schroeder H, et al. Escitalopram in adolescents with generalized anxiety disorder: a double-blind, randomized, placebo-controlled study. J Clin Psychiatry. 2020;81(5):20m13396. doi:10.4088/JCP.20m13396

GAD is highly prevalent in adolescents, and SSRIs are often used as first-line agents. However, treatment response is often variable, and clinicians often use trial-and-error to identify an appropriate medication and dose that will result in meaningful improvement. Understanding an individual’s pharmacokinetic response may help predict response and guide therapy. Adult studies have shown cytochrome P450 (CYP) 2C19 metabolizes several SSRIs, including escitalopram, with faster CYP2C19 metabolism leading to decreased plasma concentrations. Strawn et al¹² studied the effects of escitalopram in adolescents with GAD as well as the effects of CYP2C19 metabolism.

Study design

A double-blind, placebo-controlled trial evaluated 51 adolescents (age 12 to 17) who met DSM-IV-TR criteria for GAD. They had a baseline Pediatric Anxiety Rating Scale (PARS) score ≥15 and a Clinical Global Impressions–Severity (CGI-S) Scale score ≥4.
Participants were randomized to escitalopram (n = 26; scheduled titration to 15 mg/d, then flexible to 20 mg/d), or placebo (n = 25) and monitored for 8 weeks.
Patients with panic disorder, agoraphobia, or social anxiety disorder were also enrolled, but GAD was the primary diagnosis.
The primary outcome was change in PARS score and change from baseline in CGI-S and Clinical Global Impressions–Improvement (CGI-I) scale scores, with assessments completed at Week 1, Week 2, Week 4, Week 6, and Week 8, or at early termination.
Genomic DNA was obtained via buccal swab to assess 9 alleles of CYP2C19. Plasma concentrations of escitalopram and its major metabolite, desmethylescitalopram, were collected to assess plasma escitalopram and desmethylescitalopram area under the curve for 24 hours (AUC_0-24) and maximum plasma concentration (C_MAX).

Outcomes

Escitalopram was superior to placebo, evident by statistically significantly greater changes in PARS and CGI scores.
Greater improvement over time on PARS was correlated with intermediate CYP2C19 metabolizers, and greater response as measured by CGI-I was associated with having at least 1 long allele of SLC6A4 and being an intermediate CYP2C19 metabolizer.
While plasma escitalopram exposure (AUC_0-24) significantly decreased and desmethylcitalopram-to-escitalopram ratios increased with faster CYP2C19 metabolism at 15 mg/d, escitalopram exposure at the 15 mg/d dose and escitalopram-to-desmethylcitalopram ratios did not differ at Week 8 between responders and nonresponders. Patients with activation symptoms had higher C_MAX and AUC_0-24.
Changes in vital signs, corrected QT interval, and adverse events were similar in both groups.

Conclusions/limitations

For adolescents with GAD, escitalopram showed a benefit compared to placebo.
Allelic differences in CYP2C19 metabolism may lead to variations in pharmacokinetics, and understanding a patient’s CYP2C19 phenotype may help guide dosing escitalopram and predicting adverse effects.
This study enrolled a small, predominantly female, White, treatment-naïve sample, which may limit conclusions on allelic differences. Additionally, the sample included adolescents with severe anxiety and comorbid anxiety conditions, which may limit generalizability.

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References

Termination of pregnancy for medical reasons: A mental health perspective

Generalized anxiety disorder: 8 studies of biological interventions

FIRST OF 2 PARTS

References

1. Strawn JR, Mills JA, Schroeder H, et al. Escitalopram in adolescents with generalized anxiety disorder: a double-blind, randomized, placebo-controlled study. J Clin Psychiatry. 2020;81(5):20m13396. doi:10.4088/JCP.20m13396

Study design

Outcomes

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