L-Theanine in The Adjunctive Treatment of Generalized Anxiety Disorder: A Double-Blind, Randomised, Placebo-Controlled Trial

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Introduction

 

Generalized Anxiety Disorder (GAD) is a psychiatric condition associated with persistent, excessive, and unrealistic worry. It is not focused on a specific object or situation. Multiple factors contribute to the development of GAD. Biologic, familial, and environmental factors are considered important.

 

Behavioral inhibition, an early temperament associated with aversion to novel situations, has been found to be associated with late development of anxiety disorders. Patients with GAD may experience somatic symptoms such as shortness of breath, rapid heartbeat, sweating, nausea or diarrhea, frequent urination, cold and clammy hands, dry mouth, and trouble swallowing.  Some experience insomnia or sleep disturbances.

 

Cognitive Behavioral Therapy or CBT, a form of psychotherapy, is an effective first-line treatment for Generalized Anxiety Disorder (GAD). Aside from it, antidepressants and anxiolytics are also first-line treatments.

 

The remission rates for GAD range from 30 to 50% with use of antidepressants. This leaves room for the addition of other agents for complete or an almost total remission. Benzodiazepines, pregabalin, and antipsychotics are used as adjunctive agents to enhance the effectiveness of antidepressants in those who are non-responsive.

 

Nutraceuticals are pharmaceutical grade nutrients or plant-based compounds with potential efficacy and good safety profile. Their use is recently being considered to act as adjuncts in psychiatric disorders due to their bioactive effects.

 

The leaves of Camelia sinensis, the evergreen shrub, are used to produce tea. Tea leaves contain L-theanine or LT, an amino acid. LT has been shown to be beneficial in the treatment of anxiety and sleep disturbance as suggested by previous studies.

 

Relevance

 

The anxiolytic and hypnotic properties of L-theanine have been shown by preclinical and clinical studies. However, clinical trials investigating its therapeutic effects in anxiety disorders are lacking or have yet to be made. 


Objectives

 

The 2018 study by Sarris et al. aims to establish the efficacy and safety of LT as an adjunctive agent in the treatment of GAD. The authors hypothesized that LT can reduce anxiety symptoms as well as decrease insomnia severity.

 

Highlights  

 

The study is a randomized, double-blind, placebo controlled one which compared the use of adjunctive LT to adjunctive placebo in the treatment of patients with GAD who do not respond to antidepressant.

 

This was conducted in Australia at the following centers: The Melbourne Clinic The Royal Brisbane and Women’s Hospital, and the NICM Health Research Institute in New South. The study spanned from 2016 to 2018.

 

Eligibility criteria included subjects aged between 18 and 75 years with a primary diagnosis of GAD at study entry confirmed via the MINI International Neuropsychiatric Interview version 6.0 [MINI 6.0] and Hamilton Anxiety Rating Scale [HAMA] score ≥16); taking a therapeutic dose of an antidepressant for GAD for at least four-weeks.

 

Randomization was done through an independent computer-generated block. Subjects either received LT at 450 mg/day in addition to their current antidepressant (given as one 225 mg capsule twice per day) or placebo for the first four weeks of the study.

 

The LT of study subjects who did not achieve a ≥35% reduction in their baseline HAMA score at the end of the 4-week trial was uptitrated to two capsules, twice per day (900 mg/day, or matching placebo) for another four weeks.

 

In the last two weeks of the study, subjects were advised to stop (week 8 to week 10) taking the capsules. During this time, potential ongoing therapeutic activity or withdrawal effect were monitored. Anxiety, sleep quality, and cognition outcomes were all assessed.

 

LT did not demonstrate any beneficial effect over placebo on measures of anxiety, mood, worry or cognition but it improved self-reported sleep satisfaction in GAD and insomnia symptoms in a subset of individuals.

 

There was a significant treatment effect of LT on the sleep satisfaction item as well as a significant Group × Time interaction in individuals who did not meet threshold criteria for clinical insomnia. As such, LT may be beneficial in improving sleep in individuals with mild insomnia symptoms.

 

LT was well tolerated. It did not produce any serious adverse event. It is worth noting that the therapeutic effect of LT reaches a plateau at 400 mg/day, whereas this study uptitrated the dose to 900 mg/day in non-responders at 4 weeks. The study by Ota et al. in 2014 found that 200 mg/day and 400 mg/day of LT, but not 600 mg/ day, increased sensorimotor gating in 14 healthy controls.

 

The significant difference in psychotherapy treatment between the two groups may have had an impact on the results. There was a challenge in treating the LT group due to non-response to both antidepressant and psychotherapy and a higher mean age.

 

The lack of objective measurement of sleep is one limitation of the study. The authors suggest the use of actigraphy or polysomnography to know the effect of LT on sleep parameters.

 

Conclusion

 

While this pilot study found no evidence to support the efficacy of adjunctive LT in the treatment of GAD, sleep satisfaction and symptoms of sleep disturbance in mild insomnia were noted to be improved. However, a larger study with insomnia as the primary outcome is required to validate this finding.

 

References:

  • Sarris, J., Byrne, G., Cribb, L., Oliver, G., et al., 2018. L-Theanine In The Adjunctive Treatment Of Generalized Anxiety Disorder: A Double-Blind, Randomised, Placebo-Controlled Trial, Journal of Psychiatric Research 110 (2019) 31-37, Received 26 August 2018; Received in revised form 6 December 2018; Accepted 7 December 2018, https://doi.org/10.1016/j.jpsy...
  • Carpenter, J.K., Andrews, L.A., Witcraft, S.M., Powers, M.B., Smits, J.A.J., Hofmann, S.G., 2018. Cognitive behavioral therapy for anxiety and related disorders: a meta-analysis of randomized placebo-controlled trials. Depress. Anxiety. https://doi.org/10.1002/da.22728.
  • Reinhold, J.A., Rickels, K., 2015. Pharmacological treatment for generalized anxiety disorder in adults: an update. Expert Opin. Pharmacother. 16, 1669–1681. https:// doi.org/10.1517/14656566.2015.1059424.
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  • Sarris, J., Kavanagh, D.J., Byrne, G., 2010. Adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines. J. Psychiatr. Res. https://doi.org/10.1016/j.jpsychires.2009.06.003.
  • Sarris, J., Murphy, J., Mischoulon, D., Fava, M., Berk, M., Ng, C., 2016. Adjunctive nutrient nutraceuticals for depression: a systematic review and meta-analyses. Am. J. Psychiatry 173, 575–587. Ota, M., Wakabayashi, C., Matsuo, J., Kinoshita, Y., Hori, H., Hattori, K., et al., 2014. Effect of L-theanine on sensorimotor gating in healthy human subjects. Psychiatr. Clin. Neurosci. 68 (5), 337–343.