Optimising clinical management in generalised anxiety disorder

Generalised anxiety disorder (GAD) is characterised by excessive, out of proportion, hard to control, anxiety and worry that can impact daily life. Here we discuss symptoms of GAD, comorbid factors and neurological findings along with how best to screen for and treat this anxiety disorder.


Generalised anxiety disorder (GAD) is one of several anxiety disorders, including panic disorder and specific phobias.1 In Europe, GAD is estimated to affect around 8.9 million people and is around twice as prevalent in women than in men.1

Millions of people are affected by generalised anxiety disorder

According to DSM-5, diagnostic criteria for GAD includes having at least 6 months where more days than not a person experiences excessive, out of proportion and hard to control, anxiety and worry about events or activities. These symptoms may interfere with daily life and are associated with at least three of: feeling restless, keyed up or on edge; being easily fatigued; feeling irritable; having muscle tension; experiencing sleep disturbance and having difficulties concentrating and/or with the mind going blank.2Unlike a panic attack, which can be a spiking form of anxiety, GAD in general remains at a similar level over a long period of time.3

GAD can impact a person’s work and social life in both the short- and long-term. For instance, when a person avoids a situation they perceive as dangerous such as travel or large events. GAD may manifest as not only excessive personal worry but also about a person’s loved ones.3 Long term, GAD can persist over many years or decades with the Nottingham Study of Neurotic Disorder finding nearly 60% of people diagnosed with GAD still had it when assessed both 12 and 30 years later.4

GAD can impact a person’s work and social life


Neurological findings

Brain imaging studies have found the amygdala (involved in emotional processing, especially fear), the prefrontal cortex (PFC) and the anterior cingulate cortex (both involved in executive functions and emotional regulation), along with connections between these and other brain regions, to be the areas most affected in people with GAD. Additionally found are smaller hippocampal volumes, with implications in memory and extinction of fear, and hypothalamic-pituitary-adrenal axis hyperactivity. 5

With these in mind, it has been proposed that in GAD ‘apprehensive expectations’ lead to amygdala hyperactivation, autonomic hyperactivity and cortisol secretion, with GAD symptoms being an attempt toward autonomic arousal downregulation. Chronic cortisol secretion is linked to decreased amygdala and PFC functional connectivity, leading to increased anxiety and decreased emotional regulation.5


Assessment of GAD

A quick two-question screen can be used for initial assessment of GAD

A quick two-question screen (the GAD-2) can be useful for initial assessment of a person suspected of having GAD. This involves questioning how often a person was bothered by feeling nervous, anxious or on edge and by being unable to stop or control worry over the previous 2 weeks.6

There are several scales to assess GAD, including self-assessment measures such as the Penn State Worry Questionnaire (PSWQ) for screening7 and the 7-item GAD scale to ascertain symptom severity.8 Clinically applied measures to assess anxiety include the Hamilton Anxiety Rating Scale 9 and the 14-item Anxiety portion of the Hospital Anxiety and Depression Scale (HAM-A).10

The HAM-A include items covering mood problems (e.g., depressed, anxious symptoms); physical symptoms (e.g., respiratory, cardiovascular, autonomic, genitourinary changes); behavioural differences; insomnia; and fears, tension and intellectual disturbances. These are each rated on a scale from 0 (absent) to 4 (severe) with a total anxiety score of 8−14 indicating mild anxiety and of ≥24 indicating severe anxiety.10,11


Differential diagnosis of GAD

Differential diagnosis and assessment of co-morbidity is important in GAD as symptoms may not only be present in other psychiatric disorders, but can also be present in other medical conditions such as pheochromocytoma or hyperthyroidism.2,12 Lifetime co-morbidity is particularly prevalent with one study of 494 people with GAD finding 86% had comorbid MDD and 74% had another anxiety disorder, including 49% with panic disorder and 48% with social anxiety disorder.13

GAD is often comorbid with major depressive disorder and/or another anxiety disorder

MDD seems to be a particularly disposing factor for GAD with one meta-analysis finding an odds ratio of 11.7 (95% confidence intervals 5.2, 26.3)14 and an analysis of community-based surveys showing a hazard ratio of 6.6 (95% confidence intervals 5.7, 7.7) even with a 15 year gap between MDD and GAD development.15


Treatment for GAD

GAD treatment guidelines recommend psychotherapy and pharmacotherapy, or a combination of both.16-19 Cognitive behaviour therapy (CBT) can significantly reduce GAD symptoms18 while a selective serotonin reuptake inhibitor or a serotonin-noradrenalin reuptake inhibitor is recommended as the first-line of medication.16-19 One large meta-analysis found that effect sizes of GAD treatments are higher with pharmacological therapy alone than with psychotherapy alone but the largest effects were observed for CBT plus pharmacotherapy.20

It is of note though that fewer than one-third of people with GAD have their condition adequately managed.16 Treatment plans should be built around considerations for illness severity, accessibility, cost, tolerability and safety.16 Also importantly, one conclusion of the above meta-analysis was that patient preference of pharmacotherapy or psychotherapy is a vital factor to consider.20

Guidelines recommend psychotherapy (CBT) and pharmacotherapy, or a combination of both, for GAD

Exercise may also be a key therapy for GAD with a recent 30 day study showing that anxiety symptoms, as assessed with the PSWQ, significantly lessened in people who undertook exercise training, more so in those who underwent high intensity training compared to low intensity training.21 Similarly, a meta-analysis found that exercise had a small but significant effect on decreasing anxiety symptoms, though this cohort included those with a variety of anxiety and related disorders.22

Educational financial support was provided by Otsuka Pharmaceuticals Europe Limited and H. Lundbeck A/S.



GAD : Generalized Anxiety Disorder 
DSM : Diagnostic and Statistical Manual of mental disorders  
PFC : Prefrontal cortex
PSWQ : Penn State Worry Questionnaire 
HAM-A : Hamilton Anxiety Rating Scale 
MDD : Major Depressive Disorder 
CBT : Cognitive behaviour therapy  

BE-NOTPR-0177, approval date : 08.2022

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.


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16. Andrews G, et al. Aust N Z J Psychiatry 2018; 52: 1109−1172.

17. Baldwin DS, et al. J Psychopharmacol 2014; 28: 403−439.

18. Katzman MA, et al. BMC Psychiatry 2014; 14 Suppl 1: S1.

19. Bandelow B, et al. World J Biol Psychiatry 2008; 9: 248−312.

20. Bandelow B, et al. Int Clin Psychopharmacol 2015; 30: 183−192.

21. Plag J, et al. J Anxiety Disord 2020; 76: 102311.

22. Ramos-Sanchez CP, et al. Psychiatry Res 2021; 302: 114046.


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