PD is defined as an abrupt surge of intense fear or discomfort reaching a peak within minutes. GAD is defined as excessive anxiety and worry for at least six months, and difficulty controlling the worrying.  GAD is associated with three or more of the following symptoms for at least six months:³

• Restlessness
• Feeling keyed up or on edge
• Being easily fatigued
• Difficulty in concentrating or mind going blank
• Irritability
• Muscle tension
• Sleep disturbance
• Irritability

Furthermore, GAD results in significant distress or impairment in social and occupational areas and is not attributable to any physical cause.³

GAD has a lifetime prevalence of ~6.2%, social anxiety disorder (SAD) ~13%, and PD with or without agoraphobia 5.2%.  Apart from GAD and SAD, other anxiety disorders include separation anxiety disorder, phobias, selective mutism, substance/medication-induced anxiety disorder, anxiety disorder due to another medical condition, and anxiety not otherwise specified.4,5

Anxiety disorders typically begin in childhood and early adulthood, and symptoms appear to decline with age. They can be chronic and are characterised by periods of remission and recurrence. However, full recovery is possible.^4,5

Risk factors

Risk factors for anxiety disorders include lower socioeconomic status, female gender, psychosocial, and physical as well as psychiatric health factors. Among these are marital status (particularly being widowed or divorced), exposure to stressful life events, use of tobacco and alcohol, presence of other psychiatric disorders, health ailments, and a family history of psychiatric disorders.⁵

Patients living with GAD often have other psychiatric conditions like major depressive disorder (52.6%), specific (25.6%) and social phobias (26.1%), as well as substance misuse disorder (22.5%). Anxiety disorders rank as the 6^th leading cause of global disability. GAD leads to reduced quality of life, role functioning, and increased disability days, comparable to major depressive disorder.¹

How are anxiety disorders diagnosed?

Various tools have been devised to screen for anxiety disorders, making them accessible for implementation in primary care settings. Widely used screening tools include for example the Hamilton Anxiety Rating Scale (HAM-A), GAD scale, the anxiety subscale of the Edinburgh Postnatal Depression Scale (EPDS), the Geriatric Anxiety Scale, and the Geriatric Anxiety Inventory.⁵

According to the authors of the 2023 United States Preventative Services Task Force (USPSTF) screening recommendations for anxiety disorders in adults, it is important to note that relying solely on anxiety screening tools is inadequate for a definitive diagnosis of anxiety disorders. Should a screening test yield a positive outcome for an anxiety disorder, further confirmatory diagnostic assessment is imperative.⁵

Although the recommendations do not expand on what further confirmatory assessments include, the authors advocate that clinical judgment, considering risk factors, comorbid conditions, and life events, should guide additional assessments for high-risk patients. This approach should extend to continually assessing emerging risks during pregnancy and the postpartum period.⁵

Treating GAD

The 2023 World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) as first-line treatments.⁴

A recommended trial of at least 12 weeks is recommended for the first-line treatment, but if the patient does not show improvement within the first four weeks, it may indicate treatment resistance.⁴

A 2019 recent meta-analysis - the largest contemporary review of pharmacological agents for the treatment of GAD by use of network analysis (89 trials involving 25 441 patients - indicated that duloxetine (mean difference [MD] in change in HAM-A −3.13), pregabalin (MD −2.79), venlafaxine (MD −2.69), and escitalopram (MD −2.45) were more efficacious than placebo with relatively good acceptability.⁷

Mirtazapine, sertraline, fluoxetine, buspirone, and agomelatine were also found to be efficacious and well tolerated but these findings were limited by small sample sizes. Quetiapine (MD −3.60) had the largest effect on HAM-A but it was poorly tolerated (odds ratio 1.44) when compared with placebo. Likewise, paroxetine and benzodiazepines were effective but also poorly tolerated when compared with placebo.⁷

However, as mentioned SSRIs and SNRIs are the mainstay of pharmacotherapy for GAD. It is recommended to continue taking antidepressants for a duration of six to 12 months to minimise the risk of relapse. While ~16% of patients experience relapse despite sustained antidepressant use, discontinuing these medications within the first year can lead to symptom recurrence in up to 50% of patients using SSRIs or SNRIs.⁶

Psychotherapy proves equally potent to pharmacotherapy in managing GAD, Cognitive behavioural therapy (CBT) is the first-line psychotherapy for anxiety disorders.^4,6

CBT can either be used alone or in combination with pharmacotherapy. The combined approach is likely to yield superior outcomes compared to individual treatments.⁶

What about treatment-resistant GAD?

Treatment resistance in anxiety disorders is divided into:¹

• Pseudo-resistance: Causes include the use of ineffective pharmacotherapy, inadequate dosing, or treatment duration as well as poor adherence to treatment.
• True resistance: This may result from substance use (such as alcohol or caffeine), sleep deprivation, an incorrect initial diagnosis of GAD and/or undiagnosed comorbid psychiatric conditions, or rarely, an underdiagnosed medical illness (such as hyperthyroidism).

Strategies to manage treatment resistance include switching to a different SSRI or SNRI, pregabalin, agomelatine, vilazodone, buspirone, imipramine, hydroxyzine, quetiapine, and trazodone.¹

Specific benzodiazepines (alprazolam, bromazepam, diazepam, and lorazepam) are suggested after the initial treatment failure, provided the patient does not have a history of substance use disorder but should not be used for an extended period. Another option is combining pharmacotherapy (the addition of olanzapine to fluoxetine, or the addition of pregabalin to a SSRI or SNRI).^1,6

Is ‘complete’ recovery possible?

A 2020 study by researchers from the University of Toronto (Canada) investigated three levels of recovery in a large, representative sample of >2000 patients with a history of GAD.⁸

Complete recovery is defined as ‘the state of having both the presence of positive mental health (eg feeling good about oneself, one's relationships with others, one's connections to community or society and being able to function well in daily activities) and the absence of current mental illness’. Incomplete mental health is associated with an increased burden of disease, limitations in activities and ability to work, healthcare utilisation, and mortality.⁸

The team found that >70% of patients in their study with a history of GAD achieved remission (the absence or near absence of symptoms) for at least one year and almost three in every five had been free of all suicidal thoughts, psychiatric disease, and substance dependence. However, the percentage of complete recovery was markedly lower for those with a history of GAD (40%) in comparison to those who never had GAD (76%).⁸

The authors stressed that patients who failed to achieve complete recovery had a history of adverse childhood experiences including physical and sexual abuse as well as exposure to parental domestic violence.⁸

Conclusion

GAD is a common psychiatric disorder seen in clinical practice. Guidelines recommend SSRIs and SNRIs as first-line treatment. CBT has also been shown to be effective in patients living with GAD. When selecting treatment, clinicians should consider patient preference, current and prior treatments, medical and psychiatric comorbid illnesses, age, sex, and reproductive planning, as well as cost and access to care.⁵

References

1. Fagan HA, Baldwin DS. Pharmacological Treatment of Generalised Anxiety Disorder: Current Practice and Future Directions. Expert Rev Neurother, 2023.
2. Cackovic C, Nazir S, Marwaha R. Panic Disorder. [Updated 2022 Jun 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430973/
3. Munir S, Takov V. Generalized Anxiety Disorder. [Updated 2022 Oct 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441870/
4. Bandelow B, Allgulander C, Baldwin DS, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the treatment of anxiety, obsessive-compulsive, and posttraumatic stress disorders - Version 3. Part I: Anxiety disorders. World J Biol Psychiatry, 2023.
5. Barry MJ, Nicholson WK, Silverstein M, et al. Screening for Anxiety Disorders in Adults. US Preventive Services Task Force Recommendation Statement. JAMA, 2023.
6. De George KC, Grover M, Streeter GS. Generalized Anxiety Disorder and Panic Disorder in Adults. Am Fam Physician, 2022.
7. Slee A, Nazareth I, Bondaronek P, et al. Pharmacological treatments for generalised anxiety disorder [published correction appears in Lancet. 2019; 393(10182): 1698]. The Lancet, 2019.
8. Fuller-Thomson E, Ryckman K. Achieving complete mental health despite a history of generalized anxiety disorders: Findings from a large, nationally representative Canadian survey. J Affect Disord, 2020.