Generalised Anxiety Disorder – Diagnosis and Management

DIAGNOSIS

The diagnosis of GAD consists of two main components:

1.Excessive Worry:

• Over a succession of everyday things (some within their control and some not (e.g. relationships, family, finances, work, study, illness, community, and world affairs)
• Over things within their control going wrong in catastrophic and improbable ways.

2. Persistent restlessness

• A feeling of being on edge or muscle tension

DSM-5 diagnosis of GAD:

1.Excessive anxiety and worry

• Apprehensive expectation
• Occurring more days than not for at least 6 months
• About a number of events or activities (such as work or school performance)

2. The individual finds it difficult to control the worry

3. The anxiety and worry are associated with  3 or more of the following symptoms:

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

People with GAD seek reassurance to reduce immediate worry, avoid events that could have negative consequences and spend considerable time preparing for events to minimize worry.

GAD is on average only diagnosed 10 years after onset at which point the patient has gone to the doctors due to comorbid issues such as panic disorder, depression, or chronic pain disorders. [Andrews et al 2018]

Therefore, all patients that are diagnosed with anxiety should be screened for depression as well.

ASSESSMENT

The initial assessment should address behaviour and somatic symptoms; the evaluation of psychosocial stress and developmental issues in the context of past medical history can be used to exclude other organic causes.

Tests for thyroid function, blood glucose level, echocardiography, and a toxicology screen are important at this early stage.

Screening questions:

• Do you think you are a worrier by nature?
• If yes, ask: When you do worry, what is the worst thing that can happen?

Rating Scales: 

1. Brief GAD-7 self-report assessment is a validated diagnostic tool that detects a patient’s latent anxiety and how this affects their ability to respond to an item in a particular manner. There are 7 questions and the responses can be either: “not at all”, “several days”, “over half the days”, and “nearly every day” [Spitzer et al 2006]:

1. Feeling nervous, anxious, or on edge.
2. Not being able to stop or control worrying.
3. Worrying too much about different things.
4. Trouble relaxing.
5. Being so restless that it is hard to sit still.
6. Becoming easily annoyed or irritable.
7. Feeling afraid as if something awful might happen.

2. Penn State Worry Questionnaire-3 (PSWQ-3) is an ultra-brief 3-item version of the PSWQ, which has 16-items. [Meyer et al 1990]; [Berle et al 2011] The 3-item version is suggested to have similar psychometric properties as the full PSWG version and has been confirmed to detect a good measure of pathological worry:

• Many situations make me worry.
• Once I start worrying, I cannot stop.
• I worry all the time.

3. In youth populations, the Paediatric Anxiety Rating Scale (PARS):  has been used in multiple psychopharmacological studies involving youth with GAD. [Birmaher et al 2003]; [Walkup et al 2008]; [Strawn et al 2015] PARS includes a 50-item checklist that encompasses anxiety related to social, performance, separation, generalised, specific phobias, as well as somatic symptoms.

DIFFERENTIATING GAD FROM NON-PATHOLOGICAL WORRY

The art in making the diagnosis of GAD is to shift the focus from the problem being worried about today, to the act of worrying. The question ‘Do you think you are a worrier by nature?’ often leads to a discussion of how worrying – not today’s target for worry – is the core issue.

• The amount of worry is more frequent, more extreme, and out of keeping with the threat posed by the adverse event.
• People with GAD report spending much more time per day worrying than non-clinical populations
• People with GAD worry about the future even when things are going well (e.g. worrying about the health of children even when they are not sick). [Andrews et al., 2018]
• The worry is highly pervasive, pronounced, difficult to control, and frequently occurs without precipitant (e.g. patients report that the worry is intrusive, hard to stop, comes into their minds when they want to concentrate on other things).
• The history of excessive worry has a long duration (years rather than hours or days).
• The worrying impacts on the patient’s quality of life; it is distressing or disabling (e.g. it is associated with muscle tension, impaired sleep, relationship difficulties, and reduced work productivity)

DIFFERENTIATING GAD FROM DEPRESSION AND OCD

Read Obsessive-Compulsive Disorder (OCD) – A Primer on Neurobiology, Diagnosis and Treatment

Read Melancholic and Psychotic Depression – Review of Diagnosis and Management

MANAGEMENT

As with all disorders across the anxiety spectrum, a pragmatic approach that includes psychoeducation and information on lifestyle factors (e.g. healthy lifestyle choices concerning diet, exercise, and sleep) is encouraged. [Andrews et al. 2018]

CBT is considered more effective than other psychotherapies and should include 8 to 12 sessions. Interestingly, the Cochrane Database of Systematic Reviews suggests that 5 to 8 sessions may produce more benefits in GAD patients than ≥9 sessions of CBT. [Hunot et al. 2007]

Treatment

Delivery of CBT (face-to-face or digitally) is the first-choice option as there is evidence that both forms of CBT are more effective than pharmacotherapy. [Cuijpers et al. 2014] However, this is also dependent on severity, as well as patient preference, accessibility, cost, and tolerability. CBT has three stages:

1. The first stage is structured to include education about worrying and the factors that facilitate or hinder therapy. Cardio exercise is encouraged three times per week, and the topic of misuse of alcohol and drugs is broached.
2. Progressive muscle relaxation and breathing training to improve physical symptoms as well as reducing cognitive symptoms to challenge unhelpful thinking.
3. Cognitive strategies include: Learning to tolerate doubt and uncertainty; Challenging unhelpful beliefs about worry; Shifting attention away from worry; Modifying core beliefs; In addition, patients are confronted with behaviour avoidance using graded exposure.
4. The final stage is aimed at relapse prevention so that any benefits are maintained at 3-months, 1-year, or 3-years post-treatment. Identification of early warning signs is an important feature as well as future goal setting.

CBT should be started as early as possible, and if this is not feasible, then digital CBT should be initiated. [Robinson et al. 2010]

CBT should be individual rather than group CBT as there is an earlier improvement and greater reductions in worry and depressive symptoms as well as higher adherence rates (9% vs 24% attrition rates, respectively). [Hunot et al. 2007]; [Covin et al. 2008]

Other psychotherapy alternatives, such as applied relaxation, mindfulness, and acceptance-based interventions, have limited evidence.

Medication: 

SSRIs (e.g. sertraline, paroxetine, and escitalopram) and SNRIs (e.g. venlafaxine and duloxetine) are supported by RCT data to reduce symptoms and remission rates, respectively. [Andrews et al. 2018]

In the elderly, SSRIs and SNRIs can be associated with SIADH and hyponatraemia. Clinicians should also be aware of an increased risk of GI bleeding in the elderly with SSRIs and SNRIs. Due to the risks associated with medication CBT is considered first line.

MONITORING PROGRESS: NON-RESPONSE TO INITIAL STEPS IN TREATMENT

After 4 to 6 weeks of either CBT or medication, the response should be reviewed for efficacy and safety. [Andrews et al. 2018]

If there is a partial efficacy, then treatment continues.

However, if not, then modifications can be made based on what treatment strategy was initially decided.

• If dCBT was selected, then face-to-face CBT should be attempted; if face-to-face CBT was selected, then add an SSRI; if pharmacotherapy was selected, then add CBT or increase drug dosage.
• If these modifications are unsuccessful after a further 4 weeks, then a combination of CBT and SSRI should be attempted if not already done. CBT session frequency can be increased, but a second opinion and another review of the diagnosis and comorbidities may be necessary.
• Pregabalin and short-term agomelatine treatment have also shown to have a degree of efficacy and should be considered if there hasn’t been a response to an SSRI/SNRI. However, agomelatine is not approved for the treatment of GAD in Australia.
• An alternative approach is with the use of benzodiazepines but only for short-term regular use. However, there are significant side effects and as such, are generally not recommended for the treatment of GAD in primary or secondary care.
• Buspirone and imipramine are effective, but have significant side effects and should be reserved for situations where standard care is ineffective. Beta-blockers should not be used.
• Response to antidepressant treatment for GAD is relatively slow and may take 12 weeks for a response with response rates continue to increase over 6 months.
• When starting ADs start low and increase gradually due to the risk of worsening anxiety/agitation with SSRIs and SNRIs. Given the absence of a clear dose-response relationship, pharmacotherapy should be given at the minimum therapeutic dose for an initial period of 4weeks before assessing response.

Important points about pregabalin:

• The exact mechanism of action of pregabalin is unknown, but it is known to reduce excitatory neurotransmitter release by binding to the α₂-δ protein subunit of voltage-gated calcium channels. Binding to these calcium channels, which are located on the presynaptic neurons, reduces calcium efflux and ultimately reduces the release of excitatory neurotransmitters into the synapse.
• Pregabalin is a structural analogue of GABA, like gabapentin, but does not interact with GABA A or B receptors or influence GABA uptake. Pregabalin has been found to have a much higher binding affinity for the α₂-δ1 protein subunit compared to gabapentin, by about six times.
• There has been increasing concern around the misuse of pregabalin. [Swanell C., 2018]

PHARMACOLOGICAL MANAGEMENT OF GAD

A recent network meta-analysis across 89 trials and including a total of 25,441 patients with GAD, compared treatment efficacy by determining the effect on the Hamilton Anxiety Scale Score (HAM-A). The researchers estimated the mean treatment difference (MD) from baseline along with a 95% credible interval (95% CrI). [Slee A et al., 2019]

1. Quetiapine (MD -3.60; 95% CrI -4.83 to -2.39)
2. Duloxetine (MD -3.13; 95% CrI -4.13 to -2.13)
3. Pregabalin (MD -2.79; 95% CrI -3.69 to -1.91)
4. Venlafaxine (MD -2.69; 95% CrI -3.50 to -1.89)
5. Escitalopram (MD -2.45, 95% CrI -3.27 to -1.63)

The researchers also extracted data on trial discontinuation as a measure of treatment acceptability. Here, it was observed that patients administered quetiapine were less likely to complete the trial compared to placebo.

In comparison, duloxetine, pregabalin, venlafaxine and escitalopram had much lower discontinuation rates.

Other well studied pharmacological options for GAD with established efficacy include paroxetine (MD -2.29; 95% CrI -3.11 to -1.47) and benzodiazepines (MD -2.29; 95% CrI -3.19 to -1.39). Although these drugs have a moderate effect on HAM-A, in practice, these treatments come with a much higher discontinuation rate compared to placebo.

This analysis also showed that while mirtazapine, sertraline, fluoxetine, buspirone, and agomelatine were effective and well-tolerated treatment options; these findings were limited by their small sample sizes (n=318, n=485, n=264, n=311, and n=202, respectively).

Important points to note:

• As of April 2019 in the UK, pregabalin is now controlled under the Misuse of Drugs Act 1971 as a class C substance. Clinicians should exercise caution when prescribing pregabalin.
• Benzodiazepines are severely limited by their poor acceptability rating, cognitive impairment, and their potential for addiction and dependence.
• Agomelatine is a novel treatment option that shows good efficacy; however, trial data is scarce and impacted by the absence of comorbid disorders in enrolled patients. A systematic review and network meta-analysis of remission rates and tolerability in GAD reported only agomelatine showed better remission rates with good tolerability. Duloxetine, escitalopram, venlafaxine, paroxetine, and quetiapine were effective but with poor tolerability. [Kong et al, 2020]. 
• Agomelatine has now been approved by the TGA in Australia for GAD. [TGA PI]
• Vilazodone is a novel antidepressant (SSRI and a 5-HT_1A receptor partial agonist). However, its poor efficacy and acceptability profiles, as well as premium pricing, do not support its use in GAD patients.
• Vortioxetine is another novel and more recently approved antidepressant, and although it is well-tolerated, it did not show efficacy in GAD.

Learn more about Anxiety disorder guidelines in this presentation by Prof Sean Hood. 

SUMMARY

Worry is a normal part of life; however, GAD is an excessive and chronic disorder that significantly affects normal day-to-day functioning and overall quality of life.

Clinicians should be aware of the myriad of comorbid disorders that often present with GAD.

Evidence suggests psychoeducation and lifestyle changes as well as CBT as the most effective forms of therapy. SSRIs /SNRIs are effective medications that can be considered first-line or if CBT is ineffective.

Diagnosis and response to therapy can be evaluated using a variety of screening tools; however, successful outcomes will likely require a tailored approach to the individual patient.

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